FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Swindle, EJ Blume, C Collins, P Metcalfe, DD Holgate, ST Davies, DE AF Swindle, Emily J. Blume, Cornelia Collins, Peter Metcalfe, Dean D. Holgate, Stephen T. Davies, Donna E. TI Mast cells support rhinovirus but not respiratory syncytial virus replication and contribute to the pro-inflammatory response to rhinovirus SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract C1 [Swindle, Emily J.; Blume, Cornelia; Holgate, Stephen T.; Davies, Donna E.] Univ Southampton, Acad Unit Clin & Expt Sci, Southampton, Hants, England. [Collins, Peter; Metcalfe, Dean D.] NIAID, NIH, Bethesda, MD 20892 USA. EM e.j.swindle@soton.ac.uk RI Davies, Donna/H-2993-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 6014 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370404867 ER PT J AU Swindle, EJ Blume, C Collins, P Metcalfe, DD Holgate, ST Davies, DE AF Swindle, Emily J. Blume, Cornelia Collins, Peter Metcalfe, Dean D. Holgate, Stephen T. Davies, Donna E. TI LSC 2013 abstract - Mast cells support rhinovirus but not respiratory syncytial virus replication and contribute to the pro-inflammatory response to rhinovirus SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract C1 [Swindle, Emily J.; Blume, Cornelia; Holgate, Stephen T.; Davies, Donna E.] Univ Southampton, Acad Unit Clin & Expt Sci, Southampton, Hants, England. [Collins, Peter; Metcalfe, Dean D.] NIAID, NIH, Bethesda, MD 20892 USA. EM e.j.swindle@soton.ac.uk RI Davies, Donna/H-2993-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 6014 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370400127 ER PT J AU Banks, NK Brown, L Hughes, J Solomon, B Muenke, M Page, DC AF Banks, N. K. Brown, L. Hughes, J. Solomon, B. Muenke, M. Page, D. C. TI PHENOTYPIC DIVERSITY AMONGST PATIENTS WITH AN ISODICENTRIC Y CHROMOSOME. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Banks, N. K.; Solomon, B.; Muenke, M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Brown, L.; Hughes, J.; Page, D. C.] Howard Hughes Med Inst, Whitehead Inst, Cambridge, MA USA. [Brown, L.; Hughes, J.; Page, D. C.] MIT, Dept Biol, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1027 BP S445 EP S445 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502040 ER PT J AU Banks, NK Johnston, JJ Gonsalves, SG Biesecker, LG AF Banks, N. K. Johnston, J. J. Gonsalves, S. G. Biesecker, L. G. TI PREVALENCE AND REPRODUCTIVE PHENOTYPE OF USP9Y MUTATIONS IN AN UNSELECTED POPULATION. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Banks, N. K.; Johnston, J. J.; Gonsalves, S. G.; Biesecker, L. G.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1009 BP S439 EP S439 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502022 ER PT J AU Banks, NK Norian, JM Henne, MB AF Banks, N. K. Norian, J. M. Henne, M. B. TI THE STATE OF INSURANCE MANDATES AND INTRACYTOPLASMIC SPERM INJECTION (ICSI) USE IN THE UNITED STATES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Banks, N. K.] NHGRI, NIH, Bethesda, MD 20892 USA. [Norian, J. M.] HRC Fertil, Pasadena, CA USA. [Henne, M. B.] Dept Def Pharmacoecon Ctr, Ft Sam Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-296 BP S90 EP S91 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500294 ER PT J AU Banks, NK Norian, JM Henne, MB AF Banks, N. K. Norian, J. M. Henne, M. B. TI CLINIC VOLUME AND INTRACYTOPLASMIC SPERM INJECTION (ICSI) USE IN THE UNITED STATES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Banks, N. K.] NHGRI, NIH, Bethesda, MD 20892 USA. [Norian, J. M.] HRC Fertil, Pasadena, CA USA. [Henne, M. B.] Dept Def Pharmacoecon Ctr, Ft Sam Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-145 BP S43 EP S44 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500145 ER PT J AU Bolnick, JM Zhou, Y Kilburn, BA Fisher, SJ Armant, DR AF Bolnick, J. M. Zhou, Y. Kilburn, B. A. Fisher, S. J. Armant, D. R. TI HBEGF CAN INDUCE CELL INVASION AND PROMOTE SURVIVAL OF FIRST TRIMESTER TROPHOBLAST. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Bolnick, J. M.; Kilburn, B. A.; Armant, D. R.] Wayne State Univ, Detroit, MI USA. [Zhou, Y.; Fisher, S. J.] UCSF, San Francisco, CA USA. [Armant, D. R.] NICHD, PRAE, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-513 BP S297 EP S297 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501292 ER PT J AU Bolnick, JM Kilburn, BA Singh, M Diamond, MP Awonuga, A Armant, DR AF Bolnick, J. M. Kilburn, B. A. Singh, M. Diamond, M. P. Awonuga, A. Armant, D. R. TI SILDENAFIL STIMULATES EXTRAVILLOUS TROPHOBLAST DIFFERENTIATION THROUGH CGMP DOWNSTREAM SIGNALING SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Bolnick, J. M.; Kilburn, B. A.; Singh, M.; Awonuga, A.; Armant, D. R.] Wayne State Univ, Detroit, MI USA. [Diamond, M. P.] Georgia Regents Univ, Athens, GA USA. [Armant, D. R.] NICHD, PRAE, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-252 BP S77 EP S77 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500252 ER PT J AU Bolnick, JM Kilburn, BA Singh, M Diamond, MP Hertz, M Armant, DR AF Bolnick, J. M. Kilburn, B. A. Singh, M. Diamond, M. P. Hertz, M. Armant, D. R. TI SILDENAFIL PREVENTS APOPTOSIS OF FIRST TRIMESTER TROPHOBLAST CELLS EXPOSED TO ENVIRONMENTAL STRESS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Bolnick, J. M.; Kilburn, B. A.; Singh, M.; Hertz, M.; Armant, D. R.] Wayne State Univ, Detroit, MI USA. [Diamond, M. P.] Georgia Regents Univ, Athens, GA USA. [Armant, D. R.] NICHD, PRAE, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-169 BP S51 EP S51 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500169 ER PT J AU Cooper, JC Wolff, EF Levy, G Levens, ED DeCherney, AH Hill, MJ AF Cooper, J. C. Wolff, E. F. Levy, G. Levens, E. D. DeCherney, A. H. Hill, M. J. TI METHOTREXATE (MTX) TREATMENT FOR ECTOPIC PREGNANCY (EP) AND PREGNANCY OF UNKNOWN LOCATION (PUL): IS THERE AN ADVERSE EFFECT ON OVARIAN RESERVE? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Wolff, E. F.; Levy, G.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Levens, E. D.; Hill, M. J.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Cooper, J. C.] Washington Hosp Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-41 BP S160 EP S160 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500522 ER PT J AU Cox, J Heitmann, R Hailstorks, T Armstrong, A AF Cox, J. Heitmann, R. Hailstorks, T. Armstrong, A. TI MRI EVIDENCE OF EMBRYO IMPLANTATION ONTO THE FIBROMUSCULAR UTERINE SEPTUM. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Cox, J.; Heitmann, R.; Hailstorks, T.; Armstrong, A.] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-810 BP S382 EP S382 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501584 ER PT J AU Devine, K Driggers, PH Chu, TJ DeCherney, AH Segars, JH AF Devine, K. Driggers, P. H. Chu, T. J. DeCherney, A. H. Segars, J. H. TI TISSUE-SPECIFIC KNOCKOUT OFA-KINASE ANCHORING PROTEIN 13 (AKAP13) - A POTENTIAL MURINE MODEL FOR POLYCYSTIC OVARIAN SYNDROME. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Devine, K.; Driggers, P. H.; Chu, T. J.; DeCherney, A. H.; Segars, J. H.] Eunice Kennedy Shriver Inst Child Hlth & Human De, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-202 BP S61 EP S62 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500202 ER PT J AU Devine, K Richter, KS Levens, ED DeCherney, AH Stillman, R Widra, EA AF Devine, K. Richter, K. S. Levens, E. D. DeCherney, A. H. Stillman, R. Widra, E. A. TI SINGLE THAWED BLASTOCYST TRANSFER MAXIMIZES LIVEBORN CHILDREN PER EMBRYO WHILE MINIMIZING PRETERM BIRTH: ANALYSIS OF 1691 FROZEN BLASTOCYST TRANSFERS (FBT) SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Richter, K. S.; Levens, E. D.; Stillman, R.; Widra, E. A.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Devine, K.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-46 BP S15 EP S15 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500047 ER PT J AU Eisenberg, ML Kime, SD Chen, Z Sundaram, R Schisterman, EF Louis, GMB AF Eisenberg, M. L. Kime, S. D. Chen, Z. Sundaram, R. Schisterman, E. F. Louis, G. M. Buck TI THE RELATIONSHIP BETWEEN MALE BODY MASS INDEX, ADIPOSITY, AND ACTIVITY LEVEL ON SEMEN QUALITY: DATA FROM THE LIFE STUDY. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Eisenberg, M. L.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Kime, S. D.; Chen, Z.; Sundaram, R.; Schisterman, E. F.; Louis, G. M. Buck] NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-408 BP S124 EP S124 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500405 ER PT J AU Eltoukhi, HM Hill, MJ Zarek, SM DeCherney, AH Richter, KS Wolff, EE AF Eltoukhi, H. M. Hill, M. J. Zarek, S. M. DeCherney, A. H. Richter, K. S. Wolff, E. F. TI RELATIONSHIP BETWEEN ENDOMETRIAL THICKNESS AND ASSISTED REPRODUCTIVE TECHNOLOGY (ART) OUTCOMES IN ENDOMETRIOSIS PATIENTS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Eltoukhi, H. M.; Hill, M. J.; Zarek, S. M.; DeCherney, A. H.; Wolff, E. F.] NICHHD, Program Reprod & Adult Endocrinol, Eunice Kennedy Shriver, NIH, Bethesda, MD 20892 USA. [Richter, K. S.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-830 BP S387 EP S387 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501603 ER PT J AU Fru, KN Hill, MJ Bertone-Johnson, ER DeCherney, AH Levens, ED Whitcomb, BW AF Fru, K. N. Hill, M. J. Bertone-Johnson, E. R. DeCherney, A. H. Levens, E. D. Whitcomb, B. W. TI OOCYTE DONOR ANTI-MULLERIAN HORMONE (AMH) AND ANTRAL FOLLICLE COUNT (AFC) PREDICT DONOR OOCYTE YIELD AND RECIPIENT IMPLANTATION. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Fru, K. N.; Hill, M. J.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child & Human De, Reprod Endocrinol & Infertil Program Reprod & Adu, NIH, Bethesda, MD USA. [Bertone-Johnson, E. R.; Whitcomb, B. W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Levens, E. D.] Shady Grove Fertil Resprod Sci Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-461 BP S140 EP S140 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500457 ER PT J AU Fru, KN Hill, MJ Bertone-Johnson, ER DeCherney, AH Whitcomb, BW Levens, ED AF Fru, K. N. Hill, M. J. Bertone-Johnson, E. R. DeCherney, A. H. Whitcomb, B. W. Levens, E. D. TI TOTAL NUMBER OF OOCYTES RETRIEVED BUT NOT FOLLICLE STIMULATING HORMONE (FSH) DOSE VARIES ACROSS MULTIPLE CYCLES IN REPEAT OOCYTE DONORS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Fru, K. N.; Hill, M. J.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child & Human De, Reprod Endocrinol & Infertil Program Reprod & Adu, NIH, Bethesda, MD USA. [Bertone-Johnson, E. R.; Whitcomb, B. W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Levens, E. D.] Shady Grove Fertil Resprod Sci Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-170 BP S52 EP S52 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500170 ER PT J AU Heitmann, RJ Richter, KS Devine, K McKeeby, J DeCherney, AH Widra, EA AF Heitmann, R. J. Richter, K. S. Devine, K. McKeeby, J. DeCherney, A. H. Widra, E. A. TI INCREASED LIVE BIRTHS AMONG PATIENTS USING INTAMUSCULAR VERSUS VAGINAL PROGESTERONE FOR LUTEAL PHASE SUPPORT DURING FROZEN BLASTOCYST TRANSFER. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Heitmann, R. J.; Devine, K.; DeCherney, A. H.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Heitmann, R. J.; Richter, K. S.; Devine, K.; McKeeby, J.; Widra, E. A.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1078 BP S459 EP S460 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502091 ER PT J AU Heitmann, RJ Hill, MJ James, AN Csokmay, JM Segars, JH Payson, MD AF Heitmann, R. J. Hill, M. J. James, A. N. Csokmay, J. M. Segars, J. H. Payson, M. D. TI IMPLANTATION AND ONGOING PREGNANCY ARE INCREASED AS A RESULT OF IMPROVEMENTS IN AIR HANDLING AND LABORATORY ENVIRONMENT. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Heitmann, R. J.; Hill, M. J.; Csokmay, J. M.; Segars, J. H.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Heitmann, R. J.; Hill, M. J.; Csokmay, J. M.; Segars, J. H.; Payson, M. D.] Walter Reed Natl Mil Med Ctr, Div Reprod Endocrinol, Bethesda, MD USA. [James, A. N.] ART Inst Washington, Bethesda, MD USA. [Payson, M. D.] Dominion Fertil, Arlington, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-479 BP S145 EP S146 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500475 ER PT J AU Hill, MJ Whitcomb, BW Lewis, TD Levens, ED DeCherney, AH Propst, AM AF Hill, M. J. Whitcomb, B. W. Lewis, T. D. Levens, E. D. DeCherney, A. H. Propst, A. M. TI PROGESTERONE LUTEAL SUPPORT FOLLOWING OVULATION INDUCTION AND INTRAUTERINE INSEMINATION CYCLES: A SYSTEMATIC REVIEW AND META-ANALYSIS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Hill, M. J.; Lewis, T. D.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod Endocrinol & Infertil, Bethesa, MD USA. [Whitcomb, B. W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Levens, E. D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Propst, A. M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-529 BP S301 EP S301 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501308 ER PT J AU Hill, MJ Richter, KS Zarek, SM DeCherney, AH Osheroff, JE Levens, ED AF Hill, M. J. Richter, K. S. Zarek, S. M. DeCherney, A. H. Osheroff, J. E. Levens, E. D. TI SINGLE AND DOUBLE DONOR SPERM INTRAUTERINE INSEMINATION CYCLES FOR MALE FACTOR INFERTILITY: DOES DOUBLE IUI INCREASE CLINICAL PREGNANCY RATES? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Hill, M. J.; Zarek, S. M.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Richter, K. S.; Osheroff, J. E.; Levens, E. D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-231 BP S71 EP S71 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500231 ER PT J AU Hillman, JK Butts, SF Playford, MP Mehta, NN Dokras, A AF Hillman, J. K. Butts, S. F. Playford, M. P. Mehta, N. N. Dokras, A. TI ATHEROGENIC LIPOPROTEIN PROFILE AND DECREASED HDL FUNCTION SUPPORT INCREASED RISK OF CARDIOVASCULAR DISEASE (CVD) IN YOUNG WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCOS) SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Hillman, J. K.; Butts, S. F.; Dokras, A.] Univ Penn, Philadelphia, PA 19104 USA. [Playford, M. P.; Mehta, N. N.] NHLBI, Sect Inflammat & Cardiometab Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-726 BP S358 EP S358 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501501 ER PT J AU Hurliman, A Casson, P Ashikaga, T Brown, S Bates, GW AF Hurliman, A. Casson, P. Ashikaga, T. Brown, S. Bates, G. W. CA Reprod Med Network TI INCREASING ANDROGEN RECEPTOR GENE CAG REPEAT ARE ASSOCIATED WITH IMPROVED RESPONSE TO CLOMIPHENE CITRATE: AN EXPLORATORY SUB-ANALYSIS OF THE PREGNANCY IN POLYCYSTIC OVARY SYNDROME TRIAL (PPCOS I). SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Hurliman, A.; Casson, P.; Ashikaga, T.; Brown, S.] Univ Vermont, Burlington, VT USA. [Bates, G. W.] Univ Alabama Birmingham, Birmingham, AL USA. [Reprod Med Network] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-12 BP S4 EP S4 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500013 ER PT J AU Johnstone, E Dorais, J Parsons, P Louis, G Hammoud, A Peterson, CM AF Johnstone, E. Dorais, J. Parsons, P. Louis, G. Hammoud, A. Peterson, C. M. TI INCREASED TRACE METALS IN BLOOD AND URINE ARE ASSOCIATED WITH UTERINE LEIOMYOMATA. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Johnstone, E.; Dorais, J.; Hammoud, A.; Peterson, C. M.] Univ Utah, Salt Lake City, UT USA. [Louis, G.] NIH, Bethesda, MD 20892 USA. [Parsons, P.] Univ Albany, Albany, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-952 BP S422 EP S423 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501723 ER PT J AU Louis, GMB Druschel, C Sundaram, R Bell, E Yeung, E Kus, C AF Louis, G. M. Buck Druschel, C. Sundaram, R. Bell, E. Yeung, E. Kus, C. TI POPULATION BASED METHODOLOGY FOR ASSESSING INFERTILITY TREATMENT AND CHILD HEALTH, UPSTATE KIDS STUDY. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Louis, G. M. Buck; Sundaram, R.; Yeung, E.] NICHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Druschel, C.] NYS Dept Hlth, Congenital Malformat Registry, Albany, NY USA. [Bell, E.] SUNY Albany, Dept Environm Hlth, Albany, NY 12222 USA. [Bell, E.] SUNY Albany, Dept Epidemiol, Albany, NY 12222 USA. [Kus, C.] NYS Dept Hlth, Div Family Hlth, Albany, NY USA. RI Yeung, Edwina/F-5992-2015 OI Yeung, Edwina/0000-0002-3851-2613 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1186 BP S490 EP S490 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502196 ER PT J AU Louis, GMB Sundaram, R Sweeney, A Schisterman, EF Kannan, K AF Louis, G. M. Buck Sundaram, R. Sweeney, A. Schisterman, E. F. Kannan, K. TI BISPHENOL A, PHTHALATES AND COUPLE FECUNDITY, THE LIFE STUDY. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Louis, G. M. Buck; Sundaram, R.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Sweeney, A.] Texas A&M Rural Sch Publ Hlth, College Stn, TX USA. [Kannan, K.] NYS Dept Hlth, Wadsworth Ctr, Albany, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-2 BP S1 EP S1 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500003 ER PT J AU Malik, M Deng, J Britten, J Levy, G Segars, J Catherino, WH AF Malik, M. Deng, J. Britten, J. Levy, G. Segars, J. Catherino, W. H. TI ESTROGEN AND PROGESTERONE STIMULATE EXTRACELLULAR MATRIX PRODUCTION IN MYOMETRIUM AND LEIOMYOMA 3-DIMENSIONAL CULTURES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Malik, M.; Deng, J.; Britten, J.; Levy, G.; Segars, J.; Catherino, W. H.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Levy, G.; Segars, J.; Catherino, W. H.] Eunice Kennedy Shriver NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-880 BP S401 EP S401 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501652 ER PT J AU Malik, M Britten, J Deng, J Segars, J Catherino, WH AF Malik, M. Britten, J. Deng, J. Segars, J. Catherino, W. H. TI PREVENTING MISLEADING RESULTS PRIOR TO CLINICAL TRIALS: EXTRACELLULAR MATRIX IN 3-DIMENSIONAL LEIOMYOMA CULTURES WAS MAINTAINED DESPITE TREATMENT WITH THE ROCK INHIBITOR FASUDIL. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Malik, M.; Britten, J.; Deng, J.; Segars, J.; Catherino, W. H.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Segars, J.; Catherino, W. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-881 BP S401 EP S402 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501653 ER PT J AU Mumford, SL Sundaram, R Schisterman, EF Barr, DB Sweeney, AM Louis, GMB AF Mumford, S. L. Sundaram, R. Schisterman, E. F. Barr, D. Boyd Sweeney, A. M. Louis, G. M. Buck TI URINARY LIGNAN CONCENTRATIONS AND COUPLE FECUNDITY: THE LIFE STUDY SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Mumford, S. L.; Sundaram, R.; Schisterman, E. F.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Barr, D. Boyd] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Sweeney, A. M.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-265 BP S81 EP S81 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500264 ER PT J AU Muneyyirci-Delale, O Charles, C Sinaii, N Anopa, J Dalloul, M Stratton, P AF Muneyyirci-Delale, O. Charles, C. Sinaii, N. Anopa, J. Dalloul, M. Stratton, P. TI CHANGES IN BONE DENSITY IN WOMEN WITH ENDOMETRIOSIS ON LEUPROLIDE VS NORETHINDRONE TREATMENT SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Muneyyirci-Delale, O.; Charles, C.; Anopa, J.; Dalloul, M.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Muneyyirci-Delale, O.] Kings Cty Hosp Ctr, Brooklyn, NY USA. [Sinaii, N.] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Stratton, P.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-335 BP S102 EP S103 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500333 ER PT J AU Schisterman, EF Browne, RW Barr, DB Chen, Z Mumford, SL Louis, GMB AF Schisterman, E. F. Browne, R. W. Barr, D. Boyd Chen, Z. Mumford, S. L. Louis, G. M. Buck TI LIPID LEVELS AND COUPLE FECUNDITY: THE LIFE STUDY SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Schisterman, E. F.; Chen, Z.; Mumford, S. L.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Browne, R. W.] SUNY Buffalo, Dept Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. [Barr, D. Boyd] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-667 BP S341 EP S341 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501444 ER PT J AU Schisterman, EF Silver, RM Mumford, SL Galai, N Wactawski-Wende, J Stanford, JB AF Schisterman, E. F. Silver, R. M. Mumford, S. L. Galai, N. Wactawski-Wende, J. Stanford, J. B. TI RANDOMIZED CLINICAL TRIAL OF PRECONCEPTION LOW DOSE ASPIRIN USE AND TIME-TO-PREGNANCY: THE EAGER TRIAL. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Schisterman, E. F.; Mumford, S. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Silver, R. M.; Stanford, J. B.] Univ Utah, Salt Lake City, UT USA. [Galai, N.] Univ Haifa, IL-31999 Haifa, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-327 BP S100 EP S100 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500325 ER PT J AU Schliep, KC Mumford, SL Chen, Z Sharp, HT Peterson, CM Louis, GMB AF Schliep, K. C. Mumford, S. L. Chen, Z. Sharp, H. T. Peterson, C. M. Louis, G. M. Buck TI RELATING PELVIC PAIN TYPOLOGY AND LOCATION TO ENDOMETRIOSIS DIAGNOSIS AMONG BOTH WOMEN SEEKING AND NOT SEEKING CLINICAL CARE. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Schliep, K. C.; Mumford, S. L.; Chen, Z.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Sharp, H. T.; Peterson, C. M.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-754 BP S366 EP S366 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501529 ER PT J AU Sharan, C Halder, S Nair, S Segars, J Al-Hendy, A AF Sharan, C. Halder, S. Nair, S. Segars, J. Al-Hendy, A. TI PARICALCITOL, VITAMIN D3 RECEPTOR AGONIST IS SUPERIOR TO VITAMIN D3 IN REDUCING PROLIFERATION OF HUMAN UTERINE LEIOMYOMA CELLS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Sharan, C.; Halder, S.; Nair, S.; Al-Hendy, A.] Meharry Med Coll, CWHR, Nashville, TN 37208 USA. [Segars, J.] NICHD, Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-882 BP S402 EP S402 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501654 ER PT J AU Stratton, P Sinaii, N Khachikyan, I Ortiz, R Gemmill, J Shah, J AF Stratton, P. Sinaii, N. Khachikyan, I. Ortiz, R. Gemmill, J. Shah, J. TI INTERRELATIONSHIP AMONG LEVATOR SPASM, SENSITIZATION, MYOFASCIAL DYSFUNCTION, ANXIETY AND DEPRESSION IN PATIENTS WITH ENDOMETRIOSIS AND CHRONIC PELVIC PAIN SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Stratton, P.; Khachikyan, I.; Gemmill, J.] NICHD, PRAE, Bethesda, MD USA. [Sinaii, N.] CC, BCES, Bethesda, MD USA. [Ortiz, R.; Shah, J.] CC, RM, Bethesda, MD USA. [Ortiz, R.] Loyola SOM, Maywood, IL USA. [Gemmill, J.] NYCOM, Old Westbury, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-67 BP S21 EP S21 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500068 ER PT J AU Trussell, JC Christman, GM Ohl, DA Krawetz, SA Snyder, PJ AF Trussell, J. C. Christman, G. M. Ohl, D. A. Krawetz, S. A. Snyder, P. J. CA Reproductive Med Network TI NEARLY ALL SURVEYED REPRODUCTIVE UROLOGISTS FEEL A PROSPECTIVE VARICOCELECTOMY TRIAL IS IMPORTANT AND WORTHWHILE SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Trussell, J. C.] Upstate Univ Hosp, Syracuse, NY USA. [Christman, G. M.] Univ Florida, Gainesville, FL USA. [Ohl, D. A.] Univ Michigan, Ctr Hlth, Ann Arbor, MI 48109 USA. [Krawetz, S. A.] Wayne State Univ, Detroit, MI USA. [Snyder, P. J.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Reproductive Med Network] Kennedy Shriver Natl Inst Child Hlth & Human Dev, NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-97 BP S30 EP S30 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500098 ER PT J AU Wolff, EF Libfraind, LL Weitzel, RP Tilly, J DeCherney, AH Tisdale, JE AF Wolff, E. F. Libfraind, L. L. Weitzel, R. P. Tilly, J. DeCherney, A. H. Tisdale, J. E. TI OOGONIAL STEM CELLS GENERATE MATURE OOCYTES IN AN AUTOLOGOUS RHESUS MACAQUE TRANSPLANTATION MODEL. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Wolff, E. F.; Libfraind, L. L.; DeCherney, A. H.] NICHD, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Weitzel, R. P.; Tisdale, J. E.] NHLBI, MCHB, Bethesda, MD 20892 USA. [Tilly, J.] MGH, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-133 BP S40 EP S40 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500133 ER PT J AU Yeung, EH Robledo, C Boghossian, N Ye, A Bell, E Schisterman, E AF Yeung, E. H. Robledo, C. Boghossian, N. Ye, A. Bell, E. Schisterman, E. TI MODELING THE CAUSAL EFFECT OF ASSISTED REPRODUCTIVE TECHNOLOGY (ART) ON NEURODEVELOPMENTAL IMPAIRMENT SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Yeung, E. H.; Robledo, C.; Boghossian, N.; Ye, A.; Schisterman, E.] NICHD, Epidemiol Branch, DESPR, NIH, Bethesda, MD USA. [Bell, E.] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Rensselaer, NY USA. RI Yeung, Edwina/F-5992-2015 OI Yeung, Edwina/0000-0002-3851-2613 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1093 BP S464 EP S464 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502106 ER PT J AU Zarek, SM Alford, CE Edwards, KK Segars, JH Armstrong, AY AF Zarek, S. M. Alford, C. E. Edwards, K. K. Segars, J. H. Armstrong, A. Y. TI USE OF THE LEVONORGESTREL CONTAINING INTRAUTERINE DEVICE (LNG-IUS) AS A STRATEGY TO DECREASE MATERNAL MORTALITY IN UGANDA: ESTIMATING IMPACT WITH A PREDICTION MODEL. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Zarek, S. M.; Segars, J. H.; Armstrong, A. Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Alford, C. E.] South Florida Inst Reprod Med, Naples, FL USA. [Edwards, K. K.] Howard Univ, Dept Obstet & Gynecol, Washington, DC 20059 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-584 BP S317 EP S317 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501362 ER PT J AU Zarek, SM Alford, CE Mumford, SL Edwards, KK Segars, JH Armstrong, AY AF Zarek, S. M. Alford, C. E. Mumford, S. L. Edwards, K. K. Segars, J. H. Armstrong, A. Y. TI ESTIMATED REDUCTION OF VERTICAL TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) WITH THE LEVONORGESTREL INTRAUTERINE DEVICE (LNG-IUS): USE OF A PREDICTION MODEL TO ESTIMATE THE IMPACT OF LNG-IUS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Zarek, S. M.; Segars, J. H.; Armstrong, A. Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Alford, C. E.] South Florida Inst Reprod Med, Naples, FL USA. [Mumford, S. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Edwards, K. K.] Howard Univ, Dept Obstet & Gynecol, Washington, DC 20059 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-582 BP S316 EP S317 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501360 ER PT J AU Zarek, SM Hill, MJ Eltoukhi, HM DeCherney, AH Widra, E Wolff, EF AF Zarek, S. M. Hill, M. J. Eltoukhi, H. M. DeCherney, A. H. Widra, E. Wolff, E. F. TI THE EFFECT OF PEAK ENDOMETRIAL THICKNESS ON LIVE BIRTH RATES IN PATIENTS UNDERGOING ASSISTED REPRODUCTIVE TECHNOLOGY: AN ANALYSIS OF 4,086 ART CYCLES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Zarek, S. M.; Hill, M. J.; Eltoukhi, H. M.; DeCherney, A. H.; Wolff, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Widra, E.] Shady Grove Fertil Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-415 BP S126 EP S126 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500412 ER PT J AU Zarek, SM Hill, MJ Eltoukhi, HM Richter, KS DeCherney, AH Wolff, EF AF Zarek, S. M. Hill, M. J. Eltoukhi, H. M. Richter, K. S. DeCherney, A. H. Wolff, E. F. TI RACE/ETHNICITY ASSOCIATED WITH INCREASED PEAK ENDOMETRIAL THICKNESS AND DECREASED LIVE BIRTH RATE: AN ANALYSIS OF 4,086 ASSISTED REPRODUCTIVE TECHNOLOGY (ART) CYCLES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Zarek, S. M.; Hill, M. J.; Eltoukhi, H. M.; DeCherney, A. H.; Wolff, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Richter, K. S.] Shady Grove Fertil Ctr, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-266 BP S81 EP S81 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500265 ER PT J AU Duan, XH Markello, T Adams, D Toro, C Tifft, C Gahl, WA Boerkoel, CF AF Duan, Xiaohong Markello, Thomas Adams, David Toro, Camilo Tifft, Cynthia Gahl, William A. Boerkoel, Cornelius F. TI Cultural differences define diagnosis and genomic medicine practice: implications for undiagnosed diseases program in China SO FRONTIERS OF MEDICINE LA English DT Editorial Material DE genetics; cultural differences; undiagnosed diseases program AB Despite the current acceleration and increasing leadership of Chinese genetics research, genetics and its clinical application have largely been imported to China from the Occident. Neither genetics nor the scientific reductionism underpinning its clinical application is integral to the traditional Chinese worldview. Given that disease concepts and their incumbent diagnoses are historically derived and culturally meaningful, we hypothesize that the cultural expectations of genetic diagnoses and medical genetics practice differ between the Occident and China. Specifically, we suggest that an undiagnosed diseases program in China will differ from the recently established Undiagnosed Diseases Program at the United States National Institutes of Health; a culturally sensitive concept will integrate traditional Chinese understanding of disease with the scientific reductionism of Occidental medicine. C1 [Duan, Xiaohong] Fourth Mil Med Univ, Sch Stomatol, Clin Oral Rare Dis & Genet Dis, Dept Oral Biol, Xian 710032, Peoples R China. [Markello, Thomas; Adams, David; Toro, Camilo; Tifft, Cynthia; Gahl, William A.; Boerkoel, Cornelius F.] NIH, Undiagnosed Dis Program, Off Rare Dis Res, Bethesda, MD 20892 USA. [Markello, Thomas; Adams, David; Toro, Camilo; Tifft, Cynthia; Gahl, William A.; Boerkoel, Cornelius F.] NHGRI, Bethesda, MD 20892 USA. RP Duan, XH (reprint author), Fourth Mil Med Univ, Sch Stomatol, Clin Oral Rare Dis & Genet Dis, Dept Oral Biol, Xian 710032, Peoples R China. EM xhduan@fmmu.edu.cn FU Intramural NIH HHS [Z99 HG999999, ZIA HG000215-10] NR 37 TC 0 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2095-0217 EI 2095-0225 J9 FRONT MED-PRC JI Front. Med. PD SEP PY 2013 VL 7 IS 3 BP 389 EP 394 DI 10.1007/s11684-013-0281-3 PG 6 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA V41UO UT WOS:000209571300015 PM 23856975 ER PT J AU de Bielke, MGS Yancoski, J Oliveira, JB Danielian, S AF de Bielke, M. G. Simesen Yancoski, J. Oliveira, J. B. Danielian, S. TI Particular Behavior of an Extracellular Missense FAS Mutation (p.C107Y) Identified in High Frequency in Argentinean Patients with Autoimmune Lymphoproliferative Syndrome SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 3rd Meeting of the Latin-American-Society-for-Immunodeficiencies (LASID) CY OCT 17-19, 2013 CL Santiago, CHILE SP Latin Amer Soc Immunodeficiencies C1 Hosp Peditaria Garrahan, Buenos Aires, DF, Argentina. [de Bielke, M. G. Simesen; Yancoski, J.; Oliveira, J. B.; Danielian, S.] NIH, Serv Immunol, Dept Lab Med, Ctr Clin, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD SEP PY 2013 VL 33 SU 3 MA 55 BP S116 EP S116 PG 1 WC Immunology SC Immunology GA AY1ZI UT WOS:000347388100036 ER PT J AU Coller-Monarez, S Groseclose, SL Kurilla, MG Berg, JM AF Coller-Monarez, Susan Groseclose, Samuel L. Kurilla, Michael G. Berg, Jeremy M. TI High Priority Preparedness Research and Its Support SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Editorial Material DE federal support; Centers for Disease Control and Prevention; National Institutes of Health; preparedness; Department of Homeland Security AB The US Federal Government has considerable interest in supporting research into preparedness. Because of the diverse nature of possible threats and the responsibilities of different agencies, a number of different programs have been developed. Perspectives from representatives from 3 of the leading agencies; the Department of Homeland Security, the Centers from Disease Control and Prevention, and the National Institutes of Health, are described herein. C1 [Coller-Monarez, Susan] Dept Homeland Secur, Threat Characterizat & Attribut Branch, Chem & Biol Def Div, Sci & Technol Directorate, Alexandria, VA USA. [Groseclose, Samuel L.] Ctr Dis Control & Prevent, Sci & Policy Hlth Practice, Off Publ Hlth Preparedness & Response, Atlanta, GA USA. [Kurilla, Michael G.] NIAID, Off Biodef Res Resources & Translat Res, NIH, Bethesda, MD 20892 USA. [Kurilla, Michael G.] NIAID, Biodef Product Dev, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Berg, Jeremy M.] Univ Pittsburgh, Sci Strategy & Planning Hlth Sci, Pittsburgh, PA 15213 USA. [Berg, Jeremy M.] Univ Pittsburgh, Dept Computat & Syst Biol, 3550 Terrace St, Pittsburgh, PA USA. RP Berg, JM (reprint author), Univ Pittsburgh, Dept Computat & Syst Biol, 3550 Terrace St, Pittsburgh, PA USA. EM jberg@pitt.edu OI Berg, Jeremy/0000-0003-3022-0963 NR 4 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-4659 EI 1550-5022 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD SEP-OCT PY 2013 VL 19 SU 2 BP S9 EP S11 DI 10.1097/PHH.0b013e3182972287 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V43KM UT WOS:000209680300004 PM 23903401 ER PT J AU Linkenhoker, JR Linton, CGG AF Linkenhoker, Jan R. Linton, C. G. Garry TI Effect of Nesting Material on Body Weights of Mice Infected with Toxoplasma gondii SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID ENVIRONMENTAL ENRICHMENT; LABORATORY RODENTS; C57BL/6J MICE; BEHAVIOR; BALB/C AB Toxoplasmosis, a disease caused by the parasitic protozoan Toxoplasma gondii, can cause a number of clinical signs in mice, including weight loss. This weight loss likely is related to the host immune response and is important to monitor in Toxoplasma studies. Several studies have demonstrated that nesting material can affect body weights of mice. We therefore sought to assess the effects of nesting material on body weights of mice infected with Toxoplasma. We housed mice with or without nesting material and weighed and clinically assessed them twice weekly for 30 days prior to and 5 wk after Toxoplasma inoculation. Nesting material did not significantly alter the weights of mice after Toxoplasma inoculation but did decrease rates of growth prior to inoculation. Nesting material did not affect the clinical outcome of Toxoplasma infections, supporting the provision of nesting material in mouse Toxoplasma experiments. C1 [Linkenhoker, Jan R.; Linton, C. G. Garry] NIH, Dept Hlth & Human Serv, Off Director, Off Res Serv,Div Vet Resources, Bethesda, MD 20892 USA. RP Linkenhoker, JR (reprint author), NIH, Dept Hlth & Human Serv, Off Director, Off Res Serv,Div Vet Resources, Bethesda, MD 20892 USA. EM linkenhj@od.nih.gov FU Intramural Research Program of the NIH Division of Veterinary Resources; National Cancer Institute FX We acknowledge Dr Yin Liu and Ms Love Wade for assistance with this study and Dr Tanya Burkholder for thoughtful review of this manuscript. This research was supported by the Intramural Research Program of the NIH Division of Veterinary Resources and the National Cancer Institute. The views and opinions provided are those of the authors and do not reflect the official policy or positions of the NIH, Department of Health and Human Services, or United States Government. NR 14 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2013 VL 52 IS 5 BP 531 EP 533 PG 3 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA AN7VZ UT WOS:000340810400003 PM 24041206 ER PT J AU Mendoza, A Gharpure, R Dennis, J Webster, JD Smedley, J Khanna, C AF Mendoza, Arnulfo Gharpure, Radhika Dennis, John Webster, Joshua D. Smedley, Jeremy Khanna, Chand TI A Novel Noninvasive Method for Evaluating Experimental Lung Metastasis in Mice SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID MODELS; TUMOR AB Metastasis remains the most significant problem in the field of cancer. The biologic complexity that characterizes metastasis requires relevant in vivo models. When using murine models for pulmonary metastasis, longitudinal studies are valuable for following the progression of metastatic burden. Currently, the progression of pulmonary metastatic burden in experimental mice over time is monitored through advanced imaging approaches or the clinical assessment of morbidity. Because clinical signs of morbidity are often vague and unpredictable, an inexpensive and reproducible method to detect advanced metastatic burden-before the development of mortality-is needed. We have developed a noninvasive technique for assessing pulmonary metastatic burden in laboratory mice. The pulmonary assessment of advanced metastasis (PAAM) test is performed by restraining an awake mouse and gently applying pressure with the index finger under the xiphoid process. This pressure reduces the diaphragmatic component to respiration. Mice with advanced lung metastases show transient signs of respiratory distress within 3 s of the application of this pressure. Using PAAM in 4 distinct models (including sarcoma and mammary carcinoma histologies) of experimental (tail vein) pulmonary metastasis (n = 114 mice), among 3 independent evaluators yielded 94% positive and negative predictive values, which were validated by histologic assessment of postmortem lung tissue. PAAM is a simple, reproducible, and efficient method to assist in the detection of advanced pulmonary metastasis in mice and contributes to their humane care during longitudinal studies. C1 [Mendoza, Arnulfo; Gharpure, Radhika; Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Webster, Joshua D.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD USA. [Dennis, John; Smedley, Jeremy] SAIC Frederick Lab Anim Sci Program, Bethesda, MD USA. RP Khanna, C (reprint author), NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU NIH (National Cancer Institute, Bethesda Maryland) FX This research was supported by The Intramural Research Program of the NIH (National Cancer Institute, Bethesda Maryland). NR 12 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2013 VL 52 IS 5 BP 584 EP 589 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA AN7VZ UT WOS:000340810400012 PM 24041215 ER PT J AU Masedunskas, A Porat-Shliom, N Tora, M Milberg, O Weigert, R AF Masedunskas, Andrius Porat-Shliom, Natalie Tora, Muhibullah Milberg, Oleg Weigert, Roberto TI Intravital Microscopy for Imaging Subcellular Structures in Live Mice Expressing Fluorescent Proteins SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Cellular Biology; Issue 79; Microscopy; Confocal Microscopy; Fluorescence; Multiphoton; Exocytosis; Cell Biology; animal biology; animal models; Intravital Microscopy; Salivary glands; Exocytosis; In Vivo Imaging AB Here we describe a procedure to image subcellular structures in live rodents that is based on the use of confocal intravital microscopy. As a model organ, we use the salivary glands of live mice since they provide several advantages. First, they can be easily exposed to enable access to the optics, and stabilized to facilitate the reduction of the motion artifacts due to heartbeat and respiration. This significantly facilitates imaging and tracking small subcellular structures. Second, most of the cell populations of the salivary glands are accessible from the surface of the organ. This permits the use of confocal microscopy that has a higher spatial resolution than other techniques that have been used for in vivo imaging, such as two-photon microscopy. Finally, salivary glands can be easily manipulated pharmacologically and genetically, thus providing a robust system to investigate biological processes at a molecular level. In this study we focus on a protocol designed to follow the kinetics of the exocytosis of secretory granules in acinar cells and the dynamics of the apical plasma membrane where the secretory granules fuse upon stimulation of the beta-adrenergic receptors. Specifically, we used a transgenic mouse that co-expresses cytosolic GFP and a membrane-targeted peptide fused with the fluorescent protein tandem-Tomato. However, the procedures that we used to stabilize and image the salivary glands can be extended to other mouse models and coupled to other approaches to label in vivo cellular components, enabling the visualization of various subcellular structures, such as endosomes, lysosomes, mitochondria, and the actin cytoskeleton. C1 [Masedunskas, Andrius; Porat-Shliom, Natalie; Tora, Muhibullah; Milberg, Oleg; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Masedunskas, Andrius] Univ N Carolina, Dept Biol, Chapel Hill, NC USA. [Milberg, Oleg] Rutgers State Univ, Dept Chem & Biochem Engn, Piscataway, NJ 08855 USA. [Milberg, Oleg] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08855 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. EM weigertr@mail.nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467 FU Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research. NR 15 TC 3 Z9 3 U1 0 U2 1 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2013 IS 79 AR UNSP e50558 DI 10.3791/50558 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RI UT WOS:000209228100019 ER PT J AU Brabletz, T Lyden, D Steeg, PS Werb, Z AF Brabletz, Thomas Lyden, David Steeg, Patricia S. Werb, Zena TI Roadblocks to translational advances on metastasis research SO NATURE MEDICINE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; CIRCULATING TUMOR-CELLS; CANCER STEM-CELLS; BREAST-CANCER; DRUG-RESISTANCE; DOWN-REGULATION; COLONIZATION; MICROENVIRONMENT; PROGRESSION; MODEL C1 US Natl Canc Inst, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD USA. Univ Freiburg Med Ctr, Dept Gen & Visceral Surg, Ctr Comprehens Canc, Freiburg, Germany. Univ Freiburg Med Ctr, BIOSS Ctr Biol Signalling Studies, Freiburg, Germany. Univ Calif San Francisco, Dept Anat, San Francisco, CA USA. RP Brabletz, T (reprint author), US Natl Canc Inst, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD USA. EM thomas.brabletz@uniklinik-freiburg.de; dcl2001@med.cornell.edu; steegp@mail.nih.gov; zena.werb@ucsf.edu FU NCI NIH HHS [R01 CA129523] NR 60 TC 21 Z9 23 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD SEP PY 2013 VL 19 IS 9 BP 1104 EP 1109 DI 10.1038/nm.3327 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 213TP UT WOS:000324083500023 PM 24013756 ER PT J AU Chen, Y Schlessinger, D Nagaraja, R AF Chen, Y. Schlessinger, D. Nagaraja, R. TI T antigen transformation reveals Tp53/RB-dependent route to PLAC1 transcription activation in primary fibroblasts SO ONCOGENESIS LA English DT Article DE large T antigen; transcription; NCOA2; RXR alpha; LXR; chromatin AB PLAC1 (placenta-specific 1) is a gene that is placenta specific and transcribed very little, if at all, in any somatic tissue. It is nevertheless expressed in many cancer cell lines. To understand how cancer cells may activate the gene in nonexpressing cells, we found that a model is provided by classical transformation of normal fibroblasts by SV40 T antigen. T antigen derepressed the PLAC1 P1 promoter, with Tp53 and RB exerting critical and opposing actions and nuclear receptors, retinoid X receptor and liver X receptor, sharply increasing the level of expression. C1 [Chen, Y.; Schlessinger, D.; Nagaraja, R.] NIA, Genet Lab, Baltimore, MD 21224 USA. RP Nagaraja, R (reprint author), NIA, Genet Lab, NIH, Biomed Res Ctr,IRP, 251 Bayview Blvd,Room 10B117, Baltimore, MD 21224 USA. EM nagarajar@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was entirely funded by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. We thank Drs Wedong Wang and Paritosh Ghosh for critical reading of the manuscript and suggestions. NR 35 TC 2 Z9 2 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2157-9024 J9 ONCOGENESIS JI Oncogenesis PD SEP PY 2013 VL 2 AR UNSP e67 DI 10.1038/oncsis.2013.31 PG 8 WC Oncology SC Oncology GA V36OH UT WOS:000209220500001 PM 23999628 ER PT J AU Masood, R Hochstim, C Cervenka, B Zu, S Baniwal, SK Patel, V Kobielak, A Sinha, UK AF Masood, R. Hochstim, C. Cervenka, B. Zu, S. Baniwal, S. K. Patel, V. Kobielak, A. Sinha, U. K. TI A novel orthotopic mouse model of head and neck cancer and lymph node metastasis SO ONCOGENESIS LA English DT Article DE head and neck squamous cell carcinoma genetics; metastasis; epithelial-to-mesenchymal transition (EMT); cancer stem cells (CSCs) AB Prognosis of head and neck squamous cell carcinoma (HNSCC) is largely determined by the extent of lymph node (LN) metastasis at diagnosis, and this appears to be controlled by cancer cell genetics. To examine the role of these genes in LN metastasis, we created a human-in-mouse orthotopic model of HNSCC and performed comparative microarray analysis of gene expression between populations of HNSCC cell lines derived before and after serial transplantation and in vivo metastasis in mice. Microarray analysis comparing the USC-HN3-GFP, USC-HN3-GFP-G1 and USC-HN3-GFP-G2 cell lines identified overexpression of genes implicated in epithelial-to-mesenchymal transition and the formation of cancer stem cells, including CAV-1, TLR-4 (Toll-like receptor 4), MMP-7 (matrix metalloproteinase 7), ALDH1A3, OCT-4 and TRIM-29. Ingenuity Pathway Analysis confirmed upregulation of respective gene signaling pathways in the USC-HN1-GFP-G2 cell line. Patient HNSCC samples from advanced stages overexpressed ALDH1A3, CAV-1 and MMP-7. Our results show that CAV-1, TLR-4, MMP-7, ALDH1A3, OCT-4 and TRIM-29 have increased expression in HNSCC cells selected for an enhanced metastatic phenotype and suggest that these genes may have an important role in the metastatic potential of HNSCC cells. Inhibition of these genes may therefore have prognostic and therapeutic utility in HNSCC. C1 [Masood, R.; Hochstim, C.; Cervenka, B.; Zu, S.; Kobielak, A.; Sinha, U. K.] Univ So Calif, Keck Sch Med, Dept Otolaryngol Head & Neck Surg, Los Angeles, CA 90033 USA. [Baniwal, S. K.] Univ So Calif, Keck Sch Med, Dept Orthoped Surg, Los Angeles, CA 90033 USA. [Patel, V.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Masood, R (reprint author), Univ So Calif, Keck Sch Med, Dept Otolaryngol Head & Neck Surg, HMP 903,2011 Zonal Ave, Los Angeles, CA 90033 USA. EM masood@usc.edu FU Health Research Association; RAM capital; Zumberge foundation FX We thank Susan McDonald for her help in the patients' chart. We also thank Raj Dedhia and Farshad Chowdhury for doing the chart review of all the patients and proofreading the manuscript. This work was supported by the generous grants from the Health Research Association and RAM capital. RM had complete access to the data used in this manuscript and is without any conflict of interest. Dr Baniwal was supported from the Zumberge foundation. NR 36 TC 12 Z9 12 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2157-9024 J9 ONCOGENESIS JI Oncogenesis PD SEP PY 2013 VL 2 AR UNSP e68 DI 10.1038/oncsis.2013.33 PG 8 WC Oncology SC Oncology GA V36OH UT WOS:000209220500002 PM 24018643 ER PT J AU Coll, JA Campbell, A Chalmers, NI AF Coll, James A. Campbell, Alison Chalmers, Natalia I. TI Effects of Glass Ionomer Temporary Restorations on Pulpal Diagnosis and Treatment Outcomes in Primary Molars SO PEDIATRIC DENTISTRY LA English DT Article DE PULP THERAPY; ENDODONTICS; GLASS IONOMER CEMENTS; PRIMARY MOLARS ID MINERAL TRIOXIDE AGGREGATE; MICROBIOLOGICAL ANALYSIS; CARIOUS DENTIN; PRIMARY TEETH; CARIES; FORMOCRESOL; PULPOTOMY; THERAPY; CEMENT; TRIAL AB Purpose: To evaluate 1) if glass ionomer interim temporary restorations (ITR) placed for 1-3 months prior to vital pulp therapy (VPT) improved accuracy of diagnosing the pulp's clinical status and subsequent VPT success, and 2) the effect of the location of the carious lesion on VPT. Methods: Primary molars (N=117) receiving pulp therapy with or without ITR were evaluated retrospectively All teeth had caries extending >50 percent into dentin; caries lesion location was identified (proximal or non-proximal). Two examiners rated pulp status assessment, caries location, and pulp treatment, and correlated treatment outcomes after a mean of 34.7 months to these factors. Results: VPT failed more often in first primary molars (P<.001) than in second primary molars. Using ITR improved diagnosis of the pulp status, clinical success of VPT, (P=.013) and first molar VPT success (P=.02). First primary molars had more proximal lesions than second molars (P<.001). Failure of VPT was greater for teeth with proximal lesions (P=.03). Use of ITR significantly improved VPT in teeth with proximal lesions (P=.007) but not non-proximal lesions (P=.38). Conclusions: ITR placed prior to VPT improved pulpal diagnosis and VPT outcomes. Vital pulp therapy was less successful in primary molars with proximal lesions, and ITR significantly improved the success. C1 [Coll, James A.] Univ Maryland, Sch Dent, Dept Pediat Dent, Baltimore, MD 21201 USA. [Chalmers, Natalia I.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Coll, JA (reprint author), Univ Maryland, Sch Dent, Dept Pediat Dent, Baltimore, MD 21201 USA. EM dmd1@comcat.net NR 32 TC 1 Z9 1 U1 1 U2 2 PU AMER ACAD PEDIATRIC DENTISTRY PI CHICAGO PA 211 E CHICAGO AVENUE SUITE 1036, CHICAGO, IL 60611-2616 USA SN 0164-1263 EI 1942-5473 J9 PEDIATR DENT JI Pediatr. Dent. PD SEP-OCT PY 2013 VL 35 IS 5 BP 416 EP 421 PG 6 WC Dentistry, Oral Surgery & Medicine; Pediatrics SC Dentistry, Oral Surgery & Medicine; Pediatrics GA AP8NR UT WOS:000342336200004 PM 24290553 ER PT J AU Meganck, JA Begun, DL McElderry, JD Swick, A Kozloff, KM Goldstein, SA Morris, MD Marini, JC Caird, MS AF Meganck, J. A. Begun, D. L. McElderry, J. D. Swick, A. Kozloff, K. M. Goldstein, S. A. Morris, M. D. Marini, J. C. Caird, M. S. TI Fracture healing with alendronate treatment in the Brtl/ plus mouse model of osteogenesis imperfecta SO BONE LA English DT Article DE Osteogenesis imperfecta; Bisphosphonates; Bone; Rodent; Fracture repair ID HYPERPLASTIC CALLUS FORMATION; POLARIZED-LIGHT MICROSCOPY; ZOLEDRONIC ACID; BISPHOSPHONATE INCADRONATE; BONE STRENGTH; CHILDREN; PAMIDRONATE; COLLAGEN; REPAIR; RATS AB Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by increased skeletal fragility. Patients are often treated with bisphosphonates to attempt to reduce fracture risk. However, bisphosphonates reside in the skeleton for many years and long-term administration may impact bone material quality. Acutely, there is concern about risk of non-union of fractures that occur near the time of bisphosphonate administration. This study investigated the effect of alendronate, a potent aminobisphosphonate, on fracture healing. Using the Brtl/+ murine model of type IV OI, tibial fractures were generated in 8-week-old mice that were untreated, treated with alendronate before fracture, or treated before and after fracture. After 2, 3, or 5 weeks of healing, tibiae were assessed using microcomputed tomography (mu CT), torsion testing, quantitative histomorphometry, and Raman microspectroscopy. There were no morphologic, biomechanical or histomorphometric differences in callus between untreated mice and mice that received alendronate before fracture. Alendronate treatment before fracture did not cause a significant increase in cartilage retention in fracture callus. Both Brtl/+ and WT mice that received alendronate before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5 weeks of healing. Raman microspectroscopy results did not show any effects of alendronate in wild-type mice, but calluses from Brtl+ mice treated with alendronate during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with alendronate altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture. (C) 2013 Elsevier Inc. All rights reserved. C1 [Meganck, J. A.; Begun, D. L.; Swick, A.; Kozloff, K. M.; Goldstein, S. A.; Caird, M. S.] Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, Ann Arbor, MI 48109 USA. [Meganck, J. A.; Begun, D. L.; Swick, A.; Kozloff, K. M.; Goldstein, S. A.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [McElderry, J. D.; Morris, M. D.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Marini, J. C.] NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. RP Caird, MS (reprint author), Univ Michigan, Dept Orthopaed Surg, Mott Childrens Hosp, 1540 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM Jeff.Meganck@caliperls.com; dbegun@umich.edu; jdmac@umich.edu; aswick3@gmail.com; kenkoz@umich.edu; stevegld@umich.edu; mdmorris@umich.etlu; oidoc@helix.nih.gov; sugiyama@med.umich.edu FU National Science Foundation; University of Michigan Musculoskeletal Core Center [NIH AR46024]; regenerative sciences training grant [NIH T90 DK070071]; University of Michigan Department of Orthopaedic Surgery; National Institutes of Health [R01 AR047969]; NICHD FX The authors would like to thank Bonnie Nolan, Kathy Sweet, Sharon Reske, Xixi Wang, Jason Combs, Dennis Kayner, and Charles Roehm. Thanks also to Ling ling Zhang for statistical support. The authors would also like to acknowledge support from the National Science Foundation Graduate Research Fellowship Program (JAM), the University of Michigan Musculoskeletal Core Center (SAG; NIH AR46024), the regenerative sciences training grant (SAG; NIH T90 DK070071), the University of Michigan Department of Orthopaedic Surgery (MSC), the National Institutes of Health (MDM; R01 AR047969), and NICHD Intramural Funding (JCM). These funding sources did not have involvement in the study design; collection, analysis, or interpretation of data; or in the report or its publication submission. NR 54 TC 11 Z9 11 U1 3 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD SEP PY 2013 VL 56 IS 1 BP 204 EP 212 DI 10.1016/j.bone.2013.06.003 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 189WS UT WOS:000322299600028 PM 23774443 ER PT J AU Rossi, PIA Musante, I Summa, M Pittaluga, A Emionite, L Ikehata, M Rastaldi, MP Ravazzolo, R Puliti, A AF Rossi, Pia Irene Anna Musante, Ilaria Summa, Maria Pittaluga, Anna Emionite, Laura Ikehata, Masami Rastaldi, Maria Pia Ravazzolo, Roberto Puliti, Aldamaria TI Compensatory Molecular and Functional Mechanisms in Nervous System of the Grm1(crv4) Mouse Lacking the mGlu1 Receptor: A Model for Motor Coordination Deficits SO CEREBRAL CORTEX LA English DT Article DE evoked-glutamate release; Grm1(crv4) mouse; mGlu1 receptor; mGlu5 receptor; mouse cortex ID METABOTROPIC GLUTAMATE RECEPTORS; CEREBELLAR PURKINJE-CELLS; LONG-TERM POTENTIATION; MICE LACKING; MUTANT MICE; RAT-BRAIN; EXPRESSION; DIFFERENTIATION; EXOCYTOSIS; SURVIVAL AB The metabotropic glutamate type 1 (mGlu1) and type 5 (mGlu5) receptors, the only members of group I mGlu receptors, are implicated in synaptic plasticity and mechanisms of feedback control of glutamate release. They exhibit nearly complementary distributions throughout the central nervous system, well evident in the cerebellum, where mGlu1 receptor is most intensely expressed while mGlu5 receptor is not. Despite their different distribution, they show a similar subcellular localization and use common transducing pathways. We recently described the Grm1(crv4) mouse with motor coordination deficits and renal anomalies caused by a spontaneous mutation inactivating the mGlu1 receptor. To define the neuropathological mechanisms in these mice, we evaluated expression and function of the mGlu5 receptor in cerebral and cerebellar cortices. Western blot and immunofluorescence analyses showed mGlu5 receptor overexpression. Quantitative reverse transcriptase-polymerase chain reaction results indicated that the up-regulation is already evident at RNA level. Functional studies confirmed an enhanced glutamate release from cortical cerebral and cerebellar synaptosomes when compared with wild-type that is abolished by the mGlu5 receptor-specific inhibitor, 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP). Finally, acute MPEP treatment of Grm1(crv4/crv4) mice induced an evident although incomplete improvement of motor coordination, suggesting that mGlu5 receptors enhanced activity worsens, instead of improving, the motor-coordination defects in the Grm1(crv4/crv4) mice. C1 [Rossi, Pia Irene Anna; Musante, Ilaria; Ravazzolo, Roberto; Puliti, Aldamaria] Gaslini Inst, Mol Genet & Cytogenet Unit, Genoa, Italy. [Rossi, Pia Irene Anna; Musante, Ilaria; Ravazzolo, Roberto; Puliti, Aldamaria] Univ Genoa, Dept Pediat Sci, Genoa, Italy. [Summa, Maria; Pittaluga, Anna] Univ Genoa, Dept Expt Med, Sect Pharmacol & Toxicol, Genoa, Italy. [Emionite, Laura] Natl Canc Inst, Anim Facil, Genoa, Italy. [Ikehata, Masami; Rastaldi, Maria Pia] Fdn IRCCS Osped Maggiore Policlin, Renal Res Lab, Milan, Italy. [Ikehata, Masami; Rastaldi, Maria Pia] Fdn DAmico Ric Malattie Renali, Milan, Italy. RP Puliti, A (reprint author), G Gaslini Inst Children, Mol Genet Lab, Largo G Gaslini 5, I-16148 Genoa, Italy. EM apuliti@unige.it RI Pittaluga, Anna/C-5960-2008; Puliti, Aldamaria/K-7866-2016; IKEHATA, MASAMI/H-8020-2016 OI Puliti, Aldamaria/0000-0001-9310-6514; IKEHATA, MASAMI/0000-0001-9835-9991 FU Italian Ministry of Health [RFPS-4-631972]; Italian 'Ministero dell'Istruzione, dell'Universita e della Ricerca Scientifica' (MIUR) FX This work was supported by RFPS-4-631972 grant 'Genetic Bases of Birth Defects' from the Italian Ministry of Health to R. R. and by grant from the Italian 'Ministero dell'Istruzione, dell'Universita e della Ricerca Scientifica' (MIUR) to A.P. NR 51 TC 4 Z9 4 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2013 VL 23 IS 9 BP 2179 EP 2189 DI 10.1093/cercor/bhs200 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 194VP UT WOS:000322661100015 PM 22791805 ER PT J AU Hunter, AM Leuchter, AF Power, RA Muthen, B McGrath, PJ Lewis, CM Cook, IA Garriock, HA McGuffin, P Uher, R Hamilton, SP AF Hunter, Aimee M. Leuchter, Andrew F. Power, Robert A. Muthen, Bengt McGrath, Patrick J. Lewis, Cathryn M. Cook, Ian A. Garriock, Holly A. McGuffin, Peter Uher, Rudolf Hamilton, Steven P. TI A genome-wide association study of a sustained pattern of antidepressant response SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Antidepressant; Genetics; STAR*D; GENDEP; Growth mixture modeling; Citalopram ID STAR-ASTERISK-D; CHONDROITIN SULFATE PROTEOGLYCANS; MAJOR DEPRESSIVE DISORDER; SET ENRICHMENT ANALYSIS; CLINICAL-PRACTICE; GENETIC-VARIATION; PHARMACOGENETICS; TRAJECTORIES; EFFICACY; GENDEP AB Genome-wide association studies (GWAS) have failed to replicate common genetic variants associated with antidepressant response, as defined using a single endpoint. Genetic influences may be discernible by examining individual variation between sustained versus unsustained patterns of response, which may distinguish medication effects from non-specific, or placebo responses to active medication. We conducted a GWAS among 1116 subjects with Major Depressive Disorder from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who were characterized using Growth Mixture Modeling as showing a sustained versus unsustained pattern of clinical response over 12 weeks of treatment with citalopram. Replication analyses examined 585 subjects from the Genome-based Therapeutic Drugs for Depression (GENDEP) trial. The strongest association with sustained as opposed to unsustained response in STAR*D involved a single nucleotide polymorphism (SNP; rs10492002) within the acyl-CoA synthetase short-chain family member 3 gene (ACSS3, p-value =4.5 x 10(-6), odds ratio = 0.61). No SNPs met our threshold for genome-wide significance. SNP data were available in GENDEP for 18 of the top 25 SNPs in STAR*D. The most replicable association was with SNP rs7816924 (p = 0.008, OR= 1.58); no SNP met the replication p-value threshold of 0.003. Joint analysis of these 18 SNPs resulted in the strongest signal coming from rs7816924 (p = 2.11 x 10(-7)), which resides in chondroitin sulfate N-acetylgalactosaminyltransferase 1 gene (CSGALNACT1). An exploratory genetic pathway analysis revealed evidence for an involvement of the KEGG pathway of long-term potentiation (FDR=.02). Results suggest novel genetic associations to sustained response. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Hunter, Aimee M.; Leuchter, Andrew F.; Cook, Ian A.] Univ Calif Los Angeles, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Power, Robert A.; Lewis, Cathryn M.; McGuffin, Peter; Uher, Rudolf] Kings Coll London, Inst Psychiat, London, England. [Muthen, Bengt] Univ Calif Los Angeles, Grad Sch Educ & Informat Studies, Los Angeles, CA 90024 USA. [McGrath, Patrick J.] Columbia Univ, Coll Physicians & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY 10027 USA. [Garriock, Holly A.; Hamilton, Steven P.] Univ Calif San Francisco, Dept Psychiat, Inst Human Genet, San Francisco, CA 94143 USA. [Garriock, Holly A.] NIMH, Div Dev Trajectories, Bethesda, MD USA. [Uher, Rudolf] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. RP Hunter, AM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza,Rm 57-455, Los Angeles, CA 90024 USA. EM amhunter@ucla.edu RI McGrath, Patrick/I-6410-2013; McGuffin, Peter/A-1565-2012; Uher, Rudolf/A-5477-2008; Lewis, Cathryn/A-5225-2010; Power, Robert/B-3482-2012; OI McGrath, Patrick/0000-0001-7217-7321; McGuffin, Peter/0000-0002-9888-2907; Uher, Rudolf/0000-0002-2998-0546; Lewis, Cathryn/0000-0002-8249-8476; Garriock, Holly/0000-0002-0629-5917; Hamilton, Steven/0000-0001-8106-6260 FU NIMH [N01MH90003, MH072802, 1R34MH085933-01]; European Commission [LSHB-CT-2003-503428]; GlaxoSmithKline [G0701420]; UK National Institute for Health Research of the Department of Health; U.K. Medical research council; European Commission Innovative Medicine Initiative Joint Undertaking (IMI-JU) [115008]; Canada Research Chairs program FX Clinical data used in the GWAS were obtained from the limited access datasets distributed from the NIMH-supported "Sequenced Treatment Alternatives to Relieve Depression" (STAR*D) (Contract # N01MH90003 to the University of Texas Southwestern Medical Center). Genotyping of the STAR*D sample was supported by NIMH grant MH072802 to S.P. Hamilton. Analysis of STAR*D clinical data and response trajectories was supported by NIMH grant 1R34MH085933-01 to A.M. Hunter. This manuscript reflects the views of the authors and may not reflect the opinions or views of the STAR*D Study Investigators or the NIH.; Data for replication analyses were obtained from the GENDEP project which was funded by the European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. H. Lundbeck provided nortriptyline and escitalopram for the GENDEP study. GlaxoSmithKline and the UK National Institute for Health Research of the Department of Health contributed to the funding of the sample collection at the Institute of Psychiatry London. GENDEP genotyping was funded by a joint grant from the U.K. Medical research council and GlaxoSmithKline (G0701420) and the European Commission Innovative Medicine Initiative Joint Undertaking (IMI-JU) grant no 115008. R. Uher is supported by the Canada Research Chairs program (http://www.chairs-chaires.gc.ca/) and the European Commission Innovative Medicine Initiative Joint Undertaking (IMI-JU) grant no 115008. NR 41 TC 16 Z9 17 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD SEP PY 2013 VL 47 IS 9 BP 1157 EP 1165 DI 10.1016/j.jpsychires.2013.05.002 PG 9 WC Psychiatry SC Psychiatry GA 191LF UT WOS:000322413800005 PM 23726668 ER PT J AU Teicher, BA AF Teicher, Beverly A. TI Perspective: Opportunities in recalcitrant, rare and neglected tumors SO ONCOLOGY REPORTS LA English DT Article DE pancreatic cancer; sarcoma small cell lung cancer; recalicitrant tumors; rare tumors; neglected tumors ID CELL LUNG-CANCER; PANCREATIC-CANCER; HIF-1 INHIBITORS; SOLID TUMORS; IN-VITRO; ANTICANCER; EXPRESSION; LINES; THERAPY; HYPOXIA AB The 'Recalcitrant Cancer Research Act of 2012' defines recalcitrant cancers as having a 5-year survival rate of <20% and estimated to cause the death of at least 30,000 individuals in the US each year. Cancers specifically mentioned in the act are lung and pancreatic cancers. In addition to recalcitrant tumors, rare tumors are often neglected in the drug discovery arena. Sarcomas are similar to 1% of cancers. The NCI Specialized Programs of Research Excellence (SPOREs) provide disease-focused cancer center grants specifically to accelerate the impact of laboratory research on the treatment of patients. There are 3 SPOREs focused on pancreatic cancer, 7 SPOREs focused on lung cancer and 1 SPORE focused on sarcoma. Through the Developmental Therapeutics Program (DTP), NCI maintains the infrastructure and expertise for the operation of cell-free and cell-based high-, medium- and low-throughput assays. The current effort is on sarcoma, SCLC and pancreatic lines. The DTP functional genomics laboratory provides molecular analyses including gene expression microarrays, exon arrays, microRNA arrays, multiplexing gene assays, plus others as tools to identify potential drug targets and to determine the role of selected genes in the mechanism(s) of drug action and cellular responses to stressors. The DTP tumor microenvironment laboratory focuses on the discovery of targets and the development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes. The DTP maintains a group focused on determining the mechanism(s) of action and identifying potential surrogate markers of activity for select compounds integrating proteomics, transcriptomics and molecular biology platforms. In conclusion, the NCI has active SPORE programs and an internal effort focused on recalcitrant, rare and neglected cancers which are generating data toward improving treatment of these difficult diseases. C1 NCI, Mol Pharmacol Branch, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Teicher, BA (reprint author), NCI, Mol Pharmacol Branch, Dev Therapeut Program, Room 4-W602,9606 Med Ctr Dr,MSC 9735, Bethesda, MD 20892 USA. EM teicherba@mail.nih.gov NR 51 TC 4 Z9 4 U1 0 U2 9 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X EI 1791-2431 J9 ONCOL REP JI Oncol. Rep. PD SEP PY 2013 VL 30 IS 3 BP 1030 EP 1034 DI 10.3892/or.2013.2581 PG 5 WC Oncology SC Oncology GA 191AJ UT WOS:000322384700002 PM 23820887 ER PT J AU Birbaumer, N Ayala, GG Cohen, L Murguialday, AR AF Birbaumer, Niels Ayala, Guillermo Gallegos Cohen, Leonardo Murguialday, Ander Ramos TI BRAIN-MACHINE-INTERFACES (BMI) IN COMPLETE PARALYSIS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 02-06, 2013 CL Florence, ITALY SP Soc Psychophysiol Res DE Paralysis; Brain-Machine-Interface; Stroke C1 [Birbaumer, Niels; Ayala, Guillermo Gallegos; Murguialday, Ander Ramos] Univ Tubingen, Tubingen, Germany. [Cohen, Leonardo] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2013 VL 50 SU 1 SI SI BP S40 EP S41 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 199LH UT WOS:000322995500231 ER PT J AU Esposito, G Nakazawa, J Venuti, P Bornstein, MH AF Esposito, Gianluca Nakazawa, Jun Venuti, Paola Bornstein, Marc H. TI Componential deconstruction of infant distress vocalizations via tree-based models: A study of cry in autism spectrum disorder and typical development SO RESEARCH IN DEVELOPMENTAL DISABILITIES LA English DT Article DE Cry; Autism; Autistic disorder; Perception of cry in Japan; Tree-based models; Perception ID YOUNG-CHILDREN; PERCEPTIONS; HYPOTHESIS AB Understanding early episodes of cry is essential to improve caregiver-child interaction and child well-being. Caregiver perceptions of cry are based on interpretations of different acoustic characteristics of the cry, including the length of the pauses, the number of utterances, and the fundamental frequency. In this study, we used tree-based models to establish a hierarchy of effect in terms of how these acoustic characteristics influence perceptions of cries of children with autism compared to cries of typically developing children. In two studies, one in Italy and the other in Japan, we found that cries of children with autism are perceived more negatively. We also found that the length of the pauses, more than the number of utterances or fundamental frequency, determines listeners' negative perceptions. Implications for early caregiver-child interactions are discussed. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Esposito, Gianluca] RIKEN Brain Sci Inst, Unit Affiliat Social Behav, Wako, Saitama, Japan. [Esposito, Gianluca; Venuti, Paola] Univ Trento, Dept Psychol & Cognit Sci, Trento, Italy. [Nakazawa, Jun] Chiba Univ, Fac Educ, Dept Dev Sci, Chiba, Japan. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Esposito, G (reprint author), RIKEN Brain Sci Inst, Unit Affiliat Social Behav, Wako, Saitama, Japan. EM gesposito@brain.riken.jp; nakazawa@faculty.chiba-u.jp RI Esposito, Gianluca/B-1374-2012; Esposito, Gianluca/K-9353-2013 OI Esposito, Gianluca/0000-0002-9442-0254; Esposito, Gianluca/0000-0002-9442-0254 FU Intramural NIH HHS [ZIA HD001119-25] NR 39 TC 11 Z9 11 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-4222 J9 RES DEV DISABIL JI Res. Dev. Disabil. PD SEP PY 2013 VL 34 IS 9 BP 2717 EP 2724 DI 10.1016/j.ridd.2013.05.036 PG 8 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 191OT UT WOS:000322423200032 PM 23774058 ER PT J AU Jeong, J Lisinski, I Kadegowda, AKG Shin, H Wooding, FBP Daniels, BR Schaack, J Mather, IH AF Jeong, Jaekwang Lisinski, Ivonne Kadegowda, Anil K. G. Shin, Hyunsu Wooding, F. B. Peter Daniels, Brian R. Schaack, Jerome Mather, Ian H. TI A Test of Current Models for the Mechanism of Milk-Lipid Droplet Secretion SO TRAFFIC LA English DT Article DE butyrophilin; exocrine biology; lactation; milk-lipid secretion; mouse; perilipin-2; xanthine oxidoreductase ID FAT-GLOBULE-MEMBRANE; MAMMARY EPITHELIAL-CELLS; DIFFERENTIATION-RELATED PROTEIN; BOVINE-MILK; XANTHINE-OXIDOREDUCTASE; APICAL MEMBRANE; BUTYROPHILIN; GLAND; GLYCOPROTEIN; LACTATION AB Milk lipid is secreted by a unique process, during which triacylglycerol droplets bud from mammary cells coated with an outer bilayer of apical membrane. In all current schemes, the integral protein butyrophilin 1A1 (B ) is postulated to serve as a transmembrane scaffold, which interacts either with itself or with the peripheral proteins, xanthine oxidoreductase (XOR) and possibly perilipin-2 (PLIN2), to form an immobile bridging complex between the droplet and apical surface. In one such scheme, B on the surface of cytoplasmic lipid droplets interacts directly with B in the apical membrane without binding to either XOR or PLIN2. We tested these models using both biochemical and morphological approaches. B was concentrated in the apical membrane in all species examined and contained mature N-linked glycans. We found no evidence for the association of unprocessed B with intracellular lipid droplets. B -enhanced green fluorescent protein was highly mobile in areas of mouse milk-lipid droplets that had not undergone post-secretion changes, and endogenous mouse B comprised only 0.5-0.7% (w/w) of the total protein, i.e. over 50-fold less than in the milk-lipid droplets of cow and other species. B is the major component of an immobile global adhesive complex and suggest that interactions between B and other proteins at the time of secretion are more transient than previously predicted. B in lipid droplets marks it as a potential mobile signaling molecule in milk. C1 [Jeong, Jaekwang; Lisinski, Ivonne; Kadegowda, Anil K. G.; Shin, Hyunsu; Mather, Ian H.] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Wooding, F. B. Peter] Univ Cambridge, Physiol Lab, Cambridge CB2 3EG, England. [Daniels, Brian R.] NICHHD, Bethesda, MD 20892 USA. [Schaack, Jerome] Univ Colorado, Denver Sch Med, Dept Microbiol, Aurora, CO 80045 USA. RP Mather, IH (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM imather@umd.edu FU USDA NRI Program [2005-04637]; NICHD-NIH [1R01 HD048588-01A1]; Maryland Agricultural Experiment Station FX We thank Tim Reardon and Liane West for animal care and maintenance and Dr Dale Hailey (University of Washington, Seattle, WA) for Clontech vectors. Dr Roberto Weigert (IMTU, NIDCR, National Institutes of Health, Bethesda, MD) provided access to the Olympus confocal microscope and Imaris software. This work was funded by grants from the USDA NRI Program (2005-04637), NICHD-NIH (1R01 HD048588-01A1) and the Maryland Agricultural Experiment Station to I. H. M. None of the authors have conflicts of interest to declare. NR 58 TC 11 Z9 11 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 J9 TRAFFIC JI Traffic PD SEP PY 2013 VL 14 IS 9 BP 974 EP 986 DI 10.1111/tra.12087 PG 13 WC Cell Biology SC Cell Biology GA 195SB UT WOS:000322722800003 PM 23738536 ER PT J AU Ghirlando, R Balbo, A Piszczek, G Brown, PH Lewis, MS Brautigam, CA Schuck, P Zhao, HY AF Ghirlando, Rodolfo Balbo, Andrea Piszczek, Grzegorz Brown, Patrick H. Lewis, Marc S. Brautigam, Chad A. Schuck, Peter Zhao, Huaying TI Improving the thermal, radial, and temporal accuracy of the analytical ultracentrifuge through external references SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Sedimentation velocity; Sedimentation equilibrium; Hydrodynamic modeling ID VELOCITY ANALYTICAL ULTRACENTRIFUGATION; PROTEIN-PROTEIN INTERACTIONS; SEDIMENTATION-VELOCITY; LAMM EQUATION; TEMPERATURE-MEASUREMENT; COMPUTER; EQUILIBRIUM; THERMOMETER; DISTRIBUTIONS; CONFORMATION AB Sedimentation velocity (SV) is a method based on first principles that provides a precise hydrodynamic characterization of macromolecules in solution. Due to recent improvements in data analysis, the accuracy of experimental SV data emerges as a limiting factor in its interpretation. Our goal was to unravel the sources of experimental error and develop improved calibration procedures. We implemented the use of a Thermochron iButton temperature logger to directly measure the temperature of a spinning rotor and detected deviations that can translate into an error of as much as 10% in the sedimentation coefficient. We further designed a precision mask with equidistant markers to correct for instrumental errors in the radial calibration that were observed to span a range of 8.6%. The need for an independent time calibration emerged with use of the current data acquisition software (Zhao et al., Anal. Biochem., 437 (2013) 104-108), and we now show that smaller but significant time errors of up to 2% also occur with earlier versions. After application of these calibration corrections, the sedimentation coefficients obtained from 11 instruments displayed a significantly reduced standard deviation of approximately 0.7%. This study demonstrates the need for external calibration procedures and regular control experiments with a sedimentation coefficient standard. Published by Elsevier Inc. C1 [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Balbo, Andrea; Brown, Patrick H.; Lewis, Marc S.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Brautigam, Chad A.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Schuck, Peter; Zhao, Huaying] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov; zhaoh3@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank Erby Perdue for his expert advice and for taking excellent care of our analytical ultracentrifuges and thank Dr. Nicole Morgan for helpful discussions. This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 71 TC 21 Z9 21 U1 1 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 1 PY 2013 VL 440 IS 1 BP 81 EP 95 DI 10.1016/j.ab.2013.05.011 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 191MP UT WOS:000322417500015 PM 23711724 ER PT J AU Yan, PK Zhang, WX Turkbey, B Choyke, PL Li, XL AF Yan, Pingkun Zhang, Wuxia Turkbey, Baris Choyke, Peter L. Li, Xuelong TI Global structure constrained local shape prior estimation for medical image segmentation SO COMPUTER VISION AND IMAGE UNDERSTANDING LA English DT Article DE Target-oriented shape modeling; Manifold learning; Manifold assumption; Medical image segmentation ID DIMENSIONALITY REDUCTION; MODELS; OBJECTS; SPACE; MRI AB Organ shape plays an important role in clinical diagnosis, surgical planning and treatment evaluation. Shape modeling is a critical factor affecting the performance of deformable model based segmentation methods for organ shape extraction. In most existing works, shape modeling is completed in the original shape space, with the presence of outliers. In addition, the specificity of the patient was not taken into account. This paper proposes a novel target-oriented shape prior model to deal with these two problems in a unified framework. The proposed method measures the intrinsic similarity between the target shape and the training shapes on an embedded manifold by manifold learning techniques. With this approach, shapes in the training set can be selected according to their intrinsic similarity to the target image. With more accurate shape guidance, an optimized search is performed by a deformable model to minimize an energy functional for image segmentation, which is efficiently achieved by using dynamic programming. Our method has been validated on 2D prostate localization and 3D prostate segmentation in MRI scans. Compared to other existing methods, our proposed method exhibits better performance in both studies. (C) 2013 Elsevier Inc. All rights reserved. C1 [Yan, Pingkun; Zhang, Wuxia; Li, Xuelong] Chinese Acad Sci, Ctr OPT IMagery Anal & Learning OPTIMAL, State Key Lab Transient Opt & Photon, Xian Inst Opt & Precis Mech, Xian 710119, Shaanxi, Peoples R China. [Turkbey, Baris; Choyke, Peter L.] NCI, NIH, Bethesda, MD 20892 USA. RP Yan, PK (reprint author), Chinese Acad Sci, Ctr OPT IMagery Anal & Learning OPTIMAL, State Key Lab Transient Opt & Photon, Xian Inst Opt & Precis Mech, Xian 710119, Shaanxi, Peoples R China. EM pingkun@ieee.org FU National Basic Research Program of China (973 Program) [2012CB719905]; National Natural Science Foundation of China [61125106, 61172142, 91120302, 61072093] FX This work is supported by the National Basic Research Program of China (973 Program) (Grant No. 2012CB719905) and by the National Natural Science Foundation of China (Grant Nos: 61125106, 61172142, 91120302, and 61072093). NR 34 TC 8 Z9 9 U1 1 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1077-3142 J9 COMPUT VIS IMAGE UND JI Comput. Vis. Image Underst. PD SEP PY 2013 VL 117 IS 9 BP 1017 EP 1026 DI 10.1016/j.cviu.2013.03.006 PG 10 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 182EK UT WOS:000321724300005 ER PT J AU Ma, J Lu, L AF Ma, Jun Lu, Le TI Hierarchical segmentation and identification of thoracic vertebra using learning-based edge detection and coarse-to-fine deformable model SO COMPUTER VISION AND IMAGE UNDERSTANDING LA English DT Article DE Supervised edge detection; Coarse-to-fine shape deformation model; Shape based medical image segmentation; Vertebra segmentation; Vertebra identification; Computed tomography ID IMAGES; FEATURES; NODULES; SPINE AB Precise segmentation and identification of thoracic vertebrae is important for many medical imaging applications though it remains challenging due to the vertebra's complex shape and varied neighboring structures. In this paper, a new method based on learned bone-structure edge detectors and a coarse-to-fine deformable surface model is proposed to segment and identify vertebrae in 3D CT thoracic images. In the training stage, a discriminative classifier for object-specific edge detection is trained using steerable features and statistical shape models for 12 thoracic vertebrae are also learned. For the run-time testing, we design a new coarse-to-fine, two-stage segmentation strategy: subregions of a vertebra first deform together as a group; then vertebra mesh vertices in a smaller neighborhood move group-wise to progressively drive the deformable model towards edge response maps by optimizing a probability cost function. In this manner, the smoothness and topology of vertebrae shapes are guaranteed. This algorithm performs successfully with reliable mean point-to-surface errors 0.95 +/- 0.91 mm on 40 volumes. Consequently a vertebra identification scheme is also proposed via mean surface mesh matching. We achieve a success rate of 73.1% using a single vertebra, and over 95% for 8 or more vertebra which is comparable or slightly better than state-of-the-art [5]. Published by Elsevier Inc. C1 Siemens Mol Imaging, Hoffman Estates, IL 60192 USA. Siemens Corp Res, Princeton, NJ 08540 USA. RP Lu, L (reprint author), NIH, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jun.jm.ma@siemens.com; le.lu@nih.gov NR 30 TC 16 Z9 17 U1 0 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1077-3142 EI 1090-235X J9 COMPUT VIS IMAGE UND JI Comput. Vis. Image Underst. PD SEP PY 2013 VL 117 IS 9 BP 1072 EP 1083 DI 10.1016/j.cviu.2012.11.016 PG 12 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 182EK UT WOS:000321724300010 ER PT J AU Chang, YJ Chen, HC Pan, MH Lee, BH You, SL Lin, CY Chou, YC Hsieh, CY Cheng, YJ Liaw, KL Hsing, AW Schiffman, M Chen, CJ AF Chang, Ya-Ju Chen, Hui-Chi Pan, Mei-Hung Lee, Bor-Heng You, San-Lin Lin, Ching-Yu Chou, Yi-Chun Hsieh, Chang-Yao Cheng, Yu-Juen Liaw, Kai-Li Hsing, Ann W. Schiffman, Mark Chen, Chien-Jen CA CBCSP-HPV Study Grp TI Intratypic variants of human papillomavirus type 16 and risk of cervical Neoplasia in Taiwan SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HPV 16; variants; prevalence; cervical neoplasia; Taiwan ID 16 E6 VARIANTS; INTRAEPITHELIAL NEOPLASIA; HPV16 E6; SEQUENCE VARIANTS; NATURAL VARIANTS; GENOTYPING ARRAY; KOREAN WOMEN; CANCER; HUMAN-PAPILLOMAVIRUS-16; LESIONS AB The associations between variants of human papillomavirus (HPV) 16 and risk of cervical neoplasia have been reported, but nucleotide variations of HPV 16 in Asian populations and their association with cervical neoplasia have not been evaluated extensively. During 1991-1992, 11,923 women from seven townships in Taiwan were enrolled. The HPV DNA in cervical cells was detected and genotyped using EasyChip HPV blot. Nucleotide variations in the long control region (LCR), E6, and E7 genes were determined using DNA sequencing for 170 HPV 16-positive cervical samples. The Asian variant was the most prevalent variant (81.8%) of HPV 16 in Taiwan, and was also associated with increased prevalence of histologically confirmed cervical intraepithelial neoplasia grade 3 or worse, showing an age-adjusted odds ratio (exact confidence limits) of 10.70 (1.62-451.05; P=0.0049) compared to the HPV 16 European variant. Similar significant associations with cervical intraepithelial neoplasia grade 3 or worse were also observed for distinct nucleotide substitutions, including T178A/G, A647G, A7730C/G, T7781C, G7842A, and C24T/G. These results demonstrate that non-European variants (non-E) of HPV 16, predominantly Asian variants, are associated with increased risk for severe cervical neoplasia, compared with European variants. Molecular mechanisms accounting for varied cervical neoplasia risk among different HPV 16 variants warrant further investigation. J. Med. Virol. 85:1567-1576, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Chang, Ya-Ju; Chou, Yi-Chun; Cheng, Yu-Juen; Chen, Chien-Jen] Natl Taiwan Univ, Grad Inst Epidemiol, Taipei 10764, Taiwan. [Chen, Hui-Chi; Pan, Mei-Hung; You, San-Lin; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei 11529, Taiwan. [Lee, Bor-Heng] King Car Food Ind Co Ltd, Yuan Shan Res Inst, Ilan, Taiwan. [Lin, Ching-Yu] Taipei Med Univ, Sch Med Lab Sci & Biotechnol, Taipei, Taiwan. [Hsieh, Chang-Yao] Natl Taiwan Univ Hosp, Dept Obstet & Gynecol, Taipei, Taiwan. [Hsing, Ann W.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Chen, CJ (reprint author), Acad Sinica, Genom Res Ctr, 128 Acad Rd Sect 2, Taipei 11529, Taiwan. EM chencj@gate.sinica.edu.tw RI Chen, Chien-Jen/C-6976-2008; OI Lin, Ching-Yu/0000-0001-8269-797X FU National Science Council [94-2314-B-001-011, 95-2314-B-001-007, 96-2314-B-001-004, 97-2314-B-001-001-MY3] FX Grant sponsor: National Science Council; Grant numbers: 94-2314-B-001-011; 95-2314-B-001-007; 96-2314-B-001-004; 97-2314-B-001-001-MY3. NR 44 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD SEP PY 2013 VL 85 IS 9 BP 1567 EP 1576 DI 10.1002/jmv.23651 PG 10 WC Virology SC Virology GA 181WD UT WOS:000321699700011 PM 23852681 ER PT J AU Shebl, FM Emmanuel, B Bunts, L Biryahwaho, B Kiruthu, C Huang, ML Pfeiffer, RM Casper, C Mbulaiteye, SM AF Shebl, Fatma M. Emmanuel, Benjamin Bunts, Lisa Biryahwaho, Benon Kiruthu, Christine Huang, Meei-Li Pfeiffer, Ruth M. Casper, Corey Mbulaiteye, Sam M. TI Population-based assessment of kaposi sarcoma-associated herpesvirus DNA in plasma among Ugandans SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE Kaposi sarcoma-associated herpesvirus; *Kaposi sarcoma; plasma; epidemiology; uganda ID HUMAN-HERPESVIRUS-8 INFECTION; RISK-FACTORS; SEROLOGIC ASSAYS; HOMOSEXUAL MEN; HIV-INFECTION; EAST-AFRICA; TRANSMISSION; CANCER; ADULTS; SEROPREVALENCE AB Risk of Kaposi sarcoma (KS) is linked to detection of Kaposi sarcoma-associated herpesvirus (KSHV) DNA in plasma, but little is known about the prevalence and risk factors for plasma KSHV DNA detection among the general population where KS is endemic. Correlates of KSHV plasma detection were investigated in a population-based sample of adult Ugandans (15-59 years) who participated in an HIV/AIDS serobehavioral survey in 2004/2005. KSHV DNA was measured in plasma of 1,080 KSHV seropositive and 356 KSHV seronegative persons using polymerase chain reaction (PCR). KSHV DNA in plasma was detected in 157 (8.7%) persons; of these 149 (95%) were KSHV seropositive and 8 (5%) were seronegative. Detection of KSHV DNA in plasma was significantly associated with male sex (P<0.001), older age (P=0.003), residence in a rural versus urban area (P=0.002), geographic region (P=0.02), and being KSHV seropositive (13.8% seropositive vs. 2.3% seronegative, P<0.001). In a multivariable model, KSHV DNA plasma quantity was significantly higher in men (P=0.002), inversely associated with age (P=0.05), and residing in an urban area (P=0.01). In Uganda, KSHV is detected more frequently in the plasma of adult males and residents of rural regions, potentially explaining the increased risk of KS in these subsets of the Ugandan population. J. Med. Virol. 85:1602-1610, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Shebl, Fatma M.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Emmanuel, Benjamin; Kiruthu, Christine; Pfeiffer, Ruth M.; Mbulaiteye, Sam M.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Bunts, Lisa; Casper, Corey] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Publ Hlth Sci & Clin Res Div, Seattle, WA 98104 USA. [Biryahwaho, Benon] Uganda Virus Res Inst, Entebbe, Uganda. [Huang, Meei-Li] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Casper, Corey] Univ Washington, Dept Med, Seattle, WA USA. [Casper, Corey] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Casper, Corey] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Execut Plaza South,Rm 7080,MSC 7, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov FU Intramural NIH HHS [ZIA CP010176-12] NR 39 TC 5 Z9 5 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD SEP PY 2013 VL 85 IS 9 BP 1602 EP 1610 DI 10.1002/jmv.23613 PG 9 WC Virology SC Virology GA 181WD UT WOS:000321699700016 PM 23852686 ER PT J AU Chauchard, E Levin, KH Copersino, ML Heishman, SJ Gorelick, DA AF Chauchard, Emeline Levin, Kenneth H. Copersino, Marc L. Heishman, Stephen J. Gorelick, David A. TI Motivations to quit cannabis use in an adult non-treatment sample: Are they related to relapse? SO ADDICTIVE BEHAVIORS LA English DT Article DE Cannabis; Motivation to quit; Cessation; Relapse ID EXTRINSIC MOTIVATION; MARIJUANA USE; SMOKING-CESSATION; REASONS; SMOKERS; POPULATION; REMISSIONS; WITHDRAWAL; PATHWAY; COCAINE AB Background: The majority of cannabis smokers who quit do so without formal treatment, suggesting that motivations to quit are an important part of cessation process. However, little is known about how motivations relate to successful quitting. Method: A convenience sample of 385 non-treatment-seeking adult cannabis smokers (58% male, age 16-64 years at start of quit attempt) who made a "serious" (self-defined) quit attempt without formal treatment while not in a controlled environment were administered the 176-item Marijuana Quit Questionnaire (MJQQ) to assess their motivations to quit and outcome of the quit attempt Exploratory factor analysis was performed to identify significant motivational factors. Subgroup comparisons used t-tests and ANOVA. Cox proportional hazard regression and the General Linear Model were performed to evaluate the influence of motivational factors, gender, and age on relapse status at time of interview and risk of relapse over time, with time between quit attempt and interview as a covariate. Results: Exploratory factor analysis identified 6 motivational factors with eigenvalues >1 which accounted for 58.4% of the total variance: self-image and self-control, health concerns, interpersonal relationship concerns, legal concerns, social acceptability concerns, and self-efficacy. Women were more likely than men to be motivated by self-image/self-control, health concerns, and social acceptability concerns. Older individuals were more likely to be motivated by health concerns. At the time of interview, 339 subjects had relapsed. Self-image and self-control, health concerns, interpersonal relationship concerns, and social acceptability concerns were associated with greater likelihood of abstinence at the study interview. Legal concerns and social acceptability concerns were associated with significantly lower hazard ratios (0.88, 0.83) for relapse during the abstinent period. Conclusion: These findings show gender and age differences in motivations to quit cannabis smoking and that adult cannabis smokers have motivations to quite similar to those of adolescent cannabis smokers and of adults who quit alcohol and tobacco use without formal treatment. The findings suggest areas of focus to improve secondary prevention and psychosocial treatment efforts. Published by Elsevier Ltd. C1 [Chauchard, Emeline; Levin, Kenneth H.; Heishman, Stephen J.; Gorelick, David A.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Chauchard, Emeline] Univ Toulouse, Lab Octogone CERPP, F-31058 Toulouse 9, France. [Copersino, Marc L.] Harvard Univ, Sch Med, McLean Hosp, Belmont, MA 02478 USA. RP Gorelick, DA (reprint author), NIDA, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM emeline.chauchard@gmail.com; khlevin@gmail.com; mcopersino@mclean.harvard.edu; sheish@intra.nida.nih.gov; dgorelic@intra.nida.nih.gov FU NIH, National Institute on Drug Abuse; joint action of the Interministerial Mission for the Fight against Drugs and Drug Addiction (MILDT, French Government); University of Toulouse II, Le Mirail FX Funding for this study was provided by the Intramural Research Program, NIH, National Institute on Drug Abuse. Dr. Chauchard received funding from the joint action of the Interministerial Mission for the Fight against Drugs and Drug Addiction (MILDT, French Government) and the University of Toulouse II, Le Mirail. Neither NIH, MILDT, nor the University of Toulouse played any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 34 TC 10 Z9 10 U1 3 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD SEP PY 2013 VL 38 IS 9 BP 2422 EP 2427 DI 10.1016/j.addbeh.2013.04.002 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 179SE UT WOS:000321540800002 PM 23685328 ER PT J AU Ranzenhofer, LM Hannallah, L Field, SE Shomaker, LB Stephens, M Sbrocco, T Kozlosky, M Reynolds, J Yanovski, JA Tanofsky-Kraff, M AF Ranzenhofer, Lisa M. Hannallah, Louise Field, Sara E. Shomaker, Lauren B. Stephens, Mark Sbrocco, Tracy Kozlosky, Merel Reynolds, James Yanovski, Jack A. Tanofsky-Kraff, Marian TI Pre-meal affective state and laboratory test meal intake in adolescent girls with loss of control eating SO APPETITE LA English DT Article DE Adolescence; Loss of control eating; Negative affect; Binge eating ID ECOLOGICAL MOMENTARY ASSESSMENT; CONSTRUCT-VALIDITY; FOOD SELECTION; ADULT OBESITY; HIGH-RISK; BODY-FAT; BINGE; CHILDREN; DISORDER; OVERWEIGHT AB Loss of control eating confers risk for excess weight gain and exacerbated disordered eating. Affect theory proposes that loss of control eating is used to cope with negative mood states. Self-report data suggest that negative affect may contribute to the etiology of loss of control eating, but this theory has not been well-tested using laboratory paradigms. We examined associations between pre-meal affective states and intake during a laboratory test meal. One-hundred and ten adolescent girls with reported loss of control eating whose body mass index fell between the 75th and 97th percentile for age and sex completed state mood ratings prior to a test-meal. Results indicated that pre-meal state negative affect was associated with greater carbohydrate and less protein consumption, as well as greater snack and dessert and less fruit and dairy intake. All girls experienced significant decreases in negative affect from pre- to post-meal, but intake during the meal was unassociated with post-meal affect. In support of affect theory, negative affective states reported among girls with loss of control may be a driving factor for increased energy-dense food intake, which may play a role in excess weight gain. Published by Elsevier Ltd. C1 [Ranzenhofer, Lisa M.; Hannallah, Louise; Field, Sara E.; Shomaker, Lauren B.; Sbrocco, Tracy; Yanovski, Jack A.; Tanofsky-Kraff, Marian] USUHS, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Ranzenhofer, Lisa M.; Hannallah, Louise; Field, Sara E.; Shomaker, Lauren B.; Tanofsky-Kraff, Marian] Eunice Kennedy Shriyer Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Stephens, Mark] USUHS, Dept Family Med, Bethesda, MD 20814 USA. [Kozlosky, Merel] NIH, Dept Nutr, Ctr Clin, DHHS, Bethesda, MD 20892 USA. [Reynolds, James] NIH, Dept Nucl Med, Hatfield Clin Res Ctr, DHHS, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), USUHS, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu RI Stephens, Mark/A-2679-2015; OI Yanovski, Jack/0000-0001-8542-1637 FU NIDDK [1R01DK080906-01A1]; USUHS Grant [R072IC]; NICHD Intramural Research Program [ZIA-HO-00641] FX NIDDK Grant 1R01DK080906-01A1 (to MTK), USUHS Grant R072IC (to MTK) and NICHD Intramural Research Program ZIA-HO-00641 (to JAY). J. Yanovski and M. Kozlosky are commissioned officers in the U.S. Public Health Service (PHS). M. Stephens is active duty in the US Navy. Disclaimer: The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the PHS, the Department of the Navy, USUHS or the U.S. Department of Defense. NR 55 TC 13 Z9 13 U1 0 U2 25 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 J9 APPETITE JI Appetite PD SEP 1 PY 2013 VL 68 BP 30 EP 37 DI 10.1016/j.appet.2013.03.018 PG 8 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA 178TI UT WOS:000321469900005 PM 23603224 ER PT J AU Castilho, RM Squarize, CH Gutkind, JS AF Castilho, R. M. Squarize, C. H. Gutkind, J. S. TI Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing SO ORAL DISEASES LA English DT Review DE PTEN; TSC1/TSC2; AKT; oral wound; wound therapy ID PROTEIN-KINASE-B; HAIR FOLLICLE; STEM-CELLS; TUMOR-SUPPRESSOR; PHOSPHOINOSITIDE 3-KINASE; SKIN; PTEN; PERIOSTIN; EPIDERMIS; DIFFERENTIATION AB The molecular circuitries controlling the process of skin wound healing have gained new significant insights in recent years. This knowledge is built on landmark studies on skin embryogenesis, maturation, and differentiation. Furthermore, the identification, characterization, and elucidation of the biological roles of adult skin epithelial stem cells and their influence in tissue homeostasis have provided the foundation for the overall understanding of the process of skin wound healing and tissue repair. Among numerous signaling pathways associated with epithelial functions, the PI3K/Akt/mTOR signaling route has gained substantial attention with the generation of animal models capable of dissecting individual components of the pathway, thereby providing a novel insight into the molecular framework underlying skin homeostasis and tissue regeneration. In this review, we focus on recent findings regarding the mechanisms involved in wound healing associated with the upregulation of the activity of the PI3K/Akt/mTOR circuitry. This review highlights critical findings on the molecular mechanisms controlling the activation of mTOR, a downstream component of the PI3K-PTEN pathway, which is directly involved in epithelial migration and proliferation. We discuss how this emerging information can be exploited for the development of novel pharmacological intervention strategies to accelerate the healing of critical size wounds. C1 [Castilho, R. M.; Squarize, C. H.] Univ Michigan, Lab Epithelial Biol, Dept Periodont & Oral Med, Sch Dent, Ann Arbor, MI 48109 USA. [Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Castilho, RM (reprint author), Univ Michigan, Lab Epithelial Biol, Dept Periodont & Oral Med, 1011 N Univ Ave,Room 3323B, Ann Arbor, MI 48109 USA. EM rcastilh@umich.edu FU National Institutes of Health (NIH/NCI) [P50-CA97248]; Intramural Research Program of the US National Institutes of Health (NIH); National Institute of Dental and Craniofacial Research (NIDCR) FX The authors are supported by the National Institutes of Health (NIH/NCI) P50-CA97248 (University of Michigan Head and Neck SPORE) and by the Intramural Research Program of the US National Institutes of Health (NIH) and National Institute of Dental and Craniofacial Research (NIDCR). NR 56 TC 13 Z9 16 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD SEP PY 2013 VL 19 IS 6 BP 551 EP 558 DI 10.1111/odi.12070 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 179KH UT WOS:000321518700002 PM 23379329 ER PT J AU Warren, KE Poussaint, TY Vezina, G Hargrave, D Packer, RJ Goldman, S Wen, PY Pollack, IF Zurakowski, D Kun, LE Prados, MD Rutkowski, S Kieran, MW AF Warren, Katherine E. Poussaint, Tina Y. Vezina, Gilbert Hargrave, Darren Packer, Roger J. Goldman, Stewart Wen, Patrick Y. Pollack, Ian F. Zurakowski, David Kun, Larry E. Prados, Michael D. Rutkowski, Stefan Kieran, Mark W. TI Challenges with defining response to antitumor agents in pediatric neuro-oncology: A report from the response assessment in pediatric neuro-oncology (RAPNO) working group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE brain; imaging; pediatric; RANO; response; tumor ID INTRINSIC PONTINE GLIOMAS; HIGH-GRADE GLIOMAS; INTEROBSERVER VARIABILITY; CHEMOTHERAPY; CHILDREN; CRITERIA; CARBOPLATIN; ONCOLOGY; SURVIVAL; THERAPY AB Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations. Pediatr Blood Cancer 2013;60:1397-1401. (c) 2013 Wiley Periodicals, Inc. C1 [Warren, Katherine E.] NCI, Bethesda, MD 20892 USA. [Poussaint, Tina Y.; Zurakowski, David] Childrens Hosp, Boston, MA 02115 USA. [Vezina, Gilbert; Packer, Roger J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Hargrave, Darren] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Goldman, Stewart] Lurie Childrens Hosp Chicago, Chicago, IL USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pollack, Ian F.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Kun, Larry E.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rutkowski, Stefan] Univ Med Ctr, Hamburg, Germany. [Kieran, Mark W.] Dana Farber Childrens Hosp Canc Ctr, Boston, MA USA. RP Warren, KE (reprint author), NCI, Pediat Oncol Branch, Bldg 10 Room 1-5750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov RI Hargrave, Darren/H-1066-2014; OI Hargrave, Darren/0000-0001-8219-9807; Kieran, Mark/0000-0003-2184-7692 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research NR 25 TC 16 Z9 16 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2013 VL 60 IS 9 BP 1397 EP 1401 DI 10.1002/pbc.24562 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 181XM UT WOS:000321703900068 PM 23625747 ER PT J AU Skapek, SX Anderson, J Barr, FG Bridge, J Gastier-Foster, JM Parham, DM Rudzinski, ER Triche, T Hawkins, DS AF Skapek, Stephen X. Anderson, James Barr, Frederic G. Bridge, JuliaA. Gastier-Foster, Julie M. Parham, David M. Rudzinski, Erin R. Triche, Timothy Hawkins, Douglas S. TI PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: A children's oncology group report SO PEDIATRIC BLOOD & CANCER LA English DT Article DE PAX-FOXO1; rhabdomyosarcoma; survival ID NEGATIVE ALVEOLAR RHABDOMYOSARCOMA; GENE-EXPRESSION; RISK STRATIFICATION; PAX3; TRANSLOCATION; SARCOMAS; FKHR AB Background. Rhabdomyosarcoma (RMS) is divided into two major histological subtypes: alveolar (ARMS) and embryonal (ERMS), with most ARMS expressing one of two oncogenic genes fusing PAX3 or PAX7 with FOXO1 (P3F and P7F, respectively). The Children's Oncology Group (COG) carried out a multi-institutional clinical trial to evaluate the prognostic value of PAX-FOXO1 fusion status. Methods. Study participants were treated on COG protocol D9803 for intermediate risk ARMS or ERMS using multi-agent chemotherapy, radiotherapy, and surgery. Central diagnostic pathology review and molecular testing for fusion genes were carried out on prospectively collected specimens. Event-free (EFS) and overall survival (OS) at 5 years were correlated with histological subtype and PAX-FOXO1 status. Results. Of 616 eligible D9803 enrollees, 434 cases had adequate clinical, molecular, and pathology data for definitive classification as ERMS, ARMS P3F+ or P7F+, or ARMSn (without detectable fusion). EFS was worse for those with ARMS P3F+ (54%) and P7F+ (65%) than those with ERMS (77%; P < 0.001). EFS for ARMSn and ERMS were not statistically different (90% vs. 77%, P = 0.15). ARMS P3F+ had poorer OS (64%) than ARMS P7F+(87%), ARMSn (89%), and ERMS (82%; P=0.006). Conclusions. ARMSn has an outcome similar to ERMS and superior EFS compared to ARMS with either P3F or P7F, when given therapy designed for children with intermediate risk RMS. This prospective analysis supports incorporation of PAX-FOXO1 fusion status into risk stratification and treatment allocation. Pediatr Blood Cancer 2013;60:1411-1417. (C) 2013 Wiley Periodicals, Inc. C1 [Skapek, Stephen X.] Childrens Med Ctr, Dallas, TX 75235 USA. [Skapek, Stephen X.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Anderson, James; Bridge, JuliaA.] Univ Nebraska Med Ctr, Omaha, NE USA. [Barr, Frederic G.] NCI, Bethesda, MD 20892 USA. [Gastier-Foster, Julie M.] Ohio State Univ, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Parham, David M.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Rudzinski, Erin R.] Seattle Childrens Hosp, Seattle, WA USA. [Triche, Timothy] Univ So Calif, Childrens Hosp Los Angeles, Los Angeles, CA USA. [Hawkins, Douglas S.] Seattle Childrens Hosp, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Hawkins, Douglas S.] Univ Washington, Seattle, WA 98195 USA. RP Skapek, SX (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pediat, Ctr Canc & Blood Disorders, Childrens Med Ctr, 5323 Harry Hines Blvd,MC 9063, Dallas, TX 75390 USA. EM stephen.skapek@utsouthwestern.edu FU St. Baldrick's Foundation [179772]; NIH [CA148216, CA104896 CA098413] FX Grant sponsor: St. Baldrick's Foundation; Grant number: #179772; Grant sponsor: NIH; Grant numbers: CA148216; CA104896 CA098413. NR 27 TC 42 Z9 44 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2013 VL 60 IS 9 BP 1411 EP 1417 DI 10.1002/pbc.24532 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 181XM UT WOS:000321703900071 PM 23526739 ER PT J AU Bode, SFN Jessen, B Ammann, S Maul-Pavicic, A de Saint Basile, G Janka, G Lehmberg, K zur Stadt, U Gochuico, BR Gahl, WA Klein, C Diestelhorst, J Griese, M Frei-Jones, MJ Pace, D Davies, G Schwarz, K Griffiths, G Ehl, S AF Bode, Sebastian F. N. Jessen, Birthe Ammann, Sandra Maul-Pavicic, Andrea de Saint Basile, Genevieve Janka, Gritta Lehmberg, Kai zur Stadt, Udo Gochuico, Bernadette R. Gahl, William A. Klein, Christoph Diestelhorst, Jana Griese, Matthias Frei-Jones, Melissa J. Pace, David Davies, Graham Schwarz, Klaus Griffiths, Gillian Ehl, Stephan TI DOES HERMANSKY PUDLAK SYNDROME TYPE 2 REPRESENT AN INDICATION FOR HEMATOPOETIC STEM CELL TRANSPLANTATION? SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Bode, Sebastian F. N.; Jessen, Birthe; Ammann, Sandra; Maul-Pavicic, Andrea; Ehl, Stephan] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Bode, Sebastian F. N.; Jessen, Birthe; Ammann, Sandra; Maul-Pavicic, Andrea; Ehl, Stephan] Univ Freiburg, Freiburg, Germany. [de Saint Basile, Genevieve] Univ Paris 05, INSERM, U768, Hop Necker Enfants Malad, Paris, France. [Janka, Gritta; Lehmberg, Kai] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany. [zur Stadt, Udo] Univ Med Ctr Hamburg Eppendorf, Ctr Diagnost, Hamburg, Germany. [Gochuico, Bernadette R.; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Klein, Christoph; Diestelhorst, Jana; Griese, Matthias] Univ Munich, Dept Pediat, Dr von Hauner Childrens Hosp, Munich, Germany. [Frei-Jones, Melissa J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Pace, David] Mater Dei Hosp, Dept Paediat, Msida, Malta. [Davies, Graham] Great Ormond St Hosp Sick Children, Dept Immunol, London WC1N 3JH, England. [Schwarz, Klaus] Univ Ulm, Inst Transfus Med, D-89069 Ulm, Germany. [Griffiths, Gillian] Addenbrookes Hosp, Cambridge Inst Med Res, Cambridge, England. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2013 VL 60 IS 9 BP E72 EP E72 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 181XM UT WOS:000321703900011 ER PT J AU Galiwango, RM Musoke, R Lubyayi, L Ssekubugu, R Kalibbala, S Ssekweyama, V Mirembe, V Nakigozi, G Reynolds, SJ Serwadda, D Gray, RH Kigozi, G AF Galiwango, Ronald M. Musoke, Richard Lubyayi, Lawrence Ssekubugu, Robert Kalibbala, Sarah Ssekweyama, Viola Mirembe, Viola Nakigozi, Gertrude Reynolds, Steven J. Serwadda, David Gray, Ronald H. Kigozi, Godfrey TI Evaluation of current rapid HIV test algorithms in Rakai, Uganda SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV; Rapids testing; Rakai-Uganda; Algorithms ID FIELD AB Rapid HIV tests are a crucial component of HIV diagnosis in resource limited settings. In Uganda, the Ministry of Health allows both serial and parallel HIV rapid testing using Determine, Stat-Pak and Uni-Gold. In serial testing, a non-reactive result on Determine ends testing. The performance of serial and parallel algorithms with Determine and Stat-Pak test kits was assessed. A cross-sectional diagnostic test accuracy evaluation using three rapid HIV test kits as per the recommended parallel test algorithm was followed by EIA-WB testing with estimates of the performance of serial testing algorithm. In 2520 participants tested by parallel rapid algorithms, 0.6% had weakly reactive result. Parallel testing had 99.7% sensitivity and 99.8% specificity. If Stat-Pak was used as the first screening test for a serial algorithm, the sensitivity was 99.6% and specificity was 99.7%. However, if Determine was used as the screening test, sensitivity was 97.3% and specificity was 99.9%. Serial testing with Stat-Pak as the initial screening test performed as well as parallel testing, but Determine was a less sensitive screen. Serial testing could be cost saving. (C) 2013 Elsevier B.V. All rights reserved. C1 [Galiwango, Ronald M.; Musoke, Richard; Lubyayi, Lawrence; Ssekubugu, Robert; Kalibbala, Sarah; Ssekweyama, Viola; Mirembe, Viola; Nakigozi, Gertrude; Reynolds, Steven J.; Serwadda, David; Kigozi, Godfrey] Rakai Hlth Sci Program, Kalisizo, Uganda. [Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Reynolds, Steven J.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Serwadda, David] Makerere Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda. [Reynolds, Steven J.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Galiwango, RM (reprint author), Rakai Hlth Sci Program, Kalisizo, Uganda. EM rmgaliwango@rhsp.org FU Gates Foundation [22006.03]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported in part by the Gates Foundation under Grant number 22006.03 and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 13 TC 11 Z9 11 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD SEP PY 2013 VL 192 IS 1-2 BP 25 EP 27 DI 10.1016/j.jviromet.2013.04.003 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 174NH UT WOS:000321162200004 PM 23583487 ER PT J AU Blair, KS Otero, M Teng, C Jacobs, M Odenheimer, S Pine, DS Blair, RJR AF Blair, Karina S. Otero, Marcela Teng, Cindy Jacobs, Madeline Odenheimer, Stephanie Pine, Daniel S. Blair, R. J. R. TI Dissociable roles of ventromedial prefrontal cortex (vmPFC) and rostral anterior cingulate cortex (rACC) in value representation and optimistic bias SO NEUROIMAGE LA English DT Article DE fMRI; Ventromedial prefrontal cortex; Rostral anterior cingulate cortex; Optimistic bias ID FUTURE LIFE EVENTS; UNREALISTIC OPTIMISM; SUBJECTIVE VALUE; HUMAN BRAIN; CHOICE; SELF; RISK AB Optimistic bias (OB) is seen when individuals underestimate their probability of experiencing negative life events and overestimate their probability of experiencing positive life events. A reduced OB has been linked with increased depression symptoms. However, given the relevance of this information to mood and anxiety disorders, little is currently known regarding the neurobiology of OB. In the current study, we examine the neural basis of OB in healthy individuals (n = 33) during probability estimation of future positive and negative events occurring to themselves relative to other, comparable individuals. In line with previous work, subjects showed significant OB; they considered themselves significantly more likely to experience future positive and significantly less likely to experience future negative events relative to comparable others. Positive, relative to negative events, un-modulated by subjects' probability estimates, were associated with significantly greater activity within the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Moreover, responses within both regions to positive events negatively related to the healthy subjects' self reports of depression symptoms. However, there was no significant modulation of activity in either region by the subject's OB, objectified as the level to which they thought the event was more likely [positive events] or less likely [negative events] to occur to them relative to comparable others. In contrast, activity within the rostral anterior cingulate cortex (rACC) was positively modulated by OB for positive events and activity within the anterior insula and dorsomedial prefrontal cortex (dmPFC) was negatively modulated by OB for negative events. However, there was no significant relationship between responsiveness within these regions and self reports of depression symptoms. The data are discussed with reference to current models of vmPFC, rACC and anterior insula functioning. Published by Elsevier Inc. C1 [Blair, Karina S.; Otero, Marcela; Teng, Cindy; Jacobs, Madeline; Odenheimer, Stephanie; Pine, Daniel S.; Blair, R. J. R.] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Blair, KS (reprint author), NIMH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM peschark@mail.nih.gov OI Teng, Cindy/0000-0002-2611-1791 FU NIH: NIMH FX This research was supported by the Intramural Research Program of the NIH: NIMH. NR 25 TC 12 Z9 14 U1 5 U2 25 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2013 VL 78 BP 103 EP 110 DI 10.1016/j.neuroimage.2013.03.063 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 165MV UT WOS:000320488900011 PM 23567883 ER PT J AU Liu, JJV Hirano, Y Nascimento, GC Stefanovic, B Leopold, DA Silva, AC AF Liu, Junjie V. Hirano, Yoshiyuki Nascimento, George C. Stefanovic, Bojana Leopold, David A. Silva, Afonso C. TI fMRI in the awake marmoset: Somatosensory-evoked responses, functional connectivity, and comparison with propofol anesthesia SO NEUROIMAGE LA English DT Article DE Awake non-human primate; Functional MRI; New world monkey; Neuroanesthesia; Resting-state functional connectivity ID MEDIAN NERVE-STIMULATION; MONKEYS LATERAL BELT; BOLD SIGNAL CHANGES; AUDITORY-CORTEX; THALAMIC CONNECTIONS; CALLITHRIX-JACCHUS; NONHUMAN-PRIMATES; MACAQUE MONKEYS; CEREBRAL-CORTEX; PERCEPTUAL SUPPRESSION AB Functional neuroimaging in animal models is essential for understanding the principles of neurovascular coupling and the physiological basis of fMRI signals that are widely used to study sensory and cognitive processing in the human brain. While hemodynamic responses to sensory stimuli have been characterized in humans, animal studies are able to combine very high resolution imaging with invasive measurements and pharmacological manipulation. To date, most high-resolution studies of neurovascular coupling in small animals have been carried out in anesthetized rodents. Here we report fMRI experiments in conscious, awake common marmosets (Callithrix jacchus), and compare responses to animals anesthetized with propofol. In conscious marmosets, robust BOLD fMRI responses to somatosensory stimulation of the forearm were found in contralateral and ipsilateral regions of the thalamus, primary (SI) and secondary (SII) somatosensory cortex, and the caudate nucleus. These responses were markedly stronger than those in anesthetized marmosets and showed a monotonic increase in the amplitude of the BOLD response with stimulus frequency. On the other hand, anesthesia significantly attenuated responses in thalamus, SI and SII, and abolished responses in caudate and ipsilateral SI. Moreover, anesthesia influenced several other aspects of the fMRI responses, including the shape of the hemodynamic response function and the interareal (SI-SII) spontaneous functional connectivity. Together, these findings demonstrate the value of the conscious, awake marmoset model for studying physiological responses in the somatosensory pathway, in the absence of anesthesia, so that the data can be compared most directly to fMRI in conscious humans. Published by Elsevier Inc. C1 [Liu, Junjie V.; Hirano, Yoshiyuki; Nascimento, George C.; Stefanovic, Bojana; Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Leopold, David A.] NEI, Neurophysiol Imaging Facil, NIMH, NINDS,NIH, Bethesda, MD 20892 USA. RP Silva, AC (reprint author), NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room B1D106, Bethesda, MD 20892 USA. EM liu@junjie.com; hirano@chiba-u.jp; georgegcn@gmail.com; bojana@sri.utoronto.ca; SilvaA@ninds.nih.gov OI Leopold, David/0000-0002-1345-6360 FU NINDS, National Institutes of Health FX We thank Xianfeng (Lisa) Zhang, Julie Mackel, Peter Minnig and Dr. James O'Malley for their invaluable help in animal preparation. We also thank Dr. Brian Wandell and his colleagues at Stanford University for providing the mrVista software on their website. This research was supported by the Intramural Research Program of the NINDS, National Institutes of Health. NR 83 TC 29 Z9 29 U1 3 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2013 VL 78 BP 186 EP 195 DI 10.1016/j.neuroimage.2013.03.038 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 165MV UT WOS:000320488900018 PM 23571417 ER PT J AU Komlosh, ME Ozarslan, E Lizak, MJ Horkayne-Szakaly, I Freidlin, RZ Horkay, F Basser, PJ AF Komlosh, M. E. Oezarslan, E. Lizak, M. J. Horkayne-Szakaly, I. Freidlin, R. Z. Horkay, F. Basser, P. J. TI Mapping average axon diameters in porcine spinal cord white matter and rat corpus callosum using d-PFG MRI SO NEUROIMAGE LA English DT Article DE MRI; Average axon diameter; AAD; Pulsed-field gradient; PFG; Double wave vector; d-PFG; dPFG; 3D ID MICROSCOPIC DIFFUSION ANISOTROPY; COMPARTMENT SHAPE ANISOTROPY; FIELD GRADIENT MR; WATER DIFFUSION; ELECTRON MICROSCOPY; NMR; DIFFRACTION; TENSOR; BRAIN; SIZE AB Knowledge of microstructural features of nerve fascicles, such as their axon diameter, is crucial for understanding normal function in the central and peripheral nervous systems as well as assessing changes due to pathologies. In this study double-pulsed field gradient (d-PFG) filtered MRI was used to map the average axon diameter (AAD) in porcine spinal cord, which was then compared to AADs measured with optical microscopy of the same specimen, as a way to further validate this new MRI method. A novel 3D d-PFG acquisition scheme was used to obtain AADs in each voxel of a coronal slice of rat brain corpus callosum. AAD measurements were also acquired using optical microscopy performed on histological sections and validated using a glass capillary array phantom. (C) 2013 Elsevier Inc. All rights reserved. C1 [Komlosh, M. E.; Oezarslan, E.; Horkay, F.; Basser, P. J.] NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. [Komlosh, M. E.; Oezarslan, E.] Uniform Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Oezarslan, E.] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02215 USA. [Lizak, M. J.] NINDS, NIH MRI Res Facil, NIH, Bethesda, MD 20892 USA. [Horkayne-Szakaly, I.] Dept Def, Joint Pathol Ctr, Silver Spring, MD 20910 USA. [Freidlin, R. Z.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Komlosh, ME (reprint author), NIH, Bldg 13 Rm 3W16,13 South Dr, Bethesda, MD 20892 USA. EM komloshm@mail.nih.gov RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU CNRM; Henry Jackson Foundation; NIH [R01MH074794]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Center for Information Technology, NIH FX MK and EO were supported by funds from the CNRM and Henry Jackson Foundation. EO was supported in part by NIH R01MH074794. PJB and FH were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. RZF was supported by the Center for Information Technology, NIH. We are grateful to Mr. R R Clevenger, Mr. T. J. Hunt Mrs. Joni Taylor, Ms. G. J. Zywicke, Mr. A. D. Zetts, Mrs. K. Keeran, Mr. S. M. Kozlov, and Mr. K. R. Jeffries, from LAMS, NHLBI, and Dr. M. D. Budde from the Department of Neurosurgery, Medical College of Wisconsin for obtaining the specimens. We would also like to thank Dr. Doug Morris from the NMRF/NINDS for assistance with the instrumentation and Dan Benjamini for fruitful discussions. NR 42 TC 16 Z9 17 U1 1 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2013 VL 78 BP 210 EP 216 DI 10.1016/j.neuroimage.2013.03.074 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 165MV UT WOS:000320488900021 PM 23583426 ER PT J AU Robinson, OJ Overstreet, C Allen, PS Letkiewicz, A Vytal, K Pine, DS Grillon, C AF Robinson, Oliver J. Overstreet, Cassie Allen, Philip S. Letkiewicz, Alison Vytal, Katherine Pine, Daniel S. Grillon, Christian TI The role of serotonin in the neurocircuitry of negative affective bias: Serotonergic modulation of the dorsal medial prefrontal-amygdala 'aversive amplification' circuit SO NEUROIMAGE LA English DT Article DE Serotonin; ATD; Amygdala; dMPFC; Negative bias; Aversive amplification ID ACUTE TRYPTOPHAN DEPLETION; ANTERIOR CINGULATE CORTEX; POSTTRAUMATIC-STRESS-DISORDER; GENERALIZED ANXIETY DISORDER; FEAR EXTINCTION; BEHAVIORAL-INHIBITION; HEALTHY-VOLUNTEERS; MOOD DISORDERS; ACTIVATION; DEPRESSION AB Serotonergic medications can mitigate the negative affective biases in disorders such as depression or anxiety, but the neural mechanism by which this occurs is largely unknown. In line with recent advances demonstrating that negative affective biases may be driven by specific medial prefrontal-amygdala circuitry, we asked whether serotonin manipulation can alter affective processing within a key dorsal medial prefrontal-amygdala circuit: the putative human homologue of the rodent prelimbic-amygdala circuit or 'aversive amplification' circuit. In a double-blind, placebo-controlled crossover pharmaco-fMRI design, subjects (N = 19) performed a forced-choice face identification task with word distractors in an fMRI scanner over two separate sessions. On one session subjects received dietary depletion of the serotonin precursor tryptophan while on the other session they received a balanced placebo control diet. Results showed that dorsal medial prefrontal responding was elevated in response to fearful relative to happy faces under depletion but not placebo. This negative bias under depletion was accompanied by a corresponding increase in positive dorsal medial prefrontal-amygdala functional connectivity. We therefore conclude that serotonin depletion engages a prefrontal-amygdala circuit during the processing of fearful relative to happy face stimuli. This same 'aversive amplification' circuit is also engaged during anxiety induced by shock anticipation. As such, serotonergic projections may inhibit engagement of the 'aversive amplification' circuit and dysfunction in this projection may contribute to the negative affective bias in mood and anxiety disorders. These findings thus provide a promising explanation for the role of serotonin and serotonergic medications in the neurocircuitry of negative affective bias. Published by Elsevier Inc. C1 [Robinson, Oliver J.; Overstreet, Cassie; Allen, Philip S.; Letkiewicz, Alison; Vytal, Katherine; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. RP Robinson, OJ (reprint author), 15K North Dr, Bethesda, MD 20892 USA. EM oliver.j.robinson@gmail.com FU National Institutes of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. We are grateful to Michael Jackson, Angie Wu, Joan Mallinger and Michael Franklin for enormous amounts of help and support. NR 57 TC 14 Z9 15 U1 1 U2 35 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2013 VL 78 BP 217 EP 223 DI 10.1016/j.neuroimage.2013.03.075 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 165MV UT WOS:000320488900022 PM 23583742 ER PT J AU Rosas, SR Schouten, JT Cope, MT Kagan, JM AF Rosas, Scott R. Schouten, Jeffrey T. Cope, Marie T. Kagan, Jonathan M. TI Modeling the dissemination and uptake of clinical trials results SO RESEARCH EVALUATION LA English DT Article DE dissemination; uptake; citation milestones; scientific output ID TRANSLATIONAL RESEARCH; BIOMEDICAL-RESEARCH; TIME; IMPROVEMENT; GUIDELINES; CITATION; METRICS; SCIENCE; HEALTH AB A select set of highly cited publications from the National Institutes of Health (NIH) HIV/AIDS Clinical Trials Networks was used to illustrate the integration of time interval and citation data, modeling the progression, dissemination, and uptake of primary research findings. Following a process marker approach, the pace of initial utilization of this research was measured as the time from trial conceptualization, development and implementation, through results dissemination and uptake. Compared to earlier studies of clinical research, findings suggest that select HIV/AIDS trial results are disseminated and utilized relatively rapidly. Time-based modeling of publication results as they meet specific citation milestones enabled the observation of points at which study results were present in the literature summarizing the evidence in the field. Evaluating the pace of clinical research, results dissemination, and knowledge uptake in synthesized literature can help establish realistic expectations for the time course of clinical trials research and their relative impact toward influencing clinical practice. C1 [Rosas, Scott R.; Cope, Marie T.] Concept Syst Inc, Ithaca, NY 14850 USA. [Schouten, Jeffrey T.] Fred Hutchinson Canc Res Ctr, Off HIV AIDS Network Coordinat, Seattle, WA 98109 USA. [Kagan, Jonathan M.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Rosas, SR (reprint author), Concept Syst Inc, 136 East State St, Ithaca, NY 14850 USA. EM srosas@conceptsystems.com FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [N01AI50022, U01 AI068614, N01 AI050022] NR 24 TC 8 Z9 8 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0958-2029 J9 RES EVALUAT JI Res. Evaluat. PD SEP PY 2013 VL 22 IS 3 BP 179 EP 186 DI 10.1093/reseval/rvt005 PG 8 WC Information Science & Library Science SC Information Science & Library Science GA 173DZ UT WOS:000321059600004 PM 24808630 ER PT J AU Hargreave, M Jensen, A Deltour, I Brinton, LA Andersen, KK Kjaer, SK AF Hargreave, Marie Jensen, Allan Deltour, Isabelle Brinton, Louise A. Andersen, Klaus K. Kjaer, Susanne K. TI Increased risk for cancer among offspring of women with fertility problems SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE infertility; fertility treatment; childhood cancer ID IN-VITRO FERTILIZATION; ASSISTED REPRODUCTIVE TECHNOLOGY; CHILDRENS ONCOLOGY GROUP; CHILDHOOD LEUKEMIA; YOUNG-ADULTS; BORN; INFERTILITY; PREGNANCY; DIETHYLSTILBESTROL; RETINOBLASTOMA AB Some studies have indicated that children born after fertility treatment have a potential risk for cancer, but the results are inconsistent. Furthermore, any negative effects of fertility treatment might be due to the underlying infertility rather than to the procedure itself. In the largest cohort study to date with information on fertility, we examined whether the offspring of women with fertility problems had a higher risk for cancer than offspring of women without fertility problems. The study cohort consisted of 2,830,054 offspring born in Denmark between 1964 and 2006. Of these, 125,844 were offspring of women evaluated for infertility. Cox regression models were used to estimate the possible effect of being the offspring of a woman evaluated for infertility on the risk for cancer. Analyses were performed separately for cancer during childhood (0-19 years) and cancer in young adulthood (>20 years). We found that offspring born to women with fertility problems had higher overall risks for cancer in childhood (hazard ratio (HR), 1.18; 95% confidence interval (CI), 1.05-1.32) and in young adulthood (HR, 1.22; 95% CI, 1.04-1.43) than offspring of women without fertility problems. Offspring of women with fertility problems had significantly increased risks for leukemia in childhood (HR, 1.30; 95% CI, 1.06-1.60) and for cancer of the endocrine glands in young adulthood (HR, 2.67; 95% CI, 1.35-5.29). These findings suggest that offspring born to mothers with fertility problems are at increased risk for cancer in both childhood and young adulthood. If real, our findings of an approximate to 18% overall increase in risk for cancer in childhood and an approximate to 22% overall increase in risk for cancer in young adulthood would mean about four additional cases of childhood cancer and about nine additional cases of cancer in young adults per 100,000 exposed offspring. C1 [Hargreave, Marie; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc, Res Ctr, Unit Virus Lifestyle & Genes, DK-2100 Copenhagen, Denmark. [Deltour, Isabelle] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Andersen, Klaus K.; Kjaer, Susanne K.] Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark. [Kjaer, Susanne K.] Univ Copenhagen, Rigshosp, Dept Obstet & Gynecol, DK-1168 Copenhagen, Denmark. RP Kjaer, SK (reprint author), Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark. EM susanne@cancer.dk RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Kjaer, Susanne/0000-0002-8347-1398 FU Savvaerksejer Jeppe Juhl og Hustru Ovita Juhls Foundation FX Grant sponsor: Savvaerksejer Jeppe Juhl og Hustru Ovita Juhls Foundation NR 33 TC 7 Z9 7 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 1 PY 2013 VL 133 IS 5 BP 1180 EP 1186 DI 10.1002/ijc.28110 PG 7 WC Oncology SC Oncology GA 166MT UT WOS:000320559600018 PM 23404395 ER PT J AU Davis, MA Gray, RH Grabowski, MK Serwadda, D Kigozi, G Gravitt, PE Nalugoda, F Watya, S Wawer, MJ Quinn, TC Tobian, AAR AF Davis, Mitzie-Ann Gray, Ronald H. Grabowski, Mary K. Serwadda, David Kigozi, Godfrey Gravitt, Patti E. Nalugoda, Fred Watya, Stephen Wawer, Maria J. Quinn, Thomas C. Tobian, Aaron A. R. TI Male circumcision decreases high-risk human papillomavirus viral load in female partners: A randomized trial in Rakai, Uganda SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; male circumcision; Uganda; cervical cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity; HIV ID HIV-NEGATIVE MEN; CERVICAL-CANCER; PREVALENCE; INFECTION; PREVENTION; CLEARANCE; CYTOLOGY; AFRICA; WOMEN AB Male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) infection in female partners. We evaluated the intensity of HR-HPV viral DNA load in HIV-negative, HR-HPV-positive female partners of circumcised and uncircumcised men. HIV-negative men and their female partners were enrolled in randomized trials of MC in Rakai, Uganda. Vaginal swabs were tested for HR-HPV genotypes by Roche HPV Linear Array which provides a semi-quantitative measure of HPV DNA by the intensity of genotype-specific bands (graded:1-4). We assessed the effects of MC on female HR-HPV DNA load by comparing high intensity linear array bands (3-4) to low intensity bands (1-2) using an intention-to-treat analysis. Prevalence risk ratios (PRR) of high intensity bands in partners of intervention versus control arm men were estimated using log-binomial regression with robust variance. The trial included 335 women with male partners in the intervention arm and 340 in the control arm. At enrollment, the frequency of HR-HPV high intensity linear array bands was similar in both study arms. At 24 months follow-up, the prevalence of high intensity bands among women with detectable HR-HPV was significantly lower in partners of intervention arm (42.7%) than control arm men (55.1%, PRR=0.78, 95%CI 0.65-0.94, p=0.02), primarily among incident HR-HPV infections (PRR=0.66, 95% CI 0.50-0.87, p=0.003), but not persistent infections (PRR=1.02, 95% CI 0.83-1.24). Genotypes with high HR-HPV band intensity were more likely to persist (adjHR=1.27 95% CI 1.07-1.50), irrespective of male partner circumcision status. MC reduces HR-HPV DNA load in newly infected female partners. C1 [Davis, Mitzie-Ann] UCSD, Moores Canc Ctr, Dept Gynecol Oncol, La Jolla, CA USA. [Davis, Mitzie-Ann; Gray, Ronald H.; Grabowski, Mary K.; Gravitt, Patti E.; Wawer, Maria J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Gray, Ronald H.; Serwadda, David; Kigozi, Godfrey; Nalugoda, Fred; Wawer, Maria J.; Quinn, Thomas C.; Tobian, Aaron A. R.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Gravitt, Patti E.] Perdana Univ, Grad Sch Med, Serdang, Malaysia. [Watya, Stephen] Makerere Univ, Dept Urol, Kampala, Uganda. [Quinn, Thomas C.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21287 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU National Institutes of Health [UO1AI51171]; Bill and Melinda Gates Foundation [22006.02]; Fogarty International Center [5D43TW001508, 2D43TW000010-19-AITRP]; National Institute of Allergy and Infectious Diseases (NIAID); NIH [U01-AI-068613, 3U01-AI075115-03S1, 1K23AI093152-01A1]; NIAID; Doris Duke Charitable Foundation [22006.02] FX Grant sponsor: National Institutes of Health; Grant number: #UO1AI51171; Grant sponsor: Bill and Melinda Gates Foundation; Grant number: #22006.02; Grant sponsor: Fogarty International Center; Grant numbers: 5D43TW001508 and #2D43TW000010-19-AITRP; Grant sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Grant sponsor: NIH; Grant numbers: U01-AI-068613 and 3U01-AI075115-03S1; Grant sponsor: NIAID Intramural Program; Grant sponsor: NIH; Grant number: 1K23AI093152-01A1; Grant sponsor: Doris Duke Charitable Foundation Clinician Scientist Development Award; Grant number: #22006.02 NR 25 TC 12 Z9 13 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 1 PY 2013 VL 133 IS 5 BP 1247 EP 1252 DI 10.1002/ijc.28100 PG 6 WC Oncology SC Oncology GA 166MT UT WOS:000320559600025 PM 23400966 ER PT J AU Yewdell, JW AF Yewdell, Jonathan W. TI Amsterdamming DRiPs SO MOLECULAR IMMUNOLOGY LA English DT Review DE Antigen Processing; DRiP; MHC class I; Proteolysis; T cell; Virus ID MESSENGER-RNA; PEPTIDES; TRANSLATION AB The field of antigen processing and presentation has taken tremendous strides since the first international workshop in 1995. While much has been learned, much remains to be discovered. Here I discuss the most recent findings regarding the nature of substrates for the MHC class I antigen processing pathways which provide glimpses of the mist shrouded features remaining to be discovered. Published by Elsevier Ltd. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov FU Intramural NIH HHS [Z01 AI000542-20, Z01 AI000653-16] NR 7 TC 0 Z9 0 U1 0 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2013 VL 55 IS 2 SI SI BP 110 EP 112 DI 10.1016/j.molimm.2012.10.023 PG 3 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 129XI UT WOS:000317876900003 PM 23266429 ER PT J AU Mage, MG Dolan, MA Wang, R Boyd, LF Revilleza, MJ Robinson, H Natarajan, K Myers, NB Hansen, TH Margulies, DH AF Mage, Michael G. Dolan, Michael A. Wang, Rui Boyd, Lisa F. Revilleza, Maria Jamela Robinson, Howard Natarajan, Kannan Myers, Nancy B. Hansen, Ted H. Margulies, David H. TI A structural and molecular dynamics approach to understanding the peptide-receptive transition state of MHC-I molecules SO MOLECULAR IMMUNOLOGY LA English DT Review DE Antigen presentation; MHC-I structure and function; Peptide loading; X-ray crystallography; Molecular dynamics AB The mature conformation of major histocompatibility complex class I (MHC-I) proteins depends on the presence of bound peptides, permitting recognition at the cell surface by CD8(+) T lymphocytes. Newly synthesized MHC-I molecules in the endoplasmic reticulum are maintained in a peptide-receptive (PR) transition state by several chaperones until they are released concomitant with the loading of peptides. By determining the crystallographic structure of a region of an MHC-I molecule that is recognized by a unique monoclonal antibody and comparing this with docking and molecular dynamics simulations with the whole molecule, we demonstrate the movement of a hinged unit supporting the part of the binding groove that interacts with the amino terminal residues of the bound peptide. This unit contains a conserved 310 helix that flips from an exposed "open" position in the PR form to a "closed" position in the peptide-loaded (PL) mature molecule. These analyses indicate how this segment of the MHC-I molecule moves to help establish the A and B pockets critical for tight peptide binding and the stable structure required for antigen presentation and T cell recognition at the cell surface. Published by Elsevier Ltd. C1 [Mage, Michael G.; Wang, Rui; Boyd, Lisa F.; Revilleza, Maria Jamela; Natarajan, Kannan; Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Dolan, Michael A.] NIAID, Computat Biol Sect, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Robinson, Howard] Brookhaven Natl Lab, Natl Synchrotron Light Source, Upton, NY 11973 USA. [Myers, Nancy B.; Hansen, Ted H.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Mage, MG (reprint author), NIAID, NIH, 10 Ctr Dr,Bldg 10,Room 11N311, Bethesda, MD 20892 USA. EM mmage@mail.nih.gov; dhm@nih.gov RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health [AI019687] FX This research was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases as well as by National Institutes of Health Grant AI019687 (to T.H.H.). NR 6 TC 5 Z9 5 U1 1 U2 107 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2013 VL 55 IS 2 SI SI BP 123 EP 125 DI 10.1016/j.molimm.2012.10.021 PG 3 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 129XI UT WOS:000317876900007 PM 23200143 ER PT J AU Suway, JG White, LK Vanderwert, RE Bar-Haim, Y Pine, DS Fox, NA AF Suway, J. G. White, L. K. Vanderwert, R. E. Bar-Haim, Y. Pine, D. S. Fox, N. A. TI Modification of threat-processing in non-anxious individuals: A preliminary, behavioral and ERP study SO JOURNAL OF BEHAVIOR THERAPY AND EXPERIMENTAL PSYCHIATRY LA English DT Article DE Attention bias; Anxiety; ERP; Attention bias modification ID EVENT-RELATED POTENTIALS; ATTENTIONAL BIAS; SELECTIVE ATTENTION; ANXIETY DISORDER; PLASTICITY; REACTIVITY AB Background and objectives: Previous research suggests that attention bias toward threat contributes to the development and maintenance of anxiety. The current study extends this work by mapping the neural correlates of experimentally-induced changes in attention bias. The study examines both behavioral and psychophysiological changes associated with experimentally-induced changes in threat bias. Methods: Thirty-four non-anxious female adults were randomly assigned to one of two conditions: training attention toward threat or placebo control. Attention bias was assessed and trained via a modified dot-probe task. Participants completed pre- and post-training assessments of attention bias and stress reactivity. As well, EEG was collected during pre- and post-test assessment of attention bias using the dot-probe task. Results: Training induced significant changes in attention bias, though findings were complicated by group differences in baseline threat-bias scores. Compared to controls, those in the training group showed greater depression vulnerability to a post-training stressor and increased P2 amplitude, an ERP component associated with attention toward threat, during the dot-probe task. Limitations: Although participants were randomly assigned to groups, there were still group differences in pre-training bias scores. Also, while the use of a stress task before the initial assessment of attention bias was used to control for initial differences in stress vulnerability, this may have altered pre-bias scores since participants completed this task immediately after being stressed. Conclusions: These findings demonstrate training-induced changes in behavior and neural response patterns relevant to work on attention bias modification. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Suway, J. G.; White, L. K.; Fox, N. A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Vanderwert, R. E.] Childrens Hosp Boston, Div Dev Med, Labs Cognit Neurosci, Boston, MA USA. [Bar-Haim, Y.] Tel Aviv Univ, Sch Psychol Sci, Tel Aviv, Israel. [Bar-Haim, Y.] Tel Aviv Univ, Sch Neurosci, Tel Aviv, Israel. [Pine, D. S.] NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Program, Bethesda, MD USA. RP Suway, JG (reprint author), Univ Maryland, 3304 Benjamin Bldg, College Pk, MD 20742 USA. EM Jngold@umd.edu OI Vanderwert, Ross/0000-0002-2280-8401 FU NICHD NIH HHS [R37 HD017899, R37HD17899]; NIMH NIH HHS [1F31MH085424, F31 MH085424, P50 MH078105, P50 MH078105-01A2] NR 29 TC 5 Z9 6 U1 1 U2 69 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7916 J9 J BEHAV THER EXP PSY JI J. Behav. Ther. Exp. Psychiatry PD SEP PY 2013 VL 44 IS 3 BP 285 EP 292 DI 10.1016/j.jbtep.2012.11.006 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 120KE UT WOS:000317168400002 PM 23391516 ER PT J AU Yadav, H Lee, JH Lloyd, J Walter, P Rane, SG AF Yadav, Hariom Lee, Ji-Hyeon Lloyd, John Walter, Peter Rane, Sushil G. TI Beneficial Metabolic Effects of a Probiotic via Butyrate-induced GLP-1 Hormone Secretion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GUT-MICROBIOTA INTERACTIONS; INSULIN-RESISTANCE; PLASMA-CONCENTRATIONS; ENERGY-EXPENDITURE; FOOD-INTAKE; OBESITY; INFLAMMATION; HEALTH; FLORA; MICE AB Obesity and diabetes are associated with excess caloric intake and reduced energy expenditure resulting in a negative energy balance. The incidence of diabetes has reached epidemic proportions, and childhood diabetes and obesity are increasing alarmingly. Therefore, it is important to develop safe, easily deliverable, and economically viable treatment alternatives for these diseases. Here, we provide data supporting the candidacy of probiotics as such a therapeutic modality against obesity and diabetes. Probiotics are live bacteria that colonize the gastrointestinal tract and impart beneficial effects for health. However, their widespread prescription as medical therapies is limited primarily because of the paucity of our understanding of their mechanism of action. Here, we demonstrate that the administration of a probiotic, VSL#3, prevented and treated obesity and diabetes in several mouse models. VSL#3 suppressed body weight gain and insulin resistance via modulation of the gut flora composition. VSL#3 promoted the release of the hormone GLP-1, resulting in reduced food intake and improved glucose tolerance. The VSL#3-induced changes were associated with an increase in the levels of a short chain fatty acid (SCFA), butyrate. Using a cell culture system, we demonstrate that butyrate stimulated the release of GLP-1 from intestinal L-cells, thereby providing a plausible mechanism for VSL#3 action. These findings suggest that probiotics such as VSL#3 can modulate the gut microbiota-SCFA-hormone axis. Moreover, our results indicate that probiotics are of potential therapeutic utility to counter obesity and diabetes. C1 [Yadav, Hariom; Lee, Ji-Hyeon; Rane, Sushil G.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Lloyd, John] NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. [Walter, Peter] NIDDK, Clin Mass Spectrometry Core, NIH, Bethesda, MD 20892 USA. RP Rane, SG (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM ranes@mail.nih.gov OI Yadav, Hariom/0000-0003-4504-1597 FU National Institutes of Health from the Intramural Program of NIDDK FX This work was supported, in whole or in part, by the National Institutes of Health from the Intramural Program of NIDDK. NR 50 TC 89 Z9 94 U1 9 U2 43 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2013 VL 288 IS 35 BP 25088 EP 25097 DI 10.1074/jbc.M113.452516 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302QC UT WOS:000330619000009 PM 23836895 ER PT J AU Ying, TL Chen, WZ Feng, Y Wang, YP Gong, R Dimitrov, DS AF Ying, Tianlei Chen, Weizao Feng, Yang Wang, Yanping Gong, Rui Dimitrov, Dimiter S. TI Engineered Soluble Monomeric IgG1 CH3 Domain GENERATION, MECHANISMS OF FUNCTION, AND IMPLICATIONS FOR DESIGN OF BIOLOGICAL THERAPEUTICS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEONATAL-FC-RECEPTOR; ANTIBODY DOMAIN; INCREASED-STABILITY; CRYSTAL-STRUCTURE; BINDING-SITE; GAMMA-RIII; HALF-LIFE; GLYCOPROTEIN; FRAGMENTS; PROTEINS AB Most of the therapeutic antibodies approved for clinical use are full-size IgG1 molecules. The interaction of the IgG1 Fc with the neonatal Fc receptor (FcRn) plays a critical role in maintaining their long half-life. We have hypothesized that isolated Fc domains could be engineered to functionally mimic full-size IgG1 (nanoantibodies) but with decreased (10-fold) size. Here, we report for the first time the successful generation of a soluble, monomeric CH3 domain (mCH3). In contrast to the wild-type dimeric CH3, the mCH3 exhibited pH-dependent binding to FcRn similar to that of Fc. The binding free energy of mCH3 to FcRn was higher than that of isolated CH2 but lower than that of Fc. Therefore, CH3 may contribute a larger portion of the free energy of binding to FcRn than CH2. A fusion protein of mCH3 with an engineered antibody domain (m36.4) also bound to FcRn in a pH-dependent fashion and exhibited significantly higher neutralizing activity against HIV-1 than m36.4-Fc fusion proteins. The m36.4-mCH3 fusion protein was monomeric, stable, soluble, and expressed at a high level in Escherichia coli. We also found that engineering an additional disulfide bond in mCH3 remarkably increased its thermal stability, whereas the FcRn binding was not affected. These data suggest that mCH3 could not only help in the exploration of the dual mechanisms of the CH3 contribution to Fc functions (dimerization and FcRn interactions) but could also be used for the development of candidate therapeutics with optimized half-life, enhanced tissue penetration, access to sterically restricted binding sites, and increased therapeutic efficacy. C1 [Ying, Tianlei; Chen, Weizao; Feng, Yang; Wang, Yanping; Gong, Rui; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Wang, Yanping] SAIC Frederick Inc, Frederick, MD 21702 USA. RP Ying, TL (reprint author), NCI, Prot Interact Grp, NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM yingt@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research; National Institutes of Health, NCI [N01-CO-12400] FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research and by federal funds from the National Institutes of Health, NCI, under Contract N01-CO-12400. NR 37 TC 22 Z9 22 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2013 VL 288 IS 35 BP 25154 EP 25164 DI 10.1074/jbc.M113.484154 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302QC UT WOS:000330619000015 PM 23867459 ER PT J AU Heymann, JB Bartho, JD Rybakova, D Venugopal, HP Winkler, DC Sen, A Hurst, MRH Mitra, AK AF Heymann, J. Bernard Bartho, Joseph D. Rybakova, Daria Venugopal, Hari P. Winkler, Dennis C. Sen, Anindito Hurst, Mark R. H. Mitra, Alok K. TI Three-dimensional Structure of the Toxin-delivery Particle Antifeeding Prophage of Serratia entomophila SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COMMON EVOLUTIONARY ORIGIN; PSEUDOMONAS-AERUGINOSA; TAIL LENGTH; GRASS GRUB; SECRETION APPARATUS; AMBER DISEASE; BACTERIOPHAGE-T4; PROTEIN; SHEATH; PHAGE AB The Serratia entomophila antifeeding prophage (Afp) is a bullet-shaped toxin-delivery apparatus similar to the R-pyocins of Pseudomonas aeruginosa. Morphologically it resembles the sheathed tail of bacteriophages such as T4, including a baseplate at one end. It also shares features with the type VI secretion systems. Cryo-electron micrographs of tilted Afp specimens (up to 60 degrees) were analyzed to determine the correct cyclic symmetry to overcome the limitation imposed by exclusively side views in nominally untilted specimens. An asymmetric reconstruction shows clear 6-fold cyclic symmetry contrary to a previous conclusion of 4-fold symmetry based on analysis of only the preferred side views (Sen, A., Rybakova, D., Hurst, M. R., and Mitra, A. K. (2010) J. Bacteriol. 192, 4522-4525). Electron tomography of negatively stained Afp revealed right-handed helical striations in many of the particles, establishing the correct hand. Higher quality micrographs of untilted specimens were processed to produce a reconstruction at 2.0-nm resolution with imposed 6-fold symmetry. The helical parameters of the sheath were determined to be 8.14 nm for the subunit rise along and 40.5 degrees for the rotation angle around the helix. The sheath is similar to that of the T4 phage tail but with a different arrangement of the subdomain of the polymerizing sheath protein( s). The central tube is similar to the diameter and axial width of the Hcp1 hexamer of P. aeruginosa type VI secretion system. The tube extends through the baseplate into a needle resembling the "puncture device" of the T4 tail. The tube contains density that may be the toxin and/or a length-determining protein. C1 [Heymann, J. Bernard; Winkler, Dennis C.] NIAMS, NIH, Bethesda, MD 20892 USA. [Bartho, Joseph D.; Venugopal, Hari P.; Sen, Anindito; Mitra, Alok K.] Univ Auckland, Sch Biol Sci, Auckland 1142, New Zealand. [Rybakova, Daria; Hurst, Mark R. H.] Agresearch, Innovat Farm Syst, Christchurch 8140, New Zealand. RP Mitra, AK (reprint author), Univ Auckland, Sch Biol Sci, Thomas Bldg,3A Symonds St, Auckland 1142, New Zealand. EM a.mitra@auckland.ac.nz OI Bartho, Joseph Dale/0000-0003-3853-2347; Heymann, Bernard/0000-0002-8872-5326; Hurst, Mark/0000-0001-5826-5253 FU Faculty Research Development Fund from the University of Auckland; Foundation of Research, Science and Technology, New Zealand [C10X0804]; Intramural Research Program of NIAMS, National Institutes of Health FX This work was supported by a Faculty Research Development Fund from the University of Auckland (to A. K. M.), by Foundation of Research, Science and Technology, New Zealand Grant C10X0804 (to M. R. H. H.), and by the Intramural Research Program of NIAMS, National Institutes of Health (to J. B. H. and D. C. W.). NR 37 TC 15 Z9 15 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2013 VL 288 IS 35 BP 25276 EP 25284 DI 10.1074/jbc.M113.456145 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302QC UT WOS:000330619000026 PM 23857636 ER PT J AU Huang, CH Hsiao, HT Chu, YR Ye, YH Chen, X AF Huang, Chih-Hsiang Hsiao, Hui-Ting Chu, Yue-Ru Ye, Yihong Chen, Xin TI Derlin2 Protein Facilitates HRD1-mediated Retro-translocation of Sonic Hedgehog at the Endoplasmic Reticulum SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UBIQUITIN LIGASE COMPLEX; MISFOLDED PROTEINS; MUTANT ALPHA-1-ANTITRYPSIN; QUALITY-CONTROL; ERAD COMPLEX; DEGRADATION; DISLOCATION; MEMBRANE; RETROTRANSLOCATION; RECOGNITION AB Endoplasmic reticulum-associated degradation (ERAD) is an important system that eliminates misfolded proteins from the ER. Three derlins have been implicated in this process, but their precise function remains unknown. In this study, we report that although both derlin1 and derlin2 are capable of binding the ERAD-specific ubiquitin ligase HRD1, they associate with the HRD1-containing complex with different affinities. Accordingly, these derlins have nonredundant functions in ERAD with derlin2 being an essential functional partner for HRD1-mediated ERAD of SHH and NHK. We show that derlin2, but not derlin1 or derlin3, is required for ERAD of both glycosylated and nonglycosylated SHH, as well as NHK. Derlin2 appears to act at a post-targeting step for HRD1-dependent retro-translocation. Without derlin2, the assembly of HRD1 into a functional retro-translocation homo-oligomer proceeds normally, and substrate targeting to the HRD1 complex also occurs. However, the ERAD substrate SHH-C is largely trapped inside the ER lumen. These observations raise the possibility that derlin2 may regulate the movement of substrates through the HRD1-containing retro-translocon. Our study is the first to report that derlin2 functions with HRD1 in ERAD of certain substrates independent of their glycosylation status. The mammalian ERAD system may require multiple derlins that each functions with a distinct E3 partner to eliminate a specific subset of substrates. This is different from the model in Saccharomyces cerevisiae, in which Hrd1p alone is sufficient for retro-translocation. C1 [Huang, Chih-Hsiang; Hsiao, Hui-Ting; Chu, Yue-Ru; Chen, Xin] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Miaoli 35053, Taiwan. [Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Xin] China Med Univ, Grad Inst Basic Med Sci, Taichung 40402, Taiwan. RP Chen, X (reprint author), Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhu Nan Town 35053, Miaoli County, Taiwan. EM xchen@nhri.org.tw FU NRPGM (National Research Program for Genomic Medicine); National Science Council, Taiwan; National Health Research Institutes, Taiwan, Republic of China FX This work was supported by NRPGM (National Research Program for Genomic Medicine), National Science Council, Taiwan and National Health Research Institutes, Taiwan, Republic of China. NR 33 TC 13 Z9 13 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2013 VL 288 IS 35 BP 25330 EP 25339 DI 10.1074/jbc.M113.455212 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302QC UT WOS:000330619000031 PM 23867461 ER PT J AU Xie, YL Zimmerman, DL AF Xie, Yunlong Zimmerman, Dale L. TI Antedependence models for nonstationary categorical longitudinal data with ignorable missingness: likelihood-based inference SO STATISTICS IN MEDICINE LA English DT Article DE likelihood ratio test; Markov models; missing data; transition models ID MARKOV-CHAINS; TIME-SERIES; REGRESSION AB Time index-ordered random variables are said to be antedependent (AD) of order (p(1),p(2),...,p(n)) if the kth variable, conditioned on the p(k) immediately preceding variables, is independent of all further preceding variables. Inferential methods associated with AD models are well developed for continuous (primarily normal) longitudinal data, but not for categorical longitudinal data. In this article, we develop likelihood-based inferential procedures for unstructured AD models for categorical longitudinal data. Specifically, we derive maximum likelihood estimators (MLEs) of model parameters; penalized likelihood criteria and likelihood ratio tests for determining the order of antedependence; and likelihood ratio tests for homogeneity across groups, time invariance of transition probabilities, and strict stationarity. We give closed-form expressions for MLEs and test statistics, which allow for the possibility of empty cells and monotone missing data, for all cases save strict stationarity. For data with an arbitrary missingness pattern, we derive an efficient restricted expectation-maximization algorithm for obtaining MLEs. We evaluate the performance of the tests by simulation. We apply the methods to longitudinal studies of toenail infection severity (measured on a binary scale) and Alzheimer's disease severity (measured on an ordinal scale). The analysis of the toenail infection severity data reveals interesting nonstationary behavior of the transition probabilities and indicates that an unstructured first-order AD model is superior to stationary and other structured first-order AD models that have previously been fit to these data. The analysis of the Alzheimer's severity data indicates that the antedependence is second order with time-invariant transition probabilities, suggesting the use of a second-order autoregressive cumulative logit model. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Xie, Yunlong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Zimmerman, Dale L.] Univ Iowa, Dept Stat & Actuarial Sci, Iowa City, IA 52242 USA. RP Xie, YL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. EM yunlong.xie@nih.gov FU National Alzheimer's Coordinating Center (NACC) [U01 AG016976]; National Institutes of health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The data were from the National Alzheimer's Coordinating Center (NACC grant number, U01 AG016976). This research was supported by the Intramural Research Program of the National Institutes of health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank the Center for Information Technology, the National Institutes of Health, for providing access to the high-performance computational capabilities of the Biowulf cluster. NR 19 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2013 VL 32 IS 19 BP 3274 EP 3289 DI 10.1002/sim.5763 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 279JX UT WOS:000328957400004 PM 23436682 ER PT J AU Kubler-Kielb, J Vinogradov, E AF Kubler-Kielb, Joanna Vinogradov, Evgeny TI Reinvestigation of the structure of Brucella O-antigens SO CARBOHYDRATE RESEARCH LA English DT Article DE Brucella; LPS; Structure; NMR; MS ID LIPOPOLYSACCHARIDE; IDENTIFICATION; ELUCIDATION; CHAIN; CORE; NMR AB O-Specific polysaccharides of Brucella contain two antigenic determinants, called A and M. Most of the strains express epitope A with a small amount of epitope M, whereas Brucella melitensis strain 16 M expresses longer polymer consisting mostly of M-type epitopes. Proposed explanation was that epitope A is defined by 1-2-linked homopolymer of N-formylperosamine (Rha4NFo), while epitope M is a pentasaccharide with four 2-and one 3-substituted Rha4NFo. We reinvestigated both types of structures by 2D NMR and showed that M-epitope is a tetrasaccharide, missing one of the 2-linked Rha4NFo as compared to the previously proposed structure. Polysaccharide from B. melitensis 16 M contains a fragment of 1-2-linked polymer, capped with M-type polymer. Other strains contain one or two M-type units at the non-reducing end of the 1-2-linked O-chain. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved. C1 [Kubler-Kielb, Joanna] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Vinogradov, Evgeny] Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada. RP Vinogradov, E (reprint author), Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada. EM evguenii.vinogradov@nrc.ca OI Vinogradov, Evgeny/0000-0002-5364-1376 FU intramural program of NICHD, National Institutes of Health, Bethesda, MD FX Authors are greatly indebted to Dr. M. B. Perry (NRC Canada) for Brucella LPS samples. We thank J. Stupak and K. Chan ( NRC Canada) for recording mass spectra. This work was partially supported by the intramural program of NICHD, National Institutes of Health, Bethesda, MD. NR 11 TC 8 Z9 9 U1 2 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD AUG 30 PY 2013 VL 378 BP 144 EP 147 DI 10.1016/j.carres.2013.03.021 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 216QV UT WOS:000324299900020 PM 23664729 ER PT J AU Schotte, F Cho, HS Soman, J Wulff, M Olson, JS Anfinrud, PA AF Schotte, Friedrich Cho, Hyun Sun Soman, Jayashree Wulff, Michael Olson, John S. Anfinrud, Philip A. TI Real-time tracking of CO migration and binding in the alpha and beta subunits of human hemoglobin via 150-ps time-resolved Laue crystallography SO CHEMICAL PHYSICS LA English DT Article DE Hemoglobin; Geminate rebinding; Ligand migration; Time-resolved Laue crystallography ID X-RAY CRYSTALLOGRAPHY; MID-IR SPECTROSCOPY; LIGAND MIGRATION; GEMINATE RECOMBINATION; CONFORMATIONAL-CHANGES; MOLECULAR-DYNAMICS; CARBON-MONOXIDE; HEME-PROTEINS; MYOGLOBIN; NANOSECOND AB We have developed the method of picosecond Laue crystallography and used this capability to probe ligand dynamics in tetrameric R-state hemoglobin (Hb). Time-resolved, 2 angstrom-resolution electron density maps of photolyzed HbCO reveal the time-dependent population of CO in the binding (A) and primary docking (B) sites of both alpha and beta subunits from 100 ps to 10 mu s. The proximity of the B site in the beta subunit is about 0.25 angstrom closer to its A binding site, and its k(BA) rebinding rate (similar to 300 mu s (1)) is six times faster, suggesting distal control of the rebinding dynamics. Geminate rebinding in the beta subunit exhibits both prompt and delayed geminate phases. We developed a microscopic model to quantitatively explain the observed kinetics, with three states for the alpha subunit and four states for the beta subunit. This model provides a consistent framework for interpreting rebinding kinetics reported in prior studies of both HbCO and HbO(2). Published by Elsevier B.V. C1 [Schotte, Friedrich; Cho, Hyun Sun; Anfinrud, Philip A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Soman, Jayashree; Olson, John S.] Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77251 USA. [Soman, Jayashree; Olson, John S.] Rice Univ, WM Keck Ctr Computat Biol, Houston, TX 77251 USA. [Wulff, Michael] European Synchrotron Radiat Facil, F-38043 Grenoble, France. RP Anfinrud, PA (reprint author), NIDDK, Chem Phys Lab, NIH, 5 Mem Dr,Bldg 5,Rm 134, Bethesda, MD 20892 USA. EM anfinrud@nih.gov FU Robert A. Welch Foundation [C-612]; NIH [HL47020, GM35649]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank W. A. Eaton and E. Henry for helpful comments, and D. Bourgeois for sharing his expertise in the analysis of Laue diffraction data. The time-resolved Laue experiments were performed on the ID09B beamline at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. This work was supported by Grants from the Robert A. Welch Foundation (C-612) and the NIH (HL47020 and GM35649) to J.O., and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 38 TC 11 Z9 11 U1 3 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD AUG 30 PY 2013 VL 422 SI SI BP 98 EP 106 DI 10.1016/j.chemphys.2012.12.030 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 216UF UT WOS:000324309600013 PM 24839343 ER PT J AU Chung, HS Cellmer, T Louis, JM Eaton, WA AF Chung, Hoi Sung Cellmer, Troy Louis, John M. Eaton, William A. TI Measuring ultrafast protein folding rates from photon-by-photon analysis of single molecule fluorescence trajectories SO CHEMICAL PHYSICS LA English DT Article DE Single-molecule fluorescence; FRET; Maximum likelihood analysis; Dye blinking; Ultrafast protein folding rates; Photon trajectories; Villin subdomain ID RESONANCE ENERGY-TRANSFER; TRANSITION PATH TIMES; VILLIN HEADPIECE; SIMULATIONS; SPECTROSCOPY; KINETICS; FRET; SUBDOMAIN; DYNAMICS; STATES AB Folding and unfolding rates for the ultrafast folding villin subdomain were determined from a photon-by-photon analysis of fluorescence trajectories in single molecule FRET experiments. One of the obstacles to measuring fast kinetics in single molecule fluorescence experiments is blinking of the fluorophores on a timescale that is not well separated from the process of interest. By incorporating acceptor blinking into a two-state kinetics model, we show that it is possible to extract accurate rate coefficients on the microsecond time scale for folding and unfolding using the maximum likelihood method of Gopich and Szabo. This method yields the most likely parameters of a given model that can reproduce the observed photon trajectories. The extracted parameters agree with both the decay rate of the donor-acceptor cross correlation function and the results of ensemble equilibrium and kinetic experiments using nanosecond laser temperature jump. Published by Elsevier B.V. C1 [Chung, Hoi Sung; Cellmer, Troy; Louis, John M.; Eaton, William A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Chung, HS (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM chunghoi@niddk.nih.gov; eaton@helix.nih.gov RI Chung, Hoi Sung/C-2624-2009 FU NIDDK, NIH FX This paper is dedicated to Robin M. Hochstrasser, who has produced a constant stream of pioneering works that have defined the direction of research in molecular spectroscopy and its applications in biophysics for over 50 years. We thank Irina Gopich and Attila Szabo for numerous helpful discussions and Annie Aniana for excellent technical assistance. This work was supported by the Intramural Research Program of the NIDDK, NIH. NR 30 TC 15 Z9 15 U1 1 U2 43 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD AUG 30 PY 2013 VL 422 SI SI BP 229 EP 237 DI 10.1016/j.chemphys.2012.08.005 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 216UF UT WOS:000324309600027 PM 24443626 ER PT J AU Grant, CW Moran-Paul, CM Duclos, SK Guberski, DL Arreaza-Rubin, G Spain, LM AF Grant, Christian W. Moran-Paul, Catherine M. Duclos, Shane K. Guberski, Dennis L. Arreaza-Rubin, Guillermo Spain, Lisa M. TI Testing Agents for Prevention or Reversal of Type 1 Diabetes in Rodents SO PLOS ONE LA English DT Article ID REGULATORY T-CELLS; MIGRATION INHIBITORY FACTOR; NOD MICE; BB RAT; AUTOIMMUNE; ANTI-CD3; THERAPY; LISOFYLLINE; REMISSION; DISEASE AB We report the results of an independent laboratory's tests of novel agents to prevent or reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse, BioBreeding diabetes prone (BBDP) rat, and multiple autoimmune disease prone (MAD) rat models. Methods were developed to better mimic human clinical trials, including: prescreening, randomization, blinding, and improved glycemic care of the animals. Agents were suggested by the research community in an open call for proposals, and selected for testing by an NIDDK appointed independent review panel. Agents selected for testing to prevent diabetes at later stages of progression in a rodent model were a STAT4 antagonist (DT22669), alpha(1) anti-trypsin (Aralast NP), celastrol (a natural product with anti-inflammatory properties), and a Macrophage Inflammatory Factor inhibitor (ISO-092). Agents tested for reversal of established T1D in rodent models were: alpha(1) anti-trypsin (Aralast NP), tolerogenic peptides (Tregitopes), and a long-acting formulation of GLP-1 (PGC-GLP-1). None of these agents were seen to prevent or reverse type 1 diabetes, while the positive control interventions were effective: anti-CD3 treatment provided disease reversal in the NOD mouse, dexamethasone prevented T1D induction in the MAD rat, and cyclosporin prevented T1D in the BBDP rat. For some tested agents, details of previous formulation, delivery, or dosing, as well as laboratory procedure, availability of reagents and experimental design, could have impacted our ability to confirm prior reports of efficacy in preclinical animal models. In addition, the testing protocols utilized here provided detection of effects in a range commonly used in placebo controlled clinical trials (for example, 50% effect size), and thus may have been underpowered to observe more limited effects. That said, we believe the results compiled here, showing good control and repeatability, confirm the feasibility of screening diverse test agents in an independent laboratory. C1 [Arreaza-Rubin, Guillermo; Spain, Lisa M.] NIDDK, NIH, Bethesda, MD USA. [Grant, Christian W.; Moran-Paul, Catherine M.; Duclos, Shane K.; Guberski, Dennis L.] Biomed Res Models BRM Inc, Worcester, MA USA. [Grant, Christian W.; Moran-Paul, Catherine M.; Duclos, Shane K.; Guberski, Dennis L.] Biomed Res Models BRM Inc, Springfield, MA USA. RP Spain, LM (reprint author), NIDDK, NIH, Bethesda, MD USA. EM spainL@niddk.nih.gov FU National Institutes of Health [N01-DK-62909] FX This work was funded by the National Institutes of Health under a contract N01-DK-62909. NIH staff were involved in study design, data analysis, decision to publish, and preparation of the manuscript. NR 61 TC 9 Z9 9 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 30 PY 2013 VL 8 IS 8 AR e72989 DI 10.1371/journal.pone.0072989 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211BX UT WOS:000323880200060 PM 24023664 ER PT J AU Westphal, C Spallek, B Konkel, A Marko, L Qadri, F DeGraff, LM Schubert, C Bradbury, JA Regitz-Zagrosek, V Falck, JR Zeldin, DC Muller, DN Schunck, WH Fischer, R AF Westphal, Christina Spallek, Bastian Konkel, Anne Marko, Lajos Qadri, Fatimunnisa DeGraff, Laura M. Schubert, Carola Bradbury, J. Alyce Regitz-Zagrosek, Vera Falck, John R. Zeldin, Darryl C. Mueller, Dominik N. Schunck, Wolf-Hagen Fischer, Robert TI CYP2J2 Overexpression Protects against Arrhythmia Susceptibility in Cardiac Hypertrophy SO PLOS ONE LA English DT Article ID SOLUBLE EPOXIDE HYDROLASE; SENSITIVE K+ CHANNELS; EPOXYEICOSATRIENOIC ACIDS; ATRIAL-FIBRILLATION; ISCHEMIA/REPERFUSION INJURY; VENTRICULAR MYOCYTES; PRESSURE-OVERLOAD; MOLECULAR-CLONING; TRANSGENIC MICE; HEART-FAILURE AB Maladaptive cardiac hypertrophy predisposes one to arrhythmia and sudden death. Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) promote anti-inflammatory and antiapoptotic mechanisms, and are involved in the regulation of cardiac Ca2+-, K+- and Na+-channels. To test the hypothesis that enhanced cardiac EET biosynthesis counteracts hypertrophy-induced electrical remodeling, male transgenic mice with cardiomyocyte-specific overexpression of the human epoxygenase CYP2J2 (CYP2J2-TG) and wildtype littermates (WT) were subjected to chronic pressure overload (transverse aortic constriction, TAC) or beta-adrenergic stimulation (isoproterenol infusion, ISO). TAC caused progressive mortality that was higher in WT (42% over 8 weeks after TAC), compared to CYP2J2-TG mice (6%). In vivo electrophysiological studies, 4 weeks after TAC, revealed high ventricular tachyarrhythmia inducibility in WT (47% of the stimulation protocols), but not in CYP2J2-TG mice (0%). CYP2J2 overexpression also enhanced ventricular refractoriness and protected against TAC-induced QRS prolongation and delocalization of left ventricular connexin-43. ISO for 14 days induced high vulnerability for atrial fibrillation in WT mice (54%) that was reduced in CYP-TG mice (17%). CYP2J2 overexpression also protected against ISO-induced reduction of atrial refractoriness and development of atrial fibrosis. In contrast to these profound effects on electrical remodeling, CYP2J2 overexpression only moderately reduced TAC-induced cardiac hypertrophy and did not affect the hypertrophic response to beta-adrenergic stimulation. These results demonstrate that enhanced cardiac EET biosynthesis protects against electrical remodeling, ventricular tachyarrhythmia, and atrial fibrillation susceptibility during maladaptive cardiac hypertrophy. C1 [Westphal, Christina; Konkel, Anne; Mueller, Dominik N.; Schunck, Wolf-Hagen] Max Delbruck Ctr Mol Med, Berlin, Germany. [Spallek, Bastian; Marko, Lajos; Qadri, Fatimunnisa; Mueller, Dominik N.] Expt & Clin Res Ctr, Berlin, Germany. [DeGraff, Laura M.; Bradbury, J. Alyce; Zeldin, Darryl C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Schubert, Carola; Regitz-Zagrosek, Vera] Charite, Inst Gender Med, D-13353 Berlin, Germany. [Falck, John R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Mueller, Dominik N.] Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Dept Expt Med 1, Nurnberg, Germany. [Fischer, Robert] Charite, Clin Cardiol & Pulmonol, D-13353 Berlin, Germany. RP Schunck, WH (reprint author), Max Delbruck Ctr Mol Med, Berlin, Germany. EM schunck@mdc-berlin.de OI Marko, Lajos/0000-0003-1888-5575; Falck, John/0000-0002-9219-7845 FU Deutsche Forschungsgemeinschaft, (DFG) [Schu822/5, FOR 1054]; PreGoBio-Program of the MDC; German Competence Network Heart Failure; Intramural Research Division of the NIH; National Institute of Environmental Health Sciences [Z01 ES025034]; NIH [GM31278]; Robert A. Welch Foundation [GL625910] FX This work was supported by a grant from the Deutsche Forschungsgemeinschaft, (DFG); Schu822/5; FOR 1054. CW received a grant from the PreGoBio-Program of the MDC and BS from the German Competence Network Heart Failure. This work was also supported, in part, by the Intramural Research Division of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034), NIH GM31278 and the Robert A. Welch Foundation (GL625910). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 11 Z9 12 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 30 PY 2013 VL 8 IS 8 AR e73490 DI 10.1371/journal.pone.0073490 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211BX UT WOS:000323880200081 PM 24023684 ER PT J AU Moslehi, R Mills, JL Signore, C Kumar, A Ambroggio, X Dzutsev, A AF Moslehi, Roxana Mills, James L. Signore, Caroline Kumar, Anil Ambroggio, Xavier Dzutsev, Amiran TI Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-INTERACTION NETWORKS; EPIDERMAL-GROWTH-FACTOR; GENE-EXPRESSION; DNA-REPAIR; TRICHOTHIODYSTROPHY; CELLS; ATF3; TROPHOBLASTS; APOPTOSIS; DISORDER AB We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF) IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach. C1 [Moslehi, Roxana; Kumar, Anil] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY 12144 USA. [Moslehi, Roxana] SUNY Albany, Canc Res Ctr, Albany, NY 12144 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Bethesda, MD 20892 USA. [Signore, Caroline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH,DHHS, Bethesda, MD 20892 USA. [Ambroggio, Xavier] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20814 USA. [Dzutsev, Amiran] Sci Applicat Int Corp SAIC Frederick Inc, Frederick Natl Lab, Frederick, MD 21702 USA. [Dzutsev, Amiran] NCI, Canc Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Moslehi, R (reprint author), SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY 12144 USA. EM rmoslehi@albany.edu FU Center for Social and Demographic Analysis (CSDA) at the University at Albany from NICHD [R24 HD044943]; Intramural Research Program-NICHD, NIH FX The authors thank Dr. AR Lehmann at University of Sussex and Dr. M Hubank at University College, London for providing the XPDTTD gene expression dataset, Dr. A. Morgun at Oregon State University for advice on microarray data analysis, and Dr. V. Nagarajan at National Institute of Allergy and Infectious Diseases (NIAID), NIH for critically reviewing the methods and conclusions of the paper. Technical support provided by Mr. H. Martinez at University at Albany throughout the study has been invaluable. This study was supported in part by a grant to the Center for Social and Demographic Analysis (CSDA) at the University at Albany from NICHD; (R24 HD044943) and a research award to RM from CSDA. This research was also supported by the Intramural Research Program-NICHD, NIH. Opinions, findings and conclusions expressed here are those of the authors and do not necessarily reflect the views of the funding agencies. NR 52 TC 12 Z9 12 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD AUG 30 PY 2013 VL 3 AR 2407 DI 10.1038/srep02407 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208QW UT WOS:000323695200001 PM 23989136 ER PT J AU Tian, AL Qi, J Liu, YT Wang, FK Ito, Y Wei, Y AF Tian, Ailin Qi, Jing Liu, Yating Wang, Fengkang Ito, Yoichiro Wei, Yun TI Chiral magnetic microspheres purified by centrifugal field flow fractionation and microspheres magnetic chiral chromatography for benzoin racemate separation SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Chiral magnetic microspheres; Centrifugal field flow fractionation; Microspheres magnetic chrial chromatography; Benzoin racemate ID PERFORMANCE LIQUID-CHROMATOGRAPHY; IRON-OXIDE NANOPARTICLES; BETA-CYCLODEXTRIN; STATIONARY PHASES; NANOCRYSTALS; GOLD; ELECTROPHORESIS; SELECTOR; SHAPE; GEL AB Separation of enantiomers still remains a challenge due to their identical physical and chemical properties in a chiral environment, and the research on specific chiral selector along with separation techniques continues to be conducted to resolve individual enantiomers. In our laboratory the promising magnetic chiral microspheres Fe3O4@SiO2@cellulose-2, 3-bis (3,5-dimethylphenylcarbamate) have been developed to facilitate the resolution using both its magnetic property and chiral recognition ability. In our present studies this magnetic chiral selector was first purified by centrifuge field flow fractionation, and then used to separate benzoin racemate by a chromatographic method. Uniform-sized and masking-impurity-removed magnetic chiral selector was first obtained by field flow fractionation with ethanol through a spiral column mounted on the type-J planetary centrifuge, and using the purified magnetic chiral selector, the final chromatographic separation of benzoin racemate was successfully performed by eluting with ethanol through a coiled tube (wound around the cylindrical magnet to retain the magnetic chiral selector as a stationary phase) submerged in dry ice. In addition, an external magnetic field facilitates the recycling of the magnetic chiral selector. (C) 2013 Elsevier B.V. All rights reserved. C1 [Tian, Ailin; Qi, Jing; Liu, Yating; Wang, Fengkang; Wei, Yun] Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. [Ito, Yoichiro; Wei, Yun] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Wei, Y (reprint author), Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, 15 Beisanhuan East Rd, Beijing 100029, Peoples R China. EM weiyun@mail.buct.edu.cn FU National Natural Science Foundation of China (NSFC) [21075007]; Program for New Century Excellent Talents in University [NCET-11-0563]; Special Fund for Agro-scientific Research in the Public Interest [200803022, 201103027]; Program for Changjiang Scholars and Innovative Research Team in University [PCSIRT1205] FX The research work was supported from the National Natural Science Foundation of China (NSFC, Grant No. 21075007), Program for New Century Excellent Talents in University (NCET-11-0563), Special Fund for Agro-scientific Research in the Public Interest (project 200803022 & 201103027) and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT1205). NR 25 TC 1 Z9 1 U1 4 U2 48 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD AUG 30 PY 2013 VL 1305 BP 333 EP 337 DI 10.1016/j.chroma.2013.07.044 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 204JS UT WOS:000323362200041 PM 23891368 ER PT J AU Guyard, C Raffel, SJ Schrumpf, ME Dahlstrom, E Sturdevant, D Ricklefs, SM Martens, C Hayes, SF Fischer, ER Hansen, BT Porcella, SF Schwan, TG AF Guyard, Cyril Raffel, Sandra J. Schrumpf, Merry E. Dahlstrom, Eric Sturdevant, Daniel Ricklefs, Stacy M. Martens, Craig Hayes, Stanley F. Fischer, Elizabeth R. Hansen, Bryan T. Porcella, Stephen F. Schwan, Tom G. TI Periplasmic Flagellar Export Apparatus Protein, FliH, Is Involved in Post-Transcriptional Regulation of FlaB, Motility and Virulence of the Relapsing Fever Spirochete Borrelia hermsii SO PLOS ONE LA English DT Article ID LYME-DISEASE; SERPULINA-HYODYSENTERIAE; MURINE MODEL; LESS MUTANT; BURGDORFERI; SALMONELLA; GENE; CHEMOTAXIS; INACTIVATION; EXPRESSION AB Spirochetes are bacteria characterized in part by rotating periplasmic flagella that impart their helical or flat-wave morphology and motility. While most other bacteria rely on a transcriptional cascade to regulate the expression of motility genes, spirochetes employ post-transcriptional mechanism(s) that are only partially known. In the present study, we characterize a spontaneous non-motile mutant of the relapsing fever spirochete Borrelia hermsii that was straight, nonmotile and deficient in periplasmic flagella. We used next generation DNA sequencing of the mutant's genome, which when compared to the wild-type genome identified a 142 bp deletion in the chromosomal gene encoding the flagellar export apparatus protein FliH. Immunoblot and transcription analyses showed that the mutant phenotype was linked to the posttranscriptional deficiency in the synthesis of the major periplasmic flagellar filament core protein FlaB. Despite the lack of FlaB, the amount of FlaA produced by the fliH mutant was similar to the wild-type level. The turnover of the residual pool of FlaB produced by the fliH mutant was comparable to the wild-type spirochete. The non-motile mutant was not infectious in mice and its inoculation did not induce an antibody response. Trans-complementation of the mutant with an intact fliH gene restored the synthesis of FlaB, a normal morphology, motility and infectivity in mice. Therefore, we propose that the flagellar export apparatus protein regulates motility of B. hermsii at the post-transcriptional level by influencing the synthesis of FlaB. C1 [Guyard, Cyril] Publ Hlth Ontario, Toronto, ON, Canada. [Guyard, Cyril] Univ Toronto, Toronto, ON, Canada. [Guyard, Cyril] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Raffel, Sandra J.; Schrumpf, Merry E.; Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Dahlstrom, Eric; Sturdevant, Daniel; Ricklefs, Stacy M.; Martens, Craig; Hayes, Stanley F.; Fischer, Elizabeth R.; Hansen, Bryan T.; Porcella, Stephen F.] NIAID, Res Technol Sect, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Guyard, C (reprint author), Publ Hlth Ontario, Toronto, ON, Canada. EM cyril.guyard@gmail.com FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), USA; Public Health Ontario FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), USA (http://www.niaid.nih.gov/). CG is supported by Public Health Ontario (http://www.oahpp.ca/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 7 Z9 7 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 29 PY 2013 VL 8 IS 8 AR e72550 DI 10.1371/journal.pone.0072550 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 209DO UT WOS:000323734600028 PM 24009690 ER PT J AU Hudson, RS Yi, M Esposito, D Glynn, SA Starks, AM Yang, Y Schetter, AJ Watkins, SK Hurwitz, AA Dorsey, TH Stephens, RM Croce, CM Ambs, S AF Hudson, R. S. Yi, M. Esposito, D. Glynn, S. A. Starks, A. M. Yang, Y. Schetter, A. J. Watkins, S. K. Hurwitz, A. A. Dorsey, T. H. Stephens, R. M. Croce, C. M. Ambs, S. TI MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer SO ONCOGENE LA English DT Article DE prostate cancer; microRNA; apoptosis; disease outcome ID BREAST-CANCER; MICRORNAS; PROGRESSION; APOPTOSIS; LEUKEMIA; GENES; OVEREXPRESSION; CARCINOMA; PROFILE; FAMILY AB The miR-106b-25 microRNA (miRNA) cluster is a candidate oncogene in human prostate cancer. Here, we report that miRNAs encoded by miR-106b-25 are upregulated in both primary tumors and distant metastasis. Moreover, increased tumor miR-106b expression was associated with disease recurrence and the combination of high miR-106b and low CASP7 (caspase-7) expressions in primary tumors was an independent predictor of early disease recurrence (adjusted hazard ratio = 4.1; 95% confidence interval: 1.6-12.3). To identify yet unknown oncogenic functions of miR-106b, we overexpressed it in LNCaP human prostate cancer cells to examine miR-106b-induced global expression changes among protein-coding genes. The approach revealed that CASP7 is a direct target of miR-106b, which was confirmed by western blot analysis and a 3'-untranslated region reporter assay. Moreover, selected phenotypes induced by miR-106b knockdown in DU145 human prostate cancer cells did not develop when both miR-106b and CASP7 expression were inhibited. Further analyses showed that CASP7 is downregulated in primary prostate tumors and metastatic lesions across multiple data sets and is by itself associated with disease recurrence and disease-specific survival. Using bioinformatics, we also observed that miR-106b-25 may specifically influence focal adhesion-related pathways. This observation was experimentally examined using miR-106b-25-transduced 22Rv1 human prostate cancer cells. After infection with a miR-106b-25 lentiviral expression construct, 22Rv1 cells showed increased adhesion to basement membrane-and bone matrix-related filaments and enhanced soft agar growth. In summary, miR-106b-25 was found to be associated with prostate cancer progression and disease outcome and may do so by altering apoptosis-and focal adhesion-related pathways. C1 [Hudson, R. S.; Glynn, S. A.; Starks, A. M.; Yang, Y.; Schetter, A. J.; Dorsey, T. H.; Ambs, S.] NCI, Human Carcinogenesis Lab, Ctr Canc Res CRC, NIH, Bethesda, MD 20892 USA. [Yi, M.; Stephens, R. M.] NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21701 USA. [Esposito, D.] NCI, Protein Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Watkins, S. K.; Hurwitz, A. A.] NCI, Mol Immunoregulat Lab, Frederick, MD 21701 USA. [Croce, C. M.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res CRC, Bldg 37 Room 3050B, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Glynn, Sharon/D-7136-2013 OI Glynn, Sharon/0000-0003-1459-2580 FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Barbara J Taylor at the NCI FACS Core Laboratory for technical help. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 35 TC 39 Z9 42 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 29 PY 2013 VL 32 IS 35 BP 4139 EP 4147 DI 10.1038/onc.2012.424 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 209IG UT WOS:000323748500009 PM 22986525 ER PT J AU Ben Isaac, E Manor, U Kachar, B Yochelis, A Gov, NS AF Ben Isaac, Eyal Manor, Uri Kachar, Bechara Yochelis, Arik Gov, Nir S. TI Linking actin networks and cell membrane via a reaction-diffusion-elastic description of nonlinear filopodia initiation SO PHYSICAL REVIEW E LA English DT Article ID DISSIPATIVE SYSTEMS; DENDRITIC NETWORK; LIPID-BILAYERS; ARP2/3 COMPLEX; MYOSIN-X; MECHANICS; PROTEINS; DYNAMICS; BUNDLES; TIPS AB Reaction-diffusion models have been used to describe pattern formation on the cellular scale, and traditionally do not include feedback between cellular shape changes and biochemical reactions. We introduce here a distinct reaction-diffusion-elasticity approach: The reaction-diffusion part describes bistability between two actin orientations, coupled to the elastic energy of the cell membrane deformations. This coupling supports spatially localized patterns, even when such solutions do not exist in the uncoupled self-inhibited reaction-diffusion system. We apply this concept to describe the nonlinear (threshold driven) initiation mechanism of actin-based cellular protrusions and provide support by several experimental observations. C1 [Ben Isaac, Eyal; Gov, Nir S.] Weizmann Inst Sci, Dept Chem Phys, IL-76100 Rehovot, Israel. [Manor, Uri; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Yochelis, Arik] Ben Gurion Univ Negev, Jacob Blaustein Inst Desert Res BIDR, Swiss Inst Dryland Environm & Energy Res, Dept Solar Energy & Environm Phys, IL-84990 Midreshet Ben Gurion, Israel. [Yochelis, Arik] Ben Gurion Univ Negev, Jacob Blaustein Inst Desert Res BIDR, Swiss Inst Dryland Environm & Energy Res, Ben Gurion Natl Solar Energy Ctr, IL-84990 Midreshet Ben Gurion, Israel. RP Ben Isaac, E (reprint author), Weizmann Inst Sci, Dept Chem Phys, IL-76100 Rehovot, Israel. EM eyalbi@weizmann.ac.il; yochelis@bgu.ac.il; nir.gov@weizmann.ac.il RI Yochelis, Arik/C-6782-2013 OI Yochelis, Arik/0000-0002-1516-0766 NR 59 TC 1 Z9 1 U1 0 U2 20 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD AUG 29 PY 2013 VL 88 IS 2 AR 022718 DI 10.1103/PhysRevE.88.022718 PG 10 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 208XD UT WOS:000323714600006 PM 24032875 ER PT J AU Parker, J Sherman, E van de Raa, M van der Meer, D Samelson, LE Losert, W AF Parker, Joshua Sherman, Eilon van de Raa, Matthias van der Meer, Devaraj Samelson, Lawrence E. Losert, Wolfgang TI Automatic sorting of point pattern sets using Minkowski functionals SO PHYSICAL REVIEW E LA English DT Article ID MORPHOLOGY; CLUSTERS; ANTIGEN; MODEL AB Point pattern sets arise in many different areas of physical, biological, and applied research, representing many random realizations of underlying pattern formation mechanisms. These pattern sets can be heterogeneous with respect to underlying spatial processes, which may not be visually distiguishable. This heterogeneity can be elucidated by looking at statistical measures of the patterns sets and using these measures to divide the pattern sets into distinct groups representing like spatial processes. We introduce here a numerical procedure for sorting point pattern sets into spatially homogenous groups using functional principal component analysis (FPCA) applied to the approximated Minkowski functionals of each pattern. We demonstrate that this procedure correctly sorts pattern sets into similar groups both when the patterns are drawn from similar processes and when the second-order characteristics of the pattern are identical. We highlight this routine for distinguishing the molecular patterning of fluorescently labeled cell membrane proteins, a subject of much interest in studies investigating complex spatial signaling patterns involved in the human immune response. C1 [Parker, Joshua; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20740 USA. [Sherman, Eilon] Hebrew Univ Jerusalem, Racah Inst Phys, IL-91904 Jerusalem, Israel. [van de Raa, Matthias; van der Meer, Devaraj] Univ Twente, MESA, Phys Fluids Grp, NL-7500 AE Enschede, Netherlands. [van de Raa, Matthias; van der Meer, Devaraj] Univ Twente, Inst Nanotechnol, NL-7500 AE Enschede, Netherlands. [van de Raa, Matthias; van der Meer, Devaraj] Univ Twente, JM Burgers Ctr Fluid Dynam, NL-7500 AE Enschede, Netherlands. [Samelson, Lawrence E.] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Parker, J (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20740 USA. EM jmparker@umd.edu RI Sherman, Eilon /B-3688-2014 OI Sherman, Eilon /0000-0002-7403-6036 FU National Cancer Institute (The Center for Cancer Research); NIH [GM085574] FX The authors would like to thank Detlef Lohse for suggesting Minkowski functional analysis and Can Guven and Mark Herrera for their helpful advice during this project. This research was supported in part (L E.S.) by the Intramural Research Programs of the National Cancer Institute (The Center for Cancer Research) and by NIH Grant No. GM085574 (W.L.). NR 30 TC 2 Z9 2 U1 0 U2 7 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD AUG 29 PY 2013 VL 88 IS 2 AR 022720 DI 10.1103/PhysRevE.88.022720 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 208XD UT WOS:000323714600008 PM 24032877 ER PT J AU De, S Zhang, YQ Wolkow, CA Zou, SG Goldberg, I Becker, KG AF De, Supriyo Zhang, Yongqing Wolkow, Catherine A. Zou, Sige Goldberg, Ilya Becker, Kevin G. TI Genome-wide modeling of complex phenotypes in Caenorhabditis elegans and Drosophila melanogaster SO BMC GENOMICS LA English DT Article DE C. elegans; D. melanogaster; Worm; Fly; Aging; Gene set; Phenotype; Ontology; Network; Gene expression ID GENE SET ENRICHMENT; EXPRESSION; ASSOCIATION; PROFILES; ONTOLOGY; DISEASE; MOUSE AB Background: The genetic and molecular basis for many intermediate and end stage phenotypes in model systems such as C. elegans and D. melanogaster has long been known to involve pleiotropic effects and complex multigenic interactions. Gene sets are groups of genes that contribute to multiple biological or molecular phenomena. They have been used in the analysis of large molecular datasets such as microarray data, Next Generation sequencing, and other genomic datasets to reveal pleiotropic and multigenic contributions to phenotypic outcomes. Many model systems lack species specific organized phenotype based gene sets to enable high throughput analysis of large molecular datasets. Results and discussion: Here, we describe two novel collections of gene sets in C. elegans and D. melanogaster that are based exclusively on genetically determined phenotypes and use a controlled phenotypic ontology. We use these collections to build genome-wide models of thousands of defined phenotypes in both model species. In addition, we demonstrate the utility of these gene sets in systems analysis and in analysis of gene expression-based molecular datasets and show how they are useful in analysis of genomic datasets connecting multigenic gene inputs to complex phenotypes. Conclusions: Phenotypic based gene sets in both C. elegans and D. melanogaster are developed, characterized, and shown to be useful in the analysis of large scale species-specific genomic datasets. These phenotypic gene set collections will contribute to the understanding of complex phenotypic outcomes in these model systems. C1 [De, Supriyo; Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Genet Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Wolkow, Catherine A.] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. [Zou, Sige] NIA, Translat Gerontol Branch, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Goldberg, Ilya] NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Becker, KG (reprint author), NIA, Gene Express & Genom Unit, Genet Lab, NIH,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM beckerk@grc.nia.nih.gov RI Goldberg, Ilya/H-5307-2011; OI Goldberg, Ilya/0000-0001-8514-6110; De, Supriyo/0000-0002-2075-7655; Becker, Kevin/0000-0002-6794-6656 FU Intramural Research Program of the NIH, National Institute on Aging FX The authors would like to thank Gary Schindelman and Paul Sternberg from WormBase for providing gene-phenotype files and Dr Elin Lehrmann for critical reading of the manuscript. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 19 TC 1 Z9 1 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 28 PY 2013 VL 14 AR 580 DI 10.1186/1471-2164-14-580 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 227KN UT WOS:000325111700001 PM 23984798 ER PT J AU He, YQ Gong, L Fang, YP Zhan, Q Liu, HX Lu, YL Guo, GL Lehman-McKeeman, L Fang, JW Wan, YJY AF He, Yuqi Gong, Lei Fang, Yaping Zhan, Qi Liu, Hui-Xin Lu, Yanliu Guo, Grace L. Lehman-McKeeman, Lois Fang, Jianwen Wan, Yu-Jui Yvonne TI The role of retinoic acid in hepatic lipid homeostasis defined by genomic binding and transcriptome profiling SO BMC GENOMICS LA English DT Article DE Nuclear receptor; Retinoids x receptor; Retinoic acid receptor; Farnesnoid x receptor; Peroxisomal; proliferator-activated receptor a; Liver x receptor; Pregnane x receptor; Chromatin immunoprecipitation; Sequencing; Microarray ID X-RECEPTOR-ALPHA; HEPATOCYTE RXR-ALPHA; MOUSE-LIVER; MEDIATED PATHWAYS; NUCLEAR RECEPTOR; DEFICIENT MICE; EXPRESSION; METABOLISM; PHOSPHATIDYLETHANOLAMINE; PHOSPHATIDYLCHOLINE AB Background: The eyes and skin are obvious retinoid target organs. Vitamin A deficiency causes night blindness and retinoids are widely used to treat acne and psoriasis. However, more than 90% of total body retinol is stored in liver stellate cells. In addition, hepatocytes produce the largest amount of retinol binding protein and cellular retinoic acid binding protein to mobilize retinol from the hepatic storage pool and deliver retinol to its receptors, respectively. Furthermore, hepatocytes express the highest amount of retinoid x receptor alpha (RXRa) among all the cell types. Surprisingly, the function of endogenous retinoids in the liver has received very little attention. Results: Based on the data generated from chromatin immunoprecipitation followed by sequencing, the global DNA binding of transcription factors including retinoid x receptor a (RXRa) along with its partners i.e. retinoic acid receptor a (RARa), pregnane x receptor (PXR), liver x receptor (LXR), farnesoid x receptor (FXR), and peroxisome proliferator-activated receptor a (PPARa) has been established. Based on the binding, functional annotation illustrated the role of those receptors in regulating hepatic lipid homeostasis. To correlate the DNA binding data with gene expression data, the expression patterns of 576 genes that regulate lipid homeostasis were studied in wild type and liver RXRa-null mice treated with and without RA. The data showed that RA treatment and RXRa-deficiency had opposite effects in regulating lipid homeostasis. A subset of genes (114), which could clearly differentiate the effect of ligand treatment and receptor deficiency, were selected for further functional analysis. The expression data suggested that RA treatment could produce unsaturated fatty acids and induce triglyceride breakdown, bile acid secretion, lipolysis, and retinoids elimination. In contrast, RXRa deficiency might induce the synthesis of saturated fatty acids, triglyceride, cholesterol, bile acids, and retinoids. In addition, DNA binding data indicated extensive cross-talk among RARa, PXR, LXR, FXR, and PPARa in regulating those RA/RXRa-dependent gene expression levels. Moreover, RA reduced serum cholesterol, triglyceride, and bile acid levels in mice. Conclusions: We have characterized the role of hepatic RA for the first time. Hepatic RA mediated through RXRa and its partners regulates lipid homeostasis. C1 [He, Yuqi; Liu, Hui-Xin; Lu, Yanliu; Wan, Yu-Jui Yvonne] Univ Calif Davis, Davis Hlth Syst, Dept Med Pathol & Lab Med, Sacramento, CA 95817 USA. [Gong, Lei; Lehman-McKeeman, Lois] Bristol Myers Squibb Co, Discovery Toxicol, Princeton, NJ 08543 USA. [Fang, Yaping] Univ Kansas, Appl Bioinformat Lab, Lawrence, KS 66045 USA. [Zhan, Qi] Guangzhou Med Univ, Municipal Peoples Hosp Guangzhou 1, Dept Gastroenterol Hepatol, Guangzhou 510180, Guangdong, Peoples R China. [Guo, Grace L.] Rutgers State Univ, Dept Pharmacol & Toxicol, Ernest Mario Sch Pharm, Piscataway, NJ 08854 USA. [Fang, Jianwen] NCI, Biometr Res Branch, Rockville, MD 20850 USA. RP Wan, YJY (reprint author), Univ Calif Davis, Davis Hlth Syst, Dept Med Pathol & Lab Med, Sacramento, CA 95817 USA. EM yjywan@ucdavis.edu OI Fang, Yaping/0000-0001-6075-0768 FU NCI NIH HHS [P30 CA093373]; NIDDK NIH HHS [R01 DK092100]; NIGMS NIH HHS [R01 GM104037] NR 34 TC 8 Z9 8 U1 1 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 28 PY 2013 VL 14 AR 575 DI 10.1186/1471-2164-14-575 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 215KY UT WOS:000324210000001 PM 23981290 ER PT J AU Sarai, N Nimura, K Tamura, T Kanno, T Patel, MC Heightman, TD Ura, K Ozato, K AF Sarai, Naoyuki Nimura, Keisuke Tamura, Tomohiko Kanno, Tomohiko Patel, Mira C. Heightman, Tom D. Ura, Kiyoe Ozato, Keiko TI WHSC1 links transcription elongation to HIRA-mediated histone H3.3 deposition SO EMBO JOURNAL LA English DT Article DE BRD4; HIRA; histone H3.3 exchange; transcription elongation; WHSC1 ID RNA-POLYMERASE-II; BROMODOMAIN PROTEIN BRD4; WOLF-HIRSCHHORN-SYNDROME; INTERFERON-STIMULATED GENES; P-TEFB; VARIANT H3.3; LYSINE 36; MULTIPLE-MYELOMA; SET2 METHYLATION; NUCLEAR RECEPTOR AB Actively transcribed genes are enriched with the histone variant H3.3. Although H3.3 deposition has been linked to transcription, mechanisms controlling this process remain elusive. We investigated the role of the histone methyltransferase Wolf-Hirschhorn syndrome candidate 1 (WHSC1) (NSD2/MMSET) in H3.3 deposition into interferon (IFN) response genes. IFN treatment triggered robust H3.3 incorporation into activated genes, which continued even after cessation of transcription. Likewise, UV radiation caused H3.3 deposition in UV-activated genes. However, in Whsc1(-/-) cells IFN- or UV-triggered H3.3 deposition was absent, along with a marked reduction in IFN- or UV-induced transcription. We found that WHSC1 interacted with the bromodomain protein 4 (BRD4) and the positive transcription elongation factor b (P-TEFb) and facilitated transcriptional elongation. WHSC1 also associated with HIRA, the H3.3-specific histone chaperone, independent of BRD4 and P-TEFb. WHSC1 and HIRA co-occupied IFN-stimulated genes and supported prolonged H3.3 incorporation, leaving a lasting transcriptional mark. Our results reveal a previously unrecognized role of WHSC1, which links transcriptional elongation and H3.3 deposition into activated genes through two molecularly distinct pathways. C1 [Sarai, Naoyuki; Kanno, Tomohiko; Patel, Mira C.; Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Nimura, Keisuke; Ura, Kiyoe] Osaka Univ, Grad Sch Med, Div Gene Therapy Sci, Osaka, Japan. [Tamura, Tomohiko] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa, Japan. [Heightman, Tom D.] Univ Oxford, Struct Genom Consortium, Oxford, England. [Ura, Kiyoe] Japan Sci & Technol Agcy, PRESTO, Saitama, Japan. RP Ozato, K (reprint author), NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ozatok@dir6.nichd.nih.gov RI Patel, Mira/A-3013-2015 FU NICHD; NIH Intramural AIDS Targeted Antiviral Program, National Institutes of Health; NIH-Japan Society for Promotion of Science (JSPS) Fellowship FX We thank Drs D Singer, K Zhao, and J Zhu for critical reading of the manuscript; Mr W Huynh, Drs A Dey, and H Kurumizaka for advice on experiments. This work was supported by the Intramural Program of NICHD and the NIH Intramural AIDS Targeted Antiviral Program, National Institutes of Health. NS was partially supported by the NIH-Japan Society for Promotion of Science (JSPS) Fellowship. NR 72 TC 15 Z9 15 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 28 PY 2013 VL 32 IS 17 BP 2392 EP 2406 DI 10.1038/emboj.2013.176 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 209LM UT WOS:000323758300009 PM 23921552 ER PT J AU Osinusi, A Meissner, EG Lee, YJ Bon, D Heytens, L Nelson, A Sneller, M Kohli, A Barrett, L Proschan, M Herrmann, E Shivakumar, B Gu, WJ Kwan, R Teferi, G Talwani, R Silk, R Kotb, C Wroblewski, S Fishbein, D Dewar, R Highbarger, H Zhang, X Kleiner, D Wood, BJ Chavez, J Symonds, WT Subramanian, M McHutchison, J Polis, MA Fauci, AS Masur, H Kottilil, S AF Osinusi, Anuoluwapo Meissner, Eric G. Lee, Yu-Jin Bon, Dimitra Heytens, Laura Nelson, Amy Sneller, Michael Kohli, Anita Barrett, Lisa Proschan, Michael Herrmann, Eva Shivakumar, Bhavana Gu, Wenjuan Kwan, Richard Teferi, Geb Talwani, Rohit Silk, Rachel Kotb, Colleen Wroblewski, Susan Fishbein, Dawn Dewar, Robin Highbarger, Helene Zhang, Xiao Kleiner, David Wood, Brad J. Chavez, Jose Symonds, William T. Subramanian, Mani McHutchison, John Polis, Michael A. Fauci, Anthony S. Masur, Henry Kottilil, Shyamasundaran TI Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID UNITED-STATES; VIRUS-INFECTION; PLUS RIBAVIRIN; PEGYLATED INTERFERON; ANTIVIRAL THERAPY; TELAPREVIR; COMBINATION; PREVALENCE; BOCEPREVIR; PLACEBO AB IMPORTANCE The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations. OBJECTIVE To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics. DESIGN, SETTING, AND PATIENTS Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012). INTERVENTIONS In the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1: 1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks. MAIN OUTCOMES AND MEASURES The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]). RESULTS In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68%(95% CI, 46%-85%) in the weight-based group and 48%(95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events. CONCLUSION AND RELEVANCE In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively. C1 [Osinusi, Anuoluwapo; Meissner, Eric G.; Lee, Yu-Jin; Nelson, Amy; Sneller, Michael; Kohli, Anita; Barrett, Lisa; Shivakumar, Bhavana; Wroblewski, Susan; Zhang, Xiao; Polis, Michael A.; Fauci, Anthony S.; Kottilil, Shyamasundaran] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Osinusi, Anuoluwapo; Silk, Rachel; Kotb, Colleen] Sci Applicat Int Corp SAIC Frederick Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Bon, Dimitra; Herrmann, Eva] Goethe Univ Frankfurt, Inst Biostat & Math Modeling, D-60054 Frankfurt, Germany. [Heytens, Laura; Kwan, Richard; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Proschan, Michael] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Gu, Wenjuan; Dewar, Robin; Highbarger, Helene] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Teferi, Geb; Chavez, Jose] Unity Hlth Care Inc, Washington, DC USA. [Talwani, Rohit] Univ Maryland, Dept Infect Dis, Baltimore, MD 21201 USA. [Fishbein, Dawn] MedStar Washington Hosp Ctr, Dept Infect Dis, Washington, DC USA. [Kleiner, David] NCI, Dept Pathol, Bethesda, MD 20892 USA. [Wood, Brad J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Wood, Brad J.] NCI, Bethesda, MD 20892 USA. [Symonds, William T.; Subramanian, Mani; McHutchison, John] Gilead Sci Inc, Foster City, CA 94404 USA. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bldg 10,Room 11N204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268; Kleiner, David/0000-0003-3442-4453 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases; German Research Foundation by the clinical research unit KFO 129 FX This project was funded in whole by grant HHSN261200800001E from the National Cancer Institute, National Institutes of Health. This research was supported in part by the National Institute of Allergy and Infectious Diseases and by the German Research Foundation by the clinical research unit KFO 129. Pharmasset Pharmaceuticals and subsequently Gilead Sciences provided sofosbuvir and scientific advice. NR 23 TC 173 Z9 177 U1 1 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 28 PY 2013 VL 310 IS 8 BP 804 EP 811 DI 10.1001/jama.2013.109309 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 206YA UT WOS:000323561400020 PM 23982366 ER PT J AU Ma, SS AF Ma, Steven S. TI Reductions in Funding for Medical Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID BIOMEDICAL-RESEARCH C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Ma, SS (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 3613, Bethesda, MD 20892 USA. EM steven@stevensma.com NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 28 PY 2013 VL 310 IS 8 BP 854 EP 855 DI 10.1001/jama.2013.170804 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 206YA UT WOS:000323561400030 PM 23982376 ER PT J AU Berezhkovskii, AM Skvortsov, AT AF Berezhkovskii, Alexander M. Skvortsov, Alexei T. TI Aris-Taylor dispersion with drift and diffusion of particles on the tube wall SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID FLOWS; CHANNELS; MODELS AB A laminar stationary flow of viscous fluid in a cylindrical tube enhances the rate of diffusion of Brownian particles along the tube axis. This so-called Aris-Taylor dispersion is due to the fact that cumulative times, spent by a diffusing particle in layers of the fluid moving with different velocities, are random variables which depend on the realization of the particle stochastic trajectory in the radial direction. Conceptually similar increase of the diffusivity occurs when the particle randomly jumps between two states with different drift velocities. Here we develop a theory that contains both phenomena as special limiting cases. It is assumed (i) that the particle in the flow can reversibly bind to the tube wall, where it moves with a given drift velocity and diffusivity, and (ii) that the radial and longitudinal diffusivities of the particle in the flow may be different. We derive analytical expressions for the effective drift velocity and diffusivity of the particle, which show how these quantities depend on the geometric and kinetic parameters of the model. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Skvortsov, Alexei T.] Def Sci & Technol Org, Land Div, Fishermans Bend, Vic 3207, Australia. RP Skvortsov, AT (reprint author), Def Sci & Technol Org, Land Div, Fishermans Bend, Vic 3207, Australia. EM alex.skvortsov@dsto.defence.gov FU Intramural Research Program of the National of Institutes of Health (NIH), Center for Information Technology FX This study was supported by the Intramural Research Program of the National of Institutes of Health (NIH), Center for Information Technology. We are grateful to Vemuri Balakotaiah and Chiu-On Ng for helpful discussions. We thank Chris Woodruff for his careful reading of the paper and useful comments. NR 35 TC 9 Z9 9 U1 2 U2 13 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 28 PY 2013 VL 139 IS 8 AR 084101 DI 10.1063/1.4818733 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 211RO UT WOS:000323928000004 PM 24006968 ER PT J AU Coulibaly, YI Dembele, B Diallo, AA Kristensen, S Konate, S Dolo, H Dicko, I Sangare, MB Keita, F Boatin, BA Traore, AK Nutman, TB Klion, AD Toure, YT Traore, SF AF Coulibaly, Yaya Ibrahim Dembele, Benoit Diallo, Abdallah Amadou Kristensen, Sibylle Konate, Siaka Dolo, Housseini Dicko, Ilo Sangare, Moussa Brema Keita, Falaye Boatin, Boakye A. Traore, Abdel Kader Nutman, Thomas B. Klion, Amy D. Toure, Yeya Tiemoko Traore, Sekou Fantamady TI Wuchereria bancrofti transmission pattern in southern Mali prior to and following the institution of mass drug administration SO PARASITES & VECTORS LA English DT Article ID LYMPHATIC FILARIASIS; ANOPHELES-GAMBIAE; MOSQUITOS; ELIMINATION; IVERMECTIN; INTENSITY; DYNAMICS; VECTORS; GHANA AB Background: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of stopping transmission of lymphatic filariasis (LF) through yearly mass drug administration (MDA). Although preliminary surveys of the human population in Mali suggested that Wuchereria bancrofti infection was highly endemic in the Sikasso district, baseline entomological data were required to confirm high levels of transmission prior to the selection of villages in this region for a study of the impact of MDA on transmission of LF by anopheline vectors. Methods: W. bancrofti transmission was assessed in 2001 (pre-MDA) and 2002 (post-MDA) in the Central District of Sikasso in southern Mali by dissection of Anopheles mosquitoes caught using the human landing catch (HLC) method. The relative frequencies and molecular forms of An. gambiae complex were determined. Results: The majority (86%) of the anopheline vectors captured were identified as An. gambiae complex, and these accounted for >90% of the entomological inoculation rate (EIR) during both years of the study. There was a dramatic decrease in the number of An. gambiae complex mosquitoes captured and in the An. gambiae complex infectivity rates following MDA, accounting for the observed decrease in EIR in 2002 (from 12.55 to 3.79 infective bites per person during the transmission season). An. funestus complex mosquitoes were responsible for a low level of transmission, which was similar during both years of the study (1.2 infective bites per person during the transmission season in 2001 and 1.03 in 2002). Conclusions: Based on the entomological data from this study, the district of Sikasso was confirmed as an area of high W. bancrofti transmission. This led to the selection of this area for a multi-national study on the effects of MDA on LF transmission by anopheline vectors. Comparison of vector transmission parameters prior to and immediately following the first round of MDA demonstrated a significant decrease in overall transmission. Importantly, the dramatic variability in EIR over the transmission season suggests that the efficacy of MDA can be maximized by delivering drug at the beginning of the rainy season (just prior to the peak of transmission). C1 [Coulibaly, Yaya Ibrahim; Dembele, Benoit; Diallo, Abdallah Amadou; Konate, Siaka; Dolo, Housseini; Dicko, Ilo; Sangare, Moussa Brema; Keita, Falaye; Toure, Yeya Tiemoko; Traore, Sekou Fantamady] Univ Sci Tech & Technol Bamako USTTB, Mali Int Ctr Excellence Res ICER, Bamako, Mali. [Kristensen, Sibylle] Univ Alabama Birmingham, Dept Epidemiol & Int Hlth, Birmingham, AL USA. [Coulibaly, Yaya Ibrahim; Traore, Abdel Kader] CNAM, Bamako, Mali. [Boatin, Boakye A.] World Hlth Org, Geneva, Switzerland. [Nutman, Thomas B.; Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Coulibaly, YI (reprint author), Univ Sci Tech & Technol Bamako USTTB, Mali Int Ctr Excellence Res ICER, Bamako, Mali. EM yicoulibaly@icermali.org OI Klion, Amy/0000-0002-4986-5326 FU Special Program for Research and Training in Tropical Diseases (WHO/UNDP/World Bank) [A00583]; Division of Intramural Research, NIAID, NIH FX We would like to address special thanks to the local health care staff of Sikasso and Kolokoba, to the villagers and all the volunteers for their cooperation and participation to the field activities. The Special Program for Research and Training in Tropical Diseases (WHO/UNDP/World Bank) Grant ID A00583 and the Division of Intramural Research, NIAID, NIH funded this study. NR 21 TC 8 Z9 8 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD AUG 28 PY 2013 VL 6 AR 247 DI 10.1186/1756-3305-6-247 PG 7 WC Parasitology SC Parasitology GA 209UU UT WOS:000323786500001 PM 23981378 ER PT J AU Chen, J Qian, HH Horai, R Chan, CC Falick, Y Caspi, RR AF Chen, Jun Qian, Haohua Horai, Reiko Chan, Chi-Chao Falick, Yishay Caspi, Rachel R. TI Comparative Analysis of Induced vs. Spontaneous Models of Autoimmune Uveitis Targeting the Interphotoreceptor Retinoid Binding Protein SO PLOS ONE LA English DT Article ID ENDOTOXIN-INDUCED UVEITIS; UVEORETINITIS EAU; LIPOTEICHOIC ACID; DISEASE; MICE; RAT; MECHANISMS; IRBP; TH1; SUSCEPTIBILITY AB Animal models of autoimmunity to the retina mimic specific features of human uveitis, but no model by itself reproduces the full spectrum of human disease. We compared three mouse models of uveitis that target the interphotoreceptor retinoid binding protein (IRBP): (i) the "classical" model of experimental autoimmune uveitis (EAU) induced by immunization with IRBP; (ii) spontaneous uveitis in IRBP T cell receptor transgenic mice (R161H) and (iii) spontaneous uveitis in Autoimmune Regulator (AIRE)(-/-) mice. Disease course and severity, pathology and changes in visual function were studied using fundus imaging and histological examinations, optical coherence tomography and electroretinography. All models were on the B10.RIII background. Unlike previously reported, IRBP-induced EAU in B10.RIII mice exhibited two distinct patterns of disease depending on clinical scores developed after onset: severe monophasic with extensive destruction of the retina and rapid loss of visual signal, or lower grade with a prolonged chronic phase culminating after several months in retinal degeneration and loss of vision. R161H and AIRE(-/-) mice spontaneously developed chronic progressive inflammation; visual function declined gradually as retinal degeneration developed. Spontaneous uveitis in R161H mice was characterized by persistent cellular infiltrates and lymphoid aggregation, whereas AIRE(-/-) mice characteristically developed multi-focal infiltrates and severe choroidal inflammation. These data demonstrate variability and unique distinguishing features in the different models of uveitis, suggesting that each one can represent distinct aspects of uveitis in humans. C1 [Chen, Jun; Horai, Reiko; Falick, Yishay; Caspi, Rachel R.] NEI, Immunoregulat Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Qian, Haohua] NEI, Visual Funct Core, NIH, Bethesda, MD 20892 USA. [Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chen, J (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510275, Guangdong, Peoples R China. EM chenju@nei.nih.gov; caspir@nei.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU National Institutes of Health (NIH)/National Eye Institute (NEI) [EY000184] FX The study was supported by National Institutes of Health (NIH)/National Eye Institute (NEI) Intramural funding, project #EY000184. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 9 Z9 9 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 28 PY 2013 VL 8 IS 8 AR e72161 DI 10.1371/journal.pone.0072161 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 209DG UT WOS:000323733800034 PM 24015215 ER PT J AU Hu, Y Bai, L Geiger, T Goldberger, N Walker, RC Green, JE Wakefield, LM Hunter, KW AF Hu, Ying Bai, Ling Geiger, Thomas Goldberger, Natalie Walker, Renard C. Green, Jeffery E. Wakefield, Lalage M. Hunter, Kent W. TI Genetic Background May Contribute to PAM50 Gene Expression Breast Cancer Subtype Assignments SO PLOS ONE LA English DT Article ID INDUCED MAMMARY-TUMOR; TRANSCRIPTIONAL NETWORK; MOLECULAR PORTRAITS; CELL-LINES; MOUSE; METASTASIS; SUSCEPTIBILITY; PROGRESSION; POPULATION; PREDICTOR AB Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer. C1 [Hu, Ying] Ctr Biomed Informat & Informat Technol, Bethesda, MD USA. [Bai, Ling; Geiger, Thomas; Goldberger, Natalie; Walker, Renard C.; Green, Jeffery E.; Wakefield, Lalage M.; Hunter, Kent W.] NCI, Lab Canc Biol & Genet, CCR, NIH, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Lab Canc Biol & Genet, CCR, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU National Institutes of Health, NCI, Center for Cancer Research FX This work was supported by the National Institutes of Health, NCI, Center for Cancer Research, Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 7 Z9 7 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 28 PY 2013 VL 8 IS 8 AR e72287 DI 10.1371/journal.pone.0072287 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 209DG UT WOS:000323733800044 ER PT J AU Kim, SH Wanasen, N Paldurai, A Xiao, S Collins, PL Samal, SK AF Kim, Shin-Hee Wanasen, Nanchaya Paldurai, Anandan Xiao, Sa Collins, Peter L. Samal, Siba K. TI Newcastle Disease Virus Fusion Protein Is the Major Contributor to Protective Immunity of Genotype-Matched Vaccine SO PLOS ONE LA English DT Article ID RECOMBINANT VIRUSES; FOREIGN GENE; CHICKEN; STRAIN; EXPRESSION; OUTBREAKS; EFFICACY; HN; PATHOGENICITY; REPLICATION AB Virulent strains of Newcastle disease virus (NDV) can cause devastating disease in chickens worldwide. Although the current vaccines are substantially effective, they do not completely prevent infection, virus shedding and disease. To produce genotype-matched vaccines, a full-genome reverse genetics system has been used to generate a recombinant virus in which the F protein cleavage site has been changed to that of avirulent vaccine virus. In the other strategy, the vaccines have been generated by replacing the F and HN genes of a commercial vaccine strain with those from a genotype-matched virus. However, the protective efficacy of a chimeric virus vaccine has not been directly compared with that of a full-genome virus vaccine developed by reverse genetics. Therefore, in this study, we evaluated the protective efficacy of genotype VII matched chimeric vaccines by generating three recombinant viruses based on avirulent LaSota (genotype II) strain in which the open reading frames (ORFs) encoding the F and HN proteins were replaced, individually or together, with those of the circulating and highly virulent Indonesian NDV strain Ban/010. The cleavage site of the Ban/010 F protein was mutated to the avirulent motif found in strain LaSota. In vitro growth characteristics and a pathogenicity test indicated that all three chimeric viruses retained the highly attenuated phenotype of the parental viruses. Immunization of chickens with chimeric and full-length genome VII vaccines followed by challenge with virulent Ban/010 or Texas GB (genotype II) virus demonstrated protection against clinical disease and death. However, only those chickens immunized with chimeric rLaSota expressing the F or F plus HN proteins of the Indonesian strain were efficiently protected against shedding of Ban/010 virus. Our findings showed that genotype-matched vaccines can provide protection to chickens by efficiently preventing spread of virus, primarily due to the F protein. C1 [Kim, Shin-Hee; Wanasen, Nanchaya; Paldurai, Anandan; Xiao, Sa; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU NIAID [N01A060009]; NIAID, NIH FX This research was supported by NIAID contract N01A060009 (85% support) and the NIAID, NIH, Intramural Research Program (15% support). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 12 Z9 12 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 28 PY 2013 VL 8 IS 8 AR e74022 DI 10.1371/journal.pone.0074022 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 209DG UT WOS:000323733800108 PM 24015313 ER PT J AU Leysath, CE Phillips, DD Crown, D Fattah, RJ Moayeri, M Leppla, SH AF Leysath, Clinton E. Phillips, Damilola D. Crown, Devorah Fattah, Rasem J. Moayeri, Mahtab Leppla, Stephen H. TI Anthrax Edema Factor Toxicity Is Strongly Mediated by the N-end Rule SO PLOS ONE LA English DT Article ID BACILLUS-ANTHRACIS; LETHAL FACTOR; TOXIN; BINDING; PROTEIN; MACROPHAGES; PEPTIDASE; PROLINE; PATHWAY; CYCLASE AB Anthrax edema factor (EF) is a calmodulin-dependent adenylate cyclase that converts adenosine triphosphate (ATP) into 3'-5'-cyclic adenosine monophosphate (cAMP), contributing to the establishment of Bacillus anthracis infections and the resulting pathophysiology. We show that EF adenylate cyclase toxin activity is strongly mediated by the N-end rule, and thus is dependent on the identity of the N-terminal amino acid. EF variants having different N-terminal residues varied by more than 100-fold in potency in cultured cells and mice. EF variants having unfavorable, destabilizing N-terminal residues showed much greater activity in cells when the E1 ubiquitin ligase was inactivated or when proteasome inhibitors were present. Taken together, these results show that EF is uniquely affected by ubiquitination and/or proteasomal degradation. C1 [Leysath, Clinton E.; Phillips, Damilola D.; Crown, Devorah; Fattah, Rasem J.; Moayeri, Mahtab; Leppla, Stephen H.] Natl Inst Allergy & Infect Dis, NIH, Parasit Dis Lab, Bethesda, MD USA. RP Leppla, SH (reprint author), Natl Inst Allergy & Infect Dis, NIH, Parasit Dis Lab, Bethesda, MD USA. EM sleppla@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 2 Z9 2 U1 2 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 28 PY 2013 VL 8 IS 8 AR UNSP e74474 DI 10.1371/journal.pone.0074474 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 209DG UT WOS:000323733800114 PM 24015319 ER PT J AU Horinouchi, Y Summers, FA Ehrenshaft, M Houchi, H Tamaki, T Minakuchi, K Mason, RP AF Horinouchi, Yuya Summers, Fiona A. Ehrenshaft, Marilyn Houchi, Hitoshi Tamaki, Toshiaki Minakuchi, Kazuo Mason, Ronald P. TI Cytotoxicity evaluation of environmental chemicals via free radical detection using newly technique immuno-spin trapping, In-Cell Western and confocal microscopy SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Horinouchi, Yuya; Minakuchi, Kazuo] Tokushima Univ Hosp, Dept Pharm, Tokushima, Japan. [Horinouchi, Yuya; Tamaki, Toshiaki] Univ Tokushima, Dept Pharmacol, Inst Hlth Biosci, Grad Sch, Tokushima 770, Japan. [Summers, Fiona A.; Ehrenshaft, Marilyn; Mason, Ronald P.] NIEHS, Free Rad Metab Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Houchi, Hitoshi] Kagawa Univ Hosp, Dept Pharm, Takamatsu, Kagawa, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S102 EP S102 DI 10.1016/j.toxlet.2013.05.152 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800309 ER PT J AU Thompson, KL Chen, T Couttet, P Ellinger-Ziegelbauer, H Kanki, M Kelsall, J Boitier, E Nassirpour, R Searfoss, G Sharapova, T de la Moureyre-Spire, C Yuen, P O'Lone, R AF Thompson, K. L. Chen, T. Couttet, P. Ellinger-Ziegelbauer, H. Kanki, M. Kelsall, J. Boitier, E. Nassirpour, R. Searfoss, G. Sharapova, T. de la Moureyre-Spire, C. Yuen, P. O'Lone, R. TI Multi-laboratory assessment of best practices for quantification of microRNAs associated with isoproterenol-induced myocardial injury in the urine and plasma of rats SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Thompson, K. L.] CDER, Silver Spring, MD USA. [Chen, T.] NCTR, Jefferson, AR USA. [Couttet, P.] Novartis Pharma AG, Basel, Switzerland. [Ellinger-Ziegelbauer, H.] Bayer Pharma AG, Wuppertal, Germany. [Kanki, M.] Astellas Pharrna Inc, Osaka, Japan. [Kelsall, J.] AstraZeneca, Macclesfield, Cheshire, England. [Boitier, E.] Sanofi, Vitry Sur Seine, France. [Nassirpour, R.] Pfizer, Andover, MA USA. [Searfoss, G.] Lilly, Indianapolis, IN USA. [Sharapova, T.] Abbott Labs, Abbott Pk, IL 60064 USA. [de la Moureyre-Spire, C.] Servier, Gidy, France. [Yuen, P.] NIDDK, NIH, Bethesda, MD USA. [O'Lone, R.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S66 EP S66 DI 10.1016/j.toxlet.2013.05.037 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800199 ER PT J AU Thompson, KL Chen, T Couttet, P Ellinger-Ziegelbauer, H Kanki, M Kelsall, J Boitier, E Nassirpour, R Searfoss, G Sharapova, T de la Moureyre-Spire, C Yuen, P O'Lone, R AF Thompson, K. L. Chen, T. Couttet, P. Ellinger-Ziegelbauer, H. Kanki, M. Kelsall, J. Boitier, E. Nassirpour, R. Searfoss, G. Sharapova, T. de la Moureyre-Spire, Catherine Yuen, P. O'Lone, R. TI The HESI inter-laboratory miRNA project SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Thompson, K. L.] CDER, Silver Spring, MD USA. [Chen, T.] NCTR, Jefferson, AR USA. [Couttet, P.] Novartis Pharma AG, Basel, Switzerland. [Ellinger-Ziegelbauer, H.] Bayer Pharma AG, Wuppertal, Germany. [Kanki, M.] Astellas Pharma Inc, Osaka, Japan. [Kelsall, J.] AstraZeneca, Macclesfield, Cheshire, England. [Boitier, E.] Sanofi, Vitry Sur Seine, France. [Nassirpour, R.] Pfizer, Andover, MA USA. [Searfoss, G.] Lilly, Indianapolis, IN USA. [Sharapova, T.] Abbott Labs, Abbott Pk, IL 60064 USA. [de la Moureyre-Spire, Catherine] Servier, Gidy, France. [Yuen, P.] NIDDK, NIH, Bethesda, MD USA. [O'Lone, R.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S48 EP S48 DI 10.1016/j.toxlet.2013.06.176 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800149 ER PT J AU Cho, YT Ernst, M Fudge, JL AF Cho, Youngsun T. Ernst, Monique Fudge, Julie L. TI Cortico-Amygdala-Striatal Circuits Are Organized as Hierarchical Subsystems through the Primate Amygdala SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; HUMAN ORBITOFRONTAL CORTEX; CAUDAL VENTRAL STRIATUM; SURFACE-BASED ATLASES; HUMAN CEREBRAL-CORTEX; RHESUS-MONKEY; MACAQUE MONKEY; NUCLEUS-ACCUMBENS; BASOLATERAL AMYGDALA; CORTICOSTRIATAL CONNECTIONS AB The prefrontal and insula cortex, amygdala, and striatum are key regions for emotional processing, yet the amygdala's role as an interface between the cortex and striatum is not well understood. In the nonhuman primate ( Macaque fascicularis), we analyzed a collection of bidirectional tracer injections in the amygdala to understand how cortical inputs and striatal outputs are organized to form integrated cortico-amygdala-striatal circuits. Overall, diverse prefrontal and insular cortical regions projected to the basal and accessory basal nuclei of the amygdala. In turn, these amygdala regions projected to widespread striatal domains extending well beyond the classic ventral striatum. Analysis of the cases in aggregate revealed a topographic colocalization of cortical inputs and striatal outputs in the amygdala that was additionally distinguished by cortical cytoarchitecture. Specifically, the degree of cortical laminar differentiation of the cortical inputs predicted amygdalostriatal targets, and distinguished three main cortico-amygdala-striatal circuits. These three circuits were categorized as "primitive," "intermediate," and "developed," respectively, to emphasize the relative phylogenetic and ontogenetic features of the cortical inputs. Within the amygdala, these circuits appeared arranged in a pyramidal-like fashion, with the primitive circuit found in all examined subregions, and subsequent circuits hierarchically layered in discrete amygdala subregions. This arrangement suggests a stepwise integration of the functions of these circuits across amygdala subregions, providing a potential mechanism through which internal emotional states are managed with external social and sensory information toward emotionally informed complex behaviors. C1 [Cho, Youngsun T.; Fudge, Julie L.] Univ Rochester, Med Ctr, Dept Neurobiol & Anat, Rochester, NY 14642 USA. [Fudge, Julie L.] Univ Rochester, Med Ctr, Dept Psychiat, Rochester, NY 14642 USA. [Ernst, Monique] NIMH, NIH, Emot Dev & Affect Neurosci Branch, Bethesda, MD 20892 USA. RP Fudge, JL (reprint author), Univ Rochester, Med Ctr, Dept Neurobiol & Anat, 601 Elmwood Ave, Rochester, NY 14642 USA. EM julie_fudge@urmc.rochester.edu FU National Institutes of Mental Health [F30 MH09126, R01MH63291]; Clinical and Translational Sciences Institute [TL1RR024135] FX This work was funded through support of the National Institutes of Mental Health F30 MH09126 (Y.T.C.) and R01MH63291 (J.L.F.), and the Clinical and Translational Sciences Institute TL1RR024135 (Y.T.C.). We thank Owen Zacharias for his photography and Daniel Tylee for assistance with histology and immunocytochemistry. We also acknowledge helpful criticisms and comments on a draft of this manuscript from Dr. Lizabeth Romanski. NR 121 TC 19 Z9 19 U1 3 U2 17 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 28 PY 2013 VL 33 IS 35 BP 14017 EP 14030 DI 10.1523/JNEUROSCI.0170-13.2013 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 209AZ UT WOS:000323727000010 PM 23986238 ER PT J AU Sabino, EC Ribeiro, AL Salemi, VMC Ianni, BM Nastari, L Fernandes, F Oliveira, CD Antunes, AP Menezes, MM Patavino, GM Capuani, L de Almeida-Neto, C Sachdev, V Carrick, DM Wright, D Kavounis, K Gonzalez, TT Custer, B Busch, MP Murphy, EL Carneiro-Proietti, AB AF Sabino, Ester C. Ribeiro, Antonio L. Salemi, Vera M. C. Ianni, Barbara M. Nastari, Luciano Fernandes, Fabio Oliveira, Claudia Di Lorenzo Antunes, Andre P. Menezes, Marcia M. Patavino, Giuseppina M. Capuani, Ligia de Almeida-Neto, Cesar Sachdev, Vandana Carrick, Danielle M. Wright, David Kavounis, Katherine Gonzalez, Thelma T. Custer, Brian Busch, Michael P. Murphy, Edward L. Carneiro-Proietti, Anna-Barbara TI Response to Letters Regarding Article, "Ten-Year Incidence of Chagas Cardiomyopathy Among Asymptomatic, Trypanosoma cruzi-Seropositive Former Blood Donors" SO CIRCULATION LA English DT Letter ID ELECTROCARDIOGRAPHIC ABNORMALITIES; DISEASE; PREDICTORS C1 [Sabino, Ester C.] Univ Sao Paulo, Dept Infect Dis, Sao Paulo, Brazil. [Sabino, Ester C.] Univ Sao Paulo, Inst Trop Med, Sao Paulo, Brazil. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Fac Med, Belo Horizonte, MG, Brazil. [Salemi, Vera M. C.; Ianni, Barbara M.; Nastari, Luciano; Fernandes, Fabio] Univ Sao Paulo, Fac Med, Heart Inst InCor, Cardiomyopathy Unit, Sao Paulo, Brazil. [Oliveira, Claudia Di Lorenzo] Univ Fed Sao Joao del Rei, Divinopolis, Brazil. [Antunes, Andre P.; Menezes, Marcia M.] Prontosocor Montes Claros, Ctr Ciencias Biol & Saude, Montes Claros, MG, Brazil. [Patavino, Giuseppina M.; Capuani, Ligia; de Almeida-Neto, Cesar] Fundacao Prosangue Hemoctr Sao Paulo, Sao Paulo, Brazil. [Sachdev, Vandana] NHLBI, Bethesda, MD 20892 USA. [Carrick, Danielle M.; Wright, David; Kavounis, Katherine] Westat Corp, Rockville, MD USA. [Gonzalez, Thelma T.; Custer, Brian; Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Murphy, Edward L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Carneiro-Proietti, Anna-Barbara] Hemominas, Belo Horizonte, MG, Brazil. RP Sabino, EC (reprint author), Univ Sao Paulo, Dept Infect Dis, Sao Paulo, Brazil. RI Ribeiro, Antonio/C-2707-2009; Nastari, Luciano/C-8528-2012; de Almeida-Neto, Cesar/O-9224-2014; Fernandes, Fabio/D-5994-2012; Sabino, Ester/F-7750-2010; Salemi, Vera/C-9104-2013; Ianni, Barbara/C-7689-2012 OI Capuani, Ligia/0000-0002-3467-6805; Ribeiro, Antonio/0000-0002-2740-0042; Nastari, Luciano/0000-0002-7959-3827; Sabino, Ester/0000-0003-2623-5126; Salemi, Vera/0000-0002-7152-1810; Ianni, Barbara/0000-0002-1588-5492 NR 5 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 27 PY 2013 VL 128 IS 9 BP E137 EP E138 DI 10.1161/CIRCULATIONAHA.113.004018 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 208BF UT WOS:000323649600006 PM 23979636 ER PT J AU Tanoue, K Jenkins, LMM Durell, SR Debnath, S Sakai, H Tagad, HD Ishida, K Appella, E Mazur, SJ AF Tanoue, Kan Jenkins, Lisa M. Miller Durell, Stewart R. Debnath, Subrata Sakai, Hiroyasu Tagad, Harichandra D. Ishida, Kazushige Appella, Ettore Mazur, Sharlyn J. TI Binding of a Third Metal Ion by the Human Phosphatases PP2C alpha and Wip1 Is Required for Phosphatase Activity SO BIOCHEMISTRY LA English DT Article ID DNA-DAMAGE RESPONSE; HUMAN PROTEIN PHOSPHATASE; SERINE/THREONINE PHOSPHATASE; MYCOBACTERIUM-TUBERCULOSIS; 2C; GAMMA-H2AX; INSULIN; ACTIVATION; SUBSTRATE; PATHWAYS AB The PPM phosphatases require millimolar concentrations of Mg2+ or Mn2+ to activate phosphatase activity in vitro. The human phosphatases PP2C alpha (PPM1A) and Wip1 (PPM1D) differ in their physiological function, substrate specificity, and apparent metal affinity. A crystallographic structure of PP2C alpha shows only two metal ions in the active site. However, recent structural studies of several bacterial PP2C phosphatases have indicated three metal ions in the active site. Two residues that coordinate the third metal ion are highly conserved, suggesting that human PP2C phosphatases may also bind a third ion. Here, isothermal, titration calorimetry analysis of Mg2+ binding to PP2C alpha distinguished binding of two ions to high affinity sites from the binding of a third ion with a millimolar affinity, similar to the apparent metal affinity required for catalytic activity. Mutational analysis indicated that Asp239 and either Asp146 or Asp243 was required for low affinity binding of Mg2+, but that both Asp 146 and Asp239 were required for catalysis. Phosphatase activity assays in the presence of MgCl2, MnCl2, or mixtures of the two, demonstrate high phosphatase activity toward a phosphopeptide substrate when Mg2+ was bound to the low-affinity site, whether Mg2+ or Mn2+ ions were bound to the high affinity sites. Mutation of the corresponding putative third metal ion-coordinating residues of Wip1 affected catalytic activity similarly both in vitro and in human cells. These results suggest that phosphatase activity toward phosphopeptide substrates by PP2C alpha and Wip1 requires the binding of a Mg2+ ion to the low-affinity site. C1 [Tanoue, Kan; Jenkins, Lisa M. Miller; Durell, Stewart R.; Debnath, Subrata; Sakai, Hiroyasu; Tagad, Harichandra D.; Ishida, Kazushige; Appella, Ettore; Mazur, Sharlyn J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mazur, SJ (reprint author), 37 Convent Dr,Bldg 37 Room 2140, Bethesda, MD 20892 USA. EM mazurs@mail.nih.gov FU Center for Center Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Center Research, National Cancer Institute, National Institutes of Health. NR 59 TC 8 Z9 8 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 27 PY 2013 VL 52 IS 34 BP 5830 EP 5843 DI 10.1021/bi4005649 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 210EA UT WOS:000323810900013 PM 23906386 ER PT J AU Ferguson, JF Matthews, GJ Townsend, RR Raj, DS Kanetsky, PA Budoff, M Fischer, MJ Rosas, SE Kanthety, R Rahman, M Master, SR Qasim, A Li, MY Mehta, NN Shen, HQ Mitchell, BD O'Connell, JR Shuldiner, AR Ho, WK Young, R Rasheed, A Danesh, J He, J Kusek, JW Ojo, AO Flack, J Go, AS Gadegbeku, CA Wright, JT Saleheen, D Feldman, HI Rader, DJ Foulkes, AS Reilly, MP AF Ferguson, Jane F. Matthews, Gregory J. Townsend, Raymond R. Raj, Dominic S. Kanetsky, Peter A. Budoff, Matthew Fischer, Michael J. Rosas, Sylvia E. Kanthety, Radhika Rahman, Mahboob Master, Stephen R. Qasim, Atif Li, Mingyao Mehta, Nehal N. Shen, Haiqing Mitchell, Braxton D. O'Connell, Jeffrey R. Shuldiner, Alan R. Ho, Weang Kee Young, Robin Rasheed, Asif Danesh, John He, Jiang Kusek, John W. Ojo, Akinlolu O. Flack, John Go, Alan S. Gadegbeku, Crystal A. Wright, Jackson T., Jr. Saleheen, Danish Feldman, Harold I. Rader, Daniel J. Foulkes, Andrea S. Reilly, Muredach P. CA CRIC Study Principal Investigators TI Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease Findings From the CRIC Study (Chronic Renal Insufficiency Cohort) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE candidate genes; chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort Study (CRIC); coronary artery calcification (CAC); myocardial infarction (MI); risk factors; single nucleotide polymorphisms (SNPs) ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; MYOCARDIAL-INFARCTION; COMMON VARIANTS; BLOOD-PRESSURE; HEART-DISEASE; CALCIUM; ATHEROSCLEROSIS; HYPERTENSION; METAANALYSIS AB Objectives This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). Background CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. Methods We performed a candidate gene study (similar to 2,100 genes; similar to 50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). Results Of 268 SNPs reaching p < 5 x 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e. g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. Conclusions We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways. (C) 2013 by the American College of Cardiology Foundation C1 [Ferguson, Jane F.; Qasim, Atif; Mehta, Nehal N.; Saleheen, Danish; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Matthews, Gregory J.; Foulkes, Andrea S.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Townsend, Raymond R.; Rosas, Sylvia E.; Feldman, Harold I.] Univ Penn, Renal Electrolyte & Hypertens Div, Perelman Sch Med, Philadelphia, PA 19104 USA. [Raj, Dominic S.] George Washington Univ, Med Fac Associates, Washington, DC USA. [Kanetsky, Peter A.; Li, Mingyao; Feldman, Harold I.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.; Li, Mingyao; Feldman, Harold I.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Budoff, Matthew] Los Angeles Biomed Res Inst, Torrance, CA USA. [Fischer, Michael J.] Jesse Brown VA Med Ctr, Dept Med, Chicago, IL USA. [Fischer, Michael J.] Univ Illinois Hosp & Hlth Sci Syst, Chicago, IL USA. [Fischer, Michael J.] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Kanthety, Radhika; Rahman, Mahboob] Case Western Reserve Univ, Dept Nephrol & Hypertens, Cleveland, OH 44106 USA. [Master, Stephen R.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [Shen, Haiqing; Mitchell, Braxton D.; O'Connell, Jeffrey R.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Ho, Weang Kee; Young, Robin; Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Rasheed, Asif; Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. [Ojo, Akinlolu O.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Flack, John] Wayne State Univ, Sch Med, Dept Med, Detroit, MI 48201 USA. [Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Gadegbeku, Crystal A.] Temple Univ, Sch Med, Nephrol Sect, Dept Med, Philadelphia, PA 19122 USA. [Wright, Jackson T., Jr.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. RP Reilly, MP (reprint author), Univ Penn, Perelman Sch Med, 11-136 Translat Res Bldg,3400 Civ Ctr Blvd,Bldg 4, Philadelphia, PA 19104 USA. RI Ferguson, Jane/C-7154-2011; OI Ferguson, Jane/0000-0001-6896-1025; HO, WEANG KEE/0000-0002-8269-7344; Mitchell, Braxton/0000-0003-4920-4744 FU National Institute of Diabetes and Digestive and Kidney Diseases [5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, 5U01DK060902]; National Institutes of Health (NIH) [UL1RR024134, UL1RR025005, M01RR16500, UL1RR024989, M01RR000042, UL1RR024986, UL1RR029879, RR05096, UL1RR024131]; National Institutes of Health Research [R01-HL69313, U01-HL72515, R01-HL088119]; American Heart Association Scientist Development Grant [0830146N]; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]; University of Cambridge; Center for Non-Communicable Diseases, Pakistan; Wellcome Trust; Department of Veterans Affairs Health Services Research and Development Service; Clinical and Translational Science Award [UL1RR024134]; Diabetes and Endocrine Research Center from the NIH [P20-DK 019525]; Abbott; Reata Laboratoriea; British Heart Foundation; UK Medical Research Council; U.S. National Institutes of Health; Fogarty Foundation; UK National Institute of Health Research, Cambridge; Biomedical Research Centre; Pfizer; European Commission; Medtronics; GlaxoSmithKline; Merck Research Laboratories; Virginia Brown Fellowship for Aging and Stroke Research; NIH [K24-HL107643, R01-DK090505, U01-HL108636, R01-HL113147]; [R01-DK071224]; [R01-HL107196] FX The CRIC study is supported by cooperative agreements 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902 from the National Institute of Diabetes and Digestive and Kidney Diseases and by grants UL1RR024134, UL1RR025005, M01RR16500, UL1RR024989, M01RR000042, UL1RR024986, UL1RR029879, RR05096, and UL1RR024131 from the National Institutes of Health (NIH). This work was supported by R01-DK071224 (to Dr. Reilly). The Amish Calcification Study was supported by National Institutes of Health Research Grants R01-HL69313, U01-HL72515, and R01-HL088119, and an American Heart Association Scientist Development Grant (0830146N). Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488). Fieldwork in PROMIS was supported by grants available to investigators at the University of Cambridge and at the Center for Non-Communicable Diseases, Pakistan. Genotyping in PROMIS was supported by Wellcome Trust. Dr. Fischer is supported by a Department of Veterans Affairs Health Services Research and Development Service (Career Development Award). Dr. Foulkes is supported by R01-HL107196. PennCAC was supported by a Clinical and Translational Science Award (UL1RR024134) and a Diabetes and Endocrine Research Center (P20-DK 019525) award (both from the NIH to the University of Pennsylvania). Dr. Rosas has received grants from Abbott and Reata Laboratoriea. Dr. Danesh has received research funding from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, U.S. National Institutes of Health, Fogarty Foundation, UK National Institute of Health Research, Cambridge, Biomedical Research Centre, Pfizer, and European Commission. Dr. Wright Jr. has received grant support funding and served on the advisory board for Medtronics. Dr. Reilly has received research grant support from GlaxoSmithKline and Merck Research Laboratories; and is supported by a Virginia Brown Fellowship for Aging and Stroke Research; by K24-HL107643, R01-DK090505, U01-HL108636, and R01-HL113147 from the NIH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 52 TC 12 Z9 12 U1 3 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 27 PY 2013 VL 62 IS 9 BP 789 EP 798 DI 10.1016/j.jacc.2013.01.103 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 211IL UT WOS:000323899900005 PM 23727086 ER PT J AU Wang, MG Arteaga, D He, BJJ AF Wang, Megan Arteaga, Daniel He, Biyu J. TI Brain mechanisms for simple perception and bistable perception SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE visual perception; fMRI; MVPA; Granger causality; ambiguous images ID PRIMARY VISUAL-CORTEX; LATERAL GENICULATE-NUCLEUS; BINOCULAR-RIVALRY; AMBIGUOUS FIGURES; NEURAL ACTIVITY; CORTICAL RESPONSES; BAYESIAN-INFERENCE; PREFRONTAL CORTEX; PARIETAL CORTEX; WORKING-MEMORY AB When faced with ambiguous sensory inputs, subjective perception alternates between the different interpretations in a stochastic manner. Such multistable perception phenomena have intrigued scientists and laymen alike for over a century. Despite rigorous investigations, the underlying mechanisms of multistable perception remain elusive. Recent studies using multivariate pattern analysis revealed that activity patterns in posterior visual areas correlate with fluctuating percepts. However, increasing evidence suggests that vision-and perception at large-is an active inferential process involving hierarchical brain systems. We applied searchlight multivariate pattern analysis to functional magnetic resonance imaging signals across the human brain to decode perceptual content during bistable perception and simple unambiguous perception. Although perceptually reflective activity patterns during simple perception localized predominantly to posterior visual regions, bistable perception involved additionally many higher-order frontoparietal and temporal regions. Moreover, compared with simple perception, both top-down and bottom-up influences were dramatically enhanced during bistable perception. We further studied the intermittent presentation of ambiguous images-a condition that is known to elicit perceptual memory. Compared with continuous presentation, intermittent presentation recruited even more higher-order regions and was accompanied by further strengthened top-down influences but relatively weakened bottom-up influences. Taken together, these results strongly support an active top-down inferential process in perception. C1 [Wang, Megan; Arteaga, Daniel; He, Biyu J.] NINDS, NIH, Bethesda, MD 20892 USA. RP He, BJJ (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM biyu.he@nih.gov OI He, Biyu/0000-0003-1549-1351 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX We thank David Leopold and Panagiota Theodoni for comments on a previous draft of the manuscript and Avi Snyder and Don Zhang for sharing cortical parcellation ROIs. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 90 TC 10 Z9 12 U1 1 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 27 PY 2013 VL 110 IS 35 BP E3350 EP E3359 DI 10.1073/pnas.1221945110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ZC UT WOS:000323564600014 PM 23942129 ER PT J AU Lavine, JS King, AA Andreasen, V Bjornstad, ON AF Lavine, Jennie S. King, Aaron A. Andreasen, Viggo Bjornstad, Ottar N. TI Immune Boosting Explains Regime-Shifts in Prevaccine-Era Pertussis Dynamics SO PLOS ONE LA English DT Article ID BORDETELLA-PERTUSSIS; CHILDHOOD DISEASES; VACCINATION; EPIDEMIOLOGY; TRANSMISSION; INFERENCE; INTERFERENCE; POPULATIONS; INFECTIONS; INFANTS AB Understanding the biological mechanisms underlying episodic outbreaks of infectious diseases is one of mathematical epidemiology's major goals. Historic records are an invaluable source of information in this enterprise. Pertussis (whooping cough) is a re-emerging infection whose intermittent bouts of large multiannual epidemics interspersed between periods of smaller-amplitude cycles remain an enigma. It has been suggested that recent increases in pertussis incidence and shifts in the age-distribution of cases may be due to diminished natural immune boosting. Here we show that a model that incorporates this mechanism can account for a unique set of pre-vaccine-era data from Copenhagen. Under this model, immune boosting induces transient bursts of large amplitude outbreaks. In the face of mass vaccination, the boosting model predicts larger and more frequent outbreaks than do models with permanent or passively-waning immunity. Our results emphasize the importance of understanding the mechanisms responsible for maintaining immune memory for pertussis epidemiology. C1 [Lavine, Jennie S.; King, Aaron A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Lavine, Jennie S.; King, Aaron A.; Andreasen, Viggo; Bjornstad, Ottar N.] NIH, Fogarty Int Ctr, Bethesdsa, MD USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [King, Aaron A.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Andreasen, Viggo] Roskilde Univ, Dept Sci Syst & Models, Roskilde, Denmark. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol & Biol, University Pk, PA 16802 USA. RP King, AA (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM kingaa@umich.edu RI King, Aaron/B-8092-2012 OI King, Aaron/0000-0001-6159-3207 FU Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center, U.S. National Institutes of Health; National Institutes of Health [1-R01-AI-101155-01]; Danish Medical Research Council [272-06-0430]; Bill & Melinda Gates Foundation FX Financial support was provided by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, U.S. Department of Homeland Security and Fogarty International Center, U.S. National Institutes of Health, and by grants from the National Institutes of Health (grant #1-R01-AI-101155-01 to AAK), the Danish Medical Research Council (grant #272-06-0430 to VA), and the Bill & Melinda Gates Foundation (to ONB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 10 Z9 10 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e72086 DI 10.1371/journal.pone.0072086 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800044 PM 23991047 ER PT J AU Sharma, A Berga-Bolanos, R Sultana, DA Sen, JM AF Sharma, Archna Berga-Bolanos, Rosa Sultana, Dil Afroz Sen, Jyoti Misra TI IL-4 and IL-4 Receptor Expression Is Dispensable for the Development and Function of Natural Killer T Cells SO PLOS ONE LA English DT Article ID NKT CELLS; IMMUNE-SYSTEM; TRANSCRIPTION; LINEAGE; DIFFERENTIATION; PROGRAM; INTERLEUKIN-4; ACTIVATION; ANTI-CD3; SUBSETS AB CD4 T cells acquire functional properties including cytokine production upon antigenic stimulation through the T cell receptor (TCR) and differentiate into T helper (Th) cells. Th1 cells produce interferon (IFN)-gamma and Th2 cells produce interleukin (IL)-4. Th1 and 2 cells utilize IFN-gamma and IL-4 for further maturation and maintenance, respectively. Promyelocytic leukemia zinc finger (PLZF)-expressing invariant natural killer T (iNKT) cells develop in the thymus and acquire functional ability to produce IL-4 and IFN-gamma in the thymus in the absence of antigenic stimulation. In response to antigenic stimulation, iNKT cells rapidly produce IFN-gamma and IL-4. However, it is still unknown as to whether iNKT cells require these cytokines for maturation or survival in vivo. In this study, using IL-4- and IL-4 receptor-(IL-4R) deficient mice, we demonstrate that IL-4 as well as IL-4R expression is dispensable for the development, function and maintenance of iNKT cells. C1 [Sharma, Archna; Berga-Bolanos, Rosa; Sultana, Dil Afroz; Sen, Jyoti Misra] NIA, Immune Cells & Inflammat Sect, NIH, Baltimore, MD 21224 USA. RP Sen, JM (reprint author), NIA, Immune Cells & Inflammat Sect, NIH, Baltimore, MD 21224 USA. EM Jyoti-Sen@nih.gov RI Sharma, Archna/R-9377-2016 OI Sharma, Archna/0000-0003-4745-0220 FU National Institute on Aging at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 2 Z9 3 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e71872 DI 10.1371/journal.pone.0071872 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800022 PM 23990998 ER PT J AU Siebenhuhner, F Weiss, SA Coppola, R Weinberger, DR Bassett, DS AF Siebenhuehner, Felix Weiss, Shennan A. Coppola, Richard Weinberger, Daniel R. Bassett, Danielle S. TI Intra- and Inter-Frequency Brain Network Structure in Health and Schizophrenia SO PLOS ONE LA English DT Article ID SMALL-WORLD NETWORKS; NEURAL MASS MODEL; GRAPH-THEORETICAL ANALYSIS; SPACE SEPARATION METHOD; TIME-SERIES ANALYSIS; FUNCTIONAL NETWORKS; WORKING-MEMORY; INTERMEDIATE PHENOTYPES; SYNAPTIC PLASTICITY; CONNECTIVITY AB Empirical studies over the past two decades have provided support for the hypothesis that schizophrenia is characterized by altered connectivity patterns in functional brain networks. These alterations have been proposed as genetically mediated diagnostic biomarkers and are thought to underlie altered cognitive functions such as working memory. However, the nature of this dysconnectivity remains far from understood. In this study, we perform an extensive analysis of functional connectivity patterns extracted from MEG data in 14 subjects with schizophrenia and 14 healthy controls during a 2-back working memory task. We investigate uni-, bi- and multivariate properties of sensor time series by computing wavelet entropy of and correlation between time series, and by constructing binary networks of functional connectivity both within and between classical frequency bands (gamma, beta, alpha, and theta). Networks are based on the mutual information between wavelet time series, and estimated for each trial window separately, enabling us to consider both network topology and network dynamics. We observed significant decreases in time series entropy and significant increases in functional connectivity in the schizophrenia group in comparison to the healthy controls and identified an inverse relationship between these measures across both subjects and sensors that varied over frequency bands and was more pronounced in controls than in patients. The topological organization of connectivity was altered in schizophrenia specifically in high frequency c and b band networks as well as in the gamma-beta cross-frequency networks. Network topology varied over trials to a greater extent in patients than in controls, suggesting disease-associated alterations in dynamic network properties of brain function. Our results identify signatures of aberrant neurophysiological behavior in schizophrenia across uni-, bi- and multivariate scales and lay the groundwork for further clinical studies that might lead to the discovery of new intermediate phenotypes. C1 [Siebenhuehner, Felix; Bassett, Danielle S.] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. [Siebenhuehner, Felix] Univ Helsinki, Ctr Neurosci, Helsinki, Finland. [Weiss, Shennan A.] Columbia Univ, Dept Neurol, New York, NY USA. [Coppola, Richard] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD USA. [Bassett, Danielle S.] Univ Calif Santa Barbara, Sage Ctr Study Mind, Santa Barbara, CA 93106 USA. RP Bassett, DS (reprint author), Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. EM dbassett@physics.ucsb.edu FU Errett Fisher Foundation; Templeton Foundation; David and Lucile Packard Foundation; Public Health Service [NS44393]; Sage Center for the Study of the Mind; Institute for Collaborative Biotechnologies from the U.S. Army Research Oce [W911NF-09-D-0001]; Center for Scientic Computing at the California NanoSystems Institute and Materials Research Laboratory: a National Science Foundation (NSF) MRSEC [DMR-1121053]; NSF [CNS-0960316]; Weinberger Lab; National Institute of Mental Health Magnetoencephalography core facility FX This work was supported by the Errett Fisher Foundation, the Templeton Foundation, the David and Lucile Packard Foundation, Public Health Service Grant NS44393, Sage Center for the Study of the Mind, and the Institute for Collaborative Biotechnologies through contract no. W911NF-09-D-0001 from the U.S. Army Research Oce. The authors acknowledge support from the Center for Scientic Computing at the California NanoSystems Institute and Materials Research Laboratory: a National Science Foundation (NSF) MRSEC (DMR-1121053) and NSF CNS-0960316. The patients and normal controls were studied as part of the Clinical Brain Disorders Branch Sibling study (D.R. Weinberger PI), an investigation of the biological components of genetic risk for schizophrenia, with direct funding of the Weinberger Lab and the National Institute of Mental Health Magnetoencephalography core facility (R. Coppola). The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 140 TC 14 Z9 14 U1 3 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e72351 DI 10.1371/journal.pone.0072351 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800062 PM 23991097 ER PT J AU Kassis, JA Lilly, MA AF Kassis, Judith A. Lilly, Mary A. TI PRC2 Goes Solo in the Drosophila Female Germline SO DEVELOPMENTAL CELL LA English DT Editorial Material ID POLYCOMB; TARGETS; ELEGANS; CELLS AB Polycomb-group proteins silence gene expression through epigenetic modification of chromatin. In this issue of Developmental Cell, I ovino et al. (2013) demonstrate that Polycomb repressive complex 2 (PRC2) is required for maintenance of oocyte fate by repressing expression of two critical targets, Cyclin E and dacapo, during the early meiotic cycle. C1 [Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Lilly, Mary A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Kassis, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM jkassis@mail.nih.gov; lillym@helix.nih.gov FU Intramural NIH HHS [ZIA HD001613-15] NR 10 TC 0 Z9 0 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 26 PY 2013 VL 26 IS 4 BP 329 EP 330 DI 10.1016/j.devcel.2013.08.008 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 210RH UT WOS:000323851700003 PM 23987509 ER PT J AU Park, JH Kang, HJ Kang, SI Lee, JE Hur, J Ge, K Mueller, E Li, H Lee, BC Lee, SB AF Park, Jun Hong Kang, Hong Jun Kang, Soo Im Lee, Ji Eun Hur, Jamie Ge, Kai Mueller, Elisabetta Li, Hongjie Lee, Byeong-Chel Lee, Sean Bong TI A Multifunctional Protein, EWS, Is Essential for Early Brown Fat Lineage Determination SO DEVELOPMENTAL CELL LA English DT Article ID RNA-BINDING PROTEIN; SARCOMA GENE EWS; ADIPOSE-TISSUE; ADIPOCYTE DIFFERENTIATION; ONCOGENIC TRANSFORMATION; TRANSCRIPTIONAL CONTROL; ENERGY-EXPENDITURE; MYXOID LIPOSARCOMA; EWINGS-SARCOMA; ADULT HUMANS AB The recent surge in obesity has provided an impetus to better understand the mechanisms of adipogenesis, particularly in brown adipose tissue (BAT) because of its potential utilization for antiobesity therapy. Postnatal brown adipocytes arise from early muscle progenitors, but how brown fat lineage is determined is not completely understood. Here, we show that a multifunctional protein, Ewing Sarcoma (EWS), is essential for determining brown fat lineage during development. BATs from Ews null embryos and newborns are developmentally arrested. Ews mutant brown preadipocytes fail to differentiate due to loss of Bmp7 expression, a critical early brown adipogenic factor. We demonstrate that EWS, along with its binding partner Y-box binding protein 1 (YBX1), activates Bmp7 transcription. Depletion of either Ews or Ybx1 leads to loss of Bmp7 expression and brown adipogenesis. Remarkably, Ews null BATs and brown preadipocytes ectopically express myogenic genes. These results demonstrate that EWS is essential for early brown fat lineage determination. C1 [Park, Jun Hong; Kang, Hong Jun; Kang, Soo Im; Hur, Jamie; Mueller, Elisabetta; Li, Hongjie; Lee, Byeong-Chel; Lee, Sean Bong] NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. [Lee, Ji Eun; Ge, Kai] NIDDK, Mol Endocrinol Branch, Bethesda, MD 20892 USA. [Lee, Byeong-Chel] Univ Pittsburgh, Inst Canc, Dept Med, Pittsburgh, PA 15213 USA. [Lee, Sean Bong] Tulane Univ, Sch Med, Dept Pathol & Lab Med, New Orleans, LA 70112 USA. RP Lee, SB (reprint author), NIDDK, Genet Dev & Dis Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM slee30@tulane.edu RI Lee, Ji-Eun/F-7891-2011; OI Lee, Ji-Eun/0000-0002-3768-7016; Ge, Kai/0000-0002-7442-5138 FU Intramural Research Program of the NIDDK, NIH; Tulane University FX We thank Raimund Hirschberg (Los Angeles Biomedical Research Institute) for providing the murine Bmp7 promoter-Luc plasmids; Huiyan Lu (NIDDK) for in vitro fertilization and generation of the Ews mutant 129SvEv/Black Swiss strain; Oksana Gavrilova (NIDDK) for the temperature-controlled chamber; Sandra E. Dunn (University of British Columbia), Alexandra McPherron and Yun Kyung Lee (NIDDK), and Hyeog Kang (NHLBI) for helpful discussions; and Jan Endlich (JFE Enterprises) for TEM. This research was supported in part by the Intramural Research Program of the NIDDK, NIH, and by startup funds from Tulane University (to S.B.L.). J.H.P., H.J.K., S.I.K., J.H., and H.L. performed experiments; J.E.L., K.G., E.M., and B.-C.L. contributed critical reagents and suggestions; and J.H.P. and S.B.L. designed experiments, analyzed data, and wrote the manuscript. NR 46 TC 26 Z9 26 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 26 PY 2013 VL 26 IS 4 BP 393 EP 404 DI 10.1016/j.devcel.2013.07.002 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 210RH UT WOS:000323851700009 PM 23987512 ER PT J AU Molle, C Zhang, T de Lendonck, LY Gueydan, C Andrianne, M Sherer, F Van Simaeys, G Blackshear, PJ Leo, O Goriely, S AF Molle, Celine Zhang, Tong de Lendonck, Laure Ysebrant Gueydan, Cyril Andrianne, Mathieu Sherer, Felicie Van Simaeys, Gaetan Blackshear, Perry J. Leo, Oberdan Goriely, Stanislas TI Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NECROSIS-FACTOR-ALPHA; DENDRITIC CELLS; EPIDERMAL HYPERPLASIA; DEFICIENCY SYNDROME; TNF-ALPHA; IL-23; EXPRESSION; DEADENYLATION; DESTABILIZATION; PATHOGENESIS AB Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine-rich element (ARE)-binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow-derived dendritic cells (BMDCs) from TTP-/- mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3' untranslated region. TTP-/- mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating gamma delta T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23-IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation. C1 [Molle, Celine; Zhang, Tong; de Lendonck, Laure Ysebrant; Andrianne, Mathieu; Leo, Oberdan; Goriely, Stanislas] Univ Libre Brussels, IMI, B-6041 Gosselies, Belgium. [Gueydan, Cyril] Univ Libre Brussels, Lab Biol Mol Gene, B-6041 Gosselies, Belgium. [Sherer, Felicie; Van Simaeys, Gaetan] Univ Libre Brussels, CMMI, B-6041 Gosselies, Belgium. [Sherer, Felicie; Van Simaeys, Gaetan] Univ Libre Brussels, Hop Erasme, Dept Nucl Med, B-1070 Brussels, Belgium. [Blackshear, Perry J.] Natl Inst Environm Hlth, Lab Signal Transduct, Natl Inst Hlth Sci, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Goriely, Stanislas] WELBIO, B-6041 Gosselies, Belgium. RP Goriely, S (reprint author), Univ Libre Brussels, IMI, B-6041 Gosselies, Belgium. EM stgoriel@ulb.ac.be OI Goriely, Stanislas/0000-0002-7005-6195; Gueydan, Cyril/0000-0003-3097-7667 FU government of the Walloon Region; GlaxoSmithKline Biologicals; Fonds National de la Recherche Scientifique (FRS-FNRS, Belgium); WELBIO; Interuniversity Attraction Pole of the Belgian Federal Science Policy; Televie. S. Goriely is a research associate of the FRS-FNRS; Intramural Research Program of the NIEHS, NIH FX The Institute for Medical Immunology is sponsored by the government of the Walloon Region and GlaxoSmithKline Biologicals. This study was supported by the Fonds National de la Recherche Scientifique (FRS-FNRS, Belgium), the WELBIO, and an Interuniversity Attraction Pole of the Belgian Federal Science Policy. C. Molle is a postdoctoral fellow of the FRS-FNRS. L. Ysebrant and M. Andrianne are supported by a grant from the Televie. S. Goriely is a research associate of the FRS-FNRS.; P.J. Blackshear is supported by the Intramural Research Program of the NIEHS, NIH. NR 35 TC 24 Z9 24 U1 0 U2 12 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 26 PY 2013 VL 210 IS 9 BP 1675 EP 1684 DI 10.1084/jem.20120707 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 207ZV UT WOS:000323644800005 PM 23940256 ER PT J AU Zou, WG Greenblatt, MB Brady, N Lotinun, S Zhai, B de Rivera, H Singh, A Sun, J Gygi, SP Baron, R Glimcher, LH Jones, DC AF Zou, Weiguo Greenblatt, Matthew B. Brady, Nicholas Lotinun, Sutada Zhai, Bo de Rivera, Heather Singh, Anju Sun, Jun Gygi, Steven P. Baron, Roland Glimcher, Laurie H. Jones, Dallas C. TI The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID DOUBLECORTIN-LIKE-KINASE; CLEIDOCRANIAL DYSPLASIA; SERINE PHOSPHORYLATION; TRANSCRIPTION FACTOR; SKELETAL DEVELOPMENT; NEURONAL MIGRATION; BONE-FORMATION; STEM-CELL; MASS; DIFFERENTIATION AB Osteoblasts are responsible for the formation and mineralization of the skeleton. To identify novel regulators of osteoblast differentiation, we conducted an unbiased forward genetic screen using a lentiviral-based shRNA library. This functional genomics analysis led to the identification of the microtubule-associated protein DCAMKL1 (Doublecortin-like and CAM kinase-like 1) as a novel regulator of osteogenesis. Mice with a targeted disruption of Dcamkl1 displayed elevated bone mass secondary to increased bone formation by osteoblasts. Molecular experiments demonstrated that DCAMKL1 represses osteoblast activation by antagonizing Runx2, the master transcription factor in osteoblasts. Key elements of the cleidocranial dysplasia phenotype observed in Runx2(+/-) mice are reversed by the introduction of a Dcamkl1-null allele. Our results establish a genetic linkage between these two proteins in vivo and demonstrate that DCAMKL1 is a physiologically relevant regulator of anabolic bone formation. C1 [Zou, Weiguo; Sun, Jun] Chinese Acad Sci, State Key Lab Cell Biol, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. [Greenblatt, Matthew B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Brady, Nicholas; de Rivera, Heather; Glimcher, Laurie H.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Lotinun, Sutada; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Zhai, Bo; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Boston, MA 02115 USA. [Singh, Anju] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Jones, Dallas C.] Merck Res Labs, Boston, MA 02115 USA. RP Zou, WG (reprint author), Chinese Acad Sci, State Key Lab Cell Biol, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. EM zouwg94@sibcb.ac.cn OI Brady, Nicholas/0000-0002-2928-0232 FU National Institutes of Health [HD055601, K99AR055668]; Merck Pharmaceuticals; Thousand Young Talents Program of the Chinese government FX This work is supported by National Institutes of Health grants HD055601 (to L.H. Glimcher) and K99AR055668 (to D.C. Jones) and a grant from Merck Pharmaceuticals. W. Zou is a recipient of the Thousand Young Talents Program of the Chinese government. NR 47 TC 10 Z9 10 U1 2 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 26 PY 2013 VL 210 IS 9 BP 1793 EP 1806 DI 10.1084/jem.20111790 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 207ZV UT WOS:000323644800013 PM 23918955 ER PT J AU Rytty, R Nikkinen, J Paavola, L Abou Elseoud, A Moilanen, V Visuri, A Tervonen, O Renton, AE Traynor, BJ Kiviniemi, V Remes, AM AF Rytty, Riikka Nikkinen, Juha Paavola, Liisa Abou Elseoud, Ahmed Moilanen, Virpi Visuri, Annina Tervonen, Osmo Renton, Alan E. Traynor, Bryan J. Kiviniemi, Vesa Remes, Anne M. TI GroupICA dual regression analysis of resting state networks in a behavioral variant of forntotemporal dementia SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE default; resting state; functional MRI; dorsal attention network; frontotemporal dementia ID INDEPENDENT COMPONENT ANALYSIS; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; BRAIN ACTIVITY; FUNCTIONAL CONNECTIVITY; DIAGNOSTIC-CRITERIA; DEFAULT-MODE; GROUP PICA; MR-IMAGES; FMRI AB Functional MRI studies have revealed changes in default-mode and salience networks in neurodegenerative dementias, especially in Alzheimer's disease (AD). The purpose of this study was to analyze the whole brain cortex resting state networks (RSNs) in patients with behavioral variant frontotemporal dementia (bvFTD) by using resting state functional MRI (rfMRI). The group specific RSNs were identified by high model order independent component analysis (ICA) and a dual regression technique was used to detect between-group differences in the RSNs with p < 0.05 threshold corrected for multiple comparisons. A y-concatenation method was used to correct for multiple comparisons for multiple independent components, gray matter differences as well as the voxel level. We found increased connectivity in several networks within patients with bvFTD compared to the control group. The most prominent enhancement was seen in the right frontotemporal area and insula. A significant increase in functional connectivity was also detected in the left dorsal attention network (DAN), in anterior paracingulate-a default mode sub-network as well as in the anterior parts of the frontal pole. Notably the increased patterns of connectivity were seen in areas around atrophic regions. The present results demonstrate abnormal increased connectivity in several important brain networks including the DAN and default-mode network (DMN) in patients with bvFTD. These changes may be associated with decline in executive functions and attention as well as apathy, which are the major cognitive and neuropsychiatric defects in patients with frontotemporal dementia. C1 [Rytty, Riikka; Paavola, Liisa; Visuri, Annina] Univ Oulu, Inst Clin Med, Dept Neurol, Oulu, Finland. [Rytty, Riikka; Paavola, Liisa; Moilanen, Virpi] Oulu Univ Hosp, Dept Neurol, Oulu, Finland. [Nikkinen, Juha; Abou Elseoud, Ahmed; Tervonen, Osmo; Kiviniemi, Vesa] Univ Oulu, Inst Clin Med, Dept Radiol, Oulu, Finland. [Renton, Alan E.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Remes, Anne M.] Univ Eastern Finland, Inst Clin Med, Dept Neurol, Kuopio 70211, Finland. [Remes, Anne M.] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. RP Remes, AM (reprint author), Univ Eastern Finland, Inst Clin Med, Dept Neurol, Yliopistonranta 1,POB 1627, Kuopio 70211, Finland. EM anne.remes@uef.fi RI Traynor, Bryan/G-5690-2010 FU Finnish Academy [117111, 123772]; Finnish Medical Foundation; Finnish Neurological Foundation; Oulu University Hospital; National Graduate School of Clinical Investigation; Intramural Research Programs of the NIH; National Institute on Aging [Z01-AG000949-02]; ALS Association; AriSLA; Packard Center for ALS research; FIGC; Microsoft Research (Bryan J. Traynor); Myasthenia Gravis Foundation FX This work was supported by grants from the Finnish Academy [grants 117111 and 123772 (Vesa Kiviniemi)], Finnish Medical Foundation (Vesa Kiviniemi, Anne M. Remes), Finnish Neurological Foundation (Vesa Kiviniemi), KEVO grants from Oulu University Hospital (Vesa Kiviniemi, Anne M. Remes), National Graduate School of Clinical Investigation (Riikka Rytty), the Intramural Research Programs of the NIH, and National Institute on Aging (Z01-AG000949-02)(Bryan J. Traynor) the ALS Association, AriSLA, Packard Center for ALS research, FIGC, Microsoft Research (Bryan J. Traynor), and the Myasthenia Gravis Foundation (Bryan J. Traynor). NR 50 TC 12 Z9 12 U1 0 U2 16 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 26 PY 2013 VL 7 DI 10.3389/fnhum.2013.00461 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 205XD UT WOS:000323477200001 ER PT J AU Simons, SS Kumar, R AF Simons, S. Stoney, Jr. Kumar, Raj TI Variable steroid receptor responses: Intrinsically disordered AF1 is the key SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Steroid receptors; Selectivity in controlling gene expression; Intrinsically disordered domains; Selective receptor modulators (SRMs); A(max) and EC50; AF1 domain as a molecular rheostat ID LIGAND-BINDING DOMAIN; GLUCOCORTICOID-RECEPTOR; ESTROGEN-RECEPTOR; GENE-EXPRESSION; ANDROGEN RECEPTOR; ACTIVATION DOMAINS; HORMONE RECEPTORS; PROSTATE-CANCER; TERMINAL DOMAIN; TRANSCRIPTION AB Steroid hormones, acting through their cognate receptor proteins, see widespread clinical applications due to their ability to alter the induction or repression of numerous genes. However, steroid usage is limited by the current inability to control off-target, or non-specific, side-effects. Recent results from three separate areas of research with glucocorticoid and other steroid receptors (cofactor-induced changes in receptor structure, the ability of ligands to alter remote regions of receptor structure, and how cofactor concentration affects both ligand potency and efficacy) indicate that a key element of receptor activity is the intrinsically disordered amino-terminal domain. These results are combined to construct a novel framework within which to logically pursue various approaches that could afford increased selectivity in steroid-based therapies. Published by Elsevier Ireland Ltd. C1 [Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, LERB, NIH, Bethesda, MD 20892 USA. [Kumar, Raj] Commonwealth Med Coll, Dept Basic Sci, Scranton, PA USA. RP Simons, SS (reprint author), NIDDK, CEB, NIH, Bldg 10,Room 8N-307B, Bethesda, MD 20892 USA. EM stoneys@helix.nih.gov; rkumar@tcmedc.org FU NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX We thank Yun-Bo Shi (NICHD/NIH), Dan Larson (NCI/NIH), Hans Luecke (NIDDK/NIH), and especially James McNally (NCI/NIH) for constructive criticism. Part of this research (SSS) was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 44 TC 11 Z9 11 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD AUG 25 PY 2013 VL 376 IS 1-2 BP 81 EP 84 DI 10.1016/j.mce.2013.06.007 PG 4 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 200TZ UT WOS:000323095100009 PM 23792173 ER PT J AU Bosch, B Berger, AC Khandelwal, S Heipertz, EL Scharf, B Santambrogio, L Roche, PA AF Bosch, Berta Berger, Adam C. Khandelwal, Sanjay Heipertz, Erica L. Scharf, Brian Santambrogio, Laura Roche, Paul A. TI Disruption of Multivesicular Body Vesicles Does Not Affect Major Histocompatibility Complex (MHC) Class II-Peptide Complex Formation and Antigen Presentation by Dendritic Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHOLESTEROL HOMEOSTASIS; COMPARTMENTS; TRANSPORT; DISEASE; TRAFFICKING; MOLECULES; CLATHRIN; PATHWAY; BODIES; GENE AB The antigen processing compartments in antigen-presenting cells (APCs) have well known characteristics of multivesicular bodies (MVBs). However, the importance of MVB integrity to APC function remains unknown. In this study, we have altered the ultrastructure of the MVB by perturbing cholesterol content genetically through the use of a deletion of the lipid transporter Niemann-Pick type C1 (NPC1). Immunofluorescence and electron microscopic analyses reveal that the antigen processing compartments in NPC1(-/-) dendritic cells (DCs) have an abnormal ultrastructure in that the organelles are enlarged and the intraluminal vesicles are almost completely absent and those remaining are completely disorganized. MHC-II is restricted to the limiting membrane of these enlarged MVBs where it colocalizes with the peptide editor H2-DM. Curiously, proteolytic removal of the chaperone protein Invariant chain from MHC-II, degradation of internalized foreign antigens, and antigenic-peptide binding to nascent MHC-II are normal in NPC1(-/-) DCs. Antigen-pulsed NPC1(-/-) DCs are able to effectively activate antigen-specific CD4 T cells in vitro, and immunization of NPC1(-/-) mice reveals surprisingly normal CD4 T cell activation in vivo. Our data thus reveal that the localization of MHC-II on the intraluminal vesicles of multivesicular antigen processing compartments is not required for efficient antigen presentation by DCs. C1 [Bosch, Berta; Berger, Adam C.; Khandelwal, Sanjay; Heipertz, Erica L.; Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Scharf, Brian; Santambrogio, Laura] Albert Einstein Coll Med, Dept Pathol Microbiol & Immunol, Bronx, NY 10461 USA. RP Roche, PA (reprint author), NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU Intramural Research Program of the National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health (to P. A. R.). NR 25 TC 4 Z9 5 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2013 VL 288 IS 34 BP 24286 EP 24292 DI 10.1074/jbc.M113.461996 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NW UT WOS:000330612300001 PM 23846690 ER PT J AU Belzil, C Neumayer, G Vassilev, AP Yap, KL Konishi, H Rivest, S Sanada, K Ikura, M Nakatani, Y Nguyen, MD AF Belzil, Camille Neumayer, Gernot Vassilev, Alex P. Yap, Kyoko L. Konishi, Hiroaki Rivest, Serge Sanada, Kamon Ikura, Mitsuhiko Nakatani, Yoshihiro Minh Dang Nguyen TI A Ca2+-dependent Mechanism of Neuronal Survival Mediated by the Microtubule-associated Protein p600 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; METHYL-D-ASPARTATE; KINASE-II CLUSTERS; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; CEREBRAL-ISCHEMIA; INDUCED APOPTOSIS; CNS NEURONS; CALCIUM; CALMODULIN AB In acute and chronic neurodegeneration, Ca2+ mishandling and disruption of the cytoskeleton compromise neuronal integrity, yet abnormalities in the signaling roles of cytoskeletal proteins remain largely unexplored. We now report that the microtubule-associated protein p600 (also known as UBR4) promotes neuronal survival. Following depletion of p600, glutamate-induced Ca2+ influx through NMDA receptors, but not AMPA receptors, initiates a degenerative process characterized by endoplasmic reticulum fragmentation and endoplasmic reticulum Ca2+ release via inositol 1,4,5-trisphosphate receptors. Downstream of NMDA receptors, p600 associates with the calmodulin-calmodulin-dependent protein kinase II alpha complex. A direct and atypical p600/calmodulin interaction is required for neuronal survival. Thus, p600 counteracts specific Ca2+-induced death pathways through regulation of Ca2+ homeostasis and signaling. C1 [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. [Vassilev, Alex P.] NICHD, NIH, Bethesda, MD 20892 USA. [Yap, Kyoko L.; Ikura, Mitsuhiko] Univ Toronto, Ontario Canc Inst, Toronto, ON M5G 1L7, Canada. [Konishi, Hiroaki] Prefectural Univ Hiroshima, Fac Life & Environm Sci, Shobara, Hiroshima 7270023, Japan. [Rivest, Serge] Univ Laval, Ctr Hosp Univ Laval, Ctr Rech, Quebec City, PQ G1V 0A6, Canada. [Sanada, Kamon] Univ Tokyo, Grad Sch Sci, Mol Genet Res Lab, Bunkyo Ku, Tokyo 1130033, Japan. [Nakatani, Yoshihiro] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nguyen, MD (reprint author), Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, HMRB 151,3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. EM mdnguyen@ucalgary.ca RI SANADA, YOSHIKADO/G-5014-2014 FU Canadian Institutes of Health Research (CIHR); Human Frontier Science Program Organization (HFSPO); Brenda Strafford Chair Foundation in Alzheimer's disease; Alberta Innovates Health Solutions (AIHS); Ted Fong/Hotchkiss Brain Institute; Austrian Academy of Sciences at the University of Calgary; Achievers in Medical Sciences award; CIHR; Canadian Cancer Society; AIHS FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by an operating grant from the Canadian Institutes of Health Research (CIHR), the Human Frontier Science Program Organization (HFSPO), and the Brenda Strafford Chair Foundation in Alzheimer's disease (to M. D. N.).; Recipient of an Alberta Innovates Health Solutions (AIHS) studentship and a Ted Fong/Hotchkiss Brain Institute doctoral scholarship.; Recipient of a doctoral fellowship of the Austrian Academy of Sciences at the University of Calgary and an Achievers in Medical Sciences award.; Supported by CIHR and the Canadian Cancer Society and holder of a Canada Research Chair.; Recipient of a New Investigator Award from the CIHR and a Scholarship from AIHS. NR 53 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2013 VL 288 IS 34 BP 24452 EP 24464 DI 10.1074/jbc.M113.483107 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NW UT WOS:000330612300015 PM 23861403 ER PT J AU Thomas, AG Rojas, C Tanega, C Shen, M Simeonov, A Boxer, MB Auld, DS Ferraris, DV Tsukamoto, T Slusher, BS AF Thomas, Ajit G. Rojas, Camilo Tanega, Cordelle Shen, Min Simeonov, Anton Boxer, Matthew B. Auld, Douglas S. Ferraris, Dana V. Tsukamoto, Takashi Slusher, Barbara S. TI Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Cancer; HIV-associated dementia (HAD); Glutamate; Glutamine; Glutaminase; Kinetics ID KIDNEY-TYPE GLUTAMINASE; BLIND CLINICAL-TRIAL; PHASE-I; 6-DIAZO-5-OXO-L-NORLEUCINE DON; GLUTAMATE PRODUCTION; METABOLISM; CANCER; CELLS; ANTIOXIDANT; SANGUINARINE AB Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation Of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC(1280))) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease. (C) 2013 Elsevier Inc. All rights reserved. C1 [Thomas, Ajit G.; Rojas, Camilo; Ferraris, Dana V.; Tsukamoto, Takashi; Slusher, Barbara S.] Johns Hopkins Univ, Sch Med, Brain Sci Inst, Baltimore, MD 21205 USA. [Tanega, Cordelle; Shen, Min; Simeonov, Anton; Boxer, Matthew B.; Auld, Douglas S.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Tsukamoto, Takashi; Slusher, Barbara S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Slusher, Barbara S.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Slusher, BS (reprint author), Johns Hopkins Univ, Sch Med, Brain Sci Inst, JGR Bldg,Suite 277,855 N Wolfe St, Baltimore, MD 21205 USA. EM bslusher@jhmi.edu FU Johns Hopkins Brain Science Institute; NIH [1-R03-MH093170-01A1, 1R21NS074151-01] FX This work was supported in part by the Johns Hopkins Brain Science Institute, and NIH Grants 1-R03-MH093170-01A1 (to BSS) and 1R21NS074151-01 (to TT). NR 45 TC 12 Z9 12 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 23 PY 2013 VL 438 IS 2 BP 243 EP 248 DI 10.1016/j.bbrc.2013.06.110 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 211NT UT WOS:000323915700001 PM 23850693 ER PT J AU Oliveira, MJA van Deventer, HE Bachmann, LM Warnick, GR Nakajima, K Nakamura, M Sakurabayashi, I Kimberly, MM Shamburek, RD Korzun, WJ Myers, GL Miller, WG Remaley, AT AF Oliveira, Marcelo Jose Andrade van Deventer, Hendrick E. Bachmann, Lorin M. Warnick, G. Russell Nakajima, Katsuyuki Nakamura, Masakasu Sakurabayashi, Ikunosuke Kimberly, Mary M. Shamburek, Robert D. Korzun, William J. Myers, Gary L. Miller, W. Greg Remaley, Alan T. TI Evaluation of four different equations for calculating LDL-C with eight different direct HDL-C assays SO CLINICA CHIMICA ACTA LA English DT Article DE Cholesterol; Cardiovascular disease; Low-density lipoproteins; Friedewald equation ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; RISK; POPULATION; FORMULA; PLASMA; ULTRACENTRIFUGATION; CLASSIFICATION; ACCURACY; VALUES AB Background: Low-density lipoprotein cholesterol (LDL-C) is often calculated (cLDL-C) by the Friedewald equation, which requires high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Because there have been considerable changes in the measurement of HDL-C with the introduction of direct assays, several alternative equations have recently been proposed. Methods: We compared 4 equations (Friedewald, Vujovic, Chen, and Anandaraja) for cLDL-C, using 8 different direct HDL-C (dHDL-C) methods. LDL-C values were calculated by the 4 equations and determined by the 13 quantification reference method procedure in 164 subjects. Results: For normotriglyceridemic samples (TG < 200 mg/dl), between 6.2% and 24.8% of all results exceeded the total error goal of 12% for LDL-C, depending on the dHDL-C assay and cLDL-C equation used. Friedewald equation was found to be the optimum equation for most but not all dHDL-C assays, typically leading to less than 10% misclassification of cardiovascular risk based on LDL-C. Hypertriglyceridemic samples (>= 200 mg/dl) showed a large cardiovascular risk misclassification rate (30%-50%) for all combinations of dHDL-C assays and cLDL-C equations. Conclusion: The Friedewald equation showed the best performance for estimating LDL-C, but its accuracy varied considerably depending on the specific dHDL-C assay used. None of the cLDL-C equations performed adequately for hypertriglyceridemic samples. Published by Elsevier B.V. C1 [Oliveira, Marcelo Jose Andrade; Shamburek, Robert D.; Remaley, Alan T.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [van Deventer, Hendrick E.] Lancet Labs, ZA-0043 Pretoria, South Africa. [Bachmann, Lorin M.; Korzun, William J.; Miller, W. Greg] Virginia Commonwealth Univ, Dept Pathol, Richmond, VA 23284 USA. [Warnick, G. Russell] Hlth Diagnost Lab, Richmond, VA 23219 USA. [Nakajima, Katsuyuki] Nakajima & Associates Co, Maebashi, Guma 3710805, Japan. [Nakamura, Masakasu] Osaka Med Ctr Hlth Sci & Promot, Dept Hlth Promot & Educ, Higashinari Ku, Osaka 5370025, Japan. [Sakurabayashi, Ikunosuke] Jichi Med Univ, Shimotsuke, Tochigi, Japan. [Myers, Gary L.] Amer Assoc Clin Chem, Washington, DC USA. RP Remaley, AT (reprint author), NIH, Dept Lab Med, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM aremaley1@mail.nih.gov FU Warren Grant Magnuson Clinical Center; Intramural Research Program of the National Institutes of Health; Denka Seiken; Kyowa Medex; Sekisui Medical; Serotec; Sysmex International Reagents; UMA; Wako Pure Chemical Industries; Genzyme; Pacific Biometrics Research Foundation FX M. J. Oliveira, A. T. Remaley, and H. E. van Deventer were supported by the Warren Grant Magnuson Clinical Center, Intramural Research Program of the National Institutes of Health. G. Miller was supported by the Denka Seiken, Kyowa Medex, Sekisui Medical, Serotec, Sysmex International Reagents, UMA and Wako Pure Chemical Industries, who donated reagents, calibrators, and controls and contributed financial support to Pacific Biometrics Research Foundation. Genzyme and Pointe Scientific contributed financial support to Pacific Biometrics Research Foundation. Pacific Biometrics Research Foundation provided a grant to Virginia Commonwealth University (funded by the financial contributions noted above). Roche Diagnostics donated reagents, calibrators, controls, and a Hitachi 917 instrument NR 21 TC 12 Z9 12 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD AUG 23 PY 2013 VL 423 BP 135 EP 140 DI 10.1016/j.cca.2013.04.009 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 172BY UT WOS:000320976100025 PM 23628525 ER PT J AU Laurence, A Belkaid, Y O'Shea, JJ AF Laurence, Arian Belkaid, Yasmine O'Shea, John J. TI A Degrading View of Regulatory T Cells SO IMMUNITY LA English DT Editorial Material ID IN-VIVO; PLASTICITY; STABILITY AB Studies by van Loosdregt et al. and Chen et al. in this issue of Immunity provide evidence for previously unrecognized players that regulate FOXP3 degradation. These are interesting developments that point to unappreciated mechanisms by which inflammatory signals can impact expression of FOXP3 and possibly the stability of Treg cell phenotypes. C1 [Laurence, Arian; Belkaid, Yasmine; O'Shea, John J.] NIAMSD, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Bethesda, MD 20892 USA. EM osheaj@arb.niams.nih.gov RI Laurence, Arian/A-8770-2009 OI Laurence, Arian/0000-0003-0942-8292 NR 11 TC 2 Z9 4 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD AUG 22 PY 2013 VL 39 IS 2 BP 201 EP 203 DI 10.1016/j.immuni.2013.08.017 PG 4 WC Immunology SC Immunology GA AA2UE UT WOS:000330948800002 PM 23973216 ER PT J AU Zhou, TQ Zhu, J Wu, XL Moquin, S Zhang, BS Acharya, P Georgiev, IS Altae-Tran, HR Chuang, GY Joyce, MG Do Kwon, Y Longo, NS Louder, MK Luongo, T McKee, K Schramm, CA Skinner, J Yang, YP Yang, ZJ Zhang, ZH Zheng, AQ Bonsignori, M Haynes, BF Scheid, JF Nussenzweig, MC Simek, M Burton, DR Koff, WC Mullikin, JC Connors, M Shapiro, L Nabel, GJ Mascola, JR Kwong, PD AF Zhou, Tongqing Zhu, Jiang Wu, Xueling Moquin, Stephanie Zhang, Baoshan Acharya, Priyamvada Georgiev, Ivelin S. Altae-Tran, Han R. Chuang, Gwo-Yu Joyce, M. Gordon Do Kwon, Young Longo, Nancy S. Louder, Mark K. Luongo, Timothy McKee, Krisha Schramm, Chaim A. Skinner, Jeff Yang, Yongping Yang, Zhongjia Zhang, Zhenhai Zheng, Anqi Bonsignori, Mattia Haynes, Barton F. Scheid, Johannes F. Nussenzweig, Michel C. Simek, Melissa Burton, Dennis R. Koff, Wayne C. Mullikin, James C. Connors, Mark Shapiro, Lawrence Nabel, Gary J. Mascola, John R. Kwong, Peter D. CA NISC Comparative Sequencing Progra TI Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies SO IMMUNITY LA English DT Article ID B-CELL RECEPTORS; CD4-BINDING SITE; VACCINE EFFICACY; FOUNDER VIRUS; BINDING-SITE; BROAD; ENVELOPE; PROTEIN; REPERTOIRE; PROTECTION AB Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >10(12) antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few-likely one-ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population. C1 [Zhou, Tongqing; Zhu, Jiang; Wu, Xueling; Moquin, Stephanie; Zhang, Baoshan; Acharya, Priyamvada; Georgiev, Ivelin S.; Altae-Tran, Han R.; Chuang, Gwo-Yu; Joyce, M. Gordon; Do Kwon, Young; Longo, Nancy S.; Louder, Mark K.; Luongo, Timothy; McKee, Krisha; Yang, Yongping; Yang, Zhongjia; Zheng, Anqi; Shapiro, Lawrence; Nabel, Gary J.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Skinner, Jeff] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Connors, Mark] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Schramm, Chaim A.; Zhang, Zhenhai; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Scheid, Johannes F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Simek, Melissa; Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY 10038 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Design, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02129 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@nih.gov; pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010; OI Zhou, Tongqing/0000-0002-3935-4637; Skinner, Jeff/0000-0001-5697-0442 FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute, National Institutes of Health; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; Center for HIV/AIDS Vaccine Immunology Grant from the National Institutes from Health [AI 5U19 AI 067854-06]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank H. Coleman, M. Park, B. Schmidt, and A. Young for 454 pyrosequencing at the NIH Intramural Sequencing Center (NISC), J. Stuckey for assistance with figures, and the study participants and research staff at each of the Protocol G clinical centers, the Protocol G team members, the IAVI Human Immunology Laboratory and the Protocol G clinical investigators, including George Miiro, Anton Pozniak, Dale McPhee, Olivier Manigart, Etienne Karita, Andre Inwoley, Walter Jaoko, Jack DeHovitz, Linda-Gail Bekker, Punnee Pitisuttithum, Robert Paris, Jennifer Serwanga, and Susan Allen. We also thank Anthony West and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions or comments on the manuscript. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute, National Institutes of Health, and by grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium and by the Center for HIV/AIDS Vaccine Immunology Grant AI 5U19 AI 067854-06 from the National Institutes from Health. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 34 TC 101 Z9 102 U1 0 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD AUG 22 PY 2013 VL 39 IS 2 BP 245 EP 258 DI 10.1016/j.immuni.2013.04.012 PG 14 WC Immunology SC Immunology GA AA2UE UT WOS:000330948800008 PM 23911655 ER PT J AU Ouyang, WM Oh, SA Ma, Q Bivona, MR Zhu, JF Li, MO AF Ouyang, Weiming Oh, Soyoung A. Ma, Qian Bivona, Michael R. Zhu, Jinfang Li, Ming O. TI TGF-beta Cytokine Signaling Promotes CD8(+) T Cell Development and Low-Affinity CD4(+) T Cell Homeostasis by Regulation of Interleukin-7 Receptor alpha Expression SO IMMUNITY LA English DT Article ID ROR-GAMMA-T; NEGATIVE SELECTION; IN-VIVO; DIFFERENTIATION; NAIVE; TRANSCRIPTION; MECHANISMS; SURVIVAL; IL-7; PROLIFERATION AB Interleukin-7 receptor alpha chain (IL-7R alpha) is induced upon T cell positive selection and controls thymic CD8-lineage specification and peripheral naive T cell homeostasis. How IL-7R alpha expression is regulated in developing thymocytes is unclear. Here, we show that transforming growth factor beta (TGF-beta) signaling promoted IL-7R alpha expression and CD8(+) T cell differentiation. In addition, TGF-beta signaling was required for high IL-7R alpha expression in CD4(+) T cells bearing low-affinity T cell receptors, and the abrogation of TGF-beta receptor expression led to failed maintenance of peripheral CD4(+) T cells. Compromised IL-7R alpha expression in TGF-beta-receptor-deficient T cells was associated with increased expression of the Il7ra transcriptional repressor, Gfi-1. IL-7R alpha transgenesis or T-cell-specific ablation of Gfi-1 restored IL-7R alpha expression and largely ameliorated the development and homeostasis defects of TGF-beta-receptor-deficient T cells. These findings reveal functions for TGF-beta signaling in controlling IL-7R alpha expression and in promoting T cell repertoire diversification. C1 [Ouyang, Weiming; Oh, Soyoung A.; Ma, Qian; Bivona, Michael R.; Li, Ming O.] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. [Zhu, Jinfang] NIAID, Immunol Lab, Bethesda, MD 20892 USA. RP Li, MO (reprint author), Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. EM lim@mskcc.org RI Zhu, Jinfang/B-7574-2012 FU National Institute of Arthritis, Musculoskeletal, and Skin Diseases [RO1 AR060723]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA; [T32-CA9149-35] FX We thank K. Bottomly for providing AND mice, and A. Singer for providing IL-7R transgenic mice. The projects described were supported by grants from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (RO1 AR060723 to M.O.L.). J.Z. is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. S.A.O. is supported by T32-CA9149-35. NR 38 TC 9 Z9 11 U1 3 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD AUG 22 PY 2013 VL 39 IS 2 BP 335 EP 346 DI 10.1016/j.immuni.2013.07.016 PG 12 WC Immunology SC Immunology GA AA2UE UT WOS:000330948800015 PM 23932572 ER PT J AU Nguyen, JB Pool, CD Wong, CYB Treger, RS Williams, DL Cappello, M Lea, WA Simeonov, A Vermeire, JJ Modis, Y AF Nguyen, Jennifer B. Pool, Christopher D. Wong, Christina Y. B. Treger, Rebecca S. Williams, David L. Cappello, Michael Lea, Wendy A. Simeonov, Anton Vermeire, Jon J. Modis, Yorgo TI Peroxiredoxin-1 from the Human Hookworm Ancylostoma ceylanicum Forms a Stable Oxidized Decamer and Is Covalently Inhibited by Conoidin A SO CHEMISTRY & BIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM; CRYSTAL-STRUCTURE; 2-CYS PEROXIREDOXIN; HELMINTH INFECTIONS; IV; PEROXIDASE; REFINEMENT; MECHANISMS; CHEMISTRY; PARASITES AB Hookworms are parasitic nematodes that have a devastating impact on global health, particularly in developing countries. We report a biochemical and structural analysis of a peroxiredoxin from the hookworm Ancylostoma ceylanicum, AcePrx-1. Peroxiredoxins provide antioxidant protection and act as signaling molecules and chaperones. AcePrx-1 is expressed in adult hookworms and can be inactivated by 2,3-bis(bromomethyl)quinoxaline-1,4-dioxide (conoidin A). Conoidin A inactivates AcePrx-1 by alkylating or crosslinking the catalytic cysteines, while maintaining the enzyme in the "locally unfolded" conformation. Irreversible oxidation of the resolving cysteine may contribute additional inhibitory activity. A crystal structure of oxidized AcePrx-1 reveals a disulfide-linked decamer. A helix macrodipole near the active site increases the reactivity of the catalytic cysteines to conoidin A. This work demonstrates the promise of conoidin compounds as probes to evaluate peroxiredoxins as drug targets in human parasites. C1 [Nguyen, Jennifer B.; Modis, Yorgo] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Pool, Christopher D.; Wong, Christina Y. B.; Treger, Rebecca S.; Cappello, Michael; Vermeire, Jon J.] Yale Univ, Sch Med, Program Int Child Hlth, Child Hlth Res Ctr, New Haven, CT 06520 USA. [Pool, Christopher D.; Wong, Christina Y. B.; Treger, Rebecca S.; Cappello, Michael; Vermeire, Jon J.] Yale Univ, Sch Med, Dept Pediat, Child Hlth Res Ctr, New Haven, CT 06520 USA. [Williams, David L.] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Lea, Wendy A.; Simeonov, Anton] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Modis, Y (reprint author), Yale Univ, Dept Mol Biophys & Biochem, POB 6666, New Haven, CT 06520 USA. EM yorgo.modis@yale.edu OI Modis, Yorgo/0000-0002-6084-0429 FU Burroughs Wellcome Investigator Award; NIH [P01 GM022778, K22 AI08476, T32 GM08283]; Office of Biological of the US Department of Energy; Office of Basic Energy Sciences of the US Department of Energy FX We thank staff at beamline 24-ID-E of the Northeastern Collaborative Access Team at the Advanced Photon Source of the Argonne National Laboratory, and at the X25 and X29A beamlines of the National Synchrotron Light Source at Brookhaven National Laboratory. We thank Lisa Harrison for a critical reading of the manuscript. We acknowledge Alanna Schepartz for use of her mass spectrometer and Tae Han Kim for advice on chemical mechanisms. This work was supported by a Burroughs Wellcome Investigator Award and NIH grant P01 GM022778 (to Y.M.), and NIH grant K22 AI08476 (to J.J.V.). NIH training grant T32 GM08283 provided partial support (to J.B.N.). Use of the APS and NSLS is supported by the Offices of Biological and of Basic Energy Sciences of the US Department of Energy. NR 42 TC 5 Z9 5 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD AUG 22 PY 2013 VL 20 IS 8 BP 991 EP 1001 DI 10.1016/j.chembiol.2013.06.011 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 297RB UT WOS:000330271500005 PM 23891152 ER PT J AU Mehta, NN Li, K Szapary, P Krueger, J Brodmerkel, C AF Mehta, Nehal N. Li, Katherine Szapary, Philippe Krueger, James Brodmerkel, Carrie TI Modulation of cardiometabolic pathways in skin and serum from patients with psoriasis SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Inflammation; Atherosclerosis; Lipid metabolism; Psoriasis ID TO-SEVERE PSORIASIS; ATHEROSCLEROSIS; INFLAMMATION; MODERATE; DISEASE; RISK; MECHANISMS; MORTALITY; COHORT AB Background: Moderate-to-severe psoriasis is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD); however, the link is poorly understood. Methods: Skin and serum from patients with psoriasis were evaluated to understand if there was evidence of dysregulation in a targeted group of inflammatory and lipid genes related to ASCVD. Microarray analyses of expression of targeted ASCVD genes from skin in 89 patients with moderate-to-severe psoriasis from the ACCEPT trial were compared with non-diseased skin from healthy controls (n = 25). Serum (n = 149) was tested at baseline for monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine (MDC), and apolipoprotein-A1 (Apo-A1) comparing to healthy controls (n=162). Results: An increase in skin gene expression for MCP-1 (7.98-fold) and MDC (6.66-fold) (p < 0.001 each) was observed in lesional versus healthy skin. Significant decreases in liver X receptor-alpha (LXR-alpha) (-5.94-fold), a protective lipoprotein metabolism gene, and in peroxisome proliferator-activated receptor-alpha (PPAR-alpha) (-7.58-fold), a protective anti-inflammatory and lipid modulating gene, were observed in lesional versus healthy skin (p < 0.001 each). Serum analyses revealed that MCP-1 (502 vs. 141 pg/mL) and MDC (1240 vs. 409 pg/mL) levels were significantly elevated in psoriasis compared with healthy controls (p < 0.001 each). Dysregulated lipid metabolism was also evident in the serum, as Apo-A1, a protein product related to PPAR-alpha activation, was significantly decreased in patients with psoriasis compared with healthy controls (25.2 vs. 38.9 mg/dL; p < 0.001). Conclusions: Analyses of targeted genes and their products known to be associated with ASCVD revealed dysregulation of inflammatory (MCP-1 and MDC) and lipid metabolism (LXR-alpha, PPAR-alpha) genes in psoriasis. These findings provide evidence of a potential shared pathophysiology linking psoriasis to cardiometabolic diseases. C1 [Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, Bethesda, MD 20892 USA. [Li, Katherine; Szapary, Philippe; Brodmerkel, Carrie] Janssen Res & Dev LLC, Spring House, PA USA. [Krueger, James] Rockefeller Univ, New York, NY 10021 USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometab Dis, Bldg 10, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov FU Janssen Research & Development, LLC; Rockefeller Institute from Janssen FX This study was funded by Janssen Research & Development, LLC. N. Mehta has no conflicts of interest. K. Li, P. Szapary, and C. Brodmerkel are employees of Janssen Research & Development, LLC, and own stock in Johnson & Johnson, of which Janssen is a subsidiary. J. Krueger has received research grants on behalf of Rockefeller Institute from Janssen (formerly Centocor), honoraria from Janssen (Centocor), and has served as a consultant/advisory board member for Janssen (Centocor) and Amgen. NR 23 TC 13 Z9 13 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 22 PY 2013 VL 11 AR 194 DI 10.1186/1479-5876-11-194 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 209LN UT WOS:000323758500001 PM 23965158 ER PT J AU Abate-Daga, D Hanada, K Davis, JL Yang, JC Rosenberg, SA Morgan, RA AF Abate-Daga, Daniel Hanada, Ken-ichi Davis, Jeremy L. Yang, James C. Rosenberg, Steven A. Morgan, Richard A. TI Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes SO BLOOD LA English DT Article ID HERPESVIRUS ENTRY MEDIATOR; CANCER REGRESSION; TRANSFER IMMUNOTHERAPY; MELANOMA PATIENTS; GENE-THERAPY; SOLID TUMORS; EXHAUSTION; MOLECULES; ANTIGEN; SAFETY AB Despite significant progress in the development of adoptive cell-transfer therapies (ACTs) using gene-engineered T cells, little is known about the fate of cells following infusion. To address that, we performed a comparative analysis of gene expression between T-cell receptor-engineered lymphocytes persisting in the circulation 1 month after administration and the product that was infused. We observed that 156 genes related to immune function were differentially expressed, including underexpression of stimulators of lymphocyte function and overexpression of inhibitory genes in postinfusion cells. Of genes overexpressed postinfusion, the product of programmed cell death 1 (PDCD1), coinhibitory receptor PD-1, was expressed at a higher percentage in postinfusion lymphocytes than in the infusion product. This was associated with a higher sensitivity to inhibition of cytokine production by interaction with its ligand PD-L1. Coinhibitory receptor CD160 was also overexpressed in persisting cells, and its expression was associated with decreased reactivity, which surprisingly was found to be ligand-independent. These results contribute to a deeper understanding of the properties of transgenic lymphocytes used to treat human malignancies and may provide a rationale for the development of combination therapies as a method to improve ACT. This trial was registered at www.clinicaltrials.gov as #NCT00509288, #NCT00923195, and #NCT01273181. C1 [Abate-Daga, Daniel; Hanada, Ken-ichi; Davis, Jeremy L.; Yang, James C.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, CRC, Bldg 10,Room 3W-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 FU National Cancer Institute, Center for Cancer Research, National Institutes of Health (Bethesda, MD) FX This work was supported by the intramural program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health (Bethesda, MD). NR 49 TC 23 Z9 24 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 22 PY 2013 VL 122 IS 8 BP 1399 EP 1410 DI 10.1182/blood-2013-04-495531 PG 12 WC Hematology SC Hematology GA 204UD UT WOS:000323394300017 PM 23861247 ER PT J AU Chun, JH Telu, S Lu, SY Pike, VW AF Chun, Joong-Hyun Telu, Sanjay Lu, Shuiyu Pike, Victor W. TI Radiofluorination of diaryliodonium tosylates under aqueous-organic and cryptand-free conditions SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DRUG DEVELOPMENT; SALTS; FLUORIDATION; PET; SELECTIVITY; REACTIVITY; SOLVATION; CHEMISTRY; HYDRATION AB Positron emission tomography (PET) has growing importance as a molecular imaging technique in clinical research and drug development. Methods for producing PET radiotracers utilizing cyclotron-produced [F-18]fluoride ion (t(1/2) = 109.7 min) without the need for complete removal of irradiated target [O-18]-water and addition of cryptand are keenly sought for practical convenience and efficiency. Several structurally diverse diaryliodonium tosylates, XArl(+)Ar'Y TsO- (X = H or p-MeO), were investigated in a microfluidic apparatus for their reactivity towards radiofluorination with high specific activity (no-carrier-added) [F-18]fluoride ion in mixtures of DMF and irradiated target [O-18]water in the absence of cryptand. Salts bearing a para or ortho electron-withdrawing group Y (e.g., Y = p-CN) reacted rapidly (similar to 3 min) to give the expected major [F-18]fluoroarene product, [F-18]FArY, in useful moderate radiochemical yields even when the solvent had an [O-18]water content up to 28%. Salts bearing electron-withdrawing groups in meta position (e.g., Y = m-NO2), or an electron-donating substituent (Y = p-OMe), gave low radiochemical yields under the same conditions. C1 [Chun, Joong-Hyun; Telu, Sanjay; Lu, Shuiyu; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Lu, SY (reprint author), NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM Shuiyu.Lu@mail.nih.gov OI Lu, Shuiyu/0000-0003-0310-4318 FU Intramural Research Program of the National Institutes of Health (NIMH) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIMH). The authors are grateful to the NIH Clinical Center PET Department (Chief, Dr Peter Herscovitch) for the cyclotron production of fluorine-18. NR 40 TC 22 Z9 22 U1 1 U2 19 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 EI 1477-0539 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PD AUG 21 PY 2013 VL 11 IS 31 BP 5094 EP 5099 DI 10.1039/c3ob40742j PG 6 WC Chemistry, Organic SC Chemistry GA 197MM UT WOS:000322855300007 PM 23804017 ER PT J AU Horino, S Uchiyama, T So, T Nagashima, H Sun, S Sato, M Asao, A Haji, Y Sasahara, Y Candotti, F Tsuchiya, S Kure, S Sugamura, K Ishii, N AF Horino, Satoshi Uchiyama, Toru So, Takanori Nagashima, Hiroyuki Sun, Shu-lan Sato, Miki Asao, Atsuko Haji, Yoichi Sasahara, Yoji Candotti, Fabio Tsuchiya, Shigeru Kure, Shigeo Sugamura, Kazuo Ishii, Naoto TI Gene Therapy Model of X-linked Severe Combined Immunodeficiency Using a Modified Foamy Virus Vector SO PLOS ONE LA English DT Article ID INTERLEUKIN-2-RECEPTOR GAMMA-CHAIN; TRANSCRIPTION START REGIONS; MOUSE MODEL; LONG-TERM; HEMATOPOIETIC-CELLS; REPOPULATING CELLS; RETROVIRAL VECTORS; STEM-CELLS; INTEGRATION; TRANSDUCTION AB X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor gamma chain (gamma c) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene therapy for SCID-X1 using conventional retroviral (RV) vectors carrying the gamma c gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV) vector expressing human gamma c. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from gamma c-knockout (gamma c-KO) mice were infected with the FV vector and transplanted into gamma c-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID-X1. C1 [Horino, Satoshi; So, Takanori; Nagashima, Hiroyuki; Sun, Shu-lan; Asao, Atsuko; Haji, Yoichi; Ishii, Naoto] Tohoku Univ, Dept Microbiol & Immunol, Grad Sch Med, Sendai, Miyagi 980, Japan. [Horino, Satoshi; Uchiyama, Toru; Sato, Miki; Haji, Yoichi; Tsuchiya, Shigeru; Kure, Shigeo] Tohoku Univ, Dept Pediat, Grad Sch Med, Sendai, Miyagi 980, Japan. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Sugamura, Kazuo] Miyagi Canc Ctr, Natori, Miyagi 9811293, Japan. RP Ishii, N (reprint author), Tohoku Univ, Dept Microbiol & Immunol, Grad Sch Med, Sendai, Miyagi 980, Japan. EM ishiin@med.tohoku.ac.jp OI So, Takanori/0000-0003-3004-8526 FU Ministry of Education, Science, Sports and Culture of Japan [24659487, 24390118]; Japan Society for the Promotion of Science; Japan Science and Technology Agency [111020001010004100] FX This study was supported in part by a grant-in-aid (#24659487 and #24390118) for scientific research on priority areas from the Ministry of Education, Science, Sports and Culture of Japan, a grant-in-aid for scientific research on priority areas from the Japan Society for the Promotion of Science, and grants (#111020001010004100) from the Japan Science and Technology Agency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 36 TC 1 Z9 1 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 21 PY 2013 VL 8 IS 8 AR e71594 DI 10.1371/journal.pone.0071594 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218YW UT WOS:000324470100048 PM 23990961 ER PT J AU Mangus, CW Massey, PR Fowler, DH Amarnath, S AF Mangus, Courtney W. Massey, Paul R. Fowler, Daniel H. Amarnath, Shoba TI Rapamycin Resistant Murine Th9 Cells Have a Stable In Vivo Phenotype and Inhibit Graft-Versus-Host Reactivity SO PLOS ONE LA English DT Article ID EFFECTOR T-CELLS; PROMOTES; REJECTION; INFLAMMATION; INDUCTION; AUTOPHAGY; TH1/TC1; THERAPY; DISEASE; ASTHMA AB The cytokine micro-environment can direct murine CD4(+) T cells towards various differentiation lineages such as Th1, Th2 and Tregs even in the presence of rapamycin, which results in T cells that mediate increased in vivo effects. Recently, a new lineage of T cells known as Th9 cells that secrete increased IL-9 have been described. However, it is not known whether Th9 differentiation occurs in the presence of rapamycin or whether adoptively transferred donor Th9 cells would augment or restrict alloreactivity after experimental bone marrow transplantation. We found that CD4(+) T cells that were co-stimulated and polarized with TGF-beta and IL-4 in the presence or absence of rapamycin each yielded effector cells of Th9 phenotype that secreted increased IL-9 and expressed a transcription factor profile characteristic of both Th9 and Th2 cells (high GATA-3/low T-bet). Augmentation of T cell replete allografts with manufactured rapamycin resistant Th9 cells markedly reduced both CD4(+) and CD8(+) T cell engraftment and strongly inhibited allo-specific T cell secretion of IFN-gamma. The potency of Th9 cell inhibition of alloreactivity was similar to that of rapamycin resistant Th2 cells. Importantly, rapamycin resistant Th9 cells persisted and maintained their cytokine phenotype, thereby indicating limited differentiation plasticity of the Th9 subset. As such, Th9 differentiation proceeds in the presence of rapamycin to generate a cell therapy product that maintains high IL-9 expression in vivo while inhibiting IFN-gamma driven alloreactivity. C1 [Mangus, Courtney W.; Massey, Paul R.; Fowler, Daniel H.; Amarnath, Shoba] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Mangus, Courtney W.] NIH, Howard Hughes Med Inst, Res Scholars Program, Chevy Chase, MD USA. RP Amarnath, S (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM samarnath@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, Intramural Research Program; Howard Hughes Research Scholars Program FX This work was supported by the Center for Cancer Research, National Cancer Institute, Intramural Research Program and by the Howard Hughes Research Scholars Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 1 Z9 2 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 21 PY 2013 VL 8 IS 8 AR e72305 DI 10.1371/journal.pone.0072305 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218YW UT WOS:000324470100097 PM 23991087 ER PT J AU Ozomaro, U Cai, GQ Kajiwara, Y Yoon, S Makarov, V Delorme, R Betancur, C Ruhrmann, S Falkai, P Grabe, HJ Maier, W Wagner, M Lennertz, L Moessner, R Murphy, DL Buxbaum, JD Zuchner, S Grice, DE AF Ozomaro, Uzoezi Cai, Guiqing Kajiwara, Yuji Yoon, Seungtai Makarov, Vladimir Delorme, Richard Betancur, Catalina Ruhrmann, Stephan Falkai, Peter Grabe, Hans Joergen Maier, Wolfgang Wagner, Michael Lennertz, Leonhard Moessner, Rainald Murphy, Dennis L. Buxbaum, Joseph D. Zuechner, Stephan Grice, Dorothy E. TI Characterization of SLITRK1 Variation in Obsessive-Compulsive Disorder SO PLOS ONE LA English DT Article ID LA-TOURETTE-SYNDROME; NEURITE OUTGROWTH; ITALIAN FAMILY; ASSOCIATION; GENE; VARIANTS; VAR321 AB Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P<0.05). In addition, we showed the the N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth in this assay. These important functional differences in the N400I variant, as compared to the wildtype SLITRK1 sequence, may contribute to OCD and OC spectrum symptoms. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Examination of additional samples will help assess the role of rare SLITRK1 variation in OCD and in related psychiatric illness. C1 [Ozomaro, Uzoezi; Zuechner, Stephan] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Ozomaro, Uzoezi] Univ Miami, Miller Sch Med, Dept Neurosci, Miami, FL 33136 USA. [Cai, Guiqing; Kajiwara, Yuji; Yoon, Seungtai; Makarov, Vladimir; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, Seaver Autism Ctr Res & Treatment, New York, NY USA. [Cai, Guiqing; Kajiwara, Yuji; Yoon, Seungtai; Makarov, Vladimir; Buxbaum, Joseph D.; Grice, Dorothy E.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY USA. [Delorme, Richard] Hop Robert Debre, Child Psychiat Dept, F-75019 Paris, France. [Delorme, Richard] Inst Pasteur, Paris, France. [Betancur, Catalina] CNRS, INSERM, U952, UMR 7224, Paris, France. [Betancur, Catalina] Univ Paris 06, Paris, France. [Ruhrmann, Stephan] Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Falkai, Peter] Univ Homburg, Dept Psychiat & Psychotherapy, Homburg, Germany. [Grabe, Hans Joergen] Ernst Moritz Arndt Univ Greifswald, Dept Psychiat & Psychotherapy, Stralsund, Germany. [Maier, Wolfgang; Wagner, Michael; Lennertz, Leonhard; Moessner, Rainald] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. [Murphy, Dennis L.] NIMH, Clin Sci Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Grice, Dorothy E.] Icahn Sch Med Mt Sinai, Div Tics Obsess Compuls & Related Disorders, Dept Psychiat, New York, NY USA. RP Grice, DE (reprint author), Icahn Sch Med Mt Sinai, Div Tics Obsess Compuls & Related Disorders, Dept Psychiat, New York, NY USA. EM Dorothy.grice@mssm.edu RI Wagner, Michael/E-2325-2011; OI Wagner, Michael/0000-0003-2589-6440; Buxbaum, Joseph/0000-0001-8898-8313; Betancur, Catalina/0000-0002-3327-4804 FU National Institutes of Health under Ruth L. Kirschstein National Research Service Award [F31MH086275]; Lois Pope LIFE Fellowship; Beatrice and Samuel A. Seaver Foundation; New Jersey Center for Tourette Syndrome and Associated Disorders; National Tourette Syndrome Association; German Research Foundation DFG [Fa 731/6]; Fondamental Foundation, Creteil, France FX This work was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award (UO; F31MH086275), the Lois Pope LIFE Fellowship (UO), the Beatrice and Samuel A. Seaver Foundation (JDB), and the New Jersey Center for Tourette Syndrome and Associated Disorders and the National Tourette Syndrome Association (DEG), the German Research Foundation DFG (PF, MW, WM, HJG, grant Fa 731/6) and Fondamental Foundation, Creteil, France (R.D). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 9 Z9 10 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 21 PY 2013 VL 8 IS 8 AR e70376 DI 10.1371/journal.pone.0070376 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218YW UT WOS:000324470100023 PM 23990902 ER PT J AU Song, XH Lopez-Campistrous, A Sun, L Dower, NA Kedei, N Yang, J Kelsey, JS Lewin, NE Esch, TE Blumberg, PM Stone, JC AF Song, Xiaohua Lopez-Campistrous, Ana Sun, Lucy Dower, Nancy A. Kedei, Noemi Yang, Jing Kelsey, Jessica S. Lewin, Nancy E. Esch, Tim E. Blumberg, Peter M. Stone, James C. TI RasGRPs Are Targets of the Anti-Cancer Agent Ingenol-3-Angelate SO PLOS ONE LA English DT Article ID PROTEIN-KINASE-C; NUCLEOTIDE-RELEASING PROTEIN; DIACYLGLYCEROL-BINDING MOTIFS; PHORBOL ESTERS; SIGNALING PATHWAY; INDUCED APOPTOSIS; CELL DEVELOPMENT; RAS ACTIVATION; B-CELLS; DELTA AB Ingenol-3-angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG) analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP's C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKCd. I3A treatment of select B non-Hodgkin's lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation. C1 [Song, Xiaohua; Lopez-Campistrous, Ana; Sun, Lucy; Stone, James C.] Univ Alberta, Dept Biochem, Edmonton, AB, Canada. [Dower, Nancy A.] Univ Alberta, Dept Pediat, Edmonton, AB, Canada. [Kedei, Noemi; Yang, Jing; Kelsey, Jessica S.; Lewin, Nancy E.; Esch, Tim E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Stone, JC (reprint author), Univ Alberta, Dept Biochem, Edmonton, AB, Canada. EM jim.stone@ualberta.ca FU Canadian Institutes of Health Research (CIHR) [MOP14630]; Canadian Cancer Society Research Institute (CCSRI) [018453]; Alberta Cancer Foundation (ACF) [26050]; Alberta Ingenuity-Health Solutions [200100408]; Center for Cancer Research, National Cancer Institute, National Institutes of Health [Z1A BC 005270] FX Research was supported by grants to JCS from the Canadian Institutes of Health Research (CIHR grant MOP14630, http://www.cihr-irsc.gc.ca), Canadian Cancer Society Research Institute (CCSRI grant 018453, http://www.cancer.ca/Research.aspx), Alberta Cancer Foundation (ACF grant 26050, http://albertacancer.ca), and Alberta Ingenuity-Health Solutions (200100408 http://www.aihealthsolutions.ca). Research was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (Project Z1A BC 005270). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 7 Z9 7 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 21 PY 2013 VL 8 IS 8 AR e72331 DI 10.1371/journal.pone.0072331 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218YW UT WOS:000324470100100 PM 23991094 ER PT J AU Sun, W Park, YD Sugui, JA Fothergill, A Southall, N Shinn, P McKew, JC Kwon-Chung, KJ Zheng, W Williamson, PR AF Sun, Wei Park, Yoon-Dong Sugui, Janyce A. Fothergill, Annette Southall, Noel Shinn, Paul McKew, John C. Kwon-Chung, Kyung J. Zheng, Wei Williamson, Peter R. TI Rapid Identification of Antifungal Compounds against Exserohilum rostratum Using High Throughput Drug Repurposing Screens SO PLOS ONE LA English DT Article ID CONTAMINATED METHYLPREDNISOLONE; SERINE PALMITOYLTRANSFERASE; PHENYLMERCURIC BORATE; ESCHERICHIA-COLI; IN-VITRO; MECHANISM; INHIBITION; LOCALIZATION; INJECTIONS; MENINGITIS AB A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens. C1 [Sun, Wei; Southall, Noel; Shinn, Paul; McKew, John C.; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Park, Yoon-Dong; Sugui, Janyce A.; Kwon-Chung, Kyung J.; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Fothergill, Annette] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Williamson, Peter R.] Univ Illinois, Coll Med, Sect Infect Dis Immunol & Int Med, Chicago, IL USA. RP Zheng, W (reprint author), NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov; williamsonpr@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Program of the National Center for Advancing Translational Sciences; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Center for Advancing Translational Sciences and National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 7 Z9 7 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 21 PY 2013 VL 8 IS 8 AR e70506 DI 10.1371/journal.pone.0070506 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218YW UT WOS:000324470100027 PM 23990907 ER PT J AU Briggs, JP Killen, J AF Briggs, Josephine P. Killen, Jack TI Perspectives on Complementary and Alternative Medicine Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Briggs, Josephine P.; Killen, Jack] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Briggs, JP (reprint author), Natl Ctr Complementary & Alternat Med, 31 Ctr Dr,Bldg 31,Ste 2B11, Bethesda, MD 20814 USA. EM briggsj@mail.nih.gov NR 7 TC 6 Z9 6 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 21 PY 2013 VL 310 IS 7 BP 691 EP 692 DI 10.1001/jama.2013.6540 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 202XP UT WOS:000323254500015 PM 23990064 ER PT J AU Feenstra, B Geller, F Carstensen, L Romitti, PA Korberg, IB Bedell, B Krogh, C Fan, RZ Svenningsson, A Caggana, M Nordenskjold, A Mills, JL Murray, JC Melbye, M AF Feenstra, Bjarke Geller, Frank Carstensen, Lisbeth Romitti, Paul A. Korberg, Izabella Baranowska Bedell, Bruce Krogh, Camilla Fan, Ruzong Svenningsson, Anna Caggana, Michele Nordenskjold, Agneta Mills, James L. Murray, Jeffrey C. Melbye, Mads TI Plasma Lipids, Genetic Variants Near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GENOME-WIDE ASSOCIATION; LEMLI-OPITZ-SYNDROME; INTERSTITIAL-CELLS; CHOLESTEROL; METAANALYSIS; CAJAL; EPIDEMIOLOGY; OUTGROWTH; NERVES; COHORT AB IMPORTANCE Infantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited. OBJECTIVES To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets. DESIGN, SETTING, AND PARTICIPANTS During stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease-free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998-2005), with a total of 1663 cases and 2315 controls. MAIN OUTCOMES AND MEASURES Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis. RESULTS We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 x 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r(2) between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS. CONCLUSIONS AND RELEVANCE This study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation. C1 [Feenstra, Bjarke; Geller, Frank; Carstensen, Lisbeth; Krogh, Camilla; Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. [Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Korberg, Izabella Baranowska; Svenningsson, Anna; Nordenskjold, Agneta] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden. [Korberg, Izabella Baranowska; Svenningsson, Anna; Nordenskjold, Agneta] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden. [Bedell, Bruce; Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Fan, Ruzong; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Caggana, Michele] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12237 USA. RP Feenstra, B (reprint author), Statens Serum Inst, Dept Epidemiol Res, Artillerivej 5, DK-2300 Copenhagen S, Denmark. EM fee@ssi.dk OI Nordenskjold, Agneta/0000-0001-6638-4631; Feenstra, Bjarke/0000-0003-1478-649X FU Lundbeck Foundation [R34-A3931]; Novo Nordisk Foundation; Danish Medical Research Council [271-06-0628]; Swedish Research Council; Centers for Disease Control and Prevention [5U01DD000492]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health Genes, Environment, and Health Initiative [U01HG004423]; Oak Foundation Fellowship FX The study was supported by grants from the Lundbeck Foundation (R34-A3931), the Novo Nordisk Foundation, the Danish Medical Research Council (271-06-0628), the Swedish Research Council, the Centers for Disease Control and Prevention (5U01DD000492), and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The GWAS data for the control samples were generated for our study of preterm birth within the GENEVA consortium with funding provided through the National Institutes of Health Genes, Environment, and Health Initiative (U01HG004423). Dr Feenstra is supported by an Oak Foundation Fellowship. NR 42 TC 7 Z9 7 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 21 PY 2013 VL 310 IS 7 BP 714 EP 721 DI 10.1001/jama.2013.242978 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 202XP UT WOS:000323254500021 PM 23989729 ER PT J AU Mascia, F Lam, G Keith, C Garber, C Steinberg, SM Kohn, E Yuspa, SH AF Mascia, Francesca Lam, Gary Keith, Christopher Garber, Caroline Steinberg, Seth M. Kohn, Elise Yuspa, Stuart H. TI Genetic Ablation of Epidermal EGFR Reveals the Dynamic Origin of Adverse Effects of Anti-EGFR Therapy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; HAIR FOLLICLE; CHEMOKINE EXPRESSION; TARGETED DISRUPTION; SKIN INFLAMMATION; MICE; CANCER; DIFFERENTIATION; GEFITINIB AB Cancer patients treated with anti-EGFR (epidermal growth factor receptor) drugs often develop a dose-limiting pruritic rash of unknown etiology. The aims of our study were to define causal associations from a clinical study of cutaneous and systemic changes in patients treated with gefitinib and use these to develop and characterize a mouse model that recapitulates the human skin rash syndrome caused by anti-EGFR therapy. We examined the patients' plasma before and after treatment with gefitinib and documented changes in chemokines and leukocyte counts associated with the extent of rash or the presence of pruritus. We established a parallel mouse model by ablating EGFR in the epidermis. These mice developed skin lesions similar to the human rash. Before lesion development, we detected increased mRNA expression of chemokines in the skin associated with early infiltration of macrophages and mast cells and later infiltration of eosinophils, T cells, and neutrophils. As the skin phenotype evolved, changes in blood counts and circulating chemokines reproduced those seen in the gefitinib-treated patients. Crossing the mutant mice with mice deficient for tumor necrosis factor-alpha (TNF-alpha) receptors, MyD88, NOS2, CCR2, T cells, or B cells failed to reverse the skin phenotype. However, local depletion of macrophages provided partial resolution, suggesting that this model can identify targets that may be effective in preventing the troublesome and dose-limiting skin response to anti-EGFR drugs. These results highlight the importance of EGFR signaling in maintaining skin immune homeostasis and identify a macrophage contribution to a serious adverse consequence of cancer chemotherapy. C1 [Mascia, Francesca; Lam, Gary; Keith, Christopher; Garber, Caroline; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20852 USA. [Kohn, Elise] NCI, Mol Signaling Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov FU Center for Cancer Research Intramural Program of the NIH FX This work was supported by the Center for Cancer Research Intramural Program of the NIH. NR 39 TC 7 Z9 7 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 21 PY 2013 VL 5 IS 199 AR 200ra116 DI 10.1126/scitranslmed.3006504 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 205DT UT WOS:000323422600008 ER PT J AU Bender, JLG Lee, A Reid, JM Baruchel, S Roberts, T Voss, SD Wu, B Ahern, CH Ingle, AM Harris, P Weigel, BJ Blaney, SM AF Bender, Julia L. Glade Lee, Alice Reid, Joel M. Baruchel, Sylvain Roberts, Timothy Voss, Stephan D. Wu, Bing Ahern, Charlotte H. Ingle, Ashish M. Harris, Pamela Weigel, Brenda J. Blaney, Susan M. TI Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MULTIKINASE ANGIOGENESIS INHIBITOR; CANCER-PATIENTS; PEDIATRIC-PATIENTS; COLORECTAL-CANCER; KINASE INHIBITOR; ORAL PAZOPANIB; TRIAL; BIOMARKER; HYPERTENSION; SUNITINIB AB Purpose Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Patients and Methods Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 +/- 2 days after initiation of pazopanib at the tablet MTD. Results Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for >= six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Conclusion Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma. (C) 2013 by American Society of Clinical Oncology C1 [Bender, Julia L. Glade; Lee, Alice] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Reid, Joel M.] Mayo Clin, Ctr Canc, Rochester, MN USA. [Weigel, Brenda J.] Univ Minnesota, Amplatz Childrens Hosp, Minneapolis, MN USA. [Roberts, Timothy] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Voss, Stephan D.] Boston Childrens Hosp, Boston, MA USA. [Ahern, Charlotte H.; Blaney, Susan M.] Texas Childrens Canc Ctr, Houston, TX USA. [Ingle, Ashish M.] Childrens Oncol Grp, Operat Ctr, Arcadia, CA USA. [Harris, Pamela] NCI, Canc Treatment Expt Program, Bethesda, MD 20892 USA. [Baruchel, Sylvain; Wu, Bing] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. RP Bender, JLG (reprint author), Columbia Univ, Div Pediat Oncol, 161 Ft Washington Ave,IP-7, New York, NY 10032 USA. EM Jg589@columbia.edu FU Alex's Lemonade Stand Foundation; Columbia University's Clinical and Translational Science Awards [UL1RR024156]; GlaxoSmithKline; Phase I/Pilot Consortium Grant of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD [U01 CA97452] FX Supported in part by Alex's Lemonade Stand Foundation, Columbia University's Clinical and Translational Science Awards Grant No. UL1RR024156, GlaxoSmithKline, and the Phase I/Pilot Consortium Grant No. U01 CA97452 of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 29 TC 30 Z9 32 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2013 VL 31 IS 24 BP 3034 EP U88 DI 10.1200/JCO.2012.47.0914 PG 15 WC Oncology SC Oncology GA 301NW UT WOS:000330540000016 ER PT J AU Xue, L Cai, JY Ma, J Huang, Z Guo, MX Fu, LZ Shi, YB Li, WX AF Xue, Lu Cai, Jin-Yang Ma, Jian Huang, Zan Guo, Ming-Xiong Fu, Lie-Zhen Shi, Yun-Bo Li, Wen-Xin TI Global expression profiling reveals genetic programs underlying the developmental divergence between mouse and human embryogenesis SO BMC GENOMICS LA English DT Article DE Microarray; Mouse embryogenesis; Human embryogenesis; Organogenesis; Evolution; Protein interaction network ID HUMAN PREIMPLANTATION DEVELOPMENT; EMBRYONIC STEM-CELLS; INTERACTION NETWORKS; TRANSCRIPTOME ANALYSIS; CDNA MICROARRAY; HUMAN OOCYTES; GENOME-WIDE; BLASTOCYST; ORGANOGENESIS; GASTRULATION AB Background: Mouse has served as an excellent model for studying human development and diseases due to its similarity to human. Advances in transgenic and knockout studies in mouse have dramatically strengthened the use of this model and significantly improved our understanding of gene function during development in the past few decades. More recently, global gene expression analyses have revealed novel features in early embryogenesis up to gastrulation stages and have indeed provided molecular evidence supporting the conservation in early development in human and mouse. On the other hand, little information is known about the gene regulatory networks governing the subsequent organogenesis. Importantly, mouse and human development diverges during organogenesis. For instance, the mouse embryo is born around the end of organogenesis while in human the subsequent fetal period of ongoing growth and maturation of most organs spans more than 2/3 of human embryogenesis. While two recent studies reported the gene expression profiles during human organogenesis, no global gene expression analysis had been done for mouse organogenesis. Results: Here we report a detailed analysis of the global gene expression profiles from egg to the end of organogenesis in mouse. Our studies have revealed distinct temporal regulation patterns for genes belonging to different functional (Gene Ontology or GO) categories that support their roles during organogenesis. More importantly, comparative analyses identify both conserved and divergent gene regulation programs in mouse and human organogenesis, with the latter likely responsible for the developmental divergence between the two species, and further suggest a novel developmental strategy during vertebrate evolution. Conclusions: We have reported here the first genome-wide gene expression analysis of the entire mouse embryogenesis and compared the transcriptome atlas during mouse and human embryogenesis. Given our earlier observation that genes function in a given process tends to be developmentally co-regulated during organogenesis, our microarray data here should help to identify genes associated with mouse development and/or infer the developmental functions of unknown genes. In addition, our study might be useful for invesgtigating the molecular basis of vertebrate evolution. C1 [Xue, Lu; Cai, Jin-Yang; Ma, Jian; Huang, Zan; Guo, Ming-Xiong; Li, Wen-Xin] Wuhan Univ, Coll Life Sci, Wuhan 430072, Peoples R China. [Xue, Lu] South Cent Univ Nationalities, Coll Life Sci, Inst Med Biol, Wuhan 430074, Peoples R China. [Fu, Lie-Zhen; Shi, Yun-Bo] NICHD, Sect Mol Morphogenesis, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, Sect Mol Morphogenesis, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM shi@helix.nih.gov; liwxlab@whu.edu.cn FU National High Technology Research and Development Program of China (863 Program) [2006AA02A306]; National Natural Science Foundation of China [31271511, 31101047, 81070406]; Research Fund for the Doctoral Program of Higher Education of China [20110141110016]; Intramural Research Program of NICHD, National Institutes of Health FX We would like to thank Drs. Yu Song, zhongjie Li, Yi Lin, Haiming Hu, Wei Wang for helpful assistance and contributions in the preparation of this manuscript. We thank all the teachers and students from the lab of Virology and Molecular Oncology for their discussions and comments that improved the manuscript. This work was supported by National High Technology Research and Development Program of China (863 Program) Grant 2006AA02A306, National Natural Science Foundation of China Grant 31271511, 31101047 and 81070406, Research Fund for the Doctoral Program of Higher Education of China Grant 20110141110016. YBS and LF were supported by the Intramural Research Program of NICHD, National Institutes of Health. NR 59 TC 5 Z9 5 U1 3 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 20 PY 2013 VL 14 AR 568 DI 10.1186/1471-2164-14-568 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 274SC UT WOS:000328625500001 PM 23961710 ER PT J AU Mihaescu, R Pencina, MJ Alonso, A Lunetta, KL Heckbert, SR Benjamin, EJ Janssens, ACJW AF Mihaescu, Raluca Pencina, Michael J. Alonso, Alvaro Lunetta, Kathryn L. Heckbert, Susan R. Benjamin, Emelia J. Janssens, A. Cecile J. W. TI Incremental value of rare genetic variants for the prediction of multifactorial diseases SO GENOME MEDICINE LA English DT Article ID ATRIAL-FIBRILLATION; ATHEROSCLEROSIS RISK; COMPLEX DISEASES; COMMON; SUSCEPTIBILITY; IDENTIFICATION; PERFORMANCE; BIOMARKERS; COMMUNITY; DESIGN AB Background: It is often assumed that rare genetic variants will improve available risk prediction scores. We aimed to estimate the added predictive ability of rare variants for risk prediction of common diseases in hypothetical scenarios. Methods: In simulated data, we constructed risk models with an area under the ROC curve (AUC) ranging between 0.50 and 0.95, to which we added a single variant representing the cumulative frequency and effect (odds ratio, OR) of multiple rare variants. The frequency of the rare variant ranged between 0.0001 and 0.01 and the OR between 2 and 10. We assessed the resulting AUC, increment in AUC, integrated discrimination improvement (IDI), net reclassification improvement (NRI(>0.01)) and categorical NRI. The analyses were illustrated by a simulation of atrial fibrillation risk prediction based on a published clinical risk model. Results: We observed minimal improvement in AUC with the addition of rare variants. All measures increased with the frequency and OR of the variant, but maximum increment in AUC remained below 0.05. Increment in AUC and NRI(>0.01) decreased with higher AUC of the baseline model, whereas IDI remained constant. In the atrial fibrillation example, the maximum increment in AUC was 0.02 for a variant with frequency = 0.01 and OR = 10. IDI and NRI showed at most minimal increase for variants with frequency greater than or equal to 0.005 and OR greater than or equal to 5. Conclusions: Since rare variants are present in only a minority of affected individuals, their predictive ability is generally low at the population level. To improve the predictive ability of clinical risk models for complex diseases, genetic variants must be common and have substantial effect on disease risk. C1 [Mihaescu, Raluca; Janssens, A. Cecile J. W.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Pencina, Michael J.; Lunetta, Kathryn L.] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Pencina, Michael J.] Harvard Clin Res Inst, Boston, MA 02215 USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Lunetta, Kathryn L.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol & Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Janssens, A. Cecile J. W.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Janssens, ACJW (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Dr Molewaterpl 50, NL-3000 CA Rotterdam, Netherlands. EM cecile.janssens@emory.edu RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Janssens, A Cecile/0000-0002-6153-4976; Benjamin, Emelia/0000-0003-4076-2336 FU Netherlands Organization for Scientific Research; Centre for Medical Systems Biology in the framework of the Netherlands Genomics Initiative; Erasmus Trustfonds; National Institutes of Health/American Recovery and Reinvestment Act Risk Prediction of Atrial Fibrillation [1RC1HL101056]; National Institutes of Health/National Heart, Lung, and Blood Institute [RC1HL099452, HL068986, HL092577, HL080295, 1R01HL102214, N01-HC 25195]; American Heart Association [09SDG2280087] FX This work was supported by the Netherlands Organization for Scientific Research (Vidi grant to ACJWJ); Centre for Medical Systems Biology in the framework of the Netherlands Genomics Initiative (to ACJWJ); Erasmus Trustfonds (to RM); National Institutes of Health/American Recovery and Reinvestment Act Risk Prediction of Atrial Fibrillation (1RC1HL101056 to MP and EJB); National Institutes of Health/National Heart, Lung, and Blood Institute (RC1HL099452 to AA; HL068986 to SRH; HL092577 to EJB, KLL, and SRH; HL080295 to SRH; 1R01HL102214 to EJB; N01-HC 25195 to EJB); and the American Heart Association (09SDG2280087 to AA). NR 41 TC 4 Z9 4 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD AUG 20 PY 2013 VL 5 AR 76 DI 10.1186/gm480 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 246OD UT WOS:000326547300001 PM 23961719 ER PT J AU Chen, Y Chatterjee, SS Porcella, SF Yu, YS Otto, M AF Chen, Yan Chatterjee, Som S. Porcella, Stephen F. Yu, Yun-Song Otto, Michael TI Complete Genome Sequence of a Panton-Valentine Leukocidin-Negative Community-Associated Methicillin-Resistant Staphylococcus aureus Strain of Sequence type 72 from Korea SO PLOS ONE LA English DT Article ID VIRULENCE DETERMINANTS; SOUTH-KOREA; MRSA; INFECTION; USA300; GENES AB In the past decade, community-associated (CA-) infections with methicillin-resistant Staphylococcus aureus (MRSA) have emerged throughout the world. Different CA-MRSA strains dominate in different geographical locations. Many CA-MRSA lineages contain genes coding for the Panton-Valentine leukocidin. However, the role of this leukotoxin in CA-MRSA pathogenesis is still controversial. The genome sequences of two key PVL-positive CA-MRSA strains (USA300, USA400) have been reported, but we lack information on the more recently found PVL-negative CA-MRSA strains. One such strain is the PVL-negative ST72, the main cause of CA-MRSA infections in Korea. Here, we report the entire genome sequence of CA-MRSA ST72 and analyze its gene content with a focus on virulence factors. Our results show that this strain does not have considerable differences in virulence factor content compared to other CA-MRSA strains (USA300, USA400), indicating that other toxins do not substitute for the lack of PVL in ST72. This finding is in accordance with the notion that differential expression of widespread virulence determinants, rather than the acquisition of additional virulence factors on mobile genetic elements, such as PVL, is responsible for the increased virulence of CA-compared to hospital-associated MRSA. C1 [Chen, Yan; Chatterjee, Som S.; Otto, Michael] Natl Inst Allergy & Infect Dis, US Natl Inst Hlth, Lab Human Bacterial Pathogenesis, Pathogen Mol Genet Sect, Bethesda, MD USA. [Chen, Yan; Yu, Yun-Song] Zhejiang Univ, Coll Med, Sir Run Run Shaw Hosp, Dept Infect Dis, Hangzhou 310027, Peoples R China. [Porcella, Stephen F.] Natl Inst Allergy & Infect Dis, US Natl Inst Hlth, Res Technol Branch, Genom Unit, Hamilton, MT USA. RP Otto, M (reprint author), Natl Inst Allergy & Infect Dis, US Natl Inst Hlth, Lab Human Bacterial Pathogenesis, Pathogen Mol Genet Sect, Bethesda, MD USA. EM motto@niaid.nih.gov OI Chen, Yan/0000-0002-7679-1713; Otto, Michael/0000-0002-2222-4115 FU Intramural Program of the NIAID [ZIA AI000904-12]; Ministry of Health of the People's Republic of China [201002021] FX Intramural Program of the NIAID (ZIA AI000904-12); Ministry of Health of the People's Republic of China (no. 201002021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 8 Z9 8 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 20 PY 2013 VL 8 IS 8 AR e72803 DI 10.1371/journal.pone.0072803 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219RU UT WOS:000324527300098 PM 23977354 ER PT J AU Kang, DW Luecke, HF AF Kang, Dong Wook Luecke, Hans F. TI Facile Synthetic Routes to Prepare alpha-Muricholic Acid, Hyocholic Acid, and Their Taurine Conjugates SO BULLETIN OF THE KOREAN CHEMICAL SOCIETY LA English DT Article DE Bile acids; alpha-Muricholic acid; Hyocholic acid; Taurine conjugates; Metabolites ID BILE-ACID; EFFICIENT SYNTHESIS; METABOLITES; PEPTIDE AB alpha-Muricholic acid was synthesized through 9 steps from chenodeoxycholic acid with 26% overall yield. Hyocholic acid was synthesized through 8 steps from the same starting material with 63% overall yield. Taurine conjugates of alpha-muricholic acid and hyocholic acid were also prepared via their pentafluorophenyl ester. C1 [Kang, Dong Wook] Catholic Univ Daegu, Dept Pharmaceut Sci & Technol, Kyeongsangbuk Do 712702, South Korea. [Luecke, Hans F.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kang, DW (reprint author), Catholic Univ Daegu, Dept Pharmaceut Sci & Technol, Kyeongsangbuk Do 712702, South Korea. EM dwkang@cu.ac.kr; lueckeh@mail.nih.gov FU National Institutes of Health Intramural Research Program (NIDDK); Catholic University of Daegu FX We are extremely grateful to Drs. Matsubara Tsutomu, and Jooyoun Cho for their kind discussion, support, and collaboration. This work was supported by the National Institutes of Health Intramural Research Program (NIDDK) and Catholic University of Daegu. NR 15 TC 0 Z9 1 U1 1 U2 6 PU KOREAN CHEMICAL SOC PI SEOUL PA 635-4 YEOGSAM-DONG, KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 0253-2964 EI 1229-5949 J9 B KOREAN CHEM SOC JI Bull. Korean Chem. Soc. PD AUG 20 PY 2013 VL 34 IS 8 BP 2436 EP 2440 DI 10.5012/bkcs.2013.34.8.2436 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 210SI UT WOS:000323854400040 ER PT J AU Bok, J Zenczak, C Hwang, CH Wu, DK AF Bok, Jinwoong Zenczak, Colleen Hwang, Chan Ho Wu, Doris K. TI Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE morphogenesis; Atoh1; tonotopy ID INNER-EAR DEVELOPMENT; FATE DETERMINATION; FOXG1; MICE; IDENTIFICATION; SPECIFICATION; MORPHOGENESIS; EXPRESSION; NEURONS; ORGAN AB Neural precursor cells of the central nervous system undergo successive temporal waves of terminal division, each of which is soon followed by the onset of cell differentiation. The organ of Corti in the mammalian cochlea develops differently, such that precursors at the apex are the first to exit from the cell cycle but the last to begin differentiating as mechanosensory hair cells. Using a tissue-specific knockout approach in mice, we show that this unique temporal pattern of sensory cell development requires that the adjacent auditory (spiral) ganglion serve as a source of the signaling molecule Sonic hedgehog (Shh). In the absence of this signaling, the cochlear duct is shortened, sensory hair cell precursors exit from the cell cycle prematurely, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction. The dynamic relationship between the restriction of Shh expression in the developing spiral ganglion and its proximity to regions of the growing cochlear duct dictates the timing of terminal mitosis of hair cell precursors and their subsequent differentiation. C1 [Bok, Jinwoong] Yonsei Univ, Coll Med, Dept Anat, Dept Otorhinolaryngol,Project Med Sci BK21, Seoul 120752, South Korea. [Zenczak, Colleen; Hwang, Chan Ho; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, Rockville, MD 20850 USA. RP Bok, J (reprint author), Yonsei Univ, Coll Med, Dept Anat, Dept Otorhinolaryngol,Project Med Sci BK21, Seoul 120752, South Korea. EM bokj@yuhs.ac; wud@nidcd.nih.gov RI Bok, Jinwoong/B-8982-2016 OI Bok, Jinwoong/0000-0003-1958-1872 FU National Research Foundation of Korea [2011-0028066, 2012R1A1A2041348]; National Institute on Deafness and Other Communication Disorders FX We thank Drs. Lisa Goodrich, Jane Johnson, and Susan McConnell for mice and Drs. Lisa Cunningham, Douglas Epstein, Thomas Friedman, Andrew Griffith, James Keller, and Steven Raft for critical reading of the manuscript. This work was supported by the National Research Foundation of Korea (Grants 2011-0028066 and 2012R1A1A2041348, to J.B.) and the National Institute on Deafness and Other Communication Disorders Intramural Program (D.K.W.). NR 30 TC 18 Z9 18 U1 0 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 20 PY 2013 VL 110 IS 34 BP 13869 EP 13874 DI 10.1073/pnas.1222341110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203DU UT WOS:000323271400049 PM 23918393 ER PT J AU Furness, DN Johnson, SL Manor, U Ruttiger, L Tocchetti, A Offenhauser, N Olt, J Goodyear, RJ Vijayakumar, S Dai, YH Hackney, CM Franz, C Di Fiore, PP Masetto, S Jones, SM Knipper, M Holley, MC Richardson, GP Kachar, B Marcotti, W AF Furness, David N. Johnson, Stuart L. Manor, Uri Ruettiger, Lukas Tocchetti, Arianna Offenhauser, Nina Olt, Jennifer Goodyear, Richard J. Vijayakumar, Sarath Dai, Yuhai Hackney, Carole M. Franz, Christoph Di Fiore, Pier Paolo Masetto, Sergio Jones, Sherri M. Knipper, Marlies Holley, Matthew C. Richardson, Guy P. Kachar, Bechara Marcotti, Walter TI Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE deafness; sensory system; ion channel ID CELL STEREOCILIA; MYOSIN-XVA; FILAMENTS; GROWTH; ESPIN; MAINTENANCE; ADAPTATION; ELONGATION; DEAFNESS; DEFECTS AB Mechanotransduction in the mammalian auditory system depends on mechanosensitive channels in the hair bundles that project from the apical surface of the sensory hair cells. Individual stereocilia within each bundle contain a core of tightly packed actin filaments, whose length is dynamically regulated during development and in the adult. We show that the actin-binding protein epidermal growth factor receptor pathway substrate 8 (Eps8)L2, a member of the Eps8-like protein family, is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells. It has a spatiotemporal expression pattern that complements that of Eps8. In the cochlea, whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays. In contrast to the early profound hearing loss associated with an absence of Eps8, Eps8L2 null-mutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology. We conclude that Eps8L2 is required for the long-term maintenance of the staircase structure and mechanosensory function of auditory hair bundles. It complements the developmental role of Eps8 and is a candidate gene for progressive age-related hearing loss. C1 [Furness, David N.] Keele Univ, Inst Sci & Technol Med, Keele ST5 5BG, Staffs, England. [Johnson, Stuart L.; Olt, Jennifer; Hackney, Carole M.; Holley, Matthew C.; Marcotti, Walter] Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England. [Manor, Uri; Dai, Yuhai; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Ruettiger, Lukas; Franz, Christoph; Knipper, Marlies] Univ Tubingen, Tubingen Hearing Res Ctr, Dept Otolaryngol, D-72076 Tubingen, Germany. [Tocchetti, Arianna; Offenhauser, Nina; Di Fiore, Pier Paolo] Fdn Ist FIRC Oncol Mol IFOM, I-20139 Milan, Italy. [Goodyear, Richard J.; Richardson, Guy P.] Univ Sussex, Sch Life Sci, Brighton BN1 9QG, E Sussex, England. [Vijayakumar, Sarath; Jones, Sherri M.] Univ Nebraska, Dept Special Educ & Commun Disorders, Lincoln, NE 68583 USA. [Di Fiore, Pier Paolo] Ist Europeo Oncol, I-20141 Milan, Italy. [Di Fiore, Pier Paolo] Univ Milan, Dipartimento Sci Salute, I-20122 Milan, Italy. [Masetto, Sergio] Univ Pavia, Dept Physiol & Pharmacol Sci, I-27100 Pavia, Italy. RP Marcotti, W (reprint author), Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England. EM w.marcotti@sheffield.ac.uk RI Di Fiore, Pier Paolo/K-2130-2012; OI Di Fiore, Pier Paolo/0000-0002-2252-0950; Offenhauser, Nina/0000-0002-3316-3047; Holley, Matthew/0000-0001-9547-1953 FU Wellcome Trust [091895, 087737]; Westfield Health; fondazione cariplo [2012/5746]; Deutsche Forschungsgemeinschaft [DFG Kni 316-4-1]; Intramural Programs of the National Institute on Deafness and Other Communication Disorders; Nebraska Tobacco Settlement Biomedical Research Development Fund FX We thank Choongheon Lee for assistance with VsEP data collection. This work was supported by the following grants: Wellcome Trust (091895) and Westfield Health (W.M.), the fondazione cariplo (2012/5746) (to W.M. and S.M.), the Wellcome Trust (087737) (to G.P.R.), Deutsche Forschungsgemeinschaft DFG Kni 316-4-1 (to M.K.), the Intramural Programs of the National Institute on Deafness and Other Communication Disorders (B.K.), and the Nebraska Tobacco Settlement Biomedical Research Development Fund (to S.M.J.). S.L.J. is a Royal Society University Research Fellow. NR 40 TC 19 Z9 19 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 20 PY 2013 VL 110 IS 34 BP 13898 EP 13903 DI 10.1073/pnas.1304644110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203DU UT WOS:000323271400054 PM 23918390 ER PT J AU Le, K Li, CC Ye, G Moss, J Vaughan, M AF Le, Kang Li, Chun-Chun Ye, Guan Moss, Joel Vaughan, Martha TI Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ADP-RIBOSYLATION FACTORS; SMOOTH-MUSCLE MYOSIN; LIGHT-CHAIN PHOSPHATASE; RHO-ASSOCIATED KINASE; PROTEIN PHOSPHATASE-1; CELL-MIGRATION; RECYCLING ENDOSOMES; REDUNDANT ROLES; INTEGRIN BETA-1; TARGET SUBUNIT AB Brefeldin A-inhibited guanine nucleotide-exchange factors BIG1 and BIG2 activate, through their Sec7 domains, ADP ribosylation factors (Arfs) by accelerating the replacement of Arf-bound GDP with GTP for initiation of vesicular transport or activation of specific enzymes that modify important phospholipids. They are also implicated in regulation of cell polarization and actin dynamics for directed migration. Reciprocal coimmunoprecipitation of endogenous HeLa cell BIG1 and BIG2 with myosin IIA was demonstrably independent of Arf guanine nucleotide-exchange factor activity, because effects of BIG1 and BIG2 depletion were reversed by overexpression of the cognate BIG molecule C-terminal sequence that follows the Arf activation site. Selective depletion of BIG1 or BIG2 enhanced specific phosphorylation of myosin regulatory light chain (T18/S19) and F-actin content, which impaired cell migration in Transwell assays. Our data are clear evidence of these newly recognized functions for BIG1 and BIG2 in transduction or integration of mechanical signals from integrin adhesions and myosin IIA-dependent actin dynamics. Thus, by anchoring or scaffolding the assembly, organization, and efficient operation of multi-molecular myosin phosphatase complexes that include myosin IIA, protein phosphatase 1 delta, and myosin phosphatase-targeting subunit 1, BIG1 and BIG2 serve to integrate diverse biophysical and biochemical events in cells. C1 [Le, Kang; Li, Chun-Chun; Ye, Guan; Moss, Joel; Vaughan, Martha] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Vaughan, M (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM vaughanm@mail.nih.gov RI Le, Kang/D-1630-2016 FU Intramural Research Program of the NIH, NHLBI FX We thank Drs. Robert S. Adelstein and Mary Ann Conti [National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)] for their generous provision of expert advice and consultation, in addition to antibodies against NMHC IIB and IIC; Dr. Zissis C. Chroneos (The Pennsylvania State University) for his important gift of NMHC IIA plasmids that enabled us to demonstrate direct interactions of in vitro-synthesized proteins; and Drs. Daniela Malide and Christian Combs (Light Microscopy Core Facility, NHLBI) for their invaluable help in confocal microscopy. This research was supported by the Intramural Research Program of the NIH, NHLBI. NR 62 TC 5 Z9 5 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 20 PY 2013 VL 110 IS 34 BP E3162 EP E3170 DI 10.1073/pnas.1312531110 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203DU UT WOS:000323271400006 PM 23918382 ER PT J AU Yang, RT Daigle, BJ Muhie, SY Hammamieh, R Jett, M Petzold, L Doyle, FJ AF Yang, Ruoting Daigle, Bernie J., Jr. Muhie, Seid Y. Hammamieh, Rasha Jett, Marti Petzold, Linda Doyle, Francis J., III TI Core modular blood and brain biomarkers in social defeat mouse model for post traumatic stress disorder SO BMC SYSTEMS BIOLOGY LA English DT Article ID GENE-COEXPRESSION NETWORK; BREAST-CANCER METASTASIS; PERIPHERAL-BLOOD; EXPRESSION PROFILES; DISEASE; PATHWAY; SUSCEPTIBILITY; IDENTIFICATION; DEPRESSION; DISCOVERY AB Background: Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects a substantial portion of combat veterans and poses serious consequences to long-term health. Consequently, the identification of diagnostic and prognostic blood biomarkers for PTSD is of great interest. Previously, we assessed genome-wide gene expression of seven brain regions and whole blood in a social defeat mouse model subjected to various stress conditions. Results: To extract biological insights from these data, we have applied a new computational framework for identifying gene modules that are activated in common across blood and various brain regions. Our results, in the form of modular gene networks that highlight spatial and temporal biological functions, provide a systems-level molecular description of response to social stress. Specifically, the common modules discovered between the brain and blood emphasizes molecular transporters in the blood-brain barrier, and the associated genes have significant overlaps with known blood signatures for PTSD, major depression, and bipolar disease. Similarly, the common modules specific to the brain highlight the components of the social defeat stress response (e.g., fear conditioning pathways) in each brain sub-region. Conclusions: Many of the brain-specific genes discovered are consistent with previous independent studies of PTSD or other mental illnesses. The results from this study further our understanding of the mechanism of stress response and contribute to a growing list of diagnostic biomarkers for PTSD. C1 [Yang, Ruoting; Petzold, Linda; Doyle, Francis J., III] Univ Calif Santa Barbara, Inst Collaborat Biotechnol, Santa Barbara, CA 93106 USA. [Daigle, Bernie J., Jr.; Petzold, Linda] Univ Calif Santa Barbara, Dept Comp Sci, Santa Barbara, CA 93106 USA. [Petzold, Linda] Univ Calif Santa Barbara, Dept Mech Engn, Santa Barbara, CA 93106 USA. [Doyle, Francis J., III] Univ Calif Santa Barbara, Dept Chem Engn, Santa Barbara, CA 93106 USA. [Yang, Ruoting; Muhie, Seid Y.; Hammamieh, Rasha; Jett, Marti] USA, Ctr Environm Hlth Res, Ft Detrick, MD USA. [Yang, Ruoting] Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Doyle, FJ (reprint author), Univ Calif Santa Barbara, Inst Collaborat Biotechnol, Santa Barbara, CA 93106 USA. EM doyle@engineering.ucsb.edu FU U.S. Army Research Office (PTSD) [W911NF-10-2-0111] FX We gratefully acknowledge financial support from U.S. Army Research Office (PTSD Grant W911NF-10-2-0111). We also thank the SysBiocube team, Uma Mudunuri, Sudhir Chowbina, and Raina Kumar, for providing secure data depository system. NR 56 TC 6 Z9 6 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD AUG 20 PY 2013 VL 7 AR 80 DI 10.1186/1752-0509-7-80 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 204TH UT WOS:000323391800001 PM 23962043 ER PT J AU Sahebjam, S Bedard, PL Castonguay, V Chen, Z Reedijk, M Liu, G Cohen, B Zhang, WJ Clarke, B Zhang, T Kamel-Reid, S Chen, H Ivy, SP Razak, ARA Oza, AM Chen, EX Hirte, HW McGarrity, A Wang, L Siu, LL Hotte, SJ AF Sahebjam, S. Bedard, P. L. Castonguay, V. Chen, Z. Reedijk, M. Liu, G. Cohen, B. Zhang, W-J Clarke, B. Zhang, T. Kamel-Reid, S. Chen, H. Ivy, S. P. Razak, A. R. A. Oza, A. M. Chen, E. X. Hirte, H. W. McGarrity, A. Wang, L. Siu, L. L. Hotte, S. J. TI A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503) SO BRITISH JOURNAL OF CANCER LA English DT Article DE RO4929097; cediranib; phase I; combination study ID GAMMA-SECRETASE INHIBITOR; RENAL-CELL CARCINOMA; BREAST-CANCER; COLORECTAL-CANCER; UP-REGULATION; DOUBLE-BLIND; GROWTH; ANGIOGENESIS; EXPRESSION; POOR AB Background: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a g-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. Methods: Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. Results: In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. Conclusion: RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy. C1 [Sahebjam, S.; Bedard, P. L.; Castonguay, V.; Chen, Z.; Reedijk, M.; Liu, G.; Cohen, B.; Zhang, W-J; Clarke, B.; Zhang, T.; Kamel-Reid, S.; Razak, A. R. A.; Oza, A. M.; Chen, E. X.; McGarrity, A.; Wang, L.; Siu, L. L.] Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. [Chen, H.; Ivy, S. P.] NCI, Bethesda, MD 20852 USA. [Hirte, H. W.; Hotte, S. J.] Juravinski Canc Ctr, Hamilton, ON L8V 5C2, Canada. RP Hotte, SJ (reprint author), Juravinski Canc Ctr, 699 Concess St, Hamilton, ON L8V 5C2, Canada. EM sebastien.hotte@jcc.hhsc.ca RI Liu, Geoffrey/N-4421-2016 FU US National Cancer Institute U01 Cooperative Agreement Award [U01-CA132123] FX This study (PJC-004/CTEP 8503) is conducted by the Princess Margaret Hospital Phase I Consortium with support from the US National Cancer Institute U01 Cooperative Agreement Award (U01-CA132123). NR 31 TC 34 Z9 37 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 20 PY 2013 VL 109 IS 4 BP 943 EP 949 DI 10.1038/bjc.2013.380 PG 7 WC Oncology SC Oncology GA 205CA UT WOS:000323417100017 PM 23868004 ER PT J AU Moon, DH Lee, JM Noonan, AM Annunziata, CM Minasian, L Houston, N Hays, JL Kohn, EC AF Moon, D. H. Lee, J-M Noonan, A. M. Annunziata, C. M. Minasian, L. Houston, N. Hays, J. L. Kohn, E. C. TI Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions SO BRITISH JOURNAL OF CANCER LA English DT Article DE carboplatin; hypersensitivity; ovarian cancer; deleterious BRCA1/2 mutation ID OVARIAN-CANCER; CARCINOMA; DESENSITIZATION; MALIGNANCIES; RETREATMENT; PACLITAXEL; EXPERIENCE; CISPLATIN; SURVIVAL; PREDICT AB Background: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs). Methods: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered. Results: All women (N = 87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6-65.4), P = 0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P = 0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR. Conclusion: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs. C1 [Moon, D. H.; Lee, J-M; Noonan, A. M.; Annunziata, C. M.; Minasian, L.; Houston, N.; Hays, J. L.; Kohn, E. C.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Moon, D. H.] NIH, Med Res Scholars Program, Bethesda, MD 20892 USA. RP Lee, JM (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM leej6@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU Intramural Program of the Center for Cancer Research, National Cancer Institute; NIH Medical Research Scholars Program; NIH; Foundation for the NIH FX We thank Dr JoAnne Zujewski for her contributions in clinic and Dr Seth Steinberg for his inputs on the statistical analysis. We also thank I Prosak and H Minassie for their data management assistance. This work was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute, and olaparib was provided to the National Cancer Institute by AstraZeneca. DHM was funded through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and through the Foundation for the NIH (details on program and donors: http://www.fnih.org/work/programs-development/medical-research-scholars- program). NR 30 TC 13 Z9 14 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 20 PY 2013 VL 109 IS 4 BP 1072 EP 1078 DI 10.1038/bjc.2013.389 PG 7 WC Oncology SC Oncology GA 205CA UT WOS:000323417100032 PM 23867999 ER PT J AU Aoude, LG Wadt, K Bojesen, A Cruger, D Borg, A Trent, JM Brown, KM Gerdes, AM Jonsson, G Hayward, NK AF Aoude, Lauren G. Wadt, Karin Bojesen, Anders Cruger, Dorthe Borg, Ake Trent, Jeffrey M. Brown, Kevin M. Gerdes, Anne-Marie Jonsson, Goran Hayward, Nicholas K. TI A BAP1 Mutation in a Danish Family Predisposes to Uveal Melanoma and Other Cancers SO PLOS ONE LA English DT Article ID MALIGNANT MESOTHELIOMA; GERMLINE MUTATIONS; TUMORS AB Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer. C1 [Aoude, Lauren G.; Hayward, Nicholas K.] Queensland Inst Med Res, Oncogen Lab, Brisbane, Qld 4006, Australia. [Aoude, Lauren G.] Univ Queensland, Brisbane, Qld, Australia. [Wadt, Karin; Gerdes, Anne-Marie] Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Bojesen, Anders; Cruger, Dorthe] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Borg, Ake; Jonsson, Goran] Lund Univ, Div Oncol, Dept Clin Sci Lund, Lund, Sweden. [Trent, Jeffrey M.; Brown, Kevin M.] Translat Genom Res Inst, Phoenix, AZ USA. [Brown, Kevin M.] NCI, Lab Translat Genom, Bethesda, MD 20892 USA. RP Aoude, LG (reprint author), Queensland Inst Med Res, Oncogen Lab, Brisbane, Qld 4006, Australia. EM lauren.aoude@qimr.edu.au RI Jonsson, Goran/D-1212-2014; Aoude, Lauren/C-7484-2014; hayward, nicholas/C-1367-2015 OI Aoude, Lauren/0000-0003-1448-3923; hayward, nicholas/0000-0003-4760-1033 FU Melanoma Research Alliance; Swedish Cancer Society; Swedish Research Council; Berta Kamprad Foundation; National Health and Medical Research Council (NHMRC) of Australia; Fight for Sight, Denmark; NHMRC Senior Principal Research Fellowship; ANZ Ph.D. scholarship FX This work was supported by the Melanoma Research Alliance, the Swedish Cancer Society, the Swedish Research Council, the Berta Kamprad Foundation, the National Health and Medical Research Council (NHMRC) of Australia, and the Fight for Sight, Denmark. NKH and LGA receive salary support through a NHMRC Senior Principal Research Fellowship and ANZ Ph.D. scholarship, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 21 Z9 22 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 19 PY 2013 VL 8 IS 8 AR e72144 DI 10.1371/journal.pone.0072144 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205ER UT WOS:000323425700139 PM 23977234 ER PT J AU Burke, LS Hyland, PL Pfeiffer, RM Prescott, J Wheeler, W Mirabello, L Savage, SA Burdette, L Yeager, M Chanock, S De Vivo, I Tucker, MA Goldstein, AM Yang, XHR AF Burke, Laura S. Hyland, Paula L. Pfeiffer, Ruth M. Prescott, Jennifer Wheeler, William Mirabello, Lisa Savage, Sharon A. Burdette, Laurie Yeager, Meredith Chanock, Stephen De Vivo, Immaculata Tucker, Margaret A. Goldstein, Alisa M. Yang, Xiaohong R. TI Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; OXIDATIVE STRESS; IN-VIVO; CANCER; LOCUS; VARIANTS; EPIDEMIOLOGY; METAANALYSIS; INSTABILITY; P16(INK4A) AB Introduction: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. Materials and Methods: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. Results: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. Discussion: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk. C1 [Burke, Laura S.; Hyland, Paula L.; Pfeiffer, Ruth M.; Mirabello, Lisa; Savage, Sharon A.; Tucker, Margaret A.; Goldstein, Alisa M.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Hyland, Paula L.] NCI, Canc Prevent Fellowship Program, Off Directors, NIH,US Dept HHS, Rockville, MD USA. [Prescott, Jennifer; De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Prescott, Jennifer; De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Prescott, Jennifer; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Prescott, Jennifer; De Vivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Burdette, Laurie; Yeager, Meredith; Chanock, Stephen] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Yang, XHR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. EM royang@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Cancer Prevention Fellowship Program; Center for Cancer Training, National Cancer Institute, Bethesda, United States of America; Health and Social Care, Northern Ireland, United Kingdom FX Paula Hyland was funded by the Cancer Prevention Fellowship Program, the Center for Cancer Training, National Cancer Institute, Bethesda, United States of America and the Health and Social Care, Northern Ireland, United Kingdom. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 23 Z9 23 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 19 PY 2013 VL 8 IS 8 AR e71121 DI 10.1371/journal.pone.0071121 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205ER UT WOS:000323425700016 PM 23990928 ER PT J AU Hwang, IY Park, C Luong, T Harrison, KA Birnbaumer, L Kehrl, JH AF Hwang, Il-Young Park, Chung Luong, Thuyvi Harrison, Kathleen A. Birnbaumer, Lutz Kehrl, John H. TI The Loss of Gnai2 and Gnai3 in B Cells Eliminates B Lymphocyte Compartments and Leads to a Hyper-IgM Like Syndrome SO PLOS ONE LA English DT Article ID CHEMOKINE RECEPTOR; BONE-MARROW; ADENYLYL-CYCLASE; GERMINAL CENTER; ORGANIZATION; FOLLICLES; ORGANS; CXCR5; CCR7; MIGRATION AB B lymphocytes are compartmentalized within lymphoid organs. The organization of these compartments depends upon signaling initiated by G-protein linked chemoattractant receptors. To address the importance of the G-proteins Ga-i2 and Ga-i3 in chemoattractant signaling we created mice lacking both proteins in their B lymphocytes. While bone marrow B cell development and egress is grossly intact; mucosal sites, splenic marginal zones, and lymph nodes essentially lack B cells. There is a partial block in splenic follicular B cell development and a 50-60% reduction in splenic B cells, yet normal numbers of splenic T cells. The absence of Ga-i2 and Ga-i3 in B cells profoundly disturbs the architecture of lymphoid organs with loss of B cell compartments in the spleen, thymus, lymph nodes, and gastrointestinal tract. This results in a severe disruption of B cell function and a hyper-IgM like syndrome. Beyond the pro-B cell stage, B cells are refractory to chemokine stimulation, and splenic B cells are poorly responsive to antigen receptor engagement. Ga-i2 and Ga-i3 are therefore critical for B cell chemoattractant receptor signaling and for normal B cell function. These mice provide a worst case scenario of the consequences of losing chemoattractant receptor signaling in B cells. C1 [Hwang, Il-Young; Park, Chung; Luong, Thuyvi; Harrison, Kathleen A.; Kehrl, John H.] NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Durham, NC USA. RP Kehrl, JH (reprint author), NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health [National Institute of Allergy and Infectious Diseases]; IRP project [Z01-ES-101643] FX This research was supported by the Intramural Research Program of the National Institutes of Health [National Institute of Allergy and Infectious Diseases] and IRP project Z01-ES-101643 (LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 6 Z9 6 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 19 PY 2013 VL 8 IS 8 AR UNSP e72596 DI 10.1371/journal.pone.0072596 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205ER UT WOS:000323425700178 PM 23977324 ER PT J AU Zhang, P Maruyama, T Konkel, JE Abbatiello, B Zamarron, B Wang, ZQ Chen, WJ AF Zhang, Pin Maruyama, Takashi Konkel, Joanne E. Abbatiello, Brittany Zamarron, Brian Wang, Zhao-qi Chen, WanJun TI PARP-1 Controls Immunosuppressive Function of Regulatory T Cells by Destabilizing Foxp3 SO PLOS ONE LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE GENE; IMMUNOLOGICAL SELF-TOLERANCE; TRANSCRIPTION FACTOR FOXP3; MICE LACKING; ANTIGEN 4; TGF-BETA; ACTIVATION; RESISTANT; PLAYS AB Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme and transcription factor that is involved in inflammatory response, but its role in T cell response remains largely unknown. We show here that PARP-1 regulates the suppressive function of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Specifically, Tregs in mice with a null mutation of the PARP-1 gene (PARP-1(-/-)) showed significantly stronger suppressive activity than did wild-type Tregs in culture. We elucidate that this enhanced suppressive function is attributed to sustained higher expression of Foxp3 and CD25 in PARP-1(-/-) Tregs. Furthermore, in PARP-1(-/-) Tregs, Foxp3 protein shows substantially higher levels of binding to the conserved non-coding DNA sequence 2 (CNS2) at the foxp3 gene, a region important in maintaining Foxp3 gene expression in Tregs. Thus, our data reveal a role for PARP-1 in controlling the function of Tregs through modulation of the stable expression of Foxp3. C1 [Zhang, Pin; Maruyama, Takashi; Konkel, Joanne E.; Abbatiello, Brittany; Zamarron, Brian; Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, OIIB, NIH, Bethesda, MD USA. [Wang, Zhao-qi] Fritz Lipmann Inst eV, Leibniz Inst Age Res, D-07745 Jena, Germany. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, OIIB, NIH, Bethesda, MD USA. EM wchen@dir.nidcr.nih.gov OI Zamarron, Brian/0000-0001-6549-4230 FU Intramural Research Program of the National Institute of Dental and Craniofacial Research of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 7 Z9 7 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 19 PY 2013 VL 8 IS 8 AR e71590 DI 10.1371/journal.pone.0071590 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205ER UT WOS:000323425700072 PM 23977081 ER PT J AU Klassen, MP Yuan, Q AF Klassen, Matthew P. Yuan, Quan TI Dendrite Plasticity: Branching Out for Greener Pastures SO CURRENT BIOLOGY LA English DT Editorial Material ID NEUROBIOLOGY; MECHANISMS; BRAIN C1 [Klassen, Matthew P.] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Physiol, San Francisco, CA 94158 USA. [Yuan, Quan] NINDS, NIH, Bethesda, MD 20892 USA. RP Klassen, MP (reprint author), Univ Calif San Francisco, Howard Hughes Med Inst, Dept Physiol, San Francisco, CA 94158 USA. EM quan.yuan@nih.gov FU Howard Hughes Medical Institute NR 14 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 19 PY 2013 VL 23 IS 16 BP R687 EP R688 DI 10.1016/j.cub.2013.07.036 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 204WD UT WOS:000323401100010 PM 23968924 ER PT J AU Putney, JW AF Putney, James W., Jr. TI Calcium Signaling: Septins Organize the SOC Channel SO CURRENT BIOLOGY LA English DT Editorial Material ID OPERATED CA2+ ENTRY; MOLECULAR-BASIS; CRAC CHANNEL; MICRODOMAINS; INFLUX; SCREEN; ORAI1 C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov NR 14 TC 0 Z9 0 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 19 PY 2013 VL 23 IS 16 BP R684 EP R685 DI 10.1016/j.cub.2013.07.042 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 204WD UT WOS:000323401100008 PM 23968922 ER PT J AU Dixit, D Ghildiyal, R Anto, NP Ghosh, S Sharma, V Sen, E AF Dixit, Deobrat Ghildiyal, Ruchi Anto, Nikhil Ponnor Ghosh, Sourav Sharma, Vivek Sen, Ellora TI Guggulsterone sensitizes glioblastoma cells to Sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NF kappa B dependent manner SO CANCER LETTERS LA English DT Article DE Guggulsterone; NF kappa B; Ras; Shh; Glioblastoma ID PANCREATIC-CANCER; GLIOMA-CELLS; IN-VIVO; FARNESYLTRANSFERASE INHIBITOR; TRANSCRIPTIONAL ACTIVITY; MEDIATED APOPTOSIS; STAT3 ACTIVATION; TUMOR-GROWTH; PATHWAY; EXPRESSION AB Since Shh pathway effector, Gli1, is overexpressed in gliomas, we investigated the effect of novel Shh inhibitor SANT-1 on glioma cell viability. Though SANT-I failed to induce apoptosis, it reduced proliferation of glioma stem-like cells. Apart from canonical Shh cascade, Gli1 is also induced by non-canonical pathways including NF kappa B. Therefore, a combinatorial strategy with Ras/NF kappa B inhibitor, Guggulsterone, was employed to enhance effectiveness of SANT-1. Guggulsterone inhibited Ras and NF kappa B activity and sensitized cells to SANT-1 induced apoptosis via intrinsic apoptotic mechanism. Inhibition of either Ras or NF kappa B activity was sufficient to sensitize cells to SANT-1. Guggulsterone induced ERK activation also contributed to Caspase-9 activation. Since SANT-1 and Guggulsterone differentially target stem-like and non-stem glioma cells respectively, this combination warrants investigation as an effective anti-glioma therapy. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Dixit, Deobrat; Ghildiyal, Ruchi; Anto, Nikhil Ponnor; Ghosh, Sourav; Sen, Ellora] Natl Brain Res Ctr, Manesar 122050, Haryana, India. [Sharma, Vivek] NCI, NIH, Bethesda, MD 20896 USA. RP Sen, E (reprint author), Natl Brain Res Ctr, Gurgaon 122050, Haryana, India. EM ellora@nbrc.res.in OI Dixit, Deobrat/0000-0003-4459-3904 FU Department of Biotechnology (DBT, Government of India) [BT/PR/12924/Med/30/235/2009]; Council of Scientific and Industrial Research (CSIR, Government of India) FX The work was supported by a research Grant from the Department of Biotechnology (DBT, Government of India #BT/PR/12924/Med/30/235/2009) to ES. DD is supported by a research fellowship from Council of Scientific and Industrial Research (CSIR, Government of India). NR 56 TC 17 Z9 17 U1 0 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD AUG 19 PY 2013 VL 336 IS 2 BP 347 EP 358 DI 10.1016/j.canlet.2013.03.025 PG 12 WC Oncology SC Oncology GA 187BB UT WOS:000322089400012 PM 23548480 ER PT J AU Fagan, RL Cryderman, DE Kopelovich, L Wallrath, LL Brenner, C AF Fagan, Rebecca L. Cryderman, Diane E. Kopelovich, Levy Wallrath, Lori L. Brenner, Charles TI Laccaic Acid A Is a Direct, DNA-competitive Inhibitor of DNA Methyltransferase 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; TUMOR-SUPPRESSOR GENES; TRANSCRIPTIONAL REGULATION; EPIGENETIC REGULATION; ENZYMATIC-PROPERTIES; PPAR-GAMMA; METHYLATION; DNMT1; MOUSE; EXPRESSION AB Methylation of cytosines in CpG dinucleotides is the predominant epigenetic mark on vertebrate DNA. DNA methylation is associated with transcriptional repression. The pattern of DNA methylation changes during development and with disease. Human DNA methyltransferase 1 (Dnmt1), a 1616-amino acid multidomain enzyme, is essential for maintenance of DNA methylation in proliferating cells and is considered an important cancer drug target. Using a fluorogenic, endonuclease-coupled DNA methylation assay with an activated form of Dnmt1 engineered to lack the replication foci targeting sequence domain, we discovered that laccaic acid A (LCA), a highly substituted anthraquinone natural product, is a direct inhibitor with a 310 nM K-i. LCA is competitive with the DNA substrate in in vitro methylation assays and alters the expression of methylated genes in MCF-7 breast cancer cells synergistically with 5-aza-2'-deoxycytidine. LCA represents a novel class of Dnmt-targeted molecular probes, with biochemical properties that allow it to distinguish between non DNA-bound and DNA-bound Dnmt1. C1 [Fagan, Rebecca L.; Cryderman, Diane E.; Wallrath, Lori L.; Brenner, Charles] Univ Iowa, Carver Coll Med, Dept Biochem, Iowa City, IA 52242 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Brenner, C (reprint author), Univ Iowa, Carver Coll Med, Dept Biochem, Iowa City, IA 52242 USA. EM charles-brenner@uiowa.edu RI Brenner, Charles/D-6339-2014 OI Brenner, Charles/0000-0002-4955-3226 FU National Institutes of Health [R01CA075954]; National Cancer Institute [HHSN261200433000C]; Oberley Seed Grants from the University of Iowa Holden Comprehensive Cancer Center; American Cancer Society postdoctoral fellowship FX This work was supported by National Institutes of Health Grant R01CA075954, Contract HHSN261200433000C from the National Cancer Institute and a generous gift from the Roy J. Carver Charitable Trust (to C. B.). This work was also supported by Oberley Seed Grants from the University of Iowa Holden Comprehensive Cancer Center (to C. B. and L. L. W.), and an American Cancer Society postdoctoral fellowship (to R. L. F.). NR 59 TC 20 Z9 20 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2013 VL 288 IS 33 BP 23858 EP 23867 DI 10.1074/jbc.M113.480517 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NO UT WOS:000330611400025 PM 23839987 ER PT J AU Subramanian, P Locatelli-Hoops, S Kenealey, J DesJardin, J Notari, L Becerra, SP AF Subramanian, Preeti Locatelli-Hoops, Silvia Kenealey, Jason DesJardin, Jacqueline Notari, Luigi Becerra, S. Patricia TI Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R) IDENTIFICATION OF A FUNCTIONAL LIGAND BINDING SITE SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADIPOSE TRIGLYCERIDE LIPASE; POLYUNSATURATED FATTY-ACIDS; CEREBELLAR GRANULE CELLS; DOCOSAHEXAENOIC ACID; OXIDATIVE STRESS; NEUROPROTECTIN D1; PROSTATE-CANCER; FAMILY-MEMBERS; GENE-TRANSFER; IN-VITRO AB The extracellular pigment epithelium-derived factor (PEDF) displays retina survival activity by interacting with receptor proteins on cell surfaces. We have previously reported that PEDF binds and stimulates PEDF receptor (PEDF-R), a transmembrane phospholipase. However, the PEDF binding site of PEDF-R and its involvement in survival activity have not been identified. The purpose of this work is to identify a biologically relevant ligand-binding site on PEDF-R. PEDF bound the PEDF-R ectodomain L4 (Leu(159)-Met(325)) with affinity similar to the full-length PEDF-R (Met(1)-Leu(504)). Binding assays using synthetic peptides spanning L4 showed that PEDF selectively bound E5b (Ile(193)-Leu(232)) and P1 (Thr(210)-Leu(249)) peptides. Recombinant C-terminal truncated PEDF-R4 (Met(1)-Leu(232)) and internally truncated PEDF-R and PEDF-R4 (Delta His(203)-Leu(232)) retained phospholipase activity of the full-length PEDF-R. However, PEDF-R polypeptides without the His(203)-Leu(232) region lost the PEDF affinity that stimulated their enzymatic activity. Cell surface labeling showed that PEDF-R is present in the plasma membranes of retina cells. Using siRNA to selectively knock down PEDF-R in retina cells, we demonstrated that PEDF-R is essential for PEDF-mediated cell survival and antiapoptotic activities. Furthermore, preincubation of PEDF with P1 and E5b peptides blocked the PEDF.PEDF-R-mediated retina cell survival activity, implying that peptide binding to PEDF excluded ligand-receptor interactions on the cell surface. Our findings establish that PEDF-R is required for the survival and antiapoptotic effects of PEDF on retina cells and has determinants for PEDF binding within its L4 ectodomain that are critical for enzymatic stimulation. C1 [Subramanian, Preeti; Locatelli-Hoops, Silvia; Kenealey, Jason; DesJardin, Jacqueline; Notari, Luigi; Becerra, S. Patricia] NEI, Sect Prot Struct & Funct, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Becerra, SP (reprint author), NEI, NIH, Bldg 6,Rm 134,6 Ctr Dr, Bethesda, MD 20892 USA. EM becerrap@nei.nih.gov FU National Institutes of Health, NEI, Intramural Research Program FX This work was supported, in whole or in part, by the National Institutes of Health, NEI, Intramural Research Program. NR 64 TC 20 Z9 20 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2013 VL 288 IS 33 BP 23928 EP 23942 DI 10.1074/jbc.M113.487884 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NO UT WOS:000330611400032 PM 23818523 ER PT J AU Chen, ZG Schiffman, M Herrero, R DeSalle, R Anastos, K Segondy, M Sahasrabuddhe, VV Gravitt, PE Hsing, AW Burk, RD AF Chen, Zigui Schiffman, Mark Herrero, Rolando DeSalle, Rob Anastos, Kathryn Segondy, Michel Sahasrabuddhe, Vikrant V. Gravitt, Patti E. Hsing, Ann W. Burk, Robert D. TI Evolution and Taxonomic Classification of Alphapapillomavirus 7 Complete Genomes: HPV18, HPV39, HPV45, HPV59, HPV68 and HPV70 SO PLOS ONE LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; SQUAMOUS INTRAEPITHELIAL LESIONS; GENITAL HUMAN-PAPILLOMAVIRUS; GRADE CERVICAL LESIONS; NEUTRALIZING ANTIBODIES; MAXIMUM-LIKELIHOOD; SEQUENCE-ANALYSIS; VARIANT LINEAGES; MIXED MODELS; CANCER AB Background: The species Alphapapillomavirus 7 (alpha-7) contains human papillomavirus genotypes that account for 15% of invasive cervical cancers and are disproportionately associated with adenocarcinoma of the cervix. Complete genome analyses enable identification and nomenclature of variant lineages and sublineages. Methods: The URR/E6 region was sequenced to screen for novel variants of HPV18, 39, 45, 59, 68, 70, 85 and 97 from 1147 cervical samples obtained from multiple geographic regions that had previously been shown to contain an alpha-7 HPV isolate. To study viral heterogeneity, the complete 8 kb genome of 128 isolates, including 109 sequenced for this analysis, were annotated and analyzed. Viral evolution was characterized by constructing phylogenic trees using maximum-likelihood and Bayesian algorithms. Global and pairwise alignments were used to calculate total and ORF/region nucleotide differences; lineages and sublineages were assigned using an alphanumeric system. The prototype genome was assigned to the A lineage or A1 sublineage. Results: The genomic diversity of alpha-7 HPV types ranged from 1.1% to 6.7% nucleotide sequence differences; the extent of genome-genome pairwise intratype heterogeneity was 1.1% for HPV39, 1.3% for HPV59, 1.5% for HPV45, 1.6% for HPV70, 2.1% for HPV18, and 6.7% for HPV68. ME180 (previously a subtype of HPV68) was designated as the representative genome for HPV68 sublineage C1. Each ORF/region differed in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) / noncoding region 2 (NCR2) > upstream regulatory region (URR) > E6 / E7 > E2 / L2 > E1 / L1. Conclusions: These data provide estimates of the maximum viral genomic heterogeneity of alpha-7 HPV type variants. The proposed taxonomic system facilitates the comparison of variants across epidemiological and molecular studies. Sequence diversity, geographic distribution and phylogenetic topology of this clinically important group of HPVs suggest an independent evolutionary history for each type. C1 [Chen, Zigui; Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Schiffman, Mark; Sahasrabuddhe, Vikrant V.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Herrero, Rolando] Fdn INCIENSA, San Jose, Costa Rica. [DeSalle, Rob] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA. [Anastos, Kathryn] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Anastos, Kathryn] Montefiore Med Ctr, Bronx, NY 10467 USA. [Anastos, Kathryn; Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Publ Hlth, Bronx, NY 10467 USA. [Anastos, Kathryn; Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet, Bronx, NY 10467 USA. [Segondy, Michel] Montpellier Univ Hosp, Dept Biol & Pathol, Montpellier, France. [Sahasrabuddhe, Vikrant V.] Vanderbilt Univ, Inst Global Hlth, Nashville, TN 37235 USA. [Gravitt, Patti E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. RP Burk, RD (reprint author), Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. EM robert.burk@einstein.yu.edu RI Chen, Zigui/E-8490-2017 FU National Cancer Institute [CA78527]; Einstein-Montefiore Center for AIDS; National Institutes of Health [AI-51519]; Einstein Cancer Research Center from the National Cancer Institute [P30CA013330] FX This work was supported in part by the National Cancer Institute (CA78527), the Einstein-Montefiore Center for AIDS funded by the National Institutes of Health (AI-51519) and the Einstein Cancer Research Center (P30CA013330) from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 16 Z9 16 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 16 PY 2013 VL 8 IS 8 AR e72565 DI 10.1371/journal.pone.0072565 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207BA UT WOS:000323570200075 PM 23977318 ER PT J AU McPherron, AC AF McPherron, Alexandra C. TI Through Thick and Thin: A Circulating Growth Factor Inhibits Age-Related Cardiac Hypertrophy SO CIRCULATION RESEARCH LA English DT Editorial Material ID GROWTH/DIFFERENTIATION FACTOR 11; LEFT-VENTRICULAR MASS; HEART-FAILURE; MUSCLE MASS; MYOSTATIN EXPRESSION; SKELETAL-MUSCLE; NEGATIVE REGULATOR; BETA SUPERFAMILY; GDF11; MICE C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP McPherron, AC (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10,Room 8D12A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mcpherrona@niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Dr McPherron is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 50 TC 3 Z9 3 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG 16 PY 2013 VL 113 IS 5 BP 487 EP 491 DI 10.1161/CIRCRESAHA.113.302239 PG 5 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 203VR UT WOS:000323322600006 PM 23948581 ER PT J AU Jaffe, H Patterson, AP Lurie, N AF Jaffe, Harold Patterson, Amy P. Lurie, Nicole TI Extra Oversight for H7N9 Experiments SO SCIENCE LA English DT Letter C1 [Jaffe, Harold] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. [Patterson, Amy P.] NIH, Bethesda, MD 20852 USA. [Lurie, Nicole] Dept Hlth & Human Serv, Washington, DC 20201 USA. RP Patterson, AP (reprint author), NIH, Bethesda, MD 20852 USA. EM pattersa@od.nih.gov NR 3 TC 1 Z9 1 U1 1 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 16 PY 2013 VL 341 IS 6147 BP 713 EP 714 DI 10.1126/science.1244158 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201DZ UT WOS:000323122200017 PM 23926189 ER PT J AU Kamel, F AF Kamel, Freya TI Paths from Pesticides to Parkinson's SO SCIENCE LA English DT Editorial Material ID DISEASE; EXPOSURE; RISK; SERUM C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM kamel@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615 FU Intramural NIH HHS NR 18 TC 36 Z9 36 U1 4 U2 43 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 16 PY 2013 VL 341 IS 6147 BP 722 EP 723 DI 10.1126/science.1243619 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201DZ UT WOS:000323122200027 PM 23950519 ER PT J AU Gamaldo, CE Gamaldo, A Creighton, J Salas, RE Selnes, OA David, PM Mbeo, G Parker, BS Brown, A McArthur, JC Smith, MT AF Gamaldo, Charlene E. Gamaldo, Alyssa Creighton, Jason Salas, Rachel E. Selnes, Ola A. David, Paula M. Mbeo, Gilbert Parker, Benjamin S. Brown, Amanda McArthur, Justin C. Smith, Michael T. TI Evaluating Sleep and Cognition in HIV SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; sleep; sleep disorders; cognition; quality of life ID NECROSIS-FACTOR-ALPHA; BLOOD-BRAIN-BARRIER; NEUROCOGNITIVE DISORDERS; ANTIRETROVIRAL THERAPY; CIRCADIAN-RHYTHM; NORMATIVE DATA; EFAVIRENZ; INFECTION; DEPRIVATION; PREVALENCE AB Objective: To examine the relationship between measures of sleep quality and cognitive performance in HIV-positive individuals stable on combination antiretroviral therapy. Design: Multimethod assessments of sleep quality, patterns, and cognitive performance were assessed in a predominantly black HIV-positive cohort. Methods: Sleep quality and patterns were characterized in 36 subjects by polysomnogram, 2-week actigraphy monitoring, and validated sleep questionnaires. Cognitive performance was assessed with a battery of neuropsychological tests. Results: The majority of participants were cognitively impaired [based on Frascati (75%) criteria]. Self-reported mean scores on the Pittsburgh sleep quality index and the insomnia severity scale suggested poor sleep quality. Better cognitive performance, particularly on tasks of attention, frontal/executive function, and psychomotor/motor speed, was associated with polysomnogram sleep indices (ie, reduced wake after sleep onset, greater sleep efficiency, greater sleep latency, and greater total sleep time). Thirty-seven percent of participants had sleep patterns suggestive of chronic partial sleep deprivation, which was associated with significantly worse performance on the digit symbol test (P = 0.006), nondominant pegboard (P = 0.043), and verbal fluency tests (P = 0.044). Conclusions: Our results suggest that compromised sleep quality and duration may have a significant impact on cognitive performance in HIV-positive individuals. Future studies are warranted to determine the utility of sleep quality and quantity indices as potential predictive biomarkers for development and progression of future HIV-associated neurocognitive disorder. C1 [Gamaldo, Charlene E.; Creighton, Jason; Salas, Rachel E.; Selnes, Ola A.; David, Paula M.; Mbeo, Gilbert; Parker, Benjamin S.; Brown, Amanda; McArthur, Justin C.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Gamaldo, Alyssa] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [McArthur, Justin C.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [McArthur, Justin C.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [McArthur, Justin C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Smith, Michael T.] Johns Hopkins Univ, Dept Psychiat & Behav Med, Baltimore, MD USA. RP Gamaldo, CE (reprint author), Johns Hopkins Univ Hosp, 600 N Wolfe St,Meyer 6-119, Baltimore, MD 21287 USA. EM cgamald1@jhmi.edu FU National Center for Research Resources (NCRR) [UL1 RR 025005]; NIH Roadmap for Medical Research; National Institute of Mental Health (NIMH) [5P30MH075673-S02]; JHU NIMH Center for Novel Therapeutics of HIV; JHU Center for Mind-Body Research; NIMH; Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER); National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [UL1 RR 025005] FX Supported by grant number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This study was also supported by award 5P30MH075673-S02 from the National Institute of Mental Health (NIMH) (principal investigator, J.C.M.), a Developmental Grant from JHU NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders (to author C. E. G., principal investigator, J.C.M.), and a Developmental Grant from JHU Center for Mind-Body Research (PI Jennifer Haythornthwaite PI to author C. E. G.). The recruitment of participants was assisted by an existing cohort, funded by NIMH, the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER). The project described was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 RR 025005. NR 61 TC 10 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2013 VL 63 IS 5 BP 609 EP 616 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FN UT WOS:000330449900020 PM 23722610 ER PT J AU Thompson, IM Goodman, PJ Tangen, CM Parnes, HL Minasian, LM Godley, PA Lucia, MS Ford, LG AF Thompson, Ian M., Jr. Goodman, Phyllis J. Tangen, Catherine M. Parnes, Howard L. Minasian, Lori M. Godley, Paul A. Lucia, M. Scott Ford, Leslie G. TI Long-Term Survival of Participants in the Prostate Cancer Prevention Trial SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID 5-ALPHA-REDUCTASE INHIBITORS; FOLLOW-UP; FINASTERIDE; SENSITIVITY AB BackgroundIn the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. With up to 18 years of follow-up, we analyzed rates of survival among all study participants and among those with prostate cancer. MethodsWe collected data on the incidence of prostate cancer among PCPT participants for an additional year after our first report was published in 2003 and searched the Social Security Death Index to assess survival status through October 31, 2011. ResultsAmong 18,880 eligible men who underwent randomization, prostate cancer was diagnosed in 989 of 9423 (10.5%) in the finasteride group and 1412 of 9457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65 to 0.76; P<0.001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1.00 to 1.37; P=0.05). Of the men who died, 2538 were in the finasteride group and 2496 were in the placebo group, for 15-year survival rates of 78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97 to 1.08; P=0.46). Ten-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer. ConclusionsFinasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow-up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. (Funded by the National Cancer Institute.) The use of finasteride to prevent prostate cancer reduced the risk of low-grade tumors by 43%, as compared with placebo. High-grade tumors were more common in the finasteride group, but long-term follow-up did not show a significant between-group difference in survival. With the advent of prostate-specific antigen (PSA) testing in the late 1980s, the rate of diagnosis of prostate cancer rose dramatically. Currently, a man in the United States has a 16.5% lifetime risk of receiving a diagnosis of prostate cancer.(1) The timing and magnitude of the 44% reduction in prostate-cancer mortality after the widespread adoption of PSA testing suggest that both screening and treatment improvements have contributed to this decline.(2) Unfortunately, treatments for prostate cancer (radiation and surgery) are associated with a substantial risk of side effects, including sexual, urinary, and bowel complications, that can dramatically affect quality of life. ... C1 [Thompson, Ian M., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Goodman, Phyllis J.; Tangen, Catherine M.] SW Oncol Grp, Ctr Stat, Seattle, WA USA. [Goodman, Phyllis J.; Tangen, Catherine M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Parnes, Howard L.; Minasian, Lori M.; Ford, Leslie G.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Godley, Paul A.] Univ N Carolina, Sch Med, Div Hematol Oncol, Sch Publ Hlth, Chapel Hill, NC USA. [Godley, Paul A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Lucia, M. Scott] Univ Colorado, Denver Sch Med, Dept Pathol, Denver, CO 80202 USA. RP Thompson, IM (reprint author), Canc Therapy & Res Ctr S Texas, Suite U627,7979 Wurzbach Rd, San Antonio, TX 78229 USA. EM thompsoni@uthscsa.edu FU Public Health Service grant from Division of Cancer Prevention, National Cancer Institute [CA37429]; Ferring; Amgen; Eli Lilly FX Supported by a Public Health Service grant (CA37429) from the Division of Cancer Prevention, National Cancer Institute. Dr. Thompson reports receiving consulting fees from Ferring and being a named inventor on patent applications filed by his institution for a penile-prosthesis design for the management of erectile dysfunction and for a lab-on-a-chip procedure for point-of-service identification of biomarkers for prostate-cancer detection; and Dr. Tangen, receiving consulting fees from Amgen and Eli Lilly. No other potential conflict of interest relevant to this article was reported. NR 21 TC 75 Z9 76 U1 1 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 15 PY 2013 VL 369 IS 7 BP 603 EP 610 DI 10.1056/NEJMoa1215932 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 243YO UT WOS:000326354500006 PM 23944298 ER PT J AU Ghany, MG Liang, TJ AF Ghany, Marc G. Liang, T. Jake TI Current and Future Therapies for Hepatitis C Virus Infection REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Ghany, Marc G.; Liang, T. Jake] NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM jliang@nih.gov FU Intramural NIH HHS [Z99 DK999999, ZIA DK054505-16, ZIA DK054504-17, ZIA DK054503-16, ZIA DK054505-17, ZIA DK054504-16, ZIA DK054503-17] NR 4 TC 17 Z9 18 U1 2 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 15 PY 2013 VL 369 IS 7 BP 679 EP 680 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 243YO UT WOS:000326354500028 PM 23944318 ER PT J AU Kopelovich, L Herbert, BS AF Kopelovich, Levy Herbert, Brittney-Shea TI Heritable one-hit events defining cancer prevention? SO CELL CYCLE LA English DT Article DE cancer prevention; cancer syndromes; Knudson; two-hit; one-hit; driver mutations; passenger mutations ID ALTERED GENE-EXPRESSION; SKIN FIBROBLASTS; BREAST-CANCER; FAMILIAL SYNDROME; MUTATIONS; P53; CELLS; SUSCEPTIBILITY; MELANOMA; CARRIERS AB Over 100 y ago (1902-1914) Theodor Boveri suggested a role for mutations in cancer.(1,2) Boveri's ideas were derived from the then just-emerging chromosome theory of inheritance. While demonstrating chromosomal aberrations as a cause of genetic imbalance, Boveri suggested that possible causes of malignancy may include events such as aneuploidy that are now defined as gene mutations, asserting all the while that malignancy occurs at the cellular level. Indeed, studies to date essentially uniformly show that cancer is a genetic disease.(3,415 years of age with AS were studied at necropsy over a 50-year period by the same investigator. Of the 260 patients, the valve in 37 (14%) was congenitally unicuspid, in 123 (47%), congenitally bicuspid, and in 100 (38%), tricuspid. Aortic valve structure varied with age of death (in years; unicuspid 52 +/- 17, bicuspid 63 +/- 12, and tricuspid 70 +/- 14 years); gender (men/women: unicuspid 95%/5%, bicuspid 78%/22%, and tricuspid 63%/37%), and frequency of calcium in the mitral valve annulus and epicardial coronary arteries. The patients with cardiac-related symptoms compared with those without were more likely to have a congenitally malformed valve (unicuspid 17% vs 12%; bicuspid 51% vs 29%; tricuspid 31% vs 60%; unadjusted p = 0.013), to die from cardiac disease (86% vs 54%; unadjusted p = 0.001), and to have larger hearts (mean cardiac weight 606 +/- 138 g vs 523 +/- 121 g; unadjusted p = 0.009) and a larger quantity of calcium in the aortic valve cusps. In conclusion, the length of survival in adults with AS is related to valve structure, gender, presence of cardiac-related symptoms, cardiac mass, and quantity of calcium in the aortic valve cusps. (C) 2013 Elsevier Inc. All rights reserved. C1 [Roberts, William C.; Vowels, Travis J.; Ko, Jong M.] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. [Roberts, William C.] Baylor Univ, Med Ctr, Div Cardiol, Dept Internal Med, Dallas, TX USA. [Roberts, William C.] Baylor Univ, Med Ctr, Dept Pathol, Dallas, TX USA. [Roberts, William C.; Mathur, Raj P.; Shirani, Jamshid] NHLBI, Pathol Branch, NIH, Bethesda, MD 20892 USA. [Filardo, Giovanni] Baylor Univ, Med Ctr, Inst Hlth Care Res & Improvement, Dallas, TX USA. [Filardo, Giovanni] So Methodist Univ, Dept Stat Sci, Dallas, TX 75275 USA. RP Roberts, WC (reprint author), Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. EM wc.roberts@baylorhealth.edu FU Baylor Heart and Vascular Institute Cardiovascular Research Review Committee; Baylor Health Care System Foundation FX This work was supported by grants from the Baylor Heart and Vascular Institute Cardiovascular Research Review Committee and Baylor Health Care System Foundation. NR 21 TC 7 Z9 7 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2013 VL 112 IS 4 BP 541 EP 553 DI 10.1016/j.amjcard.2013.04.020 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 204YR UT WOS:000323407700015 PM 23726174 ER PT J AU Zarate, CA Mathews, D Ibrahim, L Chaves, JF Marquardt, C Ukoh, I Jolkovsky, L Brutsche, NE Smith, MA Luckenbaugh, DA AF Zarate, Carlos A., Jr. Mathews, Daniel Ibrahim, Lobna Chaves, Jose Franco Marquardt, Craig Ukoh, Immaculata Jolkovsky, Libby Brutsche, Nancy E. Smith, Mark A. Luckenbaugh, David A. TI A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Antidepressant; depression; glutamate; low-trapping NMDA; rapid-acting; treatment-resistant ID NMDA RECEPTOR ANTAGONISTS; ENDOTHELIAL GROWTH-FACTOR; ADD-ON TRIAL; RATING-SCALE; LOW-AFFINITY; BIPOLAR DEPRESSION; ANTIDEPRESSANT; DISORDER; KETAMINE; STATES AB Background: The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD). Methods: In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale. Results: Within 80 min, Montgomery-Asberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d=.40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d=.49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects. Conclusions: In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed. C1 [Zarate, Carlos A., Jr.; Mathews, Daniel; Ibrahim, Lobna; Chaves, Jose Franco; Marquardt, Craig; Ukoh, Immaculata; Jolkovsky, Libby; Brutsche, Nancy E.; Luckenbaugh, David A.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. US Dept HHS, Bethesda, MD USA. [Smith, Mark A.] AstraZeneca, Wilmington, DE USA. RP Zarate, CA (reprint author), NIMH, NIH, CRC, 10 Ctr Dr,Unit 7 Southeast,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, and Department of Health Human Services FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, and Department of Health & Human Services. NR 46 TC 77 Z9 78 U1 3 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2013 VL 74 IS 4 BP 257 EP 264 DI 10.1016/j.biopsych.2012.10.019 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 201PY UT WOS:000323156100006 PM 23206319 ER PT J AU Hardee, JE Benson, BE Bar-Haim, Y Mogg, K Bradley, BP Chen, G Britton, JC Ernst, M Fox, NA Pine, DS Perez-Edgar, K AF Hardee, Jillian E. Benson, Brenda E. Bar-Haim, Yair Mogg, Karin Bradley, Brendan P. Chen, Gang Britton, Jennifer C. Ernst, Monique Fox, Nathan A. Pine, Daniel S. Perez-Edgar, Koraly TI Patterns of Neural Connectivity During an Attention Bias Task Moderate Associations Between Early Childhood Temperament and Internalizing Symptoms in Young Adulthood SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Attention bias; functional connectivity; Granger causality; imaging; internalizing problems; temperament ID GENERALIZED ANXIETY DISORDER; BEHAVIORALLY INHIBITED ADOLESCENTS; ANTERIOR CINGULATE ACTIVATION; PREFRONTAL CORTEX ACTIVATION; SOCIAL ANXIETY; TRAIT ANXIETY; ANGRY FACES; IMPLICIT REGULATION; PEDIATRIC ANXIETY; CHILDREN AB Background: Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area might clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. Methods: Children were assessed for BI at multiple age points from infancy through age seven. On the basis of a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (n = 44). Participants completed an event-related functional magnetic resonance imaging attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews. Results: The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms. Conclusions: Behavioral inhibition during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology. C1 [Hardee, Jillian E.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Benson, Brenda E.; Ernst, Monique; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Chen, Gang] NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. [Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Sch Psychol, Southampton, Hants, England. [Britton, Jennifer C.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Perez-Edgar, Koraly] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Perez-Edgar, Koraly] Penn State Univ, Ctr Child Study, University Pk, PA 16802 USA. RP Perez-Edgar, K (reprint author), Penn State Univ, Dept Psychol, Ctr Child Study, 111 Moore Bldg,USB 1,Room 101G, University Pk, PA 16802 USA. EM kxp24@psu.edu RI Britton, Jennifer/J-4501-2013; Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; OI Mogg, Karin/0000-0002-2738-7378; Bradley, Brendan/0000-0003-2801-4271; Perez-Edgar, Koraly/0000-0003-4051-9563; Hardee, Jillian/0000-0001-8230-3045 FU Intramural Research Program of the National Institutes of Health; National Institutes of Health [MH073569, MH094633, MH074454, R37HD17899]; Brain and Behavior Research Foundation FX Funding was provided by the Intramural Research Program of the National Institutes of Health, grants from the National Institutes of Health to KPE (MH073569 and MH094633) and NAF (MH074454; R37HD17899), as well as from the Brain and Behavior Research Foundation (Distinguished Investigator Award) to NAF. We would like to thank the participants and families for their continued involvement in our study. NR 58 TC 30 Z9 30 U1 7 U2 32 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2013 VL 74 IS 4 BP 273 EP 279 DI 10.1016/j.biopsych.2013.01.036 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 201PY UT WOS:000323156100008 PM 23489415 ER PT J AU Aravind, L Anand, S Iyer, LM AF Aravind, L. Anand, Swadha Iyer, Lakshminarayan M. TI Novel autoproteolytic and DNA-damage sensing components in the bacterial SOS response and oxidized methylcytosine-induced eukaryotic DNA demethylation systems SO BIOLOGY DIRECT LA English DT Article ID ESCHERICHIA-COLI; POLYMERASE-IV; MUTAGENESIS; DATABASE; PROTEIN; 5-CARBOXYLCYTOSINE; REPLICATION; PREDICTION; INDUCTION; EXCISION AB The bacterial SOS response is an elaborate program for DNA repair, cell cycle regulation and adaptive mutagenesis under stress conditions. Using sensitive sequence and structure analysis, combined with contextual information derived from comparative genomics and domain architectures, we identify two novel domain superfamilies in the SOS response system. We present evidence that one of these, the SOS response associated peptidase (SRAP; Pfam: DUF159) is a novel thiol autopeptidase. Given the involvement of other autopeptidases, such as LexA and UmuD, in the SOS response, this finding suggests that multiple structurally unrelated peptidases have been recruited to this process. The second of these, the ImuB-C superfamily, is linked to the Y-family DNA polymerase-related domain in ImuB, and also occurs as a standalone protein. We present evidence using gene neighborhood analysis that both these domains function with different mutagenic polymerases in bacteria, such as Pol IV (DinB), Pol V (UmuCD) and ImuA-ImuB-DnaE2 and also other repair systems, which either deploy Ku and an ATP-dependent ligase or a SplB-like radical SAM photolyase. We suggest that the SRAP superfamily domain functions as a DNA-associated autoproteolytic switch that recruits diverse repair enzymes upon DNA damage, whereas the ImuB-C domain performs a similar function albeit in a non-catalytic fashion. We propose that C3Orf37, the eukaryotic member of the SRAP superfamily, which has been recently shown to specifically bind DNA with 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, is a sensor for these oxidized bases generated by the TET enzymes from methylcytosine. Hence, its autoproteolytic activity might help it act as a switch that recruits DNA repair enzymes to remove these oxidized methylcytosine species as part of the DNA demethylation pathway downstream of the TET enzymes. C1 [Aravind, L.; Anand, Swadha; Iyer, Lakshminarayan M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU US Department of Health and Human Services (National Library of Medicine, NIH) FX The authors' research is supported by the intramural funds of the US Department of Health and Human Services (National Library of Medicine, NIH). NR 29 TC 7 Z9 10 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD AUG 15 PY 2013 VL 8 AR 20 DI 10.1186/1745-6150-8-20 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 207DI UT WOS:000323577100001 PM 23945014 ER PT J AU Horning, SJ Haber, DA Selig, WKD Ivy, SP Roberts, SA Allen, JD Sigal, EV Sawyers, CL AF Horning, Sandra J. Haber, Daniel A. Selig, Wendy K. D. Ivy, S. Percy Roberts, Samantha A. Allen, Jeff D. Sigal, Ellen V. Sawyers, Charles L. TI Developing Standards for Breakthrough Therapy Designation in Oncology SO CLINICAL CANCER RESEARCH LA English DT Article AB In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential "breakthrough" drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a "Breakthrough Therapy", the U. S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy. (C)2013 AACR. C1 [Horning, Sandra J.] Genentech Inc, San Francisco, CA 94080 USA. [Haber, Daniel A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haber, Daniel A.; Sawyers, Charles L.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Selig, Wendy K. D.] Melanoma Res Alliance, Washington, DC USA. [Roberts, Samantha A.; Allen, Jeff D.; Sigal, Ellen V.] Friends Canc Res, Washington, DC 20036 USA. [Ivy, S. Percy] NCI, Invest Drug Branch, CTEP, Rockville, MD USA. [Sawyers, Charles L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Roberts, SA (reprint author), Friends Canc Res, 1800 M St NW,Suite 1050 South, Washington, DC 20036 USA. EM sroberts@focr.org RI Sawyers, Charles/G-5327-2016 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [R01 CA129933] NR 9 TC 10 Z9 11 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2013 VL 19 IS 16 BP 4297 EP 4304 DI 10.1158/1078-0432.CCR-13-0523 PG 8 WC Oncology SC Oncology GA 201NG UT WOS:000323147700002 PM 23719260 ER PT J AU O'Konek, JJ Kato, S Takao, S Izhak, L Xia, Z Illarionov, P Besra, GS Terabe, M Berzofsky, JA AF O'Konek, Jessica J. Kato, Shingo Takao, Satomi Izhak, Liat Xia, Zheng Illarionov, Petr Besra, Gurdyal S. Terabe, Masaki Berzofsky, Jay A. TI beta-Mannosylceramide Activates Type I Natural Killer T Cells to Induce Tumor Immunity without Inducing Long-Term Functional Anergy SO CLINICAL CANCER RESEARCH LA English DT Article AB Purpose: Most studies characterizing antitumor properties of invariant natural killer T (iNKT) cells have used the agonist, alpha-galactosylceramide (alpha-GalCer). However, alpha-GalCer induces strong, long-lasting anergy of iNKT cells, which could be a major detriment for clinical therapy. A novel iNKT cell agonist, beta-mannosylceramide (beta-ManCer), induces strong antitumor immunity through a mechanism distinct from that of alpha-GalCer. The objective of this study was to determine whether beta-ManCer induces anergy of iNKT cells. Experimental Design: Induction of anergy was determined by ex vivo analysis of splenocytes from mice pretreated with iNKT cell agonists as well as in the CT26 lung metastasis in vivo tumor model. Results: beta-ManCer activated iNKT cells without inducing long-term anergy. The transience of anergy induction correlated with a shortened duration of PD-1 upregulation on iNKT cells activated with beta-ManCer, compared with alpha-GalCer. Moreover, whereas mice pretreated with alpha-GalCer were unable to respond to a second glycolipid stimulation to induce tumor protection for up to 2 months, mice pretreated with beta-ManCer were protected from tumors by a second stimulation equivalently to vehicle-treated mice. Conclusions: The lack of long-term functional anergy induced by beta-ManCer, which allows for a second dose to still give therapeutic benefit, suggests the strong potential for this iNKT cell agonist to succeed in settings where alpha-GalCer has failed. (C)2013 AACR. C1 [O'Konek, Jessica J.; Kato, Shingo; Takao, Satomi; Izhak, Liat; Xia, Zheng; Terabe, Masaki; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Illarionov, Petr; Besra, Gurdyal S.] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England. RP Terabe, M (reprint author), NCI, Vaccine Branch, NIH, Bldg 41,Room D702H,41 Medlars Dr, Bethesda, MD 20892 USA. EM terabe@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; Gui Foundation; Medical Research Council (U.K.); Wellcome Trust [084923/B/08/7]; Royal Society Wolfson Research Merit Award FX This work was financially supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Gui Foundation. G.S. Besra received support from the Medical Research Council (U.K.), the Wellcome Trust (084923/B/08/7), a Royal Society Wolfson Research Merit Award, and James Bardrick. NR 28 TC 4 Z9 4 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2013 VL 19 IS 16 BP 4404 EP 4411 DI 10.1158/1078-0432.CCR-12-2169 PG 8 WC Oncology SC Oncology GA 201NG UT WOS:000323147700013 PM 23804426 ER PT J AU Amiri-Kordestani, L Luchenko, V Peer, CJ Ghafourian, K Reynolds, J Draper, D Frye, R Woo, S Venzon, D Wright, J Skarulis, M Figg, WD Fojo, T Bates, SE Piekarz, RL AF Amiri-Kordestani, Laleh Luchenko, Victoria Peer, Cody J. Ghafourian, Kambiz Reynolds, James Draper, Deb Frye, Robin Woo, Sue Venzon, David Wright, John Skarulis, Monica Figg, William D. Fojo, Tito Bates, Susan E. Piekarz, Richard L. TI Phase I Trial of a New Schedule of Romidepsin in Patients with Advanced Cancers SO CLINICAL CANCER RESEARCH LA English DT Article AB Purpose: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. Experimental Design: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes. Results: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m(2) on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors-defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21-112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. Conclusions: A romidepsin dose of 7 mg/m(2) administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors. (C)2013 AACR. C1 [Amiri-Kordestani, Laleh; Luchenko, Victoria; Peer, Cody J.; Draper, Deb; Frye, Robin; Woo, Sue; Figg, William D.; Fojo, Tito; Bates, Susan E.; Piekarz, Richard L.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ghafourian, Kambiz] Washington Hosp Ctr, Dept Cardiol, Bethesda, MD USA. [Reynolds, James] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Wright, John; Piekarz, Richard L.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Skarulis, Monica] NIDDK, Clin Endocrine Sect, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, Bldg 10-12N226, Bethesda, MD 20892 USA. EM batess@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU NIH, National Cancer Institute, Center for Cancer Research; CRADA FX This work has been supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by a CRADA between the NCI and Celgene Corporation. NR 42 TC 17 Z9 18 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2013 VL 19 IS 16 BP 4499 EP 4507 DI 10.1158/1078-0432.CCR-13-0095 PG 9 WC Oncology SC Oncology GA 201NG UT WOS:000323147700022 PM 23757352 ER PT J AU Lin, SW Wheeler, DC Park, Y Spriggs, M Hollenbeck, AR Freedman, DM Abnet, CC AF Lin, Shih-Wen Wheeler, David C. Park, Yikyung Spriggs, Michael Hollenbeck, Albert R. Freedman, D. Michal Abnet, Christian C. TI Prospective Study of Ultraviolet Radiation Exposure and Mortality Risk in the United States SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE epidemiology; mortality; prospective; sunlight; ultraviolet radiation; vitamin D ID NONMELANOMA SKIN-CANCER; VITAMIN-D; SOLAR-RADIATION; UV-RADIATION; SUN EXPOSURE; IMMUNE-SYSTEM; SUNLIGHT; DISEASE; ASSOCIATION; DEATH AB Geographic variations in mortality rate in the United States could be due to several hypothesized factors, one of which is exposure to solar ultraviolet radiation (UVR). Limited evidence from previous prospective studies has been inconclusive. The association between ambient residential UVR exposure and total and cause-specific mortality risks in a regionally diverse cohort (346,615 white, non-Hispanic subjects, 50-71 years of age, in the National Institutes of Health (NIH)-AARP Diet and Health Study) was assessed, with accounting for individual-level confounders. UVR exposure (averaged for 1978-1993 and 1996-2005) from NASA's Total Ozone Mapping Spectrometer was linked to the US Census Bureau 2000 census tract of participants' baseline residence. Multivariate-adjusted Cox proportional-hazards models were used to estimate hazard ratios and 95% confidence intervals. Over 12 years, UVR exposure was associated with total deaths (n = 41,425; hazard ratio for highest vs. lowest quartiles (HRQ4 (vs.) Q1) = 1.06, 95% confidence interval (CI): 1.03, 1.09; P-trend < 0.001) and with deaths (all P-trend < 0.05) due to cancer (HRQ4 (vs.) Q1 = 1.06, 95% CI: 1.02, 1.11), cardiovascular disease (HRQ4 vs. Q1 = 1.06, 95% CI: 1.00, 1.12), respiratory disease (HRQ4 (vs.) Q1 = 1.37, 95% CI: 1.21, 1.55), and stroke (HRQ4 vs. Q1 = 1.16, 95% CI: 1.01, 1.33) but not with deaths due to injury, diabetes, or infectious disease. These results suggest that UVR exposure might not be beneficial for longevity. C1 [Lin, Shih-Wen; Park, Yikyung; Freedman, D. Michal; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, Sch Med, Richmond, VA USA. [Spriggs, Michael] Informat Management Serv Inc, Silver Spring, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Lin, SW (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E404,MSC9768, Bethesda, MD 20892 USA. EM lins4@mail.nih.gov RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Park, Yikyung/0000-0002-6281-489X FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This research was supported (in part) by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 49 TC 15 Z9 15 U1 1 U2 21 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2013 VL 178 IS 4 BP 521 EP 533 DI 10.1093/aje/kws589 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200CR UT WOS:000323045400003 PM 23863757 ER PT J AU Zheng, Y Yu, B Alexander, D Manolio, TA Aguilar, D Coresh, J Heiss, G Boerwinkle, E Nettleton, JA AF Zheng, Yan Yu, Bing Alexander, Danny Manolio, Teri A. Aguilar, David Coresh, Josef Heiss, Gerardo Boerwinkle, Eric Nettleton, Jennifer A. TI Associations Between Metabolomic Compounds and Incident Heart Failure Among African Americans: The ARIC Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE heart failure; metabolomics; risk factors ID ATHEROSCLEROSIS RISK; CARDIOVASCULAR HEALTH; PHYSICAL-ACTIVITY; BLOOD-PRESSURE; MEN BORN; P-CRESOL; COMMUNITIES; DISEASE; EPIDEMIOLOGY; FRAMINGHAM AB Heart failure is more prevalent among African Americans than in the general population. Metabolomic studies among African Americans may efficiently identify novel biomarkers of heart failure. We used untargeted methods to measure 204 stable serum metabolites and evaluated their associations with incident heart failure hospitalization (n = 276) after a median follow-up of 20 years (1987-2008) by using Cox regression in data from 1,744 African Americans aged 45-64 years without heart failure at baseline from the Jackson, Mississippi, field center of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for established risk factors, we found that 16 metabolites (6 named with known structural identities and 10 unnamed with unknown structural identities, the latter denoted by using the format X-12345) were associated with incident heart failure (P < 0.0004 based on a modified Bonferroni procedure). Of the 6 named metabolites, 4 are involved in amino acid metabolism, 1 (prolylhydroxyproline) is a dipeptide, and 1 (erythritol) is a sugar alcohol. After additional adjustment for kidney function, 2 metabolites remained associated with incident heart failure (for metabolite X-11308, hazard ratio = 0.75, 95% confidence interval: 0.65, 0.86; for metabolite X-11787, hazard ratio = 1.23, 95% confidence interval: 1.10, 1.37). Further structural analysis revealed X-11308 to be a dihydroxy docosatrienoic acid and X-11787 to be an isoform of either hydroxyleucine or hydroxyisoleucine. Our metabolomic analysis revealed novel biomarkers associated with incident heart failure independent of traditional risk factors. C1 [Zheng, Yan; Yu, Bing; Boerwinkle, Eric; Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Alexander, Danny] Metabolon Inc, Durham, NC USA. [Aguilar, David] Baylor Coll Med, Div Cardiovasc, Houston, TX 77030 USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Heiss, Gerardo] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Nettleton, JA (reprint author), Suite E641,1200 Hermann Pressler St, Houston, TX 77030 USA. EM jennifer.a.nettleton@uth.tmc.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [HHSN268201100005C, HHSN 268201100006C, HHSN268201100007C, HHSN2682011-00008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [3U01HG004402-02S1]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [5K01DK082729-04]; Burroughs Wellcome Fund [1008200] FX The ARIC Study is a collaborative study supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, contracts HHSN268201100005C, HHSN 268201100006C, HHSN268201100007C, HHSN2682011-00008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. The metabolomics research was sponsored by the National Human Genome Research Institute (3U01HG004402-02S1). J. A. N is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (5K01DK082729-04). Y. Z. and B. Y. are supported in part by a training fellowship from the Burroughs Wellcome Fund (grant 1008200). NR 55 TC 14 Z9 15 U1 1 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2013 VL 178 IS 4 BP 534 EP 542 DI 10.1093/aje/kwt004 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200CR UT WOS:000323045400004 PM 23788672 ER PT J AU Madigan, D Ryan, PB Schuemie, M Stang, PE Overhage, JM Hartzema, AG Suchard, MA DuMouchel, W Berlin, JA AF Madigan, David Ryan, Patrick B. Schuemie, Martijn Stang, Paul E. Overhage, J. Marc Hartzema, Abraham G. Suchard, Marc A. DuMouchel, William Berlin, Jesse A. TI Evaluating the Impact of Database Heterogeneity on Observational Study Results SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE database; heterogeneity; methods; population characteristics; reproducibility of results; surveillance ID MEDICAL OUTCOMES PARTNERSHIP; MYOCARDIAL-INFARCTION; ORAL BISPHOSPHONATES; RISK; METAANALYSIS; CANCER AB Clinical studies that use observational databases to evaluate the effects of medical products have become commonplace. Such studies begin by selecting a particular database, a decision that published papers invariably report but do not discuss. Studies of the same issue in different databases, however, can and do generate different results, sometimes with strikingly different clinical implications. In this paper, we systematically study heterogeneity among databases, holding other study methods constant, by exploring relative risk estimates for 53 drug-outcome pairs and 2 widely used study designs (cohort studies and self-controlled case series) across 10 observational databases. When holding the study design constant, our analysis shows that estimated relative risks range from a statistically significant decreased risk to a statistically significant increased risk in 11 of 53 (21%) of drug-outcome pairs that use a cohort design and 19 of 53 (36%) of drug-outcome pairs that use a self-controlled case series design. This exceeds the proportion of pairs that were consistent across databases in both direction and statistical significance, which was 9 of 53 (17%) for cohort studies and 5 of 53 (9%) for self-controlled case series. Our findings show that clinical studies that use observational databases can be sensitive to the choice of database. More attention is needed to consider how the choice of data source may be affecting results. C1 [Madigan, David] Columbia Univ, Dept Stat, New York, NY 10027 USA. [Ryan, Patrick B.; Stang, Paul E.; Berlin, Jesse A.] Janssen Res & Dev LLC, Titusville, NJ USA. [Schuemie, Martijn] Erasmus Univ, Dept Med Informat, Med Ctr Rotterdam, NL-3000 DR Rotterdam, Netherlands. [Overhage, J. Marc] Ctr Biomed Informat, Regenstrief Inst, Indianapolis, IN USA. [Overhage, J. Marc] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hartzema, Abraham G.] Univ Florida, Coll Pharm, Gainesville, FL USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Fielding Sch Publ Hlth, Los Angeles, CA USA. [DuMouchel, William] Oracle Hlth Sci, Burlington, MA USA. [Madigan, David; Ryan, Patrick B.; Schuemie, Martijn; Stang, Paul E.; Overhage, J. Marc; Hartzema, Abraham G.; Suchard, Marc A.; DuMouchel, William; Berlin, Jesse A.] Fdn Natl Inst Hlth, Observat Med Outcomes Partnership, Bethesda, MD USA. [Hartzema, Abraham G.] US FDA, Rockville, MD 20857 USA. RP Madigan, D (reprint author), Columbia Univ, Dept Stat, 1255 Amsterdam Ave, New York, NY 10027 USA. EM david.madigan@columbia.edu OI Overhage, Joseph/0000-0003-0223-0195 FU Foundation for the National Institutes of Health through Abbott Laboratories, Ltd.; Foundation for the National Institutes of Health through Amgen, Inc.; Foundation for the National Institutes of Health through AstraZeneca, PLC; Foundation for the National Institutes of Health through Bayer Healthcare Pharmaceuticals, Inc.; Foundation for the National Institutes of Health through Bristol-Myers Squibb Company; Foundation for the National Institutes of Health through Eli Lilly Co.; Foundation for the National Institutes of Health through GlaxoSmithKline, PLC; Foundation for the National Institutes of Health through Janssen Research and Development, LLC; Foundation for the National Institutes of Health through Lundbeck, Inc.; Foundation for the National Institutes of Health through Merck Co., Inc.; Foundation for the National Institutes of Health through Novartis Pharmaceuticals Corp.; Foundation for the National Institutes of Health through Pfizer, Inc.; Foundation for the National Institutes of Health through Pharmaceutical Research Manufacturers of America; Foundation for the National Institutes of Health through F. Hoffmann-La Roche, Ltd.; Foundation for the National Institutes of Health through Sanofi, SA; Foundation for the National Institutes of Health through Schering-Plough Corp.; Foundation for the National Institutes of Health through Takeda Pharmaceutical Co., Ltd. FX The Observational Medical Outcomes Partnership is funded by the Foundation for the National Institutes of Health through generous contributions from the following: Abbott Laboratories, Ltd.; Amgen, Inc.; AstraZeneca, PLC; Bayer Healthcare Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Eli Lilly & Co.; GlaxoSmithKline, PLC; Janssen Research and Development, LLC, Lundbeck, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corp.; Pfizer, Inc.; Pharmaceutical Research Manufacturers of America; F. Hoffmann-La Roche, Ltd.; Sanofi, SA; Schering-Plough Corp.; and Takeda Pharmaceutical Co., Ltd. NR 25 TC 44 Z9 44 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2013 VL 178 IS 4 BP 645 EP 651 DI 10.1093/aje/kwt010 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200CR UT WOS:000323045400015 PM 23648805 ER PT J AU Salas, LA Cantor, KP Tardon, A Serra, C Carrato, A Garcia-Closas, R Rothman, N Malats, N Silverman, D Kogevinas, M Villanueva, CM AF Salas, Lucas A. Cantor, Kenneth P. Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Rothman, Nathaniel Malats, Nuria Silverman, Debra Kogevinas, Manolis Villanueva, Cristina M. TI Biological and Statistical Approaches for Modeling Exposure to Specific Trihalomethanes and Bladder Cancer Risk SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE chloroform; complex mixtures; logistic models; principal-components analysis; Spain; trihalomethanes; urinary bladder neoplasms ID DISINFECTION BY-PRODUCTS; EVALUATING SUFFICIENT SIMILARITY; PRINCIPAL COMPONENT ESTIMATION; DRINKING-WATER SOURCE; CHEMICAL-MIXTURES; HALOACETIC ACIDS; RECTAL CANCERS; TREATED WATER; DBP MIXTURES; REGRESSION AB Lifetime exposure to trihalomethanes (THM) has been associated with increased risk of bladder cancer. We explored methods of analyzing bladder cancer risk associated with 4 THM (chloroform, bromodichloromethane, dibromochloromethane, and bromoform) as surrogates for disinfection by-product (DBP) mixtures in a case-control study in Spain (1998-2001). Lifetime average concentrations of THM in the households of 686 incident bladder cancer cases and 750 matched hospital-based controls were calculated. Several exposure metrics were modeled through conditional logistic regression, including the following analyses: total THM (mu g/L), cytotoxicity-weighted sum of total THM (pmol/L), 4 THM in separate models, 4 THM in 1 model, chloroform and the sum of brominated THM in 1 model, and a principal-components analysis. THM composition, concentrations, and correlations varied between areas. The model for total THM was stable and showed increasing dose-response trends. Models for separate THM provided unstable estimates and inconsistent dose-response relationships. Risk estimation for specific THM is hampered by the varying composition of the mixture, correlation between species, and imprecision of historical estimates. Total THM (mu g/L) provided a proxy measure of DBPs that yielded the strongest dose-response relationship with bladder cancer risk. A variety of metrics and statistical approaches should be used to evaluate this association in other settings. C1 [Salas, Lucas A.; Kogevinas, Manolis; Villanueva, Cristina M.] Ctr Res Environm Epidemiol, Barcelona 08003, Spain. [Salas, Lucas A.; Kogevinas, Manolis; Villanueva, Cristina M.] Hosp del Mar, Med Res Inst, Barcelona, Spain. [Salas, Lucas A.] Pompeu Fabra Univ, Dept Expt & Hlth Sci, Barcelona, Spain. [Cantor, Kenneth P.; Rothman, Nathaniel; Silverman, Debra] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Tardon, Adonina] Univ Oviedo, Dept Prevent Med & Publ Hlth, Fac Med, Oviedo, Spain. [Tardon, Adonina; Kogevinas, Manolis; Villanueva, Cristina M.] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Serra, Consol] Univ Pompeu Fabra, Ctr Res Occupat Hlth, Barcelona, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Carrato, Alfredo] Ramon y Cajal Univ Hosp, Dept Med Oncol, Madrid, Spain. [Garcia-Closas, Reina] Canarias Univ Hosp, Res Unit, San Cristobal la Laguna, Spain. [Malats, Nuria] Spanish Natl Canc Res Ctr, Madrid, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. RP Villanueva, CM (reprint author), Ctr Res Environm Epidemiol, Barcelona Biomed Res Pk,Dr Aiguader 88, Barcelona 08003, Spain. EM cvillanueva@creal.cat RI Serra, C/E-6879-2014; Malats, Nuria/H-7041-2015; Villanueva, Cristina/N-1942-2014; Kogevinas, Manolis/C-3918-2017; OI Serra, C/0000-0001-8337-8356; Malats, Nuria/0000-0003-2538-3784; Villanueva, Cristina/0000-0002-0783-1259; Salas, Lucas A/0000-0002-2279-4097 FU US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [NCI NO2-CP-11015]; Spanish Health Ministry [FIS/Spain 00/0745, ISIII-GO3/174]; European Union [BMH4-98-3243]; Erasmus Columbus Master Scholarship [2009-5123/001-001-ECW]; Colciencias PhD Scholarship [529/2011] FX This study was supported in part by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (contract NCI NO2-CP-11015). The project also received funding from the Spanish Health Ministry (grants FIS/Spain 00/0745 and ISIII-GO3/174) and the European Union (grant BMH4-98-3243). The current analyses were supported by an Erasmus Columbus Master Scholarship (grant 2009-5123/001-001-ECW to L. A. Salas) and a Colciencias PhD Scholarship (grant 529/2011 to L. A. Salas). NR 50 TC 2 Z9 3 U1 1 U2 25 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2013 VL 178 IS 4 BP 652 EP 660 DI 10.1093/aje/kwt009 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200CR UT WOS:000323045400016 PM 23648803 ER PT J AU Sun, HM Xia, MH Shahane, SA Jadhav, A Austin, CP Huang, RL AF Sun, Hongmao Xia, Menghang Shahane, Sampada A. Jadhav, Ajit Austin, Christopher P. Huang, Ruili TI Are hERG channel blockers also phospholipidosis inducers? SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE hERG; Phospholipidosis; qHTS ID LONG QT SYNDROME; NMR-SPECTROSCOPY; MEMBRANE AB Both pharmacophore models of the human ether-A-go-go-related gene (hERG) channel blockers and phospholipidosis (PLO) inducers contain a hydrophobic moiety and a hydrophilic motif/positively charged center, so it is interesting to investigate the overlap between the ligand chemical spaces of both targets. We have assayed over 4000 non-redundant drug-like compounds for both their hERG inhibitory activity and PLD inducing potential in a quantitative high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compounds identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compounds were positively charged. Among the 48 compounds that induced PLD without inhibiting hERG channel, 24 compounds (50.0%) carried steroidal structures. According to our results, hERG channel blockers and PLD inducers share a large chemical space. In addition, a positively charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker. C1 [Sun, Hongmao; Xia, Menghang; Shahane, Sampada A.; Jadhav, Ajit; Austin, Christopher P.; Huang, Ruili] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Sun, HM (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM sunh7@mail.nih.gov FU NIEHS NIH HHS [Y02 ES007020] NR 18 TC 10 Z9 10 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2013 VL 23 IS 16 BP 4587 EP 4590 DI 10.1016/j.bmcl.2013.06.034 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 194DT UT WOS:000322611900019 PM 23856051 ER PT J AU Murugan, RN Jacob, B Kim, EH Ahn, M Sohn, H Seo, JH Cheong, C Hyun, JK Lee, KS Shin, SY Bang, JK AF Murugan, Ravichandran N. Jacob, Binu Kim, Eun-Hee Ahn, Mija Sohn, Hoik Seo, Ji-Hyung Cheong, Chaejoon Hyun, Jae-Kyung Lee, Kyung S. Shin, Song Yub Bang, Jeong Kyu TI Non hemolytic short peptidomimetics as a new class of potent and broad-spectrum antimicrobial agents SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Short antimicrobial peptidomimetics; Methicillin-resistance Staphylococcus aureus; Proteolytic stability ID PEPTIDES AB Since the bacterial resistance to antibiotics is increasing rapidly, numerous studies have contributed to the design and synthesis of potent synthetic mimics of antimicrobial peptides (AMPs). In an attempt to find the pharmacophore of short antimicrobial peptidomimetics through systematic tuning of hydrophobic and hydrophilic patterns, we have identified a set of short histidine-derived antimicrobial peptides (SAMPs) with potent and broad-spectrum activity. A combination of high antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), without hemolytic activity and proteolytic stability makes these molecules promising candidates for novel antimicrobial therapeutics. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Murugan, Ravichandran N.; Kim, Eun-Hee; Ahn, Mija; Seo, Ji-Hyung; Cheong, Chaejoon; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Buk, South Korea. [Jacob, Binu; Shin, Song Yub] Chosun Univ, Grad Sch, Dept Biomat, Kwangju 501759, South Korea. [Jacob, Binu; Shin, Song Yub] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea. [Sohn, Hoik] Univ Texas Austin, Dept Chem & Biochem, Coll Nat Sci, Austin, TX 78712 USA. [Hyun, Jae-Kyung] Korea Basic Sci Inst, Div Electron Micorscop Res, Taejon 305333, South Korea. [Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shin, SY (reprint author), Chosun Univ, Grad Sch, Dept Biomat, Kwangju 501759, South Korea. EM syshin@chosun.ac.kr; bangjk@kbsi.re.kr RI Jacob, Binu/K-7621-2016 OI Jacob, Binu/0000-0002-2770-8741 FU Korea Basic Science Institute [T33418, T33518]; National Cancer Institute; Korea Research Foundation; Korean Government [KRF-2011-0009039] FX This work was supported in part by the Korea Basic Science Institute's research grant T33418 (J.K.B.), T33518 (J-K.H.), the National Cancer Institute's Intramural Research grant (K.S.L.) and the Korea Research Foundation funded by the Korean Government (KRF-2011-0009039 to S.Y.S.). NR 8 TC 11 Z9 12 U1 0 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2013 VL 23 IS 16 BP 4633 EP 4636 DI 10.1016/j.bmcl.2013.06.016 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 194DT UT WOS:000322611900027 PM 23816372 ER PT J AU dos Santos, ED Hamel, E Bai, RL Burnett, JC Tozatti, CSS Bogo, D Perdomo, RT Antunes, AMM Marques, MM Matos, MDC de Lima, DP AF dos Santos, Edson dos A. Hamel, Ernest Bai, Ruoli Burnett, James C. Suniga Tozatti, Camila Santos Bogo, Danielle Perdomo, Renata T. Antunes, Alexandra M. M. Matilde Marques, M. Matos, Maria de F. C. de Lima, Denis P. TI Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Diaryl selenide; Diaryl sulfide; Combretastatin A-4; Tubulin; Cytotoxicity ID TUBULIN POLYMERIZATION; COMBRETASTATIN A-4; BIOLOGICAL EVALUATION; ANTINEOPLASTIC AGENTS; INHIBITORS; DERIVATIVES; COLCHICINE; ANALOGS; SULFUR AB We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site. (C) 2013 Elsevier Ltd. All rights reserved. C1 [dos Santos, Edson dos A.; Suniga Tozatti, Camila Santos; de Lima, Denis P.] Univ Fed Mato Grosso do Sul, Inst Quim, Lab LP4, BR-79070900 Campo Grande, MS, Brazil. [Hamel, Ernest; Bai, Ruoli] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,FNLCR, Ft Detrick, MD 21702 USA. [Burnett, James C.] NCI, Computat Drug Dev Grp, Dev Therapeut Program, FNLCR, Frederick, MD 21702 USA. [Bogo, Danielle; Perdomo, Renata T.; Matos, Maria de F. C.] Univ Fed Mato Grosso do Sul, Lab Biol Mol & Culturas Celulares CBS, BR-79070900 Campo Grande, MS, Brazil. [Antunes, Alexandra M. M.; Matilde Marques, M.] Univ Tecn Lisboa, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. RP de Lima, DP (reprint author), Univ Fed Mato Grosso do Sul, Inst Quim, Lab LP4, Av Filinto Muller, BR-79070900 Campo Grande, MS, Brazil. EM denis.lima@ufms.br RI Marques, M. Matilde/E-2535-2012; PTMS, RNEM/C-1589-2014; de Lima, Denis/D-7039-2014; Antunes, Alexandra/B-7871-2009; dos Santos, Edson/I-6324-2016 OI Marques, M. Matilde/0000-0002-7526-4962; de Lima, Denis/0000-0002-6023-4867; Antunes, Alexandra/0000-0003-1827-7369; FU CQE-IST; ERASMUS-MUNDUS; FUNDECT-MS; CNPq; PROPP-UFMS; UFMS; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) [PEst-OE/QUI/UI0100/2011, PEst-OE/QUI/UI0100/2013] FX The authors thank Dr. Roberto da Silva Gomes for providing mass spectra of some compounds. We are indebted to CQE-IST, ERASMUS-MUNDUS, FUNDECT-MS, CNPq and PROPP-UFMS for financial support and scholarships. We also thank UFMS and CQE-IST that supported this work. For J.C.B., in accordance with SAIC-Frederick, Inc. contractual requirements, the following statement is required: this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This work was also supported by Fundacao para a Ciencia e a Tecnologia (FCT, Portugal), through pluriannual funds to Centro de Quimica Estrutural (PEst-OE/QUI/UI0100/2011 and PEst-OE/QUI/UI0100/2013). NR 28 TC 11 Z9 11 U1 0 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2013 VL 23 IS 16 BP 4669 EP 4673 DI 10.1016/j.bmcl.2013.06.009 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 194DT UT WOS:000322611900035 ER PT J AU Jedhe, GS Paul, D Gonnade, RG Santra, MK Hamel, E Nguyen, TL Sanjayan, GJ AF Jedhe, Ganesh S. Paul, Debasish Gonnade, Rajesh G. Santra, Manas K. Hamel, Ernest Tam Luong Nguyen Sanjayan, Gangadhar J. TI Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Combretastatin; Tetrazole; Crystal; Colchicine; Tubulin ID ANTINEOPLASTIC AGENTS; BIOLOGICAL EVALUATION; ANTITUMOR-ACTIVITY; A-4 ANALOGS; TUBULIN; INHIBITORS; PHOSPHATE; POTENT; METABOLISM; COLCHICINE AB A series of 1,5-disubstituted tetrazole-tethered combretastatin analogues with extended hydrogen-bond donors at the ortho-positions of the aryl A and B rings were developed and evaluated for their antitubulin and antiproliferative activity. We wanted to test whether intramolecular hydrogen-bonding used as a conformational locking element in these analogues would improve their activity. The correlation of crystal structures with the antitubulin and antiproliferative profiles of the modified analogues suggested that hydrogen-bond-mediated conformational control of the A ring is deleterious to the bioactivity. In contrast, although there was no clear evidence that intramolecular hydrogen bonding to the B ring enhanced activity, we found that increased substitution on the B ring had a positive effect on antitubulin and antiproliferative activity. Among the various analogues synthesized, compounds 5d and 5e, having hydrogen-bonding donor groups at the ortho and meta-positions on the 4-methoxy phenyl B ring, are strong inhibitors of tubulin polymerization and antiproliferative agents having IC50 value in micromolar concentrations. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Jedhe, Ganesh S.; Sanjayan, Gangadhar J.] Natl Chem Lab, Div Organ Chem, Pune 411008, Maharashtra, India. [Paul, Debasish; Santra, Manas K.] Univ Pune Campus, Natl Ctr Cell Sci, Pune 411007, Maharashtra, India. [Gonnade, Rajesh G.] Natl Chem Lab, Ctr Mat Characterizat, Pune 411008, Maharashtra, India. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Tam Luong Nguyen] Frederick Natl Lab Canc Res, Target Struct Based Drug Discovery Grp, SAIC Frederick, Frederick, MD 21702 USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. EM gj.sanjayan@ncl.res.in RI Jedhe, Ganesh/M-9019-2015 OI Jedhe, Ganesh/0000-0001-7404-3677 FU CSIR, New Delhi; CSIR-Biodiversity programme [BSC-0120]; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX G.S.J. is thankful to CSIR, New Delhi, for a research fellowship. G.J.S. thanks CSIR-Biodiversity programme (BSC-0120) for funding this project. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 37 TC 10 Z9 10 U1 0 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2013 VL 23 IS 16 BP 4680 EP 4684 DI 10.1016/j.bmcl.2013.06.004 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 194DT UT WOS:000322611900037 PM 23809851 ER PT J AU Miranda, TB Voss, TC Sung, MH Baek, S John, S Hawkins, M Grontved, L Schiltz, RL Hager, GL AF Miranda, Tina B. Voss, Ty C. Sung, Myong-Hee Baek, Songjoon John, Sam Hawkins, Mary Grontved, Lars Schiltz, R. Louis Hager, Gordon L. TI Reprogramming the Chromatin Landscape: Interplay of the Estrogen and Glucocorticoid Receptors at the Genomic Level SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER-CELLS; RESPONSE ELEMENT; IN-VIVO; EXPRESSION; ACTIVATION; BINDING; DNA; DEXAMETHASONE; PROGESTERONE; ACCESSIBILITY AB Cross-talk between estrogen receptors (ER) and glucocorticoid receptors (GR) has been shown to contribute to the development and progression of breast cancer. Importantly, the ER and GR status in breast cancer cells is a significant factor in determining the outcome of the disease. However, mechanistic details defining the cellular interactions between ER and GR are poorly understood. Weinvestigated genome-wide binding profiles for ER and GR upon coactivation and characterized the status of the chromatin landscape. We describe a novel mechanism dictating the molecular interplay between ER and GR. Upon induction, GR modulates access of ER to specific sites in the genome by reorganization of the chromatin configuration for these elements. Binding to these newly accessible sites occurs either by direct recognition of ER response elements or indirectly through interactions with other factors. The unveiling of this mechanism is important for understanding cellular interactions between ER and GR and may represent a general mechanism for cross-talk between nuclear receptors in human disease. (C) 2013 AACR. C1 [Miranda, Tina B.; Voss, Ty C.; Sung, Myong-Hee; Baek, Songjoon; John, Sam; Hawkins, Mary; Grontved, Lars; Schiltz, R. Louis; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, 41 Lib Dr, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov OI Grontved, Lars/0000-0002-6735-8483 FU NIH, National Cancer Institute, Center for Cancer Research; National Institute of General Medical Sciences Pharmacological Research and Training Fellowship; Lundbeck Foundation FX This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. T. B. Miranda was supported, in part, by a National Institute of General Medical Sciences Pharmacological Research and Training Fellowship. L. Grontved was supported by a research grant from the Lundbeck Foundation. NR 40 TC 30 Z9 30 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2013 VL 73 IS 16 BP 5130 EP 5139 DI 10.1158/0008-5472.CAN-13-0742 PG 10 WC Oncology SC Oncology GA 201RX UT WOS:000323161800017 PM 23803465 ER PT J AU Sanghvi, M Ramamoorthy, A Strait, J Wainer, IW Moaddel, R AF Sanghvi, M. Ramamoorthy, A. Strait, J. Wainer, I. W. Moaddel, R. TI Development and validation of a sensitive LC-MS/MS method for the determination of fenoterol in human plasma and urine samples SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Congestive heart failure; Bioavailability; Chirobiotic T; beta(2)-Adrenergic receptor agonist ID MASS-SPECTROMETRY; SEPARATION; RAT; DERIVATIZATION; ENANTIOMERS; DERIVATIVES; METABOLISM; HPLC AB Due to the lack of sensitivity in current methods for the determination of fenoterol (Fen), a rapid LC-MS/MS method was developed for the determination of (R,R')-Fen and (R,R';S,S')-Fen in plasma and urine. The method was fully validated and was linear from 50 pg/ml to 2000 pg/ml for plasma and from 2.500 ng/ml to 160 ng/ml for urine with a lower limit of quantitation of 52.8 pg/ml in plasma. The coefficient of variation was <15% for the high QC standards and <10% for the low QC standards in plasma and was <15% for the high and low QC standards in urine. The relative concentrations of (R,R')-Fen and (S,S')Fen were determined using a chirobiotic T chiral stationary phase. The method was used to determine the concentration of (R,R')-Fen in plasma and urine samples obtained in an oral cross-over study of (R,R')Fen and (R,R';S,S')-Fen formulations. The results demonstrated a potential pre-systemic enantioselective interaction in which the (S,S')-Fen reduces the sulfation of the active (R,R')-Fen. The data suggest that a non-racemic mixture of the Fen enantiomers may provide better bioavailability of the active (R,R')-Fen for use in the treatment of cardiovascular disease. Published by Elsevier B.V. C1 [Sanghvi, M.; Ramamoorthy, A.; Wainer, I. W.; Moaddel, R.] NIA, Clin Invest Lab, Div Intramural Res Programs, NIH, Baltimore, MD 21224 USA. [Strait, J.] NIA, Cardiovasc Sci Lab, Div Intramural Res Programs, NIH, Baltimore, MD 21224 USA. RP Moaddel, R (reprint author), NIA, Clin Invest Lab, Biomed Res Ctr, NIH, 8C232,251 Bayview Blvd, Baltimore, MD 21224 USA. EM moaddelru@mail.nih.gov FU National Institute on Aging/NIH FX This research was supported by the Intramural Research Program of the National Institute on Aging/NIH. NR 24 TC 2 Z9 2 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD AUG 15 PY 2013 VL 933 BP 37 EP 43 DI 10.1016/j.jchromb.2013.06.020 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 198MM UT WOS:000322927000006 PM 23872161 ER PT J AU Zhang, JW Ferre-D'Amare, AR AF Zhang, Jinwei Ferre-D'Amare, Adrian R. TI Co-crystal structure of a T-box riboswitch stem I domain in complex with its cognate tRNA SO NATURE LA English DT Article ID AMINOACYL-TRANSFER-RNA; RIBOSOMAL-RNA; BACILLUS-SUBTILIS; RIBONUCLEASE-P; ANTITERMINATION; MOTIF; RECOGNITION; SYNTHETASE; TRNA(GLY); FEATURES AB In Gram-positive bacteria, T-box riboswitches regulate the expression of aminoacyl-tRNA synthetases and other proteins in response to fluctuating transfer RNA aminoacylation levels under various nutritional states(1). T-boxes reside in the 5'-untranslated regions of the messenger RNAs they regulate, and consist of two conserved domains. Stem I contains the specifier trinucleotide that base pairs with the anticodon of cognate tRNA. 3' to stem I is the antiterminator domain, which base pairs with the tRNA acceptor end and evaluates its aminoacylation state(2). Despite high phylogenetic conservation and widespread occurrence in pathogens, the structural basis of tRNA recognition(3,4) by this riboswitch remains ill defined. Here we demonstrate that the similar to 100-nucleotide T-box stem I is necessary and sufficient for specific, high-affinity (dissociation constant (K-d) similar to 150 nM) tRNA binding, and report the structure of Oceanobacillus iheyensis glyQ stem I in complex with its cognate tRNA at 3.2 angstrom resolution. Stem I recognizes the overall architecture of tRNA in addition to its anticodon, something accomplished by large ribonucleoproteins such as the ribosome, or proteins such as aminoacyl-tRNA synthetases(5), but is unprecedented for a compact mRNA domain. The C-shaped stem I cradles the L-shaped tRNA, forming an extended (1,604 angstrom(2)) intermolecular interface. In addition to the specifier-anticodon interaction, two interdigitated T-loops near the apex of stem I stack on the tRNA elbow in a manner analogous to those of the J11/12-J12/11 motif(6) of RNase P and the L1 stalk(7) of the ribosomal E-site. Because these ribonucleoproteins and T-boxes are unrelated, this strategy to recognize a universal tRNA feature probably evolved convergently. Mutually induced fit of stem I and the tRNA exploiting the intrinsic flexibility of tRNA and its conserved post-transcriptional modifications results in high shape complementarity, which in addition to providing specificity and affinity, globally organizes the T-box to orchestrate tRNA-dependent transcription regulation. C1 [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU National Institute for General Medical Sciences, National Institutes of Health (NIH); US Department of Energy; intramural program of the National Heart, Lung, and Blood Institute, NIH FX We thank the staff at beamlines 24-ID-C and 24-ID-E of APS and 5.0.1 and 5.0.2 of the ALS for crystallographic data collection support, G. Piszczek for ITC support, R. Levine and D.-Y. Lee for help with mass spectrometry, K. Perry and K. R. Rajashankar for assistance with initial crystallographic phasing, and N. Baird, T. Hamma, C. Jones, M. Lau, J. Posakony, A. Roll-Mecak, O. Uhlenbeck and K. Warner for discussions. This work is partly based on research conducted at the APS on the Northeastern Collaborative Access Team (NE-CAT) beamlines, and at the ALS on the Berkeley Center for Structural Biology beamlines, which are both supported by the National Institute for General Medical Sciences, National Institutes of Health (NIH). Use of ALS and APS was supported by the US Department of Energy. This work was supported in part by the intramural program of the National Heart, Lung, and Blood Institute, NIH. NR 52 TC 42 Z9 45 U1 2 U2 60 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 15 PY 2013 VL 500 IS 7462 BP 363 EP + DI 10.1038/nature12440 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201AF UT WOS:000323112400039 PM 23892783 ER PT J AU Shuch, B Hanley, J Lai, J Vourganti, S Kim, SP Setodji, CM Dick, AW Chow, WH Saigal, C AF Shuch, Brian Hanley, Janet Lai, Julie Vourganti, Srinivas Kim, Simon P. Setodji, Claude M. Dick, Andrew W. Chow, Wong-Ho Saigal, Chris CA Urologic Dis Amer Project TI Overall survival advantage with partial nephrectomy: A bias of observational data? SO CANCER LA English DT Article DE partial nephrectomy; radical nephrectomy; survival advantage; observational data; selection bias ID RENAL-CELL CARCINOMA; NEPHRON-SPARING SURGERY; CHRONIC KIDNEY-DISEASE; NORMAL CONTRALATERAL KIDNEY; RADICAL NEPHRECTOMY; MORTALITY; CANCER; TUMOR; METAANALYSIS; COMORBIDITY AB BACKGROUND: Partial nephrectomy (PN) and radical nephrectomy (RN) are standard treatments for a small renal mass. Retrospective studies suggest an overall survival (OS) advantage, however a randomized phase 3 trial suggests otherwise. The effects of both surgical modalities on OS were evaluated compared with controls. METHODS: A matched cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset. Individuals treated with PN or RN for localized renal cell carcinoma (RCC) measuring <= 4 cm were compared with 2 control groups (non-muscle-invasive bladder cancer (BCC) and noncancer controls (NCC). Using a greedy algorithm, RCC groups were matched with controls by demographics and comorbidities. OS for surgical groups and controls were compared. The cause of death was evaluated for cancer groups when differences in OS were noted. RESULTS: Patients undergoing PN and RN were matched with controls. All cancer groups had >95% 10-year cancer-specific survival (CSS). Median OS was similar between RN (9.05 years) and BCC (8.67 years; P = .067) and NCC (8.77 years; P = .49). Median OS was improved for PN (10.45 years) compared with BCC (8.75 years; P <. 001) and NCC controls (8.76 years; P < .001). A multivariate Cox hazards model demonstrated that PN improved OS compared with NCC (hazard ratio, 1.257; P < .001) and BCC (hazard ratio, 1.364; P<. 001). CONCLUSIONS: RN patients had similar OS compared with controls, suggesting that this treatment modality does not compromise survival. Patients undergoing PN had improved OS compared with controls, suggesting possible selection bias. The apparent survival advantage conferred by PN in SEER-Medicare case series is likely the result of selection bias involving unmeasured confounders. Cancer 2013; 119: 2981-9. (C) 2013 American Cancer Society. C1 [Shuch, Brian; Kim, Simon P.] Yale Univ, Sch Med, Dept Urol, New Haven, CT USA. [Shuch, Brian; Vourganti, Srinivas] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Hanley, Janet; Lai, Julie; Setodji, Claude M.; Dick, Andrew W.] RAND Corp, Santa Monica, CA USA. [Kim, Simon P.] Mayo Clin, Rochester, MN USA. [Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Saigal, Chris] Univ Calif Los Angeles, Sch Med, Dept Urol, Inst Urol Oncol, Los Angeles, CA USA. RP Shuch, B (reprint author), NCI, Urol Oncol Branch, Bldg 10 CRC Room 1-5940, Bethesda, MD 20892 USA. EM brian.shuch@yale.edu FU National Institutes of Health [HHSN276201200016C] FX The Urologic Disease of America Project is supported by National Institutes of Health grant HHSN276201200016C. NR 31 TC 29 Z9 29 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 2981 EP 2989 DI 10.1002/cncr.28141 PG 9 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400009 PM 23674264 ER PT J AU Patel, C Stenke, L Varma, S Lindberg, ML Bjorkholm, M Sjoberg, J Viktorsson, K Lewensohn, R Landgren, O Gottesman, MM Gillet, JP AF Patel, Chirayu Stenke, Leif Varma, Sudhir Lindberg, Marita Lagergren Bjorkholm, Magnus Sjoberg, Jan Viktorsson, Kristina Lewensohn, Rolf Landgren, Ola Gottesman, Michael M. Gillet, Jean-Pierre TI Multidrug resistance in relapsed acute myeloid leukemia: Evidence of biological heterogeneity SO CANCER LA English DT Article DE acute myeloid leukemia; acquired drug resistance; therapy-related drug resistance; multidrug resistance; leukemia cell lines ID P-GLYCOPROTEIN; EXPRESSION; CANCER; AML; TRANSPORTERS; CHEMOTHERAPY AB BACKGROUND: Studies of mechanisms mediating resistance to chemotherapy led to the discovery of the multidrug transporter ABCB1 (ATP-binding cassette, subfamily B, member 1), often expressed in leukemic cells of patients with acute myeloid leukemia (AML). Most clinical trials evaluating the strategy of inhibiting efflux-mediated chemotherapeutic resistance have been unsuccessful, clearly indicating the need for a better approach. METHODS: This study investigated the clinical relevance of 380 genes whose expression has been shown to affect the response to chemotherapy, mostly through in vitro studies, in 11 paired samples obtained at AML diagnosis and at relapse. The expression profiling of these 380 genes was performed using TaqMan-based quantitative reverse-transcription polymerase chain reaction. Patients had a median age of 58 years at diagnosis, a median duration of complete remission of 284.5 days, and a median overall survival of 563 days. Cytogenetic abnormalities were detected at diagnosis in 4 patients, whereas 5 displayed a normal karyotype and 2 were not investigated. RESULTS: Hierarchical clustering shows that samples taken at diagnosis and relapse clustered in pairs for 6 patients of the 11 studied, suggesting recurrence of the same leukemic blast, whereas for the other 5 patients, the data indicate their relapse blasts arose from different origins. A patient-by-patient analysis of the paired samples led to the striking observation that each had a unique gene signature representing different mechanisms of resistance. CONCLUSIONS: The data underline the need for personalized molecular analysis to tailor treatment for patients with AML. Cancer 2013; 119: 3076-83. (C) 2013 American Cancer Society. C1 [Patel, Chirayu; Gottesman, Michael M.; Gillet, Jean-Pierre] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Patel, Chirayu] HHMI NIH Res Scholars Program, Bethesda, MD USA. [Stenke, Leif; Lindberg, Marita Lagergren; Bjorkholm, Magnus] Karolinska Inst, Dept Med, Stockholm, Sweden. [Stenke, Leif; Lindberg, Marita Lagergren; Bjorkholm, Magnus; Sjoberg, Jan; Viktorsson, Kristina; Lewensohn, Rolf] St Gorans Univ Hosp, S-11281 Stockholm, Sweden. [Stenke, Leif; Lindberg, Marita Lagergren; Sjoberg, Jan; Viktorsson, Kristina; Lewensohn, Rolf] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Varma, Sudhir] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, Off Sci Management & Operat,NIH, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU HHMI-NIH Research Scholars Program; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Swedish National Board of Health and Welfare; Adolf H. Lundin Charitable Foundation FX The HHMI-NIH Research Scholars Program supported the research training of Chirayu Patel. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; the Swedish National Board of Health and Welfare; and the Adolf H. Lundin Charitable Foundation. NR 24 TC 12 Z9 12 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 3076 EP 3083 DI 10.1002/cncr.28098 PG 8 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400021 PM 23674237 ER PT J AU Chow, WH Linehan, WM Devesa, SS AF Chow, Wong-Ho Linehan, W. Marston Devesa, Susan S. TI Reply to Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics SO CANCER LA English DT Letter C1 [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chow, WH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. FU Intramural NIH HHS NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 3101 EP 3101 DI 10.1002/cncr.28125 PG 1 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400025 PM 23695994 ER PT J AU Tamma, PD Powers, JH AF Tamma, Pranita D. Powers, John H. TI Do Patient Data Really Support the Clinical and Laboratory Standards Institute Recommendation for Lowering Third-Generation Cephalosporin Interpretive Breakpoints? SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID PSEUDOMONAS-AERUGINOSA; PIPERACILLIN-TAZOBACTAM; STAPHYLOCOCCUS-AUREUS; BACTEREMIA; OUTCOMES; ENTEROBACTERIACEAE; INFECTIONS; CEFEPIME C1 [Tamma, Pranita D.] Johns Hopkins Med Inst, Div Pediat Infect Dis, Dept Pediat, Baltimore, MD 21287 USA. [Powers, John H.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Tamma, PD (reprint author), Johns Hopkins Med Inst, Div Pediat Infect Dis, Dept Pediat, 200 N Wolfe St,Ste 3155, Baltimore, MD 21287 USA. EM ptamma1@jhmi.edu NR 12 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2013 VL 57 IS 4 BP 624 EP U275 DI 10.1093/cid/cit308 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 190LV UT WOS:000322342500034 PM 23658433 ER PT J AU Klase, Z Jeang, KT AF Klase, Zachary Jeang, Kuan-Teh TI Reciprocal functional pseudotyping of HIV-1 and HTLV-1 viral genomes by the heterologous counterpart envelope proteins SO VIROLOGY LA English DT Article DE HIV-1; HTLV-1; Pseudotyping; Chimera ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL LYMPHOTROPIC VIRUS; HEPATITIS-C VIRUS; GLUCOSE-TRANSPORTER GLUT-1; MURINE LEUKEMIA-VIRUS; CD4 DOWN-MODULATION; SUPERINFECTION EXCLUSION; T-CELLS; SUPER-INFECTION; I INFECTION AB HIV-1 and HTLV-1 can infect CD4+ T cells and can co-infect the same individual. In principle, it is possible that both viruses can infect the same CD4+ T cells in dually infected persons. Currently, how efficiently HTLV-1 and HIV-1 co-infects the same cell and the full extent of their biological interactions are not well-understood. Here, we report evidence confirming that both viruses can infect the same cells and that HTLV-1 envelope (Env) can pseudotype HIV-1 viral particles and HIV-1 envelope (Env) can pseudotype HTLV-1 virions to mediate subsequent infections of substrate cells. We also show that the construction of a chimeric HTLV-1 molecular clone carrying the HIV-1 Env in place of its HTLV-1 counterpart results in a replication competent moiety. These findings raise new implications of viral complementation and assortment between HIV-1 and HTLV-1 in dually infected persons. Published by Elsevier Inc. C1 [Klase, Zachary; Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Klase, Z (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM klaseza@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 47 TC 0 Z9 0 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2013 VL 443 IS 1 BP 106 EP 112 DI 10.1016/j.virol.2013.04.027 PG 7 WC Virology SC Virology GA 189SZ UT WOS:000322289900012 PM 23747197 ER PT J AU Chess, DJ Billings, E Covian, R Glancy, B French, S Taylor, J de Bari, H Murphy, E Balaban, RS AF Chess, David J. Billings, Eric Covian, Raul Glancy, Brian French, Stephanie Taylor, Joni de Bari, Heather Murphy, Elizabeth Balaban, Robert S. TI Optical spectroscopy in turbid media using an integrating sphere: Mitochondrial chromophore analysis during metabolic transitions SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Mitochondria; Spectroscopy; Electron transport chain; Ischemia/reperfusion ID CYTOCHROME-C-OXIDASE; OXIDATIVE-PHOSPHORYLATION SYSTEM; ISOLATED CARDIAC MYOCYTES; ELECTRON-TRANSPORT CHAIN; RAT-LIVER MITOCHONDRIA; RESPIRATORY-CHAIN; IN-VIVO; IRREVERSIBLE-PROCESSES; RECIPROCAL RELATIONS; KINETIC-ANALYSIS AB Recent evidence suggests that the activity of mitochondrial oxidative phosphorylation complexes (MOPCs) is modulated at multiple sites. Here, a method of optically monitoring electron distribution within and between MOPCs is described using a center-mounted sample in an integrating sphere (to minimize scattering effects) with a rapid-scanning spectrometer. The redox-sensitive MOPC absorbances (similar to 465-630 nm) were modeled using linear least squares analysis with individual chromophore spectra. Classical mitochondrial activity transitions (e.g., ADP-induced increase in oxygen consumption) were used to characterize this approach. Most notable in these studies was the observation that intermediates of the catalytic cycle of cytochrome oxidase are dynamically modulated with metabolic state. The MOPC redox state, along with measurements of oxygen consumption and mitochondrial membrane potential, was used to evaluate the conductances of different sections of the electron transport chain. This analysis then was applied to mitochondria isolated from rabbit hearts subjected to ischemia/reperfusion (I/R). Surprisingly, I/R resulted in an inhibition of all measured MOPC conductances, suggesting a coordinated down-regulation of mitochondrial activity with this well-established cardiac perturbation. Published by Elsevier Inc. C1 [Chess, David J.; Billings, Eric; Covian, Raul; Glancy, Brian; French, Stephanie; Taylor, Joni; de Bari, Heather; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Chess, DJ (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM chessdj@mail.nih.gov RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU National Institutes of Health (NIH) FX Research was supported by the National Institutes of Health (NIH) Intramural Research Program. NR 67 TC 5 Z9 5 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 15 PY 2013 VL 439 IS 2 BP 161 EP 172 DI 10.1016/j.ab.2013.04.017 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 189RV UT WOS:000322286900013 PM 23665273 ER PT J AU Roy-Engel, AM Moss, T Maraia, RJ AF Roy-Engel, Astrid M. Moss, Thomas Maraia, Richard J. TI Meeting report for Odd Pols 2012 SO GENE LA English DT Article AB The Eighth International Biennial Conference on RNA polymerases land III (the 'Odd Pols') was held June 7-11, 2012 at The Airlie Center in Warrenton Virginia, USA. It was sponsored by the Universite Laval and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, and organized by Rich Maraia and Tom Moss. The meeting honored the memory of Pierre Thuriaux (Jan 1, 1950-March 18, 2012) and David Schneider reminisced on the important accomplishments his mentor Masayasu Nomura (1927-2011). The goal of the conference was to bring together the world's experts on RNA polymerase I and RNA polymerase III to highlight and share their latest results and varied experimental approaches. The meeting drew attendees from twelve countries and most contributed through oral and poster presentations. The talks were organized into several sessions subdivided into 10 distinct topics. The keynote speaker, Ian Willis, opened the meeting with his presentation entitled "New Regulators of Signaling to Odd Pols" and the closing presentation was given by Patrick Cramer with his presentation "Conservation of the RNA polymerase I, II and III transcription initiation machineries". Here we present some of the highlights from the meeting using summaries provided by the participants. (C) 2013 Elsevier B.V. All rights reserved. C1 [Roy-Engel, Astrid M.] Tuane Canc Ctr, Dept Epidemiol, New Orleans, LA 70112 USA. [Roy-Engel, Astrid M.] Louisiana Canc Res Consortium, New Orleans, LA 70112 USA. [Moss, Thomas] Univ Laval, Hotel Dieu Quebec, Canc Res Ctr, Quebec City, PQ G1R 2J6, Canada. [Moss, Thomas] Univ Laval, Hotel Dieu Quebec, Dept Med Biol Med Biochem & Pathol, Quebec City, PQ G1R 2J6, Canada. [Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Dfferentiat, NIH, Bethesda, MD USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Rockville, MD USA. RP Roy-Engel, AM (reprint author), Tuane Canc Ctr, Dept Epidemiol, 1430 Tulane Ave,SL-66, New Orleans, LA 70112 USA. EM aengel@tulane.edu OI Engel, Astrid/0000-0002-8884-4544 FU National Institutes of Health (NIH) [P20GM103518/P20RR020152, R01GM079709A]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Cancer Research Society (CRS/SRC); Canadian Institutes of Health Research (CIHR) [MOP-12205]; Canadian Cancer Society Research Institute (CCSRI) [2010-700477] FX The Roy-Engel lab is supported by the National Institutes of Health (NIH) P20GM103518/P20RR020152 and R01GM079709A; R.J. Maraia is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. R.J.M. is a member of the U.S. Public Health Service Commissioned Corps. Tom moss is supported by operating grants from the Cancer Research Society (CRS/SRC); the Canadian Institutes of Health Research (CIHR) (grant #MOP-12205); and the Canadian Cancer Society Research Institute (CCSRI) (grant # 2010-700477). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NIH. We thank the participants of the meeting for their contribution and their permission to include their research in this summary. We also wish to apologize to colleagues whose work was not included. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 15 PY 2013 VL 526 IS 1 SI SI BP 1 EP 6 DI 10.1016/j.gene.2013.04.009 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 193KE UT WOS:000322557900001 PM 23608169 ER PT J AU Demerath, EW Liu, CT Franceschini, N Chen, G Palmer, JR Smith, EN Chen, CTL Ambrosone, CB Arnold, AM Bandera, EV Berenson, GS Bernstein, L Britton, A Cappola, AR Carlson, CS Chanock, SJ Chen, W Chen, Z Deming, SL Elks, CE Evans, MK Gajdos, Z Henderson, BE Hu, JJ Ingles, S John, EM Kerr, KF Kolonel, LN Le Marchand, L Lu, XN Millikan, RC Musani, SK Nock, NL North, K Nyante, S Press, MF Rodriquez-Gil, JL Ruiz-Narvaez, EA Schork, NJ Srinivasan, SR Woods, NF Zheng, W Ziegler, RG Zonderman, A Heiss, G Windham, BG Wellons, M Murray, SS Nalls, M Pastinen, T Rajkovic, A Hirschhorn, J Cupples, LA Kooperberg, C Murabito, JM Haiman, CA AF Demerath, Ellen W. Liu, Ching-Ti Franceschini, Nora Chen, Gary Palmer, Julie R. Smith, Erin N. Chen, Christina T. L. Ambrosone, Christine B. Arnold, Alice M. Bandera, Elisa V. Berenson, Gerald S. Bernstein, Leslie Britton, Angela Cappola, Anne R. Carlson, Christopher S. Chanock, Stephen J. Chen, Wei Chen, Zhao Deming, Sandra L. Elks, Cathy E. Evans, Michelle K. Gajdos, Zofia Henderson, Brian E. Hu, Jennifer J. Ingles, Sue John, Esther M. Kerr, Kathleen F. Kolonel, Laurence N. Le Marchand, Loic Lu, Xiaoning Millikan, Robert C. Musani, Solomon K. Nock, Nora L. North, Kari Nyante, Sarah Press, Michael F. Rodriquez-Gil, Jorge L. Ruiz-Narvaez, Edward A. Schork, Nicholas J. Srinivasan, Sathanur R. Woods, Nancy F. Zheng, Wei Ziegler, Regina G. Zonderman, Alan Heiss, Gerardo Windham, B. Gwen Wellons, Melissa Murray, Sarah S. Nalls, Michael Pastinen, Tomi Rajkovic, Aleksandar Hirschhorn, Joel Cupples, L. Adrienne Kooperberg, Charles Murabito, Joanne M. Haiman, Christopher A. TI Genome-wide association study of age at menarche in African-American women SO HUMAN MOLECULAR GENETICS LA English DT Article ID BODY-MASS INDEX; NUTRITION EXAMINATION SURVEY; BREAST-CANCER; POSTMENOPAUSAL WOMEN; SEQUENCE VARIANTS; US GIRLS; TRANSETHNIC METAANALYSIS; GENETIC ASSOCIATION; NATIONAL-HEALTH; TWIN FAMILIES AB African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P 5 10(8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women. C1 [Demerath, Ellen W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Palmer, Julie R.; Ruiz-Narvaez, Edward A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Franceschini, Nora; Millikan, Robert C.; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Gillings Sch Publ Hlth, Chapel Hill, NC USA. [North, Kari] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Chen, Gary; Henderson, Brian E.; Ingles, Sue; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Press, Michael F.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Smith, Erin N.] Univ Calif San Diego, Div Genome Informat Sci, Dept Pediat, La Jolla, CA 92093 USA. [Murray, Sarah S.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Chen, Christina T. L.; Carlson, Christopher S.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Arnold, Alice M.; Kerr, Kathleen F.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Woods, Nancy F.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ USA. [Berenson, Gerald S.; Chen, Wei; Srinivasan, Sathanur R.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Bernstein, Leslie] Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Britton, Angela; Nalls, Michael] NIH, Natl Inst Aging, Neurogenet Lab, Bethesda, MD 20892 USA. [Cappola, Anne R.] Univ Penn, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Evans, Michelle K.] NIH, Natl Inst Aging, Clin Res Branch, Hlth Disparaties Res Sect, Baltimore, MD USA. [Chanock, Stephen J.; Nyante, Sarah] NIH, NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. [Chen, Zhao] Univ Arizona, Coll Publ Hlth, Tucson, AZ 85721 USA. [Deming, Sandra L.; Zheng, Wei] Vanderbilt Epidemiol Ctr, Dept Med, Div Epidemiol, Nashville, TN USA. [Deming, Sandra L.; Zheng, Wei] Vandebilt Ingram Canc Ctr, Nashville, TN USA. RP Haiman, CA (reprint author), Univ So Calif, Keck Sch Med, Harlyne Norris Res Tower,1450 Biggy St,Room 1504A, Los Angeles, CA 90033 USA. EM ewd@umn.edu; clk@fhcrc.org; murabito@bu.edu; haiman@usc.edu RI Bandera, Elisa/M-4169-2014; Kerr, Kathleen/A-2893-2013; OI Bandera, Elisa/0000-0002-8789-2755; Murabito, Joanne/0000-0002-0192-7516; Ruiz-Narvaez, Edward/0000-0002-0339-5824; Palmer, Julie/0000-0002-6534-335X; Nock, Nora L./0000-0002-6476-6692; Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health [HHSN268200900055C, 5215810-550000234, R01-CA100598, 1U54RR025204-01]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268 201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, N02-HL-64278]; National Human Genome Research Institute [U01HG004402]; NIH Roadmap for Medical Research Grant [UL1RR025005]; National Heart, Lung and Blood Institute (NHLBI); University of Alabama at Birmingham, Coordinating Center [N01-HC-95095]; University of Alabama at Birmingham, Field Center [N01-HC-48047]; University of Minnesota, Field Center [N01-HC-48048]; Northwestern University, Field Center [N01-HC-48049]; Kaiser Foundation Research Institute [N01-HC-48050]; Harbor-UCLA Research and Education Institute [N01-HC-05187]; University of California, Irvine [N01-HC-45134, N01-HC-95100]; Wake Forest University [N01-HC-45205]; New England Medical Center [N01-HC-45204]; National Heart, Lung and Blood Institute [K23-HL-87114, RO1-HL46380, M01-RR-00080]; National Center on Minority Health and Health Disparities through National Institutes of Health [N01-HC-95170, N01-HC-95171, N01-HC-95172]; Department of Defense Breast Cancer Research Program Era of Hope Scholar Award; Norris Foundation; CARE-National Institute for Child Health and Development grant [NO1-HD-3-3175]; CBCS - National Institutes of Health Specialized Program of Research Excellence in Breast Cancer [P50-CA58223]; Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health [P30-ES10126]; MEC - National Institutes of Health [R01-CA63464, R37-CA54281]; NHBS - National Institutes of Health [R01-CA100374]; NC-BCFR - National Institutes of Health [U01-CA69417]; SFBCS - National Institutes of Health [R01-CA77305]; United States Army Medical Research Program [DAMD17-96-6071]; National Cancer Institute, National Institutes of Health [RFA CA-95-011]; National Cancer Institute, National Institutes of Health; WCHS - U.S. Army Medical Research and Material Command (USAMRMC) [DAMD-17-01-0-0334]; Breast Cancer Research Foundation; WFBC-National Institutes of Health [R01-CA73629]; National Institute of Environmental Health Science [ES-021724]; National Institute of Child Health and Human Development [HD-061437, HD-062783]; National Institute on Aging [AG-16592]; National Institute of Health/National Center for Research Resources [UL1RR025774]; National Cancer Institute, Division of Cancer Control and Population Science [R01 CA058420, R01 CA098663]; Susan G. Komen for the Cure Foundation; National Institute of Health, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN 268201100002C, HHSN268201100003C, HHSN2682011 00004C, HHSN271201100004C]; [R21AG032598] FX Nine parent studies contributed parent study data, ancillary study data and DNA samples through the Massachusetts Institute of Technology-Broad Institute (N01-HC-65226) to create the Candidate Gene Association Resource (CARe) genotype/phenotype database for wide dissemination to the biomedical research community. Of these, four parent studies (ARIC, CARDIA, CFS and JHS) participated in this study of age at menarche. Analysis support came through National Institutes of Health (HHSN268200900055C and 5215810-550000234). Additional support for this menarche project came from R21AG032598. Information on the CARe parent studies follows here. The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268 201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, and HHSN268201100012C), (R01HL087641), (R01HL59367 and R01HL086694); National Human Genome Research Institute (U01HG004402); and National Institutes of Health contract (HHSN268200625226C). Infrastructure was partly supported by a component of the National Institutes of Health and NIH Roadmap for Medical Research Grant (UL1RR025005). Coronary Artery Risk in Young Adults (CARDIA): Work on this manuscript was supported (or partially supported) by contracts from the National Heart, Lung and Blood Institute (NHLBI): University of Alabama at Birmingham, Coordinating Center (N01-HC-95095); University of Alabama at Birmingham, Field Center (N01-HC-48047); University of Minnesota, Field Center (N01-HC-48048); Northwestern University, Field Center (N01-HC-48049); Kaiser Foundation Research Institute (N01-HC-48050); Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100); Wake Forest University (Year 20 Exam) (N01-HC-45205); New England Medical Center (Year 20 Exam) (N01-HC-45204). M.W.'s effort is supported by the National Heart, Lung and Blood Institute (K23-HL-87114). Cleveland Family Study (CFS): The Cleveland Family Study was supported by the National Heart, Lung and Blood Institute (RO1-HL46380, M01-RR-00080). Jackson Heart Study (JHS): The Jackson Heart Study is supported by the National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities through National Institutes of Health contracts (N01-HC-95170, N01-HC-95171 and N01-HC-95172).; AABC Studies (CARE, CBCS, MEC, NBHS, NC-BCFR/SFBCS, PLCO, WCHS, WFBC): This work was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C. A. H. and the Norris Foundation. Each of the participating studies was supported by the following grants: CARE-National Institute for Child Health and Development grant (NO1-HD-3-3175), CBCS - National Institutes of Health Specialized Program of Research Excellence in Breast Cancer (P50-CA58223) and Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health, grant (P30-ES10126); MEC - National Institutes of Health grants (R01-CA63464 and R37-CA54281); NHBS - National Institutes of Health grant (R01-CA100374); NC-BCFR - National Institutes of Health grant (U01-CA69417). SFBCS - National Institutes of Health grant (R01-CA77305) and United States Army Medical Research Program grant (DAMD17-96-6071). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health (RFA CA-95-011) and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators; PLCO Intramural Research Program, National Cancer Institute, National Institutes of Health; WCHS - U.S. Army Medical Research and Material Command (USAMRMC) grant (DAMD-17-01-0-0334), the National Institutes of Health grant (R01-CA100598) and the Breast Cancer Research Foundation; and WFBC-National Institutes of Health grant (R01-CA73629).; Bogalusa Heart Study (BHS): E.N.S., N.J.S. and S. S. M. are supported in part by National Institutes of Health (grant 1U54RR025204-01). W. C., S. R. S. and G. S. B. are supported from National Institute of Environmental Health Science (ES-021724); from the National Institute of Child Health and Human Development (HD-061437 and HD-062783) and from the National Institute on Aging (AG-16592). E.N.S., S. S. M. and N.J.S. are supported in part by National Institute of Health/National Center for Research Resources Grant (UL1RR025774).; Black Women's Health Study (BWHS): BWHS. research was supported from the National Cancer Institute, Division of Cancer Control and Population Science (R01 CA058420 and R01 CA098663); and by a grant from the Susan G. Komen for the Cure Foundation.; Health Across the Lifespan (HANDLS): This research was supported by the Intramural Research Program of the National Institute of Health, National Institute on Aging and the National Center on Minority Health and Health Disparities (Z01-AG000513) and human subjects protocol (# 2009-149).; Women's Health Initiative (WHI): The WHI program is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN 268201100002C, HHSN268201100003C, HHSN2682011 00004C and HHSN271201100004C). Funding for WHI SHARe genotyping was provided by the National Heart, Lung, and Blood Institute Contract (N02-HL-64278). NR 86 TC 11 Z9 11 U1 4 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2013 VL 22 IS 16 BP 3329 EP 3346 DI 10.1093/hmg/ddt181 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 190LK UT WOS:000322341300014 PM 23599027 ER PT J AU Reiner, AP Hartiala, J Zeller, T Bis, JC Dupuis, J Fornage, M Baumert, J Kleber, ME Wild, PS Baldus, S Bielinski, SJ Fontes, JD Illig, T Keating, BJ Lange, LA Ojeda, F Muller-Nurasyid, M Munzel, TF Psaty, BM Rice, K Rotter, JI Schnabel, RB Tang, WHW Thorand, B Erdmann, J Jacobs, DR Wilson, JG Koenig, W Tracy, RP Blankenberg, S Marz, W Gross, MD Benjamin, EJ Hazen, SL Allayee, H AF Reiner, Alexander P. Hartiala, Jaana Zeller, Tanja Bis, Joshua C. Dupuis, Josee Fornage, Myriam Baumert, Jens Kleber, Marcus E. Wild, Philipp S. Baldus, Stephan Bielinski, Suzette J. Fontes, Joao D. Illig, Thomas Keating, Brendan J. Lange, Leslie A. Ojeda, Francisco Mueller-Nurasyid, Martina Munzel, Thomas F. Psaty, Bruce M. Rice, Kenneth Rotter, Jerome I. Schnabel, Renate B. Tang, W. H. Wilson Thorand, Barbara Erdmann, Jeanette Jacobs, David R., Jr. Wilson, James G. Koenig, Wolfgang Tracy, Russell P. Blankenberg, Stefan Maerz, Winfried Gross, Myron D. Benjamin, Emelia J. Hazen, Stanley L. Allayee, Hooman CA CARDIoGRAM Consortium TI Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia SO HUMAN MOLECULAR GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; HIGH-DENSITY-LIPOPROTEIN; MACULAR DEGENERATION; SUSCEPTIBILITY LOCI; CARDIOVASCULAR-DISEASE; PROGNOSTIC VALUE; ASSOCIATION; COMPLEMENT; RISK; POLYMORPHISM AB Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P 4.89 10(41)) and in 1690 AA subjects (rs505102; P 1.05 10(8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P 5.21 10(12); rs35897051, P 3.32 10(8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P 2.94 10(12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a casecontrol analysis of 80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study. C1 [Reiner, Alexander P.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA. [Zeller, Tanja; Baldus, Stephan; Ojeda, Francisco; Schnabel, Renate B.; Blankenberg, Stefan] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Dupuis, Josee; Fontes, Joao D.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Dupuis, Josee; Fontes, Joao D.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Dupuis, Josee] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Fontes, Joao D.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Div Epidemiol, Sch Publ Hlth, Houston, TX 77030 USA. [Baumert, Jens; Thorand, Barbara] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Kleber, Marcus E.] LURIC Study Non Profit LLC, Freiburg, Germany. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Mannheim Med Fac, Dept Publ Hlth Social & Prevent Med, Mannheim, Germany. [Wild, Philipp S.; Munzel, Thomas F.] Johannes Gutenberg Univ Mainz, Dept Med 2, Univ Med Ctr, D-55122 Mainz, Germany. [Wild, Philipp S.; Munzel, Thomas F.] Johannes Gutenberg Univ Mainz, Ctr Thrombosis & Haemostasis, D-55122 Mainz, Germany. [Bielinski, Suzette J.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany. [Keating, Brendan J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Keating, Brendan J.] Childrens Hosp Philadelphia, Div Human Genet, Abramson Res Ctr, Philadelphia, PA 19104 USA. [Keating, Brendan J.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Lange, Leslie A.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC USA. [Mueller-Nurasyid, Martina] Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Chair Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Chair Genet Epidemiol, Munich, Germany. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Tang, W. H. Wilson; Hazen, Stanley L.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Tang, W. H. Wilson; Hazen, Stanley L.] Cleveland Clin, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH 44106 USA. [Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Erdmann, Jeanette] Med Univ Lubeck, Deutsch Zentrum Herz Kreislaufforsch eV DZHK, D-23538 Lubeck, Germany. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. [Maerz, Winfried] Synlab Ctr Lab Diagnost, Heidelberg, Germany. [Gross, Myron D.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. RP Allayee, H (reprint author), Univ So Calif, Keck Sch Med, Inst Med Genet, 2250 Alcazar St,CSC202, Los Angeles, CA 90033 USA. EM hallayee@usc.edu RI Erdmann, Jeanette/P-7513-2014; Tang, Wai Hong/I-1238-2013; Altshuler, David/A-4476-2009; Thorand, Barbara/B-5349-2014; Schreiber, Stefan/B-6748-2008; Schnabel, Renate/F-6527-2014; Deloukas, Panos/B-2922-2013; Willenborg, Christina/D-2668-2012; Boehm, Bernhard/F-8750-2015; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Bielinski, Suzette/A-2238-2009 OI Erdmann, Jeanette/0000-0002-4486-6231; Dupuis, Josee/0000-0003-2871-3603; Benjamin, Emelia/0000-0003-4076-2336; Ziegler, Andreas/0000-0002-8386-5397; Kleber, Marcus/0000-0003-0663-7275; Altshuler, David/0000-0002-7250-4107; Thorand, Barbara/0000-0002-8416-6440; Schreiber, Stefan/0000-0003-2254-7771; Deloukas, Panos/0000-0001-9251-070X; Willenborg, Christina/0000-0001-5217-6882; Gudnason, Vilmundur/0000-0001-5696-0084; Bielinski, Suzette/0000-0002-2905-5430 FU NHLBI [P01HL098055, P01HL076491, R01HL103866, P20HL113452, R01HL103931, N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133]; NINDS [NS17950]; NIA [AG-023629, AG-15928, AG-20098, AG-027058, AG08122, AG16495, AG028321]; National Center of Advancing Translational Technologies CTSI grant [UL1TR000124]; NIDDK [DK063491]; NHGRI [U01HG004402]; NIH [HHSN268200625226C]; Affymetrix, Inc [N02-HL-6-4278]; National Human Genome Research Institute [U01-HG-004729, U01-HG-004446, U01-HG-004424]; NIEHS [R01ES021801]; Helmholtz Zentrum Munchen; German Research Center for Environmental Health, Neuherberg, Germany; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network (NGFNPlus) [01GS0834]; University of Ulm; Munich Center of Health Sciences (MC Health); government of Rheinland-Pflaz [AZ 961-386261/733]; research program 'Wissen schafft Zuknunft'; 'Schwerpunkt Vaskulare Pravention' of the Johannes Gutenberg University of Mainz; Boehringer Ingelheim; PHILIPS medical systems; GHS; National Genome Network 'NGFNplus'; Federal Ministry of Education and Research, Germany [01GS0833, 01GS0831]; Agence Nationale de la Recherche, France [ANR 09 GENO 106 01]; European Community [201668]; National Heart, Lung, Blood Institute [HHSN268201200036C, HL080295, HL087652, HL105756, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, HL087641, N01-HC-25195, HL64753, HL076784, NO1-HC-48047, NO1-HC-48048, NO1-HC-48049, NO1-HC-48050, NO1-HC-95095]; [R01HL71862] FX The Cleveland Clinic GeneBank study is supported by NHLBI grants P01HL098055, P01HL076491, R01HL103866, P20HL113452 and R01HL103931. The Cardiovascular Health Study (CHS) was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. Additional support was provided by R01HL71862. DNA handling and genotyping were supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and NIDDK grant DK063491 to the Southern California Diabetes Endocrinology Research Center. [CARe: NHLBI contract HHSN268200960009C]. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grant HL087641, NHGRI contract U01HG004402 and NIH contract HHSN268200625226C. The Framingham Heart Study is supported by NHLBI contract N01-HC-25195) and Affymetrix, Inc contract N02-HL-6-4278 (for genotyping services), and by grants from NHLBI (HL64753; HL076784), NINDS (NS17950) and NIA (AG08122, AG16495, AG028321. The CARDIA study is supported by NHLBI contracts NO1-HC-48047, NO1-HC-48048, NO1-HC-48049, NO1-HC-48050 and NO1-HC-95095. Genotyping and statistical analyses of the CARDIA white participants were supported by grants U01-HG-004729, U01-HG-004446 and U01-HG-004424 from the National Human Genome Research Institute. H. A. was supported by R01ES021801 from NIEHS. The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of the Ludwig Maximilians University (LMU) innovative. The Gutenberg Health study (GHS) is funded through the government of Rheinland-Pflaz (No. AZ 961-386261/733), the research program 'Wissen schafft Zuknunft' and the 'Schwerpunkt Vaskulare Pravention' of the Johannes Gutenberg University of Mainz and its contract with Boehringer Ingelheim and PHILIPS medical systems, including an unrestricted grant for the GHS. This project has also been supported by the National Genome Network 'NGFNplus' by the Federal Ministry of Education and Research, Germany (No. 01GS0833 and 01GS0831, projects A3/D1), and by joint funding from the Agence Nationale de la Recherche, France (contract ANR 09 GENO 106 01) and from the Federal Ministry of Education and Research, Germany. LURIChas received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 201668; AtheroRemo. NR 50 TC 7 Z9 7 U1 0 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2013 VL 22 IS 16 BP 3381 EP 3393 DI 10.1093/hmg/ddt189 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 190LK UT WOS:000322341300018 PM 23620142 ER PT J AU Morrison, VA Oxman, MN Levin, MJ Schmader, KE Guatelli, JC Betts, RF Gelb, LD Pachucki, CT Keay, SK Menzies, B Griffin, MR Kauffman, CA Marques, AR Toney, JF Simberkoff, MS Serrao, R Arbeit, RD Gnann, JW Greenberg, RN Holodniy, M Keitel, WA Yeh, SS Davis, LE Crawford, GE Neuzil, KM Johnson, GR Zhang, JH Harbecke, R Chan, ISF Keller, PM Williams, HM Boardman, KD Silber, JL Annunziato, PW AF Morrison, Vicki A. Oxman, Michael N. Levin, Myron J. Schmader, Kenneth E. Guatelli, John C. Betts, Robert F. Gelb, Larry D. Pachucki, Constance T. Keay, Susan K. Menzies, Barbara Griffin, Marie R. Kauffman, Carol A. Marques, Adriana R. Toney, John F. Simberkoff, Michael S. Serrao, Richard Arbeit, Robert D. Gnann, John W. Greenberg, Richard N. Holodniy, Mark Keitel, Wendy A. Yeh, Shingshing S. Davis, Larry E. Crawford, George E. Neuzil, Kathy M. Johnson, Gary R. Zhang, Jane H. Harbecke, Rith Chan, Ivan S. F. Keller, Paul M. Williams, Heather M. Boardman, Kathy D. Silber, Jeffrey L. Annunziato, Paula W. CA Shingles Prevention Study Grp TI Safety of Zoster Vaccine in Elderly Adults Following Documented Herpes Zoster SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE zoster vaccine; herpes zoster; zoster vaccine safety; zoster vaccine in elderly persons; ACIP recommendations ID IMMUNE-RESPONSES; VIRUS; TRIAL AB After completion of the Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Studies Program Number 403), SPS participants who had initially received placebo were offered investigational zoster vaccine without charge. This provided an opportunity to determine the relative safety of zoster vaccine in older adults following documented herpes zoster (HZ). Methods. A total of 13 681 SPS placebo recipients who elected to receive zoster vaccine were followed for serious adverse events (SAE) for 28 days after vaccination. In contrast to the SPS, a prior episode of HZ was not a contraindication to receiving zoster vaccine. The SPS placebo recipients who received zoster vaccine included 420 who had developed documented HZ during the SPS. Results. The mean interval between the onset of HZ and the receipt of zoster vaccine in the 420 recipients with prior HZ was 3.61 years (median interval, 3.77 years [range, 3-85 months]); the interval was <5 years for approximately 80% of recipients. The proportion of vaccinated SPS placebo recipients with prior HZ who developed >= 1 SAE (0.95%) was not significantly different from that of vaccinated SPS placebo recipients with no prior history of HZ (0.66%), and the distribution of SAEs in the 2 groups was comparable. Conclusions. These results demonstrate that the general safety of zoster vaccine in older persons is not altered by a recent history of documented HZ, supporting the safety aspect of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommendation to administer zoster vaccine to all persons >= 60 years of age with no contraindications, regardless of a prior history of HZ. C1 [Morrison, Vicki A.] Vet Affairs Med Ctr, Minneapolis, MN USA. [Morrison, Vicki A.] Univ Minnesota, Minneapolis, MN USA. [Oxman, Michael N.; Guatelli, John C.; Harbecke, Rith; Williams, Heather M.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Oxman, Michael N.; Guatelli, John C.; Harbecke, Rith; Williams, Heather M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Levin, Myron J.] Univ Colorado Denver, Denver, CO USA. [Schmader, Kenneth E.] Durham Vet Affairs Med Ctr, GRECC, Durham, NC USA. [Schmader, Kenneth E.] Duke Univ, Med Ctr, Durham, NC USA. [Betts, Robert F.] Univ Rochester, New York, NY USA. [Gelb, Larry D.] Vet Affairs Med Ctr, St Louis, MO USA. [Pachucki, Constance T.] Hines Vet Affairs Med Ctr, Hines, IL USA. [Keay, Susan K.] Vet Affairs Maryland Hlth Care Syst, Baltimore, MD USA. [Keay, Susan K.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Menzies, Barbara; Neuzil, Kathy M.] Vet Affairs Med Ctr Puget Sound, Seattle, WA USA. [Griffin, Marie R.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Kauffman, Carol A.] Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Kauffman, Carol A.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Marques, Adriana R.] NIAID, Bethesda, MD 20892 USA. [Toney, John F.] Vet Affairs Med Ctr, Tampa, FL USA. [Simberkoff, Michael S.] VA New York Harbor Healthcare Syst, New York, NY USA. [Simberkoff, Michael S.] NYU, Sch Med, New York, NY USA. [Serrao, Richard; Arbeit, Robert D.] Boston Univ, Boston, MA 02215 USA. [Gnann, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Gnann, John W.] Univ Alabama Birmingham, Birmingham, AL USA. [Greenberg, Richard N.] Univ Kentucky, Sch Med, Lexington, KY 40506 USA. [Holodniy, Mark] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Keitel, Wendy A.] Baylor Coll Med, Houston, TX 77030 USA. [Yeh, Shingshing S.] Northport Vet Affairs Med Ctr, Northport, NY USA. [Davis, Larry E.] Vet Affairs Med Ctr, Albuquerque, NM USA. [Crawford, George E.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Johnson, Gary R.; Zhang, Jane H.] Dept Vet Affairs, Cooperat Studies Program, Coordinating Ctr, West Haven, CT USA. [Chan, Ivan S. F.; Keller, Paul M.; Silber, Jeffrey L.; Annunziato, Paula W.] Merck Sharp & Dohme Corp, Whitehouse Stn, NJ USA. [Boardman, Kathy D.] Dept Vet Affairs, Cooperat Studies Program, Clin Res Pharm Coordinating Ctr, Albuquerque, NM USA. RP Morrison, VA (reprint author), VAMC, Hematol Oncol Sect, 111E,1 Vet Dr, Minneapolis, MN 55417 USA. EM morri002@umn.edu RI Irwin, Michael/H-4870-2013; OI Irwin, Michael/0000-0002-1502-8431; Serrao, Richard/0000-0002-7440-8645 FU James R. and Jesse V. Scott Fund for Shingles Research FX The study was conducted by the Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development. Additional support was provided by Merck Sharp & Dohme, by the James R. and Jesse V. Scott Fund for Shingles Research, and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Data management and analysis support was provided at West Haven CSPCC by Karen Dellert and Kathy Newvine. NR 9 TC 18 Z9 18 U1 0 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2013 VL 208 IS 4 BP 559 EP 563 DI 10.1093/infdis/jit182 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 191KO UT WOS:000322412100005 PM 23633406 ER PT J AU Diaz, G Melis, M Tice, A Kleiner, DE Mishra, L Zamboni, F Farci, P AF Diaz, Giacomo Melis, Marta Tice, Ashley Kleiner, David E. Mishra, Lopa Zamboni, Fausto Farci, Patrizia TI Identification of microRNAs specifically expressed in hepatitis C virus-associated hepatocellular carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE liver; hepatocellular carcinoma; hepatitis C virus; microRNA; pathogenesis ID LIVER-DISEASE; CIRCULATING MICRORNAS; SUPPRESSOR GENE; CANCER; OVEREXPRESSION; MIR-21; CONTRIBUTES; METASTASIS; PROGNOSIS; TARGET AB Although several studies have investigated the association of miRNAs with hepatocellular carcinoma (HCC), the data published so far are not concordant. A reason for these discrepancies may be the fact that most studies used the nontumorous tissue surrounding the HCC lesion as a control, which is almost invariably affected by cirrhosis or chronic hepatitis, as well as other pathological conditions such as hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Moreover, HCC is often analyzed as a single group regardless of the different viral etiologies. The miRNAs differentially expressed in HCV-related HCC were investigated by comparing the tumorous tissues to a wide range of liver specimens, including healthy livers obtained from liver donors and patients who underwent liver resection for angioma, in addition to tissues from various acute and chronic liver diseases, including HCV-related cirrhosis not associated with HCC, HCV-related cirrhosis associated with HCC and HBV-associated acute liver failure. The whole set of 2,226 human miRNAs were examined, including 1,121 pre-miRNAs and 1,105 mature miRNAs, available in a microarray platform. Stringent statistical methods were applied to reduce the risk of false discoveries to less than 1%. These data identified 18 miRNAs exclusively expressed in HCV-associated HCC, characterized by high specificity and selectivity versus all other liver diseases and healthy conditions and connected into a regulatory network pivoting on p53, phosphatase and tensin homolog and all-trans retinoic acid signaling. C1 [Diaz, Giacomo] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Melis, Marta; Tice, Ashley; Farci, Patrizia] NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Mishra, Lopa] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [Zamboni, Fausto] Brotzu Hosp, Liver Transplantat Ctr, Cagliari, Italy. RP Farci, P (reprint author), NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pfarci@niaid.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Cancer Institute; Fondazione Banco di Sardegna, Sassari, Italy [739/2011.1045] FX Grant sponsors: Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Cancer Institute; Grant sponsor: Fondazione Banco di Sardegna, Sassari, Italy; Grant number: 739/2011.1045 NR 44 TC 23 Z9 23 U1 0 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2013 VL 133 IS 4 BP 816 EP 824 DI 10.1002/ijc.28075 PG 9 WC Oncology SC Oncology GA 161LM UT WOS:000320194400005 PM 23390000 ER PT J AU Hendrix, A Sormunen, R Westbroek, W Lambein, K Denys, H Sys, G Braems, G Van den Broecke, R Cocquyt, V Gespach, C Bracke, M De Wever, O AF Hendrix, An Sormunen, Raija Westbroek, Wendy Lambein, Kathleen Denys, Hannelore Sys, Gwen Braems, Geert Van den Broecke, Rudy Cocquyt, Veronique Gespach, Christian Bracke, Marc De Wever, Olivier TI Vacuolar H plus ATPase expression and activity is required for Rab27B-dependent invasive growth and metastasis of breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE proton pump; vesicle transport; exocytosis; Rab27; heat shock protein; invasion ID V-ATPASE; SUBUNIT; PROTEINS; ISOFORMS; PATHWAY AB The secretory Rab27B small GTPase promotes invasive growth and metastasis in estrogen receptor (ER) -positive breast cancer cells by orchestrating the peripheral targeting of vesicles secreting proinvasive growth regulators. Increased Rab27B expression is associated with poor prognosis in breast cancer patients. The molecular mechanisms of peripheral Rab27B secretory vesicle distribution are poorly understood. Mass spectrometry analysis on green fluorescent protein (GFP)-Rab27B vesicles prepared from GFP-Rab27B transfected MCF-7 human breast cancer cells detected eight subunits of the vacuolar H(+)-ATPase (V-ATPase) and the presence of V0a1 and V0d1 subunits was confirmed by Western blot analysis. Reversible inhibition of V-ATPase activity by bafilomycin A1 or transient silencing of V0a1 or V0d1 subunits demonstrated that V-ATPase controls peripheral localization and size of Rab27B vesicles. V-ATPase expression and activity further controls Rab27B-induced collagen type I invasion, cell-cycle progression and invasive growth in the chorioallantoic membrane assay. In agreement, Rab27B-dependent extracellular heat shock protein90 release and matrix metalloprotease-2 activation is markedly reduced by bafilomycin A1 and transient silencing of V0a1 and V0d1 subunits. Poor prognosis ER-positive primary breast tumors expressing high levels of Rab27B also expressed multiple V-ATPase subunits and showed a strong cytoplasmic and peripheral V-ATPase V1E expression. In conclusion, inhibiting V-ATPase activity by interfering agents and drugs might be an effective strategy for blocking Rab27B-dependent proinvasive secretory vesicle trafficking in ER-positive breast cancer patients. C1 [Hendrix, An; Bracke, Marc; De Wever, Olivier] Ghent Univ Hosp, Lab Expt Canc Res, Dept Radiat Oncol & Expt Canc Res, B-9000 Ghent, Belgium. [Hendrix, An; Denys, Hannelore; Cocquyt, Veronique] Ghent Univ Hosp, Dept Med Oncol, B-9000 Ghent, Belgium. [Sormunen, Raija] Univ Oulu, Dept Pathol, Electron Microscopy Lab, Bioctr Oulu, Oulu, Finland. [Westbroek, Wendy] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Lambein, Kathleen] Ghent Univ Hosp, Dept Pathol, B-9000 Ghent, Belgium. [Sys, Gwen] Ghent Univ Hosp, Dept Orthoped Surg, B-9000 Ghent, Belgium. [Braems, Geert; Van den Broecke, Rudy] Ghent Univ Hosp, Dept Gynecol, B-9000 Ghent, Belgium. [Gespach, Christian] Hop St Antoine, INSERM, Mol & Clin Oncol U938, Fac Med, F-75571 Paris, France. [Gespach, Christian] Univ Paris 06, F-75252 Paris 05, France. RP Hendrix, A (reprint author), Ghent Univ Hosp, Lab Expt Canc Res, Dept Radiat Oncol & Expt Canc Res, De Pintelaan 185, B-9000 Ghent, Belgium. EM an.hendrix@ugent.be RI de wever, olivier/J-3094-2013 OI de wever, olivier/0000-0002-5453-760X FU Fund for Scientific Spearheads of the Ghent University Hospital; Stichting tegen Kanker; Intramural Research Program of the National Human Genome Research Institute; Fund for Scientific Research-Flanders; Research Council of Ghent University FX Grant sponsors: Fund for Scientific Spearheads of the Ghent University Hospital, Stichting tegen Kanker, The Intramural Research Program of the National Human Genome Research Institute, Fund for Scientific Research-Flanders, Research Council of Ghent University NR 25 TC 26 Z9 27 U1 0 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2013 VL 133 IS 4 BP 843 EP 854 DI 10.1002/ijc.28079 PG 12 WC Oncology SC Oncology GA 161LM UT WOS:000320194400008 PM 23390068 ER PT J AU Sati, P van Gelderen, P Silva, AC Reich, DS Merkle, H de Zwart, JA Duyn, JH AF Sati, Pascal van Gelderen, Peter Silva, Afonso C. Reich, Daniel S. Merkle, Hellmut de Zwart, Jacco A. Duyn, Jeff H. TI Micro-compartment specific T*(2) relaxation in the brain SO NEUROIMAGE LA English DT Article DE Water compartment; T*(2) relaxation; Frequency shift; White matter; Brain; Demyelination ID HIGH-FIELD MRI; WHITE-MATTER CONTRAST; MYELIN WATER FRACTION; HUMAN OCCIPITAL LOBE; GRADIENT-ECHO MRI; IN-VIVO; MAGNETIC-RESONANCE; SUSCEPTIBILITY CONTRAST; FIBER ORIENTATION; MULTIPLE-SCLEROSIS AB MRI at high field can be sensitized to the magnetic properties of tissues, which introduces a signal dependence on the orientation of white matter (WM) fiber bundles relative to the magnetic field. In addition, study of the NMR relaxation properties of this signal has indicated contributions from compartmentalized water environments inside and outside the myelin sheath that may be separable. Here we further investigated the effects of water compartmentalization on the MRI signal with the goal of extracting compartment-specific information. By comparing MRI measurements of human and marmoset brain at 7 T with magnetic field modeling, we show that: (1) water between the myelin lipid bilayers, in the axonal, and in the interstitial space each experience characteristic magnetic field effects that depend on fiber orientation (2) these field effects result in characteristic relaxation properties and frequency shifts for these compartments; and (3) compartmental contributions may be separated by multi-component fitting of the MRI signal relaxation (i.e. decay) curve. We further show the potential application of these findings to the direct mapping of myelin content and assessment of WM fiber integrity with high field MRI. Published by Elsevier Inc. C1 [Sati, Pascal; Reich, Daniel S.] Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [van Gelderen, Peter; de Zwart, Jacco A.; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Merkle, Hellmut] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), Bldg 10,Room B1D724,10 Ctr Dr MSC 1400, Bethesda, MD 20892 USA. EM jeff.duyn@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) FX We thank Dr. Alan Koretsky for discussion. We also thank Xianfeng (Lisa) Zhang for the animal preparation, and Susan C Guttman and the Neuroimmunology Branch clinical group for coordinating the recruitment of human subjects. We acknowledge the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) for support. NR 62 TC 45 Z9 45 U1 0 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2013 VL 77 BP 268 EP 278 DI 10.1016/j.neuroimage.2013.03.005 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 159UX UT WOS:000320073900027 PM 23528924 ER PT J AU Best, SM AF Best, Sonja M. TI Viruses Play Dead to TAMe Interferon Responses SO CELL HOST & MICROBE LA English DT Editorial Material ID RECEPTORS; SYSTEM; FAMILY AB TAM receptors promote apoptotic cell uptake and function as inflammation suppressors. Many viruses mimic apoptotic cells, thus exploiting TAM receptors for attachment and entry. In this issue of Cell Host & Microbe, Bhattacharyya et al. show that TAM binding by enveloped viruses also induces receptor signaling to suppress cellular interferon responses. C1 NIAID, NIH, Rocky Mt Labs, Virol Lab, Hamilton, MT 59840 USA. RP Best, SM (reprint author), NIAID, NIH, Rocky Mt Labs, Virol Lab, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov FU Intramural NIH HHS [ZIA AI001125-01] NR 10 TC 0 Z9 1 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD AUG 14 PY 2013 VL 14 IS 2 BP 117 EP 118 DI 10.1016/j.chom.2013.07.014 PG 2 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1JE UT WOS:000330851600001 PM 23954149 ER PT J AU Jacques, PF Lyass, A Massaro, JM Vasan, RS D'Agostino, RB AF Jacques, Paul F. Lyass, Asya Massaro, Joseph M. Vasan, Ramachandran S. D'Agostino, Ralph B., Sr. TI Relationship of lycopene intake and consumption of tomato products to incident CVD SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Lycopene; CVD; CHD; Stroke ID FOOD FREQUENCY QUESTIONNAIRE; CORONARY-HEART-DISEASE; PLASMA CAROTENOID CONCENTRATIONS; CARDIOVASCULAR-DISEASE; VEGETABLE CONSUMPTION; MYOCARDIAL-INFARCTION; DIETARY-INTAKE; RISK FACTOR; STROKE; COHORT AB Evidence for cardioprotective effects of lycopene is inconsistent. Studies of circulating lycopene generally report inverse associations with CVD risk, but studies based on lycopene intake do not. The failure of dietary studies to support the findings based on biomarkers may be due in part to misclassification of lycopene intakes. To address this potential misclassification, we used repeated measures of intake obtained over 10 years to characterise the relationship between lycopene intake and the incidence of CVD (n 314), CHD (n 171) and stroke (n 99) in the Framingham Offspring Study. Hazard ratios (HR) for incident outcomes were derived from Cox proportional hazards regression models using logarithmically transformed lycopene intake adjusted for CVD risk factors and correlates of lycopene intake. HR were interpreted as the increased risk for a 2.7-fold difference in lycopene intake, a difference approximately equal to its interquartile range. Using an average of three intake measures with a 9-year follow-up, lycopene intake was inversely associated with CVD incidence (HR 0.83, 95% CI 0.70, 0.98). Using an average of two intake measures and 11 years of follow-up, lycopene intake was inversely associated with CHD incidence (HR 0.74, 95% CI 0.58, 0.94). Lycopene intake was unrelated to stroke incidence. The present study of lycopene intake and CVD provides supporting evidence for an inverse association between lycopene and CVD risk; however, additional research is needed to determine whether lycopene or other components of tomatoes, the major dietary source of lycopene, are responsible for the observed association. C1 [Jacques, Paul F.] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Lyass, Asya; Vasan, Ramachandran S.; D'Agostino, Ralph B., Sr.] NHLBI Framingham Heart Study, Framingham, MA 01702 USA. [Lyass, Asya; D'Agostino, Ralph B., Sr.] Boston Univ, Coll Arts & Sci, Dept Math & Stat, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Jacques, PF (reprint author), Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM paul.jacques@tufts.edu OI Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970 FU European Union LYCOCARD Project through the Ministry of Education and Cultural Affairs of the Free State of Thuringia, Germany [B514-09057]; National Institutes of Health/National Heart, Lung, and Blood Institute [N01-HC-25,195]; United States Department of Agriculture [58-1950-7-707] FX This study was supported by the European Union LYCOCARD Project through grant no. B514-09057 from the Ministry of Education and Cultural Affairs of the Free State of Thuringia, Germany, and by the National Institutes of Health/National Heart, Lung, and Blood Institute (contract N01-HC-25,195) and the United States Department of Agriculture (agreement no. 58-1950-7-707). None of the authors has a conflict of interest to declare. The authors' contributions were as follows: P. F. J., R. S. V. and R. B. D'A. contributed to the study design; J. M. M. provided the statistical guidance; A. L. performed the statistical analyses; P. F. J. drafted the manuscript; P. F. J., R. S. V., R. B. D'A., J. M. M. and A. L. contributed to the interpretation of the results and the editing of the manuscript. NR 43 TC 17 Z9 17 U1 4 U2 16 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD AUG 14 PY 2013 VL 110 IS 3 BP 545 EP 551 DI 10.1017/S0007114512005417 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 189OO UT WOS:000322276800019 PM 23317928 ER PT J AU MacIntosh, BA Ramsden, CE Faurot, KR Zamora, D Mangan, M Hibbeln, JR Mann, JD AF MacIntosh, Beth A. Ramsden, Christopher E. Faurot, Keturah R. Zamora, Daisy Mangan, Margaret Hibbeln, Joseph R. Mann, J. Douglas TI Low-n-6 and low-n-6 plus high-n-3 diets for use in clinical research SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE n-6 Fatty acids; n-3 Fatty acids; Polyunsaturated fatty acids; Dietary interventions; Headache ID POLYUNSATURATED FATTY-ACIDS; DOUBLY LABELED WATER; ALPHA-LINOLENIC ACID; HUMAN DEPOT FAT; ADIPOSE-TISSUE; MULTIPLE-PASS; ENERGY-INTAKE; DOCOSAHEXAENOIC ACID; SUPPLEMENTATION; RECALL AB Few trials have evaluated the metabolic effects and health outcomes of lowering dietary n-6 PUFA. The objectives of the present paper were (1) to report the methods employed to lower dietary n-6 PUFA, while either increasing or maintaining n-3 PUFA intake and (2) to validate our methods with 24 h recalls and erythrocyte fatty acid analyses. A total of sixty-seven subjects were randomised to either (1) an average-n-3 PUFA, low-n-6 PUFA (L6) intervention designed to lower linoleic acid (LA; <= 2.5% of energy (en%)) and arachidonic acid (<= 60 mg/d), while maintaining an average US intake of n-3 PUFA or (2) a high-n-3 PUFA, low-n-6 PUFA (H3-L6) intervention designed to lower n-6 LA, while increasing the n-3 PUFA alpha-linolenic acid (ALA; >= 1.5 en%) and EPA + DHA (>= 1000 mg/d). Pre- and intra-intervention nutrient intakes were estimated with six 24 h dietary recalls per subject. Both groups achieved the targeted reductions in dietary LA to <= 2.5 en% (median LA 2.45 (2.1, 3.1); P<0.001). Intakes of n-3 PUFA did not change for the L6 group. Target increases in n-3 ALA (median 1.6 en%, (1.3, 2.0), P<0.001) and EPA + DHA (1482 mg, (374, 2558), P<0.001) were achieved in the H3-L6 group. Dietary changes were validated by corresponding changes in erythrocyte n-6 and n-3 fatty acid composition. Dietary LA can be lowered to <= 2.5 en%, with or without concurrent increases in dietary n-3 PUFA, in an outpatient clinical trial setting using this integrated diet method. C1 [MacIntosh, Beth A.] Univ N Carolina, North Carolina Translat Clin Sci Inst, Nutr Res & Metab Core, Chapel Hill, NC 27599 USA. [Ramsden, Christopher E.; Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Faurot, Keturah R.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Faurot, Keturah R.; Zamora, Daisy] Univ N Carolina, Sch Med, Dept Phys Med & Rehabil, Program Integrat Med, Chapel Hill, NC 27599 USA. [Mangan, Margaret] Univ N Carolina, Gillings Sch Publ Hlth, Nutr Obes Res Ctr Diet Phys Activ & Body Composit, Chapel Hill, NC 27599 USA. [Mann, J. Douglas] Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27599 USA. RP MacIntosh, BA (reprint author), Univ N Carolina, North Carolina Translat Clin Sci Inst, Nutr Res & Metab Core, 101 Manning Dr,CB 7600, Chapel Hill, NC 27599 USA. EM beth_macintosh@med.unc.edu FU Mayday Fund; North Carolina Clinical and Translational Sciences Institute (NCRR, NIH) [UL1RR025747]; UNC Nutrition Obesity Research Center, CHAI Core and Nutrition Epidemiology Core (NIDDK, NIH) [DK056350]; UNC Research Fellowship in Complementary and Alternative Medicine (NCCAM, NIH) [T32-AT003378]; Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH FX The authors declare that they have no competing interests. The authors would like to thank the following individuals for their research assistance: Marjorie Busby for expertise with study design; Gus Swenson for study food production management; Dietetic Technicians Clarence Mayo, Jim Howerton and Derrick Williams for preparation of study foods; Olafur Palsson, Beth Fowler, Carol Carr, Regina McCoy and Tim McCaskill (programmer) for design and functionality of the study website; Jim Loewke for erythrocyte and nutrient composition analysis and Duk Hyun for nutrient composition analyses; Chanee Lynch for study coordination; and Rebecca Coble, Amit Ringel, Sharon Majchrzak-Hong and Joseph Graciosa for general research assistance. B. A. M. was the lead dietitian, developed the dietary intervention methods, provided nutrition counselling to research subjects and contributed to the initial draft and revisions of the manuscript. C. E. R. was the co-principal investigator and contributed to the hypotheses, grant application, study design and implementation and interpretation of the initial draft and revisions of the manuscript. K. R. F. contributed to the overall trial development and conduct, performed the statistical analysis and revised the manuscript. D. Z. assisted with manuscript preparation and statistical analysis. M. M. led the NORC research team in creating custom user recipes, collecting the 24 h dietary recalls and revised the manuscript. J. R. H. contributed to the study design and interpretation and revised the manuscript. J. D. M. was the co-principal investigator and the primary study clinician and contributed to all aspects of the project. All authors contributed to the intellectual content of the manuscript. The authors gratefully acknowledge funding support for the present trial from the Mayday Fund (primary source); the North Carolina Clinical and Translational Sciences Institute (grant UL1RR025747, NCRR, NIH); the UNC Nutrition Obesity Research Center, CHAI Core and Nutrition Epidemiology Core (grant DK056350, NIDDK, NIH); the UNC Research Fellowship in Complementary and Alternative Medicine (grant T32-AT003378, NCCAM, NIH); and the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Mayday Fund or the National Institutes of Health. NR 48 TC 16 Z9 16 U1 0 U2 12 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD AUG 14 PY 2013 VL 110 IS 3 BP 559 EP 568 DI 10.1017/S0007114512005181 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 189OO UT WOS:000322276800021 PM 23328113 ER PT J AU Li, YY Huang, WC Niu, L Umbach, DM Covo, S Li, LP AF Li, Yuanyuan Huang, Weichun Niu, Liang Umbach, David M. Covo, Shay Li, Leping TI Characterization of constitutive CTCF/cohesin loci: a possible role in establishing topological domains in mammalian genomes SO BMC GENOMICS LA English DT Article DE CTCF; Cohesin; Constitutive binding site; Chromatin interaction; Topological domain ID CCCTC-BINDING-FACTOR; C-MYC GENE; CTCF-BINDING; REGULATORY ELEMENTS; DNA-REPLICATION; CHROMATIN INTERACTIONS; HYPERSENSITIVE SITES; COHESIN; PROTEIN; ORGANIZATION AB Background: Recent studies suggested that human/mammalian genomes are divided into large, discrete domains that are units of chromosome organization. CTCF, a CCCTC binding factor, has a diverse role in genome regulation including transcriptional regulation, chromosome-boundary insulation, DNA replication, and chromatin packaging. It remains unclear whether a subset of CTCF binding sites plays a functional role in establishing/maintaining chromatin topological domains. Results: We systematically analysed the genomic, transcriptomic and epigenetic profiles of the CTCF binding sites in 56 human cell lines from ENCODE. We identified similar to 24,000 CTCF sites (referred to as constitutive sites) that were bound in more than 90% of the cell lines. Our analysis revealed: 1) constitutive CTCF loci were located in constitutive open chromatin and often co-localized with constitutive cohesin loci; 2) most constitutive CTCF loci were distant from transcription start sites and lacked CpG islands but were enriched with the full-spectrum CTCF motifs: a recently reported 33/34-mer and two other potentially novel (22/26-mer); 3) more importantly, most constitutive CTCF loci were present in CTCF-mediated chromatin interactions detected by ChIA-PET and these pair-wise interactions occurred predominantly within, but not between, topological domains identified by Hi-C. Conclusions: Our results suggest that the constitutive CTCF sites may play a role in organizing/maintaining the recently identified topological domains that are common across most human cells. C1 [Li, Yuanyuan; Huang, Weichun; Niu, Liang; Umbach, David M.; Li, Leping] Natl Inst Environm Hlth Sci, Biostat Branch, Durham, NC 27709 USA. [Covo, Shay] Hebrew Univ Jerusalem, Robert H Smith Fac Agr Food & Environm, Dept Plant Pathol & Microbiol, Rehovot, Israel. RP Li, LP (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, Durham, NC 27709 USA. EM li3@niehs.nih.gov FU Computational Biology Facility at NIEHS; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES101765] FX This research was supported by Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES101765). NR 57 TC 26 Z9 27 U1 2 U2 22 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 14 PY 2013 VL 14 AR 553 DI 10.1186/1471-2164-14-553 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 210NH UT WOS:000323840000001 PM 23945083 ER PT J AU Bhullar, J Natarajan, K Shukla, S Mathias, TJ Sadowska, M Ambudkar, SV Baer, MR AF Bhullar, Jasjeet Natarajan, Karthika Shukla, Suneet Mathias, Trevor J. Sadowska, Mariola Ambudkar, Suresh V. Baer, Maria R. TI The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions SO PLOS ONE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CANCER RESISTANCE PROTEIN; HUMAN P-GLYCOPROTEIN; TYROSINE KINASE INHIBITORS; ACUTE MYELOGENOUS LEUKEMIA; MULTIDRUG-RESISTANCE; HEMATOPOIETIC-CELLS; TRANSPORTER ABCG2; CATALYTIC CYCLE; ATP HYDROLYSIS AB The oral second-generation bis-aryl urea fms-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (AC220) has favorable kinase selectivity and pharmacokinetics. It inhibits mutant and wild-type FLT3 in vivo at 0.1 and 0.5 mu M, respectively, and has shown favorable activity and tolerability in phase I and II trials in acute myeloid leukemia, with QT prolongation as the dose-limiting toxicity. Co-administration with chemotherapy is planned. We characterized interactions of quizartinib with the ATP-binding cassette (ABC) proteins ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Its effects on uptake of fluorescent substrates and apoptosis were measured by flow cytometry, binding to ABCB1 and ABCG2 drug-binding sites by effects on [I-125] iodoarylazidoprazosin ([I-125]-IAAP) photolabeling and ATPase activity, and cell viability by the WST-1 colorimetric assay. Quizartinib inhibited transport of fluorescent ABCG2 and ABCB1 substrates in ABCG2- and ABCB1-overexpressing cells in a concentration-dependent manner, from 0.1 to 5 mu M and from 0.5 to 10 mu M, respectively, and inhibited [I-125]-IAAP photolabeling of ABCG2 and ABCB1 with IC50 values of 0.07 and 3.3 mu M, respectively. Quizartinib at higher concentrations decreased ABCG2, but not ABCB1, ATPase activity. Co-incubation with quizartinib at 0.1 to 1 mu M sensitized ABCG2-overexpressing K562/ABCG2 and 8226/MR20 cells to ABCG2 substrate chemotherapy drugs in a concentration-dependent manner in cell viability and apoptosis assays. Additionally, quizartinib increased cellular uptake of the ABCG2 substrate fluoroquinolone antibiotic ciprofloxacin, which also prolongs the QT interval, in a concentration-dependent manner, predicting altered ciprofloxacin pharmacokinetics and pharmacodynamics when co-administered with quizartinib. Thus quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. These interactions should be considered in the design of treatment regimens combining quizartinib and chemotherapy drugs and in choice of concomitant medications to be administered with quizartinib. C1 [Bhullar, Jasjeet; Natarajan, Karthika; Mathias, Trevor J.; Sadowska, Mariola; Baer, Maria R.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Baer, Maria R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. RP Baer, MR (reprint author), Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. EM mbaer@umm.edu OI Natarajan, Karthika/0000-0001-7435-1477 FU Leukemia and Lymphoma Society Translational Research Award; University of Maryland, Baltimore UMMG Cancer Research Grant [CH 649 CRF]; State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program; NCI Cancer Center Support Grant [P30 CA134274]; NIH, National Cancer Institute, Center for Cancer Research FX Leukemia and Lymphoma Society Translational Research Award (MRB), University of Maryland, Baltimore UMMG Cancer Research Grant #CH 649 CRF issued by the State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program, NCI Cancer Center Support Grant P30 CA134274, and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (SS, SVA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 5 Z9 5 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e71266 DI 10.1371/journal.pone.0071266 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500065 PM 23967177 ER PT J AU Funk, S Bogich, TL Jones, KE Kilpatrick, AM Daszak, P AF Funk, Sebastian Bogich, Tiffany L. Jones, Kate E. Kilpatrick, A. Marm Daszak, Peter TI Quantifying Trends in Disease Impact to Produce a Consistent and Reproducible Definition of an Emerging Infectious Disease SO PLOS ONE LA English DT Article ID EMERGENCE; HEALTH; EPIDEMIOLOGY; PERSPECTIVE; REGRESSION; PATHOGENS; EVOLUTION; ECOLOGY AB The proper allocation of public health resources for research and control requires quantification of both a disease's current burden and the trend in its impact. Infectious diseases that have been labeled as "emerging infectious diseases'' (EIDs) have received heightened scientific and public attention and resources. However, the label 'emerging' is rarely backed by quantitative analysis and is often used subjectively. This can lead to over-allocation of resources to diseases that are incorrectly labelled "emerging,'' and insufficient allocation of resources to diseases for which evidence of an increasing or high sustained impact is strong. We suggest a simple quantitative approach, segmented regression, to characterize the trends and emergence of diseases. Segmented regression identifies one or more trends in a time series and determines the most statistically parsimonious split(s) (or joinpoints) in the time series. These joinpoints in the time series indicate time points when a change in trend occurred and may identify periods in which drivers of disease impact change. We illustrate the method by analyzing temporal patterns in incidence data for twelve diseases. This approach provides a way to classify a disease as currently emerging, re-emerging, receding, or stable based on temporal trends, as well as to pinpoint the time when the change in these trends happened. We argue that quantitative approaches to defining emergence based on the trend in impact of a disease can, with appropriate context, be used to prioritize resources for research and control. Implementing this more rigorous definition of an EID will require buy-in and enforcement from scientists, policy makers, peer reviewers and journal editors, but has the potential to improve resource allocation for global health. C1 [Funk, Sebastian; Jones, Kate E.] Zool Soc London, Inst Zool, London NW1 4RY, England. [Funk, Sebastian; Bogich, Tiffany L.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Funk, Sebastian] London Sch Hyg & Trop Med, London WC1, England. [Bogich, Tiffany L.; Daszak, Peter] EcoHlth Alliance, New York, NY USA. [Bogich, Tiffany L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Jones, Kate E.] UCL, Dept Genet Evolut & Environm, London, England. [Kilpatrick, A. Marm] Univ Calif Santa Cruz, Dept Ecol & Evolutionary Biol, Santa Cruz, CA 95064 USA. RP Kilpatrick, AM (reprint author), Univ Calif Santa Cruz, Dept Ecol & Evolutionary Biol, Santa Cruz, CA 95064 USA. EM akilpatr@ucsc.edu; daszak@ecohealthalliance.org RI Jones, Kate/G-4768-2010; OI Jones, Kate/0000-0001-5231-3293; Bogich, Tiffany/0000-0002-8143-5289; Funk, Sebastian/0000-0002-2842-3406 FU Fogarty International Center [2R01-TW005869]; NSF [EF-0914866, DEB -1115895]; National Institute of Health [1R01AI090159]; National Science Foundation Human and Social Dynamics 'Agents of Change' award [BCS-0826779] FX This work was made possible by the generous support of the American people through the United States Agency for International Development (USAID) Emerging Pandemic Threats PREDICT; by three NIH/NSF "Ecology and Evolution of Infectious Diseases'' awards from the Fogarty International Center (2R01-TW005869) and NSF (EF-0914866 and DEB -1115895), a grant from the National Institute of Health (1R01AI090159), and by a National Science Foundation Human and Social Dynamics 'Agents of Change' award (BCS-0826779). TLB acknowledges the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U. S. Department of Homeland Security, and the Fogarty International Center, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 4 Z9 4 U1 7 U2 42 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e69951 DI 10.1371/journal.pone.0069951 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500010 PM 23967065 ER PT J AU Konstandi, M Shah, YM Matsubara, T Gonzalez, FJ AF Konstandi, Maria Shah, Yatrik M. Matsubara, Tsutomu Gonzalez, Frank J. TI Role of PPAR alpha and HNF4 alpha in Stress-Mediated Alterations in Lipid Homeostasis SO PLOS ONE LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTORS; PSYCHOLOGICAL STRESS; METABOLIC SYNDROME; TARGETED DISRUPTION; OBESITY; CATECHOLAMINES; TRIGLYCERIDE; CHOLESTEROL; SECRETION; GENE AB Stress is a risk factor for several cardiovascular pathologies. PPAR alpha holds a fundamental role in control of lipid homeostasis by directly regulating genes involved in fatty acid transport and oxidation. Importantly, PPAR alpha agonists are effective in raising HDL-cholesterol and lowering triglycerides, properties that reduce the risk for cardiovascular diseases. This study investigated the role of stress and adrenergic receptor (AR)-related pathways in PPAR alpha and HNF4 alpha regulation and signaling in mice following repeated restraint stress or treatment with AR-antagonists administered prior to stress to block AR-linked pathways. Repeated restraint stress up-regulated Ppar alpha and its target genes in the liver, including Acox, Acot1, Acot4, Cyp4a10, Cyp4a14 and Lipin2, an effect that was highly correlated with Hnf4 alpha. In vitro studies using primary hepatocyte cultures treated with epinephrine or AR-agonists confirmed that hepatic AR/cAMP/PKA/CREB- and JNK-linked pathways are involved in PPAR alpha and HNF4 alpha regulation. Notably, restraint stress, independent of PPAR alpha, suppressed plasma triglyceride levels. This stress-induced effect could be attributed in part to hormone sensitive lipase activation in the white adipose tissue, which was not prevented by the increased levels of perilipin. Overall, this study identifies a mechanistic basis for the modification of lipid homeostasis following stress and potentially indicates novel roles for PPAR alpha and HNF4 alpha in stress-induced lipid metabolism. C1 [Konstandi, Maria; Shah, Yatrik M.; Matsubara, Tsutomu; Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Konstandi, Maria] Univ Ioannina, Sch Med, Dept Pharmacol, GR-45110 Ioannina, Greece. [Shah, Yatrik M.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Konstandi, M (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM mkonstan@cc.uoi.gr FU National Cancer Institute Intramural Research Program; Molecular Life Science, University of Oslo; Norwegian Cancer Society [PR-2006-0442, PR-2007-0166] FX This study was supported by the National Cancer Institute Intramural Research Program. ML is supported as a PhD student by Molecular Life Science, University of Oslo and the study is supported by the Norwegian Cancer Society (PR-2006-0442, RAL; PR-2007-0166, RIS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 5 Z9 6 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e70675 DI 10.1371/journal.pone.0070675 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500023 PM 23967086 ER PT J AU Munro, TA Huang, XP Inglese, C Perrone, MG Van't Veer, A Carroll, FI Beguin, C Carlezon, WA Colabufo, NA Cohen, BM Roth, BL AF Munro, Thomas A. Huang, Xi-Ping Inglese, Carmela Perrone, Maria Grazia Van't Veer, Ashlee Carroll, F. Ivy Beguin, Cecile Carlezon, William A., Jr. Colabufo, Nicola A. Cohen, Bruce M. Roth, Bryan L. TI Selective kappa Opioid Antagonists nor-BNI, GNTI and JDTic Have Low Affinities for Non-Opioid Receptors and Transporters SO PLOS ONE LA English DT Article ID NOCICEPTIN/ORPHANIN FQ RECEPTOR; ALLOSTERIC MODULATION; P-GLYCOPROTEIN; SPINAL-CORD; IN-VITRO; MICE; LIGANDS; SITE; BINALTORPHIMINE; AGONISTS AB Background: Nor-BNI, GNTI and JDTic induce selective kappa opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets. Results: In binding assays, the three antagonists showed no detectable affinity (K-i >= 10 mu M) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for kappa opioid receptors, with moderate selectivity over mu and delta (3 to 44-fold). Nor-BNI bound weakly to the alpha(2C)-adrenoceptor (K-i = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the alpha(1A)-adrenoceptor (EC50 = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M-1 receptor antagonist (K-B = 3.7 mu M). JDTic bound to the noradrenaline transporter (K-i = 54 nM), but only weakly inhibited transport (IC50 = 1.1 mu M). JDTic also bound to the opioid-like receptor NOP (K-i = 12 nM), but gave little antagonism even at 30 mu M. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers. Conclusions: Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of alpha(1A)-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, kappa opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective kappa opioid antagonists. C1 [Munro, Thomas A.; Van't Veer, Ashlee; Beguin, Cecile; Carlezon, William A., Jr.; Cohen, Bruce M.] McLean Hosp, Belmont, MA 02178 USA. [Munro, Thomas A.; Van't Veer, Ashlee; Beguin, Cecile; Carlezon, William A., Jr.; Cohen, Bruce M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Munro, Thomas A.] Univ Melbourne, Sch Chem, Parkville, Vic 3052, Australia. [Munro, Thomas A.] Univ Melbourne, Inst Bio21, Parkville, Vic 3052, Australia. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Inglese, Carmela; Perrone, Maria Grazia; Colabufo, Nicola A.] Univ Bari, Dipartimento Farm Sci Farmaco, Bari, Italy. [Carroll, F. Ivy] Res Triangle Inst, Ctr Organ & Med Chem, Res Triangle Pk, NC 27709 USA. RP Munro, TA (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02178 USA. EM thomas@munro.com RI Munro, Thomas/B-2712-2009; Roth, Bryan/F-3928-2010; OI Munro, Thomas/0000-0002-3366-7149; Perrone, Maria Grazia/0000-0003-4195-5228 FU National Institute of Mental Health; National Institute of Drug Abuse [DA09045, DA030586]; Department of Defense (National Defense Science and Engineering Graduate Fellowship); Ministero dell'Istruzione, dell'Universita e della Ricerca, Italy (MIUR) [PRIN 20097FJHPZ-001] FX Funding was provided by: the National Institute of Mental Health (Psychoactive Drug Screening Program, administered by BLR); National Institute of Drug Abuse (DA09045 to FIC and DA030586 to WAC); Department of Defense (National Defense Science and Engineering Graduate Fellowship to AVV); and Ministero dell'Istruzione, dell'Universita e della Ricerca, Italy (MIUR, PRIN 20097FJHPZ-001 to NAC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 6 Z9 6 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e70701 DI 10.1371/journal.pone.0070701 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500024 PM 23976952 ER PT J AU Ono, M Inkson, CA Sonn, R Kilts, TM de Castro, LF Maeda, A Fisher, LW Robey, PG Berendsen, AD Li, L McCartney-Francis, N Brown, AC Crawford, NPS Molinolo, A Jain, A Fedarko, NS Young, MF AF Ono, Mitsuaki Inkson, Colette A. Sonn, Robert Kilts, Tina M. de Castro, Luis F. Maeda, Azusa Fisher, Larry W. Robey, Pamela G. Berendsen, Agnes D. Li, Li McCartney-Francis, Nancy Brown, Aaron C. Crawford, Nigel P. S. Molinolo, Alfredo Jain, Alka Fedarko, Neal S. Young, Marian F. TI WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone SO PLOS ONE LA English DT Article ID HUMAN CHONDROSARCOMA CELLS; PANCREATIC TUMOR-GROWTH; IN-VIVO; DIFFERENTIAL EXPRESSION; FACTOR CTGF/CCN2; BREAST-CANCER; METASTASIS; WISP-1; CYR61; MECHANISMS AB Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel (TM) barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer. C1 [Ono, Mitsuaki; Inkson, Colette A.; Sonn, Robert; Kilts, Tina M.; de Castro, Luis F.; Maeda, Azusa; Fisher, Larry W.; Robey, Pamela G.; Berendsen, Agnes D.; Li, Li; McCartney-Francis, Nancy; Brown, Aaron C.; Young, Marian F.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Molinolo, Alfredo] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Crawford, Nigel P. S.] NHGRI, Metastasis Genet Sect, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Jain, Alka; Fedarko, Neal S.] Johns Hopkins Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Ono, Mitsuaki] Okayama Univ, Dept Oral Rehabil & Regenerat Med, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. [Inkson, Colette A.] Univ Manchester, Fac Life Sci, Manchester Immunol Grp, Manchester, Lancs, England. RP Young, MF (reprint author), NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. EM myoung@dir.nicdr.nih.gov RI Robey, Pamela/H-1429-2011; OI Robey, Pamela/0000-0002-5316-5576; Fedarko, Neal/0000-0001-6055-6279; Inkson, Colette/0000-0003-1215-312X FU Division of Intramural Research, NIDCR of the Intramural Research Program, NIH, DHHS; Department of Defense [W81XWH-11-1-0239]; Howard Hughes Scholarship FX This research was supported by the Division of Intramural Research, NIDCR of the Intramural Research Program, NIH, DHHS (MO, CAI, TMK, LFCD, AM (Maeda), LWF, PGR, ADB, LL NM-F, ACB, NPSC, AM (Molinolo) and MFY), by a grant from the Department of Defense W81XWH-11-1-0239 (AJ and NSF) and by a Howard Hughes Scholarship (RS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 24 Z9 25 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e71709 DI 10.1371/journal.pone.0071709 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500098 PM 23977121 ER PT J AU Chow, MZ Boheler, KR Li, RA AF Chow, Maggie Zi Boheler, Kenneth R. Li, Ronald A. TI Human pluripotent stem cell-derived cardiomyocytes for heart regeneration, drug discovery and disease modeling: from the genetic, epigenetic, and tissue modeling perspectives SO STEM CELL RESEARCH & THERAPY LA English DT Review DE Human embryonic stem cell; Induced pluripotent stem cell; Cardiomyocyte; Epigenetic regulations; Chromatin remodeling; Histone modification; Regenerative medicine; Cardiac differentiation ID HUMAN PERIPHERAL-BLOOD; LONG-QT SYNDROME; CARDIOVASCULAR PROGENITORS; CARDIAC DIFFERENTIATION; HUMAN FIBROBLASTS; DEFINED FACTORS; VENTRICULAR CARDIOMYOCYTES; FACILITATED MATURATION; MYOCARDIAL-INFARCTION; RAT HEARTS AB Heart diseases remain a major cause of mortality and morbidity worldwide. However, terminally differentiated human adult cardiomyocytes (CMs) possess a very limited innate ability to regenerate. Directed differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into CMs has enabled clinicians and researchers to pursue the novel therapeutic paradigm of cell-based cardiac regeneration. In addition to tissue engineering and transplantation studies, the need for functional CMs has also prompted researchers to explore molecular pathways and develop strategies to improve the quality, purity and quantity of hESC-derived and iPSC-derived CMs. In this review, we describe various approaches in directed CM differentiation and driven maturation, and discuss potential limitations associated with hESCs and iPSCs, with an emphasis on the role of epigenetic regulation and chromatin remodeling, in the context of the potential and challenges of using hESC-CMs and iPSC-CMs for drug discovery and toxicity screening, disease modeling, and clinical applications. C1 [Chow, Maggie Zi; Boheler, Kenneth R.; Li, Ronald A.] Univ Hong Kong, Fac Med, Stem Cell & Regenerat Med Consortium, Hong Kong, Hong Kong, Peoples R China. [Chow, Maggie Zi; Boheler, Kenneth R.; Li, Ronald A.] Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China. [Boheler, Kenneth R.] NIA, Mol Cardiol & Stem Cell Unit, Cardiovasc Sci Lab, NIH,Gerontol Res Ctr, Baltimore, MD 21224 USA. [Li, Ronald A.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Li, RA (reprint author), Univ Hong Kong, Fac Med, Stem Cell & Regenerat Med Consortium, 5 Sassoon Rd,Hong Kong Jockey Club Bldg Interdisc, Hong Kong, Hong Kong, Peoples R China. EM ronaldli@hkucc.hku.hk NR 119 TC 10 Z9 11 U1 1 U2 44 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD AUG 14 PY 2013 VL 4 AR 97 DI 10.1186/1757-6512-4-97 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 201XA UT WOS:000323175100003 PM 23953772 ER PT J AU Murray, CJL Abraham, J Ali, MK Alvarado, M Atkinson, C Baddour, LM Bartels, DH Benjamin, EJ Bhalla, K Birbeck, G Bolliger, I Burstein, R Carnahan, E Chen, HL Chou, D Chugh, SS Cohen, A Colson, KE Cooper, LT Couser, W Criqui, MH Dabhadkar, KC Dahodwala, N Danaei, G Dellavalle, RP Des Jarlais, DC Dicker, D Ding, EL Dorsey, R Duber, H Ebel, BE Engell, RE Ezzati, M Felson, DT Finucane, MM Flaxman, S Flaxman, AD Fleming, T Forouzanfar, MH Freedman, G Freeman, MK Gabriel, SE Gakidou, E Gillum, RF Gonzalez-Medina, D Gosselin, R Grant, B Gutierrez, HR Hagan, H Havmoeller, R Hoffman, H Jacobsen, KH James, SL Jasrasaria, R Jayaraman, S Johns, N Kassebaum, N Khatibzadeh, S Knowlton, LM Lan, Q Leasher, JL Lim, S Lin, JK Lipshultz, SE London, S Lozano, R Lu, Y MacIntyre, MF Mallinger, L McDermott, MM Meltzer, M Mensah, GA Michaud, C Miller, TR Mock, C Moffitt, TE Mokdad, AA Mokdad, AH Moran, AE Mozaffarian, D Murphy, T Naghavi, M Narayan, KMV Nelson, RG Olives, C Omer, SB Ortblad, K Ostro, B Pelizzari, PM Phillips, D Pope, CA Raju, M Ranganathan, D Razavi, H Ritz, B Rivara, FP Roberts, T Sacco, RL Salomon, JA Sampson, U Sanman, E Sapkota, A Schwebel, DC Shahraz, S Shibuya, K Shivakoti, R Silberberg, D Singh, GM Singh, D Singh, JA Sleet, DA Steenland, K Tavakkoli, M Taylor, JA Thurston, GD Towbin, JA Vavilala, MS Vos, T Wagner, GR Weinstock, MA Weisskopf, MG Wilkinson, JD Wulf, S Zabetian, A Lopez, AD AF Murray, Christopher J. L. Abraham, Jerry Ali, Mohammed K. Alvarado, Miriam Atkinson, Charles Baddour, Larry M. Bartels, David H. Benjamin, Emelia J. Bhalla, Kavi Birbeck, Gretchen Bolliger, Ian Burstein, Roy Carnahan, Emily Chen, Honglei Chou, David Chugh, Sumeet S. Cohen, Aaron Colson, K. Ellicott Cooper, Leslie T. Couser, William Criqui, Michael H. Dabhadkar, Kaustubh C. Dahodwala, Nabila Danaei, Goodarz Dellavalle, Robert P. Des Jarlais, Don C. Dicker, Daniel Ding, Eric L. Dorsey, Ray Duber, Herbert Ebel, Beth E. Engell, Rebecca E. Ezzati, Majid Felson, David T. Finucane, Mariel M. Flaxman, Seth Flaxman, Abraham D. Fleming, Thomas Forouzanfar, Mohammad H. Freedman, Greg Freeman, Michael K. Gabriel, Sherine E. Gakidou, Emmanuela Gillum, Richard F. Gonzalez-Medina, Diego Gosselin, Richard Grant, Bridget Gutierrez, Hialy R. Hagan, Holly Havmoeller, Rasmus Hoffman, Howard Jacobsen, Kathryn H. James, Spencer L. Jasrasaria, Rashmi Jayaraman, Sudha Johns, Nicole Kassebaum, Nicholas Khatibzadeh, Shahab Knowlton, Lisa Marie Lan, Qing Leasher, Janet L. Lim, Stephen Lin, John Kent Lipshultz, Steven E. London, Stephanie Lozano, Rafael Lu, Yuan MacIntyre, Michael F. Mallinger, Leslie McDermott, Mary M. Meltzer, Michele Mensah, George A. Michaud, Catherine Miller, Ted R. Mock, Charles Moffitt, Terrie E. Mokdad, Ali A. Mokdad, Ali H. Moran, Andrew E. Mozaffarian, Dariush Murphy, Tasha Naghavi, Mohsen Narayan, K. M. Venkat Nelson, Robert G. Olives, Casey Omer, Saad B. Ortblad, Katrina Ostro, Bart Pelizzari, Pamela M. Phillips, David Pope, C. Arden, III Raju, Murugesan Ranganathan, Dharani Razavi, Homie Ritz, Beate Rivara, Frederick P. Roberts, Thomas Sacco, Ralph L. Salomon, Joshua A. Sampson, Uchechukwu Sanman, Ella Sapkota, Amir Schwebel, David C. Shahraz, Saeid Shibuya, Kenji Shivakoti, Rupak Silberberg, Donald Singh, Gitanjali M. Singh, David Singh, Jasvinder A. Sleet, David A. Steenland, Kyle Tavakkoli, Mohammad Taylor, Jennifer A. Thurston, George D. Towbin, Jeffrey A. Vavilala, Monica S. Vos, Theo Wagner, Gregory R. Weinstock, Martin A. Weisskopf, Marc G. Wilkinson, James D. Wulf, Sarah Zabetian, Azadeh Lopez, Alan D. CA Us Burden Dis Collaborators TI The State of US Health, 1990-2010 Burden of Diseases, Injuries, and Risk Factors SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BODY-MASS INDEX; ADJUSTED LIFE YEARS; GLOBAL BURDEN; SYSTEMATIC ANALYSIS; UNITED-STATES; PUBLIC-HEALTH; CARDIOVASCULAR-DISEASE; BUILT ENVIRONMENT; PHYSICAL-ACTIVITY; BLOOD-PRESSURE AB IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations. C1 [Murray, Christopher J. L.; Alvarado, Miriam; Atkinson, Charles; Bolliger, Ian; Burstein, Roy; Carnahan, Emily; Chou, David; Colson, K. Ellicott; Dicker, Daniel; Duber, Herbert; Engell, Rebecca E.; Flaxman, Abraham D.; Gakidou, Emmanuela; Gonzalez-Medina, Diego; James, Spencer L.; Jasrasaria, Rashmi; Johns, Nicole; Lim, Stephen; MacIntyre, Michael F.; Mallinger, Leslie; Mokdad, Ali A.; Mokdad, Ali H.; Murphy, Tasha; Naghavi, Mohsen; Ortblad, Katrina; Phillips, David; Ranganathan, Dharani; Roberts, Thomas; Sanman, Ella; Vos, Theo; Wulf, Sarah] Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Couser, William; Ebel, Beth E.; Kassebaum, Nicholas; Mock, Charles; Olives, Casey; Rivara, Frederick P.; Vavilala, Monica S.] Univ Washington, Seattle, WA 98195 USA. [Abraham, Jerry] Univ Texas San Antonio, Sch Med, San Antonio, TX USA. [Omer, Saad B.; Steenland, Kyle] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Ali, Mohammed K.; Dabhadkar, Kaustubh C.; Narayan, K. M. Venkat; Zabetian, Azadeh] Emory Univ, Atlanta, GA 30322 USA. [Baddour, Larry M.; Gabriel, Sherine E.] Mayo Clin, Rochester, MN USA. [Danaei, Goodarz; Ding, Eric L.; Finucane, Mariel M.; Khatibzadeh, Shahab; Knowlton, Lisa Marie; Lin, John Kent; Lu, Yuan; Singh, Gitanjali M.; Tavakkoli, Mohammad; Weisskopf, Marc G.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bartels, David H.; Jayaraman, Sudha; Mozaffarian, Dariush] Harvard Univ, Sch Med, Boston, MA USA. [Bhalla, Kavi] Harvard Univ, Boston, MA 02115 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Felson, David T.] Boston Univ, Boston, MA 02215 USA. [Birbeck, Gretchen] Michigan State Univ, E Lansing, MI USA. [Chen, Honglei; London, Stephanie] NIEHS, Res Triangle Pk, NC 27709 USA. [Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Grant, Bridget; Hoffman, Howard; Mensah, George A.] NIH, Bethesda, MD 20892 USA. [Nelson, Robert G.] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Wagner, Gregory R.] NIOSH, Baltimore, MD USA. [Chugh, Sumeet S.; Havmoeller, Rasmus] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Cohen, Aaron] Hlth Effects Inst, Boston, MA USA. [Cooper, Leslie T.] Loyola Univ, Sch Med, Chicago, IL 60611 USA. [Criqui, Michael H.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Dahodwala, Nabila; Silberberg, Donald] Univ Penn, Philadelphia, PA 19104 USA. [Dellavalle, Robert P.] Denver VA Med Ctr, Denver, CO USA. [Des Jarlais, Don C.] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Dorsey, Ray; Shivakoti, Rupak] Johns Hopkins Univ, Baltimore, MD USA. [Ezzati, Majid] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC HPA Ctr Environm & Hlth, London, England. [Flaxman, Seth] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Gillum, Richard F.] Howard Univ, Coll Med, Washington, DC USA. [Gosselin, Richard] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gutierrez, Hialy R.] Mailman Sch Publ Hlth, New York, NY USA. [Moran, Andrew E.] Columbia Univ, New York, NY USA. [Hagan, Holly; Thurston, George D.] NYU, New York, NY USA. [Jacobsen, Kathryn H.] George Mason Univ, Fairfax, VA 22030 USA. [Leasher, Janet L.] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Lipshultz, Steven E.; Sacco, Ralph L.; Wilkinson, James D.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Lopez, Alan D.] Univ Melbourne, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Lozano, Rafael] Inst Nacl Salud Publ, Ctr Invest Sistemas Salud, Cuernavaca, Morelos, Mexico. [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Meltzer, Michele] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Michaud, Catherine] China Med Board, Boston, MA USA. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Moffitt, Terrie E.] Duke Univ, Durham, NC USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ostro, Bart] Calif Environm Protect Agcy, Sacramento, CA USA. [Pelizzari, Pamela M.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Pope, C. Arden, III] Brigham Young Univ, Provo, UT 84602 USA. [Raju, Murugesan] Univ Missouri, Mason Eye Inst, Columbia, MO 65211 USA. [Razavi, Homie] Ctr Dis Anal, Louisville, CO USA. [Ritz, Beate] Univ Calif Los Angeles, Los Angeles, CA USA. [Sampson, Uchechukwu] Vanderbilt Univ, Nashville, TN 37235 USA. [Sapkota, Amir] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Shahraz, Saeid] Brandeis Univ, Waltham, MA USA. [Shibuya, Kenji] Univ Tokyo, Dept Global Hlth Policy, Tokyo, Japan. [Singh, David] Queens Med Ctr, Honolulu, HI USA. [Sleet, David A.] Natl Ctr Injury Prevent & Control, Atlanta, GA USA. [Taylor, Jennifer A.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Towbin, Jeffrey A.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Weinstock, Martin A.] Brown Univ, Providence, RI 02912 USA. RP Murray, CJL (reprint author), Inst Hlth Metr & Evaluat, 2301 5th Ave,Ste 600, Seattle, WA 98121 USA. EM cjlm@uw.edu RI Lopez, Alan D/F-1487-2010; Dellavalle, Robert/L-2020-2013; Moffitt, Terrie/D-5295-2011; Narayan, K.M. Venkat /J-9819-2012; Ritz, Beate/E-3043-2015; Sapkota, Amir/A-5968-2011; Bolliger, Ian/C-4207-2016; Jacobsen, Kathryn/B-5857-2008; Salomon, Joshua/D-3898-2009; OI Chen, Honglei/0000-0003-3446-7779; London, Stephanie/0000-0003-4911-5290; Lopez, Alan D/0000-0001-5818-6512; Mock, Charles/0000-0002-0564-568X; Ding, Eric/0000-0002-5881-8097; singh, jasvinder/0000-0003-3485-0006; Johns, Nicole/0000-0003-4513-4582; Mensah, George/0000-0002-0387-5326; Benjamin, Emelia/0000-0003-4076-2336; Miller, Ted/0000-0002-0958-2639; Dellavalle, Robert/0000-0001-8132-088X; Moffitt, Terrie/0000-0002-8589-6760; Narayan, K.M. Venkat /0000-0001-8621-5405; Bolliger, Ian/0000-0001-8055-297X; Jacobsen, Kathryn/0000-0002-4198-6246; Salomon, Joshua/0000-0003-3929-5515; Pelizzari, Pamela/0000-0002-6992-9462; Ranganathan, Dharani/0000-0001-6506-2825 FU National Institutes of Health, the National Institute of Environmental Health Sciences; Bill and Melinda Gates Foundation FX This study is supported in part by the Intramural Program of the National Institutes of Health, the National Institute of Environmental Health Sciences, and in part by the Bill and Melinda Gates Foundation. NR 81 TC 551 Z9 556 U1 40 U2 252 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 14 PY 2013 VL 310 IS 6 BP 591 EP 608 DI 10.1001/jama.2013.13805 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 200HI UT WOS:000323058400015 PM 23842577 ER PT J AU Nablo, BJ Panchal, RG Bavari, S Nguyen, TL Gussio, R Ribot, W Friedlander, A Chabot, D Reiner, JE Robertson, JWF Balijepalli, A Halverson, KM Kasianowicz, JJ AF Nablo, Brian J. Panchal, Rekha G. Bavari, Sina Nguyen, Tam L. Gussio, Rick Ribot, Wil Friedlander, Art Chabot, Donald Reiner, Joseph E. Robertson, Joseph W. F. Balijepalli, Arvind Halverson, Kelly M. Kasianowicz, John J. TI Anthrax toxin-induced rupture of artificial lipid bilayer membranes SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID SYMMETRICAL TETRAALKYLAMMONIUM IONS; IRREVERSIBLE ELECTRICAL BREAKDOWN; STERIC-BLOCK OLIGONUCLEOTIDES; CELL PENETRATING PEPTIDES; EFFICIENT GENE-TRANSFER; PROTECTIVE ANTIGEN; BACILLUS-ANTHRACIS; LETHAL FACTOR; PROTEIN TRANSLOCATION; EDEMA FACTOR AB We demonstrate experimentally that anthrax toxin complexes rupture artificial lipid bilayer membranes when isolated from the blood of infected animals. When the solution pH is temporally acidified to mimic that process in endosomes, recombinant anthrax toxin forms an irreversibly bound complex, which also destabilizes membranes. The results suggest an alternative mechanism for the translocation of anthrax toxin into the cytoplasm. C1 [Nablo, Brian J.; Reiner, Joseph E.; Robertson, Joseph W. F.; Balijepalli, Arvind; Kasianowicz, John J.] NIST, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Panchal, Rekha G.; Bavari, Sina; Ribot, Wil; Friedlander, Art; Chabot, Donald; Halverson, Kelly M.] US Army Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Nguyen, Tam L.; Gussio, Rick] NCI, Dev Therapeut Program, Target Struct Based Drug Discovery Grp, SAIC, Frederick, MD 21702 USA. [Balijepalli, Arvind] NHLBI, Lab Computat Biol, Rockville, MD 20852 USA. RP Kasianowicz, JJ (reprint author), NIST, Phys Measurement Lab, Gaithersburg, MD 20899 USA. EM john.kasianowicz@nist.gov OI Reiner, Joseph/0000-0002-1056-8703 FU NIST-NRC; NIH-NIST-NRC; NIST Office of Law Enforcement Standards FX This work is supported, in part, by a NIST-NRC Research Associateship (B.J.N.), a NIH-NIST-NRC Research Associateship (A.B.), and the NIST Office of Law Enforcement Standards (J.J.K.). Certain commercial equipment, instruments, or materials are identified in this paper to adequately specify the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. In conducting the research described in this paper, the investigators adhered to the "Guide for Care and Use of Laboratory Animals" as promulgated by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. The facilities are fully accredited by the American Association for Accreditation of Laboratory Animal Care. NR 130 TC 6 Z9 6 U1 3 U2 16 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 14 PY 2013 VL 139 IS 6 AR 065101 DI 10.1063/1.4816467 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 201YB UT WOS:000323177900055 PM 23947891 ER PT J AU Shipman, SL Herring, BE Suh, YH Roche, KW Nicoll, RA AF Shipman, Seth L. Herring, Bruce E. Suh, Young Ho Roche, Katherine W. Nicoll, Roger A. TI Distance-Dependent Scaling of AMPARs Is Cell-Autonomous and GluA2 Dependent SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CA1 PYRAMIDAL NEURONS; RECEPTOR TRAFFICKING; HIPPOCAMPAL-NEURONS; SUBUNIT COMPOSITION; CORNICHON PROTEINS; SYNAPSES; PLASTICITY; AMPLITUDE; REQUIRES; NUMBER AB The extensive dendritic arbor of a pyramidal cell introduces considerable complexity to the integration of synaptic potentials. Propagation of dendritic potentials is largely passive, in contrast to regenerative axonal potentials that are maintained by voltage-gated sodium channels, leading to a declination in amplitude as dendritic potentials travel toward the soma in a manner that disproportionally affects distal synaptic inputs. To counteract this amplitude filtering, Schaffer collateral synapses onto CA1 pyramidal cells contain a varying number of AMPA receptors (AMPARs) per synapse that increases with distance from the soma, a phenomenon known as distance-dependent scaling. Here, we undertake an investigation into the molecular mechanisms of distance-dependent scaling. Using dendritic recordings from rat pyramidal neurons, we confirm the basic scaling phenomenon and find that it is expressed and can be manipulated cell autonomously. Finally, we show that it depends on the presence of both a reserve pool of AMPARs and the AMPAR subunit GluA2. C1 [Shipman, Seth L.; Herring, Bruce E.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Shipman, Seth L.; Herring, Bruce E.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA. [Shipman, Seth L.] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94158 USA. [Suh, Young Ho; Roche, Katherine W.] NINDS, US NIH, Bethesda, MD 20892 USA. RP Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, 600 16th St,Genentech Hall N272D, San Francisco, CA 94158 USA. EM roger.nicoll@ucsf.edu OI Roche, Katherine/0000-0001-7282-6539 FU U.S. National Institute of Mental Health [R37 MH038256-29]; National Institute of Neurological Disorders and Stroke FX This work was supported by a grant from the U.S. National Institute of Mental Health (R37 MH038256-29), and by the Intramural Research Program of National Institute of Neurological Disorders and Stroke (Y.H.S. and K.W.R.). We are grateful to Dan Johnston and the members of his laboratory, specifically Darrin Brager and Rishi Narayanan, for assistance with dendritic recording methodology. NR 27 TC 9 Z9 9 U1 1 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 14 PY 2013 VL 33 IS 33 BP 13312 EP 13319 DI 10.1523/JNEUROSCI.0678-13.2013 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 201PV UT WOS:000323155700006 PM 23946389 ER PT J AU Murnane, KS Winschel, J Schmidt, KT Stewart, LM Rose, SJ Cheng, KJ Rice, KC Howell, LL AF Murnane, Kevin S. Winschel, Jake Schmidt, Karl T. Stewart, LaShaya M. Rose, Samuel J. Cheng, Kejun Rice, Kenner C. Howell, Leonard L. TI Serotonin 2A Receptors Differentially Contribute to Abuse-Related Effects of Cocaine and Cocaine-Induced Nigrostriatal and Mesolimbic Dopamine Overflow in Nonhuman Primates SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; MEDIAL PREFRONTAL CORTEX; CONSCIOUS RHESUS-MONKEYS; SEEKING BEHAVIOR; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; INDUCED REINSTATEMENT; 5-HT2A RECEPTORS; DORSAL STRIATUM; RELEASE; DRUG AB Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug-and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. C1 [Murnane, Kevin S.; Winschel, Jake; Schmidt, Karl T.; Stewart, LaShaya M.; Rose, Samuel J.; Howell, Leonard L.] Emory Univ, Yerkes Natl Primate Res Ctr, Div Neuropharmacol & Neurol Dis, Atlanta, GA 30322 USA. [Howell, Leonard L.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Howell, LL (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd, Atlanta, GA 30322 USA. EM lhowell@emory.edu FU United States Public Health Service [DA010344, DA012514, RR00165]; National Institutes of Health Office of Research Infrastructure Programs [0DP510D11132]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX These studies were supported by United States Public Health Service Grants DA010344, DA012514, and RR00165, and is currently supported by the National Institutes of Health Office of Research Infrastructure Programs Grant 0DP510D11132. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. We thank both Juliet Brown and Lisa Neidert for their expert technical assistance. NR 52 TC 13 Z9 13 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 14 PY 2013 VL 33 IS 33 BP 13367 EP 13374 DI 10.1523/JNEUROSCI.1437-13.2013 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 201PV UT WOS:000323155700011 PM 23946394 ER PT J AU Chen, K Tjandra, N AF Chen, Kang Tjandra, Nico TI Determining Interdomain Structure and Dynamics of a Retroviral Capsid Protein in the Presence of Oligomerization: Implication for Structural Transition in Capsid Assembly SO BIOCHEMISTRY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; ROTATIONAL DIFFUSION TENSOR; NMR STRUCTURE DETERMINATION; INFECTIOUS-ANEMIA VIRUS; N-TERMINAL DOMAIN; MULTIDOMAIN PROTEINS; GLOBULAR-PROTEINS; RELAXATION RATES; MOLECULAR SHAPE; IN-VITRO AB Capsid (CA) proteins from all retroviruses, including HIV-1, are structurally homologous dual-domain helical proteins. They form a capsid lattice composed of unitary symmetric CA hexamers. X-ray crystallography has shown that within each hexamer a monomeric CA adopts a single conformation, where most helices are parallel to the symmetry axis. In solution, large differences in averaged NMR spin relaxation rates for the two domains were observed, suggesting they are dynamically independent. One relevant question for the capsid assembly remains: whether the interdomain conformer within a hexamer unit needs to be induced or pre-exists within the conformational space of a monomeric CA. The latter seems more consistent with the relaxation data. However, possible CA protein oligomerization and the structure of each domain will affect relaxation measurements and data interpretation. This study, using CA proteins from equine infectious anemia virus (EIAV) as an example, demonstrates a linear extrapolation approach to obtain backbone N-15 spin relaxation time ratios T-1/T-2 for a monomeric EIAV-CA in the presence of oligomerization equilibrium. The interdomain motion turns out to be limited. The large difference in the domain averaged < T-1/T-2 > for a CA monomer is a consequence of the orthogonal distributions of helices in the two domains. The new monomeric interdomain conformation in solution is significantly different from that in CA hemmer. Therefore, if capsid assembly follows a nucleation propagation process, the interdomain conformational change might be a key step during the nucleation, as the configuration in hexagonal assembly is never formed by diffusion of its two domains in solution. C1 [Chen, Kang; Tjandra, Nico] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute of the NIH FX The project was funded by the Intramural Research Programs of the National Heart, Lung, and Blood Institute of the NIH. NR 51 TC 3 Z9 3 U1 0 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 13 PY 2013 VL 52 IS 32 BP 5365 EP 5371 DI 10.1021/bi400592d PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202DM UT WOS:000323193700006 PM 23906107 ER PT J AU Marine, JE Shetty, V Chow, GV Wright, JG Gerstenblith, G Najjar, SS Lakatta, EG Fleg, JL AF Marine, Joseph E. Shetty, Veena Chow, Grant V. Wright, Jeanette G. Gerstenblith, Gary Najjar, Samer S. Lakatta, Edward G. Fleg, Jerome L. TI Prevalence and Prognostic Significance of Exercise-Induced Nonsustained Ventricular Tachycardia in Asymptomatic Volunteers BLSA (Baltimore Longitudinal Study of Aging) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aging; exercise testing; ventricular tachycardia ID CARDIOVASCULAR-DISEASE ENTERPRISES; APPARENTLY HEALTHY-VOLUNTEERS; HYPERTROPHIC CARDIOMYOPATHY; MAJOR SHAREHOLDERS; SUDDEN-DEATH; HUMAN HEART; RISK; ARRHYTHMIAS; PREDICTOR; ARTERIAL AB Objectives This study sought to determine the clinical predictors and prognostic significance of exercise-induced nonsustained ventricular tachycardia (NSVT) in a large population of asymptomatic volunteers. Background Prior studies have reported variable risk associated with exercise-induced ventricular arrhythmia. Methods Subjects in the BLSA (Baltimore Longitudinal Study of Aging) free of known cardiovascular disease who completed at least 1 symptom-limited exercise treadmill test between 1977 and 2001 were included. NSVT episodes were characterized by QRS morphology, duration, and rate. Subjects underwent follow-up clinical evaluation every 2 years. Results The 2,099 subjects (mean age: 52 years; 52.2% male) underwent a mean of 2.7 exercise tests, in which 79 (3.7%) developed NSVT with exercise on at least 1 test. The median duration of NSVT was 3 beats (<= 5 beats in 84%), and the median rate was 175 beats/min. Subjects with (vs. without) NSVT were older (67 +/- 12 years vs. 51 +/- 17 years, p < 0.0001) and more likely to be male (80% vs. 51%, p < 0.0001) and to have baseline electrocardiographic abnormalities (50% vs. 17%, p < 0.0001) or ischemic ST-segment changes with exercise (20% vs. 10%, p = 0.004). Over a mean follow-up of 13.5 +/- 7.7 years, 518 deaths (24.6%) occurred. After multivariable adjustment for age, sex, and coronary risk factors, exercise-induced NSVT was not significantly associated with total mortality (hazard ratio: 1.30; 95% confidence interval: 0.89 to 1.90; p = 0.17). Conclusions Exercise-induced NSVT occurred in nearly 4% of this asymptomatic adult cohort. This finding increased with age and was more common in men. After adjustment for clinical variables, exercise-induced NSVT did not independently increase the risk of total mortality. (C) 2013 by the American College of Cardiology Foundation C1 [Marine, Joseph E.; Chow, Grant V.; Gerstenblith, Gary] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Shetty, Veena; Wright, Jeanette G.; Najjar, Samer S.; Lakatta, Edward G.] NIA, Baltimore, MD 21224 USA. [Najjar, Samer S.] Washington Hosp Ctr, MedStar Hlth Res Inst, Washington, DC 20010 USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. RP Fleg, JL (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8147, Bethesda, MD 20892 USA. EM flegj@nhlbi.nih.gov FU National Institute on Aging of the National Institutes of Health; MedStar Research Institute; HeartWare Inc. FX This research was supported in part by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health and the MedStar Research Institute. Dr. Najjar has received research support from HeartWare Inc. All other authors have reported that they have no relationships relevant to the content of this paper to disclose. NR 19 TC 12 Z9 13 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 13 PY 2013 VL 62 IS 7 BP 595 EP 600 DI 10.1016/j.jacc.2013.05.026 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 207MQ UT WOS:000323605200006 PM 23747767 ER PT J AU Liao, QH Bai, T Zhou, L Vong, S Guo, JQ Lv, W Dong, LB Xiang, NJ Li, Z Huai, Y Zhou, JF Li, XD Chen, RY Xu, Z Uyeki, TM Shu, YL Yu, H AF Liao, Qiaohong Bai, Tian Zhou, Lei Vong, Sirenda Guo, Junqiao Lv, Wei Dong, Libo Xiang, Nijuan Li, Zi Huai, Yang Zhou, Jianfang Li, Xiaodan Chen, Ray Y. Xu, Zhen Uyeki, Timothy M. Shu, Yuelong Yu, Hongjie TI Seroprevalence of Antibodies to Highly Pathogenic Avian Influenza A (H5N1) Virus among Close Contacts Exposed to H5N1 Cases, China, 2005-2008 SO PLOS ONE LA English DT Article AB To assess the extent of highly pathogenic avian influenza (HPAI) A (H5N1) virus transmission, we conducted sero-epidemiologic studies among close contacts exposed to H5N1 cases in mainland China during 2005-2008. Blood specimens were collected from 87 household members and 332 social contacts of 23 H5N1 index cases for HPAI H5N1 serological testing by modified horse red-blood-cell hemagglutinin inhibition and microneutralization assays. All participants were interviewed with a standardized questionnaire to collect information about the use of personal protective equipment, illness symptoms, exposure to an H5N1 case during the infectious period, and poultry exposures. Two (2.3%) household contacts tested positive for HPAI H5N1 virus antibody, and all social contacts tested negative. Both seropositive cases had prolonged, unprotected, close contact with a different H5N1 index case, including days of bed-care or sleeping together during the index case's infectious period, and did not develop any illness. None of the 419 close contacts used appropriate personal protective equipment including 17% who reported providing bedside care or having physical contact with an H5N1 case for at least 12 hours. Our findings suggest that HPAI H5N1 viruses that circulated among poultry in mainland China from 2005-2008 were not easily transmitted to close contacts of H5N1 cases. C1 [Liao, Qiaohong; Xu, Zhen; Yu, Hongjie] Chinese Ctr Dis Control & Prevent China CDC, Div Infect Dis, Key Lab Surveillance & Early Warning Infect Dis, Beijing, Peoples R China. [Bai, Tian; Dong, Libo; Li, Zi; Zhou, Jianfang; Li, Xiaodan; Shu, Yuelong] Natl Hlth & Family Planning Commiss, Natl Inst Viral Dis Control & Prevent Chinese, Chinese Ctr Dis Control & Prevent, Key Lab Med Virol, Beijing, Peoples R China. [Zhou, Lei; Xiang, Nijuan] China CDC, Publ Hlth Emergency Ctr, Beijing, Peoples R China. [Vong, Sirenda] World Hlth Org WHO Beijing Off, Beijing, Peoples R China. [Guo, Junqiao] Liaoning Ctr Dis Control & Prevent, Shenyang, Liaoning, Peoples R China. [Lv, Wei] Guangxi Ctr Dis Control & Prevent, Nanning, Guangxi, Peoples R China. [Huai, Yang] US Ctr Dis Control & Prevent, Int Emerging Infect Program, Beijing, Peoples R China. [Chen, Ray Y.] NIAID, NIH, Bethesda, MD 20892 USA. [Uyeki, Timothy M.] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Shu, YL (reprint author), Natl Hlth & Family Planning Commiss, Natl Inst Viral Dis Control & Prevent Chinese, Chinese Ctr Dis Control & Prevent, Key Lab Med Virol, Beijing, Peoples R China. EM yshu@cnic.org.cn; yuhj@chinacdc.cn OI Chen, Ray/0000-0001-6344-1442 FU National Institute of Allergy and Infectious Diseases (NIAID); U.S. National Institutes of Health [U19 AI51915]; Ministry of Science and Technology (MOST) of the People's Republic of China [2004BA519A71, 2006BAD06A02] FX This study was supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (Comprehensive International Program for Research on AIDS grant U19 AI51915, http://www.niaid.nih.gov/Pages/default.aspx), and from the Ministry of Science and Technology (MOST) of the People's Republic of China (2004BA519A71 and 2006BAD06A02, http://www.most.gov.cn/). The NIAID was involved in the study design, data interpretation, and review and approval of the manuscript. The China MOST had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this study are those of the authors and do not represent the policy of their institutions. NR 45 TC 3 Z9 3 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 13 PY 2013 VL 8 IS 8 AR e71765 DI 10.1371/journal.pone.0071765 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201BN UT WOS:000323115800078 PM 23967241 ER PT J AU Trabzuni, D Ryten, M Emmett, W Ramasamy, A Lackner, KJ Zeller, T Walker, R Smith, C Lewis, PA Mamais, A de Silva, R Vandrovcova, J Hernandez, D Nalls, MA Sharma, M Garnier, S Lesage, S Simon-Sanchez, J Gasser, T Heutink, P Brice, A Singleton, A Cai, HB Schadt, E Wood, NW Bandopadhyay, R Weale, ME Hardy, J Plagnol, V AF Trabzuni, Daniah Ryten, Mina Emmett, Warren Ramasamy, Adaikalavan Lackner, Karl J. Zeller, Tanja Walker, Robert Smith, Colin Lewis, Patrick A. Mamais, Adamantios de Silva, Rohan Vandrovcova, Jana Hernandez, Dena Nalls, Michael A. Sharma, Manu Garnier, Sophie Lesage, Suzanne Simon-Sanchez, Javier Gasser, Thomas Heutink, Peter Brice, Alexis Singleton, Andrew Cai, Huaibin Schadt, Eric Wood, Nicholas W. Bandopadhyay, Rina Weale, Michael E. Hardy, John Plagnol, Vincent CA Int Parkinson Dis Genomics TI Fine-Mapping, Gene Expression and Splicing Analysis of the Disease Associated LRRK2 Locus SO PLOS ONE LA English DT Article AB Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56 x 10(-8), case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms. C1 [Trabzuni, Daniah; Ryten, Mina; Lewis, Patrick A.; Mamais, Adamantios; de Silva, Rohan; Vandrovcova, Jana; Wood, Nicholas W.; Bandopadhyay, Rina; Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Emmett, Warren; Plagnol, Vincent] UCL, Genet Inst, London, England. [Ramasamy, Adaikalavan; Weale, Michael E.] Kings Coll London, Guys Hosp, Dept Med & Mol Genet, London, England. [Lackner, Karl J.] Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, Mainz, Germany. [Zeller, Tanja] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Walker, Robert; Smith, Colin] Univ Edinburgh, Dept Neuropathol, MRC Sudden Death Brain Bank Project, Edinburgh, Midlothian, Scotland. [Lewis, Patrick A.] Univ Reading, Sch Pharm, Reading, Berks, England. [Mamais, Adamantios; de Silva, Rohan; Vandrovcova, Jana; Bandopadhyay, Rina; Hardy, John] Reta Lila Weston Inst Neurol Studies, London, England. [Hernandez, Dena; Nalls, Michael A.; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Sharma, Manu; Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, Div Neurodegenerat Disorders, Tubingen, Germany. [Garnier, Sophie] Univ Paris 06, INSERM, UMRS 937, Paris, France. [Lesage, Suzanne; Brice, Alexis] Univ Paris 06, CRICM, CNRS,UMR 7225, INSERM,Hosp Pitie Salpetriere,UMRS 975, Paris, France. [Simon-Sanchez, Javier; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands. [Cai, Huaibin] NIA, Unit Transgenesis, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Schadt, Eric] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, New York, NY USA. RP Plagnol, V (reprint author), UCL, Genet Inst, London, England. EM v.plagnol@ucl.ac.uk RI Hardy, John/C-2451-2009; Lewis , Patrick/C-3674-2009; Singleton, Andrew/C-3010-2009; Trabzuni, Daniah/C-4034-2012; Weale, Michael/F-2587-2010; Bandopadhyay, Rina /C-7926-2009; de Silva, Rohan/C-1734-2008; Ramasamy, Adaikalavan/G-2632-2010; Wood, Nicholas/C-2505-2009; OI Trabzuni, Daniah/0000-0003-4826-9570; Weale, Michael/0000-0003-4593-1186; de Silva, Rohan/0000-0002-5052-5775; Plagnol, Vincent/0000-0002-5597-9215; Lewis, Patrick/0000-0003-4537-0489; Ramasamy, Adaikalavan/0000-0002-7598-2892; Wood, Nicholas/0000-0002-9500-3348; Walker, Robert/0000-0001-7383-7846 FU Medical Research Council (MRC) through the MRC Sudden Death Brain Bank; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Michael J. Fox Foundation LRRK2 consortium grant; Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]; Department of Health's NIHR Biomedical Research Centres funding scheme; National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Institute of Environmental Health Sciences; National Human Genome Research Institute; National Institutes of Health; Department of Health and Human Services [Z01 AG000949-02, Z01-ES101986]; US Department of Defense [W81XWH-09-2-0128]; National Institutes of Health [NS057105, RR024992]; American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St. Louis Chapter of the APDA; Forschungszentrumfur-Umwelt und Gesundheit (GSF); German Federal Ministry of Education, Science, Research, and Technology; State of Bavaria; German National Genome Network [01GS08134]; German Ministry for Education and Research; German Federal Ministry of Education and Research (BMBF) NGFN [01GR0468]; ERA-Net NEURON [01GW0908]; Helmholtz Alliance Mental Health in an Ageing Society (HelMA) [HA-215]; Initiative and Networking Fund of the Helmholtz Association; Hersenstichting Nederland; Neuroscience Campus Amsterdam; section of Medical genomics, the Prinses Beatrix Fonds; [G0901254]; [G0802462]; [F1002] FX This work was supported by the Medical Research Council (MRC) through the MRC Sudden Death Brain Bank (C. S.) and by a Project Grant (G0901254 to J.H. and M. W.) and Training Fellowship (G0802462 to M. R.). D. T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. P. A. L. is a Parkinson's UK research fellow (fellowship F1002). A. M. and C. M. are supported by a Michael J. Fox Foundation LRRK2 consortium grant to P. A. L. and R. B. This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. This work was undertaken in part at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. This US work was supported in part by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services; project numbers Z01 AG000949-02 and Z01-ES101986. In addition this study was supported by the US Department of Defense, award number W81XWH-09-2-0128. Funding to support collection of a portion of the samples was obtained from the National Institutes of Health (grants NS057105 and RR024992), the American Parkinson Disease Association (APDA), Barnes Jewish Hospital Foundation, and the Greater St. Louis Chapter of the APDA. The KORA research platform (KORA: Cooperative Research in the Region of Augsburg; http://www.gsf.de/KORA) was initiated and financed by the Forschungszentrumfur-Umwelt und Gesundheit (GSF), which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. The study was additionally funded by the German National Genome Network (NGFNplus #01GS08134; German Ministry for Education and Research) and by the German Federal Ministry of Education and Research (BMBF) NGFN (01GR0468) and in the frame of ERA-Net NEURON (01GW0908). This work was also supported by the Helmholtz Alliance Mental Health in an Ageing Society (HelMA, HA-215) funded by the Initiative and Networking Fund of the Helmholtz Association. The authors also want to thank the Hersenstichting Nederland (http://www.hersenstichting.nl), the Neuroscience Campus Amsterdam and the section of Medical genomics, the Prinses Beatrix Fonds (http://www.prinsesbeatrixfonds.nl) for sponsoring this work. The authors have no conflicting financial, personal, or professional interests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 11 Z9 11 U1 0 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 13 PY 2013 VL 8 IS 8 AR e70724 DI 10.1371/journal.pone.0070724 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201BN UT WOS:000323115800015 PM 23967090 ER PT J AU Yang, YJ Tao-Cheng, JH Bayer, KU Reese, TS Dosemeci, A AF Yang, Yijung Tao-Cheng, Jung-Hwa Bayer, K. Ulrich Reese, Thomas S. Dosemeci, Ayse TI Camkii-Mediated Phosphorylation Regulates Distributions of Syngap-alpha 1 and -alpha 2 at the Postsynaptic Density SO PLOS ONE LA English DT Article AB SynGAP, a protein abundant at the postsynaptic density (PSD) of glutamatergic neurons, is known to modulate synaptic strength by regulating the incorporation of AMPA receptors at the synapse. Two isoforms of SynGAP, alpha 1 and alpha 2, which differ in their C-termini, have opposing effects on synaptic strength. In the present study, antibodies specific for SynGAP-alpha 1 and SynGAP-alpha 2 are used to compare the distribution patterns of the two isoforms at the postsynaptic density (PSD) under basal and excitatory conditions. Western immunoblotting shows enrichment of both isoforms in PSD fractions isolated from adult rat brain. Immunogold electron microscopy of rat hippocampal neuronal cultures shows similar distribution of both isoforms at the PSD, with a high density of immunolabel within the PSD core under basal conditions. Application of NMDA promotes movement of SynGAP-alpha 1 as well as SynGAP-alpha 2 out of the PSD core. In isolated PSDs both isoforms of SynGAP can be phosphorylated upon activation of the endogenous CaMKII. Application of tatCN21, a cell-penetrating inhibitor of CaMKII, to hippocampal neuronal cultures blocks NMDA-induced redistribution of SynGAP-alpha 1 and SynGAP-alpha 2. Thus CaMKII activation promotes the removal of two distinct C-terminal SynGAP variants from the PSD. C1 [Yang, Yijung; Reese, Thomas S.; Dosemeci, Ayse] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Tao-Cheng, Jung-Hwa] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. [Bayer, K. Ulrich] Univ Colorado, Denver Sch Med, Dept Pharmacol, Aurora, CO USA. RP Dosemeci, A (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM dosemeca@mail.nih.gov FU NINDS, National Institutes of Health (NIH); NIH [R01 NS081248] FX This research was supported by the Intramural Research Program NINDS, National Institutes of Health (NIH) and NIH grant R01 NS081248 (to KUB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 5 Z9 5 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 13 PY 2013 VL 8 IS 8 AR e71795 DI 10.1371/journal.pone.0071795 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201BN UT WOS:000323115800080 PM 23967245 ER PT J AU Gartner, JJ Parker, SCJ Prickett, TD Dutton-Regester, K Stitzel, ML Lin, JC Davis, S Simhadri, VL Jha, S Katagiri, N Gotea, V Teer, JK Wei, XM Morken, MA Bhanot, UK Chen, G Elnitski, LL Davies, MA Gershenwald, JE Carter, H Karchin, R Robinson, W Robinson, S Rosenberg, SA Collins, FS Parmigiani, G Komar, AA Kimchi-Sarfaty, C Hayward, NK Margulies, EH Samuels, Y AF Gartner, Jared J. Parker, Stephen C. J. Prickett, Todd D. Dutton-Regester, Ken Stitzel, Michael L. Lin, Jimmy C. Davis, Sean Simhadri, Vijaya L. Jha, Sujata Katagiri, Nobuko Gotea, Valer Teer, Jamie K. Wei, Xiaomu Morken, Mario A. Bhanot, Umesh K. Chen, Guo Elnitski, Laura L. Davies, Michael A. Gershenwald, Jeffrey E. Carter, Hannah Karchin, Rachel Robinson, William Robinson, Steven Rosenberg, Steven A. Collins, Francis S. Parmigiani, Giovanni Komar, Anton A. Kimchi-Sarfaty, Chava Hayward, Nicholas K. Margulies, Elliott H. Samuels, Yardena CA NISC Comparative Sequencing Progra TI Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TERT PROMOTER MUTATIONS; HUMAN CANCER; POSITIVE SELECTION; EVOLUTION; REVEALS; DISEASE; CONSTRAINT; SUBSTRATE; GENE; SITE AB Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies. C1 [Gartner, Jared J.; Parker, Stephen C. J.; Prickett, Todd D.; Stitzel, Michael L.; Gotea, Valer; Teer, Jamie K.; Wei, Xiaomu; Morken, Mario A.; Elnitski, Laura L.; Collins, Francis S.; Margulies, Elliott H.; Samuels, Yardena; NISC Comparative Sequencing Progra] NHGRI, Bethesda, MD 20892 USA. [Davis, Sean; Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. [Dutton-Regester, Ken; Hayward, Nicholas K.] Queensland Inst Med Res, Div Genet & Computat Biol, Brisbane, Qld 4006, Australia. [Lin, Jimmy C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Simhadri, Vijaya L.; Katagiri, Nobuko; Kimchi-Sarfaty, Chava] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Jha, Sujata; Komar, Anton A.] Cleveland State Univ, Ctr Gene Regulat Hlth & Dis, Cleveland, OH 44115 USA. [Jha, Sujata; Komar, Anton A.] Cleveland State Univ, Dept Biol Geol & Environm Sci, Cleveland, OH 44115 USA. [Bhanot, Umesh K.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Chen, Guo; Davies, Michael A.; Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Carter, Hannah; Karchin, Rachel] Johns Hopkins Univ, Inst Computat Med, Dept Biomed Engn, Baltimore, MD 21218 USA. [Robinson, William; Robinson, Steven] Univ Colorado, Sch Med, Div Med Oncol, Aurora, CO 80045 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Margulies, Elliott H.] Illumina United Kingdom, Saffron Walden CB10 1XL, Essex, England. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Samuels, Y (reprint author), NHGRI, Bethesda, MD 20892 USA. EM yardena.samuels@weizmann.ac.il RI Karchin, Rachel/A-3385-2010; hayward, nicholas/C-1367-2015; OI hayward, nicholas/0000-0003-4760-1033; Bhanot, Umeshkumar/0000-0001-6656-1239; Davis, Sean/0000-0002-8991-6458; Gotea, Valer/0000-0001-7857-3309 FU NIGMS Postdoctoral Research Associate (PRAT) Fellowship; Intramural Research Programs of the National Human Genome Research Institute; Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; estate of Alice Schwarz-Gardos; estate of John Hunter; Knell Family; Peter and Patricia Gruber Award; National Cancer Institute [R21CA152432]; National Institutes of Health; University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence [P50 CA093459]; Cancer Center Support Grant (CCSG) Core Grant [NCI 5P30 CA006516-46]; Human Frontier Science Program [RGP0024]; National Health and Medical Research Council of Australia [1026112, 613686]; National Cancer Institute; Eli Lilly and Company FX We thank Drs. Chris Schmidt and Peter Parsons for establishment of the majority of melanoma cell lines and V. Maduro, H. Ozel Abaan, and P. Cruz for generating the sequence data analyzed here. We thank Dr. V. G. Prieto for pathologic review of the biospecimens from the Melanoma Informatics, Tissue Resource, and Pathology Core (MelCore) at MD Anderson. We thank Dr. T. Wolfsberg for bioinformatics help, J. Jiang for sequencing help, and J. Fekecs and D. Leja for graphical assistance. We thank Drs. T. Barber and M. Willard for critical comments on the manuscript. S.C.J.P. is supported by an NIGMS Postdoctoral Research Associate (PRAT) Fellowship. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the estate of Alice Schwarz-Gardos, the estate of John Hunter, the Knell Family, the Peter and Patricia Gruber Award, National Cancer Institute Grant R21CA152432 (to R.K.), the National Institutes of Health, University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence Grant P50 CA093459, Cancer Center Support Grant (CCSG) Core Grant NCI 5P30 CA006516-46 (to G.P.), the Human Frontier Science Program RGP0024 Grant (to A.A.K.), National Health and Medical Research Council of Australia Grants 1026112 and 613686, and a public-private partnership between the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, and Eli Lilly and Company coordinated by the Foundation for the National Institutes of Health. NR 35 TC 63 Z9 64 U1 0 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13481 EP 13486 DI 10.1073/pnas.1304227110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200063 PM 23901115 ER PT J AU Panigrahy, D Kalish, BT Huang, S Bielenberg, DR Le, HD Yang, J Edin, ML Lee, CR Benny, O Mudge, DK Butterfield, CE Mammoto, A Mammoto, T Inceoglu, B Jenkins, RL Simpson, MA Akino, T Lih, FB Tomer, KB Ingber, DE Hammock, BD Falck, JR Manthati, VL Kaipainen, A D'Amore, PA Puder, M Zeldin, DC Kieran, MW AF Panigrahy, Dipak Kalish, Brian T. Huang, Sui Bielenberg, Diane R. Le, Hau D. Yang, Jun Edin, Matthew L. Lee, Craig R. Benny, Ofra Mudge, Dayna K. Butterfield, Catherine E. Mammoto, Akiko Mammoto, Tadanori Inceoglu, Bora Jenkins, Roger L. Simpson, Mary A. Akino, Tomoshige Lih, Fred B. Tomer, Kenneth B. Ingber, Donald E. Hammock, Bruce D. Falck, John R. Manthati, Vijaya L. Kaipainen, Arja D'Amore, Patricia A. Puder, Mark Zeldin, Darryl C. Kieran, Mark W. TI Epoxyeicosanoids promote organ and tissue regeneration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autacoid; organ regeneration; small molecule mediator; angiocrine; VEGF ID SOLUBLE EPOXIDE HYDROLASE; ENDOTHELIAL GROWTH-FACTOR; EPOXYEICOSATRIENOIC ACIDS; LIVER-REGENERATION; ANGIOCRINE SIGNALS; TUMOR-GROWTH; STEM-CELLS; IN-VIVO; ANGIOGENESIS; EXPRESSION AB Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis. C1 [Panigrahy, Dipak; Kalish, Brian T.; Bielenberg, Diane R.; Le, Hau D.; Benny, Ofra; Mudge, Dayna K.; Butterfield, Catherine E.; Mammoto, Akiko; Mammoto, Tadanori; Akino, Tomoshige; Ingber, Donald E.; Puder, Mark; Kieran, Mark W.] Harvard Univ, Sch Med, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Kalish, Brian T.; Le, Hau D.; Puder, Mark] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Panigrahy, Dipak; Kieran, Mark W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Panigrahy, Dipak; Mudge, Dayna K.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02115 USA. [Panigrahy, Dipak; Mudge, Dayna K.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Le, Hau D.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02115 USA. [Huang, Sui] Inst Syst Biol, Seattle, WA 98109 USA. [Yang, Jun; Inceoglu, Bora; Hammock, Bruce D.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Yang, Jun] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA. [Edin, Matthew L.; Lih, Fred B.; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. [Jenkins, Roger L.; Simpson, Mary A.] Lahey Clin Med Ctr, Dept Transplantat, Burlington, MA 01805 USA. [Ingber, Donald E.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Falck, John R.; Manthati, Vijaya L.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75235 USA. [Kaipainen, Arja] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA. [D'Amore, Patricia A.] Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol,Massachusetts Eye & Ear, Boston, MA 02114 USA. RP Panigrahy, D (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. EM dpanigra@bidmc.harvard.edu; bdhammock@ucdavis.edu; zeldin@niehs.nih.gov; mark_kieran@dfci.harvard.edu RI Yang, Jun/B-2262-2010; OI Yang, Jun/0000-0002-4630-3838; Kieran, Mark/0000-0003-2184-7692; Falck, John/0000-0002-9219-7845; Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301; Inceoglu, Bora/0000-0002-8473-6036 FU National Cancer Institute Grant [RO1CA148633-01A4]; Stop and Shop Pediatric Brain Tumor Fund; C. J. Buckley Pediatric Brain Tumor Fund; Joshua Ryan Rappaport Fellowship; Children's Hospital Boston Surgical Foundation; Vascular Biology Program; Howard Hughes Medical Institute Research Fellowship; Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [Z01 025034, Z01 050167]; NIH [R01 GM088199, GM31278, R01 ES002710, R01 ES013933, CA045548]; Robert A. Welch Foundation [GL625910]; NIEHS Superfund Basic Research Program NIH [P42 ES004699] FX We thank Kristin Johnson for photography and preparation of the figures; J. Alyce Bradbury, Joan P. Graves, Laura M. DeGraff, and Ricky Sanchez for excellent technical assistance; and Sung Hee Hwang for sEHi. This work was supported by National Cancer Institute Grant RO1CA148633-01A4 (to D.P.); the Stop and Shop Pediatric Brain Tumor Fund (M.W.K.); the C. J. Buckley Pediatric Brain Tumor Fund (M.W.K.); the Joshua Ryan Rappaport Fellowship (H.D.L.); the Children's Hospital Boston Surgical Foundation and the Vascular Biology Program (M.P. and H.D.L.); a Howard Hughes Medical Institute Research Fellowship (to B.T.K.); Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) (Z01 025034 to D.C.Z.; Z01 050167 to K.B.T.); NIH Grant R01 GM088199 (to C.R.L.); NIH Grant GM31278 and Robert A. Welch Foundation Grant GL625910 (to J.R.F.); NIEHS Superfund Basic Research Program NIH Grant P42 ES004699 and NIH Grants R01 ES002710 and R01 ES013933 (to B.D.H.); and NIH Grant CA045548 (to D.E.I.). B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Foundation. NR 47 TC 42 Z9 45 U1 2 U2 40 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13528 EP 13533 DI 10.1073/pnas.1311565110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200071 PM 23898174 ER PT J AU Chen, J Feigenbaum, L Awasthi, P Butcher, DO Anver, MR Golubeva, YG Bamford, R Zhang, XJ St Claire, MB Thomas, CJ Discepolo, V Jabri, B Waldmann, TA AF Chen, Jing Feigenbaum, Lionel Awasthi, Parirokh Butcher, Donna O. Anver, Miriam R. Golubeva, Yelena G. Bamford, Richard Zhang, Xiaojie St Claire, Mark B. Thomas, Craig J. Discepolo, Valentina Jabri, Bana Waldmann, Thomas A. TI Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15R alpha SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NATURAL-KILLER-CELL; CD8 T-CELLS; ENTEROVIRUS INFECTION; TRANS PRESENTATION; CUTTING EDGE; RECENT-ONSET; IN-VIVO; TYPE-1; MELLITUS; ISLETS AB Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15R alpha levels in human T1D. To investigate the role of IL-15/IL-15R alpha in the pathogenesis of T1D, we generated double transgenic mice with pancreatic beta-cell expression of IL-15 and IL-15R alpha. The mice developed hyperglycemia, marked mononuclear cell infiltration, beta-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15R beta (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15R alpha expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15R alpha in human T1D. Taken together our data suggest that disordered IL-15 and IL-15R alpha may be involved in T1D pathogenesis and the IL-15/IL15R alpha system and its signaling pathway may be rational therapeutic targets for early T1D. C1 [Chen, Jing; Waldmann, Thomas A.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Feigenbaum, Lionel; Awasthi, Parirokh; Butcher, Donna O.; Anver, Miriam R.; Golubeva, Yelena G.] NCI, Lab Anim Sci Program, SAIC Frederick Inc, Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Bamford, Richard] Transponics, Jacobus, PA 17407 USA. [Zhang, Xiaojie; St Claire, Mark B.] NIDDK, Lab Anim Sci Sect, Bethesda, MD 20892 USA. [Thomas, Craig J.] NHGRI, NIH, Chem Genom Ctr, Rockville, MD 20850 USA. [Discepolo, Valentina; Jabri, Bana] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Discepolo, Valentina] Univ Naples Federico II, Dept Pediat, I-80131 Naples, Italy. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU intramural research program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH); federal funds from NCI, NIH [HHSN261200800001E] FX We thank Dr. Oksana Gavrilova (National Institute of Diabetes and Digestive and Kidney Diseases) for the technical support of islet isolation and Dr. Jun-Li Liu (McGill University) for kindly providing us the rat insulin promoter construct. This work was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH) and in part by federal funds from NCI, NIH, under Contract HHSN261200800001E. NR 39 TC 19 Z9 19 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13534 EP 13539 DI 10.1073/pnas.1312911110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200072 PM 23904478 ER PT J AU Manoli, I Sysol, JR Li, LL Houillier, P Garone, C Wang, C Zerfas, PM Cusmano-Ozog, K Young, S Trivedi, NS Cheng, J Sloan, JL Chandler, RJ Abu-Asab, M Tsokos, M Elkahloun, AG Rosen, S Enns, GM Berry, GT Hoffmann, V DiMauro, S Schnermann, J Venditti, CP AF Manoli, Irini Sysol, Justin R. Li, Lingli Houillier, Pascal Garone, Caterina Wang, Cindy Zerfas, Patricia M. Cusmano-Ozog, Kristina Young, Sarah Trivedi, Niraj S. Cheng, Jun Sloan, Jennifer L. Chandler, Randy J. Abu-Asab, Mones Tsokos, Maria Elkahloun, Abdel G. Rosen, Seymour Enns, Gregory M. Berry, Gerard T. Hoffmann, Victoria DiMauro, Salvatore Schnermann, Jurgen Venditti, Charles P. TI Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cobalamin; chronic renal failure; megamitochondria; organic acidemia ID GENE DELIVERY RESCUES; NEUTROPHIL GELATINASE; MOUSE MODEL; MICE; ACIDOSIS; EXCRETION; LIPOCALIN; BIOMARKER; ACIDURIA; HUMANS AB Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA. C1 [Manoli, Irini; Sysol, Justin R.; Wang, Cindy; Sloan, Jennifer L.; Chandler, Randy J.; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Li, Lingli; Houillier, Pascal; Schnermann, Jurgen] NIDDK, Kidney Dis Branch, Bethesda, MD 20814 USA. [Houillier, Pascal] Paris Descartes Univ, INSERM, Georges Pompidou European Hosp, AP HP,Unite Mixte Rech S 872,Dept Physiol, F-75015 Paris, France. [Garone, Caterina; DiMauro, Salvatore] Columbia Univ, Med Ctr, Coll Phys & Surg, New York, NY 10032 USA. [Garone, Caterina] Univ Bologna & Turin, Human Genet Joint PhD Program, I-10126 Turin, Italy. [Zerfas, Patricia M.; Hoffmann, Victoria] NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. [Cusmano-Ozog, Kristina; Enns, Gregory M.] Stanford Univ, Div Med Genet, Stanford, CA 94305 USA. [Young, Sarah] Duke Univ, Med Ctr, Div Med Genet, Biochem Genet Lab, Durham, NC 27713 USA. [Trivedi, Niraj S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Cheng, Jun] NHGRI, Embryon Stem Cell & Transgen Mouse Core Facil, NIH, Bethesda, MD 20892 USA. [Abu-Asab, Mones; Tsokos, Maria] NIH, Ultrastruct Pathol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Rosen, Seymour] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Rosen, Seymour] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Berry, Gerard T.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Venditti, CP (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov OI Garone, Caterina/0000-0003-4928-1037; Berry, Gerard/0000-0001-5299-3313; Abu-Asab, Mones/0000-0002-4047-1232; Manoli, Irini/0000-0003-1543-2941 FU Intramural Research Program of the National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute; Office of the Director of the National Institutes of Health; Angels; Philippe Foundation; Oak Ridge Institute for Science and Education; Paris Descartes University, France FX We thank all patients and their families; Shelley Hoogstraten-Miller for veterinary support; Irene Ginty, Cherry Yang, Tina Aroyo, Theresa Ferrine, and Lemlem Alemu for mouse maintenance; and Isa Bernardini and Roxanne Fischer for processing patient samples. This work was supported by the Intramural Research Program of the National Human Genome Research Institute (I.M., J.R.S., C.W., N.S.T., J.C., J.L.S., R.J.C., A.G.E., and C.P.V.), the National Institute of Diabetes and Digestive and Kidney Diseases (L.L., P.H., and J.S.), the National Cancer Institute (M.A.-A. and M.T.), and the Office of the Director (P.M.Z. and V.H.) of the National Institutes of Health. J.R.S. and C.W. were also supported by the Angels for Alyssa (MMA Research Fund). P.H. was supported by the Philippe Foundation, the Oak Ridge Institute for Science and Education, and Paris Descartes University, France. NR 31 TC 23 Z9 25 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13552 EP 13557 DI 10.1073/pnas.1302764110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200075 PM 23898205 ER PT J AU Johnson, TP Patel, K Johnson, KR Maric, D Calabresi, PA Hasbun, R Nath, A AF Johnson, Tory P. Patel, Karan Johnson, Kory R. Maric, Dragan Calabresi, Peter A. Hasbun, Rodrigo Nath, Avindra TI Induction of IL-17 and nonclassical T-cell activation by HIV-Tat proteinj SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CNS inflammation; chronic inflammation; lymphocyte; central nervous system; chromatin ID RECONSTITUTION INFLAMMATORY SYNDROME; ENDOTHELIAL GROWTH-FACTOR; ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; IN-VIVO; INFECTION; TRANSACTIVATION; RECEPTOR; INTERLEUKIN-8; ACETYLATION AB Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17-expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat's role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation. C1 [Johnson, Tory P.; Patel, Karan; Johnson, Kory R.; Maric, Dragan; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Hasbun, Rodrigo] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Houston, TX 77030 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov FU National Institutes of Health [R01NS039253, R01NS056884, F31NS063855]; intramural National Institute of Neurological Disorders and Stroke funds FX We thank Richa Tyagi, Lee Blosser, Caroline Anderson, Lena Hu, and Abdel Elkahloun for technical assistance; Abhik Ray-Chaudhury for interpretation of histopathological findings; Scott Letendre for providing CSF samples; and Pablo Okhuysen for requesting brain biopsy specimen. We thank Michael C. Haffner for assistance in manuscript preparation and useful discussions. This work was supported by National Institutes of Health Grants R01NS039253, R01NS056884, and F31NS063855 and intramural National Institute of Neurological Disorders and Stroke funds. NR 40 TC 64 Z9 64 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13588 EP 13593 DI 10.1073/pnas.1308673110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200081 PM 23898208 ER PT J AU Tomasi, D Wang, GJ Volkow, ND AF Tomasi, Dardo Wang, Gene-Jack Volkow, Nora D. TI Energetic cost of brain functional connectivity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fMRI connectivity; PET-FDG; allometric scaling; energy budget; graph theory ID SMALL-WORLD; ALZHEIMERS-DISEASE; CORTICAL HUBS; LOW-FREQUENCY; NETWORKS; MRI; FLUCTUATIONS; ORGANIZATION; DYNAMICS; IMAGES AB The brain's functional connectivity is complex, has high energetic cost, and requires efficient use of glucose, the brain's main energy source. It has been proposed that regions with a high degree of functional connectivity are energy efficient and can minimize consumption of glucose. However, the relationship between functional connectivity and energy consumption in the brain is poorly understood. To address this neglect, here we propose a simple model for the energy demands of brain functional connectivity, which we tested with positron emission tomography and MRI in 54 healthy volunteers at rest. Higher glucose metabolism was associated with proportionally larger MRI signal amplitudes, and a higher degree of connectivity was associated with nonlinear increases in metabolism, supporting our hypothesis for the energy efficiency of the connectivity hubs. Basal metabolism (in the absence of connectivity) accounted for 30% of brain glucose utilization, which suggests that the spontaneous brain activity accounts for 70% of the energy consumed by the brain. The energy efficiency of the connectivity hubs was higher for ventral precuneus, cerebellum, and subcortical hubs than for cortical hubs. The higher energy demands of brain communication that hinges upon higher connectivity could render brain hubs more vulnerable to deficits in energy delivery or utilization and help explain their sensitivity to neurodegenerative conditions, such as Alzheimer's disease. C1 [Tomasi, Dardo; Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. [Wang, Gene-Jack] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Wang, Gene-Jack] SUNY Stony Brook, Dept Radiol, Stony Brook, NY 11794 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), NIAAA, Bethesda, MD 20892 USA. EM tomasidg@mail.nih.gov RI Tomasi, Dardo/J-2127-2015 FU National Institutes of Alcohol Abuse and Alcoholism [2R01AA09481]; National Center for Research Resources [GCRC 5-M01-RR-10710] FX We thank Ruben Baler, Ruiliang Wang, David Alexoff, Christopher Wong, Millard Jayne, Paul Vaska, David Schlyer, Karen Apelskog-Torres, Barbara Hubbard, and Joanna S. Fowler for assistance in various aspects of these studies. This work was accomplished with support from National Institutes of Alcohol Abuse and Alcoholism Grant 2R01AA09481 and National Center for Research Resources Grant GCRC 5-M01-RR-10710. NR 44 TC 92 Z9 95 U1 1 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13642 EP 13647 DI 10.1073/pnas.1303346110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200090 PM 23898179 ER PT J AU Mazouzi, A Vigouroux, A Aikeshev, B Brooks, PJ Saparbaev, MK Morera, S Ishchenko, AA AF Mazouzi, Abdelghani Vigouroux, Armelle Aikeshev, Bulat Brooks, Philip J. Saparbaev, Murat K. Morera, Solange Ishchenko, Alexander A. TI Insight into mechanisms of 3 '-5 ' exonuclease activity and removal of bulky 8,5 '-cyclopurine adducts by apurinic/apyrimidinic endonucleases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oxidative DNA damage; endonuclease IV; DNA glycosylase; base excision repair; damage specific endonuclease ID INCISION REPAIR PATHWAY; NUCLEOTIDE EXCISION-REPAIR; SINGLE-STRAND BREAKS; OXIDATIVE DNA-DAMAGE; ESCHERICHIA-COLI; HUMAN-CELLS; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; APE1; LESIONS AB 8,5'-cyclo-2'-deoxyadenosine (cdA) and 8,5'-cyclo-2'-deoxyguanosine generated in DNA by both endogenous oxidative stress and ionizing radiation are helix-distorting lesions and strong blocks for DNA replication and transcription. In duplex DNA, these lesions are repaired in the nucleotide excision repair (NER) pathway. However, lesions at DNA strand breaks are most likely poor substrates for NER. Here we report that the apurinic/apyrimidinic (AP) endonucleases-Escherichia coli Xth and human APE1-can remove 5'S cdA (S-cdA) at 3' termini of duplex DNA. In contrast, E. coli Nfo and yeast Apn1 are unable to carry out this reaction. None of these enzymes can remove S-cdA adduct located at 1 or more nt away from the 3' end. To understand the structural basis of 3' repair activity, we determined a high-resolution crystal structure of E. coli Nfo-H69A mutant bound to a duplex DNA containing an alpha-anomeric 2'-deoxyadenosine: T base pair. Surprisingly, the structure reveals a bound nucleotide incision repair (NIR) product with an abortive 3'-terminal dC close to the scissile position in the enzyme active site, providing insight into the mechanism for Nfo-catalyzed 3'-> 5' exonuclease function and its inhibition by 3'-terminal S-cdA residue. This structure was used as a template to model 3'-terminal residues in the APE1 active site and to explain biochemical data on APE1-catalyzed 3' repair activities. We propose that Xth and APE1 may act as a complementary repair pathway to NER to remove S-cdA adducts from 3' DNA termini in E. coli and human cells, respectively. C1 [Mazouzi, Abdelghani; Aikeshev, Bulat; Saparbaev, Murat K.; Ishchenko, Alexander A.] Univ Paris 11, Lab Stabilite Genet & Oncogenese, Inst Cancerol Gustave Roussy, CNRS,Unite Mixte Rech 8200, F-94805 Villejuif, France. [Vigouroux, Armelle; Morera, Solange] CNRS, Lab Enzymol & Biochim Struct, F-91198 Gif Sur Yvette, France. [Aikeshev, Bulat] LN Gumilev Eurasian Natl Univ, Astana 010008, Kazakhstan. [Brooks, Philip J.] NIAAA, Lab Neurogenet, Bethesda, MD 20892 USA. [Brooks, Philip J.] NIAAA, Div Metab & Hlth Effects, Bethesda, MD 20892 USA. [Brooks, Philip J.] NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Morera, S (reprint author), CNRS, Lab Enzymol & Biochim Struct, F-91198 Gif Sur Yvette, France. EM morera@lebs.cnrs-gif.fr; ichtchen@igr.fr RI Ishchenko, Alexander/D-4133-2013; Saparbaev, Murat/N-3225-2015 OI Saparbaev, Murat/0000-0002-4630-1074 FU Fondation de France [2012 00029161]; Russian Federal Program "Scientific and education personnel for innovative Russia" [8473]; Centre National de la Recherche Scientifique funds [PICS N5479-Russie]; Agence Nationale pour la Recherche Blanc [ANR-09-GENO-000]; Electricite de France Contrat Radioprotection; Institut de Cancerologie Gustave-Roussy; Bolashak International Program, Kazakhstan; Agence Nationale pour la Recherche FX We thank Dr. Jacques Laval for critical reading of the manuscript and thoughtful discussions, and Dr. Beatriz Guimaraes for help in data collection on PROXIMA I at SOLEIL. This work was supported by Fondation de France Grant 2012 00029161 (to A.A.I.) (www.fondationdefrance.org); Russian Federal Program "Scientific and education personnel for innovative Russia" for 2009-2013 No. 8473 (to A.A.I.) (www.fcpk.ru); Centre National de la Recherche Scientifique funds to S.M. and Grant PICS N5479-Russie (to M.K.S.) (www.cnrs.fr); Agence Nationale pour la Recherche Blanc 2010 Projet ANR-09-GENO-000 (to M.K.S.) (www.agence-nationale-recherche.fr); and Electricite de France Contrat Radioprotection RB 2012 (to M.K.S.) (www.edf.fr). The crystallization work has benefited from the Laboratoire d'Enzymologie et Biochimie Structurales (LEBS) facilities of the IMAGIF Structural Biology and Proteomic Unit in the "Centre de Recherche de Gif" (www.imagif.cnrs.fr). A.M. and B.A. were supported by the student scholarships from Institut de Cancerologie Gustave-Roussy (www.igr.fr) and the Bolashak International Program, Kazakhstan (www.bolashak.gov.kz), respectively. Funding for open access charge was provided by Agence Nationale pour la Recherche. NR 46 TC 17 Z9 17 U1 0 U2 19 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP E3071 EP E3080 DI 10.1073/pnas.1305281110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200009 PM 23898172 ER PT J AU Espeland, MA Shumaker, SA Leng, I Manson, JE Brown, CM LeBlanc, ES Vaughan, L Robinson, J Rapp, SR Goveas, JS Lane, D Wactawski-Wende, J Stefanick, ML Li, WJ Resnick, SM AF Espeland, Mark A. Shumaker, Sally A. Leng, Iris Manson, JoAnn E. Brown, Candice M. LeBlanc, Erin S. Vaughan, Leslie Robinson, Jennifer Rapp, Stephen R. Goveas, Joseph S. Lane, Dorothy Wactawski-Wende, Jean Stefanick, Marcia L. Li, Wenjun Resnick, Susan M. CA WHIMSY Study Grp TI Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years SO JAMA INTERNAL MEDICINE LA English DT Article ID HEALTH INITIATIVE MEMORY; CONJUGATED EQUINE ESTROGENS; RANDOMIZED CONTROLLED-TRIAL; ALZHEIMERS-DISEASE; BRAIN VOLUMES; DEMENTIA; IMPAIRMENT; REPLACEMENT; MENOPAUSE; WHIMS AB IMPORTANCE Postmenopausal hormone therapy with conjugated equine estrogens (CEEs) may adversely affect older women's cognitive function. It is not known whether this extends to younger women. OBJECTIVE To test whether prescribing CEE-based hormone therapy to postmenopausal women aged 50 to 55 years has longer-term effects on cognitive function. DESIGN Trained, masked staff assessed participants with an annual telephone-administered cognitive battery that included measures of global and domain-specific cognitive functions. Cognitive testing was conducted an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years, and repeated 1 year later. Enrollment occurred from 1996 through 1999. SETTING Forty academic research centers. PARTICIPANTS The study population comprised 1326 postmenopausal women, who had begun treatment in 2 randomized placebo-controlled clinical trials of hormone therapy when aged 50 to 55 years. INTERVENTION The clinical trials in which the women had participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate over a mean of 7.0 years. MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function. Secondary outcomes were verbal memory, attention, executive function, verbal fluency, and working memory. RESULTS Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean (95% CI) intervention effect of 0.02 (-0.08 to 0.12) standard deviation units (P = .66). Similarly, no overall differences were found for any individual cognitive domain (all P > .15). Prespecified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of -0.17 (-0.33 to -0.02) and -0.25 (-0.42 to -0.08), respectively; however, this may be a chance finding. CONCLUSIONS AND RELEVANCE CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50 to 55 years. We are not able to address whether initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term. C1 [Espeland, Mark A.; Leng, Iris] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Shumaker, Sally A.; Vaughan, Leslie] Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC 27157 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med,Dept Epidemiol, Boston, MA 02115 USA. [Brown, Candice M.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC 27157 USA. [LeBlanc, Erin S.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Robinson, Jennifer] Univ Iowa, Dept Epidemiol, Div Cardiol, Iowa City, IA USA. [Robinson, Jennifer] Univ Iowa, Dept Med, Div Cardiol, Iowa City, IA 52242 USA. [Rapp, Stephen R.] Wake Forest Sch Med, Dept Psychiat & Behav Med, Winston Salem, NC 27157 USA. [Goveas, Joseph S.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Lane, Dorothy] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Stefanick, Marcia L.] Stanford Univ, Dept Med, Prevent Res Ctr, Palo Alto, CA 94304 USA. [Li, Wenjun] Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Worcester, MA USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Espeland, MA (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mespelan@wakehealth.edu RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 FU National Institute on Aging [HHSN-271-2011-00004C]; National Heart, Lung, and Blood Institute, US Department of Health and Human Services FX This study was supported by the National Institute on Aging, Contract No. HHSN-271-2011-00004C. WHIMSY is funded by the National Institute on Aging, Contract No. HHSN-271-2011-00004C, and the WHI program is funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services. NR 35 TC 38 Z9 39 U1 0 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG 12 PY 2013 VL 173 IS 15 BP 1429 EP 1436 DI 10.1001/jamainternmed.2013.7727 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 218NY UT WOS:000324440400008 PM 23797469 ER PT J AU Cadet, JL Jayanthi, S McCoy, MT Ladenheim, B St-Preux, F Lehrmann, E De, S Becker, KG Brannock, C AF Cadet, Jean Lud Jayanthi, Subramaniam McCoy, Michael T. Ladenheim, Bruce St-Preux, Fabienne Lehrmann, Elin De, Supriyo Becker, Kevin G. Brannock, Christie TI Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum SO BMC GENOMICS LA English DT Article DE ChIP sequencing; Neural networks; Epigenetics; Histone acetylation; Microarray ID TRANSCRIPTION FACTOR-BINDING; IMMEDIATE-EARLY GENES; HISTONE ACETYLATION; SYNAPTIC PLASTICITY; NEUROPEPTIDE-B; C-FOS; CHROMATIN-STRUCTURE; MESOLIMBIC SYSTEM; CAUDATE DOPAMINE; CHRONIC COCAINE AB Background: METH is an illicit drug of abuse that influences gene expression in the rat striatum. Histone modifications regulate gene transcription. Methods: We therefore used microarray analysis and genome-scale approaches to examine potential relationships between the effects of METH on gene expression and on DNA binding of histone H4 acetylated at lysine 4 (H4K5Ac) in the rat dorsal striatum of METH-naive and METH-pretreated rats. Results: Acute and chronic METH administration caused differential changes in striatal gene expression. METH also increased H4K5Ac binding around the transcriptional start sites (TSSs) of genes in the rat striatum. In order to relate gene expression to histone acetylation, we binned genes of similar expression into groups of 100 genes and proceeded to relate gene expression to H4K5Ac binding. We found a positive correlation between gene expression and H4K5Ac binding in the striatum of control rats. Similar correlations were observed in METH-treated rats. Genes that showed acute METH-induced increased expression in saline-pretreated rats also showed METH-induced increased H4K5Ac binding. The acute METH injection caused similar increases in H4K5Ac binding in METH-pretreated rats, without affecting gene expression to the same degree. Finally, genes that showed METH-induced decreased expression exhibited either decreases or no changes in H4K5Ac binding. Conclusion: Acute METH injections caused increased gene expression of genes that showed increased H4K5Ac binding near their transcription start sites. C1 [Cadet, Jean Lud; Jayanthi, Subramaniam; McCoy, Michael T.; Ladenheim, Bruce; St-Preux, Fabienne; Brannock, Christie] NIDA, Mol Neuropsychiat Res Branch, DHHS, NIH,Intramural Res Program, Baltimore, MD 21224 USA. [Lehrmann, Elin; De, Supriyo; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Res Branch, DHHS, NIH,Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov OI Lehrmann, Elin/0000-0002-9869-9475; De, Supriyo/0000-0002-2075-7655; Becker, Kevin/0000-0002-6794-6656 FU Intramural Research Program of the DHHS/NIH/NIDA; DHHS/NIH/NIA FX This work was supported by funds of the Intramural Research Program of the DHHS/NIH/NIDA and DHHS/NIH/NIA. NR 98 TC 13 Z9 13 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 12 PY 2013 VL 14 AR 545 DI 10.1186/1471-2164-14-545 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 202YE UT WOS:000323256200001 PM 23937714 ER PT J AU Gremel, CM Costa, RM AF Gremel, Christina M. Costa, Rui M. TI Premotor cortex is critical for goal-directed actions SO FRONTIERS IN COMPUTATIONAL NEUROSCIENCE LA English DT Article DE premotor cortex; goal-directed actions; habitual actions; value-based decision making; action selection ID SUPPLEMENTARY MOTOR AREA; MEDIAL PREFRONTAL CORTEX; REINFORCER DEVALUATION; NEURONAL-ACTIVITY; ACTION SELECTION; HABIT FORMATION; FRONTAL-CORTEX; STRIATUM; PROJECTIONS; RATS AB Shifting between motor plans is often necessary for adaptive behavior. When faced with changing consequences of one's actions, it is often imperative to switch from automatic actions to deliberative and controlled actions. The pre-supplementary motor area (pre-SMA) in primates, akin to the premotor cortex (M2) in mice, has been implicated in motor learning and planning, and action switching. We hypothesized that M2 would be differentially involved in goal-directed actions, which are controlled by their consequences vs. habits, which are more dependent on their past reinforcement history and less on their consequences. To investigate this, we performed M2 lesions in mice and then concurrently trained them to press the same lever for the same food reward using tow different schedules of reinforcement that differentially bias towards the use of goal-directed versus habitual action strategies. We then probed whether actions were dependent on their M2 lesions did not affect the acquisition of lever-pressing. However, in mice with M2 lesions, lever-pressing was insensitive to changes in expected outcome value following goal-directed training. However, habitual actions were intact. We confirmed a role for M2 in goal-directed but not habitual actions in separate groups of mice trained on the individual schedules biasing towards goal-directed versus habitual actions. These data indicate that M2 is critical for actions to be updated based on their consequences, and suggest that habitual action strategies may not require processing by M2 and the updating of motor plans. C1 [Gremel, Christina M.; Costa, Rui M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 90034 USA. [Costa, Rui M.] Champalimaud Inst Unknown, Champalimaud Neurosci Programme, Lisbon, Portugal. RP Costa, RM (reprint author), Champalimaud Fdn, Champalimaud Neurosci Programme, Champalimaud Inst Unknown, Av De Brasilia, P-1400038 Lisbon, Portugal. EM rui.costa@neuro.fchampalimaud.org OI Costa, Rui/0000-0003-0495-8374 FU NIAAA Division of Intramural Clinical and Biological Research; European Research Council [243393]; HHMI International Early Career Scientist Grant FX Christina M. Gremel performed the experiments and analyzed the data. Christina M. Gremel and Rui M. Costa designed the experiments, and wrote the paper. This work was supported by NIAAA Division of Intramural Clinical and Biological Research, and European Research Council Grant (243393) and HHMI International Early Career Scientist Grant to Rui M. Costa. NR 40 TC 11 Z9 11 U1 3 U2 23 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5188 J9 FRONT COMPUT NEUROSC JI Front. Comput. Neurosci. PD AUG 12 PY 2013 VL 7 AR UNSP 110 DI 10.3389/fncom.2013.00110 PG 8 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 205BV UT WOS:000323416600001 PM 23964233 ER PT J AU Luo, HT Sun, SL Li, P Bu, DC Cao, HM Zhao, Y AF Luo, Haitao Sun, Silong Li, Ping Bu, Dechao Cao, Haiming Zhao, Yi TI Comprehensive Characterization of 10,571 Mouse Large Intergenic Noncoding RNAs from Whole Transcriptome Sequencing SO PLOS ONE LA English DT Article ID HUMAN GENOME; HUMAN-CELLS; REVEALS; ANNOTATION; SEQ; EXPRESSION; DIFFERENTIATION; QUANTIFICATION; IDENTIFICATION; LANDSCAPE AB Large intergenic noncoding RNAs (lincRNAs) have been recognized in recent years to constitute a significant portion of the mammalian transcriptome, yet their biological functions remain largely elusive. This is partly due to an incomplete annotation of tissue-specific lincRNAs in essential model organisms, particularly in mice, which has hindered the genetic annotation and functional characterization of these novel transcripts. In this report, we performed ab initio assembly of 1.9 billion tissue-specific RNA-sequencing reads across six tissue types, and identified 3,965 novel expressed lincRNAs in mice. Combining these with 6,606 documented lincRNAs, we established a comprehensive catalog of 10,571 transcribed lincRNAs. We then systemically analyzed all mouse lincRNAs to reveal that some of them are evolutionally conserved and that they exhibit striking tissue-specific expression patterns. We also discovered that mouse lincRNAs carry unique genomic signatures, and that their expression level is correlated with that of neighboring protein-coding transcripts. Finally, we predicted that a large portion of tissue-specific lincRNAs are functionally associated with essential biological processes including the cell cycle and cell development, and that they could play a key role in regulating tissue development and functionality. Our analyses provide a framework for continued discovery and annotation of tissue-specific lincRNAs in model organisms, and our transcribed mouse lincRNA catalog will serve as a roadmap for functional analyses of lincRNAs in genetic mouse models. C1 [Luo, Haitao; Sun, Silong; Bu, Dechao; Zhao, Yi] Chinese Acad Sci, Inst Comp Technol, Adv Comp Res Lab, Bioinformat Res Grp, Beijing, Peoples R China. [Li, Ping; Cao, Haiming] NHLBI, NIH, Bethesda, MD 20892 USA. RP Cao, HM (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM haiming.cao@nih.gov; biozy@ict.ac.cn RI Zhao, Yi/A-2962-2011; Cao, Haiming/P-4634-2016 OI Zhao, Yi/0000-0001-6046-8420; FU National High Technology Research and Development Program of China (863 Program) [2012AA022501]; Division of Intramural Research of the National Heart Lung and Blood Institute of the NIH, USA [HL006103-02] FX This work was supported by a grant from the National High Technology Research and Development Program of China (863 Program) (No. 2012AA022501); Ping Li and Haiming Cao are funded by the Division of Intramural Research of the National Heart Lung and Blood Institute (HL006103-02) of the NIH, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 19 Z9 22 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 12 PY 2013 VL 8 IS 8 AR e70835 DI 10.1371/journal.pone.0070835 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200UV UT WOS:000323097300057 PM 23951020 ER PT J AU Li, JY Valentin, A Kulkarni, V Rosati, M Beach, RK Alicea, C Hannaman, D Reed, SG Felber, BK Pavlakis, GN AF Li, Jinyao Valentin, Antonio Kulkarni, Viraj Rosati, Margherita Beach, Rachel Kelly Alicea, Candido Hannaman, Drew Reed, Steven G. Felber, Barbara K. Pavlakis, George N. TI HIV/SIV DNA vaccine combined with protein in a co-immunization protocol elicits highest humoral responses to envelope in mice and macaques SO VACCINE LA English DT Article DE Vaccination; Immunization; Electroporation; Antibody; Neutralizing antibody; Adjuvant; Cellular responses; Humoral responses; Dendritic cell maturation ID HUMAN-IMMUNODEFICIENCY-VIRUS; RHESUS MACAQUES; IMMUNE-RESPONSES; SIVMAC251 CHALLENGE; T-CELLS; INDUCTION; INFECTION; VIREMIA; GAG; IMMUNOGENICITY AB Vaccination with HIV/SIV DNAs elicits potent T-cell responses. To improve humoral immune responses, we combined DNA and protein in a co-immunization protocol using in vivo electroporation in mice and macaques. DNA&protein co-immunization induced higher antibody responses than DNA or protein alone, or DNA prime/protein boost in mice. DNA&protein co-immunization induced similar levels of cellular responses as those obtained by DNA only vaccination. The inclusion of SW or HIV Env gp120 protein did not impair the development of cellular immune responses elicited by DNA present in the vaccine regimen. In macaques, the DNA&protein co-immunization regimen also elicited higher levels of humoral responses with broader cross-neutralizing activity. Despite the improved immunogenicity of DNA&protein co-immunization, the protein formulation with the EM-005 (GLA-SE) adjuvant further increased the anti-Env humoral responses. Dissecting the contribution of EM-005, we found that its administration upregulated the expression of co-stimulatory molecules and stimulated cytokine production, especially IL-6, by dendritic cells in vivo. These terminally differentiated, mature, dendritic cells possibly promote higher levels of humoral responses, supporting the inclusion of the EM-005 adjuvant with the vaccine. Thus, DNA&protein co-immunization is a promising strategy to improve the rapidity of development, magnitude and potency of the humoral immune responses. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Li, Jinyao; Valentin, Antonio; Rosati, Margherita; Beach, Rachel Kelly; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Kulkarni, Viraj; Beach, Rachel Kelly; Alicea, Candido; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Hannaman, Drew] ICHOR Med Syst Inc, San Diego, CA 92121 USA. [Reed, Steven G.] Infect Dis Res Inst, Seattle, WA 98104 USA. RP Pavlakis, GN (reprint author), NCI, POB B,Bldg 535,Room 210, Frederick, MD 21702 USA. EM pavlakig@mail.nih.gov FU National Cancer Institute, National Institutes of Health (NCI/NIH) FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH). NR 50 TC 24 Z9 26 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 12 PY 2013 VL 31 IS 36 BP 3747 EP 3755 DI 10.1016/j.vaccine.2013.04.037 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 204YT UT WOS:000323407900019 PM 23624057 ER PT J AU Yao, JZ Wlodawer, A Guo, H AF Yao, Jianzhuang Wlodawer, Alexander Guo, Hong TI Understanding the Autocatalytic Process of Pro-kumamolisin Activation from Molecular Dynamics and Quantum Mechanical/Molecular Mechanical (QM/MM) Free-Energy Simulations SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE acid; base catalysis; autocatalysis; enzymes; molecular dynamics; zymogens ID SERINE-CARBOXYL PEPTIDASE; ANGSTROM CRYSTAL-STRUCTURE; TETRAHEDRAL ADDUCT; PROTEINASE C1 [Yao, Jianzhuang; Guo, Hong] Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN 37996 USA. [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Guo, H (reprint author), Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN 37996 USA. EM hguo1@utk.edu RI Guo, Hong/E-6357-2010 FU National Science Foundation (NSF) [0817940]; NSF; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Toru Nakayama and Dr. Qin Xu for helpful discussions and Professor Martin Karplus for a gift of the CHARMM program. This work was supported by the National Science Foundation (NSF) (Grant number: 0817940 to H. G.) and the NSF TeraGrid resources provided by the University of Texas at Austin, as well as by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 24 TC 1 Z9 1 U1 0 U2 19 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD AUG 12 PY 2013 VL 19 IS 33 BP 10849 EP 10852 DI 10.1002/chem.201301310 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 194IX UT WOS:000322626500017 PM 23821374 ER PT J AU Karev, GP Koonin, EV AF Karev, Georgy P. Koonin, Eugene V. TI Parabolic replicator dynamics and the principle of minimum Tsallis information gain SO BIOLOGY DIRECT LA English DT Article DE Replicator equation; Parabolic growth; Tsallis entropy; Non-extensive statistical mechanics; MaxEnt principle ID SELECTION; ENTROPY; GROWTH; TEMPLATES; SURVIVAL; PATTERNS; PHYSICS; ORIGIN; LIFE AB Background: Non-linear, parabolic (sub-exponential) and hyperbolic (super-exponential) models of prebiological evolution of molecular replicators have been proposed and extensively studied. The parabolic models appear to be the most realistic approximations of real-life replicator systems due primarily to product inhibition. Unlike the more traditional exponential models, the distribution of individual frequencies in an evolving parabolic population is not described by the Maximum Entropy (MaxEnt) Principle in its traditional form, whereby the distribution with the maximum Shannon entropy is chosen among all the distributions that are possible under the given constraints. We sought to identify a more general form of the MaxEnt principle that would be applicable to parabolic growth. Results: We consider a model of a population that reproduces according to the parabolic growth law and show that the frequencies of individuals in the population minimize the Tsallis relative entropy (non-additive information gain) at each time moment. Next, we consider a model of a parabolically growing population that maintains a constant total size and provide an "implicit" solution for this system. We show that in this case, the frequencies of the individuals in the population also minimize the Tsallis information gain at each moment of the 'internal time" of the population. Conclusions: The results of this analysis show that the general MaxEnt principle is the underlying law for the evolution of a broad class of replicator systems including not only exponential but also parabolic and hyperbolic systems. The choice of the appropriate entropy (information) function depends on the growth dynamics of a particular class of systems. The Tsallis entropy is non-additive for independent subsystems, i.e. the information on the subsystems is insufficient to describe the system as a whole. In the context of prebiotic evolution, this "non-reductionist" nature of parabolic replicator systems might reflect the importance of group selection and competition between ensembles of cooperating replicators. Reviewers: This article was reviewed by Viswanadham Sridhara (nominated by Claus Wilke), Puushottam Dixit (nominated by Sergei Maslov), and Nick Grishin. For the complete reviews, see the Reviewers' Reports section. C1 [Karev, Georgy P.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX We thank Artem Novozhilov for critical reading of the manuscript. The authors' research is supported by intramural funds of the US Department of Health and Human Services (to National Library of Medicine). NR 35 TC 2 Z9 2 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD AUG 11 PY 2013 VL 8 AR 19 DI 10.1186/1745-6150-8-19 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 207DH UT WOS:000323577000001 PM 23937956 ER PT J AU Visvanathan, K Hurley, P Bantug, E Brown, P Col, NF Cuzick, J Davidson, NE DeCensi, A Fabian, C Ford, L Garber, J Katapodi, M Kramer, B Morrow, M Parker, B Runowicz, C Vogel, VG Wade, JL Lippman, SM AF Visvanathan, Kala Hurley, Patricia Bantug, Elissa Brown, Powel Col, Nananda F. Cuzick, Jack Davidson, Nancy E. DeCensi, Andrea Fabian, Carol Ford, Leslie Garber, Judy Katapodi, Maria Kramer, Barnett Morrow, Monica Parker, Barbara Runowicz, Carolyn Vogel, Victor G., III Wade, James L. Lippman, Scott M. TI Use of Pharmacologic Interventions for Breast Cancer Risk Reduction: American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT BREAST; BOWEL PROJECT P-1; POSTMENOPAUSAL OSTEOPOROTIC WOMEN; CONTINUING OUTCOMES RELEVANT; PRIMARY-CARE PHYSICIANS; PREVENTION TRIAL; RANDOMIZED-TRIAL; TAMOXIFEN PROPHYLAXIS; CARDIOVASCULAR EVENTS; TECHNOLOGY-ASSESSMENT AB Purpose To update the 2009 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. Methods A systematic review of randomized controlled trials and meta-analyses published from June 2007 through June 2012 was completed using MEDLINE and Cochrane Collaboration Library. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. Guideline recommendations were revised based on an Update Committee's review of the literature. Results Nineteen articles met the selection criteria. Six chemoprevention agents were identified: tamoxifen, raloxifene, arzoxifene, lasofoxifene, exemestane, and anastrozole. Recommendations In women at increased risk of BC age >= 35 years, tamoxifen (20 mg per day for 5 years) should be discussed as an option to reduce the risk of estrogen receptor (ER) -positive BC. In postmenopausal women, raloxifene (60 mg per day for 5 years) and exemestane (25 mg per day for 5 years) should also be discussed as options for BC risk reduction. Those at increased BC risk are defined as individuals with a 5-year projected absolute risk of BC >= 1.66% (based on the National Cancer Institute BC Risk Assessment Tool or an equivalent measure) or women diagnosed with lobular carcinoma in situ. Use of other selective ER modulators or other aromatase inhibitors to lower BC risk is not recommended outside of a clinical trial. Health care providers are encouraged to discuss the option of chemoprevention among women at increased BC risk. The discussion should include the specific risks and benefits associated with each chemopreventive agent. (C) 2013 by American Society of Clinical Oncology C1 [Visvanathan, Kala] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Bantug, Elissa] Johns Hopkins Med & Sidney Kimmel Comprehens Canc, Baltimore, MD USA. [Ford, Leslie; Kramer, Barnett] NCI, Bethesda, MD 20892 USA. [Brown, Powel] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Col, Nananda F.] Univ New England, Biddeford, ME USA. [Cuzick, Jack] Queen Mary Univ London, London, England. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Davidson, Nancy E.] Med Ctr Canc Ctr, Pittsburgh, PA USA. [Vogel, Victor G., III] Geisinger Med Ctr Canc Inst, Danville, PA USA. [DeCensi, Andrea] Ente Osped Osped Galliera, Genoa, Italy. [Fabian, Carol] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Garber, Judy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Katapodi, Maria] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Morrow, Monica] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Parker, Barbara; Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Runowicz, Carolyn] Florida Int Univ, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Wade, James L.] Canc Care Specialists Cent Illinois, Decatur, IL USA. RP Visvanathan, K (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org FU AstraZeneca; Novartis; Pfizer FX Research Funding: Jack Cuzick, AstraZeneca; Judy Garber, AstraZeneca, Novartis, Pfizer NR 65 TC 104 Z9 105 U1 0 U2 13 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2013 VL 31 IS 23 BP 2942 EP + DI 10.1200/JCO.2013.49.3122 PG 22 WC Oncology SC Oncology GA 301NP UT WOS:000330539300020 PM 23835710 ER PT J AU Zhang, HE Meltzer, P Davis, S AF Zhang, Hongen Meltzer, Paul Davis, Sean TI RCircos: an R package for Circos 2D track plots SO BMC BIOINFORMATICS LA English DT Article DE Software; RCircos; R package; Circos; Genomic data visualization ID GENOMIC DATA; GRAPHICS AB Background: Circos is a Perl language based software package for visualizing similarities and differences of genome structure and positional relationships between genomic intervals. Running Circos requires extra data processing procedures to prepare plot data files and configure files from datasets, which limits its capability of integrating directly with other software tools such as R. Recently published R Bioconductor package ggbio provides a function to display genomic data in circular layout based on multiple other packages, which increases its complexity of usage and decreased the flexibility in integrating with other R pipelines. Results: We implemented an R package, RCircos, using only R packages that come with R base installation. The package supports Circos 2D data track plots such as scatter, line, histogram, heatmap, tile, connectors, links, and text labels. Each plot is implemented with a specific function and input data for all functions are data frames which can be objects read from text files or generated with other R pipelines. Conclusion: RCircos package provides a simple and flexible way to make Circos 2D track plots with R and could be easily integrated into other R data processing and graphic manipulation pipelines for presenting large-scale multi-sample genomic research data. It can also serve as a base tool to generate complex Circos images. C1 [Zhang, Hongen; Meltzer, Paul; Davis, Sean] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Davis, S (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bldg 37,Room 6138,37 Convent Dr, Bethesda, MD 20892 USA. EM sdavis2@mail.nih.gov OI Davis, Sean/0000-0002-8991-6458 FU NCI intramural research Funding in Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA FX This study was supported by NCI intramural research Funding in Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. The package was developed and tested with the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). NR 7 TC 56 Z9 56 U1 7 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 10 PY 2013 VL 14 AR 244 DI 10.1186/1471-2105-14-244 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 209VT UT WOS:000323789400001 PM 23937229 ER PT J AU Byeon, B Wang, W Barski, A Ranallo, RT Bao, K Schones, DE Zhao, KJ Wu, C Wu, WH AF Byeon, Boseon Wang, Wei Barski, Artem Ranallo, Ryan T. Bao, Kan Schones, Dustin E. Zhao, Keji Wu, Carl Wu, Wei-Hua TI The ATP-dependent Chromatin Remodeling Enzyme Fun30 Represses Transcription by Sliding Promoter-proximal Nucleosomes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA END RESECTION; SACCHAROMYCES-CEREVISIAE; HISTONE VARIANTS; CHROMOSOME-I; FREE REGIONS; GENOME; YEAST; COMPLEX; H2A.Z; POSITIONS AB The evolutionarily conserved ATP-dependent chromatin remodeling enzyme Fun30 has recently been shown to play important roles in heterochromatin silencing and DNA repair. However, how Fun30 remodels nucleosomes is not clear. Here we report a nucleosome sliding activity of Fun30 and its role in transcriptional repression. We observed that Fun30 repressed the expression of genes involved in amino acid and carbohydrate metabolism, the stress response, and meiosis. In addition, Fun30 was localized at the 5' and 3' ends of genes and within the open reading frames of its targets. Consistent with its role in gene repression, we observed that Fun30 target genes lacked histone modifications often associated with gene activation and showed an increased level of ubiquitinated histone H2B. Furthermore, a genome-wide nucleosome mapping analysis revealed that the length of the nucleosome-free region at the 5' end of a subset of genes was changed in Fun30-depleted cells. In addition, the positions of the -1, +2, and +3 nucleosomes at the 5' end of target genes were shifted significantly, whereas the position of the +1 nucleosome remained largely unchanged in the fun30 Delta mutant. Finally, we demonstrated that affinity-purified, single-component Fun30 exhibited a nucleosome sliding activity in an ATP-dependent manner. These results define a role for Fun30 in the regulation of transcription and indicate that Fun30 remodels chromatin at the 5' end of genes by sliding promoter-proximal nucleosomes. C1 [Byeon, Boseon; Wang, Wei; Bao, Kan; Wu, Wei-Hua] Georgia Regents Univ, Inst Mol Med & Genet, Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA. [Barski, Artem; Schones, Dustin E.; Zhao, Keji] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. [Ranallo, Ryan T.; Wu, Carl; Wu, Wei-Hua] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Wu, WH (reprint author), Georgia Regents Univ, Inst Mol Med & Genet, Med Coll Georgia, CA-3012,1462 Laney Walker Blvd, Augusta, GA 30912 USA. EM wwu@gru.edu OI Barski, Artem/0000-0002-1861-5316 FU NHLBI National Institutes of Health; NCI National Institutes of Health [1K22CA122453] FX This work was supported, in whole or in part, by NHLBI National Institutes of Health intramural research support (to K. Z.), NCI National Institutes of Health intramural research support (to C. W.), and NCI National Institutes of Health Grant 1K22CA122453 (to W.-H. W.). NR 62 TC 9 Z9 9 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 9 PY 2013 VL 288 IS 32 BP 23182 EP 23193 DI 10.1074/jbc.M113.471979 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302IN UT WOS:000330598200025 PM 23779104 ER PT J AU Seok, S Kanamaluru, D Xiao, Z Ryerson, D Choi, SE Suino-Powell, K Xu, HE Veenstra, TD Kemper, JK AF Seok, Sunmi Kanamaluru, Deepthi Xiao, Zhen Ryerson, Daniel Choi, Sung-E Suino-Powell, Kelly Xu, H. Eric Veenstra, Timothy D. Kemper, Jongsook Kim TI Bile Acid Signal-induced Phosphorylation of Small Heterodimer Partner by Protein Kinase C zeta Is Critical for Epigenomic Regulation of Liver Metabolic Genes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR-RECEPTOR-SHP; FARNESOID X RECEPTOR; OBESITY; REPRESSION; EXPRESSION; MICE; FXR; BIOSYNTHESIS; MICRORNA-34A; CHOLESTASIS AB Bile acids (BAs) are recently recognized key signaling molecules that control integrative metabolism and energy expenditure. BAs activate multiple signaling pathways, including those of nuclear receptors, primarily farnesoid X receptor (FXR), membrane BA receptors, and FXR-induced FGF19 to regulate the fed-state metabolism. Small heterodimer partner (SHP) has been implicated as a key mediator of these BA signaling pathways by recruitment of chromatin modifying proteins, but the key question of how SHP transduces BA signaling into repressive histone modifications at liver metabolic genes remains unknown. Here we show that protein kinase C zeta (PKC zeta) is activated by BA or FGF19 and phosphorylates SHP at Thr-55 and that Thr-55 phosphorylation is critical for the epigenomic coordinator functions of SHP. PKC zeta is coimmunopreciptitated with SHP and both are recruited to SHP target genes after bile acid or FGF19 treatment. Activated phosphorylated PKC zeta and phosphorylated SHP are predominantly located in the nucleus after FGF19 treatment. Phosphorylation at Thr-55 is required for subsequent methylation at Arg-57, a naturally occurring mutation site in metabolic syndrome patients. Thr-55 phosphorylation increases interaction of SHP with chromatin modifiers and their occupancy at selective BA-responsive genes. This molecular cascade leads to repressive modifications of histones at metabolic target genes, and consequently, decreased BA pools and hepatic triglyceride levels. Remarkably, mutation of Thr-55 attenuates these SHP-mediated epigenomic and metabolic effects. This study identifies PKC zeta as a novel key upstream regulator of BA-regulated SHP function, revealing the role of Thr-55 phosphorylation in epigenomic regulation of liver metabolism. C1 [Seok, Sunmi; Kanamaluru, Deepthi; Ryerson, Daniel; Choi, Sung-E; Kemper, Jongsook Kim] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Xiao, Zhen; Veenstra, Timothy D.] SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Suino-Powell, Kelly; Xu, H. Eric] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA. RP Kemper, JK (reprint author), Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. EM jongsook@illinois.edu FU National Institutes of Health [DK71662, DK66202, DK62777, DK95842]; National Institutes of Health NCI [HHSN261200800001E] FX This work was supported, in whole or in part, by National Institutes of Health Grants DK71662 (to H. E. X.), DK66202 (to H. E. X.), DK62777 (to J. K. K.), and DK95842 (to J. K. K.) and federal funds from National Institutes of Health NCI Contract HHSN261200800001E. NR 39 TC 19 Z9 20 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 9 PY 2013 VL 288 IS 32 BP 23252 EP 23263 DI 10.1074/jbc.M113.452037 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302IN UT WOS:000330598200032 PM 23824184 ER PT J AU Vaidyanathan, VG Liang, FT Beard, WA Shock, DD Wilson, SH Cho, BP AF Vaidyanathan, Vaidyanathan G. Liang, Fengting Beard, William A. Shock, David D. Wilson, Samuel H. Cho, Bongsup P. TI Insights into the Conformation of Aminofluorene-Deoxyguanine Adduct in a DNA Polymerase Active Site SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; TRANSLESION SYNTHESIS; AROMATIC-AMINES; STRUCTURAL INSIGHTS; MUTAGENIC RELEVANCE; KLENOW FRAGMENT; I KLENOW; BETA; FIDELITY; REPLICATION AB The active site conformation of the mutagenic fluoroamino-fluorene-deoxyguanine adduct (dG-FAF, N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene) has been investigated in the presence of Klenow fragment of Escherichia coli DNA polymerase I (Kfexo(-)) and DNA polymerase beta (pol beta) using F-19 NMR, insertion assay, and surface plasmon resonance. In a single nucleotide gap, the dG-FAF adduct adopts both a major-groove-oriented and base-displaced stacked conformation, and this heterogeneity is retained upon binding pol beta. The addition of a non-hydrolysable 2'-deoxycytosine-5'-[(alpha,beta)-methyleno] triphosphate (dCMPcPP) nucleotide analog to the binary complex results in an increase of the major groove conformation of the adduct at the expense of the stacked conformation. Similar results were obtained with the addition of an incorrect dAMPcPP analog but with formation of the minor groove binding conformer. In contrast, dG-FAF adduct at the replication fork for the Kfexo(-) complex adopts a mix of the major and minor groove conformers with minimal effect upon the addition of non-hydrolysable nucleotides. For pol beta, the insertion of dCTP was preferred opposite the dG-FAF adduct in a single nucleotide gap assay consistent with 19F NMR data. Surface plasmon resonance binding kinetics revealed that pol beta binds tightly with DNA in the presence of correct dCTP, but the adduct weakens binding with no nucleotide specificity. These results provide molecular insights into the DNA binding characteristics of FAF in the active site of DNA polymerases and the role of DNA structure and sequence on its coding potential. C1 [Vaidyanathan, Vaidyanathan G.; Liang, Fengting; Cho, Bongsup P.] Univ Rhode Isl, Coll Pharm, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA. [Beard, William A.; Shock, David D.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cho, BP (reprint author), Univ Rhode Isl, Coll Pharm, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA. EM bcho@uri.edu FU National Institutes of Health (NIH) [CA098296, P20 RR016457]; NIEHS, NIH [Z01-ES050158, Z01-ES050161]; NIH [1U19CA105010] FX This work was supported, in whole or in part, by National Institutes of Health (NIH) Grants CA098296 (NCI) and P20 RR016457 (Center for Research Resources) (to B. P. C.) and Research Projects Z01-ES050158 and Z01-ES050161 in the Intramural Research Program of NIEHS, NIH, and in association with NIH Grant 1U19CA105010 (to S. H. W.). NR 61 TC 4 Z9 4 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 9 PY 2013 VL 288 IS 32 BP 23573 EP 23585 DI 10.1074/jbc.M113.476150 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302IN UT WOS:000330598200061 PM 23798703 ER PT J AU Luo, M Velikovsky, CA Yang, XB Siddiqui, MA Hong, X Barchi, JJ Gildersleeve, JC Pancer, Z Mariuzza, RA AF Luo, Ming Velikovsky, C. Alejandro Yang, Xinbo Siddiqui, Maqbool A. Hong, Xia Barchi, Joseph J., Jr. Gildersleeve, Jeffrey C. Pancer, Zeev Mariuzza, Roy A. TI Recognition of the Thomsen-Friedenreich Pancarcinoma Carbohydrate Antigen by a Lamprey Variable Lymphocyte Receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR RECOGNITION; STRUCTURAL INSIGHTS; BINDING; THERMODYNAMICS; GLYCOSYLATION; ANTIBODIES; EVOLUTION; LECTINS; SPECIFICITY; CANCER AB Variable lymphocyte receptors (VLRs) are leucine-rich repeat proteins that mediate adaptive immunity in jawless vertebrates. VLRs were recently shown to recognize glycans, such as the tumor-associated Thomsen-Friedenreich antigen (TF alpha; Gal beta 1-3GalNAc alpha), with a selectivity rivaling or exceeding that of lectins and antibodies. To understand the basis for TF alpha recognition by one such VLR (VLRB.aGPA.23), we measured thermodynamic parameters for the binding interaction and determined the structure of the VLRB.aGPA.23-TF alpha complex to 2.2 angstrom resolution. In the structure, four tryptophan residues form a tight hydrophobic cage encasing the TF alpha disaccharide that completely excludes buried water molecules. This cage together with hydrogen bonding of sugar hydroxyls to polar side chains explains the exquisite selectivity of VLRB.aGPA.23. The topology of the glycan-binding site of VLRB.aGPA.23 differs markedly from those of lectins or antibodies, which typically consist of long, convex grooves for accommodating the oligosaccharide. Instead, the TF alpha disaccharide is sandwiched between a variable loop and the concave surface of the VLR formed by the beta-strands of the leucine-rich repeat modules. Longer oligosaccharides are predicted to extend perpendicularly across the beta-strands, requiring them to bend to match the concavity of the VLR solenoid. C1 [Luo, Ming; Velikovsky, C. Alejandro; Yang, Xinbo; Mariuzza, Roy A.] Univ Maryland, Inst Biosci & Biotechnol Res, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. [Luo, Ming] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China. [Luo, Ming] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Anhui, Peoples R China. [Velikovsky, C. Alejandro; Yang, Xinbo; Mariuzza, Roy A.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Siddiqui, Maqbool A.; Barchi, Joseph J., Jr.; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Hong, Xia; Pancer, Zeev] Univ Maryland, Sch Med, Inst Marine & Environm Technol, Baltimore, MD 21202 USA. [Hong, Xia; Pancer, Zeev] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21202 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM rmariuzz@umd.edu RI Gildersleeve, Jeffrey/N-3392-2014; Barchi Jr., Joseph/N-3784-2014 FU National Institutes of Health (NIH) [AI036900, AI083892]; NIH, NCI; National Science Foundation [MCB-0614672]; China Scholarship Council FX This work was supported, in whole or in part, by National Institutes of Health (NIH) Grants AI036900 (to R. A. M.) and AI083892 (to Z. P.) and by the intramural research program of the NIH, NCI (to J. J. B. and J. C. G.). This work was also supported by National Science Foundation Grant MCB-0614672 (to Z. P.).; Supported by the Joint Supervision Ph.D. Project of the China Scholarship Council. NR 37 TC 9 Z9 9 U1 1 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 9 PY 2013 VL 288 IS 32 BP 23597 EP 23606 DI 10.1074/jbc.M113.480467 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302IN UT WOS:000330598200063 PM 23782692 ER PT J AU Roukos, V Voss, TC Schmidt, CK Lee, S Wangsa, D Misteli, T AF Roukos, Vassilis Voss, Ty C. Schmidt, Christine K. Lee, Seungtaek Wangsa, Darawalee Misteli, Tom TI Spatial Dynamics of Chromosome Translocations in Living Cells SO SCIENCE LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-PKCS; MOBILITY; RECOMBINATION; REPAIR AB Chromosome translocations are a hallmark of cancer cells. We have developed an experimental system to visualize the formation of translocations in living cells and apply it to characterize the spatial and dynamic properties of translocation formation. We demonstrate that translocations form within hours of the occurrence of double-strand breaks (DSBs) and that their formation is cell cycle-independent. Translocations form preferentially between prepositioned genome elements, and perturbation of key factors of the DNA repair machinery uncouples DSB pairing from translocation formation. These observations generate a spatiotemporal framework for the formation of translocations in living cells. C1 [Roukos, Vassilis; Schmidt, Christine K.; Misteli, Tom] NCI, Bethesda, MD 20892 USA. [Voss, Ty C.] NCI, High Throughput Imaging Facil, Bethesda, MD 20892 USA. [Lee, Seungtaek] PerkinElmer Hlth Sci Inc, Waltham, MA 02451 USA. [Wangsa, Darawalee] NCI, Genet Branch, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov RI Roukos, Vassilis/K-6248-2012; OI Schmidt, Christine/0000-0002-8363-7933 FU National Institutes of Health (NIH), NCI, Center for Cancer Research; EMBO FX We thank T. Tsukamoto, M. Jasin, E. Heard, D. Jullien, and M. Dundr for reagents; B. J. Taylor, S. Banerjee, J. Simone, and K. McKinnon for help with FACS experiments; T. Karpova (NCI Fluorescence Imaging Microscopy Facility) for help with microscopy; and T. Ried and K. Meaburn for expertise with SKY analysis and FISH. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research, and by an EMBO long-term fellowship (C. K. S.). We dedicate this work to the memory of Dr. Michael Potter, NCI, a giant in the field of chromosome translocations. NR 16 TC 82 Z9 82 U1 5 U2 41 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 9 PY 2013 VL 341 IS 6146 BP 660 EP 664 DI 10.1126/science.1237150 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 197XC UT WOS:000322884800040 PM 23929981 ER PT J AU Kim, EJ Kang, DW Leucke, HF Bond, MR Ghosh, S Love, DC Ahn, JS Kang, DO Hanover, JA AF Kim, Eun J. Kang, Dong W. Leucke, Hans F. Bond, Michelle R. Ghosh, Salil Love, Dona C. Ahn, Jong-Seog Kang, Dae-Ook Hanover, John A. TI Optimizing the selectivity of DIFO-based reagents for intracellular bioorthogonal applications SO CARBOHYDRATE RESEARCH LA English DT Article DE Copper-catalyzed azide-alkyne cycloaddition; Strain-promoted azide-alkyne cycloaddition; O-GlcNAc; Glycoconjugates ID FREE CLICK CHEMISTRY; AZIDE-ALKYNE CYCLOADDITION; CELL-SURFACE; 1,3-DIPOLAR CYCLOADDITIONS; TERMINAL ALKYNES; LIVING SYSTEMS; PROTEINS; VISUALIZATION; CYCLOOCTYNES; LIGATION AB One of the most commonly employed bioorthogonal reactions with azides is copper-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC, a 'click' reaction). More recently, the strain-promoted azide-alkyne [3+2] cycloaddition (SPAAC, a copper-free 'click' reaction) was developed, in which an alkyne is sufficiently strained to promote rapid cycloaddition with an azide to form a stable triazole conjugate. In this report, we show that an internal alkyne in a strained ring system with two electron-withdrawing fluorine atoms adjacent to the carbon-carbon triple bond reacts to yield covalent adducts not only with azide moieties but also reacts with free sulfhydryl groups abundant in the cytosol. We have identified conditions that allow the enhanced reactivity to be tolerated when using such conformationally strained reagents to enhance reaction rates and selectivity for bioorthogonal applications such as O-GlcNAc detection. Published by Elsevier Ltd. C1 [Kim, Eun J.] Daegu Univ, Dept Sci Educ Chem Major, Gyeongbuk 712714, South Korea. [Kang, Dong W.] Catholic Univ Daegu, Dept Pharmaceut Sci & Technol, Gyeongbuk 712702, South Korea. [Leucke, Hans F.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Bond, Michelle R.; Ghosh, Salil; Love, Dona C.; Hanover, John A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Ahn, Jong-Seog] KRIBB, Biotherapeut Res Inst, Chem Biol Res Ctr, Cheongwon 363883, South Korea. [Kang, Dae-Ook] Changwon Natl Univ, Coll Nat Sci, Dept Biochem & Hlth Sci, Chang Won 641773, South Korea. RP Hanover, JA (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM jah@helix.nih.gov FU NIDDK intramural funds (NIH); National Research Foundation of Korea [2011-0027257] FX This work was supported by the NIDDK intramural funds (NIH) and the National Research Foundation of Korea (2011-0027257). NR 39 TC 11 Z9 11 U1 0 U2 57 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 EI 1873-426X J9 CARBOHYD RES JI Carbohydr. Res. PD AUG 9 PY 2013 VL 377 BP 18 EP 27 DI 10.1016/j.carres.2013.05.014 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 182MM UT WOS:000321747000004 PM 23770695 ER PT J AU Miller, TW Kaur, S Ivins-O'Keefe, K Roberts, DD AF Miller, Thomas W. Kaur, Sukhbir Ivins-O'Keefe, Kelly Roberts, David D. TI Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation SO MATRIX BIOLOGY LA English DT Article DE Thrombospondin-1; CD47; Hydrogen sulfide; T lymphocytes; Extracellular signal-regulated kinase; Redox signaling ID ISCHEMIA-REPERFUSION INJURY; CYSTATHIONINE-GAMMA-LYASE; MICROTUBULE-ORGANIZING CENTER; INFLAMMATORY-BOWEL-DISEASE; ANIMATION-LIKE STATE; NITRIC-OXIDE; ENDOTHELIAL-CELLS; PLATELET-AGGREGATION; GRANULE POLARIZATION; MYOCARDIAL-ISCHEMIA AB Thrombospondin-1 is a potent suppressor of T cell activation via its receptor CD47. However, the precise mechanism for this inhibition remains unclear. Because H2S is an endogenous potentiator of T cell activation and is necessary for full T cell activation, we hypothesized that thrombospondin-1 signaling through CD47 inhibits T cell activation by antagonizing H2S signaling. Primary T cells from thrombospondin-1 null mice were more sensitive to H2S-dependent activation assessed by proliferation and induction of interleukin-2 and CD69 mRNAs. Exogenous thrombospondin-1 inhibited H2S responses in wild type and thrombospondin-1 null T cells but enhanced the same responses in CD47 null T cells. Fibronectin, which shares integrin and glycosaminoglycan binding properties with thrombospondin-1 but not CD47 binding, did not inhibit H2S signaling. A CD47-binding peptide derived from thrombospondin-1 inhibited H2S-induced activation, whereas two other functional sequences from thrombospondin-1 enhanced H2S signaling. Therefore, engaging CD47 is necessary and sufficient for thrombospondin-1 to inhibit H2S-dependent T cell activation. H2S stimulated T cell activation by potentiating MEK-dependent ERR phosphorylation, and thrombospondin-1 inhibited this signaling in a CD47-dependent manner. Thrombospondin-1 also limited activation-dependent T cell expression of the H2S bio-synthetic enzymes cystathionine beta-synthase and cystathionine gamma-lyase, thereby limiting the autocrine role of H2S in T cell activation. Thus, thrombospondin-1 signaling through CD47 is the first identified endogenous inhibitor of H2S signaling and constitutes a novel mechanism that negatively regulates T cell activation. Published by Elsevier B.V. C1 [Miller, Thomas W.; Kaur, Sukhbir; Ivins-O'Keefe, Kelly; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NIH, Bldg 10 Room 2A33,10 Ctr Dr MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; Miller, Thomas/G-1215-2011 OI Roberts, David/0000-0002-2481-2981; Miller, Thomas/0000-0001-8645-2785 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 85 TC 12 Z9 14 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD AUG 8 PY 2013 VL 32 IS 6 BP 316 EP 324 DI 10.1016/j.matbio.2013.02.009 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 218TR UT WOS:000324455900004 PM 23499828 ER PT J AU Purdue, MP Hofmann, JN Kemp, TJ Chaturvedi, AK Lan, Q Park, JH Pfeiffer, RM Hildesheim, A Pinto, LA Rothman, N AF Purdue, Mark P. Hofmann, Jonathan N. Kemp, Troy J. Chaturvedi, Anil K. Lan, Qing Park, Ju-Hyun Pfeiffer, Ruth M. Hildesheim, Allan Pinto, Ligia A. Rothman, Nathaniel TI A prospective study of 67 serum immune and inflammation markers and risk of non-Hodgkin lymphoma SO BLOOD LA English DT Article ID GROWTH-FACTOR RECEPTOR-1; B-CELL LYMPHOMA; ANGIOGENIC FACTORS; SOLUBLE CD30; TNF RECEPTOR; FUTURE RISK; CYTOKINES; CONSORTIUM; INTERLYMPH; LEUKEMIA AB Although severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), the importance of subclinical immunologic effects is unclear. We compared baseline serum levels of 67 immune and inflammation markers between 301 patients with NHL diagnosed 51 years after blood collection and 301 control patients within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We observed associations with NHL for elevated B-cell-attracting chemokine 1 (BCA-1; fourth quartile vs first: odds ratio [OR], 2.7; 95% confidence interval [CI], 1.7-4.2; P-trend = 1.0 x 10(-6)), soluble tumor necrosis factor receptor 2 (sTNFR2; OR, 3.4; 95% CI, 2.0-5.8; P-trend = 1.1 x 10(-6)), and soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 2.3; 95% CI, 1.4-3.9; P-trend = .0005) that remained significant after Bonferroni correction, simultaneous model adjustment, and restriction to cases diagnosed 8 to 13 years after blood collection. Associations with other markers were observed, although none remained associated with NHL after adjustment for BCA-1, sTNFR2, and sVEGFR2. Our findings suggest that circulating BCA-1, sTNFR2, and sVEGFR2 are associated with NHL risk well in advance of diagnosis. Additional research is needed to replicate these findings and elucidate the underlying biologic mechanisms. C1 [Purdue, Mark P.; Hofmann, Jonathan N.; Chaturvedi, Anil K.; Lan, Qing; Pfeiffer, Ruth M.; Hildesheim, Allan; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Kemp, Troy J.; Pinto, Ligia A.] SAIC Frederick Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Park, Ju-Hyun] Dungun Univ Seoul, Seoul, South Korea. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E604, Rockville, MD 20850 USA. EM purduem@mail.nih.gov RI Hildesheim, Allan/B-9760-2015; Purdue, Mark/C-9228-2016; Chaturvedi, Anil/J-2024-2015 OI Hildesheim, Allan/0000-0003-0257-2363; Purdue, Mark/0000-0003-1177-3108; Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. NR 34 TC 22 Z9 22 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 8 PY 2013 VL 122 IS 6 BP 951 EP 957 DI 10.1182/blood-2013-01-481077 PG 7 WC Hematology SC Hematology GA 197VE UT WOS:000322879100018 PM 23814017 ER PT J AU McDonnell, SRP Hwang, SR Rolland, D Murga-Zamalloa, C Basrur, V Conlon, KP Fermin, D Wolfe, T Raskind, A Ruan, CH Jiang, JK Thomas, CJ Hogaboam, CM Burant, CF Elenitoba-Johnson, KSJ Lim, MS AF McDonnell, Scott R. P. Hwang, Steven R. Rolland, Delphine Murga-Zamalloa, Carlos Basrur, Venkatesha Conlon, Kevin P. Fermin, Damian Wolfe, Thomas Raskind, Alexander Ruan, Chunhai Jiang, Jian-Kang Thomas, Craig J. Hogaboam, Cory M. Burant, Charles F. Elenitoba-Johnson, Kojo S. J. Lim, Megan S. TI Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma SO BLOOD LA English DT Article ID PYRUVATE-KINASE M2; TYROSINE PHOSPHORYLATION; TUMOR-GROWTH; AEROBIC GLYCOLYSIS; CANCER METABOLISM; PROMOTE; DEHYDROGENASE; INHIBITION; PROTEIN; IDENTIFICATION AB The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis. C1 [McDonnell, Scott R. P.; Hwang, Steven R.; Rolland, Delphine; Murga-Zamalloa, Carlos; Basrur, Venkatesha; Conlon, Kevin P.; Fermin, Damian; Wolfe, Thomas; Hogaboam, Cory M.; Elenitoba-Johnson, Kojo S. J.; Lim, Megan S.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Raskind, Alexander; Ruan, Chunhai; Burant, Charles F.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Jiang, Jian-Kang; Thomas, Craig J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Lim, MS (reprint author), Biomed Sci Res Bldg,Room 2039,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM meganlim@med.umich.edu RI hogaboam, cory /M-3578-2014; OI Burant, Charles/0000-0001-9189-5003 FU Michigan Regional Comprehensive Metabolomics Resource Core [1U24 DK097153]; National Institutes of Health, National Cancer Institute [R01 CA140806-01, R01 DE119249, R01 CA136905, 5T32 GM070449, 1F31 CA171373-01]; A. Alfred Taubman Institute FX This work was supported by the Michigan Regional Comprehensive Metabolomics Resource Core (1U24 DK097153), National Institutes of Health, National Cancer Institute grants R01 CA140806-01 (to M.S.L), R01 DE119249, R01 CA136905 (to K.S.J.E.-J.), 5T32 GM070449 (to T.W.), and 1F31 CA171373-01 (to S.R.P.M.), and the A. Alfred Taubman Institute (to C.F.B.). NR 39 TC 19 Z9 20 U1 1 U2 17 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD AUG 8 PY 2013 VL 122 IS 6 BP 958 EP 968 DI 10.1182/blood-2013-01-482026 PG 11 WC Hematology SC Hematology GA 197VE UT WOS:000322879100019 PM 23814019 ER PT J AU Lee, YT de Vasconcellos, JF Yuan, J Byrnes, C Noh, SJ Meier, ER Kim, KS Rabel, A Kaushal, M Muljo, SA Miller, JL AF Lee, Y. Terry de Vasconcellos, Jaira F. Yuan, Joan Byrnes, Colleen Noh, Seung-Jae Meier, Emily R. Kim, Ki Soon Rabel, Antoinette Kaushal, Megha Muljo, Stefan A. Miller, Jeffery L. TI LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo SO BLOOD LA English DT Article ID GENOME-WIDE ASSOCIATION; SICKLE-CELL-DISEASE; BETA-THALASSEMIA; MESSENGER-RNAS; STEM-CELLS; LIN28; IDENTIFICATION; MICRORNA; LIN-28; GENE AB Reactivation of fetal hemoglobin (HbF) holds therapeutic potential for sickle cell disease and beta-thalassemias. In human erythroid cells and hematopoietic organs, LIN28B and its targeted let-7 microRNA family, demonstrate regulated expression during the fetal-to-adult developmental transition. To explore the effects of LIN28B in human erythroid cell development, lentiviral transduction was used to knockdown LIN28B expression in erythroblasts cultured from human umbilical cord CD34+ cells. The subsequent reduction in LIN28B expression caused increased expression of let-7 and significantly reduced HbF expression. Conversely, LIN28B overexpression in cultured adult erythroblasts reduced the expression of let-7 and significantly increased HbF expression. Cellular maturation was maintained including enucleation. LIN28B expression in adult erythroblasts increased the expression of gamma-globin, and the HbF content of the cells rose to levels >30% of their hemoglobin. Expression of carbonic anhydrase I, glucosaminyl (N-acetyl) transferase 2, and miR-96 (three additional genes marking the transition from fetal-to-adult erythropoiesis) were reduced by LIN28B expression. The transcription factor BCL11A, a well-characterized repressor of gamma-globin expression, was significantly down-regulated. Independent of LIN28B, experimental suppression of let-7 also reduced BCL11A expression and significantly increased HbF expression. LIN28B expression regulates HbF levels and causes adult human erythroblasts to differentiate with a more fetal-like phenotype. C1 [Lee, Y. Terry; de Vasconcellos, Jaira F.; Byrnes, Colleen; Noh, Seung-Jae; Meier, Emily R.; Kim, Ki Soon; Rabel, Antoinette; Kaushal, Megha; Miller, Jeffery L.] NIDDK, Mol Genom & Therapeut Sect, Mol Med Branch, Bethesda, MD 20892 USA. [Yuan, Joan; Muljo, Stefan A.] NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9N311, Bethesda, MD 20892 USA. EM jm7f@nih.gov RI Muljo, Stefan/F-5671-2015 OI Muljo, Stefan/0000-0003-1013-446X FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases FX The Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases supported this work. A provisional patent application was filed by the US government (National Institutes of Health) in conjunction with this work. NR 50 TC 31 Z9 31 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 8 PY 2013 VL 122 IS 6 BP 1034 EP 1041 DI 10.1182/blood-2012-12-472308 PG 8 WC Hematology SC Hematology GA 197VE UT WOS:000322879100027 PM 23798711 ER PT J AU Flanders, A Stetler-Stevenson, M Landgren, O AF Flanders, Aaron Stetler-Stevenson, Maryalice Landgren, Ola TI Minimal residual disease testing in multiple myeloma by flow cytometry: major heterogeneity SO BLOOD LA English DT Letter C1 [Flanders, Aaron; Landgren, Ola] NCI, Multiple Myeloma Sect, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Sect, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, NIH, Ctr Canc Res, Metab Branch,Multiple Myeloma Sect, 9000 Rockville Pike,Bldg 10 Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov NR 5 TC 31 Z9 32 U1 0 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 8 PY 2013 VL 122 IS 6 BP 1088 EP 1089 DI 10.1182/blood-2013-05-506170 PG 4 WC Hematology SC Hematology GA 197VE UT WOS:000322879100034 PM 23929839 ER PT J AU Kato, GJ Nouraie, SM Gladwin, MT AF Kato, Gregory J. Nouraie, Seyed Mehdi Gladwin, Mark T. TI Lactate dehydrogenase and hemolysis in sickle cell disease SO BLOOD LA English DT Letter ID ANEMIA; CRISIS; DEATH C1 [Kato, Gregory J.] NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Nouraie, Seyed Mehdi] Howard Univ, Ctr Sickle Cell Dis, Coll Med, Washington, DC USA. [Nouraie, Seyed Mehdi] Howard Univ, Coll Med, Dept Internal Med, Washington, DC USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Vasc Med Inst, Pittsburgh, PA USA. RP Kato, GJ (reprint author), NIH, 9000 Rockville Pike,MSC 1476,Bldg 10 CRC,Room 5-5, Bethesda, MD 20892 USA. EM gkato@nhlbi.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 9 TC 11 Z9 11 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 8 PY 2013 VL 122 IS 6 BP 1091 EP 1092 DI 10.1182/blood-2013-05-505016 PG 4 WC Hematology SC Hematology GA 197VE UT WOS:000322879100036 PM 23929841 ER PT J AU Grillon, C Franco-Chaves, JA Mateus, CF Ionescu, DF Zarate, CA AF Grillon, Christian Franco-Chaves, Jose A. Mateus, Camilo F. Ionescu, Dawn F. Zarate, Carlos A. TI Major Depression Is Not Associated with Blunting of Aversive Responses; Evidence for Enhanced Anxious Anticipation SO PLOS ONE LA English DT Article ID FEAR-POTENTIATED STARTLE; PANIC DISORDER PATIENTS; POSTTRAUMATIC-STRESS-DISORDER; UNIPOLAR DEPRESSION; LEARNED HELPLESSNESS; INCREASED AMYGDALA; MODULATED STARTLE; VIETNAM VETERANS; ACOUSTIC STARTLE; CONTEXTUAL FEAR AB According to the emotion-context insensitivity (ECI) hypothesis, major depressive disorder (MDD) is associated with a diminished ability to react emotionally to positive stimuli and with blunting of defensive responses to threat. That defensive responses are blunted in MDD seems inconsistent with the conceptualization and diagnostic nosology of MDD. The present study tested the ECI hypothesis in MDD using a threat of shock paradigm. Twenty-eight patients with MDD (35.5+/-10.4 years) were compared with 28 controls (35.1+/-7.4 years). Participants were exposed to three conditions: no shock, predictable shock, and unpredictable shock. Startle magnitude was used to assess defensive responses. Inconsistent with the ECI hypothesis, startle potentiation to predictable and unpredictable shock was not reduced in the MDD group. Rather, MDD patients showed elevated startle throughout testing as well as increased contextual anxiety during the placement of the shock electrodes and in the predictable condition. A regression analysis indicated that illness duration and Beck depression inventory scores explained 37% (p<.005) of the variance in patients' startle reactivity. MDD is not associated with emotional blunting but rather enhanced defensive reactivity during anticipation of harm. These results do not support a strong version of the ECI hypothesis. Understanding the nature of stimuli or situations that lead to blunted or enhanced defensive reactivity will provide better insight into dysfunctional emotional experience in MDD. C1 [Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Franco-Chaves, Jose A.; Mateus, Camilo F.; Ionescu, Dawn F.; Zarate, Carlos A.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. EM Christian.grillon@nih.gov RI Ionescu, Dawn/K-5675-2015 FU Intramural Research Program of the National Institutes of Mental Health [MH002798] FX Financial support of this study was provided by the Intramural Research Program of the National Institutes of Mental Health (MH002798). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 13 Z9 13 U1 4 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 8 PY 2013 VL 8 IS 8 AR e70969 DI 10.1371/journal.pone.0070969 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201ER UT WOS:000323124000036 PM 23951057 ER PT J AU Nishijima, T Gatanaga, H Shimbo, T Komatsu, H Endo, T Horiba, M Koga, M Naito, T Itoda, I Tei, M Fujii, T Takada, K Yamamoto, M Miyakawa, T Tanabe, Y Mitsuya, H Oka, S AF Nishijima, Takeshi Gatanaga, Hiroyuki Shimbo, Takuro Komatsu, Hirokazu Endo, Tomoyuki Horiba, Masahide Koga, Michiko Naito, Toshio Itoda, Ichiro Tei, Masanori Fujii, Teruhisa Takada, Kiyonori Yamamoto, Masahiro Miyakawa, Toshikazu Tanabe, Yoshinari Mitsuya, Hiroaki Oka, Shinichi CA SPARE Study Team TI Switching Tenofovir/Emtricitabine plus Lopinavir/r to Raltegravir plus Darunavir/r in Patients with Suppressed Viral Load Did Not Result in Improvement of Renal Function but Could Sustain Viral Suppression: A Randomized Multicenter Trial SO PLOS ONE LA English DT Article ID HIV-INFECTED PATIENTS; TENOFOVIR DISOPROXIL FUMARATE; ANTIRETROVIRAL-NAIVE PATIENTS; TUBULAR DYSFUNCTION; HIV-1-INFECTED PATIENTS; MITOCHONDRIAL TOXICITY; CREATININE CLEARANCE; SPARING REGIMEN; THERAPY; SAFETY AB Background: Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load. Methods: This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation. Results: 58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary beta 2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 mu g/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD). Conclusions: Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary beta 2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL +DRV/r showed favorable viral efficacy in patients with suppressed viral load. C1 [Nishijima, Takeshi; Gatanaga, Hiroyuki; Oka, Shinichi] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan. [Nishijima, Takeshi; Gatanaga, Hiroyuki; Oka, Shinichi] Kumamoto Univ, Sch Med, Ctr AIDS Res, Kumamoto 860, Japan. [Shimbo, Takuro] Natl Ctr Global Hlth & Med, Ctr Clin Sci, Dept Clin Study & Informat, Tokyo, Japan. [Komatsu, Hirokazu] Saku Cent Hosp, Dept Community Care, Nagano, Japan. [Endo, Tomoyuki] Hokkaido Univ Hosp, Dept Hematol, Sapporo, Hokkaido 060, Japan. [Horiba, Masahide] Higashisaitama Natl Hosp, Div Resp Med, Saitama, Japan. [Koga, Michiko] Univ Tokyo, Inst Med Sci, Adv Clin Res Ctr, Div Infect Dis, Tokyo, Japan. [Naito, Toshio] Juntendo Univ, Sch Med, Dept Gen Med, Tokyo 113, Japan. [Itoda, Ichiro] Shirakaba Clin, Tokyo, Japan. [Tei, Masanori] Saku Cent Hosp, Dept Integrated Med, Nagano, Japan. [Fujii, Teruhisa] Hiroshima Univ Hosp, Div Blood Transfus, Hiroshima, Japan. [Takada, Kiyonori] Ehime Univ Hosp, Postgrad Clin Training Ctr, Matsuyama, Ehime, Japan. [Yamamoto, Masahiro] Natl Hosp Org, Kyushu Med Ctr, Clin Res Inst, Fukuoka, Japan. [Miyakawa, Toshikazu; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Infect Dis & Hematol, Kumamoto 860, Japan. [Tanabe, Yoshinari] Niigata Univ, Med & Dent Hosp, Div Infect Control & Prevent, Niigata, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Oka, S (reprint author), Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan. EM oka@acc.ncgm.go.jp RI Kumamoto University, CAIDS/G-8446-2013 FU Ministry of Health, Labor, and Welfare of Japan [H22-AIDS-001] FX This work was supported by a Grant-in-Aid for the research on HIV/AIDS (H22-AIDS-001) from the Ministry of Health, Labor, and Welfare of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 16 Z9 17 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 8 PY 2013 VL 8 IS 8 AR e73639 DI 10.1371/journal.pone.0073639 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201ER UT WOS:000323124000097 PM 23951362 ER PT J AU White, MT Smith, DL AF White, Michael T. Smith, David L. TI Synergism from combinations of infection-blocking malaria vaccines SO MALARIA JOURNAL LA English DT Article DE Malaria; Vaccine; Infection; Pre-erythrocytic; Synergy ID PLASMODIUM-FALCIPARUM; EFFICACY; SPOROZOITES; PROTECTION; IMMUNITY; RATES AB Plasmodium falciparum infections present novel challenges for vaccine development, including parasite replication dynamics not previously encountered for viral pathogens, and enormous diversity in target antigens. These challenges are illustrated by using a mathematical model to describe the association between the proportion of pre-erythrocytic or blood-stage parasites eliminated by vaccine-induced immune responses and the proportion of infections prevented. It is hypothesized that due to the requirement for all sporozoites to be eliminated to prevent infection, combining infection-blocking vaccines that confer protection through different biological mechanisms could lead to synergistic combinations of efficacy. Vaccines targeting blood-stage parasites may also combine synergistically if they combine to reduce the parasite multiplication rate to below the threshold of 1. C1 [White, Michael T.] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London, England. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Smith, David L.] NIH, Fogarty Int Ctr, Baltimore, MD USA. RP White, MT (reprint author), Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London, England. EM m.white08@imperial.ac.uk RI Smith, David/L-8850-2013 OI Smith, David/0000-0003-4367-3849 FU Medical Research Council studentship; Bell & Melinda Gates Foundation FX Dr Sandy Douglas is thanked for helpful comments on the draft manuscript. MTW was funded by a Medical Research Council studentship and a grant from the Bell & Melinda Gates Foundation. NR 11 TC 3 Z9 3 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 8 PY 2013 VL 12 AR 280 DI 10.1186/1475-2875-12-280 PG 3 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 206HG UT WOS:000323509100001 PM 23927630 ER PT J AU Hu, YJ Berndt, SI Gustafsson, S Ganna, A Hirschhorn, J North, KE Ingelsson, E Lin, DY AF Hu, Yi-Juan Berndt, Sonja I. Gustafsson, Stefan Ganna, Andrea Hirschhorn, Joel North, Kari E. Ingelsson, Erik Lin, Dan-Yu CA Genetic Invest ANthropometric Trai TI Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; EFFICIENCY; LOCI; MAP AB Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recoVered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available. C1 [Hu, Yi-Juan] Emory Univ, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Berndt, Sonja I.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gustafsson, Stefan; Ganna, Andrea; Ingelsson, Erik] Univ Uppsala Hosp, Dept Med Sci, Mol Epidemiol & Sci Life Lab, S-75185 Uppsala, Sweden. [Ganna, Andrea] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Hirschhorn, Joel] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel] Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Hirschhorn, Joel] Broad Inst, Metab Initiat & Program Med & Populat Genet, Cambridge, MA 02142 USA. [Hirschhorn, Joel] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Lin, DY (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. EM lin@bios.unc.edu RI Ripatti, Samuli/H-9446-2014; Polasek, Ozren/B-6002-2011; Tregouet, David-Alexandre/E-3961-2016; Rudan, Igor/I-1467-2012; Feitosa, Mary/K-8044-2012; Boehm, Bernhard/F-8750-2015; Milani, Lili/C-8759-2011; Colaus, PsyColaus/K-6607-2013; Kiemeney, Lambertus/D-3357-2009; den Heijer, Martin/J-8036-2015; Gudnason, Vilmundur/K-6885-2015; Deloukas, Panos/B-2922-2013; Palmer, Lyle/K-3196-2014; Hypponen, Elina/B-2596-2014; Strawbridge, Rona/H-5422-2012; Fall, Tove/O-7226-2014; Medland, Sarah/C-7630-2013; Smith, Albert Vernon/K-5150-2015; OI Ripatti, Samuli/0000-0002-0504-1202; Polasek, Ozren/0000-0002-5765-1862; Rudan, Igor/0000-0001-6993-6884; Feitosa, Mary/0000-0002-0933-2410; Franke, Lude/0000-0002-5159-8802; Shungin, Dmitry/0000-0001-7900-5856; Magi, Reedik/0000-0002-2964-6011; Kivimaki, Mika/0000-0002-4699-5627; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Esko, Tonu/0000-0003-1982-6569; Kristiansson, Kati/0000-0003-4688-107X; Milani, Lili/0000-0002-5323-3102; Kiemeney, Lambertus/0000-0002-2368-1326; den Heijer, Martin/0000-0003-3620-5617; Gudnason, Vilmundur/0000-0001-5696-0084; Deloukas, Panos/0000-0001-9251-070X; Palmer, Lyle/0000-0002-1628-3055; Hypponen, Elina/0000-0003-3670-9399; Strawbridge, Rona/0000-0001-8506-3585; Medland, Sarah/0000-0003-1382-380X; Medina-Gomez, Carolina/0000-0001-7999-5538; Ouwehand, Willem/0000-0002-7744-1790; Kleber, Marcus/0000-0003-0663-7275; Ganna, Andrea/0000-0002-8147-240X; Hunt, Sarah/0000-0002-8350-1235; Smith, Albert Vernon/0000-0003-1942-5845; Paternoster, Lavinia/0000-0003-2514-0889; Lakka, Timo/0000-0002-9199-2871; Franks, Paul/0000-0002-0520-7604; Scherag, Andre/0000-0002-9406-4704; Kumari, Meena/0000-0001-9716-1035; Kuulasmaa, Kari/0000-0003-2165-1411; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Vandenput, Liesbeth/0000-0002-1712-6131 FU National Institutes of Health [R01CA082659, P01CA142538, U01HG004803, HHSN268200625226C, UL1RR025005]; Division of Cancer Epidemiology and Genetics, National Cancer Institute; National Heart, Lung, and Blood Institute [HHSN26820110005C, HHSN26820110006C, HHSN26820110007C, HHSN26820110008C, HHSN26820 110009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN26800625226C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402] FX This research was supported by the National Institutes of Health awards R01CA082659 (D.-Y.L.), P01CA142538 (D.-Y.L.), and U01HG004803 (D.-Y.L., K.E.N.) and by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (S.I.B.). ARIC is a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN26820110005C, HHSN26820110006C, HHSN26820110007C, HHSN26820110008C, HHSN26820 110009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, and HHSN26800625226C) and grants R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contribution. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and the National Institutes of Health Roadmap for Medical Research. NR 24 TC 20 Z9 21 U1 2 U2 39 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG 8 PY 2013 VL 93 IS 2 BP 236 EP 248 DI 10.1016/j.ajhg.2013.06.011 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 202AP UT WOS:000323186200004 PM 23891470 ER PT J AU Cheng, CY Schache, M Ikram, MK Young, TL Guggenheim, JA Vitart, V MacGregor, S Verhoeven, VJM Barathi, VA Liao, JM Hysi, PG Bailey-Wilson, JE St Pourcain, B Kemp, JP McMahon, G Timpson, NJ Evans, DM Montgomery, GW Mishra, A Wang, YX Wang, JJ Rochtchina, E Polasek, O Wright, AF Amin, N van Leeuwen, EM Wilson, JF Pennell, CE van Duijn, CM de Jong, PTVM Vingerling, JR Zhou, X Chen, P Li, RY Tay, WT Zheng, YF Chew, M Burdon, KP Craig, JE Iyengar, SK Igo, RP Lass, JH Chew, EY Haller, T Mihailov, E Metspalu, A Wedenoja, J Simpson, CL Wojciechowski, R Hohn, R Mirshahi, A Zeller, T Pfeiffer, N Lackner, KJ Bettecken, T Meitinger, T Oexle, K Pirastu, M Portas, L Nag, A Williams, KM Yonova-Doing, E Klein, R Klein, BE Hosseini, SM Paterson, AD Makela, KM Lehtimaki, T Kahonen, M Raitakari, O Yoshimura, N Matsuda, F Chen, LJ Pang, CP Yip, SP Yap, MKH Meguro, A Mizuki, N Inoko, H Foster, PJ Zhao, JH Vithana, E Tai, ES Fan, Q Xu, L Campbell, H Fleck, B Rudan, I Aung, T Hofman, A Uitterlinden, AG Bencic, G Khor, CC Forward, H Parssinen, O Mitche, P Rivadeneira, F Hewitt, AW Williams, C Oostra, BA Teo, YY Hammond, CJ Stambolian, D Mackey, DA Klaver, CCW Wong, TY Saw, SM Baird, PN AF Cheng, Ching-Yu Schache, Maria Ikram, M. Kamran Young, Terri L. Guggenheim, Jeremy A. Vitart, Veronique MacGregor, Stuart Verhoeven, Virginie J. M. Barathi, Veluchamy A. Liao, Jiemin Hysi, Pirro G. Bailey-Wilson, Joan E. St Pourcain, Beate Kemp, John P. McMahon, George Timpson, Nicholas J. Evans, David M. Montgomery, Grant W. Mishra, Aniket Wang, Ya Xing Wang, Jie Jin Rochtchina, Elena Polasek, Ozren Wright, Alan F. Amin, Najaf van Leeuwen, Elisabeth M. Wilson, James F. Pennell, Craig E. van Duijn, Cornelia M. de Jong, Paulus T. V. M. Vingerling, Johannes R. Zhou, Xin Chen, Peng Li, Ruoying Tay, Wan-Ting Zheng, Yingfeng Chew, Merwyn Burdon, Kathryn P. Craig, Jamie E. Iyengar, Sudha K. Igo, Robert P., Jr. Lass, Jonathan H., Jr. Chew, Emily Y. Haller, Toomas Mihailov, Evelin Metspalu, Andres Wedenoja, Juho Simpson, Claire L. Wojciechowski, Robert Hoehn, Rene Mirshahi, Alireza Zeller, Tanja Pfeiffer, Norbert Lackner, Karl J. Bettecken, Thomas Meitinger, Thomas Oexle, Konrad Pirastu, Mario Portas, Laura Nag, Abhishek Williams, Katie M. Yonova-Doing, Ekaterina Klein, Ronald Klein, Barbara E. Hosseini, S. Mohsen Paterson, Andrew D. Makela, Kari-Matti Lehtimaki, Terho Kahonen, Mika Raitakari, Olli Yoshimura, Nagahisa Matsuda, Fumihiko Chen, Li Jia Pang, Chi Pui Yip, Shea Ping Yap, Maurice K. H. Meguro, Akira Mizuki, Nobuhisa Inoko, Hidetoshi Foster, Paul J. Zhao, Jing Hua Vithana, Eranga Tai, E-Shyong Fan, Qiao Xu, Liang Campbell, Harry Fleck, Brian Rudan, Igor Aung, Tin Hofman, Albert Uitterlinden, Andre G. Bencic, Goran Khor, Chiea-Chuen Forward, Hannah Parssinen, Olavi Mitchell, Paul Rivadeneira, Fernando Hewitt, Alex W. Williams, Cathy Oostra, Ben A. Teo, Yik-Ying Hammond, Christopher J. Stambolian, Dwight Mackey, David A. Klaver, Caroline C. W. Wong, Tien-Yin Saw, Seang-Mei Baird, Paul N. CA Consortium Refractive Error Myopia Fuchs Genetics Multictr Study Grp Wellcome Trust Case Control Consor Diabet Control Complications Trial TI Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID URBAN INDIAN POPULATION; SINGAPORE MALAY EYE; BLUE MOUNTAINS EYE; VISUAL IMPAIRMENT; SUSCEPTIBILITY LOCI; CORNEAL CURVATURE; SPHERICAL EQUIVALENT; CHINESE CHILDREN; MYOPIA; PREVALENCE AB Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways. C1 [Cheng, Ching-Yu; Schache, Maria; Barathi, Veluchamy A.; Liao, Jiemin; Aung, Tin; Khor, Chiea-Chuen; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Singapore, Dept Ophthalmol, Singapore 119228, Singapore. [Cheng, Ching-Yu; Schache, Maria; Barathi, Veluchamy A.; Liao, Jiemin; Tai, E-Shyong; Aung, Tin; Khor, Chiea-Chuen; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Hlth Syst, Singapore 119228, Singapore. [Cheng, Ching-Yu; Zhou, Xin; Chen, Peng; Li, Ruoying; Tai, E-Shyong; Fan, Qiao; Teo, Yik-Ying; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Cheng, Ching-Yu; Zhou, Xin; Chen, Peng; Li, Ruoying; Tai, E-Shyong; Fan, Qiao; Teo, Yik-Ying; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Hlth Syst, Singapore 117597, Singapore. [Cheng, Ching-Yu; Ikram, M. Kamran; Barathi, Veluchamy A.; Liao, Jiemin; Tay, Wan-Ting; Zheng, Yingfeng; Chew, Merwyn; Vithana, Eranga; Aung, Tin; Wong, Tien-Yin; Saw, Seang-Mei] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore. [Cheng, Ching-Yu; Ikram, M. Kamran; Saw, Seang-Mei] Duke Natl Univ Singapore, Grad Sch Med, Off Clin Sci, Ctr Quantitat Med, Singapore 169857, Singapore. [Schache, Maria; Wang, Jie Jin; Hewitt, Alex W.; Mackey, David A.; Baird, Paul N.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia. [Ikram, M. Kamran; Verhoeven, Virginie J. M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, NL-3000 CA Rotterdam, Netherlands. [Young, Terri L.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Young, Terri L.] Duke Natl Univ Singapore, Grad Sch Med, Div Neurosci & Behav Disorders, Singapore 169857, Singapore. [Guggenheim, Jeremy A.; Yap, Maurice K. H.] Hong Kong Polytech Univ, Sch Optometry, Ctr Myopia Res, Kowloon, Hong Kong, Peoples R China. [Vitart, Veronique; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, Human Genet Unit, MRC, Edinburgh EH4 2XU, Midlothian, Scotland. [MacGregor, Stuart; Montgomery, Grant W.; Mishra, Aniket] Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Verhoeven, Virginie J. M.; Amin, Najaf; van Leeuwen, Elisabeth M.; van Duijn, Cornelia M.; Vingerling, Johannes R.; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Barathi, Veluchamy A.; Tai, E-Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore 169857, Singapore. [Hysi, Pirro G.; Nag, Abhishek; Williams, Katie M.; Yonova-Doing, Ekaterina; Hammond, Christopher J.] Kings Coll London, Sch Med, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Bailey-Wilson, Joan E.; Simpson, Claire L.; Wojciechowski, Robert] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. [St Pourcain, Beate; Kemp, John P.; McMahon, George; Timpson, Nicholas J.; Evans, David M.] Univ Bristol, Sch Social & Community Med, Ctr Causal Anal Translat Epidemiol, MRC, Bristol BS8 2BN, Avon, England. [St Pourcain, Beate; Kemp, John P.; McMahon, George; Timpson, Nicholas J.; Evans, David M.; Williams, Cathy] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [Wang, Ya Xing; Xu, Liang] Capital Univ Med Sci, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing 100730, Peoples R China. [Wang, Jie Jin; Rochtchina, Elena; Mitchell, Paul] Univ Sydney, Westmead Millennium Inst, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW 2145, Australia. [Polasek, Ozren] Univ Split, Fac Med, Split 21000, Croatia. [Wilson, James F.; Campbell, Harry; Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Pennell, Craig E.; Forward, Hannah] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci, NL-1105 BA Amsterdam, Netherlands. [de Jong, Paulus T. V. M.] Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. [de Jong, Paulus T. V. M.] Leids Univ, Med Ctr, NL-2300 RC Leiden, Netherlands. [Burdon, Kathryn P.; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Iyengar, Sudha K.; Igo, Robert P., Jr.; Lass, Jonathan H., Jr.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Iyengar, Sudha K.; Lass, Jonathan H., Jr.] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA. [Iyengar, Sudha K.; Lass, Jonathan H., Jr.] Univ Hosp Cleveland, Inst Eye, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Ctr Clin Invest, Cleveland, OH 44106 USA. [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Haller, Toomas; Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Mihailov, Evelin] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Wedenoja, Juho] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki 00014, Finland. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Hoehn, Rene; Mirshahi, Alireza; Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, D-55131 Mainz, Germany. [Zeller, Tanja] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, D-20246 Hamburg, Germany. [Lackner, Karl J.] Univ Med Ctr Mainz, Dept Clin Chem & Lab Med, D-55131 Mainz, Germany. [Bettecken, Thomas; Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany. [Meitinger, Thomas; Oexle, Konrad] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany. [Pirastu, Mario; Portas, Laura] Natl Res Council Italy, Inst Populat Genet, I-07100 Sassari, Italy. [Klein, Ronald; Klein, Barbara E.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53705 USA. [Hosseini, S. Mohsen; Paterson, Andrew D.] Univ Toronto, Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Hosseini, S. Mohsen; Paterson, Andrew D.] Univ Toronto, Inst Med Sci, Toronto, ON M5G 1X8, Canada. [Makela, Kari-Matti; Lehtimaki, Terho] Univ Tampere, Tampere Univ Hosp, Filmlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Makela, Kari-Matti; Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere 33520, Finland. [Kahonen, Mika] Univ Tampere, Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Tampere 33521, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20041, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20041, Finland. [Yoshimura, Nagahisa] Kyoto Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Kyoto 6068507, Japan. [Matsuda, Fumihiko] Kyoto Univ, Grad Sch Med, Dept Human Dis Genom, Kyoto 6068501, Japan. [Chen, Li Jia] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Ophthalmol & Visual Sci, Shatin, Hong Kong, Peoples R China. [Pang, Chi Pui] Chinese Univ Hong Kong, Hong Kong Eye Hosp, Dept Ophthalmol & Visual Sci, Kowloon, Hong Kong, Peoples R China. [Yip, Shea Ping] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [Meguro, Akira; Mizuki, Nobuhisa] Yokohama City Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Yokohama, Kanagawa 2360004, Japan. [Inoko, Hidetoshi] Tokai Univ, Sch Med, Dept Genet Informat, Div Mol Life Sci, Tokyo, Kanagawa 2591193, Japan. [Foster, Paul J.] Moorfields Eye Hosp, NIHR Biomed Res Ctr, London EC1V 2PD, England. [Foster, Paul J.] UCL Inst Ophthalmol, London EC1V 2PD, England. [Zhao, Jing Hua] Univ Cambridge, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge CB2 0QQ, England. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore 119228, Singapore. [Fleck, Brian] Princess Alexandra Eye Pavil, Edinburgh EH3 9HA, Midlothian, Scotland. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Bencic, Goran] Sisters Mercy Univ Hosp, Dept Ophthalmol, Zagreb 10000, Croatia. [Khor, Chiea-Chuen] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Parssinen, Olavi] Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla 40014, Finland. [Parssinen, Olavi] Univ Jyvaskyla, Gerontol Res Ctr, Jyvaskyla 40014, Finland. [Parssinen, Olavi] Cent Hosp Cent Finland, Dept Ophthalmol, Jyvaskyla 40620, Finland. [Hewitt, Alex W.; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117546, Singapore. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. RP Saw, SM (reprint author), Natl Univ Singapore, Dept Ophthalmol, Singapore 119228, Singapore. EM seang_mei_saw@nuhs.edu.sg; pnb@unimelb.edu.au RI Yap, Maurice/K-4927-2016; wang, YA XING/K-9671-2016; Mackey, David/H-5340-2014; van der Geest, Rob/J-8193-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery, Grant/B-7148-2008; Delcourt, Cecile/I-2627-2013; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Yip, Shea Ping/A-1185-2016; Klaver, Caroline/A-2013-2016; Paterson, Andrew/A-4088-2011; Fox, Laura /C-6249-2016; Hewitt, Alex/D-1936-2013; Rudan, Igor/I-1467-2012; Mitchell, Paul/P-1498-2014; Biino, Ginevra/B-5334-2013; Chen, Peng/E-5546-2015; Jankowski, Janusz/H-2706-2012; Cheng, Ching-Yu/K-7017-2013; Burdon, Kathryn/A-5026-2009; Macgregor, Stuart/C-6442-2009; Chen, Li Jia/I-5078-2014; Pang, Chi/I-5388-2014; Deloukas, Panos/B-2922-2013; Wang, Jie Jin/P-1499-2014; Blackwell, Jenefer/H-3015-2015; DeAngelis, e/J-7863-2015 OI Kemp, John/0000-0002-9105-2249; Ikram, Mohammad Kamran/0000-0003-0173-9571; Evans, David/0000-0003-0663-4621; Williams, Katie M/0000-0003-4596-3938; Wedenoja, Juho/0000-0002-6155-0378; Timpson, Nicholas/0000-0002-7141-9189; Tai, E Shyong/0000-0003-2929-8966; Baird, Paul/0000-0002-1305-3502; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Hohn, Rene /0000-0003-2870-1469; St Pourcain, Beate/0000-0002-4680-3517; Klein, Ronald/0000-0002-4428-6237; Khor, Chiea Chuen/0000-0002-1128-4729; Hammond, Christopher/0000-0002-3227-2620; Yap, Maurice/0000-0003-4687-4101; wang, YA XING/0000-0003-2749-7793; Mackey, David/0000-0001-7914-4709; Hosseini, Mohsen/0000-0003-3626-9928; Guggenheim, Jeremy/0000-0001-5164-340X; Bailey-Wilson, Joan/0000-0002-9153-2920; Wojciechowski, Robert/0000-0002-9593-4652; van der Geest, Rob/0000-0002-9084-5597; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery, Grant/0000-0002-4140-8139; Delcourt, Cecile/0000-0002-2099-0481; Rivadeneira, Fernando/0000-0001-9435-9441; Yip, Shea Ping/0000-0002-2170-8185; Paterson, Andrew/0000-0002-9169-118X; Hewitt, Alex/0000-0002-5123-5999; Rudan, Igor/0000-0001-6993-6884; Biino, Ginevra/0000-0002-9936-946X; Chen, Peng/0000-0002-1422-4641; Jankowski, Janusz/0000-0003-2130-9181; Cheng, Ching-Yu/0000-0003-0655-885X; Burdon, Kathryn/0000-0001-8217-1249; Macgregor, Stuart/0000-0001-6731-8142; Chen, Li Jia/0000-0003-3500-5840; Deloukas, Panos/0000-0001-9251-070X; Wang, Jie Jin/0000-0001-9491-4898; FU 23andMe FX The authors thank the staff and participants of all studies for their important contributions. Complete funding information and acknowledgements are provided in the Supplemental Data. ALSPAC thanks 23andMe for funding the generation of the ALSPAC GWA data. NR 81 TC 32 Z9 34 U1 1 U2 54 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG 8 PY 2013 VL 93 IS 2 BP 264 EP 277 DI 10.1016/j.ajhg.2013.06.016 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 202AP UT WOS:000323186200006 PM 24144296 ER PT J AU Zariwala, MA Gee, HY Kurkowiak, M Al-Mutairi, DA Leigh, MW Hurd, TW Hjeij, R Dell, SD Chaki, M Dougherty, GW Adan, M Spear, PC Esteve-Rudd, J Loges, NT Rosenfeld, M Diaz, KA Olbrich, H Wolf, WE Sheridan, E Batten, TFC Halbritter, J Porath, JD Kohl, S Lovric, S Hwang, DY Pittman, JE Burns, KA Ferkol, TW Sagel, SD Olivier, KN Morgan, LC Werner, C Raidt, J Pennekamp, P Sun, ZX Zhou, WB Airik, R Natarajan, S Allen, SJ Amirav, I Wieczorek, D Landwehr, K Nielsen, K Schwerk, N Sertic, J Kohler, G Washburn, J Levy, S Fan, SL Koerner-Rettberg, C Amselem, S Williams, DS Mitchell, BJ Drummond, LA Otto, EA Omran, H Knowles, MR Hildebrandt, F AF Zariwala, Maimoona A. Gee, Heon Yung Kurkowiak, Malgorzata Al-Mutairi, Dalal A. Leigh, Margaret W. Hurd, Toby W. Hjeij, Rim Dell, Sharon D. Chaki, Moumita Dougherty, Gerard W. Adan, Mohamed Spear, Philip C. Esteve-Rudd, Julian Loges, Niki T. Rosenfeld, Margaret Diaz, Katrina A. Olbrich, Heike Wolf, Whitney E. Sheridan, Eamonn Batten, Trevor F. C. Halbritter, Jan Porath, Jonathan D. Kohl, Stefan Lovric, Svjetlana Hwang, Daw-Yang Pittman, Jessica E. Burns, Kimberlie A. Ferkol, Thomas W. Sagel, Scott D. Olivier, Kenneth N. Morgan, Lucy C. Werner, Claudius Raidt, Johanna Pennekamp, Petra Sun, Zhaoxia Zhou, Weibin Airik, Rannar Natarajan, Sivakumar Allen, Susan J. Amirav, Israel Wieczorek, Dagmar Landwehr, Kerstin Nielsen, Kim Schwerk, Nicolaus Sertic, Jadranka Koehler, Gabriele Washburn, Joseph Levy, Shawn Fan, Shuling Koerner-Rettberg, Cordula Amselem, Serge Williams, David S. Mitchell, Brian J. Drummond, Lain A. Otto, Edgar A. Omran, Heymut Knowles, Michael R. Hildebrandt, Friedhelm TI ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DYNEIN REGULATORY COMPLEX; CELL-CYCLE; MUTATIONS; CILIOGENESIS; DEFECTS; CILIOPATHY; MOTILITY; DISEASE; HUMANS; GENES AB Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. C1 [Zariwala, Maimoona A.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Gee, Heon Yung; Halbritter, Jan; Porath, Jonathan D.; Kohl, Stefan; Lovric, Svjetlana; Hwang, Daw-Yang; Airik, Rannar; Hildebrandt, Friedhelm] Harvard Univ, Boston Childrens Hosp, Sch Med, Div Nephrol,Dept Med, Boston, MA 02115 USA. [Kurkowiak, Malgorzata; Hjeij, Rim; Dougherty, Gerard W.; Loges, Niki T.; Olbrich, Heike; Werner, Claudius; Raidt, Johanna; Pennekamp, Petra; Omran, Heymut] Univ Childrens Hosp Muenster, Dept Gen Pediat, D-48149 Munster, Germany. [Kurkowiak, Malgorzata] Polish Acad Sci, Inst Human Genet, Dept Mol & Clin Genet, PL-60479 Poznan, Poland. [Kurkowiak, Malgorzata] Int Inst Mol & Cell Biol, PL-02109 Warsaw, Poland. [Al-Mutairi, Dalal A.] Kuwait Univ, Fac Med, Hlth Sci Ctr, Dept Pathol, Safat 13110, Kuwait. [Batten, Trevor F. C.] Univ Leeds, Fac Med & Hlth, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. [Leigh, Margaret W.; Pittman, Jessica E.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA. [Hurd, Toby W.] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Dell, Sharon D.] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Chaki, Moumita; Diaz, Katrina A.; Zhou, Weibin; Natarajan, Sivakumar; Allen, Susan J.; Otto, Edgar A.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Adan, Mohamed; Drummond, Lain A.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Spear, Philip C.; Mitchell, Brian J.] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Esteve-Rudd, Julian; Williams, David S.] Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Dept Ophthalmol & Neurobiol, Los Angeles, CA 90095 USA. [Rosenfeld, Margaret] Univ Washington, Sch Med, Seattle Childrens Hosp, Seattle, WA 98105 USA. [Wolf, Whitney E.; Burns, Kimberlie A.; Knowles, Michael R.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. [Sheridan, Eamonn] St James Univ Hosp, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [Ferkol, Thomas W.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Sagel, Scott D.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Morgan, Lucy C.] Concord Hosp, Dept Resp Med, Concord 2139, NSW, Australia. [Sun, Zhaoxia] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Amirav, Israel] Bar Ilan Univ, Fac Med, Ziv Med Ctr, Dept Pediat, IL-13100 Safed, Israel. [Wieczorek, Dagmar] Univ Duisburg Essen, Univ Klinikum Essen, Inst Human Genet, D-45122 Essen, Germany. [Landwehr, Kerstin] Evangel Krankenhaus Bielefeld, Klin Kinder & Jugendmed, D-33617 Bielefeld, Nordrhein Westf, Germany. [Nielsen, Kim] Copenhagen Univ Hosp, Rigshosp, Dept Paediat & Adolescent Med, Paediat Pulm Serv, DK-2100 Copenhagen, Denmark. [Schwerk, Nicolaus] Hannover Med Sch, Univ Childrens Hosp, Dept Pneumol Allergy & Neonatol, D-30625 Hannover, Germany. [Sertic, Jadranka] Univ Zagreb, Sch Med, Zagreb Clin Hosp, Clin Inst Lab Diag, Zagreb 10000, Croatia. [Koehler, Gabriele] Univ Hosp Muenster, Dept Pathol, D-48149 Munster, Germany. [Washburn, Joseph] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Levy, Shawn] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Fan, Shuling] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Koerner-Rettberg, Cordula] Ruhr Univ Bochum, St Josef Hosp, Klin Kinder & Jugendmed, D-44791 Bochum, Germany. [Amselem, Serge] Univ Paris 06, INSERM, Unite Mixte Rech S933, F-75012 Paris, France. [Drummond, Lain A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Hildebrandt, Friedhelm] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hildebrandt, F (reprint author), Harvard Univ, Boston Childrens Hosp, Sch Med, Div Nephrol,Dept Med, Boston, MA 02115 USA. EM knowles@med.unc.edu; friedhelm.hildebrandt@childrens.harvard.edu RI Spear, Philip/L-5446-2014; OI Spear, Philip/0000-0002-7657-3433; Otto, Edgar/0000-0002-2387-9973; Batten, Trevor/0000-0003-3988-5603; Mitchell, Brian/0000-0001-6281-1536 FU National Institutes of Health (NIH) [DK068306, DK090917, DK091405, DK053093, DK070263, EY013408, DK092808-01A1, 5 U54 HL096458-06]; NIH from the National Center for Advancing Translational Sciences [UL1 TR000083, UL1 TR000154]; project "Studies of nucleic acids and proteins from basic to applied research"; Foundation for Polish Science; European Union Regional Development Fund; Department of Pathology, Faculty of Medicine, Kuwait University; Office of the Director; Office of Rare Diseases Research; National Heart, Lung, and Blood Institute (NHLBI); NIH NHLBI [5 R01HL071798]; Deutsche Forschungsgemeinschaft [DFG Om 6/4, Om 6/5, GRK1104, SFB592]; IZKF Munster; Cell Dynamics and Disease graduate school; project SYSCILIA from the European Community FX We are grateful to all individuals with primary ciliary dyskinesia (PCD) and family members for their participation, as well as Michele Manion, who founded the United States PCD Foundation. We thank the German support group "Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V." This research was supported by grants from the National Institutes of Health (NIH) to F.H. (DK068306 and DK090917), to W.Z. (DK091405), to I.A.D. (DK053093 and DK070263), to D.S.W (EY013408), and to Z.S. (DK092808-01A1). This work was supported in part by NIH grants UL1 TR000083 and UL1 TR000154 from the National Center for Advancing Translational Sciences. M.K. is supported by the project "Studies of nucleic acids and proteins from basic to applied research," sponsored by the International PhD Projects Programme of Foundation for Polish Science. The project is cofinanced by the European Union Regional Development Fund. D.A.M. was supported by the Department of Pathology, Faculty of Medicine, Kuwait University. M.A.Z., M.W.L., S.D.D., M.R., T.W.F., S.D.S., J.E.P., K.N.O., and M.R.K. are supported by NIH research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by the Office of Rare Diseases Research and the National Heart, Lung, and Blood Institute (NHLBI). M.A.Z. and M.R.K. are supported by NIH NHLBI grant 5 R01HL071798. H.O. is supported by the Deutsche Forschungsgemeinschaft (DFG Om 6/4 and Om 6/5, GRK1104, and SFB592), IZKF Munster, the Cell Dynamics and Disease graduate school, and project SYSCILIA from the European Community. Additional acknowledgements are provided in the Supplemental Data. NR 33 TC 43 Z9 49 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG 8 PY 2013 VL 93 IS 2 BP 336 EP 345 DI 10.1016/j.ajhg.2013.06.007 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 202AP UT WOS:000323186200014 PM 23891469 ER PT J AU Kim, BW Cho, H Chung, JY Conway, C Ylaya, K Kim, JH Hewitt, SM AF Kim, Bo Wook Cho, Hanbyoul Chung, Joon-Yong Conway, Catherine Ylaya, Kris Kim, Jae-Hoon Hewitt, Stephen M. TI Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE HIF-1 alpha; c-Met; Cervical cancer; Prognosis; Automated digital image analysis ID SQUAMOUS-CELL-CARCINOMAS; HEPATOCYTE GROWTH-FACTOR; INDUCIBLE FACTOR 1-ALPHA; C-MET OVEREXPRESSION; GENE-EXPRESSION; HUMAN-PAPILLOMAVIRUS; COLORECTAL-CANCER; PANCREATIC-CANCER; FACTOR RECEPTOR; UTERINE CERVIX AB Background: Hypoxia inducible factor-1 alpha (HIF-1 alpha), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c-Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome. Methods: The study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer (n = 179), and matched nonadjacent normal tissues (n = 357). Immunohistochemistry (IHC) was performed to identify HIF-1 alpha, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated. Results: HIF-1 alpha, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1 alpha and c-Met were significantly different in FIGO stage (P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis (P < 0.001 and P = 0.010, respectively). HIF-1 alpha expression was correlated with c-Met expression in cervical cancer (P < 0.001). High expression of HIF-1 alpha and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer. Conclusions: We demonstrate that c-Met correlates with HIF-1 alpha and is a poor prognostic factor in survival in cervical cancer. C1 [Kim, Bo Wook; Chung, Joon-Yong; Conway, Catherine; Ylaya, Kris; Hewitt, Stephen M.] NIH, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,Natl Canc Inst, Bethesda, MD 20892 USA. [Kim, Bo Wook; Chung, Joon-Yong; Conway, Catherine; Ylaya, Kris; Hewitt, Stephen M.] NIH, Appl Mol Pathol Lab, Pathol Lab, Ctr Canc Res,Natl Canc Inst, Bethesda, MD 20892 USA. [Cho, Hanbyoul; Kim, Jae-Hoon] Yonsei Univ, Gangnam Severance Hosp, Coll Med, Dept Obstet & Gynecol, Seoul 135720, South Korea. [Kim, Bo Wook] Korea Canc Ctr Hosp, Dept Obstet & Gynecol, Seoul 139706, South Korea. RP Kim, JH (reprint author), Yonsei Univ, Gangnam Severance Hosp, Coll Med, Dept Obstet & Gynecol, 146-92 Dogok Dong, Seoul 135720, South Korea. EM jaehoonkim@yuhs.ac; genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; basic Science Research Program through the National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0005230, 2011-0010286, 2011-0007146]; faculty research grants from Yonsei University College of Medicine [3-2010-0072, 6-2011-0073] FX This work was supported in part by Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and grants from the basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0005230, 2011-0010286 and 2011-0007146) and faculty research grants from Yonsei University College of Medicine for 2010 and 2011 (3-2010-0072 and 6-2011-0073). We would like to express special thanks to Dr. S. Pastorekova who friendly provided anti-CA9 antibodies (M75 antibody). NR 44 TC 14 Z9 18 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 8 PY 2013 VL 11 AR 185 DI 10.1186/1479-5876-11-185 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 200ME UT WOS:000323072300001 PM 23927384 ER PT J AU Casellas, R Resch, W Hakim, O Nussenzweig, MC AF Casellas, Rafael Resch, Wolfgang Hakim, Ofir Nussenzweig, Michel C. TI The Origin of B Cell Recurrent Chromosomal Translocations: Proximity versus DNA Damage SO MOLECULAR CELL LA English DT Letter ID SEQUENCING REVEALS; REARRANGEMENTS; LYMPHOCYTES; GENOME; BREAKS C1 [Casellas, Rafael; Resch, Wolfgang] NIAMS, NIH, Bethesda, MD 20892 USA. [Casellas, Rafael] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hakim, Ofir] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, HHMI, New York, NY 10065 USA. RP Casellas, R (reprint author), NIAMS, NIH, Bethesda, MD 20892 USA. EM rafael.casellas@nih.gov; nussen@rockefeller.edu FU Intramural NIH HHS [Z01 AR041148-03] NR 9 TC 4 Z9 4 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 8 PY 2013 VL 51 IS 3 BP 275 EP 276 DI 10.1016/j.molcel.2013.07.020 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 200RK UT WOS:000323086400001 PM 23932709 ER PT J AU Hudson, KL Collins, FS AF Hudson, Kathy L. Collins, Francis S. TI Family matters SO NATURE LA English DT Editorial Material ID GENOMIC RESEARCH; IDENTIFIABILITY C1 [Hudson, Kathy L.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Hudson, KL (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kathy.hudson@nih.gov NR 7 TC 16 Z9 16 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 8 PY 2013 VL 500 IS 7461 BP 141 EP 142 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 197CH UT WOS:000322825500011 PM 23925224 ER PT J AU Jaffe, HW Patterson, AP Lurie, N AF Jaffe, Harold W. Patterson, Amy P. Lurie, Nicole TI Extra oversight for H7N9 experiments SO NATURE LA English DT Letter C1 [Jaffe, Harold W.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Patterson, Amy P.] NIH, Bethesda, MD 20892 USA. [Lurie, Nicole] US Dept HHS, Washington, DC 20201 USA. RP Jaffe, HW (reprint author), Ctr Dis Control & Prevent, Atlanta, GA USA. EM pattersa@od.nih.gov NR 1 TC 4 Z9 4 U1 0 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 8 PY 2013 VL 500 IS 7461 BP 151 EP 151 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 197CH UT WOS:000322825500017 PM 23925232 ER PT J AU Rando, TA Finkel, T AF Rando, Thomas A. Finkel, Toren TI Cardiac Aging and Rejuvenation A Sense of Humors? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Rando, Thomas A.] Stanford Univ, Stanford, CA 94305 USA. [Finkel, Toren] NHLBI, NIH, Bethesda, MD 20892 USA. RP Rando, TA (reprint author), Stanford Univ, Stanford, CA 94305 USA. FU NIA NIH HHS [R01 AG047820, P01 AG036695, R37 AG023806] NR 5 TC 8 Z9 8 U1 1 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 8 PY 2013 VL 369 IS 6 BP 575 EP 576 DI 10.1056/NEJMcibr1306063 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 197HX UT WOS:000322842000016 PM 23924010 ER PT J AU Cong, WN Wang, R Cai, H Daimon, CM Scheibye-Knudsen, M Bohr, VA Turkin, R Wood, WH Becker, KG Moaddel, R Maudsley, S Martin, B AF Cong, Wei-na Wang, Rui Cai, Huan Daimon, Caitlin M. Scheibye-Knudsen, Morten Bohr, Vilhelm A. Turkin, Rebecca Wood, William H., III Becker, Kevin G. Moaddel, Ruin Maudsley, Stuart Martin, Bronwen TI Long-Term Artificial Sweetener Acesulfame Potassium Treatment Alters Neurometabolic Functions in C57BL/6J Mice SO PLOS ONE LA English DT Article ID MITOCHONDRIAL COMPLEX-I; TACHYKININ NK2 RECEPTOR; BODY-SURFACE AREA; ALZHEIMERS-DISEASE; NONNUTRITIVE SWEETENERS; SYNAPTIC PLASTICITY; GLUCOSE-HOMEOSTASIS; METABOLIC SYNDROME; CEREBRAL-ISCHEMIA; ENERGY-METABOLISM AB With the prevalence of obesity, artificial, non-nutritive sweeteners have been widely used as dietary supplements that provide sweet taste without excessive caloric load. In order to better understand the overall actions of artificial sweeteners, especially when they are chronically used, we investigated the peripheral and central nervous system effects of protracted exposure to a widely used artificial sweetener, acesulfame K (ACK). We found that extended ACK exposure (40 weeks) in normal C57BL/6J mice demonstrated a moderate and limited influence on metabolic homeostasis, including altering fasting insulin and leptin levels, pancreatic islet size and lipid levels, without affecting insulin sensitivity and bodyweight. Interestingly, impaired cognitive memory functions (evaluated by Morris Water Maze and Novel Objective Preference tests) were found in ACK-treated C57BL/6J mice, while no differences in motor function and anxiety levels were detected. The generation of an ACK-induced neurological phenotype was associated with metabolic dysregulation (glycolysis inhibition and functional ATP depletion) and neurosynaptic abnormalities (dysregulation of TrkB-mediated BDNF and Akt/Erk-mediated cell growth/survival pathway) in hippocampal neurons. Our data suggest that chronic use of ACK could affect cognitive functions, potentially via altering neuro-metabolic functions in male C57BL/6J mice. C1 [Cong, Wei-na; Wang, Rui; Cai, Huan; Daimon, Caitlin M.; Turkin, Rebecca; Martin, Bronwen] NIA, Metab Unit, Clin Invest Lab, Baltimore, MD 21224 USA. [Scheibye-Knudsen, Morten; Bohr, Vilhelm A.] NIA, Sect DNA Repair, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Wood, William H., III; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Genet Lab, Baltimore, MD 21224 USA. [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Neurosci Lab, Baltimore, MD 21224 USA. [Moaddel, Ruin] NIA, Bioanalyt Chem & Drug Discovery Sect, Clin Invest Lab, Baltimore, MD 21224 USA. RP Martin, B (reprint author), NIA, Metab Unit, Clin Invest Lab, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov RI Cai, Huan/B-6578-2016; OI Cai, Huan/0000-0001-7731-8891; Scheibye-Knudsen, Morten/0000-0002-6637-1280; Becker, Kevin/0000-0002-6794-6656 FU Intramural Research Program of the National Institute on Aging at the National Institutes of Health FX This work was carried out with the support of the Intramural Research Program of the National Institute on Aging at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 7 Z9 7 U1 2 U2 53 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2013 VL 8 IS 8 AR e70257 DI 10.1371/journal.pone.0070257 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ZE UT WOS:000323109700025 PM 23950916 ER PT J AU Graf, EH Pace, MJ Peterson, BA Lynch, LJ Chukwulebe, SB Mexas, AM Shaheen, F Martin, JN Deeks, SG Connors, M Migueles, SA O'Doherty, U AF Graf, Erin H. Pace, Matthew J. Peterson, Bennett A. Lynch, Lindsay J. Chukwulebe, Steve B. Mexas, Angela M. Shaheen, Farida Martin, Jeffrey N. Deeks, Steven G. Connors, Mark Migueles, Stephen A. O'Doherty, Una TI Gag-Positive Reservoir Cells Are Susceptible to HIV-Specific Cytotoxic T Lymphocyte Mediated Clearance SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VIVO; ANTIRETROVIRAL THERAPY; ELITE CONTROLLERS; PERIPHERAL-BLOOD; LATENT INFECTION; PLASMA VIREMIA; IMMUNE CONTROL; EX-VIVO; REPLICATION AB Resting CD4+T cells infected with HIV persist in the presence of suppressive anti-viral therapy (ART) and are barriers to a cure. One potential curative approach, therapeutic vaccination, is fueled by recognition of the ability of a subset of elite controllers (EC) to control virus without therapy due to robust anti-HIV immune responses. Controllers have low levels of integrated HIV DNA and low levels of replication competent virus, suggesting a small reservoir. As our recent data indicates some reservoir cells can produce HIV proteins (termed GPR cells for Gag-positive reservoir cells), we hypothesized that a fraction of HIV-expressing resting CD4+T cells could be efficiently targeted and cleared in individuals who control HIV via anti-HIV cytotoxic T lymphocytes (CTL). To test this we examined if superinfected resting CD4+T cells from EC express HIV Gag without producing infectious virus and the susceptibility of these cells to CTL. We found that resting CD4+T cells expressed HIV Gag and were cleared by autologous CD8+T cells from EC. Importantly, we found the extent of CTL clearance in our in vitro assay correlates with in vivo reservoir size and that a population of Gag expressing resting CD4+T cells exists in vivo in patients well controlled on therapy. C1 [Graf, Erin H.; Pace, Matthew J.; Lynch, Lindsay J.; Chukwulebe, Steve B.; Mexas, Angela M.; O'Doherty, Una] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Peterson, Bennett A.; Connors, Mark; Migueles, Stephen A.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Shaheen, Farida] Univ Penn, Ctr AIDS Res, Philadelphia, PA 19104 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP O'Doherty, U (reprint author), Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM unao@mail.med.upenn.edu FU National Institutes of Health (NIH) [AI087461]; NIH T32 training grant [AI00762]; Merck FX This work presented was funded by the National Institutes of Health (NIH) grant AI087461, the NIH T32 training grant AI00762, and Merck. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 19 Z9 19 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2013 VL 8 IS 8 AR e71879 DI 10.1371/journal.pone.0071879 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ZE UT WOS:000323109700122 PM 23951263 ER PT J AU Meier, ER Byrnes, C Lee, YT Wright, EC Schechter, AN Luban, NLC Miller, JL AF Meier, Emily Riehm Byrnes, Colleen Lee, Y. Terry Wright, Elizabeth C. Schechter, Alan N. Luban, Naomi L. C. Miller, Jeffery L. TI Increased Reticulocytosis during Infancy Is Associated with Increased Hospitalizations in Sickle Cell Anemia Patients during the First Three Years of Life SO PLOS ONE LA English DT Article ID FETAL-HEMOGLOBIN; ADVERSE OUTCOMES; DISEASE; CHILDREN; COHORT; PREDICTION; SEVERITY; TRIAL AB Objective: Among older children with sickle cell anemia, leukocyte counts, hemoglobin, and reticulocytosis have previously been suggested as disease severity markers. Here we explored whether these blood parameters may be useful to predict early childhood disease severity when tested in early infancy, defined as postnatal ages 60-180 days. Study Design: Data from fifty-nine subjects who were followed at Children's National Medical Center's Sickle Cell Program for at least three years was retrospectively analyzed. Comparisons were made between white blood cell counts, hemoglobin and reticulocyte levels measured at ages 60-180 days and the clinical course of sickle cell anemia during infancy and childhood. Results: A majority of subjects had demonstrable anemia with increased reticulocytosis. Only increased absolute reticulocyte levels during early infancy were associated with a significant increase in hospitalization during the first three years of life. Higher absolute reticulocyte counts were also associated with a markedly shorter time to first hospitalizations and a four-fold higher cumulative frequency of clinical manifestations over the first three years of life. No significant increase in white blood cell counts was identified among the infant subjects. Conclusions: These data suggest that during early infancy, increased reticulocytosis among asymptomatic SCA subjects is associated with increased severity of disease in childhood. C1 [Meier, Emily Riehm; Byrnes, Colleen; Lee, Y. Terry; Schechter, Alan N.; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. [Meier, Emily Riehm; Luban, Naomi L. C.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Bethesda, MD USA. [Meier, Emily Riehm; Luban, Naomi L. C.] George Washington Univ, Med Ctr, Dept Pediat, Washington, DC 20037 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. EM jm7f@nih.gov OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Marshall B. Coyne Foundation FX The Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases supported this work. Emily R. Meier is also supported by funds from the Marshall B. Coyne Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 6 Z9 6 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2013 VL 8 IS 8 AR e70794 DI 10.1371/journal.pone.0070794 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ZE UT WOS:000323109700054 PM 23951011 ER PT J AU Smith, DL Perkins, TA Tusting, LS Scott, TW Lindsay, SW AF Smith, David L. Perkins, T. Alex Tusting, Lucy S. Scott, Thomas W. Lindsay, Steven W. TI Mosquito Population Regulation and Larval Source Management in Heterogeneous Environments SO PLOS ONE LA English DT Article ID DAR-ES-SALAAM; AEDES-AEGYPTI DIPTERA; LIFE TABLE MODEL; MALARIA TRANSMISSION; VECTOR CONTROL; CULEX-TRITAENIORHYNCHUS; ANOPHELES-STEPHENSI; SIMULATION-MODEL; ESSENTIAL OILS; LARGE-SCALE AB An important question for mosquito population dynamics, mosquito-borne pathogen transmission and vector control is how mosquito populations are regulated. Here we develop simple models with heterogeneity in egg laying patterns and in the responses of larval populations to crowding in aquatic habitats. We use the models to evaluate how such heterogeneity affects mosquito population regulation and the effects of larval source management (LSM). We revisit the notion of a carrying capacity and show how heterogeneity changes our understanding of density dependence and the outcome of LSM. Crowding in and productivity of aquatic habitats is highly uneven unless egg-laying distributions are fine-tuned to match the distribution of habitats' carrying capacities. LSM reduces mosquito population density linearly with coverage if adult mosquitoes avoid laying eggs in treated habitats, but quadratically if eggs are laid in treated habitats and the effort is therefore wasted (i.e., treating 50% of habitat reduces mosquito density by approximately 75%). Unsurprisingly, targeting (i.e. treating a subset of the most productive pools) gives much larger reductions for similar coverage, but with poor targeting, increasing coverage could increase adult mosquito population densities if eggs are laid in higher capacity habitats. Our analysis suggests that, in some contexts, LSM models that accounts for heterogeneity in production of adult mosquitoes provide theoretical support for pursuing mosquito-borne disease prevention through strategic and repeated application of modern larvicides. C1 [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Malaria Res Inst, Baltimore, MD USA. [Smith, David L.; Perkins, T. Alex; Scott, Thomas W.; Lindsay, Steven W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Perkins, T. Alex; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Tusting, Lucy S.] London Sch Hyg & Trop Med, Dept Dis Control, London WC1, England. [Lindsay, Steven W.] Univ Durham, Sch Biol & Biomed Sci, Durham, England. RP Smith, DL (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM dlsmith@jhsph.edu RI Smith, David/L-8850-2013; OI Smith, David/0000-0003-4367-3849; Tusting, Lucy/0000-0002-6897-8625 FU Bloomberg Family Foundation; National Institutes of Health/National Institute of Allergy and Infectious Diseases [U19AI089674]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX DLS acknowledges funding from the Bloomberg Family Foundation. DLS and SWL acknowledge funding from National Institutes of Health/National Institute of Allergy and Infectious Diseases (U19AI089674). DLS, TAP, SWL, and TWS acknowledge funding from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 51 TC 14 Z9 14 U1 0 U2 37 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2013 VL 8 IS 8 AR e71247 DI 10.1371/journal.pone.0071247 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ZE UT WOS:000323109700089 PM 23951118 ER PT J AU Hoffman, DA AF Hoffman, Dax A. TI K+ Channel Regulation of Multicompartmental Signal Integration SO NEURON LA English DT Editorial Material ID NEOCORTICAL PYRAMIDAL NEURONS; DENDRITIC INTEGRATION; ACTION-POTENTIALS; PLASTICITY; INPUT AB Determining how neurons integrate different streams of information is critical to understanding circuit computational functions. In this issue of Neuron, Harnett et al. (2013) show that voltage-gated K+ channels control multiple layers of dendritic integration in layer 5 pyramidal neurons. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Hoffman, DA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM hoffmand@mail.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU Intramural NIH HHS [Z99 HD999999] NR 15 TC 1 Z9 1 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD AUG 7 PY 2013 VL 79 IS 3 BP 403 EP 405 DI 10.1016/j.neuron.2013.07.017 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 200QX UT WOS:000323085100001 PM 23931989 ER PT J AU Britt, JP Bonci, A AF Britt, Jonathan P. Bonci, Antonello TI Alcohol and Tobacco: How Smoking May Promote Excessive Drinking SO NEURON LA English DT Editorial Material ID NICOTINE; ETHANOL; DEPENDENCE AB Cigarette smokers tend to drink more alcohol than their nonsmoking peers. In this issue of Neuron, Doyon et al. (2013) found that nicotine-induced increases in stress hormones can augment ethanol self-administration in rats, suggesting that a drug interaction may contribute to this phenomenon. C1 [Britt, Jonathan P.; Bonci, Antonello] NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Baltimore, MD 21224 USA. [Bonci, Antonello] Johns Hopkins Univ, Solomon H Snyder Neurosci Inst, Sch Med, Baltimore, MD 21205 USA. RP Bonci, A (reprint author), NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Baltimore, MD 21224 USA. EM antonello.bonci@nih.gov RI Britt, Jonathan/D-8877-2011 OI Britt, Jonathan/0000-0003-3044-9565 FU Intramural Research Program of the National Institute of Health, National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute of Health, National Institute on Drug Abuse. NR 12 TC 3 Z9 3 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD AUG 7 PY 2013 VL 79 IS 3 BP 406 EP 407 DI 10.1016/j.neuron.2013.07.018 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 200QX UT WOS:000323085100002 PM 23931990 ER PT J AU Pan, BF Geleoc, GS Asai, Y Horwitz, GC Kurima, K Ishikawa, K Kawashima, Y Griffith, AJ Holt, JR AF Pan, Bifeng Geleoc, Gwenaelle S. Asai, Yukako Horwitz, Geoffrey C. Kurima, Kiyoto Ishikawa, Kotaro Kawashima, Yoshiyuki Griffith, Andrew J. Holt, Jeffrey R. TI TMC1 and TMC2 Are Components of the Mechanotransduction Channel in Hair Cells of the Mammalian Inner Ear SO NEURON LA English DT Article ID MECHANOELECTRICAL TRANSDUCER CHANNELS; MECHANOSENSITIVE CHANNELS; FUNCTIONAL MATURATION; SENSORY TRANSDUCTION; MOUSE COCHLEA; C. ELEGANS; ADAPTATION; CALCIUM; DOMINANT; DEAFNESS AB Sensory transduction in auditory and vestibular hair cells requires expression of transmembrane channel-like (Tmc) 1 and 2 genes, but the function of these genes is unknown. To investigate the hypothesis that TMC1 and TMC2 proteins are components of the mechanosensitive ion channels that convert mechanical information into electrical signals, we recorded whole-cell and single-channel currents from mouse hair cells that expressed Tmc1, Tmc2, or mutant Tmc1. Cells that expressed Tmc2 had high calcium permeability and large single-channel currents, while cells with mutant Tmc1 had reduced calcium permeability and reduced single-channel currents. Cells that expressed Tmc1 and Tmc2 had a broad range of single-channel currents, suggesting multiple heteromeric assemblies of TMC subunits. The data demonstrate TMC1 and TMC2 are components of hair cell transduction channels and contribute to permeation properties. Gradients in TMC channel composition may also contribute to variation in sensory transduction along the tonotopic axis of the mammalian cochlea. C1 [Pan, Bifeng; Geleoc, Gwenaelle S.; Asai, Yukako; Horwitz, Geoffrey C.; Holt, Jeffrey R.] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Otolaryngol,FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Kurima, Kiyoto; Ishikawa, Kotaro; Kawashima, Yoshiyuki; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, 5 Res Court,Room 2B-29, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov; jeffrey.holt@childrens.harvard.edu FU NIDCD [Z01-DC000060-10]; NIH [R01-DC05439, R01-DC008853] FX We thank Erin Child for technical assistance, Lin Huang for assistance with statistical analysis, and Martin Hrabe de Angelis and Helmut Fuchs for providing Beethoven mice. We thank John Assad, David Clapham, David Corey, Tom Friedman, Matt Kelley, Tom Schwarz, and Clifford Woolf for helpful discussions and critical review of an earlier version of the manuscript. This work was supported by NIDCD intramural research funds Z01-DC000060-10 (A.J.G.); NIH grants R01-DC05439 (J.R.H.) and R01-DC008853 (G.S.G.). K.K. and A.J.G. hold US Patents: 7,166,433 (Transductin-2 and Applications to Hereditary Deafness; abandoned in 2009), 7,192,705 (Transductin-1 and Applications to Hereditary Deafness), and 7,659,115 (Nucleic Acid Encoding Human Transductin-1 Polypeptide). These patents have never been licensed and generate no income or royalties. B.P. collected all electrophysiology data from inner hair cells and helped analyze data. G.S.G. collected electrophysiology data from vestibular hair cells and helped analyze the data. G.C.H. collected electrophysiology data from vestibular hair cells, performed ABRs, and helped analyze data. Y.A. generated adenoviral vectors and performed qRT-PCR experiments. K.K. generated Tmc constructs. K.I. performed cell count analysis of Tmc1 mutant mice. Y.K. acquired SEM images of hair cells. A.J.G. contributed to conception of the study and provided critical comments on the data and manuscript. J.R.H. conceived and designed the experiments, analyzed the data, generated the figures, and wrote the paper. All authors provided comments and approved the final submission of the manuscript. NR 40 TC 82 Z9 83 U1 4 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 7 PY 2013 VL 79 IS 3 BP 504 EP 515 DI 10.1016/j.neuron.2013.06.019 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 200QX UT WOS:000323085100011 PM 23871232 ER PT J AU Hong, CH Falvey, C Harris, TB Simonsick, EM Satterfield, S Ferrucci, L Metti, AL Patel, KV Yaffe, K AF Hong, Chang Hyung Falvey, Cherie Harris, Tamara B. Simonsick, Eleanor M. Satterfield, Suzanne Ferrucci, Luigi Metti, Andrea L. Patel, Kushang V. Yaffe, Kristine TI Anemia and risk of dementia in older adults Findings from the Health ABC study SO NEUROLOGY LA English DT Article ID ALZHEIMER-DISEASE; HEMOGLOBIN CONCENTRATION; CARDIOVASCULAR HEALTH; COGNITIVE IMPAIRMENT; ERYTHROPOIETIN; MORTALITY; PREVALENCE; OUTCOMES; DECLINE; COHORT AB Objective: To determine whether anemia is associated with incident dementia in older adults. Methods: We studied 2,552 older adults (mean age 76.1 years; 38.9% black; 51.8% female) participating in the Health, Aging, and Body Composition study and free of dementia at baseline. We defined anemia using WHO criteria (hemoglobin concentration <13 g/dL for men and <12 g/dL for women). Dementia diagnosis was determined by dementia medication use, hospital records, or a change in Modified Mini-Mental State (3MS) score of more than 1.5 SD from mean. Discrete time Cox proportional hazard regression models were used to examine the hazard for developing dementia associated with anemia. Results: Of 2,552 participants, 392 (15.4%) older adults had anemia at baseline. Over 11 years of follow-up, 455 (17.8%) participants developed dementia. In the unadjusted model, those with baseline anemia had an increased risk of dementia (23% vs 17%, hazard ratio = 1.64; 95% confidence interval 1.30, 2.07) compared to those without anemia. The association remained significant after adjusting for demographics, APOE epsilon 4, baseline 3MS score, comorbidities, and renal function. Additional adjustment for other anemia measures (mean corpuscular volume, red cell distribution width), erythropoietin, and C-reactive protein did not appreciably change the results. There was no interaction by sex and race on risk of developing dementia. Conclusion: Among older adults, anemia is associated with an increased risk of developing dementia. Findings suggest that further study of anemia as a risk factor for dementia and a target for intervention for cognitive health is warranted. C1 [Hong, Chang Hyung] Ajou Univ Sch Med, Dept Psychiat, Suwon, South Korea. [Hong, Chang Hyung] Ajou Univ Sch Med, Inst Aging, Suwon, South Korea. [Falvey, Cherie; Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA USA. [Falvey, Cherie; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Satterfield, Suzanne] Univ Tennessee Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Metti, Andrea L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. EM kristine.yaffe@ucsf.edu FU NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459]; NIH; National Institute of Aging; National Institute of Aging [K24AG031155]; American Health Assistance Foundation [A201-0029] FX NIA contract numbers: N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106. NIA grant numbers: R01-AG028050, NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH and National Institute of Aging. Dr. Yaffe is supported in part by a National Institute of Aging Grant (K24AG031155) and a grant from the American Health Assistance Foundation (A201-0029). NR 34 TC 28 Z9 28 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 6 PY 2013 VL 81 IS 6 BP 528 EP 533 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 304JH UT WOS:000330742400007 PM 23902706 ER PT J AU Blackler, AR Morgan, NY Gao, B Olano, LR Armani, MD Romantseva, E Kakareka, JW Bonner, RF Mukherjee, S Xiao, B Tran, K Pohida, TJ Emmert-Buck, MR Tangrea, MA Markey, SP AF Blackler, A. R. Morgan, N. Y. Gao, B. Olano, L. R. Armani, M. D. Romantseva, E. Kakareka, J. W. Bonner, R. F. Mukherjee, S. Xiao, B. Tran, K. Pohida, T. J. Emmert-Buck, M. R. Tangrea, M. A. Markey, S. P. TI Proteomic Analysis of Nuclei Dissected from Fixed Rat Brain Tissue Using Expression Microdissection SO ANALYTICAL CHEMISTRY LA English DT Article ID LASER CAPTURE MICRODISSECTION; TANDEM MASS-SPECTROMETRY; PROMOTER METHYLATION; STATISTICAL-MODEL; PROTEIN; CELLS; CANCER AB Expression microdissection (xMD) is a high-throughput, operator-independent technology that enables the procurement of specific cell populations from tissue specimens. In this method, histological sections are first stained for cellular markers via either chemical or immuno-guided methods, placed in close contact with an ethylene vinyl acetate (EVA) film, and exposed to a light source. The focal, transient heating of the stained cells or subcellular structures melts the EVA film selectively to the targets for procurement. In this report, we introduce a custom-designed flashcube system that permits consistent and reproducible microdissection of nuclei across an FFPE rat brain tissue section in milliseconds. In addition, we present a method to efficiently recover and combine captured proteins from multiple xMD films. Both light and scanning electron microscopy demonstrated captured nuclear structures. Shotgun proteomic analysis of the samples showed a significant enrichment in nuclear localized proteins, with an average 25% of recovered proteins localized to the nucleus, versus 15% for whole tissue controls (p<0.001). Targeted mass spectrometry using multiple reaction monitoring (MRM) showed more impressive data, with a 3-fold enrichment in histones, and a concurrent depletion of proteins localized to the cytoplasm, cytoskeleton, and mitochondria. These data demonstrate that the flashcube-xMD technology is applicable to the proteomic study of a broad range of targets in molecular pathology. C1 [Blackler, A. R.; Armani, M. D.; Mukherjee, S.; Emmert-Buck, M. R.; Tangrea, M. A.] NCI, NIH, Bethesda, MD 20892 USA. [Morgan, N. Y.; Romantseva, E.] Natl Inst Biomed Imaging & Biomed Engn, NIH, Bethesda, MD 20892 USA. [Gao, B.; Markey, S. P.] NIMH, NIH, Bethesda, MD 20892 USA. [Olano, L. R.] NIAID, RTB, NIH, Bethesda, MD 20892 USA. [Kakareka, J. W.; Xiao, B.; Pohida, T. J.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Bonner, R. F.; Tran, K.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Emmert-Buck, MR (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM buckm@mail.nih.gov OI Kakareka, John/0000-0003-0072-0035 FU NIH [ZIA MH002919, 1ZIABC010729]; Center for Cancer Research; NCI; NIBIB FX This work was supported in part by the intramural program at the NIH (Grants ZIA MH002919 and 1ZIABC010729), including the Center for Cancer Research, NCI, NIBIB, and an NIH Directors award. Special thanks goes to the NIAID Research Technologies Branch for sample analysis and bioinformatics assistance. Thanks to Kris Ylaya and Qiang Du, M.D. for tissue sectioning and to Jeff Hanson for assistance with the Arcturus XT instrument. We benefitted from helpful technical discussions and assistance from NIH scientists J. Lippincott-Schwartz, C. Ott, D. Sackett, D. Johann, B. Martin, J. Kowalak, A. J. Makusky, M. Gucek, and A. Aponte. The loan from Agilent of a 6490 triple quadrupole mass spectrometer with chipcube and 1260 HPLC and autosampler stack contributed to the successful MRM analyses and is gratefully acknowledged. NR 29 TC 4 Z9 4 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD AUG 6 PY 2013 VL 85 IS 15 BP 7139 EP 7145 DI 10.1021/ac400691k PG 7 WC Chemistry, Analytical SC Chemistry GA 199RW UT WOS:000323014000025 PM 23799655 ER PT J AU Kaplan, BB Kar, AN Gioio, AE Aschrafi, A AF Kaplan, Barry B. Kar, Amar N. Gioio, Anthony E. Aschrafi, Armaz TI MicroRNAs in the axon and presynaptic nerve terminal SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE axonal mRNAs; mitochondrial mRNAs; intra-axonal protein synthesis; translational regulation; energy metabolism; ROS generation; axonal growth ID LOCAL PROTEIN-SYNTHESIS; SYMPATHETIC NEURONS; MESSENGER-RNA; OXIDATIVE-PHOSPHORYLATION; CORTICAL-NEURONS; TRANSLATION; CYTOSKELETAL; SYNAPSE; GROWTH; ROLES AB The distal structural/functional domains of the neuron, to include the axon and presynaptic nerve terminal, contain a large, heterogeneous population of mRNAs and an active protein synthetic system. These local components of the genetic expression machinery play a critical role in the development, function, and long-term viability of the neuron. In addition to the local mRNA populations these presynaptic domains contain a significant number of non-coding RNAs that regulate gene expression post-transcriptionally. Here, we review a small, but rapidly evolving literature on the composition and function of microRNAs that regulate gene expression locally in the axon and nerve terminal. In this capacity, these small regulatory RNAs have a profound effect on axonal protein synthesis, local energy metabolism, and the modulation of axonal outgrowth and branching. C1 [Kaplan, Barry B.; Kar, Amar N.; Gioio, Anthony E.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Aschrafi, Armaz] Radboud Univ Nijmegen, Ctr Med, Dept Cognit Neurosci, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. RP Kaplan, BB (reprint author), NIMH, Mol Biol Lab, NIH, 9000 Rockville Pike,Bldg 10,Room 4N213, Bethesda, MD 20892 USA. EM barry.kaplan@nih.gov OI Kar, Amar/0000-0003-2380-7504 FU Division of Intramural Research Programs of the National Institute of Mental Health [ZO1MH00276] FX The authors work was supported by the Division of Intramural Research Programs of the National Institute of Mental Health (ZO1MH00276). We thank Noreen Gervasi, Mi Hellifors, Margaret Macgibeny, Orlangie Natera-Naranjo, and Sanah Vohra for invaluable contributions to the authors' research endeavors. NR 26 TC 21 Z9 21 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD AUG 6 PY 2013 VL 7 AR 126 DI 10.3389/fncel.2013.00126 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 205BA UT WOS:000323414200001 PM 23964201 ER PT J AU Weinstein, SJ Virtamo, J Albanes, D AF Weinstein, S. J. Virtamo, J. Albanes, D. TI Pigmentation-related phenotypes and risk of prostate cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostate cancer; MC1R; vitamin D; hair colour; red hair; pigmentation traits ID ULTRAVIOLET-RADIATION; MELANOCORTIN-1 RECEPTOR; MC1R VARIANTS; SKIN TYPE; RED HAIR; MELANOMA; ASSOCIATIONS; METAANALYSIS; CLONING; COLON AB Background: Solar ultraviolet radiation exposure has been inversely related to prostate cancer incidence and mortality, possibly mediated through vitamin D status. Pigmentation-related traits influence endogenous vitamin D synthesis and may alter risk of prostate cancer. Methods: We examined prostate cancer in relation to hair and eye colour, and skin phototype in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Incident cancer was diagnosed in 1982 out of 20 863 men. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazards models. Results: Prostate cancer risk did not differ by eye colour or skin phototype. Men with naturally red hair were significantly less likely to develop prostate cancer (HR=0.46, 95% CI 0.24-0.89) than men with light brown hair (reference). Conclusion: The red hair phenotype, which results from polymorphisms in the melanocortin-1-receptor (MC1R) gene, is associated with lower risk of prostate cancer. This pigmentation-related trait may influence prostate cancer development either directly, through genetic effects or regulatory mechanisms related to MC1R, another nearby gene, or other pigmentation genes, or indirectly, through associations with other exposures such as sunlight or vitamin D status. C1 [Weinstein, S. J.; Albanes, D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FIN-00300 Helsinki, Finland. RP Weinstein, SJ (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM weinstes@mail.nih.gov RI Albanes, Demetrius/B-9749-2015 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; US Public Health Service contracts from the Department of Health and Human Services, National Cancer Institute [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. In addition, this research was supported by the US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the Department of Health and Human Services, National Cancer Institute. NR 25 TC 0 Z9 0 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 6 PY 2013 VL 109 IS 3 BP 747 EP 750 DI 10.1038/bjc.2013.385 PG 4 WC Oncology SC Oncology GA 197CA UT WOS:000322824700029 PM 23860522 ER PT J AU Arem, H Gunter, MJ Cross, AJ Hollenbeck, AR Sinha, R AF Arem, H. Gunter, M. J. Cross, A. J. Hollenbeck, A. R. Sinha, R. TI A prospective investigation of fish, meat and cooking-related carcinogens with endometrial cancer incidence SO BRITISH JOURNAL OF CANCER LA English DT Article DE endometrial cancer; meat; fish; meat mutagens; epidemiology ID FOOD FREQUENCY QUESTIONNAIRE; NATIONWIDE CASE-CONTROL; DIETARY FACTORS; UNITED-STATES; ANIMAL FOODS; RISK; CONSUMPTION; ASSOCIATION; SWEDEN; HEALTH AB Background: There are limited prospective studies of fish and meat intakes with risk of endometrial cancer and findings are inconsistent. Methods: We studied associations between fish and meat intakes and endometrial cancer incidence in the large, prospective National Institutes of Health-AARP Diet and Health Study. Intakes of meat mutagens 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and benzo(a) pyrene (BaP) were also calculated. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We observed no associations with endometrial cancer risk comparing the highest to lowest intake quintiles of red (HR=0.91, 95% CI 0.77-1.08), white (0.98, 0.83-1.17), processed meats (1.02, 0.86-1.21) and fish (1.10, 95% CI 0.93-1.29). We also found no associations between meat mutagen intakes and endometrial cancer. Conclusion: Our findings do not support an association between meat or fish intakes or meat mutagens and endometrial cancer. C1 [Arem, H.; Cross, A. J.; Sinha, R.] Natl Canc Inst, Natl Inst Hlth, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Gunter, M. J.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Hollenbeck, A. R.] AARP, Washington, DC USA. RP Arem, H (reprint author), Natl Canc Inst, Natl Inst Hlth, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM Aremhe2@mail.nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; Florida Department of Health; [T32 CA105666] FX This work was supported in part by the pre-doctoral training grant T32 CA105666. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract with the Florida Department of Health. The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or the Department of Health. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Center for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. NR 29 TC 6 Z9 7 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 6 PY 2013 VL 109 IS 3 BP 756 EP 760 DI 10.1038/bjc.2013.252 PG 5 WC Oncology SC Oncology GA 197CA UT WOS:000322824700031 PM 23695021 ER PT J AU Bodelon, C Wentzensen, N Schonfeld, SJ Visvanathan, K Hartge, P Park, Y Pfeiffer, RM AF Bodelon, C. Wentzensen, N. Schonfeld, S. J. Visvanathan, K. Hartge, P. Park, Y. Pfeiffer, R. M. TI Hormonal risk factors and invasive epithelial ovarian cancer risk by parity SO BRITISH JOURNAL OF CANCER LA English DT Article DE ovarian cancer; parity; nulliparity; risk factors; epidemiology ID POSTMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES; ASSOCIATION; PREMENOPAUSAL; DESIGN; BREAST AB Background: Recent studies have suggested that several ovarian cancer risk factors differ by parity status, but these findings have not been confirmed. We evaluated whether known risk factors of ovarian cancer differ between nulliparous and parous women using data from two large prospective cohorts. Methods: Data from the National Institutes of Health-AARP Diet and Health Study and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were combined for this analysis. Cox regression models were used to estimate associations with ovarian cancer risk. Risk heterogeneity by parity status was assessed using likelihood-ratio tests. Results: Among the 125 437 women included in the analysis, there were 16 589 (13%) nulliparous women and 108 848 (87%) parous women. Of the 623 women diagnosed with invasive epithelial ovarian cancer, 102 (16%) were nulliparous and 521 (84%) were parous. While parity reduced ovarian cancer risk, no differences were found for other risk factors by parity. Among ever users of hormone therapy, body mass index suggestively increased the risk of ovarian cancer by 1.5-fold in nulliparous but not parous women (P-heterogeneity=0.08). Conclusion: While nulliparous women have higher ovarian cancer risk than parous women, our findings suggest that the relative effects of most other risk factors do not differ by parity. C1 [Bodelon, C.; Wentzensen, N.; Schonfeld, S. J.; Hartge, P.; Park, Y.; Pfeiffer, R. M.] Natl Canc Inst, NIH, Div Canc Epidemiol & Genet, Rockville, MD USA. [Schonfeld, S. J.] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Visvanathan, K.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Visvanathan, K.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Bodelon, C (reprint author), Natl Canc Inst, NIH, Div Canc Epidemiol & Genet, Rockville, MD USA. EM clara.bodelon@nih.gov OI Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Cancer Institute; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; Florida Department of Health, Tallahassee, Florida FX This research was supported by the Intramural Research Program of the National Cancer Institute and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. PLCO: We thank the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr Tom Riley and staff, Information Management Services, Inc., Ms Barbara O'Brien and staff, Westat, Inc. Most importantly, we acknowledge the PLCO study participants for their contributions to making this study possible. NIH-AARP: We are also indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia. Cancer incidence data from California were collected by the California Cancer Registry, California Department of Public Health's Cancer Surveillance and Research Branch, Sacramento, California. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, Lansing, Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (Miami, Florida) under contract with the Florida Department of Health, Tallahassee, Florida. The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Health Sciences Center School of Public Health, New Orleans, Louisiana. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health, Trenton, New Jersey. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry, Raleigh, North Carolina. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services, Phoenix, Arizona. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, State Health Division, State of Nevada Department of Health and Human Services, Las Vegas, Nevada. NR 22 TC 4 Z9 4 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 6 PY 2013 VL 109 IS 3 BP 769 EP 776 DI 10.1038/bjc.2013.344 PG 8 WC Oncology SC Oncology GA 197CA UT WOS:000322824700033 PM 23820255 ER PT J AU Amburgey, K Bailey, A Hwang, JH Tarnopolsky, MA Bonnemann, CG Medne, L Mathews, KD Collins, J Daube, JR Wellman, GP Callaghan, B Clarke, NF Dowling, JJ AF Amburgey, Kimberly Bailey, Angela Hwang, Jean H. Tarnopolsky, Mark A. Bonnemann, Carsten G. Medne, Livija Mathews, Katherine D. Collins, James Daube, Jasper R. Wellman, Gregory P. Callaghan, Brian Clarke, Nigel F. Dowling, James J. TI Genotype-phenotype correlations in recessive RYR1-related myopathies SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Genotype-phenotype relationships; RYR1; Congenital myopathies ID CENTRAL CORE DISEASE; MULTI-MINICORE DISEASE; MUSCLE RYANODINE RECEPTOR; CA2+ RELEASE CHANNEL; RYR1 MUTATIONS; MALIGNANT HYPERTHERMIA; CONGENITAL MYOPATHIES; 1 GENE; COMMON-CAUSE; IDENTIFICATION AB Background: RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed. Methods: In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases. Results: Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore. Conclusions: These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies. C1 [Amburgey, Kimberly; Bailey, Angela; Dowling, James J.] Univ Michigan, Ctr Med, Dept Pediat, Taubman Med Res Inst, Ann Arbor, MI 48109 USA. [Hwang, Jean H.; Clarke, Nigel F.] Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia. [Tarnopolsky, Mark A.] McMaster Univ, Med Ctr, Dept Neuromuscular & Neurometabol Dis, Hamilton, ON, Canada. [Bonnemann, Carsten G.] NIH, Neuromuscular & Neurogenet Disorders Childhood Se, Bethesda, MD 20892 USA. [Medne, Livija] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Mathews, Katherine D.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Mathews, Katherine D.] Univ Iowa, Dept Neurol, Carver Coll Med, Iowa City, IA 52242 USA. [Collins, James] Cincinnati Childrens Hosp Med Ctr, Dept Pediat Neurol, Cincinnati, OH 45229 USA. [Daube, Jasper R.] Mayo Fdn Med Educ & Res, Dept Neurol, Rochester, MN USA. [Wellman, Gregory P.] Delta Pathol Grp, Shreveport, LA USA. [Callaghan, Brian] Univ Michigan, Med Ctr, Dept Neurol, Ann Arbor, MI 48109 USA. [Clarke, Nigel F.] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2145, Australia. RP Clarke, NF (reprint author), Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Level 3,Res Bldg Locked Bag 4001, Sydney, NSW 2145, Australia. EM nigel.clarke@health.nsw.gov.au; jamedowl@med.umich.edu OI Bailey, Angela/0000-0002-3757-6754 FU NIH [K08AR054835]; National Health & Medical Research Council [1035828, 1022707]; Albert Einstein College of Medicine; Taubman Research Institute FX This work has been supported by a grant from the NIH (K08AR054835 to JJD) and the National Health & Medical Research Council (NC; grants 1035828 & 1022707). JH is also supported by the Albert Einstein College of Medicine Senior Research Fellowship. Additional support comes from the Taubman Research Institute Emerging Scholar fund. We thank Liz Barnes from the NHMRC Clinical Trials Centre at University of Sydney for the statistical analysis. NR 44 TC 15 Z9 15 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD AUG 6 PY 2013 VL 8 AR 117 DI 10.1186/1750-1172-8-117 PG 12 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 201GX UT WOS:000323129800001 PM 23919265 ER PT J AU Zhang, R Jha, BK Ogden, KM Dong, BH Zhao, L Elliott, R Patton, JT Silverman, RH Weiss, SR AF Zhang, Rong Jha, Babal K. Ogden, Kristen M. Dong, Beihua Zhao, Ling Elliott, Ruth Patton, John T. Silverman, Robert H. Weiss, Susan R. TI Homologous 2 ',5 '-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Reoviridae; Nidovirales; RNA capping enzyme; interferon-stiumulated gene ID MOUSE HEPATITIS-VIRUS; ROTAVIRUS OPEN CORES; MURINE CORONAVIRUS; 2',5'-OLIGOADENYLATE SYNTHETASE; 2-5A-DEPENDENT RNASE; PROSTATE-CANCER; INFECTED-CELLS; STRAIN A59; INTERFERON; PROTEIN AB Efficient and productive virus infection often requires viral countermeasures that block innate immunity. The IFN-inducible 2',5'-oligoadenylate (2-5A) synthetases (OASs) and ribonuclease (RNase) L are components of a potent host antiviral pathway. We previously showed that murine coronavirus (MHV) accessory protein ns2, a 2H phosphoesterase superfamily member, is a phosphodiesterase (PDE) that cleaves 2-5A, thereby preventing activation of RNase L. The PDE activity of ns2 is required for MHV replication in macrophages and for hepatitis. Here, we show that group A rotavirus (RVA), an important cause of acute gastroenteritis in children worldwide, encodes a similar PDE. The RVA PDE forms the carboxy-terminal domain of the minor core protein VP3 (VP3-CTD) and shares sequence and predicted structural homology with ns2, including two catalytic HxT/S motifs. Bacterially expressed VP3-CTD exhibited 2',5'-PDE activity, which cleaved 2-5A in vitro. In addition, VP3-CTD expressed transiently in mammalian cells depleted 2-5A levels induced by OAS activation with poly (rI):poly(rC), preventing RNase L activation. In the context of recombinant chimeric MHV expressing inactive ns2, VP3-CTD restored the ability of the virus to replicate efficiently in macrophages or in the livers of infected mice, whereas mutant viruses expressing inactive VP3-CTD (H718A or H798R) were attenuated. In addition, chimeric viruses expressing either active ns2 or VP3-CTD, but not nonfunctional equivalents, were able to protect ribosomal RNA from RNase L-mediated degradation. Thus, VP3-CTD is a 2',5'-PDE able to functionally substitute for ns2 in MHV infection. Remarkably, therefore, two disparate RNA viruses encode proteins with homologous 2',5'-PDEs that antagonize activation of innate immunity. C1 [Zhang, Rong; Zhao, Ling; Elliott, Ruth; Weiss, Susan R.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Zhang, Rong] Chinese Acad Agr Sci, Shanghai Vet Res Inst, Dept Swine Infect Dis, Shanghai 200241, Peoples R China. [Jha, Babal K.; Dong, Beihua; Silverman, Robert H.] Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA. [Ogden, Kristen M.; Patton, John T.] NIAID, Rotavirus Mol Biol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Weiss, SR (reprint author), Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. EM SILVERR@ccf.org; weisssr@mail.med.upenn.edu RI Patton, John/P-1390-2014; OI Jha, Babal/0000-0002-7660-5255 FU National Institutes of Health [RO1-AI104887, R56-AI-095285]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; China Scholarship council FX We thank Sasha Stone and L. Dillon Birdwell for technical help. This work was supported by National Institutes of Health Grants RO1-AI104887 (to S.R.W. and R.H.S.) and R56-AI-095285 (to S.R.W.) and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (J.T.P. and K.M.O.). R.Z. was supported in part by the China Scholarship council. NR 45 TC 41 Z9 42 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2013 VL 110 IS 32 BP 13114 EP 13119 DI 10.1073/pnas.1306917110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196JQ UT WOS:000322771100064 PM 23878220 ER PT J AU Belgard, TG Montiel, JF Wang, WZ Garcia-Moreno, F Margulies, EH Ponting, CP Molnar, Z AF Belgard, T. Grant Montiel, Juan F. Wang, Wei Zhi Garcia-Moreno, Fernando Margulies, Elliott H. Ponting, Chris P. Molnar, Zoltan TI Adult pallium transcriptomes surprise in not reflecting predicted homologies across diverse chicken and mouse pallial sectors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cerebral cortex; Wulst; equivalent circuit hypothesis; brain evolution; dorsal ventricular ridge ID EVOLUTION; NEOCORTEX; BRAIN; EXPRESSION; ORIGINS; CORTEX; TELENCEPHALON; AMNIOTES; PATTERNS AB The thorniest problem in comparative neurobiology is the identification of the particular brain region of birds and reptiles that corresponds to the mammalian neocortex [Butler AB, Reiner A, Karten HJ (2011) Ann N Y Acad Sci 1225:14-27; Wang Y, Brzozowska-Prechtl A, Karten HJ (2010) Proc Natl Acad Sci USA 107(28):12676-12681]. We explored which genes are actively transcribed in the regions of controversial ancestry in a representative bird (chicken) and mammal (mouse) at adult stages. We conducted four analyses comparing the expression patterns of their 5,130 most highly expressed one-to-one orthologous genes that considered global patterns of expression specificity, strong gene markers, and coexpression networks. Our study demonstrates transcriptomic divergence, plausible convergence, and, in two exceptional cases, conservation between specialized avian and mammalian telencephalic regions. This large-scale study potentially resolves the complex relationship between developmental homology and functional characteristics on the molecular level and settles long-standing evolutionary debates. C1 [Belgard, T. Grant; Ponting, Chris P.] Univ Oxford, MRC, Funct Genom Unit, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. [Belgard, T. Grant; Margulies, Elliott H.] NHGRI, NIH, Bethesda, MD 20892 USA. [Montiel, Juan F.; Wang, Wei Zhi; Garcia-Moreno, Fernando; Molnar, Zoltan] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Montiel, Juan F.] Univ Diego Portales, Fac Med, Ctr Biomed Res, Santiago 8370068, Chile. RP Molnar, Z (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. EM grant@grantbelgard.com; chris.ponting@dpag.ox.ac.uk; zoltan.molnar@dpag.ox.ac.uk OI Montiel, Juan F/0000-0001-8919-4662; Molnar, Zoltan/0000-0002-6852-6004; Belgard, Tildon/0000-0002-6962-7894; Ponting, Chris/0000-0003-0202-7816; Garcia-Moreno, Fernando/0000-0001-9048-4237 FU Intramural Program of the National Human Genome Research Institute; Medical Research Council; Biotechnology and Biological Sciences Research Council; Human Frontiers Science Program postdoctoral fellowship; Parkinson's UK; European Research Council; Marshall Scholarship, New College, Oxford; NIH-Oxford-Cambridge Scholars Program; Becas Chile Postdoctoral Fellowship FX We thank E. D. Green and R. A. Chodroff for their roles in project conceptualization, T. M. Sirey and L. Bluy for RNA extractions, H. Ozel Abaan for the chicken poly(A) selection, the National Institutes of Health (NIH) Intramural Sequencing Center for library preparation and sequencing, J. L. Becker and M. W. Lesko for maintaining computational infrastructure, L. Goodstadt for ruffus, L. Puelles and C. Nellaker for helpful discussions, H. Kaune and A. F. P. Cheung for help in chicken brain collection, and M. Neubrandt for help in brain sectioning. This work was supported by the Intramural Program of the National Human Genome Research Institute, the Medical Research Council, Biotechnology and Biological Sciences Research Council, a Human Frontiers Science Program postdoctoral fellowship, Parkinson's UK, the European Research Council, the Marshall Scholarship, New College, Oxford, the NIH-Oxford-Cambridge Scholars Program, and the Becas Chile Postdoctoral Fellowship. NR 23 TC 28 Z9 28 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2013 VL 110 IS 32 BP 13150 EP 13155 DI 10.1073/pnas.1307444110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196JQ UT WOS:000322771100070 PM 23878249 ER PT J AU Dimitrov, EL Kuo, J Kohno, K Usdin, TB AF Dimitrov, Eugene L. Kuo, Jonathan Kohno, Kenji Usdin, Ted B. TI Neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE supraspinal pain; allodynia; partial sciatic nerve ligation; Freund's adjuvant ID LOCUS-COERULEUS NEURONS; PERIPHERAL-NERVE INJURY; RAT SPINAL-CORD; PARATHYROID-HORMONE-2 RECEPTOR; LENTIVIRAL VECTORS; CERULEUS NEURONS; CELL GROUPS; AMITRIPTYLINE; NOCICEPTION; PROJECTIONS AB Nociceptive information is modulated by a large number of endogenous signaling agents that change over the course of recovery from injury. This plasticity makes understanding regulatory mechanisms involved in descending inhibition of pain scientifically and clinically important. Neurons that synthesize the neuropeptide TIP39 project to many areas that modulate nociceptive information. These areas are enriched in its receptor, the parathyroid hormone 2 receptor (PTH2R). We previously found that TIP39 affects several acute nociceptive responses, leading us to now investigate its potential role in chronic pain. Following nerve injury, both PTH2R and TIP39 knockout mice developed less tactile and thermal hypersensitivity than controls and returned to baseline sensory thresholds faster. Effects of hindpaw inflammatory injury were similarly decreased in knockout mice. Blockade of alpha-2 adrenergic receptors increased the tactile and thermal sensitivity of apparently recovered knockout mice, returning it to levels of neuropathic controls. Mice with locus coeruleus (LC) area injection of lentivirus encoding a secreted PTH2R antagonist had a rapid, alpha-2 reversible, apparent recovery from neuropathic injury similar to the knockout mice. Ablation of LC area glutamatergic neurons led to local PTH2R-ir loss, and barley lectin was transferred from local glutamatergic neurons to GABA interneurons that surround the LC. These results suggest that TIP39 signaling modulates sensory thresholds via effects on glutamatergic transmission to brain-stem GABAergic interneurons that innervate noradrenergic neurons. TIP39's normal role may be to inhibit release of hypoalgesic amounts of norepinephrine during chronic pain. The neuropeptide may help maintain central sensitization, which could serve to enhance guarding behavior. C1 [Dimitrov, Eugene L.; Kuo, Jonathan; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. [Kohno, Kenji] Nara Inst Sci & Technol, Grad Sch Biol Sci, Lab Mol & Cell Genet, Ikoma Nara 6300192, Japan. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov FU National Institute of Meantal Health Intramural Research Program FX Technical support was provided by Milan Rusnak. Support was provided by the National Institute of Meantal Health Intramural Research Program. NR 44 TC 6 Z9 6 U1 2 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2013 VL 110 IS 32 BP 13156 EP 13161 DI 10.1073/pnas.1306342110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196JQ UT WOS:000322771100071 PM 23878240 ER PT J AU Hinck, AP Huang, T AF Hinck, Andrew P. Huang, Tao TI TGF-beta Antagonists: Same Knot, but Different Hold SO STRUCTURE LA English DT Editorial Material ID INSIGHTS C1 [Hinck, Andrew P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Huang, Tao] NCI, Struct Biophys Lab, Frederick, MD 21702 USA. RP Hinck, AP (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM hinck@uthscsa.edu FU NCI NIH HHS [P30 CA054174, R01 CA172886]; NIGMS NIH HHS [R01 GM058670] NR 10 TC 3 Z9 3 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG 6 PY 2013 VL 21 IS 8 BP 1269 EP 1270 DI 10.1016/j.str.2013.07.015 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 198MV UT WOS:000322927900003 PM 23931139 ER PT J AU Nemecek, D Boura, E Wu, WM Cheng, NQ Plevka, P Qiao, J Mindich, L Heymann, JB Hurley, JH Steven, AC AF Nemecek, Daniel Boura, Evzen Wu, Weimin Cheng, Naiqian Plevka, Pavel Qiao, Jian Mindich, Leonard Heymann, J. Bernard Hurley, James H. Steven, Alasdair C. TI Subunit Folds and Maturation Pathway of a dsRNA Virus Capsid SO STRUCTURE LA English DT Article ID RNA BACTERIOPHAGE PHI-6; MINUS-STRAND SYNTHESIS; CRYOELECTRON MICROSCOPY; ANGSTROM RESOLUTION; ATOMIC-STRUCTURE; BINDING-SITES; UCSF CHIMERA; PROTEIN P7; MECHANISM; VISUALIZATION AB The cystovirus phi 6 shares several distinct features with other double-stranded RNA (dsRNA) viruses, including the human pathogen, rotavirus: segmented genomes, nonequivalent packing of 120 subunits in its icosahedral capsid, and capsids as compartments for transcription and replication. phi 6 assembles as a dodecahedral procapsid that undergoes major conformational changes as it matures into the spherical capsid. We determined the crystal structure of the capsid protein, P1, revealing a flattened trapezoid subunit with an alpha-helical fold. We also solved the procapsid with cryo-electron microscopy to comparable resolution. Fitting the crystal structure into the procapsid disclosed substantial conformational differences between the two P1 conformers. Maturation via two intermediate states involves remodeling on a similar scale, besides huge rigid-body rotations. The capsid structure and its stepwise maturation that is coupled to sequential packaging of three RNA segments sets the cystoviruses apart from other dsRNA viruses as a dynamic molecular machine. C1 [Nemecek, Daniel; Wu, Weimin; Cheng, Naiqian; Heymann, J. Bernard; Steven, Alasdair C.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Boura, Evzen; Hurley, James H.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Nemecek, Daniel; Plevka, Pavel] Masaryk Univ, Cent European Inst Technol, Brno 62500, Czech Republic. [Boura, Evzen] Inst Organ Chem & Biochem AS CR, Vvi, Prague 16600 6, Czech Republic. [Plevka, Pavel] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Qiao, Jian; Mindich, Leonard] Univ Med & Dent New Jersey, Publ Hlth Res Inst Ctr, Dept Microbiol, Newark, NJ 07103 USA. RP Steven, AC (reprint author), NIAMSD, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Boura, Evzen/G-5275-2014; Plevka, Pavel/H-8661-2014; OI Plevka, Pavel/0000-0003-4215-3315; Heymann, Bernard/0000-0002-8872-5326 FU NIAMS; NIDDK; IATAP grants; ASCR (RVO) [61388963]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported by the intramural research programs of NIAMS and NIDDK and by IATAP grants (to J.H.H. for E.B. and to A.C.S.) and by ASCR (RVO: 61388963 to E.B.). Crystallographic data were collected at the Southeast Regional Collaborative Access Team 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31-109-Eng-38. NR 51 TC 20 Z9 20 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG 6 PY 2013 VL 21 IS 8 BP 1374 EP 1383 DI 10.1016/j.str.2013.06.007 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 198MV UT WOS:000322927900013 PM 23891288 ER PT J AU Prasad, V AF Prasad, Vinay TI Taking care of sick patients SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 EI 1488-2329 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD AUG 6 PY 2013 VL 185 IS 11 BP 1008 EP 1008 DI 10.1503/cmaj.130047 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 196ZR UT WOS:000322816700037 PM 23877668 ER PT J AU Anderson, ARA Tomlin, CJ Couch, J Gallahan, D AF Anderson, Alexander R. A. Tomlin, Claire J. Couch, Jennifer Gallahan, Dan TI Mathematics of the Integrative Cancer Biology Program SO INTERFACE FOCUS LA English DT Editorial Material DE mathematical oncology; National Cancer Institute; Integrative Cancer Biology Program C1 [Anderson, Alexander R. A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Tomlin, Claire J.] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA. [Couch, Jennifer; Gallahan, Dan] NCI, Div Canc Biol, Rockville, MD 20850 USA. RP Anderson, ARA (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. EM alexander.anderson@moffitt.org RI Anderson, Alexander/A-2713-2011 OI Anderson, Alexander/0000-0002-2536-4383 NR 13 TC 1 Z9 1 U1 0 U2 10 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2042-8898 J9 INTERFACE FOCUS JI Interface Focus PD AUG 6 PY 2013 VL 3 IS 4 SI SI DI 10.1098/rsfs.2013.0023 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 170MA UT WOS:000320853900011 ER PT J AU Tao-Cheng, JH Yang, Y Bayer, KU Reese, TS Dosemeci, A AF Tao-Cheng, J-H. Yang, Y. Bayer, K. U. Reese, T. S. Dosemeci, A. TI EFFECTS OF CaMKII INHIBITOR TATCN21 ON ACTIVITY-DEPENDENT REDISTRIBUTION OF CaMKII IN HIPPOCAMPAL NEURONS SO NEUROSCIENCE LA English DT Article DE synapse; CaMKII inhibitor; tatCN21; polyribosomes; electron microscopy; PSD ID PROTEIN-KINASE-II; POSTSYNAPTIC DENSITY; CA-2+ CALMODULIN; MESSENGER-RNAS; FEAR MEMORY; RAT-BRAIN; SYNAPSES; STORAGE; SPINES AB TatCN21 is a membrane permeable calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor derived from the inhibitor protein CaMKIIN. TatCN21 has been used to demonstrate the involvement of CaMKII in a variety of physiological and pathological phenomena, and it also limits excitotoxic damage in neurons. Here we use preembedding immunogold electron microscopy to examine the effect of tatCN21 on the redistribution of CaMKII in cultured hippocampal neurons. Incubation of cultures with tatCN21 (20 mu M for 20 min) prior to exposure to N-methyl-oasparic acid (NMDA) (50 mu M for 2 min) inhibited both the accumulation of CaMKII at postsynaptic densities (PSDs) and CaMKII clustering in the dendrites. Under these conditions, CaMKII also formed morphologically distinct aggregates with polyribosomes near the PSD and in dendrites. Formation of these CaMKII-polyribosome aggregates requires the presence of both tatCN21 and calcium, and was augmented upon exposure to high K+ or NMDA. CaMKII-polyribosome aggregates formed consistently with 20 mu M tatCN21, but minimally or not at all with 5 mu M. However, these aggregates are not induced by another CaMKII inhibitor, KN93. Formation of CaMKII-polyribosome aggregates was completely reversible within 1 h after washout of tatCN21. Effects of tatCN21 were largely restricted to dendrites, with minimal effect in the soma. The effects of tatCN21 on CaMKII distribution can be used to dissect the mechanism of CaMKII involvement in cellular events. Published by Elsevier Ltd. on behalf of IBRO. C1 [Tao-Cheng, J-H.] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. [Yang, Y.; Reese, T. S.; Dosemeci, A.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Bayer, K. U.] Univ Colorado Denver, Dept Pharmacol, Sch Med, Aurora, CO USA. RP Tao-Cheng, JH (reprint author), 49 Convent Dr,Room 3A50, Bethesda, MD 20892 USA. EM chengs@ninds.nih.gov FU NIH, NINDS; [R01NS052644] FX We thank Christine A. Winters for hippocampal neuronal cultures, Virginia Crocker and Rita Azzam for expert EM technical support, and Dr. Paul Gallant for helpful discussions and the perfusion-fixed brain in Fig. 3D. Supported by the Intramural Research Program of the NIH, NINDS, and by R01NS052644 (to K.U.B.). NR 26 TC 8 Z9 8 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG 6 PY 2013 VL 244 BP 188 EP 196 DI 10.1016/j.neuroscience.2013.03.063 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 163OW UT WOS:000320347800016 PM 23583761 ER PT J AU Dickey, JS Gonzalez, Y Aryal, B Mog, S Nakamura, AJ Redon, CE Baxa, U Rosen, E Cheng, G Zielonka, J Parekh, P Mason, KP Joseph, J Kalyanaraman, B Bonner, W Herman, E Shacter, E Rao, VA AF Dickey, Jennifer S. Gonzalez, Yanira Aryal, Baikuntha Mog, Steven Nakamura, Asako J. Redon, Christophe E. Baxa, Ulrich Rosen, Elliot Cheng, Gang Zielonka, Jacek Parekh, Palak Mason, Karen P. Joseph, Joy Kalyanaraman, Balaraman Bonner, William Herman, Eugene Shacter, Emily Rao, V. Ashutosh TI Mito-Tempol and Dexrazoxane Exhibit Cardioprotective and Chemotherapeutic Effects through Specific Protein Oxidation and Autophagy in a Syngeneic Breast Tumor Preclinical Model SO PLOS ONE LA English DT Article ID RAT MAMMARY-CARCINOMA; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; CARDIAC TROPONIN-T; CELL CLONES; INTERCELLULAR COMMUNICATION; ANTIOXIDANT PROPERTIES; METASTATIC CAPACITY; GROWTH-INHIBITION; SERUM-ALBUMIN; DNA-DAMAGE AB Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-alpha) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of mitochondrially-directed agents to mitigate oxidative stress-induced cardiotoxicity. Our findings also emphasize the novel role of specific protein oxidation markers and autophagic mechanisms for cardioprotection. C1 [Dickey, Jennifer S.; Gonzalez, Yanira; Aryal, Baikuntha; Rosen, Elliot; Mason, Karen P.; Shacter, Emily; Rao, V. Ashutosh] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Mog, Steven] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Nakamura, Asako J.; Redon, Christophe E.; Parekh, Palak; Bonner, William] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Baxa, Ulrich] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Adv Technol Program, Frederick, MD USA. [Cheng, Gang; Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. [Cheng, Gang; Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman] Med Coll Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA. [Herman, Eugene] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Rao, VA (reprint author), US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM ashutosh.rao@fda.hhs.gov RI Zielonka, Jacek/N-9546-2014; Parekh, Palak/B-7042-2015 OI Zielonka, Jacek/0000-0002-2524-0145; Parekh, Palak/0000-0001-9201-5194 FU Food and Drug Administration (FDA) Critical Path Initiative; National Cancer Institute-FDA Interagency Oncology Task Force Fellowship Program; National Cancer Institute [HHSN261200800001E, R01 CA152810] FX The authors would like to acknowledge support from the Food and Drug Administration (FDA) Critical Path Initiative and the National Cancer Institute-FDA Interagency Oncology Task Force Fellowship Program. The electron microscopy work was funded in part from the National Cancer Institute, Contract # HHSN261200800001E. The Mito-Tempol (4) synthesis was supported by a grant from the National Cancer Institute, R01 CA152810. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 21 Z9 22 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e70575 DI 10.1371/journal.pone.0070575 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000090 PM 23940596 ER PT J AU Ho, J Ondos, J Ning, H Smith, S Kreisl, T Iwamoto, F Sul, J Kim, L McNeil, K Krauze, A Shankavaram, U Fine, HA Camphausen, K AF Ho, Jennifer Ondos, John Ning, Holly Smith, Sharon Kreisl, Teri Iwamoto, Fabio Sul, Joohee Kim, Lyndon McNeil, Kate Krauze, Andra Shankavaram, Uma Fine, Howard A. Camphausen, Kevin TI Chemoirradiation for Glioblastoma Multiforme: The National Cancer Institute Experience SO PLOS ONE LA English DT Article ID NEWLY-DIAGNOSED GLIOBLASTOMA; RECURSIVE PARTITIONING ANALYSIS; HIGH-GRADE GLIOMAS; RADIATION-THERAPY; PROGNOSTIC-SIGNIFICANCE; ADJUVANT TEMOZOLOMIDE; VOLUMETRIC-ANALYSIS; MALIGNANT GLIOMAS; PHASE-II; SURVIVAL AB Purpose: Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established. Experimental Design: The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging. Results: At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005. Conclusions: Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients. C1 [Ho, Jennifer; Smith, Sharon; Krauze, Andra; Shankavaram, Uma; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kreisl, Teri; Iwamoto, Fabio; Sul, Joohee; McNeil, Kate; Fine, Howard A.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Ondos, John; Ning, Holly] Radiat Management Associates, Bethesda, MD USA. [Kim, Lyndon] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU National Cancer Institute, NIH FX This work was supported by the intramural research program of the National Cancer Institute, NIH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 4 Z9 6 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e70745 DI 10.1371/journal.pone.0070745 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000128 PM 23940635 ER PT J AU Jacob, ST Pavlinac, PB Nakiyingi, L Banura, P Baeten, JM Morgan, K Magaret, A Manabe, Y Reynolds, SJ Liles, WC Wald, A Joloba, ML Mayanja-Kizza, H Scheld, WM AF Jacob, Shevin T. Pavlinac, Patricia B. Nakiyingi, Lydia Banura, Patrick Baeten, Jared M. Morgan, Karen Magaret, Amalia Manabe, Yuka Reynolds, Steven J. Liles, W. Conrad Wald, Anna Joloba, Moses L. Mayanja-Kizza, Harriet Scheld, W. Michael TI Mycobacterium tuberculosis Bacteremia in a Cohort of HIV-Infected Patients Hospitalized with Severe Sepsis in Uganda-High Frequency, Low Clinical Sand Derivation of a Clinical Prediction Score SO PLOS ONE LA English DT Article ID SUB-SAHARAN AFRICA; DIAGNOSTIC-ACCURACY; SEPTIC SHOCK; ADULTS; IMMUNODEFICIENCY; CONFIRMATION; PREVALENCE; MANAGEMENT; TANZANIA; AREAS AB Background: When manifested as Mycobacterium tuberculosis (MTB) bacteremia, disseminated MTB infection clinically mimics other serious blood stream infections often hindering early diagnosis and initiation of potentially life-saving anti-tuberculosis therapy. In a cohort of hospitalized HIV-infected Ugandan patients with severe sepsis, we report the frequency, management and outcomes of patients with MTB bacteremia and propose a risk score based on clinical predictors of MTB bacteremia. Methods: We prospectively enrolled adult patients with severe sepsis at two Ugandan hospitals and obtained blood cultures for MTB identification. Multivariable logistic regression modeling was used to determine predictors of MTB bacteremia and to inform the stratification of patients into MTB bacteremia risk categories based on relevant patient characteristics. Results: Among 368 HIV-infected patients with a syndrome of severe sepsis, eighty-six (23%) had MTB bacteremia. Patients with MTB bacteremia had a significantly lower median CD4 count (17 vs 64 lymphocytes/mm(3), p<0.001) and a higher 30-day mortality (53% vs 32%, p = 0.001) than patients without MTB bacteremia. A minority of patients with MTB bacteremia underwent standard MTB diagnostic testing (24%) or received empiric anti-tuberculosis therapy (15%). Independent factors associated with MTB bacteremia included male sex, increased heart rate, low CD4 count, absence of highly active anti-retroviral therapy, chief complaint of fever, low serum sodium and low hemoglobin. A risk score derived from a model containing these independent predictors had good predictive accuracy [area under the curve = 0.85, 95% CI 0.80-0.89]. Conclusions: Nearly 1 in 4 adult HIV-infected patients hospitalized with severe sepsis in 2 Ugandan hospitals had MTB bacteremia. Among patients in whom MTB was suspected, standard tests for diagnosing pulmonary MTB were inaccurate for correctly classifying patients with or without bloodstream MTB infection. A MTB bacteremia risk score can improve early diagnosis of MTB bacteremia particularly in settings with increased HIV and MTB co-infection. C1 [Jacob, Shevin T.; Baeten, Jared M.; Liles, W. Conrad; Wald, Anna] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Jacob, Shevin T.] Univ Washington, Int Resp & Severe Illness Ctr INTERSECT, Seattle, WA 98195 USA. [Pavlinac, Patricia B.; Baeten, Jared M.; Wald, Anna] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Nakiyingi, Lydia; Mayanja-Kizza, Harriet] Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda. [Nakiyingi, Lydia] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Banura, Patrick] Masaka Reg Referral Hosp, Masaka, Uganda. [Baeten, Jared M.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Morgan, Karen] Joint Clin Res Ctr, JCRC TB Lab, Mengo, Uganda. [Magaret, Amalia; Wald, Anna] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Magaret, Amalia] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Manabe, Yuka; Reynolds, Steven J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Reynolds, Steven J.; Wald, Anna] Rakai Hlth Sci Program, Kalisizo, Uganda. [Reynolds, Steven J.] NIH, Dept Intramural Res, Bethesda, MD 20892 USA. [Joloba, Moses L.] Makerere Univ, Dept Med Microbiol, Kampala, Uganda. [Scheld, W. Michael] Univ Virginia, Dept Med, Charlottesville, VA USA. RP Jacob, ST (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA. EM sjacob2@uw.edu FU Pfizer, Inc.; Rakai Health Sciences Program through the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [K24 (AI 071113)]; University of Washington STD/AIDS Research Training Program from the National Institutes of Health [T32 (AI007140)] FX Primary funding for the study was from an Investigator-Initiated Award provided by Pfizer, Inc. Pfizer, Inc. had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review or approval of the manuscript. Additional non-grant support was provided by the Rakai Health Sciences Program through the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. In addition, AW is supported by a National Institutes of Health K24 (AI 071113) and PP is supported by the University of Washington STD/AIDS Research Training Program, T32 (AI007140) from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 21 Z9 21 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e70305 DI 10.1371/journal.pone.0070305 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000051 PM 23940557 ER PT J AU Lam, TK Moore, SC Brinton, LA Smith, L Hollenbeck, AR Gierach, GL Freedman, ND AF Lam, Tram Kim Moore, Steve C. Brinton, Louise A. Smith, Llewellyn Hollenbeck, Albert R. Gierach, Gretchen L. Freedman, Neal D. TI Anthropometric Measures and Physical Activity and the Risk of Lung Cancer in Never-Smokers: A Prospective Cohort Study SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; WAIST CIRCUMFERENCE; WOMENS HEALTH; OLDER WOMEN; ASSOCIATION; MORTALITY; DISEASE; FAT; METAANALYSIS; RELIABILITY AB Worldwide, lung cancer in never-smokers is ranked the seventh most common cause of cancer death; however, the etiology of lung cancer in never-smokers is unclear. We investigated associations for body mass index (BMI) at various ages, waist circumference, hip circumference, and physical activity with lung cancer in 158,415 never-smokers of the NIH-AARP Diet and Health Study. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards models. Over 11 years of follow-up, 532 lung cancer cases occurred. The risk estimate for obese (BMI >= 30 kg/m(2)) participants at baseline was 1.21 (95% CI = 0.95-1.53) relative to those with a normal BMI between 18.5 <= BMI<25.0. Overweight (25.0 <= BMI<30.0) at age 18 (HRoverweight-vs-normal = 1.51; 95% CI = 1.01-2.26) and time spent sitting (HR approximate to 3 hrs-vs<3 (hrs) = 1.32; 95% CI = 1.00-1.73) was each associated with lung cancer after adjustment for baseline BMI, as was waist (HRQ4vs-Q1 = 1.75; 95% CI = 1.09-2.79) and hip circumference (HRQ4-vs-Q1 = 0.62; 95% CI = 0.39-0.99), after mutual adjustment for each other and baseline BMI. No associations were observed for vigorous activity or television watching. In summary, using a large prospective cohort study, we found no evidence that BMI at baseline or middle age was associated with decreased lung cancer risk in never smokers. If anything, we observed some evidence for positive associations with a larger BMI or waist circumference. C1 [Lam, Tram Kim] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Moore, Steve C.; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Brinton, Louise A.; Gierach, Gretchen L.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Smith, Llewellyn] Williams Coll, Williamstown, MA 01267 USA. [Hollenbeck, Albert R.] AARP, Org & Tracking Res Dept, Washington, DC USA. RP Lam, TK (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM lamt@mail.nih.gov RI Brinton, Louise/G-7486-2015; Freedman, Neal/B-9741-2015; Moore, Steven/D-8760-2016; Gierach, Gretchen/E-1817-2016 OI Brinton, Louise/0000-0003-3853-8562; Freedman, Neal/0000-0003-0074-1098; Moore, Steven/0000-0002-8169-1661; Gierach, Gretchen/0000-0002-0165-5522 NR 32 TC 13 Z9 13 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e70672 DI 10.1371/journal.pone.0070672 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000114 PM 23940620 ER PT J AU Madsen, DH Jurgensen, HJ Ingvarsen, S Melander, MC Albrechtsen, R Hald, A Holmbeck, K Bugge, TH Behrendt, N Engelholm, LH AF Madsen, Daniel H. Jurgensen, Henrik J. Ingvarsen, Signe Melander, Maria C. Albrechtsen, Reidar Hald, Andreas Holmbeck, Kenn Bugge, Thomas H. Behrendt, Niels Engelholm, Lars H. TI Differential Actions of the Endocytic Collagen Receptor uPARAP/Endo180 and the Collagenase MMP-2 in Bone Homeostasis SO PLOS ONE LA English DT Article ID PLASMINOGEN-ACTIVATOR RECEPTOR; MANNOSE RECEPTOR; MATRIX-METALLOPROTEINASE-2 GENE; MATRIX METALLOPROTEINASES; MULTICENTRIC OSTEOLYSIS; DENATURED COLLAGEN; IV COLLAGENASE; HUMAN BREAST; TUMOR-CELLS; IN-VIVO AB A well-coordinated remodeling of uncalcified collagen matrices is a pre-requisite for bone development and homeostasis. Collagen turnover proceeds through different pathways, either involving extracellular reactions exclusively, or being dependent on endocytic processes. Extracellular collagen degradation requires the action of secreted or membrane attached collagenolytic proteases, whereas the alternative collagen degradation pathway proceeds intracellularly after receptor-mediated uptake and delivery to the lysosomes. In this study we have examined the functional interplay between the extracellular collagenase, MMP-2, and the endocytic collagen receptor, uPARAP, by generating mice with combined deficiency of both components. In both uPARAP-deficient and MMP-2-deficient adult mice the length of the tibia and femur was decreased, along with a reduced bone mineral density and trabecular bone quality. An additional decrease in bone length was observed when combining the two deficiencies, pointing to both components being important for the remodeling processes in long bone growth. In agreement with results found by others, a different effect of MMP-2 deficiency was observed in the distinct bone structures of the calvaria. These membranous bones were found to be thickened in MMP-2-deficient mice, an effect likely to be related to an accompanying defect in the canalicular system. Surprisingly, both of the latter defects in MMP-2-deficient mice were counteracted by concurrent uPARAP deficiency, demonstrating that the collagen receptor does not support the same matrix remodeling processes as the MMP in the growth of the skull. We conclude that both uPARAP and MMP-2 take part in matrix turnover processes important for bone growth. However, in some physiological situations, these two components do not support the same step in the growth process. C1 [Madsen, Daniel H.; Jurgensen, Henrik J.; Ingvarsen, Signe; Melander, Maria C.; Hald, Andreas; Behrendt, Niels; Engelholm, Lars H.] Univ Copenhagen, Rigshosp, Finsen Lab, Biotech Res & Innovat Ctr, DK-2100 Copenhagen, Denmark. [Albrechtsen, Reidar] Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark. [Albrechtsen, Reidar] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. [Holmbeck, Kenn] Natl Inst Dent & Craniofacial Res, Matrix Metalloproteinase Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Madsen, Daniel H.; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD USA. RP Madsen, DH (reprint author), Univ Copenhagen, Rigshosp, Finsen Lab, Biotech Res & Innovat Ctr, DK-2100 Copenhagen, Denmark. EM daniel.madsen@nih.gov OI Albrechtsen, Reidar/0000-0003-4180-1827; Madsen, Daniel Hargboel/0000-0002-3183-6201; Engelholm, Lars/0000-0002-6616-1232 FU Danish Cancer Society; Danish Medical Research Council; Danish Cancer Research Foundation; Novo Nordisk Foundation; Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer); European Community [201279]; Lundbeck Foundation; "Grosserer Alfred Nielsen og Hustrus" foundation; NIDCR; Copenhagen University Hospital; University of Copenhagen, Faculty of Science FX This work was supported by the Danish Cancer Society, the Danish Medical Research Council, the Danish Cancer Research Foundation, the Novo Nordisk Foundation, the Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer) and the European Community's Seventh Framework Programme FP7/2007-2011 under grant agreement no201279 (NB), by the Lundbeck Foundation (NB and LHE), the "Grosserer Alfred Nielsen og Hustrus" foundation (LHE) and by the NIDCR Intramural Research Program (THB and KH). The work was supported by personal grants from Copenhagen University Hospital (DHM and HJJ), the Lundbeck Foundation (DHM) and from the University of Copenhagen, Faculty of Science (SI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 7 Z9 7 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e71261 DI 10.1371/journal.pone.0071261 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000202 PM 23940733 ER PT J AU SanGiovanni, JP Lee, PH AF SanGiovanni, John Paul Lee, Phil H. TI AMD-Associated Genes Encoding Stress-Activated MAPK Pathway Constituents Are Identified by Interval-Based Enrichment Analysis SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MACULAR DEGENERATION; PROTEIN-KINASES; THERAPEUTIC TARGETS; INDUCED RETINOPATHY; UNITED-STATES; JNK; POLYMORPHISMS; PATHOGENESIS; INHIBITION AB Purpose: To determine whether common DNA sequence variants within groups of genes encoding elements of stress-activated mitogen-activated protein kinase (MAPK) signaling pathways are, in aggregate, associated with advanced AMD (AAMD). Methods: We used meta-regression and exact testing methods to identify AAMD-associated SNPs in 1177 people with AAMD and 1024 AMD-free elderly peers from 3 large-scale genotyping projects on the molecular genetics of AMD. SNPs spanning independent AAMD-associated genomic intervals were examined with a multi-locus-testing method (INRICH) for enrichment within five sets of genes encoding constituents of stress-activated MAPK signaling cascades. Results: Four-of-five pathway gene sets showed enrichment with AAMD-associated SNPs; findings persisted after adjustment for multiple testing in two. Strongest enrichment signals (P = 0.006) existed in a c-Jun N-terminal kinase (JNK)/MAPK cascade (Science Signaling, STKE CMP_10827). In this pathway, seven independent AAMD-associated regions were resident in 6 of 25 genes examined. These included sequence variants in: 1) three MAP kinase kinase kinases (MAP3K4, MAP3K5, MAP3K9) that phosphorylate and activate the MAP kinase kinases MAP2K4 and MAP2K7 (molecules that phosphorylate threonine and tyrosine residues within the activation loop of JNK); 2) a target of MAP2K7 (JNK3A1) that activates complexes involved in transcriptional regulation of stress related genes influencing cell proliferation, apoptosis, motility, metabolism and DNA repair; and 3) NR2C2, a transcription factor activated by JNK1A1 (a drugable molecule influencing retinal cell viability in model systems). We also observed AAMD-related sequence variants resident in genes encoding PPP3CA (a drugable molecule that inactivates MAP3K5), and two genes (TGFB2, TGFBR2) encoding factors involved in MAPK sensing of growth factors/cytokines. Conclusions: Linkage disequilibrium (LD)-independent genomic enrichment analysis yielded associations of AAMD with aggregates of functionally related genes encoding constituents of the JNK MAPK signaling pathway. FDA-approved drugs now exist to target constituents of stress-activated MAPK pathways and may offer reasonable approaches to preventing or treating AAMD. C1 [SanGiovanni, John Paul] NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. [Lee, Phil H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit,Ctr Human Genet Res, Boston, MA USA. RP SanGiovanni, JP (reprint author), NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. EM jpsangio@post.harvard.edu FU National Eye Institute FX Funding for NEI-AMD was provided by the National Eye Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e71239 DI 10.1371/journal.pone.0071239 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000199 PM 23940728 ER PT J AU Krug, K Cicmil, N Parker, AJ Cumming, BG AF Krug, Kristine Cicmil, Nela Parker, Andrew J. Cumming, Bruce G. TI A Causal Role for V5/MT Neurons Coding Motion-Disparity Conjunctions in Resolving Perceptual Ambiguity SO CURRENT BIOLOGY LA English DT Article ID DECISION-RELATED ACTIVITY; VISUAL AREA V5/MT; BINOCULAR DISPARITY; STEREOSCOPIC DEPTH; CORTICAL AREA; MT; MACAQUE; MICROSTIMULATION; DIRECTION; CHOICE AB Judgments about the perceptual appearance of visual objects require the combination of multiple parameters, like location, direction, color, speed, and depth. Our understanding of perceptual judgments has been greatly informed by studies of ambiguous figures, which take on different appearances depending upon the brain state of the observer. Here we probe the neural mechanisms hypothesized as responsible for judging the apparent direction of rotation of ambiguous structure from motion (SFM) stimuli. Resolving the rotation direction of SFM cylinders requires the conjoint decoding of direction of motion and binocular depth signals [1, 2]. Within cortical visual area V5/MT of two macaque monkeys, we applied electrical stimulation at sites with consistent multiunit tuning to combinations of binocular depth and direction of motion, while the monkey made perceptual decisions about the rotation of SFM stimuli. For both ambiguous and unambiguous SFM figures, rotation judgments shifted as if we had added a specific conjunction of disparity and motion signals to the stimulus elements. This is the first causal demonstration that the activity of neurons in V5/MT contributes directly to the perception of SFM stimuli and by implication to decoding the specific conjunction of disparity and motion, the two different visual cues whose combination drives the perceptual judgment. C1 [Krug, Kristine; Cicmil, Nela; Parker, Andrew J.] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. [Cumming, Bruce G.] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. RP Krug, K (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Sherrington Bldg, Oxford OX1 3PT, England. EM kristine.krug@dpag.ox.ac.uk RI Parker, Andrew/I-7867-2013; OI Parker, Andrew/0000-0001-5800-0407; Krug, Kristine/0000-0001-7119-9350 FU Wellcome Trust; US National Institutes of Health FX K.K. is a Royal Society University Research Fellow; N.C. held an Usher Cunningham Studentship (DPAG and Exeter College, Oxford). We would like to thank Greg DeAngelis for allowing us to use his data and Rachel Denison for help with the analysis. This work was supported by the Wellcome Trust and the Intramural Research Program of the US National Institutes of Health. NR 31 TC 17 Z9 18 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 5 PY 2013 VL 23 IS 15 BP 1454 EP 1459 DI 10.1016/j.cub.2013.06.023 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198NS UT WOS:000322930200023 PM 23871244 ER PT J AU Lloyd-Smith, JO AF Lloyd-Smith, James O. TI Vacated niches, competitive release and the community ecology of pathogen eradication SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE pathogen eradication; competitive release; ecological niche; monkeypox; zoonosis; emerging infectious disease ID INFECTIOUS-DISEASES; RINDERPEST ERADICATION; MONKEYPOX VIRUS; TRANSMISSIBLE DISEASES; SMALLPOX VACCINATION; POLIO ERADICATION; PUBLIC-HEALTH; EMERGENCE; CONGO; EPIDEMIOLOGY AB A recurring theme in the epidemiological literature on disease eradication is that each pathogen occupies an ecological niche, and eradication of one pathogen leaves a vacant niche that favours the emergence of new pathogens to replace it. However, eminent figures have rejected this view unequivocally, stating that there is no basis to fear pathogen replacement and even that pathogen niches do not exist. After exploring the roots of this controversy, I propose resolutions to disputed issues by drawing on broader ecological theory, and advance a new consensus based on robust mechanistic principles. I argue that pathogen eradication (and cessation of vaccination) leads to a 'vacated niche', which could be re-invaded by the original pathogen if introduced. Consequences for other pathogens will vary, with the crucial mechanisms being competitive release, whereby the decline of one species allows its competitors to perform better, and evolutionary adaptation. Hence, eradication can cause a quantitative rise in the incidence of another infection, but whether this leads to emergence as an endemic pathogen depends on additional factors. I focus on the case study of human monkeypox and its rise following smallpox eradication, but also survey how these ideas apply to other pathogens and discuss implications for eradication policy. C1 [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lloyd-Smith, JO (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, 610 Charles E Young Dr South, Los Angeles, CA 90095 USA. EM jlloydsmith@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU NSF [EF-0928690]; De Logi Chair in Biological Sciences; RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX I thank Petra Klepac, Anne Rimoin, Bryan Grenfell, Peter Hudson, and members of my research group at UCLA for illuminating discussions. I am grateful for the support of NSF grant no. EF-0928690, the De Logi Chair in Biological Sciences, and the RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 81 TC 17 Z9 17 U1 2 U2 36 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD AUG 5 PY 2013 VL 368 IS 1623 SI SI AR UNSP 20120150 DI 10.1098/rstb.2012.0150 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 173XC UT WOS:000321114700013 PM 23798698 ER PT J AU Smith, DL Cohen, JM Chiyaka, C Johnston, G Gething, PW Gosling, R Buckee, CO Laxminarayan, R Hay, SI Tatem, AJ AF Smith, David L. Cohen, Justin M. Chiyaka, Christinah Johnston, Geoffrey Gething, Peter W. Gosling, Roly Buckee, Caroline O. Laxminarayan, Ramanan Hay, Simon I. Tatem, Andrew J. TI A sticky situation: the unexpected stability of malaria elimination SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE malaria elimination; malaria eradication; backwards bifurcation ID SUB-SAHARAN AFRICA; PLASMODIUM-FALCIPARUM INFECTION; COMPETITIVE DISPLACEMENT; WESTERN KENYA; UNITED-STATES; SOUTH-AFRICA; TRANSMISSION; ERADICATION; BURDEN; ENDEMICITY AB Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Elimination's 'stickiness' must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health system's increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria elimination's stickiness at moderate-to-low transmission in areas with well-developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame. C1 [Smith, David L.; Johnston, Geoffrey] Johns Hopkins Bloomberg, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Smith, David L.; Johnston, Geoffrey] Johns Hopkins Bloomberg, Sch Publ Hlth, Malaria Res Inst, Baltimore, MD USA. [Smith, David L.; Chiyaka, Christinah; Johnston, Geoffrey] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Smith, David L.; Laxminarayan, Ramanan] Ctr Dis Dynam Econ & Policy, Washington, DC USA. [Smith, David L.; Hay, Simon I.; Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Cohen, Justin M.] Clinton Hlth Access Initiat, Boston, MA USA. [Gething, Peter W.; Hay, Simon I.] Univ Oxford, Dept Zool, Oxford, England. [Gosling, Roly] Univ Calif San Francisco, Global Hlth Grp, Malaria Eliminat Initiat, San Francisco, CA 94143 USA. [Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. RP Smith, DL (reprint author), Johns Hopkins Bloomberg, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. EM dlsmith@jhsph.edu RI Smith, David/L-8850-2013; Hay, Simon/F-8967-2015; OI Smith, David/0000-0003-4367-3849; Hay, Simon/0000-0002-0611-7272; Cohen,