FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Horvath, A Mathyakina, L Vong, Q Baxendale, V Pang, ALY Chan, WY Stratakis, CA AF Horvath, A Mathyakina, L Vong, Q Baxendale, V Pang, ALY Chan, WY Stratakis, CA TI Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; CELL LUNG-CANCER; SUBUNIT TYPE 1A; CARNEY COMPLEX; REGULATORY SUBUNIT; ALLELIC VARIATION; CANDIDATE GENES; ADRENAL-CORTEX; HIGH-FREQUENCY; TUMORS AB Context: Adrenocortical tumors have been studied at the molecular genetic and cytogenetic levels, but the gene expression profiles of normal and tumor adrenal tissue have not been extensively investigated. Objective: The objective of this study was to obtain information about transcriptome differences in hyperplastic adrenal cells. Design and Patients: We performed serial analysis of gene expression (SAGE) on control adrenal tissue and primary pigmented nodular adrenocortical disease (PPNAD) tissue from two adolescent female patients. Main Outcome Measure: The main outcome measure was to provide quantitative datasets of the vast majority of the transcripts implicated in normal and pathogenic adrenal functioning. Results: The libraries of 28,705 and 31,278 tags represented 14,846 and 16,698 unique mRNAs from the control and PPNAD tissue, respectively. A total of 842 tags from the two libraries did not match any known sequences. We found 127 tags, including 70 no-match tags, to be expressed almost exclusively in control and/or PPNAD adrenals and to be absent or very rare in other human tissues. Examples of well-characterized genes expressed at significantly higher levels in PPNAD included steroidogenic acute regulator, chromogranin A, and those coding for the steroidogenic enzymes P450 cytochromes CYP17A1 and CYP21A2. Pathway analysis revealed Wnt signaling as the most up-regulated in PPNAD. These data were confirmed for selected genes by quantitative RT-PCR and/or immunohistochemistry. Conclusions: This study was the first of its kind for adrenal tissue and provides important information about the adrenal transcriptome and aberrant signaling in an inherited form of adrenocortical hyperplasia. C1 Natl Inst Child Hlth & Human Dev, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Child Hlth & Human Dev, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Natl Inst Child Hlth & Human Dev, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bldg 10,Room 1-1330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU NICHD NIH HHS [Z01 HD 000642-04] NR 59 TC 48 Z9 51 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2006 VL 91 IS 2 BP 584 EP 596 DI 10.1210/jc.2005-1301 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 010CC UT WOS:000235161200038 PM 16278264 ER PT J AU Helliwell, RJA Keelan, JA Marvin, KW Adams, L Chang, MC Anand, A Sato, TA O'Carroll, S Chaiworapongsa, T Romero, RJ Mitchell, MD AF Helliwell, RJA Keelan, JA Marvin, KW Adams, L Chang, MC Anand, A Sato, TA O'Carroll, S Chaiworapongsa, T Romero, RJ Mitchell, MD TI Gestational age-dependent up-regulation of prostaglandin D synthase (PGDS) and production of PGDS-derived antiinflammatory prostaglandins in human placenta SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID JEG3 CHORIOCARCINOMA CELLS; ADHESION MOLECULE-1 ICAM-1; PRO-INFLAMMATORY CYTOKINES; ACTIVATED RECEPTOR-GAMMA; LABOR-ASSOCIATED CHANGES; HUMAN MYOMETRIUM; LIPOCALIN-TYPE; GROWTH-FACTOR; INVITRO CHARACTERIZATION; ALLERGIC INFLAMMATION AB Context: The importance of prostaglandin ( PG) signaling pathways to the maintenance of pregnancy and initiation of labor is well recognized. However, the complexity of these pathways and the mechanism(s) of their coordinated regulation in physiological and pathological conditions are only now being appreciated. Objectives: In this report we provide new evidence of a complete pathway for the biosynthesis and actions of PGD(2) and its metabolites within human gestational tissues. Materials and Methods: Using immunohistochemistry and Northern and Western blotting, we demonstrate the dynamic regulation of H-type PGD synthase (PGDS) in placenta during gestation; in contrast, L-type PGDS and its PG products were detected in amniotic fluid, with increased amounts associated with labor. Results: Placental tissues were shown to express both forms of the PGD(2) receptor identified to date, D prostanoid(1) (DP(1)) and DP(2)/chemotactic receptor on type 2 helper T cells, with a distribution consistent with the villous placenta being a major target, as well as source, of PGD(2). In vitro, placental PGD2 production was shown to be stimulated upon inflammatory activation, whereas PGD(2) and its J series metabolites exerted potent inhibitory effects on placental cytokine production. Conclusions: These findings suggest that PGDS-derived prostanoids play important physiological roles in the placenta, such as immunoregulation and feto-placental communication, while potentially having a regulatory role in the processes of parturition. C1 Univ Auckland, Fac Med & Hlth Sci, Liggins Inst, Auckland, New Zealand. Univ Auckland, Fac Med & Hlth Sci, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand. Univ Auckland, Fac Med & Hlth Sci, Natl Res Ctr Growth & Dev, Auckland, New Zealand. Natl Inst Child Hlth & Human Dev, Perinatal Res Branch, NIH, Detroit, MI 48201 USA. RP Mitchell, MD (reprint author), Univ Auckland, Fac Med & Hlth Sci, Liggins Inst, Private Bag 92019, Auckland, New Zealand. EM m.mitchell@auckland.ac.nz RI Mitchell, Murray/A-8639-2010; Keelan, Jeffrey/G-2170-2011 OI Mitchell, Murray/0000-0002-6167-7176; Keelan, Jeffrey/0000-0002-5403-6266 NR 73 TC 26 Z9 26 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2006 VL 91 IS 2 BP 597 EP 606 DI 10.1210/jc.2005-1982 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 010CC UT WOS:000235161200039 PM 16291703 ER PT J AU Oral, EA Javor, ED Ding, L Uzel, G Cochran, EK Young, JR DePaoli, AM Holland, SM Gorden, P AF Oral, EA Javor, ED Ding, L Uzel, G Cochran, EK Young, JR DePaoli, AM Holland, SM Gorden, P TI Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TUMOR-NECROSIS-FACTOR; IMMUNE-RESPONSE; AUTOIMMUNE ENCEPHALOMYELITIS; GENERALIZED LIPODYSTROPHY; FACTOR-ALPHA; MICE; DEFICIENCY; INFLAMMATION; MONOCYTES; FEMALE AB Context: We conducted this study to understand the role of leptin therapy in immunomodulation. Objective: Our objective was to study lymphocyte subpopulations and in vitro peripheral blood mononuclear cell (PBMC) activation during a study evaluating the effects of leptin on metabolic functions in severe lipodystrophy (serum leptin levels < 4 ng/ml). Design and Setting: We conducted an open-label study with patients serving as their own control at the Clinical Research Center of the National Institutes of Health. Patients: Ten patients (age range, 15-63 yr; one male and nine females) with generalized forms of lipodystrophy were studied. Intervention: Patients were treated with recombinant human leptin to achieve high normal concentrations for 4 to 8 months. Results: Leptin levels increased from 1.8 +/- 0.4 to 16.5 +/- 3.9 ng/dl (P < 0.001), whereas metabolic control improved [glycosylated hemoglobin (HbA(1c)) fell from 9.3 +/- 0.4 to 7.1 +/- 1.4%, P < 0.001, and triglycerides decreased by 45 +/- 11% from a mean of 1490 +/- 710 mg/dl, P = 0.001]. Lymphocyte subsets were studied by flow cytometry at baseline and at 4 and 8 months of therapy. PBMC responsiveness was evaluated by cytokine release and proliferation after stimulation with phytohemagglutinin, phytohemagglutinin plus IL-12, lipopolysaccharide, and lipopolysaccharide plus interferon-gamma at baseline and 4 months. Various T lymphocyte subsets were significantly lower than age- and sex-matched controls at baseline; however, the CD4/CD8 ratio was normal. The relative percentages of B lymphocytes and monocytes were elevated, although the absolute levels were normal. Leptin therapy induced significant changes in T lymphocyte subsets, which normalized both the absolute number of T lymphocyte subsets and relative percentages of all lineages. Additionally, in vitro TNF-alpha secreted from PBMC of patients was significantly increased to normal after 4 months of leptin therapy compared with baseline. Conclusion: These data support existing evidence that leptin has a modest immunomodulatory effect in hypoleptinemic humans. C1 Natl Inst Allergy & Infect Dis, Clin Endocrinol Branch, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Inst Inst Diabet Digest & Kidney Dis, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Lab Clin Infect Dis, Bethesda, MD 20892 USA. Amgen Inc, Thousand Oaks, CA USA. RP Gorden, P (reprint author), Univ Michigan, Dept Internal Med, Div Endocrinol & Metab, E Med Ctr Dr,3920 Taubman Ctr,Box 0354, Ann Arbor, MI 48109 USA. EM PhillipG@intra.niddk.nih.gov OI Oral, Elif/0000-0002-9171-1144 NR 34 TC 30 Z9 32 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2006 VL 91 IS 2 BP 621 EP 628 DI 10.1210/jc.2005-1220 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 010CC UT WOS:000235161200042 PM 16317060 ER PT J AU Ma, CS Pittaluga, S Avery, DT Hare, NJ Maric, I Klion, AD Nichols, KE Tangye, SG AF Ma, CS Pittaluga, S Avery, DT Hare, NJ Maric, I Klion, AD Nichols, KE Tangye, SG TI Selective generation of functional somatically mutated IgM(+)CD27(+), but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SECONDARY LYMPHOID-TISSUES; DOMAIN-CONTAINING PROTEINS; PRIMARY IMMUNE-RESPONSE; HELPER T-CELLS; GERMINAL-CENTERS; SECRETING CELLS; HUMORAL IMMUNITY; AFFINITY MATURATION; ANTIBODY-RESPONSES; ENCODING GENE AB Individuals with X-linked lymphoproliferative disease (XLP) display defects in B cell differentiation in vivo. Specifically, XLP patients do not generate a normal number of CD27(+) memory B cells, and those few that are present are IgM(+). Recent studies have suggested that IgM(+)CD27(+) B cells are not true memory cells, but rather B cells that guard against T cell-independent pathogens. Here we show that human XLP IgM(+)CD27(+) B cells resemble normal memory B cells both morphologically and phenotypically. Additionally, IgM(+)CD27(+) B cells exhibited functional characteristics of normal memory B cells, including the ability to secrete more Ig than naive B cells in response to both T cell-dependent and -independent stimuli. Analysis of spleens from XLP patients revealed a paucity of germinal centers (GCs), and the rare GCs detected were poorly formed. Despite this, Ig variable region genes expressed by XLP IgM(+)CD27(+) B cells had undergone somatic hypermutation to an extent comparable to that of normal memory B cells. These findings reveal a differential requirement for the generation of IgM(+) and Ig isotype-switched memory B cells, with the latter only being generated by fully formed GCs. Production of affinity-matured IgM by IgM(+)CD27(+) B cells may protect against pathogens to which a normal immune response is elicited in XLP patients. C1 Inst Canc Med & Cell Biol, Lymphocyte Differeneiat Lab, Centenary Inst Canc Med & Cell Biol, Newtown, NSW 2042, Australia. Univ Sydney, Dept Expt Med, Sydney, NSW 2006, Australia. NCI, Pathol Lab, Hematopathol Sect, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Bethesda, MD 20892 USA. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Div Pediat Oncol, Philadelphia, PA 19104 USA. RP Tangye, SG (reprint author), Inst Canc Med & Cell Biol, Lymphocyte Differeneiat Lab, Centenary Inst Canc Med & Cell Biol, Locked Bag No 6, Newtown, NSW 2042, Australia. EM s.tangye@centenary.usyd.edu.au RI Ma, Cindy/B-2340-2012; Tangye, Stuart/H-4023-2014; OI Klion, Amy/0000-0002-4986-5326 FU NIAID NIH HHS [U01AI30070, N01AI30070] NR 72 TC 86 Z9 90 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2006 VL 116 IS 2 BP 322 EP 333 DI 10.1172/JCI25720 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 008MA UT WOS:000235043600008 PM 16424938 ER PT J AU Antachopoulos, C Meletiadis, J Roilides, E Sein, T Walsh, TJ AF Antachopoulos, C Meletiadis, J Roilides, E Sein, T Walsh, TJ TI Rapid susceptibility testing of medically important zygomycetes by XTT assay SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID IN-VITRO SUSCEPTIBILITIES; FILAMENTOUS FUNGI; AMPHOTERICIN-B; NCCLS METHOD; POSACONAZOLE; ZYGOMYCOSIS; MUCORMYCOSIS; ITRACONAZOLE; VORICONAZOLE; CASPOFUNGIN AB The XTT colorimetric assay quantifies fungal growth by measuring fungal metabolism and has been used successfully for susceptibility testing of Aspergillus species after 24 and 48 h of incubation. In the present study using 14 clinical isolates of Zygomycetes (Rhizopus oryzae [5 isolates], Cunninghamella spp. [3 isolates], Mucor spp. [3 isolates], and Absidia corymbifera [3 isolates]), significant metabolic activity was demonstrated before visual or spectrophotometric detection of fungal growth by performing the XTT assay as early as 6 h after inoculation. Testing of susceptibility to amphotericin B, posaconazolle, and voriconazolle was subsequently performed using the XTT method (100 mu g/ml XTT, 25 mu M menadione) at 6, 8, or 12 h after inoculation and the CLSI (formerly NCCLS) M38-A method with visual and spectrophotometric MIC determinations at 24 h after inoculation. Concentration-effect curves obtained with the use of the E-max model (a sigmoid curve with variable slope) were comparable between the early XTT and spectrophotometric readings at 24 h. Complete inhibition of early metabolic activity with the azoles was delayed in comparison to that with amphotericin B. Using appropriate cutoff levels, agreement was demonstrated between the early XTT and 24-h spectrophotometric or visual readings. In particular, for MIC-0 (the lowest drug concentration showing absence of visual growth) of amphotericin B, overall agreement levels were 90 to 93% for the 6-h XTT assay and 100% for the 8- and 12-h time points. For MIC-0 of posaconazole, agreement levels were 86% for the 6-h XTT and 93 to 100% for the 8- and 12-h time points. The overall agreement levels for MIC-0 and MIC-2 (the lowest drug concentration showing prominent reduction of growth compared with the control well) of voriconazole (compared with 24-h spectrophotometric readings) were 93 to 98% for the 8- and 12-h XTT assays. These results support the use of the XTT method for rapid MIC determination for Zygomycetes. C1 NCI, Pediat Oncol Branch, CRC, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, CRC, Immunocompromised Host Sect, Rm 1-5750,MSC 1100,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov FU Intramural NIH HHS NR 22 TC 30 Z9 30 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 2006 VL 44 IS 2 BP 553 EP 560 DI 10.1128/JCM.44.2.553-560.2006 PG 8 WC Microbiology SC Microbiology GA 012MV UT WOS:000235344200041 PM 16455912 ER PT J AU Malin, JL Schneider, EC Epstein, AM Adams, J Emanuel, EJ Kahn, KL AF Malin, JL Schneider, EC Epstein, AM Adams, J Emanuel, EJ Kahn, KL TI Results of the national initiative for cancer care quality: How can we improve the quality of cancer care in the United States? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-17, 2005 CL Orlando, FL SP Amer Soc Clin Oncol ID STAGE BREAST-CARCINOMA; OF-CARE; COLORECTAL-CANCER; ONCOLOGY PRACTICE; GUIDELINES; REGISTRIES; OUTCOMES; SYSTEM AB Purpose In 1999, the National Cancer Policy Board called attention to the quality of cancer care in the United States and recommended establishing a quality monitoring system with the capability of regularly reporting on the quality of care for patients with cancer. Methods Using data from a patient survey 4 years after diagnosis and review of medical records, we determined the percentage of stage I to III breast cancer and stage II to III colorectal cancer survivors in five metropolitan statistical areas (MSAs) across the United States who received recommended care specified by a comprehensive set of explicit quality measures. Results Two thousand three hundred sixty-six (63%) of 3,775 eligible patients responded to the survey, and 85% consented to have their medical records reviewed. Our final analytic sample (n = 1,765) included 47% of the eligible patients. Patients with breast and colorectal cancer received 86% of recommended care (95% Cl, 86% to 87%) and 78% of recommended care (95% Cl, 77% to 79%), respectively. Adherence to quality measures was less than 85% for 18 of the 36 breast cancer measures, and significant variation across MSAs was observed for seven quality measures. The percent adherence was less than 85% for 14 of the 25 colorectal cancer measures, and one quality measure demonstrated statistically significant variation across the MSAs. Conclusion Initial management of patients with breast and colorectal cancer in the United States seemed consistent with evidence-based practice; however, substantial variation in adherence to some quality measures point to significant opportunities for improvement. C1 One Amgen Ctr, Thousand Oaks, CA USA. RAND Corp, Santa Monica, CA USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA USA. Harvard Univ, Dept Hlth Policy & Management, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. Brigham & Womens Hosp, Div Gen Med, Sect Hlth Policy, Boston, MA USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD USA. RP Malin, JL (reprint author), One Amgen Ctr, Dr,MS 28-3-A, Thousand Oaks, CA USA. EM jmalin@amgen.com OI Schneider, Eric/0000-0002-1132-5084 NR 27 TC 198 Z9 198 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2006 VL 24 IS 4 BP 626 EP 634 DI 10.1200/JCO.2005.03.3365 PG 9 WC Oncology SC Oncology GA 014QT UT WOS:000235495700016 PM 16401682 ER PT J AU Hyman, J AF Hyman, J TI The importance of assessing confounding and effect modification in research involving periodontal disease and systemic diseases SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Editorial Material ID CIGARETTE-SMOKING C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. RP Hyman, J (reprint author), Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. EM hymanj@email.nidr.nih.gov NR 10 TC 44 Z9 44 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD FEB PY 2006 VL 33 IS 2 BP 102 EP 103 DI 10.1111/j.1600-051X.2005.00881.x PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 007QM UT WOS:000234984400004 PM 16441732 ER PT J AU Ciraulo, DA Hitzemann, RJ Somoza, E Knapp, CM Rotrosen, J Sarid-Segal, O Ciraulo, AM Greenblatt, DJ Chiang, CN AF Ciraulo, DA Hitzemann, RJ Somoza, E Knapp, CM Rotrosen, J Sarid-Segal, O Ciraulo, AM Greenblatt, DJ Chiang, CN TI Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE opioid dependence; partial agonist; naloxone; sublingual ID OPIOID-DEPENDENT HUMANS; RANDOMIZED-TRIAL; ENTEROHEPATIC CIRCULATION; METHADONE-MAINTENANCE; HEROIN DEPENDENCE; NALOXONE; DETOXIFICATION; COMBINATION; NORBUPRENORPHINE; FORMULATIONS AB In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest. C1 Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. Boston Vet Affairs Healthcare Syst, Boston, MA USA. Oregon Hlth Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. Univ Cincinnati, Cincinnati Addict Res Ctr, Cincinnati, OH USA. Cincinnati VA Med Ctr, Cincinnati, OH USA. NYU, Sch Med, Dept Psychiat, New York, NY USA. VA New York Harbor Healthcare, New York, NY USA. Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02111 USA. NIDA, Bethesda, MD 20892 USA. RP Ciraulo, DA (reprint author), Boston Univ, Sch Med, Div Psychiat, Doctors Off Bldg,Suite 914,720 Harrison Ave, Boston, MA 02118 USA. OI Knapp, Clifford/0000-0003-4482-7678; Ciraulo, Domenic/0000-0001-7706-8765 FU NIDA NIH HHS [N01 DA-6-8054, N01 DA-28837, N01 DA-7-8074, N01 DA-4-8306] NR 42 TC 22 Z9 22 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 2006 VL 46 IS 2 BP 179 EP 192 DI 10.1177/0091270005284192 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 005XF UT WOS:000234859000007 PM 16432270 ER PT J AU Conway, KP Compton, W Stinson, FS Grant, BF AF Conway, KP Compton, W Stinson, FS Grant, BF TI Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: Results from the national epidemiologic survey on alcohol and related conditions SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; PSYCHIATRIC-DISORDERS; UNITED-STATES; III-R; MENTAL-DISORDERS; ICD-10 ALCOHOL; RELIABILITY; DEPENDENCE; DIAGNOSES AB Objective: To present nationally representative data on the lifetime prevalence and comorbidity of 8 specific drug use disorders, separately for abuse and dependence, and mood and anxiety disorders. Method: Data come from a representative sample (N = 43,093) of the United States civilian, noninstitutional population 18 years and older. Diagnoses of mood, anxiety, and drug Use disorders were based upon face-to-face personal interviews using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version (AUDADIS-IV). Results: Associations between specific mood and anxiety disorders and specific drug use disorders were virtually all positive and statistically significant (p < .05). In general, associations were greater for dependence than abuse. greater for mood than anxiety disorders, and in some instances stronger among women than men (p < .05). Large odds ratios also were observed tor individuals with comorbid mood and anxiety disorders. Conclusion: The comorbidity between specific mood and anxiety disorders and specific drug use disorders is pervasive in the U.S. population. Findings suggest that comorbid psychiatric disorders may increase the risk of greater involvement in more serious illicit drug use disorders and that the greater comorbidity between mood and anxiety and drug use disorders among women may reflect greater deviance and psychopathology among drug-using women than men. Findings also suggest that drug abuse prevention and intervention efforts should address other psychiatric conditions. Further. definitions of drug use disorder phenotypes should give careful consideration to other psychiatric conditions as meaningful characteristics of case heterogeneity. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Bethesda, MD 20892 USA. Natl Inst Drug Abuse, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Rm 3077,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov OI Conway, Kevin/0000-0002-7638-339X NR 35 TC 325 Z9 334 U1 4 U2 37 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2006 VL 67 IS 2 BP 247 EP 257 PG 12 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 020SP UT WOS:000235931000011 PM 16566620 ER PT J AU Kang, MS Park, MS Kwon, SW Ma, SA Cho, DY Kim, DY Kim, Y AF Kang, MS Park, MS Kwon, SW Ma, SA Cho, DY Kim, DY Kim, Y TI Amyloid-producing odontogenic tumour (Calcifying epithelial odontogenic tumour) in the mandible of a bengal tiger (Panthera tigris tigris) SO JOURNAL OF COMPARATIVE PATHOLOGY LA English DT Article DE amyloid; mandible; odontogenic tumour; tiger; tumour ID CATS; DOG; AMELOBLASTOMA AB A 13-year-old male tiger (Panthera tigris tigris) had a marked mandibular swelling noticed 12 months earlier and associated with progressive anorexia and weight loss. Radiological and post-mortem examination revealed a mass (13 X 15 cm) which was Firm and poorly defined, with destruction of the adjacent bone tissue. Histologically, the mass was poorly demarcated, with infiltrative growth, and composed of nests, cords and islands of epithelial cells with characteristic basal cell features. Also observed were extensive squamous metaplasia, ghost cells, stellate reticulum, and fibroblastic connective tissue stroma containing inflammatory cells. A prominent feature of this tumour consisted of abundant nodular deposits of congophilic amyloid-like material with partial mineralization (Liesegang rings). Immunohistochemistry, the neoplastic cells and the amyloid-like material were positive for pancytokeratin and negative for vimentin. The findings supported tire diagnosis of an amyloid-producing odontogenic tumour (APOT), also known as calcifying epithelial odontogenic tumour in man and animals. (c) 2005 Published by Elsevier Ltd. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Seoul Natl Univ, Coll Vet Med, Dept Vet Pathol, Seoul 151742, South Korea. Everland Zool Gardens, Yongin 449715, Gyounggi, South Korea. Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Baton Rouge, LA 70803 USA. RP Kim, Y (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 14 TC 7 Z9 7 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0021-9975 J9 J COMP PATHOL JI J. Comp. Pathol. PD FEB-APR PY 2006 VL 134 IS 2-3 BP 236 EP 240 DI 10.1016/j.jcpa.2005.09.004 PG 5 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 039VR UT WOS:000237336100014 PM 16540113 ER PT J AU Roma, PG Silberberg, A Ruggiero, AM Suomi, SJ AF Roma, Peter G. Silberberg, Alan Ruggiero, Angela M. Suomi, Stephen J. TI Capuchin monkeys, inequity aversion, and the frustration effect SO JOURNAL OF COMPARATIVE PSYCHOLOGY LA English DT Article DE capuchin monkey; Cebus apella; inequity aversion; frustration effect ID ECONOMICS; CONTRAST; CHOICE AB Each of 4 female capuchin monkeys ("model") was paired with another female capuchin ("witness") in an adjacent cage. In Phases I and 3, a model could remove a grape from the experimenter's hand while the witness watched. The witness was then offered a slice of cucumber, a less preferred food. Trials alternated between subjects 50 times, defining a session. In Phases 2 and 4, both were offered cucumber. Witness rejections of cucumber were infrequent and were not dependent on whether models received grape or cucumber. When models were offered cucumber, they rejected it at higher rates than did witnesses. These results fail to support findings of Brosnan and de Waal. An account based on the frustration effect accommodates these results and those of Brosnan and de Waal. C1 American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. NICHHD, Comparat Ethol Lab, Bethesda, MD USA. RP Roma, PG (reprint author), American Univ, Dept Psychol, Psychopharmacol Lab, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM PeteRoma@gmail.com NR 19 TC 71 Z9 75 U1 2 U2 11 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7036 J9 J COMP PSYCHOL JI J. Comp. Psychol. PD FEB PY 2006 VL 120 IS 1 BP 67 EP 73 DI 10.1037/0735-7036.120.1.67 PG 7 WC Behavioral Sciences; Psychology; Psychology, Multidisciplinary; Zoology SC Behavioral Sciences; Psychology; Zoology GA 071LR UT WOS:000239604200008 PM 16551166 ER PT J AU Silberberg, A Roma, PG Ruggiero, AM Suomi, SJ AF Silberberg, Alan Roma, Peter G. Ruggiero, Angela M. Suomi, Stephen J. TI On inequity aversion in nonhuman primates SO JOURNAL OF COMPARATIVE PSYCHOLOGY LA English DT Article DE inequity aversion; frustration effect; capuchin monkeys; Cebus apella AB P. G. Roma, A. Silberberg, A. M. Ruggiero, and S. J. Suomi (2006) noted that the results S. F. Brosnan and F. B. M. de Waal (2003) attributed to inequity aversion could also be explained as a frustration effect. Roma et al. redressed this confound by designing a procedure that could have supported either of these interpretations. Nevertheless, they found that only a frustration effect accounted for both their data and those of Brosnan and de Waal (2003). The criticisms Brosnan and de Waal (2006) offered of Roma et al. ignored the fact that Brosnan and de Waal's (2003) research design was not capable of offering an unequivocal demonstration of inequity aversion. This conclusion holds no matter what the claimed inadequacies of Roma et al.'s procedures might have been. Caution is urged in inferring the existence of inequity aversion in nonhuman primates. C1 American Univ, Dept Psychol, Washington, DC 20016 USA. NICHHD, Comparat Ethol Lab, Bethesda, MD USA. RP Roma, PG (reprint author), American Univ, Dept Psychol, 4400 Massacusetts Ave NW, Washington, DC 20016 USA. EM PeteRoma@gmail.com NR 3 TC 3 Z9 3 U1 2 U2 7 PU AMER PSYCHOLOGICAL ASSOC/EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7036 J9 J COMP PSYCHOL JI J. Comp. Psychol. PD FEB PY 2006 VL 120 IS 1 BP 76 EP 76 DI 10.1037/0735-7036.120.1.76 PG 1 WC Behavioral Sciences; Psychology; Psychology, Multidisciplinary; Zoology SC Behavioral Sciences; Psychology; Zoology GA 071LR UT WOS:000239604200010 PM 16551168 ER PT J AU Hastings, WA Yingling, YG Chirikjian, GS Shapiro, BA AF Hastings, WA Yingling, YG Chirikjian, GS Shapiro, BA TI Structural and dynamical classification of RNA single-base bulges for nanostructure design SO JOURNAL OF COMPUTATIONAL AND THEORETICAL NANOSCIENCE LA English DT Article DE RNA structural motif; RNA bulge; molecular dynamics; RNA design ID 5S RIBOSOMAL-RNA; DOUBLE-STRANDED-RNA; A-MINOR MOTIF; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; CONFORMATIONAL-ANALYSIS; 3-DIMENSIONAL STRUCTURES; GENERALIZED BORN; EXTENDED DUPLEX; DNA AB A comprehensive examination of the bulge motif is presented for a set of twenty single-base bulge structures obtained from the Protein Data Bank. Examples of the bulge motif found in X-ray-crystal and NMR structures are analyzed using molecular dynamics simulations. Three classes of the single-base bulge motif are defined according to the bulge residue type, and its surrounding base-pairs. The first class contains bulges in a stacked conformation, while the other two classes have the bulge predominantly or exclusively in a looped-out conformation. In the first class the bulges participate in hydrogen bond interactions with one of the neighboring base-pairs. While this modifies the backbone of the structure, the overall backbone shape typically remains relatively constant due to the absence of distal bonding across the helix grooves. In contrast, most of the bulges in the looped-out conformations (second and third class) create a more flexible and a more distinctive kink or induced bending along the backbone. In the second class, the orientation of bulge bases depends on their type and surrounding sequences, whereas the third class contains only cytosine bulges that prefer to remain exclusively in the looped-out conformation. An ultimate goal of this study is to utilize the bulge classes and the structural characteristics of the bulges for the design of RNA-bulge-based nanotemplates. C1 NCI, Ctr Canc Res Nanobiol, NCI Frederick, Frederick, MD 21702 USA. Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res Nanobiol, NCI Frederick, Frederick, MD 21702 USA. RI Yingling, Yaroslava/B-2901-2008; Chirikjian, Gregory/A-3314-2010 OI Yingling, Yaroslava/0000-0002-8557-9992; NR 60 TC 4 Z9 5 U1 0 U2 1 PU AMER SCIENTIFIC PUBLISHERS PI STEVENSON RANCH PA 25650 NORTH LEWIS WAY, STEVENSON RANCH, CA 91381-1439 USA SN 1546-1955 J9 J COMPUT THEOR NANOS JI J. Comput. Theor. Nanosci. PD FEB PY 2006 VL 3 IS 1 BP 63 EP 77 PG 15 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 012AK UT WOS:000235310400005 ER PT J AU Miura, K Optican, LM AF Miura, K Optican, LM TI Membrane channel properties of premotor excitatory burst neurons may underlie saccade slowing after lesions of omnipause neurons SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE Hodgkin-Huxley; eye movements; model; RIP; raphe interpositus nucleus; NMDA receptors; glycine; glutamate; saccades ID PONTINE RETICULAR-FORMATION; ALERT SQUIRREL-MONKEY; MOUSE-BRAIN NEURONS; EYE-MOVEMENTS; SUPERIOR COLLICULUS; DISTRIBUTED MODEL; HYPOTHETICAL EXPLANATION; PREPOSITUS-HYPOGLOSSI; RECEPTOR CURRENTS; CALCIUM-CHANNELS AB Chemical lesions of the brain stem region containing glycinergic omnipause neurons (OPNs) cause saccade slowing with no change in latency. To explore the mechanisms responsible for this deficit, simulation studies were performed with a conductance-based model of premotor excitatory burst neurons (EBNs) that incorporated multiple membrane channels, including the T-type calcium channel. The peak speed of a normal saccade was determined by the T- and NMDA currents in EBNs after the OPNs shut off. After OPN lesions, the model made slow saccades, because the EBN activity was lower than normal due to a reduced T-current (caused by the loss of hyperpolarization), and a reduced NMDA current (caused by a reduced glycine concentration around the receptors). Thus, we propose that two biophysical mechanisms are responsible for saccade slowing after OPN lesions: reduced T-current and reduced NMDA current, both of which are caused by the loss of glycine from OPNs. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Dept Integrat Brain Sci, Kyoto 6068501, Japan. RP Optican, LM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. EM LanceOptican@nih.gov NR 62 TC 32 Z9 32 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD FEB PY 2006 VL 20 IS 1 BP 25 EP 41 DI 10.1007/s10827-006-4258-y PG 17 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 038BS UT WOS:000237193500002 PM 16511656 ER PT J AU Che, Y Brooks, BR Marshall, GR AF Che, Ye Brooks, Bernard R. Marshall, Garland R. TI Development of small molecules designed to modulate protein-protein interactions SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Review DE conformational analysis; drug design; peptidomimetics; protein-protein interaction; protein-surface mimetics; privileged scaffold; template design ID CIS AMIDE BOND; SHORT TEMPLATED PEPTIDES; DE-NOVO DESIGN; REVERSE-TURN CONSTRAINTS; ALPHA-HELIX FORMATION; N-TERMINAL TEMPLATES; PROLINE-RICH MOTIFS; BETA-D-GLUCOSE; CONFORMATIONAL-ANALYSIS; AMINO-ACIDS AB Protein-protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein-protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the "privileged-structure hypothesis" [Che, Ph.D. Thesis, Washington University, 2003] - that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists - to address the challenges inherent in the discovery of small-molecule inhibitors of protein-protein interactions. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Washington Univ, Ctr Computat Biol, St Louis, MO 63110 USA. Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Che, Y (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM chey@nhlbi.nih.gov RI Che, Ye/A-3449-2008; OI Marshall, Garland/0000-0002-3098-0332 FU Intramural NIH HHS; NIGMS NIH HHS [GM 68460] NR 165 TC 48 Z9 49 U1 2 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD FEB PY 2006 VL 20 IS 2 BP 109 EP 130 DI 10.1007/s10822-006-9040-8 PG 22 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA 053YQ UT WOS:000238342700004 PM 16622794 ER PT J AU Hatakeyama, J Philp, D Hatakeyama, Y Haruyama, N Shum, L Aragon, MA Yuan, Z Gibson, CW Sreenath, T Kleinman, HK Kulkarni, AB AF Hatakeyama, J Philp, D Hatakeyama, Y Haruyama, N Shum, L Aragon, MA Yuan, Z Gibson, CW Sreenath, T Kleinman, HK Kulkarni, AB TI Amelogenin-mediated regulation of osteoclastogenesis, and periodontal cell proliferation and migration SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE amelogenins; LRAP; osteoclastogenesis; knockout mice ID ENAMEL MATRIX PROTEINS; GENE SPLICE PRODUCTS; KAPPA-B LIGAND; RECEPTOR ACTIVATOR; LIGAMENT CELLS; MODEL; DIFFERENTIATION; AMELOBLASTS; CULTURE; MICE AB We previously reported that amelogenin isoforms M180 and leucine-rich amelogenin peptide ( LRAP) are expressed in the periodontal region, and that their absence is associated with increased cementum defects in amelogenin-knockout ( KO) mice. The aim of the present study was to characterize the functions of these isoforms in osteoclastogenesis and in the proliferation and migration of cementoblast/periodontal ligament cells. The co-cultures of wild-type (WT) osteoclast progenitor and KO cementoblast/periodontal ligament cells displayed more tartrate-resistant acid phosphatase (TRAP)-positive cells than the co-cultures of WT cells. The addition of LRAP to both co-cultures significantly reduced RANKL expression and the TRAP-positive cells. Proliferation and migration rates of the KO cementoblast/periodontal ligament cells were lower than those of WT cells and increased with the addition of either LRAP or P172 (a porcine homolog of mouse M180). Thus, we demonstrate the regulation of osteoclastogenesis by LRAP, and the proliferation and migration of cementoblast/periodontal ligament cells by LRAP and P172. C1 Natl Inst Dent & Craniofacial Res, Funct Genom Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Cell Biol Sect, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. NIAMSD, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD USA. Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, NIH, 30 Convent Dr,MSC 4395,Bldg 30,Room 122, Bethesda, MD 20892 USA. EM ak40m@nih.gov RI Haruyama, Naoto/D-1993-2011 OI Haruyama, Naoto/0000-0001-6225-5816 FU Intramural NIH HHS; NIDCR NIH HHS [DE 011089] NR 24 TC 41 Z9 44 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD FEB PY 2006 VL 85 IS 2 BP 144 EP 149 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 005RQ UT WOS:000234841900006 PM 16434732 ER PT J AU Balla, T AF Balla, T TI Phosphoinositide-derived messengers in endocrine signaling SO JOURNAL OF ENDOCRINOLOGY LA English DT Review ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; PLECKSTRIN-HOMOLOGY-DOMAIN; G-BETA-GAMMA; PHOSPHATIDYLINOSITOL TRANSFER PROTEIN; OXYSTEROL-BINDING-PROTEIN; CAPACITATIVE CA2+ ENTRY; HAMSTER OVARY CELLS; PHOSPHOLIPASE-C; PLASMA-MEMBRANE; LIGAND-BINDING AB One of the fundamental questions in endocrinology is how circulating or locally produced homones affect target cell functions by activating specific receptors linked to numerous signal-transduction pathways. Art important subset of G protein-coupled cell-surface receptors can activate phospholipase C enzymes to hydrolyze a small but critically important class of phospholipids, the phosphomositides. Although this signaling pathway has been extensively explored over the last 20 years, this has proven to be only the tip of the iceberg, and the multiplicity and diversity of the cellular functions controlled by phosphoinositides have surpassed any imagination. Phospho-inositides have been found to be key regulators of ion channels and transporters, and controllers of vesicular trafficking, and the transport of lipids between intracellular membranes. Essentially, the), organize the recruitment and regulation of signaling protein complexes in specific membrane compartments. While many of these processes have been classically studied by cell biologists, molecular eudocrinology cannot ignore these recent advances, and now needs to integrate the cell biologist's views in the modem concept of how hormones affect cell functions artd how derailment of simple molecular events can lead to complex endocrine and metabolic disorders. C1 NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Balla, T (reprint author), NICHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A35,49 Convent Dr, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov OI Balla, Tamas/0000-0002-9077-3335 FU Intramural NIH HHS NR 207 TC 56 Z9 57 U1 0 U2 6 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD FEB PY 2006 VL 188 IS 2 BP 135 EP 153 DI 10.1677/joe.1.06595 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 013YE UT WOS:000235445100001 PM 16461542 ER PT J AU Ayotte, JD Baris, D Cantor, KP Colt, J Robinson, GR Lubin, JH Karagas, M Hoover, RN Fraumeni, JF Silverman, DT AF Ayotte, JD Baris, D Cantor, KP Colt, J Robinson, GR Lubin, JH Karagas, M Hoover, RN Fraumeni, JF Silverman, DT TI Bladder cancer mortality and private well use in New England: an ecological study SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID RURAL NEW-ENGLAND; DRINKING-WATER; UNITED-STATES; POPULATION; EXPOSURE; REGION AB Study objective: To investigate the possible relation between bladder cancer mortality among white men and women and private water use in New England, USA, where rates have been persistently raised and use of private water supplies (wells) common. Design: Ecological study relating age adjusted cancer mortality rates for white men and women during 1985 - 1999 and proportion of persons using private water supplies in 1970. After regressing mortality rates on population density, Pearson correlation coefficients were computed between residual rates and the proportion of the population using private water supplies, using the state economic area as the unit of calculation. Calculations were conducted within each of 10 US regions. Setting: The 504 state economic areas of the contiguous United States. Participants: Mortality analysis of 11 cancer sites, with the focus on bladder cancer. Main results: After adjusting for the effect of population density, there was a statistically significant positive correlation between residual bladder cancer mortality rates and private water supply use among both men and women in New England (men, r = 0.42; women, r = 0.48) and New York/ New Jersey (men, r = 0.49; women, r = 0.62). Conclusions: Use of well water from private sources, or a close correlate, may be an explanatory variable for the excess bladder cancer mortality in New England. Analytical studies are underway to clarify the relation between suspected water contaminants, particularly arsenic, and raised bladder cancer rates in northern New England. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. US Geol Survey, New Hampshire Vermont Water Sci Ctr, Pembroke, NH USA. US Geol Survey, Natl Ctr, Reston, VA 22092 USA. Dartmouth Coll, Sch Med, Lebanon, NH 03756 USA. RP Cantor, KP (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS-8106, Bethesda, MD 20892 USA. EM cantork@nih.gov FU Intramural NIH HHS NR 29 TC 26 Z9 26 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD FEB PY 2006 VL 60 IS 2 BP 168 EP 172 DI 10.1136/jech.2005.038620 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 002ZR UT WOS:000234651900017 PM 16415269 ER PT J AU Buchholz, DR Paul, BD Shi, YB AF Buchholz, DR Paul, BD Shi, YB TI Gene-specific function of thyroid hormone receptor during development in the frog Xenopus laevis SO JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-COMPARATIVE EXPERIMENTAL BIOLOGY LA English DT Meeting Abstract CT 15th International Congress of Comparative Endocrinology CY MAY 22-27, 2005 CL Boston, MA SP Amer Head & Neck Soc C1 NICHD, Lab Gene Regulat & Dev, Bethesda, MD USA. EM dbuchholz@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1548-8969 J9 J EXP ZOOL PART A JI J. Exp. Zool. Part A PD FEB 1 PY 2006 VL 305A IS 2 BP 114 EP 114 PG 1 WC Zoology SC Zoology GA 012MX UT WOS:000235344400031 ER PT J AU Green, ED AF Green, ED TI Comparative genome sequencing: Using evolution to decode the human genome SO JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-COMPARATIVE EXPERIMENTAL BIOLOGY LA English DT Meeting Abstract CT 15th International Congress of Comparative Endocrinology CY MAY 22-27, 2005 CL Boston, MA SP Amer Head & Neck Soc C1 NHGRI, NIH, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1548-8969 J9 J EXP ZOOL PART A JI J. Exp. Zool. Part A PD FEB 1 PY 2006 VL 305A IS 2 BP 129 EP 129 PG 1 WC Zoology SC Zoology GA 012MX UT WOS:000235344400093 ER PT J AU Menon, JG Buchholz, D AF Menon, JG Buchholz, D TI Hormones, oxidative stress and tissue remodeling during anuran metamorphosis. SO JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-COMPARATIVE EXPERIMENTAL BIOLOGY LA English DT Meeting Abstract CT 15th International Congress of Comparative Endocrinology CY MAY 22-27, 2005 CL Boston, MA SP Amer Head & Neck Soc C1 NIH, Bethesda, MD 20892 USA. William Paterson Univ New Jersey, Wayne, NJ USA. EM menonj@wpunj.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1548-8969 J9 J EXP ZOOL PART A JI J. Exp. Zool. Part A PD FEB 1 PY 2006 VL 305A IS 2 BP 155 EP 155 PG 1 WC Zoology SC Zoology GA 012MX UT WOS:000235344400195 ER PT J AU Shi, Q Ganguly, S Coon, SL Aitken, A Weller, JL Schram, V Klein, DC AF Shi, Q Ganguly, S Coon, SL Aitken, A Weller, JL Schram, V Klein, DC TI Characterization of the 14-3-3 family in rat pineal gland SO JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-COMPARATIVE EXPERIMENTAL BIOLOGY LA English DT Meeting Abstract CT 15th International Congress of Comparative Endocrinology CY MAY 22-27, 2005 CL Boston, MA SP Amer Head & Neck Soc C1 NIH, Bethesda, MD 20892 USA. Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. EM shiq@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1548-8969 J9 J EXP ZOOL PART A JI J. Exp. Zool. Part A PD FEB 1 PY 2006 VL 305A IS 2 BP 176 EP 176 PG 1 WC Zoology SC Zoology GA 012MX UT WOS:000235344400280 ER PT J AU Gross, CP Filardo, G Singh, HS Freedman, AN Farrell, MH AF Gross, CP Filardo, G Singh, HS Freedman, AN Farrell, MH TI The relation between projected breast cancer risk, perceived cancer risk, and mammography use - Results from the National Health Interview Survey SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE breast cancer; screening; mammography; risk assessment ID FAMILY-HISTORY; REPEAT MAMMOGRAPHY; WOMEN; CHEMOPREVENTION; SURVEILLANCE; PREVALENCE; PERCEPTION; TAMOXIFEN; DIAGNOSIS; OLDER AB BACKGROUND: Although the use of mammography on at regular intervals can save lives, not all women obtain the repeat mammography recommended in guidelines. OBJECTIVE: To assess the associations between routine mammography use, perceived cancer risk, and actual projected cancer risk. METHODS: We include women who were 45 to 75 years of age and who had responded to the 2000 National Health Interview Survey. Women who reported that they believed their risk of getting cancer in the future was "medium" or "high" were considered jointly as "medium/high-risk perception.""Routine mammography use" was defined as having >= 3 mammograms in the previous 6 years. We used logistic regression to determine the independent relation between cancer risk perception, projected breast cancer risk, and routine mammography use. RESULTS: Of the 6,002 women who met our inclusion criteria, 63.1% reported routine mammography use. About 76% of women in the highest quartile of projected breast cancer risk reported routine mammography use, compared with only 68%, 64%, and 51% in the third, second, and first quartiles, respectively (P <.001 chi-square test for trend). After adjusting for indicators of access to care, sociodemographic and behavioral factors, and perceived cancer risk, women in the highest quartiles of projected cancer risk were significantly more likely to report routine mammogram use than women in the lowest quartile (odds ratio [OR] of women in third and fourth quartiles were 1.57 [1.24 to 1.99], and 2.23 [1.73 to 2.87] vs the lowest quartile, respectively). Women with a higher perceived cancer risk were significantly more likely to undergo routine mammography (adjusted OR: 1.29 [1.12 to 1.48] P=.001). Cancer risk perceptions tended to be higher among women who were younger age, obese, smokers, depressed, or reported one of the following breast cancer risk factors: family breast cancer history, prior abnormal mammogram, and early age at menarche. CONCLUSION: Actual and perceived risk were independent predictors of routine mammography use, suggesting that efforts to incorporate risk profiles into clinical decision making may need to involve more than just relaying information about projected risks to patients, but also to explore how risk perceptions can be affected by this information. C1 Yale Univ, Sch Med, Primary Care Ctr, Dept Med,Sect Gen Internal Med, New Haven, CT 06520 USA. Baylor Hlth Care Syst, Inst Hlth Care Res & Improvement, Dallas, TX USA. So Methodist Univ, Dept Stat Sci, Dallas, TX 75275 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Med Coll Wisconsin, Div Gen Internal Med, Madison, WI USA. RP Gross, CP (reprint author), Yale Univ, Sch Med, Primary Care Ctr, Dept Med,Sect Gen Internal Med, 333 Cedar St,POB 208025, New Haven, CT 06520 USA. EM cary.gross@yale.edu OI Farrell, Michael/0000-0002-2842-0205 FU NCI NIH HHS [1K07CA-90402, K07 CA090402]; NHLBI NIH HHS [7K01HL7253001]; NIA NIH HHS [P30 AG021342, P30AG21342] NR 42 TC 28 Z9 28 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2006 VL 21 IS 2 BP 158 EP 164 DI 10.1111/j.1525-1497.2005.00312.x PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 019WK UT WOS:000235867800013 PM 16390511 ER PT J AU Kaiser, WJ Chaudhry, Y Sosnovtsev, SV Goodfellow, IG AF Kaiser, WJ Chaudhry, Y Sosnovtsev, SV Goodfellow, IG TI Analysis of protein-protein interactions in the feline calicivirus replication complex SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID DEPENDENT RNA-POLYMERASE; VIRUS-RNA; NONSTRUCTURAL PROTEIN; ENDOPLASMIC-RETICULUM; VIRAL PROTEIN; DISEASE VIRUS; LINKAGE MAP; VPG; POLIOVIRUS; IDENTIFICATION AB Caliciviruses are a major cause of gastroenteritis in humans and cause a wide variety of other diseases in animals. Here, the characterization of protein-protein interactions between the individual proteins of Feline calicivirus (FCV), a model system for other members of the family Caliciviridae, is reported. Using the yeast two-hybrid system combined with a number of other approaches, it is demonstrated that the p32 protein (the picornavirus 2B analogue) of FCV interacts with p39 (2C), p30 (3A) and p76 (3CD). The FCV protease/RNA polymerase (ProPol) p76 was found to form homo-oligomers, as well as to interact with VPg and ORF2, the region encoding the major capsid protein VP1. A weak interaction was also observed between p76 and the minor capsid protein encoded by ORF3 (VP2). ORF2 protein was found to interact with VPg, p76 and VP2. The potential roles of the interactions in calicivirus replication are discussed. C1 Univ Reading, Sch Biol Sci, Reading RG6 6AJ, Berks, England. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Goodfellow, IG (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Virol, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM I.Goodfellow@ic.ac.uk OI Goodfellow, Ian/0000-0002-9483-510X FU Wellcome Trust [, 069526] NR 35 TC 26 Z9 30 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD FEB PY 2006 VL 87 BP 363 EP 368 DI 10.1099/vir.0.81456-0 PN 2 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 006OM UT WOS:000234906800014 PM 16432023 ER PT J AU Anlauf, M Schafer, MKH Schwark, T von Wurmb-Schwark, N Brand, V Sipos, B Horny, HP Parwaresch, R Hartschuh, W Eiden, LE Kloppel, G Weihe, E AF Anlauf, M Schafer, MKH Schwark, T von Wurmb-Schwark, N Brand, V Sipos, B Horny, HP Parwaresch, R Hartschuh, W Eiden, LE Kloppel, G Weihe, E TI Vesicular monoamine transporter 2 (VMAT2) expression in hematopoietic cells and in patients with systemic mastocytosis SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE chronic myeloproliferative disease; histamine mast cell; mastocytosis; tryptase; vesicular monoamine transporter ID MAST-CELLS; AMINE TRANSPORTER; NEUROTRANSMITTER TRANSPORTERS; GENERALIZED MASTOCYTOSIS; DIFFERENTIAL EXPRESSION; NEUROENDOCRINE TUMORS; ENDOCRINE TUMORS; NERVOUS-SYSTEM; HISTAMINE; LYMPHOCYTES AB Uptake of monoamines into secretory granules is mediated by the vesicular monoamine transporters VMAT1 and VMAT2. In this study, we analyzed their expression in inflammatory and hematopoietic cells and in patients suffering from systemic mastocytosis (SM) and chronic myelogenous leukemia (CIVIL). Normal human and monkey tissue specimens and tissues from patients suffering from SM and CIVIL were analyzed by means of immunohistochemistry, radioactive in situ hybridization, real time RT-PCR, double fluorescence confocal laser scanning microscopy, and immunoelectron microscopy. In normal tissue specimens, VMAT2, but not VMAT1, was expressed in mast cells, megakaryocytes, thrombocytes, basophil granulocytes, and cutaneous Langerhans cells. Further hematopoietic and lymphoid cells showed no expression of VMATs. VMAT2 was expressed in all types of SM, as indicated by coexpression with the mast cell marker tryptase. In CIVIL, VMAT2 expression was retained in neoplastic megakaryocytes and basophil granulocytes. In conclusion, the identification of VMAT2 in mast cells, megakaryocytes, thrombocytes, basophil granulocytes, and cutaneous Langerhans cells provides evidence that these cells possess molecular mechanisms for monoamine storage and handling. VMAT2 identifies normal and neoplastic mast cells, megakaryocytes, and basophil granulocytes and may therefore become a valuable tool for the diagnosis of mastocytosis and malignant systemic diseases involving megakaryocytes and basophil granulocytes. C1 Univ Kiel, Dept Pathol, D-24105 Kiel, Germany. Univ Kiel, Dept Anat, D-24105 Kiel, Germany. Univ Kiel, Dept Forens Med, D-24105 Kiel, Germany. Univ Kiel, Dept Hematopathol, D-24105 Kiel, Germany. Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, Marburg, Germany. Med Univ Lubeck, Dept Pathol, D-23538 Lubeck, Germany. Univ Heidelberg, Dept Dermatol, D-6900 Heidelberg, Germany. NIMH, Mol Neurosci Sect, Lab Cell & Mol Regulat, Bethesda, MD 20892 USA. RP Anlauf, M (reprint author), Univ Kiel, Dept Pathol, Michaelisstr 11, D-24105 Kiel, Germany. EM manlauf@path.uni-kief.de RI von Wurmb-Schwark, Nicole/E-4857-2010; Schwark, Thorsten/E-6321-2010; OI Eiden, Lee/0000-0001-7524-944X NR 65 TC 20 Z9 20 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD FEB PY 2006 VL 54 IS 2 BP 201 EP 213 DI 10.1369/jhc.5A6739.2005 PG 13 WC Cell Biology SC Cell Biology GA 007PP UT WOS:000234981900009 PM 16116033 ER PT J AU Burgess, SJ Marusina, AI Pathmanathan, I Borrego, F Coligan, JE AF Burgess, SJ Marusina, AI Pathmanathan, I Borrego, F Coligan, JE TI IL-21 down-regulates NKG2D/DAP10 express on human NK and CD8(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COMMON GAMMA-CHAIN; CUTTING EDGE; TUMOR REJECTION; NKG2D RECEPTOR; MIC LIGANDS; IN-VIVO; ACTIVATION; IMMUNORECEPTOR; INTERLEUKIN-21; IL-15 AB IL-21 is a recently described cytokine, produced by activated Th cells, that shares significant homology with members of the IL-2 family of cytokines. IL-21 mediates its biological effects via the IL-21R in conjunction with the common receptor gamma-chain that is also shared by members of the IL-2 family. We report that culture of human primary NK and CD8(+) T cells with IL-21 in combination with IL-2 results in significant reduction of the cell surface expression of NKG2D, compared with that in cells treated with IL-2 alone. The reduced expression of NKG2D after IL-21 culture had functional consequences for NK cell function, as assessed by NKG2D-mediated redirected lysis assays and degranulation assays, compared with NK cells treated with IL-2 alone. IL-21-mediated NKG2D down-regulation in human NK cells correlated with a marked reduction of DNAX-activating protein of 10 kDa (DAP10) transcription in cells treated with IL-2 in combination with IL-21 compared with cells stimulated with only IL-2. This was attributed to a dramatic reduction in DAP10 promoter activity, as assessed by a DAP10 luciferase reporter construct. In contrast to NKG2D expression, IL-21 was able to induce the expression, of the NK activation receptors NKp30 and 2134 as well as the costimulatory receptor CD28 on CD8(+) T cells. These data indicate that IL-21 is able to channel NK and CD8(+) T cell function by altering the expression pattern of activation/costimulatory receptors. C1 NIAID, Receptor Cell Biol Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Lab Allerg Dis, NIH, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov FU Intramural NIH HHS NR 47 TC 69 Z9 75 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2006 VL 176 IS 3 BP 1490 EP 1497 PG 8 WC Immunology SC Immunology GA 004QF UT WOS:000234766600026 PM 16424177 ER PT J AU Cuss, AK Avery, DT Cannons, JL Yu, LJ Nichols, KE Shaw, PJ Tangye, SG AF Cuss, AK Avery, DT Cannons, JL Yu, LJ Nichols, KE Shaw, PJ Tangye, SG TI Expansion of functionally immature transitional B cells is associated with human-immunodeficient states characterized by impaired humoral immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LINKED LYMPHOPROLIFERATIVE-DISEASE; COMMON VARIABLE IMMUNODEFICIENCY; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BONE-MARROW-TRANSPLANTATION; HEAT-STABLE ANTIGEN(HI); CENTER FOUNDER CELLS; HUMAN SPLEEN; INCREASED FREQUENCY; SOMATIC MUTATION; SECRETING CELLS AB X-linked lymphoproliferative disease (XLP) is a severe immunodeficiency associated with a marked reduction in circulating memory B cells. Our investigation of the B cell compartment of XLP patients revealed an increase in the frequency of a population of B cells distinct from those previously defined. This population displayed increased expression of CD10, CD24, and CD38, indicating that it could consist of circulating immature/transitional B cells. Supporting this possibility, CD10(+) CD24(high) CD38(high) B cells displayed other immature characteristics, including unmutated Ig V genes and elevated levels of surface IgM; they also lacked expression of Bcl-2 and a panel of activation molecules. The capacity of CD24(high) CD38(high) B cells to proliferate, secrete Ig, and migrate in vitro was greatly reduced compared with mature B cell populations. Moreover, CD24(high) CD38(high) B cells were increased in the peripheral blood of neonates, patients with common variable immunodeficiency, and patients recovering from hemopoietic stem cell transplant. Thus, an expansion of functionally immature B cells may contribute to the Immoral immunodeficient state that is characteristic of neonates, as well as patients with XLP or common variable immunodeficiency, and those recovering from a stem cell transplant. Further investigation of transitional B cells will improve our understanding of human B cell development and how alterations to this process may precipitate immunodeficiency or autoimmunity. C1 Centenary Inst Canc Med & Cell Biol, Newtown, NSW 2042, Australia. Univ Sydney, Dept Expt Med, Sydney, NSW 2006, Australia. Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD 20892 USA. Childrens Hosp, Div Pediat Oncol, Philadelphia, PA 19104 USA. Chindrens Hosp, Oncol Unit, Westmead, NSW, Australia. RP Tangye, SG (reprint author), Centenary Inst Canc Med & Cell Biol, Locked Bag 6, Newtown, NSW 2042, Australia. EM s.tangye@centenary.usyd.edu.au RI Tangye, Stuart/H-4023-2014 NR 61 TC 123 Z9 125 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2006 VL 176 IS 3 BP 1506 EP 1516 PG 11 WC Immunology SC Immunology GA 004QF UT WOS:000234766600028 PM 16424179 ER PT J AU Duverger, A Jackson, RJ van Ginkel, FW Fischer, R Tafaro, A Leppla, SH Fujihashi, K Kiyono, H McGhee, JR Boyaka, PN AF Duverger, A Jackson, RJ van Ginkel, FW Fischer, R Tafaro, A Leppla, SH Fujihashi, K Kiyono, H McGhee, JR Boyaka, PN TI Bacillus anthracis edema toxin acts as an adjuvant for mucosal immune responses to nasally administered vaccine antigens SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; LABILE ENTERO-TOXIN; CHOLERA-TOXIN; ESCHERICHIA-COLI; LETHAL TOXIN; PROTECTIVE ANTIGEN; MEDIATED DELIVERY; ADAPTIVE IMMUNITY; PROTEIN ANTIGENS; DENDRITIC CELLS AB Anthrax edema toxin (EdTx) is an AB-type toxin that binds to anthrax toxin receptors on target cells via the binding subunit, protective Ag (PA). Edema factor, the enzymatic A subunit of EdTx, is an adenylate cyclase. We found that nasal delivery of EdTx enhanced systemic immunity to nasally coadministered OVA and resulted in high OVA-specific plasma IgA and IgG (mainly IgG1 and IgG2b). The edema factor also enhanced immunity to the binding PA subunit itself and promoted high levels of plasma IgG and IgA responses as well as neutralizing PA Abs. Mice given OVA and EdTx also exhibited both PA- and OVA-specific IgA and IgG Ab responses in saliva as well as IgA Ab responses in vaginal washes. EdTx as adjuvant triggered OVA- and PA-specific CD4(+) T cells which secreted IFN-gamma and selected Th2-type cytokines. The EdTx up-regulated costimulatory molecule expression by APCs but was less effective than cholera toxin for inducing IL-6 responses either by APCs in vitro or in nasal washes in vivo. Finally, nasally administered EdTx did not target CNS tissues and did not induce IL-1 mRNA responses in the nasopharyngeal-associated lymphoepithelial tissue or in the olfactory bulb epithelium. Thus, EdTx derivatives could represent an alternative to the ganglioside-binding enterotoxin adjuvants and provide new tools for inducing protective immunity to PA-based anthrax vaccines. C1 Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Pediat Dent, Birmingham, AL 35294 USA. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Inst Med Sci, Dept Microbiol & Immunol, Div Mucosal Immunol, Tokyo, Japan. RP Boyaka, PN (reprint author), Univ Alabama, Dept Microbiol, 722 Bevill BIomed Res Bldg,845 19th St S, Birmingham, AL 35294 USA. EM prosper@uab.edu FU NIAID NIH HHS [AI 18958, AI43197]; NIDCD NIH HHS [DC 04976]; NIDCR NIH HHS [DE 12242]; NIDDK NIH HHS [DK 44240] NR 64 TC 41 Z9 44 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2006 VL 176 IS 3 BP 1776 EP 1783 PG 8 WC Immunology SC Immunology GA 004QF UT WOS:000234766600057 PM 16424208 ER PT J AU Sospedra, M Muraro, PA Stefanova, I Zhao, YD Chung, K Li, YL Giulianotti, M Simon, R Mariuzza, R Pinilla, C Martin, R AF Sospedra, M Muraro, PA Stefanova, I Zhao, YD Chung, K Li, YL Giulianotti, M Simon, R Mariuzza, R Pinilla, C Martin, R TI Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; MYELIN BASIC-PROTEIN; MAJOR HISTOCOMPATIBILITY COMPLEX; STRUCTURAL BASIS; PEPTIDE-BINDING; CRYSTAL-STRUCTURE; CROSS-REACTIVITY; ZETA-CHAIN; TCR; RECOGNITION AB The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4(+) T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of live in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes > 30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction. C1 NIAID, Cellular Immunol Sect, Neuroimmunol Branch, Natl Inst Neurol Disorders & Stroke,NIH, Bethesda, MD 20892 USA. NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Computat & Syst Biol Grp, Biometr Res Branch, NIH, Rockville, MD 20852 USA. Univ Maryland, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. Mixture Sci, San Diego, CA 92121 USA. Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. RP Martin, R (reprint author), Hosp Univ Vall Hebron, Institutio Catalana Recerca & Estudis Avancats, Unitat Neuroimmunol Clin, Pg Vall Hebron 119-129, Barcelona 08035, Spain. EM roland.martin@icrea.es FU NIAID NIH HHS [R37 AI036900-14, R37 AI036900, R37 AI036900-12] NR 61 TC 31 Z9 31 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2006 VL 176 IS 3 BP 1951 EP 1961 PG 11 WC Immunology SC Immunology GA 004QF UT WOS:000234766600076 PM 16424227 ER PT J AU Mbulaiteye, SM Walters, M Engels, EA Bakaki, PM Ndugwa, CM Owor, AM Goedert, JJ Whitby, D Biggar, RJ AF Mbulaiteye, SM Walters, M Engels, EA Bakaki, PM Ndugwa, CM Owor, AM Goedert, JJ Whitby, D Biggar, RJ TI High levels of Epstein-Barr virus DNA in saliva and peripheral blood from Ugandan mother-child pairs SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 8th International Conference on Malignancies in AIDS and Other Immunodeficiencies CY APR 29-30, 2004 CL Bethesda, MD ID SARCOMA-ASSOCIATED HERPESVIRUS; SICKLE-CELL-DISEASE; HUMAN-HERPESVIRUS-8 INFECTION; LYMPHOPROLIFERATIVE DISEASE; NASOPHARYNGEAL CARCINOMA; QUANTIFICATION; MALARIA; TIME AB In Africa, Epstein-Barr virus (EBV) is associated with Burkitt lymphoma. We measured levels of EBV DNA in saliva and buffy coats from 233 asymptomatic Ugandan children with sickle cell disease and their mothers by quantitative real-time polymerase chain reaction. EBV DNA was detected in saliva from 90% of the children ( median [interquartile range {IQR}] level, 5.2 [4.2-6.0] log(10) copies/mL of saliva) and 79% of the mothers ( median [ IQR] level, 4.8 [3.7-5.6] log(10) copies/mL of saliva) (). EBV DNA was detected in buffy coats P < 001 from 86% of the children ( median [ IQR] level, 2.5 [2.2-2.9] log(10) copies/peripheral white blood cells 6 1 x 10 [PWBCs]) and 72% of the mothers ( median [ IQR] level, 2.7 [2.4-3.1] log(10) copies/1 x 10(6) PWBCs) (P = .24 Detection of EBV DNA in saliva was positively correlated with detection in buffy coats. EBV DNA was detected more frequently in saliva and buffy coats than was human herpesvirus 8 DNA. Our results indicate that EBV infection persists, with virus readily detectable in saliva and buffy coats from persons without apparent symptoms in Africa. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD USA. NCI, Viral Epidemiol Sect, AIDS Vaccine Program, Sci Applicat Int Corp, Frederick, MD 21701 USA. Makerere Univ, Sch Med, Kampala, Uganda. Mulago Hosp, Kampala, Uganda. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Execut Plaza S,Room 8006, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov FU NCI NIH HHS [N02-CP-91027]; PHS HHS [N01-C0-12400] NR 15 TC 33 Z9 35 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2006 VL 193 IS 3 BP 422 EP 426 DI 10.1086/499277 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 005NL UT WOS:000234831000012 PM 16388490 ER PT J AU Yao, K Hisada, M Maloney, E Yamano, Y Hanchard, B Wilks, R Rios, M Jacobson, S AF Yao, K Hisada, M Maloney, E Yamano, Y Hanchard, B Wilks, R Rios, M Jacobson, S TI Human T lymphotropic virus types I and II Western blot seroindeterminate status and its association with exposure to prototype HTLV-I SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; CELL LEUKEMIA; NEUROLOGICAL DISEASE; PLASMODIUM-FALCIPARUM; CEREBROSPINAL-FLUID; CENTRAL-AFRICA; CD8(+) CELLS; RISK-FACTORS; SAO-PAULO; FOLLOW-UP AB Human T lymphotropic virus types I and II (HTLV-I/II) Western blot (WB) seroindeterminate status, which is defined as an incomplete banding pattern of HTLV protein Gag (p19 or p24) or Env (GD21 or rgp46), is commonly observed. To investigate the significance of this finding, we examined HTLV-I/II serostatus and HTLV-I proviral load in 2 groups of individuals with WB seroindeterminate status. Low proviral loads were detected in 42% of patients with neurologic symptoms and 44% of voluntary blood donors. These data suggest that a subset of WB seroindeterminate individuals may be infected with prototype HTLV-I. To confirm this hypothesis, we evaluated HTLV-I/II serostatus and proviral load in prospectively collected specimens from 66 WB seronegative patients who had received HTLV-I-infected blood products by transfusion. Eight individuals developed WB seroindeterminate profiles after the transfusion. In addition, using a human leukocyte antigen type A*201-restricted HTLV-I Tax11-19 tetramer, we detected virus-specific CD8(+) T cells in peripheral blood mononuclear cells from WB seroindeterminate patients. These CD8+ T cells were effective at targeting HTLV-I-infected cells. Collectively, the results suggest that HTLV-I/II WB seroindeterminate status may reflect a history of HTLV- I exposure. Our findings warrant further investigation of the possible clinical outcomes associated with WB seroindeterminate status. C1 NINDS, Neuroimmunol Branch, NIH, Viral Immunol Sect, Bethesda, MD 20892 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. US FDA, Rockville, MD 20857 USA. Univ W Indies, Mona Kingston, Jamaica. RP Jacobson, S (reprint author), NINDS, Neuroimmunol Branch, NIH, Viral Immunol Sect, 9000 Rockville Pike,Bldg 10,Ste 5N214, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 40 TC 14 Z9 15 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2006 VL 193 IS 3 BP 427 EP 437 DI 10.1086/499273 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 005NL UT WOS:000234831000013 PM 16388491 ER PT J AU Yang, Q Yamada, A Kimura, S Peters, JM Gonzalez, FJ AF Yang, Qian Yamada, Atsushi Kimura, Shioko Peters, Jeffrey M. Gonzalez, Frank J. TI Alterations in skin and stratified epithelia by constitutively activated PPAR alpha SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID NUCLEAR HORMONE-RECEPTORS; GENE-EXPRESSION; KERATINOCYTE DIFFERENTIATION; EPIDERMAL DIFFERENTIATION; PEROXISOME PROLIFERATORS; MOUSE KERATINOCYTES; CELL-PROLIFERATION; GAMMA ACTIVATORS; MAMMALIAN-CELLS; FATTY-ACIDS AB Peroxisome proliferator-activated receptor (PPAR)alpha is a pleiotropic regulator in many cell types and has recently been implicated in skin homeostasis. To determine the role of PPAR alpha in skin physiology, transgenic mice were generated using the tetracycline Tet-off regulatory system to target constitutively activated PPAR alpha to the epidermis and other stratified epithelia by the bovine keratin K5 promoter. Expression of the transgene during early development resulted in postnatal lethality within 2 days after birth. A thin epidermis, few hair follicles, and abnormal development of the tongue were observed in neonatal transgenic mice. Early mortality was not observed when transgenic PPAR a expression was diminished by administration of doxycycline (dox) to the mothers. The alterations noted in neonatal mice were not observed in adult mice upon re-expression of the PPAR alpha transgene by withdrawing dox. Attenuated hyperplasia of interfollicular epidermis after topical application of the tumor promotor 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was observed in adult mice expressing the PPAR alpha transgene. In addition, expression of the PPAR alpha transgene in mammary gland during pregnancy resulted in abnormal development of this organ and impaired lactation. Further investigations using primary keratinocytes revealed that expression of the transgene in keratinocytes resulted in increased differentiation and decreased proliferation, which may contribute to the observed phenotype in the transgenic mice. Thus, these results indicate that PPAR alpha plays an important role in the development of stratified epithelia including skin, tongue, and mammary gland. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Vet Sci, University Pk, PA 16802 USA. Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3106B, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Peters, Jeffrey/D-8847-2011 FU Intramural NIH HHS; NCI NIH HHS [CA89607, CA97999] NR 64 TC 17 Z9 17 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2006 VL 126 IS 2 BP 374 EP 385 DI 10.1038/sj.jid.5700056 PG 12 WC Dermatology SC Dermatology GA 062TV UT WOS:000238968400020 PM 16374467 ER PT J AU Lim, YJ Kim, YW Choe, YH Ki, CS Park, SK AF Lim, YJ Kim, YW Choe, YH Ki, CS Park, SK TI Risk factor analysis for development of asymptomatic carotid stenosis in Koreans SO JOURNAL OF KOREAN MEDICAL SCIENCE LA English DT Article DE carotid stenosis; atherosclerosis; risk factors ID ATHEROSCLEROSIS; DISEASE; FRAMINGHAM; STROKE AB Many risk factors for atherosclerosis have been proposed to identify high risk individuals. We conducted a retrospective study to determine the risk factors for development of carotid stenosis (CS) in Koreans. Database of 2,805 subjects who underwent a check up of carotid artery for health examination were analyzed. Stenosis (%) of common carotid artery or proximal internal carotid artery was examined with ultrasonography. Subjects were divided into 2 groups (Group I; CS <10%, Group II; CS >= 30%). We compared demographic, laboratory and clinical data between 2 groups to determine the risk factors of CS. One hundred ninety seven subjects (7.0%) were categorized as Group II. At age- and sex-adjusted multivariate analysis, diabetes mellitus, hypertension, cerebrovascular disease, ischemic heart disease, hyperlipidemia, aspirin medication, current smoking, fasting glucose, total cholesterol, low density lipoprotein-cholesterol (LDL-C) and leukocyte count were significant risk factors of CS. At stepwise logistic regression analysis, age, hypertension, hyperlipidemia, LDL-C and leukocyte count were independent risk factors. At subgroup analysis by smoking, age and leukocyte count were independent risk factors in smoker and age and hypertension in nonsmoker. C1 Sungkyunkwan Univ Sch Med, Samsung Med Ctr, Dept Surg, Div Vasc Surg, Seoul 135710, South Korea. Dongguk Univ Coll Med, Dongguk Univ Int Hosp, Dept Internal Med, Goyang, South Korea. Sungkyunkwan Univ Sch Med, Samsung Med Ctr, Dept Radiol, Seoul 135710, South Korea. Sungkyunkwan Univ Sch Med, Samsung Med Ctr, Dept Lab Med, Ctr Imaging Sci, Seoul 135710, South Korea. Konkuk Univ Coll Med, Dept Prevent Med, Chungju, South Korea. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kim, YW (reprint author), Sungkyunkwan Univ Sch Med, Samsung Med Ctr, Dept Surg, Div Vasc Surg, 50 Irwon Dong, Seoul 135710, South Korea. EM ywkim@smc.samsung.co.kr RI Ki, Chang Seok/C-9599-2011; Park, Sue Kyung/J-2757-2012; ki, cs/O-5931-2014; OI Ki, Chang-Seok/0000-0001-7679-8731 NR 15 TC 3 Z9 3 U1 0 U2 3 PU KOREAN ACAD MEDICAL SCIENCES PI SEOUL PA 302 75 DONG DU ICHON, DONG YONGSAN KU, SEOUL 140 031, SOUTH KOREA SN 1011-8934 J9 J KOREAN MED SCI JI J. Korean Med. Sci. PD FEB PY 2006 VL 21 IS 1 BP 15 EP 19 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 017LB UT WOS:000235694000004 PM 16479058 ER PT J AU Wagner, S Law, MP Riemann, B Pike, VW Breyholz, HJ Holtke, C Faust, A Renner, C Schober, O Schafers, M Kopka, K AF Wagner, S Law, MP Riemann, B Pike, VW Breyholz, HJ Holtke, C Faust, A Renner, C Schober, O Schafers, M Kopka, K TI Synthesis of an F-18-labelled high affinity beta(1)-adrenoceptor PET radioligand based on ICI 89,406 SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE ICI 89,406 derivative; beta(1)-adrenoceptor selective ligand; PET radioligand ID POSITRON-EMISSION-TOMOGRAPHY; SELECTIVE BETA-1-ADRENOCEPTOR LIGAND; CARDIAC SYMPATHETIC INNERVATION; BETA-ADRENOCEPTOR ANTAGONIST; ADRENERGIC-RECEPTOR DENSITY; HEART-FAILURE; IN-VIVO; CARDIOMYOPATHY; ICI-89,406; CGP-12177 AB To date, some non-selective beta-adrenoceptor (beta-AR) positron emission tomography (PET) radioligands are in clinical use, but no PET radioligand for the selective imaging of cardiac beta(1)-ARs is clinically available. Therefore, the aim of this study was to develop a potential high-affinity PET radioligand for the beta(1)-subtype of ARs. Here, the synthesis and in vitro evaluation of (S)- and (R)-N-[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl-N'-[4-(2-fluoro-ethoxy)-phenyl]-urea (8a-b), derivatives of the well-characterized beta(1)-AR selective antagonist, ICI 89,406, are described. The (S)-isomer 8a shows both higher beta(1)-AR selectivity and beta(1)-AR affinity than the (R)-enantiomer 8b (selectivity: 40800 vs 1580; affinity: K-11 = 0.049 nM vs K-11 = 0.297 nM). Therefore, the F-18-labelled analogue 8e of compound 8a was synthesized. While the direct nucleophilic F-18-fluorination of the tosylate precursor 8d produced 8e in low radiochemical yields (<= 2.9% decay-corrected) and specific activities (<= 3.5 GBq/mu mol at the end of synthesis (EOS), n = 9) the alternative two-step synthesis of 8e from ethylene glycol di-p-tosylate 9, [F-18]fluoride ion and phenol precursor 8f gave satisfying results (16.4 +/- 3.2% radiochemical yield (decay-corrected), 99.7 +/- 0.5% radiochemical purity, 40 +/- 8 GBq/mu mol specific activity at the EOS within 174 +/- 3 min from the end of bombardment (EOB) (n = 5)). Copyright (c) 2006 John Wiley & Sons, Ltd. C1 Univ Hosp Munster, Dept Nucl Med, D-48149 Munster, Germany. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Interdisciplinary Ctr Clin Res IZKF Munster, D-48149 Munster, Germany. RP Wagner, S (reprint author), Univ Hosp Munster, Dept Nucl Med, Albert Schweitzer Str 33, D-48149 Munster, Germany. EM stwagner@uni-muenster.de RI Schober, Otmar/A-8670-2008 NR 46 TC 9 Z9 9 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD FEB PY 2006 VL 49 IS 2 BP 177 EP 195 DI 10.1002/jlcr.1037 PG 19 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 021IM UT WOS:000235976900011 ER PT J AU Teleshova, N Kenney, J Williams, V Van Nest, G Marshall, J Lifson, JD Sivin, I Dufour, J Bohm, R Gettie, A Pope, M AF Teleshova, N. Kenney, J. Williams, V. Van Nest, G. Marshall, J. Lifson, J. D. Sivin, I. Dufour, J. Bohm, R. Gettie, A. Pope, M. TI CpG-C ISS-ODN activation of blood-derived B cells from healthy and chronic immunodeficiency virus-infected macaques SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE B lymphocyte; immunostimulation; primate; SIV ID PLASMACYTOID DENDRITIC CELLS; IMMUNE-DEFICIENCY-SYNDROME; DOUBLE-STRANDED-RNA; PBL-SCID MICE; IN-VIVO; RHESUS MACAQUES; IFN-ALPHA; T-CELLS; MONOCLONAL-ANTIBODIES; ENVELOPE GLYCOPROTEIN AB Cytosine-phosphate-guanine class C (CpG-C) immunostimulatory sequence oligodeoxy-nucleotides (ISS-ODNs) activate human B cells and dendritic cells (DCs), properties that suggest potential use as a novel adjuvant to enhance vaccine efficacy. After demonstrating that the CpG-C ISS-ODN C274 activates macaque DCs, we examined in vitro activation of macaque B cells by C274 as a prelude to evaluation of this molecule as an adjuvant in the testing of candidate human immunodeficiency virus vaccines in the rhesus macaque-simian immunodeficiency virus (SIV) model. C274 induced macaque CD20(+) B cells to proliferate more strongly than CD40 ligand or CpG-B ISS-ODN. C274 enhanced B cell survival; increased viability was most evident after 3-7 days of culture. Increased expression of CD40, CD80, and CD86 by B cells was apparent within 24 h of exposure to C274 and persisted for up to 1 week. C274-stimulated, B cell-enriched and peripheral blood mononuclear cell suspensions from naive and immunodeficiency virus-infected monkeys secreted several cytokines [e.g., interleukin (IL)-3, IL-6, IL-12, interferon-alpha] and chemokines [e.g., monocyte chemoattractant protein-1/CC chemokine ligand 2 (CCL2), macrophage-inflammatory protein-1 alpha/CCL3, IL-8/CXC chemokine ligand 8]. In comparison, exposure of macaque B cells to SIV had minimal impact on surface phenotype, despite inducing cytokine and chemokine production in cells from infected and uninfected animals. These observations emphasize the need to identify strategies to optimally boost immune function, as immunodeficiency viruses themselves only partially activate B cells and DCs. The ability of C274 to stimulate B cells and DCs in healthy and infected monkeys suggests its possible use as a broad-acting adjuvant to be applied in the rhesus macaque model for the development of preventative and therapeutic vaccines. C1 Populat Council, Ctr Biomed Res, New York, NY 10021 USA. Dynavax Technol, Berkeley, CA USA. NCI, Sci Applicat Int Corp, AIDS Vaccine Program, Frederick, MD 21701 USA. Tulane Univ, Tulane Natl Primate Res Ctr, New Orleans, LA 70118 USA. Aaron Diamond AIDS Res Ctr, New York, NY USA. RP Pope, M (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM rnpope@popcouncil.org FU NCI NIH HHS [N01-CO-12400]; NCRR NIH HHS [RR00164]; NIAID NIH HHS [R01 AI040877, R21 AI060405]; NIDCR NIH HHS [DE016256] NR 89 TC 17 Z9 18 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2006 VL 79 IS 2 BP 257 EP 267 DI 10.1189/jlb.0205084 PG 11 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 119LX UT WOS:000243014900001 PM 16443827 ER PT J AU Kulka, M Fukuishi, N Rottem, M Mekori, YA Metcalfe, DD AF Kulka, Marianna Fukuishi, Nobuyuki Rottem, Menachem Mekori, Yoseph A. Metcalfe, Dean D. TI Mast cells, which interact with Escherichia coli, up-regulate genes associated with innate immunity and become less responsive to Fc epsilon RI-mediated activation SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE IgE; MIP-3 beta; CCL-19; CCL-18 ID FACTOR-ALPHA RESPONSE; CLASS-II MOLECULES; MHC CLASS-II; IFN-GAMMA; IN-VIVO; EXPRESSION; RECEPTORS; INFECTION; CHEMOKINE; IL-10 AB Mast cells, which are associated with T helper cell type 2-dependent inflammation, have now been implicated in the innate immune response. To further characterize how mast cells are programmed to respond to infectious organisms, we used expression profiling using DNA microarray analysis of gene expression by human mast cells (huMC) during ingestion of Escherichia coli and examined immunoglobulin E (IgE)-mediated degranulation. Analysis of data revealed that specific groups of genes were modulated, including genes encoding transcription factors, cell signaling molecules, cell cycle regulators, enzymes, cytokines, novel chemokines of the CC family, adhesion molecules, and costimulatory molecules. Enzyme-linked immunosorbent assay analysis confirmed the production of tumor necrosis factor and the chemokines CC chemokine ligand (CCL)-1/I-309, CCL-19/macrophage-inflammatory protein-3 beta (MIP-3 beta), and CCL-18/MIP-4; flow cytometry confirmed the up-regulation of carcinoembryonic antigen-related cell adhesion molecule 1, the integrin CD49d, and CD80. Coincubation with E. coli down-regulated Fc receptor for IgE I (Fc epsilon RI) expression and Fe epsilon RI-mediated hnMC degranulation. These data are consistent with the concept that bacterial exposure directs mast cell responses toward innate immunity and away from IgE-mediated effects. C1 NIAID, NIH, LAD, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Allergy Immunol Div, Chicago, IL 60611 USA. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. Meir Hosp, Dept Med, Kefar Sava, Israel. RP Metcalfe, DD (reprint author), NIAID, NIH, LAD, Bldg 10,Rm 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM dmetcalfe@niaid.nih.gov FU Intramural NIH HHS NR 41 TC 28 Z9 29 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2006 VL 79 IS 2 BP 339 EP 350 DI 10.1189/jlb.1004600 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 119LX UT WOS:000243014900010 PM 16282532 ER PT J AU Garg, H Blumenthal, R AF Garg, Himanshu Blumenthal, Robert TI HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE hemifusion; Env glycoprotein; CXCR4 ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 ENVELOPE GLYCOPROTEIN; CHEMOKINE RECEPTOR CXCR4; CYTOCHROME-C RELEASE; CD4 T-CELLS; OXIDATIVE STRESS; MONOCLONAL-ANTIBODY; AMPLIFICATION LOOP; CASPASE ACTIVATION; MEMBRANE-FUSION AB Apoptotic loss of CD4+ T cells has been proposed as a mechanism of T cell depletion in human immunodeficiency virus (HIV) infections resulting in immunodeficiency. The Env glycoprotein has been implicated in apoptosis of uninfected bystander cells via gp120 binding to CD4/CXC chemokine receptor 4 as well as the fusion/hemifusion process mediated by gp41. Using an in vitro model of coculture of Env-expressing cells as effectors and CD4+ T cells as targets, we find that apoptosis mediated by Env glycoprotein in bystander cells in fact correlates with gp41-induced hemifusion. Further, the apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production. HIV gp41-induced mitochondrial depolarization is inhibited by protease inhibitor nelfinavir but not by other HIV protease inhibitors or inhibitors of calpain and cathepsin. This "kiss of death" (hemifusion) signaling pathway is independent of p38 mitogen-activated protein kinase and p53, making it distinct from the apoptosis seen in syncytia. We also show that virion-induced apoptosis is gp41-dependent. Our findings provide new insights into the mechanism via which HIV gp41 mediates apoptosis in bystander cells. C1 NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Ctr Canc Res, Nanobiol Program, NIH, POB B,Bldg 369,Room 152,Miller Dr, Frederick, MD 21702 USA. EM blumen@helix.nih.gov FU Intramural NIH HHS NR 52 TC 37 Z9 38 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2006 VL 79 IS 2 BP 351 EP 362 DI 10.1189/jlb.0805430 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 119LX UT WOS:000243014900011 PM 16330530 ER PT J AU Petrache, HI Tristram-Nagle, S Harries, D Kucerka, N Nagle, JF Parsegian, VA AF Petrache, HI Tristram-Nagle, S Harries, D Kucerka, N Nagle, JF Parsegian, VA TI Swelling of phospholipids by monovalent salt SO JOURNAL OF LIPID RESEARCH LA English DT Article DE bending rigidity; halides; hydration; ion binding; lipid head group; membrane interactions; solvation ID HYDRATED BILAYER DISPERSIONS; X-RAY-SCATTERING; LIPID-BILAYERS; PHOSPHATIDYLCHOLINE BILAYERS; LECITHIN BILAYERS; GEL PHASE; H-2 NMR; VESICLES; ANIONS; MEMBRANES AB Critical to biological processes such as membrane fusion and secretion, ion-lipid interactions at the membrane-water interface still raise many unanswered questions. Using reconstituted phosphatidylcholine membranes, we confirm here that multilamellar vesicles swell in salt solutions, a direct indication that salt modifies the interactions between neighboring membranes. By varying sample histories, and by comparing with data from ion carrier-containing bilayers, we eliminate the possibility that swelling is an equilibration artifact. Although both attractive and repulsive forces could be modified by salt, we show experimentally that swelling is driven primarily by weakening of the van der Waals attraction. To isolate the effect of salt on van der Waals interactions, we focus on high salt concentrations at which any possible electrostatic interactions are screened. By analysis of X-ray diffraction data, we show that salt does not alter membrane structure or bending rigidity, eliminating the possibility that repulsive fluctuation forces change with salt. By measuring changes in interbilayer separation with applied osmotic stress, we have determined, using the standard paradigm for bilayer interactions, that 1 M concentrations of KBr or KCl decrease the van der Waals strength by 50%. By weakening van der Waals attractions, salt increases energy barriers to membrane contact, possibly affecting cellular communication and biological signaling. Petrache, H. I., S. Tristram-Nagle, D. Harries, N. Kucerka, J. F. Nagle, and V. A. Parsegian. Swelling of phospholipids by monovalent salt. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Carnegie Mellon Univ, Biol Phys Grp, Dept Phys, Pittsburgh, PA 15213 USA. Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Petrache, HI (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM petrachh@mail.nih.gov RI Harries, Daniel/F-7016-2012; Tristram-Nagle, Prof. Stephanie/N-7811-2014; Nagle, John/B-1917-2015 OI Harries, Daniel/0000-0002-3057-9485; Tristram-Nagle, Prof. Stephanie/0000-0003-2271-7056; Nagle, John/0000-0002-9844-5934 FU NIGMS NIH HHS [DMR0225180, GM-44976-11, R01 GM044976, R01 GM044976-17] NR 51 TC 81 Z9 85 U1 3 U2 33 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 2006 VL 47 IS 2 BP 302 EP 309 DI 10.1194/jlr.M500401-JLR200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 005SS UT WOS:000234844700006 PM 16267342 ER PT J AU Pursley, RH Salem, G Devasahayam, N Subramanian, S Koscielniak, J Krishna, MC Pohida, TJ AF Pursley, RH Salem, G Devasahayam, N Subramanian, S Koscielniak, J Krishna, MC Pohida, TJ TI Integration of digital signal processing technologies with pulsed electron paramagnetic resonance imaging SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE EPR; TLSS; Fourier transform; DSP; FPGA; digital signal processing ID SPECTROSCOPY; EPR AB The integration of modern data acquisition and digital signal processing (DSP) technologies with Fourier transform electron paramagnetic resonance (FT-EPR) imaging at radiofrequencies (RF) is described. The FT-EPR system operates at a Larmor frequency (L-f) of 300 MHz to facilitate in vivo studies. This relatively low frequency L-f, in conjunction with our similar to 10 MHz signal bandwidth, enables the use of direct free induction decay time-locked subsampling (TLSS). This particular technique provides advantages by eliminating the traditional analog intermediate frequency downconversion stage along with the corresponding noise sources. TLSS also results in manageable sample rates that facilitate the design of DSP-based data acquisition and image processing platforms. More specifically, we utilize a high-speed field programmable gate array (FPGA) and a DSP processor to perform advanced real-time signal and image processing. The migration to a DSP-based configuration offers the benefits of improved EPR system performance, as well as increased adaptability to various EPR system configurations (i.e., software configurable systems instead of hardware reconfigurations). The required modifications to the FT-EPR system design are described, with focus on the addition of DSP technologies including the application-specific hardware, software, and firmware developed for the FPGA and DSP processor. The first results of using real-time DSP technologies in conjunction with direct detection bandpass sampling to implement EPR imaging at RF frequencies are presented. (c) 2005 Elsevier Inc. All rights reserved. C1 NIH, Signal Proc & Instrumentat Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Frederick, MD 21702 USA. RP Pursley, RH (reprint author), NIH, Signal Proc & Instrumentat Sect, Div Computat Biosci, Ctr Informat Technol, 12 South Dr,Bldg 12A-2025, Bethesda, MD 20892 USA. EM pursley@nih.gov FU CIT NIH HHS [Z01 CT000261-09]; Intramural NIH HHS NR 18 TC 7 Z9 7 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2006 VL 178 IS 2 BP 220 EP 227 DI 10.1016/j.jmr.2005.10.001 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 011DZ UT WOS:000235249500006 PM 16243552 ER PT J AU Hourani, R Horska, A Albayram, S Brant, LJ Melhem, E Cohen, KJ Burger, PC Weingart, JD Carson, B Wharam, MD Barker, PB AF Hourani, R Horska, A Albayram, S Brant, LJ Melhem, E Cohen, KJ Burger, PC Weingart, JD Carson, B Wharam, MD Barker, PB TI Proton magnetic resonance spectroscopic imaging to differentiate between nonneoplastic lesions and brain tumors in children SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE brain; choline; N-acetyl aspartate; creatine; pediatric tumors; proton MRSI ID MR SPECTROSCOPY; DEMYELINATING LESIONS; MULTIPLE-SCLEROSIS; ASTROCYTOMAS; CHILDHOOD; METABOLITES; RECURRENT; GLIOMAS; BIOPSY AB Purpose: To investigate whether in vivo proton magnetic resonance spectroscopic imaging (MRSI) can differentiate between 1) tumors and nonneoplastic brain lesions. and 2) high- and low-grade tumors in children. Materials and Methods: Thirty-two children (20 males and 12 females, mean age = 10 5 years) with primary brain lesions were evaluated retrospectively. Nineteen patients had a neuropathologically confirmed brain tumor, and 13 patients had a benign lesion. Multislice proton MRSI was per-formed at TE = 280 msec. Ratios of N-acetyl aspartate/ choline (NAA/Cho), NAA/creatine (Cr), and Cho/Cr were evaluated in the lesion and the contralateral hemisphere. Normalized lesion peak areas (Cho(norm), Cr-norm, and NAA(norm)) expressed relative to the contralateral hemisphere were also calculated. Discriminant function analysis was used for statistical evaluation. Results: Considering all possible combinations of metabolite ratios, the best discriminant function to differentiate between nonneoplastic lesions and brain tumors was found to include only the ratio of Cho/Cr (Wilks'lambda, P = 0.0 12: 78. 1% of original grouped cases correctly classified). The best discriminant function to differentiate between high- and low-grade tumors included the ratios of NAA/Cr and Cho(norm) (Wilks' lambda. P = 0.001: 89.5% of original grouped cases correctly classified). Cr levels in low-grade tumors were slightly lower than or comparable to control regions and ranged from 53% to 165% of the control values in high-grade tumors. Conclusion: Proton MRSI may have a promising role in differentiating pediatric brain lesions. and an important diagnostic value. particularly for inoperable or inaccessible lesions. C1 Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD USA. Univ Penn, Div Neuroradiol, Dept Radiol, Philadelphia, PA USA. Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. Johns Hopkins Univ, Dept Neurol Surg, Baltimore, MD USA. Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Kennedy Krieger Inst, FM Kirby Res Ctr, Baltimore, MD USA. RP Horska, A (reprint author), Johns Hopkins Univ, Dept Radiol & Radiol Sci, 217 Traylor Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM ahorska@jhmi.edu RI Melhem, Elias/E-5205-2013 FU NCRR NIH HHS [P41RR15241]; NINDS NIH HHS [NS042851] NR 39 TC 27 Z9 28 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD FEB PY 2006 VL 23 IS 2 BP 99 EP 107 DI 10.1002/jmri.20480 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 011JL UT WOS:000235264300001 PM 16374884 ER PT J AU Lowe, RH Barnes, AJ Lehrmann, E Freed, WJ Kleinman, JE Hyde, TM Herman, MM Huestis, MA AF Lowe, RH Barnes, AJ Lehrmann, E Freed, WJ Kleinman, JE Hyde, TM Herman, MM Huestis, MA TI A validated positive chemical ionization GC/MS method for the identification and quantification of amphetamine, opiates, cocaine, and metabolites in human postmortem brain SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE drugs of abuse; GC/MS; brain; cocaine; opiates ID SOLID-PHASE EXTRACTION; CHROMATOGRAPHY/TANDEM MASS-SPECTROMETRY; GAS-CHROMATOGRAPHY; LIQUID-CHROMATOGRAPHY; DRUG DISCOVERY; METHAMPHETAMINE; EXPOSURE; PLASMA; BLOOD; MICE AB A sensitive and specific method for the simultaneous detection and quantification of amphetamine, opiates, and cocaine and metabolites in human postmortem brain was developed and validated. Analytes of interest included amphetamine, morphine, codeine, 6-acetylmorphine, cocaine, benzoylecgonine, ecgonine methyl ester, ecgonine ethyl ester, cocaethylene, and anhydroecgonine methyl ester. The method employed ultrasonic homogenization of brain tissue in pH 4.0 sodium acetate buffer and solid phase extraction. Extracts were derivatized with N-methyl-N-(tert-butyldimethylsilyl) trifluoroacetamide and N,O-bis(trimethylsilyl) trifluoroacetamide. Separation and quantification were accomplished on a bench-top positive chemical ionization capillary gas chromatograph/mass spectrometer with selected ion monitoring. Eight deuterated analogs were used as internal standards. Limits of quantification were 50 ng/g of brain. Calibration curves were linear to 1000 ng/g for anhydroecgonine methyl ester and 6-acetylmorphine, and to 2000 ng/g for all other analytes. Accuracy across the linear range of the assay ranged from 90.2 to 112.2%, and precision, as percent relative standard deviation, was less than 16.6%. Quantification of drug concentrations in brain is a useful research tool in neurobiology and in forensic and postmortem toxicology, identifying the type, relative magnitude, and recency of abused drug exposure. This method will be employed to quantify drug concentrations in human postmortem brain in support of basic and clinical research on the physiologic, biochemical, and behavioral effects of drugs in humans. Copyright (c) 2005 John Wiley & Sons, Ltd. C1 NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. NIMH, Clin Brain Disorders Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Lehrmann, Elin/0000-0002-9869-9475 FU Intramural NIH HHS NR 28 TC 16 Z9 16 U1 1 U2 12 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD FEB PY 2006 VL 41 IS 2 BP 175 EP 184 DI 10.1002/jms.975 PG 10 WC Biophysics; Chemistry, Organic; Spectroscopy SC Biophysics; Chemistry; Spectroscopy GA 016BV UT WOS:000235596500005 PM 16382483 ER PT J AU Van Maldergem, L Siitonen, HA Jalkh, N Chouery, E De Roy, M Delague, V Muenke, M Jabs, EW Cai, J Wang, LL Plon, SE Fourneau, C Kestila, M Gillerot, Y Megarbane, A Verloes, A AF Van Maldergem, L Siitonen, HA Jalkh, N Chouery, E De Roy, M Delague, V Muenke, M Jabs, EW Cai, J Wang, LL Plon, SE Fourneau, C Kestila, M Gillerot, Y Megarbane, A Verloes, A TI Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID ROTHMUND-THOMSON-SYNDROME; RAPADILINO-SYNDROME; FANCONI-ANEMIA; PATELLAR APLASIA; HYDROCEPHALUS; TWIST; MANIFESTATIONS; HETEROGENEITY; PHENOTYPE; ANOMALIES AB Baller-Gerold syndrome (BGS) is a rare autosomal recessive condition with radial aplasia/hypoplasia and craniosynostosis (OMIM 218600). Of >20 cases reported so far, a few appear atypical and have been reassigned to other nosologic entities, including Fanconi anaemia, Roberts SC phocomelia, and Pfeiffer syndromes after demonstration of corresponding cytogenetic or molecular abnormalities. Clinical overlap between BGS, Rothmund-Thomson syndrome (RTS), and RAPADILINO syndrome is noticeable. Because patients with RAPADILINO syndrome and a subset of patients with RTS have RECQL4 mutations, we reassessed two previously reported BGS families and found causal mutations in RECQL4 in both. In the first family, four affected offspring had craniosynostosis and radial defect and one of them developed poikiloderma. In this family, compound heterozygosity for a R1021W missense mutation and a g. 2886delT frameshift mutation of exon 9 was found. In the second family, the affected male had craniosynostosis, radial ray defect, poikiloderma, and short stature. He had a homozygous splice site mutation (IVS17- 2A>C). In both families, the affected offspring had craniosynostosis, radial defects, and growth retardation, and two developed poikiloderma. Our results confirm that BGS in a subgroup of patients is due to RECQL4 mutations and could be integrated into a clinical spectrum that encompasses RTS and RAPADILINO syndrome. C1 Inst Pathol & Genet, Ctr Genet Humaine, Loverval, Belgium. Natl Publ Hlth Inst, Dept Mol Med, Helsinki, Finland. Fac Med St Joseph, Serv Genet, Beirut, Lebanon. Fac Med Timone, INSERM, U491, Marseille, France. NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. Baylor Coll Med, Hematol Serv, Houston, TX 77030 USA. Robert Debre Hosp, Clin Genet Unit, Paris, France. Robert Debre Hosp, INSERM, E9935, Paris, France. RP Van Maldergem, L (reprint author), 10 Rue Treille, B-1050 Brussels, Belgium. EM vmald@skypro.be RI delague, valerie/K-5837-2013; OI delague, valerie/0000-0003-2652-362X; , Alain/0000-0003-4819-0264; Jabs, Ethylin/0000-0001-8983-5466 NR 36 TC 105 Z9 107 U1 1 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2006 VL 43 IS 2 BP 148 EP 152 DI 10.1136/jmg.2005.031781 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 010IZ UT WOS:000235182900008 PM 15964893 ER PT J AU Paisan-Ruiz, C Evans, EW Jain, S Xiromerisiou, G Gibbs, JR Eerola, J Gourbali, V Hellstrom, O Duckworth, J Papadimitriou, A Tienari, PJ Hadjigeorgiou, GM Singleton, AB AF Paisan-Ruiz, C Evans, EW Jain, S Xiromerisiou, G Gibbs, JR Eerola, J Gourbali, V Hellstrom, O Duckworth, J Papadimitriou, A Tienari, PJ Hadjigeorgiou, GM Singleton, AB TI Testing association between LRRK2 and Parkinson's disease and investigating linkage disequilibrium SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID AUTOSOMAL-DOMINANT PARKINSONISM; MUTATION; GENE; IDENTIFICATION AB Background: We and others recently identified the gene underlying PARK8 linked Parkinson's disease (PD). This gene, LRRK2, contains mutations that cause an autosomal dominant PD, including a mutation, G2019S, which is the most common PD causing mutation identified to date. Common genetic variability in genes that contain PD causing mutations has previously been implicated as a risk factor for typical sporadic disease. Methods: We undertook a case-control association analysis of LRRK2 in two independent European PD cohorts using 31 tagging single nucleotide polymorphisms (tSNPs) and five potentially functional SNPs. To assess the structure of this locus in different populations, we have performed linkage disequilibrium (LD) analysis using these variants in a human diversity panel. Results: We show that common genetic variability in LRRK2 is not associated with risk for PD in the European populations studied here. We also show inter-population variability in the strength of LD across this locus. Conclusions: To our knowledge this is the first comprehensive analysis of common variability within LRRK2 as a risk factor for PD. C1 NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Thessaly, Sch Med, Dept Neurol, Neurogenet Unit, Larisa, Greece. Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. Univ Helsinki, Biomedicum Helsinki, Program Neurosci, Helsinki, Finland. Seinajoki Cent Hosp, Dept Neurol, Seinajoki, Finland. RP Singleton, AB (reprint author), NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bldg 35 Room 1A1000 MSC 3707,9000 Rockville Pike, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Paisan-Ruiz, Coro/C-2912-2009; Singleton, Andrew/C-3010-2009; Gibbs, J. Raphael/A-3984-2010; Tienari, Pentti/A-4893-2012 FU Intramural NIH HHS NR 16 TC 31 Z9 31 U1 2 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2006 VL 43 IS 2 AR e9 DI 10.1136/jmg.2005.036889 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 010IZ UT WOS:000235182900023 PM 16467219 ER PT J AU Volotao, EM Soares, CC Maranhao, SG Rocha, LN Hoshino, Y Santos, N AF Volotao, EM Soares, CC Maranhao, SG Rocha, LN Hoshino, Y Santos, N TI Rotavirus surveillance in the city of Rio de Janeiro-Brazil during 2000-2004: Detection of unusual strains with G8P[4] or G10P[9] specificities SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE gastroenteritis; rotaviruses; genotyping ID POLYMERASE CHAIN-REACTION; HOSPITALIZED CHILDREN; BOVINE ROTAVIRUS; GENETIC-VARIATION; DE-JANEIRO; P-TYPE; MOLECULAR CHARACTERIZATION; REASSORTANT ROTAVIRUSES; MONOCLONAL-ANTIBODIES; PROBE HYBRIDIZATION AB Rotavirus diarrhea is a potentially life-threatening disease that affects millions of children annually around the world. Because protection against rotavirus disease is thought to be type specific, continuous rotavirus surveillance before and after implementation of a vaccine is still of essential importance. Rotavirus surveillance has been conducted in the city of Rio de Janeiro, Brazil since 1982. In the present study, we report rotavirus surveillance data in Rio de Janeiro city from 2000 to 2004. One hundred twenty nine of 1,568 (8.2%) stool samples, collected from children with acute diarrhea between January 2000 and July 2004 were rotavirus-positive. One hundred twenty eight of the 129 (99.2%) rotavirus-positive samples were genotyped for G and/or P specificity. G1 was the predominant strain (49.6%, 64/ 129) followed by G9 (30.2%, 39/129), and G4 (17.8%, 23/129); G2 and G3 viruses were not detected. One sample (0.8%) was non-typeable. P genotypes were determined for 124 of the 129 (96%) samples, and P[8] was the predominant genotype (90.6%, 117/129). Genotypes P[4] and P[9] were detected in two (1.6%) samples each; one (0.8%) sample presented P[6] genotype; and five (3.8%) samples were non-typeable. Two samples (1.6%) presented mixed P genotypes (P[6] + P[8]). Two unusual strains were isolated: a G8P[4] strain isolated from a non-hospitalized child with diarrhea and a G10P[9] strain isolated from a hospitalized child with diarrhea. C1 Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, BR-21941590 Rio De Janeiro, Brazil. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Santos, N (reprint author), Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, Cidade Univ,CCS-B1 I,Ilha Fundao, BR-21941590 Rio De Janeiro, Brazil. EM nsantos@micro.ufrj.br RI Santos, Norma/H-6986-2015 OI Santos, Norma/0000-0002-5123-9172 NR 79 TC 37 Z9 37 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD FEB PY 2006 VL 78 IS 2 BP 263 EP 272 DI 10.1002/jmv.20535 PG 10 WC Virology SC Virology GA 001LA UT WOS:000234533400016 PM 16372291 ER PT J AU Xu, JL Izmirlian, G AF Xu, JL Izmirlian, G TI Estimation of location parameters for spherically symmetric distributions SO JOURNAL OF MULTIVARIATE ANALYSIS LA English DT Article DE James-Stein type estimators; location parameters; spherical distributions; quadratic loss; risk function ID MINIMAX ESTIMATION; QUADRATIC LOSS; SHRINKAGE ESTIMATORS AB Estimation of the location parameters of a p x 1 random vector (X) under bar with a spherically symmetric distribution is considered under quadratic loss. The conditions of Brandwein and Strawderman [Ann. Statist. 19(1991) 1639-1650] under which estimators of the form (X) under bar + a (g) under bar((X) under bar) dominate (X) under bar are (i) parallel to g parallel to(2)/2 <= - h <= - del circle g, where -h is superharmonic, (ii) E((theta) under bar)[R(2)h((V) under bar)] is nonincreasing in R, where (V) under bar has a uniform distribution in the sphere centered at (theta) under bar with a radius R, and (iii) 0 < a <= 1/[pE(<(0)under bar>)(parallel to(X) under bar parallel to(-2))]. In this paper, we not only drop their condition (ii) to show the dominance of (X) under bar + a (g) under bar over ((X) under bar), but also obtain a new bound for a which is sometimes better than that obtained by Brandwein and Strawderman. Specifically, the new bound of a is 0 < a < [mu(1)/(p(2) mu(-1)][1 - (p - 1)mu(1) /(p mu(-1)mu(2))](-1) with mu(i) = E((0) under bar)(parallel to(X) under bar parallel to(i)) for i = -1, 1, 2. The generalization to concave loss functions is also considered. Additionally, we investigate estimators of the location parameters when the scale is unknown and the observation contains a residual vector. (C) 2005 Elsevier Inc. All rights reserved. C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Xu, JL (reprint author), NCI, Biometry Res Grp, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM jianxu@helix.nih.gov NR 19 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0047-259X J9 J MULTIVARIATE ANAL JI J. Multivar. Anal. PD FEB PY 2006 VL 97 IS 2 BP 514 EP 525 DI 10.1016/j.jmva.2005.03.013 PG 12 WC Statistics & Probability SC Mathematics GA 995PN UT WOS:000234116400012 ER PT J AU Basselin, M Villacreses, NE Langenbach, R Ma, KZ Bell, JM Rapoport, SI AF Basselin, M Villacreses, NE Langenbach, R Ma, KZ Bell, JM Rapoport, SI TI Resting and arecoline-stimulated brain metabolism and signaling involving arachidonic acid are altered in the cyclooxygenase-2 knockout mouse SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonic acid; arecoline; brain; cyclooxygenase-2 knockout; muscarinic receptor; phospholipase A2 ID PHOSPHOLIPASE A(2) ACTIVATION; PROTEIN-KINASE-C; RAT-BRAIN; IN-VIVO; UNANESTHETIZED RATS; PARKINSONS-DISEASE; LIPID-PEROXIDATION; FATTY-ACIDS; INDUCIBLE CYCLOOXYGENASE; DOCOSAHEXAENOIC ACID AB Studies were performed to determine if cyclooxygenase (COX)-2 regulates muscarinic receptor-initiated signaling involving brain phospholipase A(2) (PLA(2)) activation and arachidonic acid (AA; 20 : 4n-6) release. AA incorporation coefficients, k* (brain [1-C-14]AA radioactivity/integrated plasma radioactivity), representing this signaling, were measured following the intravenous injection of [1-C-14]AA using quantitative autoradiography, in each of 81 brain regions in unanesthetized COX-2 knockout (COX-2(-/-)) and wild-type (COX-2(+/+)) mice. Mice were administered arecoline (30 mg/kg i.p.), a non-specific muscarinic receptor agonist, or saline i.p. (baseline control). At baseline, COX-2(-/-) compared with COX-2(+/+) mice had widespread and significant elevations of k*. Arecoline increased k* significantly in COX-2(+/+) mice compared with saline controls in 72 of 81 brain regions, but had no significant effect on k* in any region in COX-2(-/-) mice. These findings, when related to net incorporation rates of AA from brain into plasma, demonstrate enhanced baseline brain metabolic loss of AA in COX-2(-/-) compared with COX-2(+/+) mice, and an absence of a normal k* response to muscarinic receptor activation. This response likely reflects selective COX-2-mediated conversion of PLA(2)-released AA to prostanoids. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov FU Intramural NIH HHS NR 99 TC 27 Z9 27 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2006 VL 96 IS 3 BP 669 EP 679 DI 10.1111/j.1471-4159.2005.03612.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 003GV UT WOS:000234670700006 PM 16405503 ER PT J AU Sartorius, LJ Nagappan, G Lipska, BK Lu, B Sei, Y Ren-Patterson, R Li, Z Weinberger, DR Harrison, PJ AF Sartorius, LJ Nagappan, G Lipska, BK Lu, B Sei, Y Ren-Patterson, R Li, Z Weinberger, DR Harrison, PJ TI Alternative splicing of human metabotropic glutamate receptor 3 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE brain; metabotropic glutamate receptor 3; mRNA; post-mortem; schizophrenia ID GLUTAMATE-RECEPTOR AGONIST; MESSENGER-RNA DECAY; GROUP-II; SCHIZOPHRENIA; MGLUR3; ACTIVATION; LY354740; RELEASE; GRM3; ATTENUATION AB The metabotropic glutamate receptor 3 (GRM3, mGluR3) is important in regulating synaptic glutamate. Here, we report the existence of three splice variants of GRM3 in human brain arising from exon skipping events. The transcripts are expressed in prefrontal cortex, hippocampus and cerebellum, and in B lymphoblasts. We found no evidence for alternative splicing of GRM2. The most abundant GRM3 variant lacks exon 4 (GRM3 Delta 4). In silico translation analysis of GRM3 Delta 4 predicts a truncated protein with a conserved extracellular ligand binding domain, absence of a seven-transmembrane domain, and a unique 96-amino acid C-terminus. When expressed in rat hippocampal neurons, GRM3 Delta 4 is translated into a 60 kDa protein. Immunostaining and cell fractionation data indicate that the truncated protein is primarily membrane-associated. An antibody developed against the GRM3 Delta 4 C-terminus detects a protein of approximately 60 kDa in human brain lysates and in B lymphoblasts, suggesting translation of GRM3 Delta 4 in vivo. The existence of the GRM3 Delta 4 isoform is relevant in the light of the reported association of non-coding single nucleotide polymorphisms (SNPs) in GRM3 with schizophrenia, and with the potential of GRM3 as a therapeutic target for several neuropsychiatric disorders. C1 NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford, England. NICHD, Sect Neural Dev & Plastic, NIH, Bethesda, MD USA. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, Room 4 S-235,10 Ctr Dr, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov RI Lu, Bai/A-4018-2012 FU Intramural NIH HHS NR 34 TC 33 Z9 39 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2006 VL 96 IS 4 BP 1139 EP 1148 DI 10.1111/j.1471-4159.2005.03609.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 007NA UT WOS:000234975200023 PM 16417579 ER PT J AU Hansson, AC Sommer, WH Metsis, M Stromberg, I Agnati, LF Fuxe, K AF Hansson, AC Sommer, WH Metsis, M Stromberg, I Agnati, LF Fuxe, K TI Corticosterone actions on the hippocampal brain-derived neurotrophic factor expression are mediated by exon IV promoter SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE neurotrophin; brain-derived neurotrophic factor; adrenalectomy; glucocorticoids; rat brain neurotrophin; brain-derived neurotrophic factor; adrenalectomy; glucocorticoids; rat brain ID MESSENGER-RNA LEVELS; RECEPTOR IMMUNOREACTIVE NEURONS; FACTOR GENE-EXPRESSION; NERVE GROWTH-FACTOR; RAT-BRAIN; GLUCOCORTICOID-RECEPTOR; BDNF PROTEIN; STRESS; CELLS; MECHANISM AB Brain-derived neurotrophic factor (BDNF) expression is strongly regulated by adrenocorticosteroids via activated gluco- and mineralocorticoid receptors. Four separate promoters are located upstream of the BDNF noncoding exons I to IV and may thus be involved in adrenocorticosteroid-mediated gene regulation. In adrenalectomised rats, corticosterone (10 mg/kg s.c.) induces a robust down-regulation of both BDNF mRNA and protein levels in the hippocampus peaking at 2-8 h. To study the role of the individual promoters in the corticosterone response, we employed exon-specific riboprobe in situ hybridisation as well as real-time polymerase chain reaction (PCR) in the dentate gyrus. We found a down-regulation, mainly of exon IV and the protein-coding exon V, in nearby all hippocampal subregions, but exon II was only down-regulated in the dentate gyrus. Exon I and exon III transcripts were not affected by corticosterone treatment. The results could be confirmed with real-time PCR in the dentate gyrus. It appears as if the exon IV promoter is the major target for corticosterone-mediated transcriptional regulation of BDNF in the hippocampus. C1 NIAAA, NIH, Clin Sci Lab, Bethesda, MD 20892 USA. Karolinska Inst, Dept Neurosci, Stockholm, Sweden. Karolinska Inst, Dept Biochem & Biophys, Stockholm, Sweden. Umea Univ, Dept Integrat Med Biol, Umea, Sweden. Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. RP Hansson, AC (reprint author), NIAAA, NIH, Clin Sci Lab, Bldg 10,CRC,Room 1-5330 E,10 Ctr Dr MSC 1108, Bethesda, MD 20892 USA. EM anita.hansson@mail.nih.gov RI Metsis, Madis/F-7080-2016; OI Metsis, Madis/0000-0003-1667-677X; Fuxe, Kjell/0000-0001-8491-4288 NR 58 TC 61 Z9 63 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD FEB PY 2006 VL 18 IS 2 BP 104 EP 114 DI 10.1111/j.1365-2826.2005.01390.x PG 11 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 003GY UT WOS:000234671000003 PM 16420279 ER PT J AU Muraro, PA Cassiani-Ingoni, R Chung, K Packer, AN Sospedra, M Martin, R AF Muraro, PA Cassiani-Ingoni, R Chung, K Packer, AN Sospedra, M Martin, R TI Clonotypic analysis of cerebrospinal fluid T cells during disease exacerbation and remission in a patient with multiple sclerosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE multiple sclerosis; T cell receptors; CDR3 spectratyping; cerebrospinal fluid ID V-BETA REPERTOIRE; OLIGOCLONAL EXPANSION; RECEPTOR REPERTOIRE; CLONAL EXPANSIONS; NERVOUS-SYSTEM; TCR REPERTOIRE; BLOOD; TRANSPLANTATION; LYMPHOCYTES; DIVERSITY AB Migration of autoreactive T cells into the central nervous system (CNS) compartment is thought to be an important step in the pathogenesis of multiple sclerosis (MS). To follow the evolution of T cell repertoire in the CNS of a patient with relapsing-remitting MS, we analyzed cerebrospinal fluid (CSF) cells obtained during an acute clinical exacerbation, and subsequent disease remission after 13 months of immunomodulatory therapy. T cell receptor CDR3 region length distribution was significantly altered during the relapse, demonstrating the presence of clonally expanded T cells in the CSF. CDR3 spectratyping is a valuable approach to identify disease-associated T cells in the CNS. Published by Elsevier B.V. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Muraro, PA (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Sr MSC 1400, Bethesda, MD 20892 USA. EM murarop@ninds.nih.gov OI Muraro, Paolo/0000-0002-3822-1218 FU Intramural NIH HHS NR 27 TC 17 Z9 17 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD FEB PY 2006 VL 171 IS 1-2 BP 177 EP 183 DI 10.1016/j.jneuroim.2005.10.002 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 009LW UT WOS:000235114500018 PM 16298432 ER PT J AU Hikosaka, O Nakamura, K Nakahara, H AF Hikosaka, O Nakamura, K Nakahara, H TI Basal ganglia orient eyes to reward SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review ID MONKEY CAUDATE NEURONS; NIGRA PARS RETICULATA; DORSOLATERAL PREFRONTAL CORTEX; INTRACELLULAR HORSERADISH-PEROXIDASE; MEMBRANE-POTENTIAL FLUCTUATIONS; SENSORIMOTOR-RELATED STRIATUM; CONDITIONED PLACE PREFERENCE; PRIMATE SUPERIOR COLLICULUS; VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION AB Basal ganglia orient eyes to reward. J Neurophysiol 95: 567-584, 2006. doi: 10.1152/jn. 00458.2005. Expectation of reward motivates our behaviors and influences our decisions. Indeed, neuronal activity in many brain areas is modulated by expected reward. However, it is still unclear where and how the reward-dependent modulation of neuronal activity occurs and how the reward-modulated signal is transformed into motor outputs. Recent studies suggest an important role of the basal ganglia. Sensorimotor/cognitive activities of neurons in the basal ganglia are strongly modulated by expected reward. Through their abundant outputs to the brain stem motor areas and the thalamocortical circuits, the basal ganglia appear capable of producing body movements based on expected reward. A good behavioral measure to test this hypothesis is saccadic eye movement because its brain stem mechanism has been extensively studied. Studies from our laboratory suggest that the basal ganglia play a key role in guiding the gaze to the location where reward is available. Neurons in the caudate nucleus and the substantia nigra pars reticulata are extremely sensitive to the positional difference in expected reward, which leads to a bias in excitability between the superior colliculi such that the saccade to the to-be-rewarded position occurs more quickly. It is suggested that the reward modulation occurs in the caudate where cortical inputs carrying spatial signals and dopaminergic inputs carrying reward-related signals are integrated. These data support a specific form of reinforcement learning theories, but also suggest further refinement of the theory. C1 NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. RIKEN, Lab Math Neurosci, Brain Res Inst, Saitama, Japan. RP Hikosaka, O (reprint author), NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. EM oh@lsr.nei.nih.gov RI Nakahara, Hiroyuki/N-5411-2015 OI Nakahara, Hiroyuki/0000-0001-6891-1175 NR 205 TC 186 Z9 192 U1 1 U2 18 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2006 VL 95 IS 2 BP 567 EP 584 DI 10.1152/jn.00458.2005 PG 18 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 004NN UT WOS:000234759600001 PM 16424448 ER PT J AU Lupica, CR Brodie, MS AF Lupica, CR Brodie, MS TI Queer currents, steady rhythms, and drunken DA neurons. Focus on "hyperpolarization-activated cation current (I-h) is an ethanol target in midbrain dopamine neurons of mice" SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Editorial Material ID VENTRAL TEGMENTAL AREA; THALAMIC RELAY NEURONS; PACEMAKER CHANNELS; FIRING RATE; RATS; INVOLVEMENT; EXCITATION; RECEPTORS; FAMILY; BRAIN C1 NIDA, IRP, NIH,Dept Hlth & Human Serv, Electrophysiol Sect,Cellular Neurobiol Branch, Baltimore, MD 21224 USA. Univ Illinois, Coll Med, Dept Physiol & Biophys, Chicago, IL USA. RP Lupica, CR (reprint author), NIDA, IRP, NIH,Dept Hlth & Human Serv, Electrophysiol Sect,Cellular Neurobiol Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM clupica@intra.nida.nih.gov NR 28 TC 7 Z9 7 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2006 VL 95 IS 2 BP 585 EP 586 DI 10.1152/jn.00957.2005 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 004NN UT WOS:000234759600002 PM 16424449 ER PT J AU Gustafson, N Gireesh-Dharmaraj, E Czubayko, U Blackwell, KT Plenz, D AF Gustafson, N Gireesh-Dharmaraj, E Czubayko, U Blackwell, KT Plenz, D TI A comparative voltage and current-clamp analysis of feedback and feedforward synaptic transmission in the striatal microcircuit in vitro SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SPINY PROJECTION NEURONS; RAT NEOSTRIATUM; NUCLEUS-ACCUMBENS; DOPAMINERGIC MODULATION; RECEPTOR ACTIVATION; DENDRITIC CALCIUM; SLICE PREPARATION; SUBSTANTIA-NIGRA; CORTICAL INPUTS; OUTPUT NEURONS AB Striatal spiny projection (SP) neurons control movement initiation by integrating cortical inputs and inhibiting basal ganglia outputs. Central to this control lies a "microcircuit" that consists of a feedback pathway formed by axon collaterals between GABAergic SP neurons and a feedforward pathway from fast spiking (FS) GABAergic interneurons to SP neurons. Here, somatically evoked postsynaptic potentials (PSPs) and currents (PSCs) were compared for both pathways with dual whole cell patch recording in voltage- and current-clamp mode using cortex-striatum-substantia nigra organotypic cultures. On average, feedforward inputs were 1 ms earlier, more reliable, and about twice as large in amplitude compared with most feedback inputs. On the other hand, both pathways exhibited widely varying, partially overlapping amplitude distributions. This variability was already established for single FS neurons targeting many SP neurons. In response to precisely timed action potential bursts, feedforward and feedback inputs consistently showed short-term depression <= 50 - 70% in voltage- clamp, although feedback inputs also displayed strong augmentation in current-clamp in line with previous reports. The augmentation of feedback inputs was absent in gramicidin D perforated-patch recording, which also showed the natural reversal potential for both inputs to be near firing threshold. Preceding depolarizing feedback inputs during the down state did not consistently change subsequent postsynaptic action potentials. We conclude that feedback and feedforward inputs have their dominant effect during the up-state. The reversal potential close to the up-state potential, which supports shunting operation with millisecond precision and the strong synaptic depression, should enable both pathways to carry time-critical information. C1 NIMH, Unit Neural Network Physiol LSN, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. George Mason Univ, Krasnow Inst Adv Studies, Fairfax, VA 22030 USA. George Mason Univ, Sch Computat Sci, Fairfax, VA 22030 USA. RP Plenz, D (reprint author), NIMH, Unit Neural Network Physiol LSN, Porter Neurosci Res Ctr, Rm 3A-100,35 Convent Dr, Bethesda, MD 20892 USA. EM plenzd@mail.nih.gov FU Intramural NIH HHS; NIAAA NIH HHS [R01 AA016022] NR 52 TC 52 Z9 54 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2006 VL 95 IS 2 BP 737 EP 752 DI 10.1152/jn.00802.2005 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 004NN UT WOS:000234759600018 PM 16236782 ER PT J AU Kishimoto, Y Nakazawa, K Tonegawa, S Kirino, Y Kano, M AF Kishimoto, Y Nakazawa, K Tonegawa, S Kirino, Y Kano, M TI Hippocampal CA3 NMDA receptors are crucial for adaptive timing of trace eyeblink conditioned response SO JOURNAL OF NEUROSCIENCE LA English DT Article DE NMDA receptor; hippocampus; area CA3; eyeblink conditioning; nonspatial associative memory; mouse ID PLACE CELLS; MEMORY; LESIONS; RABBITS; MICE; FEAR; RAT; POTENTIATION; ASSOCIATION; ACQUISITION AB Classical conditioning of the eyeblink reflex is a simple form of associative learning for motor responses. To examine the involvement of hippocampal CA3 NMDA receptors (NRs) in nonspatial associative memory, mice lacking an NR1 subunit selectively in adult CA3 pyramidal cells [CA3-NR1 knock-out (KO) mice] were subjected to eyeblink conditioning paradigms. Mice received paired presentations of an auditory conditioned stimulus (CS) and a periorbital shock unconditioned stimulus (US). With repeated presentation of the CS followed by the US, wild-type mice learned to blink in anticipation of the US before its onset. We first confirmed that wild-type mice require an intact hippocampus in the trace version of eyeblink conditioning in which the CS and US do not overlap, creating a stimulus-free time gap of 500 ms. Under the same condition, CA3-NR1 KO mice successfully acquired conditioned responses (CRs) during the 10 d acquisition sessions, whereas the extinction of CRs was impaired on the first day of extinction sessions. Importantly, CA3-NR1 KO mice were impaired in the formation of an adaptively timed CR during the first five trials in the daily acquisition sessions. The aberrantly timed CR was also observed in the extinction sessions in accordance with the impaired extinction of CRs. These results indicate that CA3-NR1 KO mice are unable to rapidly retrieve adaptive CR timing, suggesting that CA3 NRs play a crucial role in the memory of adaptive CR timing in trace conditioning. C1 Kanazawa Univ, Grad Sch Med Sci, Dept Cellular Neurophysiol, Kanazawa, Ishikawa 9208640, Japan. Univ Tokyo, Sch Pharmaceut Sci, Lab Neurobiophys, Tokyo 1130033, Japan. NIMH, NIH, Bethesda, MD 20892 USA. MIT, Neurosci Res Ctr, Ctr Canc Res,Howard Hughes Med Inst, RIKEN,Picower Ctr Learning & Memory, Cambridge, MA 02139 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Kano, M (reprint author), Osaka Univ, Grad Sch Med, Dept Cellular Neurosci, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM mkano@cns.med.osaka-u.ac.jp RI Nakazawa, Kazutoshi/J-6195-2015 OI Nakazawa, Kazutoshi/0000-0001-5699-9093 FU Intramural NIH HHS NR 48 TC 40 Z9 41 U1 0 U2 1 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 FEB 1 PY 2006 VL 26 IS 5 BP 1562 EP 1570 DI 10.1523/JNEUROSCI.4142-05.2006 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 008MC UT WOS:000235043800024 PM 16452679 ER PT J AU Vexler, A Liu, AY Schisterman, EF Wu, CQ AF Vexler, Albert Liu, Aiyi Schisterman, Enrique F. Wu, Chengqing TI Note on distribution-free estimation of maximum linear separation of two multivariate distributions SO JOURNAL OF NONPARAMETRIC STATISTICS LA English DT Article DE non-parametric Behrens-Fisher problem; measure of separation; kernel estimation; stress-strength problem; receiver operating characteristic curves; linear combination ID CONFIDENCE-BOUNDS; COMBINATIONS; CURVES AB We consider the linear separation of two continuous multivariate distributions. Under mild conditions, the optimal linear separation exists uniquely. A kernel-smoothed approach is proposed to estimate the optimal linear combination and the corresponding separation measure. The proposed method yields consistent estimators allowing the construction of confidence intervals. C1 NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP Vexler, A (reprint author), NICHHD, Biometry & Math Stat Branch, US Dept HHS, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM vexlera@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X NR 15 TC 8 Z9 8 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1048-5252 J9 J NONPARAMETR STAT JI J. Nonparametr. Stat. PD FEB PY 2006 VL 18 IS 2 BP 145 EP 158 DI 10.1080/10485250600662260 PG 14 WC Statistics & Probability SC Mathematics GA 061MG UT WOS:000238876000003 ER PT J AU Kim, JS Ichise, M Sangare, J Innis, RB AF Kim, JS Ichise, M Sangare, J Innis, RB TI PET imaging of serotonin transporters with [C-11]DASB: Test-retest reproducibility using a multilinear reference tissue parametric imaging method SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE PET; parametric imaging; reproducibility; linearized reference tissue model; [C-11]DASB; serotonin transporters; non-invasive quantification ID POSITRON-EMISSION-TOMOGRAPHY; OBSESSIVE-COMPULSIVE DISORDER; HUMAN-BRAIN; RECEPTOR-BINDING; REGIONAL-DISTRIBUTION; IMIPRAMINE BINDING; IN-VITRO; RADIOTRACERS; -DASB; DEPRESSION AB Parametric imaging of serotonin transporters (SERT) with C-11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([C-11]DASB) PET is a useful data analysis tool. The purpose of this study was to evaluate the reproducibility of measurements of SERT binding potential (BP) and relative blood flow (R-1) by a 2-parameter multilinear reference tissue parametric imaging method (MRTM2) for human [C-11]DASB studies. Methods: Eight healthy subjects (3 men, 5 women; age, 26 +/- 9 y) underwent 2 [C-11]DASB PET scans separated by 1 h on the same day (dose, 703 +/- 111 MBq). Parametric images of BP and R-1 were generated by MRTM2 using the cerebellum as a reference region. The k(2)' (clearance rate constant from the reference region) required by MRTM2 was estimated by the 3-parameter MRTM. Reproducibility of BP and R-1 measurements was evaluated by calculating bias (100 x (retest - test/ test), variability (SD of the bias), and reliability (intraclass correlation coefficient = rho) for several representative regions of interest (ROIs). BP and R-1 were estimated for ROI time-activity curves fitted by MRTM2 and were compared with those based on the parametric images. Results: The test-retest (0.066 +/- 0.013/ 0.06 +/- 0.011 min(-1)) MRTM k(2)' reproducibility was excellent with small bias (3%) and variability (16%) and high reliability (0.95). Retest BP values were consistently lower than those of test BP values in all regions (a mean negative bias of similar to 6%; P < 0.001). The test-retest BP variability was relatively small, ranging from 4% to 13%, with rho ranging from 0.44 to 0.85. In contrast to BP, test-retest R-1 values were similar with negligible bias of <= 0.1 %. The test-retest R-1 variability was excellent and smaller than that of BP ranging from 3% to 6%, with rho ranging from 0.58 to 0.95. BP and R-1 values estimated by the ROI time-activity curve-fitting method were slightly lower (similar to 3% and similar to 1%, respectively) than those by the parametric imaging method (P < 0.001). However, the test-retest bias and variability of BP and R, were very similar for both ROI and parametric methods. Conclusion: Our results suggest that [C-11]DASB parametric imaging of BP and R-1 with the noninvasive MRTM2 method is reproducible and reliable for PET studies of SERT. C1 Univ Ulsan, Coll Med, Asan Med Ctr, Dept Nucl Med, Seoul 138736, South Korea. NIMH, Mol Imaging Branch, Bethesda, MD USA. Harvard Univ, Sch Med, Brain Mol Imaging Program, Nucl Med Div,Brigham & Womens Hosp, Boston, MA USA. RP Kim, JS (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Nucl Med, 388-1 Poongnap Dong, Seoul 138736, South Korea. EM jaeskim@amc.seoul.kr NR 39 TC 43 Z9 43 U1 0 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2006 VL 47 IS 2 BP 208 EP 214 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 011QP UT WOS:000235283500019 PM 16455625 ER PT J AU Tipre, DN Zoghbi, SS Liow, JS Green, MV Seidel, J Ichise, M Innis, RB Pike, VW AF Tipre, DN Zoghbi, SS Liow, JS Green, MV Seidel, J Ichise, M Innis, RB Pike, VW TI PET imaging of brain 5-HT1A receptors in rat in vivo with F-18-FCWAY and improvement by successful inhibition of radioligand defluorination with miconazole SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE F-18-FCWAY; miconazole; defluorination; 5-HT1A receptors; rat; PET ID POSITRON-EMISSION-TOMOGRAPHY; H-2-RECEPTOR ANTAGONISTS; CYTOCHROMES P450; IDENTIFICATION; METABOLISM; SCANNER; BINDING; AGENTS; VITRO AB F-18-FCWAY (F-18-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluoirination of F-18-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities. Methods: PET of rat head after administration of F-18-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of F-18-FCWAY in vivo as represented by radioactivity (F-18-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of F-18-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis. Results: PET confirmed the potential of F-18-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of F-18-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of F-18-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment. Conclusion: Miconazole treatment, by eliminating defluorination of F-18-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. F-18-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Trident Imaging Inc, Rockville, MD USA. Natl Inst Biomed Imaging & Bioengn, Imaging Phys Lab, NIH, Bethesda, MD USA. RP Tipre, DN (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 1,Room B3-10,1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. EM dnyanesht@yahoo.com FU Intramural NIH HHS NR 34 TC 42 Z9 45 U1 0 U2 4 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2006 VL 47 IS 2 BP 345 EP 353 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 011QP UT WOS:000235283500036 PM 16455642 ER PT J AU Cantwell, MM Millen, AE Carroll, R Mittl, BL Hermansen, S Brinton, LA Potischman, N AF Cantwell, MM Millen, AE Carroll, R Mittl, BL Hermansen, S Brinton, LA Potischman, N TI A debriefing session with a nutritionist can improve dietary assessment using food diaries. SO JOURNAL OF NUTRITION LA English DT Article DE food diaries; dietary assessment; attenuation ID FREQUENCY QUESTIONNAIRE; BREAST-CANCER; URINARY NITROGEN; VALIDATION; REPRODUCIBILITY; POTASSIUM; VALIDITY; RECORDS; COHORT; BLOCK AB The objective of the current study was to evaluate the effect of a debriefing call on nutrient intake estimates using two 3-d food diaries among women participating in the Women's Health and Interview Study (WISH) Diet Validation Study. Subjects were 207 women with complete data and six 24-h recalls (24-HR) by telephone over 8 mo followed by two 3-d food diaries during the next 4 mo. Nutrient intake was assessed using the food diaries before and after a debriefing session by telephone. The purpose of the debriefing call was to obtain more detailed information on the types and amounts of fat in the diet. However, due to the ubiquitous nature of fat in the diet, the debriefing involved providing more specific detail on many aspects of the diet. There was a significant difference in macronutrient and micronutrient intake estimates after the debriefing. Estimates of protein, carbohydrate, and fiber intake were significantly higher and total fat, monounsaturated fat, saturated fat, vitamin A, vitamin C, a-tocopherol, folic acid, and calcium intake were significantly lower after the debriefing (P < 0.05). The limits of agreement between the food diaries before and after the debriefing were especially large for total fat intake, which could be under- or overestimated by similar to 15 g/d. The debriefing call improved attenuation coefficients associated with measurement error for vitamin C, folic acid, iron, alpha tocopherol, vitamin A, and calcium estimates. A hypothetical relative risk (RR) = 2.0 could be attenuated to 1.16 for folic acid intake assessed without a debriefing but to only 1.61 with a debriefing. Depending on the nutrients of interest, the inclusion of a debriefing can reduce the potential attenuation of RR in studies evaluating diet disease associations. C1 NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. Westat Incorp, Rockville, MD USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, NIH, Bethesda, MD 20892 USA. RP Cantwell, MM (reprint author), NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM cantwelm@mail.nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 19 TC 8 Z9 8 U1 1 U2 8 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2006 VL 136 IS 2 BP 440 EP 445 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 006JU UT WOS:000234894600017 PM 16424125 ER PT J AU Higgins, RD Raju, TNK Perlman, J Azzopardi, DV Blackmon, LR Clark, RH Edwards, AD Ferriero, DM Gluckman, PD Gunn, AJ Jacobs, SE Eicher, DJ Jobe, AH Laptook, AR LeBlanc, MH Palmer, C Shankaran, S Soll, RF Stark, AR Thoresen, M Wyatt, J AF Higgins, RD Raju, TNK Perlman, J Azzopardi, DV Blackmon, LR Clark, RH Edwards, AD Ferriero, DM Gluckman, PD Gunn, AJ Jacobs, SE Eicher, DJ Jobe, AH Laptook, AR LeBlanc, MH Palmer, C Shankaran, S Soll, RF Stark, AR Thoresen, M Wyatt, J CA NICHD Hypothermia Workshop Speaker TI Hypothermia and perinatal asphyxia: Executive summary of the National Institute of Child Health and Human Development workshop SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID MILD SYSTEMIC HYPOTHERMIA; CEREBRAL HYPOXIA-ISCHEMIA; WHOLE-BODY HYPOTHERMIA; NEONATAL ENCEPHALOPATHY; MODERATE HYPOTHERMIA; SELECTIVE HEAD; FETAL SHEEP; POSTISCHEMIC SEIZURES; BRAIN; NEUROPROTECTION AB The National Institute of Child Health and Human Development (NICHD) held a workshop on hypothermia as a potential treatment modality for perinatal hypoxic-ischemic encephalopathy (HIE) in May 2005. A panel of experts summarized the current evidence on the efficacy and safety of hypothermia and reviewed knowledge gaps. The panel concluded that mild, therapeutic hypothermia offered a potential for short-term benefits (up to 18 months of age) when used under strict experimental protocols in term infants. However, these findings have not been tested in preterm infants or severely growth-restricted infants with asphyxia. Many questions still remained about the optimal use of hypothermia for HIE in term infants, including the incidence of possible rare, short-, and long-term side effects. Moreover, the longer-term benefits in neurodevelopmental outcomes after hypothermia for HIE remain to be shown. Because of these and other reasons, the panel concluded that at the current time, therapeutic hypothermia for perinatal HIE should be considered an evolving therapy, the longer-term safety and efficacy of which are still to be established. The panel offered a framework for patient care emphasizing the need for standardized protocols for treatment and follow-up, including school-age outcome assessments. Research priorities were also recommended. The panel strongly urged that the ongoing hypothermia trials should be continued to enable assessment of its efficacy and safety. It recommended the formation of national and international HIE registries, so that scientific progress in this field can be assessed continuously to develop, refine, and optimize therapies for HIE. C1 NICHD, Pregnancy & Pennatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. RP Higgins, RD (reprint author), NICHD, Pregnancy & Pennatol Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Execut Blvd,Room 4B03B MSC 7510, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov FU Medical Research Council [G0200270, G0100126] NR 27 TC 100 Z9 103 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD FEB PY 2006 VL 148 IS 2 BP 170 EP 175 DI 10.1016/j.peds.2005.12.009 PG 6 WC Pediatrics SC Pediatrics GA 020SC UT WOS:000235929600007 PM 16492424 ER PT J AU Striegel-Moore, RH Thompson, D Affenito, SG Franko, DL Obarzanek, E Barton, BA Schreiber, GB Daniels, SR Schmidt, M Crawford, PB AF Striegel-Moore, RH Thompson, D Affenito, SG Franko, DL Obarzanek, E Barton, BA Schreiber, GB Daniels, SR Schmidt, M Crawford, PB TI Correlates of beverage intake in adolescent girls: The National Heart, Lung, and Blood Institute Growth and Health Study SO JOURNAL OF PEDIATRICS LA English DT Article ID WEIGHT CHANGE; CONSUMPTION; CHILDREN; OBESITY; CALCIUM; CHOICES; EPIDEMIC; DIET AB Objectives To examine longitudinal changes in consumption of 6 types of beverages (milk, diet and regular soda, fruit juice, fruit-flavored drinks, and coffee/tea) in girls and determine the relationship between beverage intake, body mass index (BMI), and nutrient intake. Study design Three-day food diaries were included from black (1210) and white (1161) girls who participated in the National Heart, Lung, and Blood Institute Growth and Health Study. Diaries were recorded during annual visits beginning at ages 9 or 10 years until age 19 years. Mixed models estimated the association of (1) visit and race with average daily consumption of beverages and (2) beverage intake with BMI and average daily intake of total calories. sucrose, fructose, total sugars, and calcium. Results For girls of both races, milk consumption decreased and soda consumption increased with time. Changes in beverage intake with time varied by race for all beverages except fruit juice. For A beverage categories, consumption was associated with caloric intake. Of all beverages, increasing soda consumption predicted the greatest increase of BMI and the lowest increase in calcium intake. Conclusions Public health efforts are needed to help adolescents gain access to and choose healthful beverages and decrease intake of beverages of minimal nutritional value. C1 Wesleyan Univ, Dept Psychol, Middletown, CT 06459 USA. Maryland Med Res Inst, Baltimore, MD USA. St Joseph Coll, Dept Nutr, Hartford, CT USA. Northeastern Univ, Dept Counseling & Appl Educ Psychol, Boston, MA 02115 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Westat Corp, Rockville, MD USA. Cincinnati Childrens Hosp Med Ctr, Dept Cardiol, Cincinnati, OH USA. Cincinnati Childrens Hosp Med Ctr, Dietary Data Entry Ctr, Cincinnati, OH USA. Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. RP Striegel-Moore, RH (reprint author), Wesleyan Univ, Dept Psychol, 207 High St, Middletown, CT 06459 USA. EM rstriegel@wesleyan.edu OI Barton, Bruce/0000-0001-7878-8895; weissman, ruth/0000-0001-6121-4641 FU NHLBI NIH HHS [U01 HL 48941-44, HC 55023-26]; NIDDK NIH HHS [HL/DK 71122] NR 27 TC 150 Z9 154 U1 0 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD FEB PY 2006 VL 148 IS 2 BP 183 EP 187 DI 10.1016/j.jpeds.2005.11.025 PG 5 WC Pediatrics SC Pediatrics GA 020SC UT WOS:000235929600010 PM 16492426 ER PT J AU Hassan, S Romero, R Hendler, I Gomez, R Khalek, N Espinoza, J Nien, JK Berry, SM Bujold, E Camacho, N Sorokin, Y AF Hassan, S Romero, R Hendler, I Gomez, R Khalek, N Espinoza, J Nien, JK Berry, SM Bujold, E Camacho, N Sorokin, Y TI A sonographic short cervix as the only clinical manifestation of intra-amniotic infection SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE cervical insufficiency; cervical length; chorioamnionitis; intra-amniotic infection; microbial invasion of the amniotic cavity; preterm delivery; short cervix; ultrasound ID SPONTANEOUS PRETERM DELIVERY; POLYMERASE-CHAIN-REACTION; AMNIOTIC-FLUID GLUCOSE; BLOOD-CELL COUNT; UREAPLASMA-UREALYTICUM; MICROBIAL INVASION; ULTRASONOGRAPHIC ASSESSMENT; INFLAMMATORY LESIONS; MYCOPLASMA-HOMINIS; PREMATURE RUPTURE AB Objective: A sonographically short cervix is a powerful predictor of spontaneous preterm delivery. However, the etiology and optimal management of a patient with a short cervix in the mid-trimester of pregnancy remain uncertain. Microbial invasion of the amniotic cavity (MIAC) and intra-amniotic inflammation are frequently present in patients with spontaneous preterm labor or acute cervical insufficiency. This study was conducted to determine the rate of MIAC and intra-amniotic inflammation in patients with a cervical length < 25 mm in the mid-trimester. Study design: A retrospective cohort study was conducted of patients referred to our high risk clinic because of a sonographic short cervix or a history of a previous preterm birth. Amniocenteses were performed for the evaluation of MIAC and for karyotype analysis in patients with a short cervix. Fluid was cultured for aerobic and anaerobic bacteria, as well as genital mycoplasmas. Patients with MIAC were treated with antibiotics selected by their physician. Results: Of 152 patients with a short cervix at 14-24 weeks, 57 had amniotic fluid analysis. The prevalence of MIAC was 9% (5/57). Among these patients, the rate of preterm delivery (< 32 weeks) was 40% (2/5). Microorganisms isolated from amniotic fluid included Ureaplasma urealyticum (n = 4) and Fusobacterium nucleatum ( n = 1). Patients with a positive culture for Ureaplasma urealyticum received intravenous Azithromycin. Three patients with Ureaplasma urealyticum had a sterile amniotic fluid culture after treatment, and subsequently delivered at term. The patient with Fusobacterium nucleatum developed clinical chorioamnionitis and was induced. Conclusion: (1) Sub-clinical MIAC was detected in 9% of patients with a sonographically short cervix (< 25 mm); and ( 2) maternal parenteral treatment with antibiotics can eradicate MIAC caused by Ureaplasma urealyticum. This was associated with delivery at term in the three patients whose successful treatment was documented by microbiologic studies. C1 Wayne State Univ, Hutzel Womens Hosp, Div Maternal Fetal Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHD, DHHS, Perinatol Res Branch, NIH, Bethesda, MD USA. Pontificia Univ Catolica Chile, Ctr Perinatla Diagnosis & Res, Hosp Dr Sotero del Rio, Puente Alto, Chile. William Beaumont Hosp, Dept Obstet & Gynecol, Royal Oak, MI USA. RP Hassan, S (reprint author), Wayne State Univ, Hutzel Womens Hosp, Div Maternal Fetal Med, Dept Obstet & Gynecol, 3990 John R,7 Brush N,MFM Mail Drawer 163, Detroit, MI 48201 USA. EM shassan@med.wayne.edu FU Intramural NIH HHS; NICHD NIH HHS [K12 HD001254, 2K12 HD 01254-06, Z01 HD002400-14] NR 56 TC 93 Z9 96 U1 0 U2 5 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD FEB PY 2006 VL 34 IS 1 BP 13 EP 19 DI 10.1515/JPM.2006.002 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 008ZY UT WOS:000235082100002 PM 16489881 ER PT J AU Goncalves, LF Espinoza, J Romero, R Kusanovic, JP Swope, B Nien, JK Erez, O Soto, E Treadwell, MC AF Goncalves, LF Espinoza, J Romero, R Kusanovic, JP Swope, B Nien, JK Erez, O Soto, E Treadwell, MC TI Four-dimensional ultrasonography of the fetal heart using a novel Tomographic Ultrasound Imaging display SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE congenital heart disease; fetal echocardiography; four-dimensional; prenatal diagnosis; spatiotemporal; spatiotemporal image correlation; three-dimensional; 3D; 4D ID VENTRICULAR SEPTAL-DEFECT; COLOR DOPPLER ULTRASOUND; PRENATAL-DIAGNOSIS; 3-DIMENSIONAL ULTRASOUND; GREAT-ARTERIES; ECHOCARDIOGRAPHIC ANALYSIS; OUTFLOW TRACTS; DISEASE; VOLUME; 3D AB Objective: The objective of this study was to investigate the feasibility of examining the fetal heart with Tomographic Ultrasound Imaging (TUI) using four-dimensional (4D) volume datasets acquired with spatiotemporal image correlation (STIC). Material and methods: One hundred and ninety-five fetuses underwent 4D ultrasonography ( US) of the fetal heart with STIC. Volume datasets were acquired with B-mode ( n = 195) and color Doppler imaging (CDI) (n = 168), and were reviewed offline using TUI, a new display modality that automatically slices 3D/ 4D volume datasets, providing simultaneous visualization of up to eight parallel planes in a single screen. Visualization rates for standard transverse planes used to examine the fetal heart were calculated and compared for volumes acquired with B-mode or CDI. Diagnoses by TUI were compared to postnatal diagnoses. Results: ( 1) The four- and five-chamber views and the three-vessel and trachea view were visualized in 97.4% (190/195), 88.2% (172/195), and 79.5% (142/195), respectively, of the volume datasets acquired with B-mode; ( 2) these views were visualized in 98.2% (165/ 168), 97.0% (163/168), and 83.6% (145/168), respectively, of the volume datasets acquired with CDI; ( 3) CDI contributed additional diagnostic information to 12.5% ( 21/168), 14.2% (24/168) and 10.1% (17/168) of the four- and five-chamber and the three- vessel and trachea views; ( 4) cardiac anomalies other than isolated ventricular septal defects were identified by TUI in 16 of 195 fetuses (8.2%) and, among these, CDI provided additional diagnostic information in 5 (31.3%); ( 5) the sensitivity, specificity, positive- and negative-predictive values of TUI to diagnose congenital heart disease in cases where both B-mode and CDI volume datasets were acquired prenatally were 92.9%, 98.8%, 92.9% and 98.8%, respectively. Conclusion: Standard transverse planes commonly used to examine the fetal heart can be automatically displayed with TUI in the majority of fetuses undergoing 4D US with STIC. Due to the retrospective nature of this study, the results should be interpreted with caution and independently confirmed before this methodology is introduced into clinical practice. C1 Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,DHHS,NIH,Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHHD, DHHS, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,DHHS,NIH,Dept Obstet & Gynecol, 3990 John R,Box 4, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU NICHD NIH HHS [Z01 HD002401-13] NR 77 TC 33 Z9 45 U1 0 U2 3 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD FEB PY 2006 VL 34 IS 1 BP 39 EP 55 DI 10.1515/JPM.2006.006 PG 17 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 008ZY UT WOS:000235082100006 PM 16489885 ER PT J AU Forkert, PG Millen, B Lash, LH Putt, DA Ghanayem, BI AF Forkert, PG Millen, B Lash, LH Putt, DA Ghanayem, BI TI Pulmonary bronchiolar cytotoxicity and formation of dichloroacetyl lysine protein adducts in mice treated with trichloroethylene SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RAT-LIVER; SPECIES-DIFFERENCES; MURINE LUNG; MOUSE LUNG; METABOLISM; CYP2E1; CARCINOGENICITY; BIOACTIVATION; OXIDE; 1,1-DICHLOROETHYLENE AB This study was undertaken to test the hypothesis that bronchiolar damage induced by trichloroethylene (TCE) is associated with bioactivation within the Clara cells with the involvement of CYP2E1 and CYP2F2. Histopathology confirmed dose-dependent Clara cell injury and disintegration of the bronchiolar epithelium in CD-1 mice treated with TCE doses of 500 to 1000 mg/kg i.p. Immunohistochemical studies, using an antibody that recognizes dichloroacetyl lysine adducts, revealed dose-dependent formation of adducts in the bronchiolar epithelium. Localization of dichloroacetyl adducts in the Clara cells coincided with damage to this cell type in TCE-treated mice. Pretreatment of CD-1 mice with diallyl sulfone, an inhibitor of CYP2E1 and CYP2F2, abrogated the formation of the dichloroacetyl adducts and protected against TCE-induced bronchiolar cytotoxicity. Treatment of wild-type and CYP2E1-null mice with TCE (750 mg/kg i.p.) also elicited bronchiolar damage that correlated with the formation of adducts in the Clara cells. Immunoblotting, using lung microsomes from TCE-treated CD-1 mice, showed dose-dependent production of dichloroacetyl adducts that comigrated with CYP2E1 and CYP2F2. However, TCE treatment resulted in a loss of immunoreactive CYP2E1 and CYP2F2 proteins and p-nitrophenol hydroxylation, a catalytic activity associated with both cytochrome P450 enzymes. The TCE metabolite, chloral hydrate, was formed in incubations of TCE with lung microsomes from CD-1, wild-type, and CYP2E1-null mice. The levels were higher in CD-1 than in either wild-type or CYP2E1-null mice, although levels were higher in CYP2E1-null than in wild-type mice. These findings supported the contention that TCE bioactivation within the Clara cells, predominantly involving CYP2F2, correlated with bronchiolar cytotoxicity in mice. C1 Queens Univ, Dept Anat & Cell Biol, Kingston, ON K7L 3N6, Canada. Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA. NIH, Lab Pharmacol & Chem, Res Triangle Pk, NC USA. RP Forkert, PG (reprint author), Queens Univ, Dept Anat & Cell Biol, Kingston, ON K7L 3N6, Canada. EM forkertp@post.queensu.ca OI Lash, Lawrence/0000-0003-3239-4481 FU NIEHS NIH HHS [ES08408] NR 37 TC 14 Z9 17 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2006 VL 316 IS 2 BP 520 EP 529 DI 10.1124/jpet.105.093062 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 004NH UT WOS:000234759000005 PM 16269531 ER PT J AU Hechler, B Nonne, C Roh, EJ Cattaneo, M Cazenave, JP Lanza, F Jacobson, KA Gachet, C AF Hechler, B Nonne, C Roh, EJ Cattaneo, M Cazenave, JP Lanza, F Jacobson, KA Gachet, C TI MRS2500 [2-Iodo-N-6-methyl-(N)-methanocarba-2 '-deoxyadenosine-3 ',5 '-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y(1) receptor with strong antithrombotic activity in mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ADENINE-NUCLEOTIDE ANALOGS; P2 RECEPTORS; P2Y(1)-DEFICIENT MICE; IN-VIVO; THROMBOSIS; AGGREGATION; INHIBITION; THROMBOEMBOLISM; CONFORMATION; RESISTANCE AB The platelet P2Y(1) ADP receptor is an attractive target for new antiplatelet drugs. However, because of the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y(1) receptor could efficiently inhibit experimental thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y(1) receptor antagonist MRS2500 [2-iodo-N-6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate] could inhibit platelet function ex vivo and experimental thrombosis in mice in vivo. MRS2500 was injected intravenously into mice, and its effect on ex vivo platelet aggregation and in several models of thrombosis in vivo was determined. MRS2500 displayed high potency and stable and selective P2Y(1) receptor inhibition ex vivo. Although MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. MRS2500 also potently inhibited localized arterial thrombosis in a model of laser-induced vessel wall injury with two degrees of severity. Moreover, combination of MRS2500 with clopidogrel, the irreversible inhibitor of the platelet P2Y(12) receptor for ADP, led to increased antithrombotic efficacy compared with each alone. These results add further evidence for a role of the P2Y(1) receptor in thrombosis and validate the concept that targeting the P2Y(1) receptor could be a relevant alternative or complement to current antiplatelet strategies. C1 INSERM, U311, Etabliss Francais, F-67065 Strasbourg, France. Univ Strasbourg 1, Strasbourg, France. NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ Milan, Dipartimento Med Chirurgia & Odontoiatria, Osped San Paolo, Unita Ematol & Trombosi, Milan, Italy. RP Gachet, C (reprint author), INSERM, U311, Etabliss Francais, 10 Rue Spielmann,BP 36, F-67065 Strasbourg, France. EM christian.gachet@efs-alsace.fr RI Jacobson, Kenneth/A-1530-2009; Lanza, Francois/H-9252-2016; Hechler, Beatrice/D-4227-2017; Gachet, Christian/H-9156-2016; OI Jacobson, Kenneth/0000-0001-8104-1493; Lanza, Francois/0000-0002-5802-4748; Cattaneo, Marco/0000-0002-7343-4534 FU Intramural NIH HHS [Z01 DK031116-20] NR 33 TC 85 Z9 90 U1 1 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2006 VL 316 IS 2 BP 556 EP 563 DI 10.1124/jpet.105.094037 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 004NH UT WOS:000234759000009 PM 16236815 ER PT J AU Loffler, M Bilban, M Reimers, M Waldhausl, W Stulnig, TM AF Loffler, M Bilban, M Reimers, M Waldhausl, W Stulnig, TM TI Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID LIVER-X-RECEPTOR; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; ADIPOSE-TISSUE; INSULIN SENSITIVITY; MESSENGER-RNA; LXR-ALPHA; ACTIVATION; METABOLISM; INHIBITION; OBESITY AB Agonists of the nuclear receptors peroxisome proliferator-activated receptor ( PPAR) gamma, PPAR alpha, and liver X receptors (LXRs) reduce blood glucose in type 2 diabetic patients and comparable mouse models. Since the capacity of these drugs to normalize hepatic gene expression is not known, we compared groups of obese diabetic db/db mice treated with agonists for PPAR gamma [rosiglitazone (Rosi); 10 mg/kg/day], PPAR alpha [Wy 14643 ( Wy; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl) thioacetic acid); 30 mg/kg/day], and LXR [T0901317 (T09; N-(2,2,2-trifluoroethyl)N-[ 4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]benzenesulfonamide); 40 mg/kg/day] and from untreated nondiabetic litter mates (db/+) by oligonucleotide microarrays and quantitative reverse transcriptase-polymerase chain reaction. The 10-day treatment period of db/db mice with Rosi, Wy, and T09 altered expression of 300, 620, and 735 genes including agonist-specific target genes, respectively. However, from the 337 genes differentially regulated in untreated db/+ versus db/db animals, only 34 (10%), 51 (15%), and 82 (24%) were regulated in the direction of the db/+ group by Rosi, Wy, and T09, respectively. Gene expression normalization by drug treatment involved glucose homeostasis, lipid homeostasis, and local glucocorticoid activation. In addition, our data pointed to hitherto unknown interference of these nuclear receptors with growth hormone receptor gene expression and endoplasmic reticulum stress. However, many diabetes-associated gene alterations remained unaffected or were even aggravated by nuclear receptor agonist treatment. These results suggest that diabetes-induced gene expression is minimally reversed by potent blood glucose-lowering nuclear receptor agonists. C1 Med Univ Vienna, Dept Internal Med 3, Clin Div Endocrinol & Metab, A-1090 Vienna, Austria. Austrian Acad Sci, Ctr Mol Med, A-1010 Vienna, Austria. Med Univ Vienna, Clin Inst Med & Chem Lab Diagnost, A-1090 Vienna, Austria. Ludwig Boltzmann Inst Clin & Expt Oncol, Vienna, Austria. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Stulnig, TM (reprint author), Med Univ Vienna, Dept Internal Med 3, Clin Div Endocrinol & Metab, Waehringer Guertel 18, A-1090 Vienna, Austria. EM thomas.stulnig@meduniwien.ac.at RI Loffler, Michael/F-1748-2013; OI Loffler, Michael/0000-0002-6529-9723; Stulnig, Thomas/0000-0003-3300-6161 NR 40 TC 17 Z9 18 U1 2 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2006 VL 316 IS 2 BP 797 EP 804 DI 10.1124/jpet.105.093831 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 004NH UT WOS:000234759000036 PM 16260581 ER PT J AU Gay, EA Klein, RC Yakel, JL AF Gay, EA Klein, RC Yakel, JL TI Apolipoprotein e-derived peptides block alpha 7 neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID THROMBIN-CLEAVAGE FRAGMENT; E-MIMETIC PEPTIDES; ALZHEIMERS-DISEASE; NEUROTOXICITY; BRAIN; INJURY; ACTIVATION; RESPONSES; CALCIUM; CELLS AB For decades, the pathology of Alzheimer's disease has been associated with dysfunction of cholinergic signaling; however, the cellular mechanisms by which nicotinic acetylcholine receptor ( nAChR) function is impaired in Alzheimer's disease are as yet unknown. The most significant genetic risk factor for the development of Alzheimer's disease is inheritance of the epsilon 4 allele of apolipoprotein E ( apoE). Recent data have demonstrated the ability of apoE-derived peptides to inhibit nAChRs in rat hippocampus. In the current study, the functional interaction between nAChRs and apoE-derived peptides was investigated in Xenopus oocytes expressing selected nAChRs. Both a 17-amino acid peptide fragment, apoE(133-149), and an eight-amino acid peptide, apoE(141-148), were able to maximally block acetylcholine (ACh)-mediated peak current responses for homomeric alpha 7 nAChRs. ApoE peptide inhibition was dose-dependent and voltage- and activity-independent. The current findings suggest that apoE peptides are noncompetitive for acetylcholine and do not block functional alpha-bungarotoxin binding. ApoE peptides had a significantly decreased ability to inhibit ACh-mediated peak current responses for alpha 4 beta 2 and alpha 2 beta 2 nAChRs. Amino acid substitutions in the apoE peptide sequence suggest that the arginines are critical for peptide blockade of the alpha 7 nAChR. The current data suggest that apoE fragments can disrupt nAChR signaling through a direct blockade of alpha 7 nAChRs. These results may be useful in elucidating the mechanisms underlying memory loss and cognitive decline seen in Alzheimer's disease as well as aid in the development of novel therapeutics using apoE-derived peptides. C1 Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, Dept Hlth & Human Serv, F2-08,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov NR 40 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2006 VL 316 IS 2 BP 835 EP 842 DI 10.1124/jpet.105.095505 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 004NH UT WOS:000234759000041 PM 16249370 ER PT J AU Lawrence, JJ Statland, JM Grinspan, ZM McBain, CJ AF Lawrence, JJ Statland, JM Grinspan, ZM McBain, CJ TI Cell type-specific dependence of muscarinic signalling in mouse hippocampal stratum oriens interneurones SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID RAT HIPPOCAMPUS; PYRAMIDAL CELLS; THETA-OSCILLATIONS; IN-VIVO; NETWORK OSCILLATIONS; CHOLINERGIC SYSTEM; INHIBITORY INTERNEURONS; SUBUNIT COMPOSITION; GABAERGIC NEURONS; ACTION-POTENTIALS AB Cholinergic signalling is critically involved in learning and memory processes in the hippocampus, but the postsynaptic impact of cholinergic modulation on morphologically defined subtypes of hippocampal interneurones remains unclear. We investigated the influence of muscarinic receptor (mAChR) activation on stratum oriens interneurones using whole-cell patch clamp recordings from hippocampal slices in vitro. Upon somatic depolarization, mAChR activation consistently enhanced firing frequency and produced large, sustained afterdepolarizations (ADPs) of stratum oriens-lacunosum moleculare (O-LM) interneurones. In contrast, stratum oriens cell types with axon arborization patterns different from O-LM cells not only lacked large muscarinic ADPs but also appeared to exhibit distinct responses to mAChR activation. The ADP in O-LM cells, mediated by M-1/M-3 receptors, was associated with inhibition of an M current, inhibition of a slow calcium-activated potassium current, and activation of a calcium-dependent non-selective cationic current (I-CAT). An examination of ionic conductances generated by firing revealed that calcium entry through I-CAT controls the emergence of the mAChR-mediated ADP. Our results indicate that cholinergic specializations are present within anatomically distinct subpopulations of hippocampal interneurones, suggesting that there may be organizing principles to cholinergic control of GABA release in the hippocampus. C1 NICHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP NICHD, Lab Cellular & Synapt Neurophysiol, NIH, Bldg 35,Rm 3C907, Bethesda, MD 20892 USA. EM lawrenjo@mail.nih.gov OI Grinspan, Zachary/0000-0001-6705-0932 FU Intramural NIH HHS NR 59 TC 67 Z9 67 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB 1 PY 2006 VL 570 IS 3 BP 595 EP 610 DI 10.1113/jphysiol.2005.100875 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 003HS UT WOS:000234673000016 PM 16322052 ER PT J AU Blonder, J Yu, LR Radeva, G Chan, KC Lucas, DA Waybright, TJ Issaq, HJ Sharom, FJ Veenstra, TD AF Blonder, J Yu, LR Radeva, G Chan, KC Lucas, DA Waybright, TJ Issaq, HJ Sharom, FJ Veenstra, TD TI Combined chemical and enzymatic stable isotope labeling for quantitative profiling of detergent-insoluble membrane proteins isolated using triton X-100 and Brij-96 SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE quantitative proteomics; combined O-16/O-18 and ICAT stable isotopic labeling; Triton X-100 and Brij-96 detergent-insoluble membrane proteins ID BASOPHILIC LEUKEMIA-CELLS; MASS-SPECTROMETRY; COMPARATIVE PROTEOMICS; LIPID RAFTS; AFFINITY TAG; IDENTIFICATION; CHROMATOGRAPHY; GLYCOPROTEIN; MICRODOMAINS; EXPRESSION AB Effective quantitative profiling of detergent-insoluble membrane proteins using high-throughput mass spectrometry (MS)-based proteomics would allow a better understanding of physiological and pathological processes that take place at the cell surface. To increase the coverage of proteins present in detergent-resistant membrane microdomains (DRMMs), a combination of O-16/O-18 and isotope coded affinity tags (ICAT) labeling was used in a comparative analysis of detergent-insoluble membrane proteins isolated from rat basophilic leukemia cells (RBL-2H3), with either Triton X-100 or Brij-96. The analysis resulted in the quantification of 738 unique proteins from Triton X-100 and Brij-96 isolated DRMMs, significantly exceeding the number of proteins quantified from either single labeling technique. Twenty-five noncysteine-containing proteins were quantified, as well as 32 cysteine-containing proteins that would have been missed if either O-16/O-18 or ICAT labeling had been used exclusively, which illustrate better proteome coverage and enhanced ability to quantitate. The comparative analysis revealed that proteins were more readily extracted using Triton X-100 than Brij-96; however, Triton X-100 also extracted larger quantities of non-DRMMs-associated proteins. This result confirms previous, targeted studies suggesting that DRMMs isolated using Triton X-100 and Brij-96 differ in their protein content. C1 SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI, Ft Detrick, MD 21702 USA. Univ Guelph, Dept Mol & Cellular Biol, Guelph, ON N1G 2W1, Canada. RP Blonder, J (reprint author), SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI, Ft Detrick, MD 21702 USA. EM blonder@ncifcrf.gov RI Sharom, Frances/A-1613-2010 OI Sharom, Frances/0000-0002-9521-5367 FU NCI NIH HHS [N01 CO012400, N01-CO12400, N01CO12400] NR 37 TC 42 Z9 47 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2006 VL 5 IS 2 BP 349 EP 360 DI 10.1021/pr050355n PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 012DE UT WOS:000235317600016 PM 16457601 ER PT J AU Brosschot, JF Gerin, W Thayer, JF AF Brosschot, JF Gerin, W Thayer, JF TI The perseverative cognition hypothesis: A review of worry, prolonged stress-related physiological activation, and health SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Review DE prolonged physiological stress-related activation; recovery; worry; rumination; perseverative cognition; literature review ID GENERALIZED ANXIETY DISORDER; HEART-RATE-VARIABILITY; ELEVATED BLOOD-PRESSURE; EMOTIONAL REACTIVITY; PSYCHOPHYSIOLOGICAL RESPONSES; AUTONOMIC CHARACTERISTICS; CARDIOVASCULAR RECOVERY; PSYCHOLOGICAL STRESS; PHYSICAL HEALTH; ELDERLY SAMPLE AB Perseverative cognition, as manifested in worry and rumination, is a common response to stress, but biopsychological models of stress and health have largely ignored it. These models have generally focused on physiological activation that occurs during stress and have insufficiently addressed effects that occur in anticipation of, or following, stressful events. We argue that perseverative cognition moderates the health consequences of stressors because it can prolong stress-related affective and physiological activation, both in advance of and following stressors. We review evidence that worry, rumination, and anticipatory stress are associated with enhanced cardiovascular, endocrinological, immunological, and neurovisceral activity. The findings yield preliminary support for our hypothesis, suggesting that perseverative cognition might act directly on somatic disease via enhance activation via the cardiovascular, immune, endocrine, and neurovisceral systems. (c) 2006 Elsevier Inc. All rights reserved. C1 Leiden Univ, Dept Psychol, Div Clin & Hlth Psychol, NL-2300 RB Leiden, Netherlands. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. NIA, Baltimore, MD 21224 USA. RP Brosschot, JF (reprint author), Leiden Univ, Dept Psychol, Div Clin & Hlth Psychol, POB 9555, NL-2300 RB Leiden, Netherlands. EM brosschot@fsw.leidenuniv.nl; wg131@columbia.edu; jtl2f@nih.gov NR 86 TC 428 Z9 432 U1 33 U2 179 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD FEB PY 2006 VL 60 IS 2 BP 113 EP 124 DI 10.1016/j.jpsychores.2005.06.074 PG 12 WC Psychiatry SC Psychiatry GA 012YV UT WOS:000235377700001 PM 16439263 ER PT J AU Chaizhunusova, N Yang, TC Land, C Luckyanov, N Wu, H Apsalikov, KN Madieva, M AF Chaizhunusova, N Yang, TC Land, C Luckyanov, N Wu, H Apsalikov, KN Madieva, M TI Biodosimetry study in Dolon and Chekoman villages in the vicinity of Semipalatinsk Nuclear Test Site SO JOURNAL OF RADIATION RESEARCH LA English DT Article; Proceedings Paper CT 3rd Dosimetry Workshop on the Semipalatinsk Nuclear Test Site Area CY MAR 09-11, 2005 CL Hiroshima Univ, Hiroshima, JAPAN HO Hiroshima Univ ID HYBRIDIZATION; FREQUENCY; EXCHANGES AB In this paper, the results of a biodosimetry investigation are reported for two villages in the area of the Semipalatinsk nuclear testing site: Chekoman and Dolon. Chekoman village is considered to be relatively less affected by radiation in comparison with Dolon village. The distance between the two villages is about 100 km and the life styles of the residents are similar. Chromosome aberrations in lymphocytes collected from the residents of the two villages were analyzed using the fluorescence in situ hybridization technique. Our results showed that the average frequency of stable translocations for the Dolon group was significantly greater that of the Chekoman group. The elevated level of stable translocations with the Dolon residents corresponds to a dose of about 180 mSv. C1 Sci Res Inst Radiat Med & Ecol, Semipalatinsk 490050, Kazakhstan. NASA, Lyndon B Johnson Space Ctr, Radiat Biophys Lab, Houston, TX 77058 USA. NCI, Bethesda, MD 20892 USA. NASA, Lyndon B Johnson Space Ctr, Kelsey Selbold Clin, Houston, TX 77058 USA. RP Chaizhunusova, N (reprint author), Sci Res Inst Radiat Med & Ecol, Post Box 49, Semipalatinsk 490050, Kazakhstan. EM nii_rm@semsk.kz RI Apsalikov, Kazbek/C-2974-2014 NR 15 TC 4 Z9 5 U1 0 U2 4 PU JAPAN RADIATION RESEARCH SOC PI CHIBA PA C/O NAT INST RADIOLOGICAL SCI 9-1 ANAGAWA-4-CHOME INAGE-KU, CHIBA, 263, JAPAN SN 0449-3060 J9 J RADIAT RES JI J. Radiat. Res. PD FEB PY 2006 VL 47 SU A BP A165 EP A169 DI 10.1269/jrr.47.A165 PG 5 WC Biology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA 043KL UT WOS:000237599800023 PM 16571933 ER PT J AU Gordeev, K Shinkarev, S Ilyin, L Bouville, A Hosh, M Luckyanov, N Simon, SL AF Gordeev, K Shinkarev, S Ilyin, L Bouville, A Hosh, M Luckyanov, N Simon, SL TI Retrospective dose assessment for the population living in areas of local fallout from the Semipalatinsk Nuclear Test Site - Part II: Internal exposure to thyroid SO JOURNAL OF RADIATION RESEARCH LA English DT Article; Proceedings Paper CT 3rd Dosimetry Workshop on the Semipalatinsk Nuclear Test Site Area CY MAR 09-11, 2005 CL Hiroshima Univ, Hiroshima, JAPAN HO Hiroshima Univ ID KAZAKSTAN AB A methodology to assess internal exposure to thyroid from radioiodines for the residents living in settlements located in the vicinity of the Semipalatinsk Nuclear Test Site is described that is the result of many years of research, primarily at the Moscow Institute of Biophysics. This methodology introduces two important concepts. First, the biologically active fraction, is defined as the fraction of the total activity on fallout particles with diameter less than 50 microns. That fraction is retained by vegetation and will ultimately result in contamination of dairy products. Second, the relative distance is derived as a dimensionless quantity from information on test yield, maximum height of cloud, and average wind velocity and describes how the biologically active fraction is distributed with distance from the site of the explosion. The parameter is derived in such a way that at locations with equal values of relative distance, the biologically active fraction will be the same for any test. The estimates of internal exposure to thyroid for the residents of Dolon and Kanonerka villages, for which the external exposure were assessed and given in a companion paper (Gordeev et al. 2006) in this conference, are presented. The main sources of uncertainty in the estimates are identified. C1 Minist Publ Hlth & Social Dev, State Res Ctr, Inst Biophys, Moscow 123182, Russia. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. Hiroshima Univ, Res Inst Radiat Biol & Med, Minami Ku, Hiroshima 7348557, Japan. RP Shinkarev, S (reprint author), Minist Publ Hlth & Social Dev, State Res Ctr, Inst Biophys, 46 Zhivopisnaya St, Moscow 123182, Russia. EM sshinkarev@atom.ru RI Shinkarev, Sergey /B-3254-2017 NR 9 TC 7 Z9 7 U1 2 U2 3 PU JAPAN RADIATION RESEARCH SOC PI CHIBA PA C/O NAT INST RADIOLOGICAL SCI 9-1 ANAGAWA-4-CHOME INAGE-KU, CHIBA, 263, JAPAN SN 0449-3060 J9 J RADIAT RES JI J. Radiat. Res. PD FEB PY 2006 VL 47 SU A BP A137 EP A141 DI 10.1269/jrr.47.A137 PG 5 WC Biology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA 043KL UT WOS:000237599800019 PM 16571928 ER PT J AU Gordeev, K Shinkarev, S Ilyin, L Bouville, A Hosh, M Luckyanov, N Simon, SL AF Gordeev, Konstantin Shinkarev, Sergey Ilyin, Leonid Bouville, Andr Hoshi, Masaharu Luckyanov, Nickolas Simon, Steven L. TI Retrospective dose assessment for the population living in areas of local fallout from the Semipalatinsk Nuclear Test Site - Part I: External exposure SO JOURNAL OF RADIATION RESEARCH LA English DT Article; Proceedings Paper CT 3rd Dosimetry Workshop on the Semipalatinsk Nuclear Test Site Area CY MAR 09-11, 2005 CL Hiroshima Univ, Hiroshima, JAPAN HO Hiroshima Univ ID DOLON VILLAGE; KAZAKSTAN; DOSIMETRY; RESIDENTS; VICINITY AB A short analysis of all 111 atmospheric events conducted at the Semipalatinsk Test Site (STS) in 1949-1962 with regard to significant off-site exposure (more than 5 mSv of the effective dose during the first year after the explosion) has been made. The analytical method used to assess external exposure to the residents living in settlements near the STS is described. This method makes use of the archival data on the radiological conditions, including the measurements of exposure rate. Special attention was given to the residents of Dolon and Kanonerka villages exposed mainly as a result of the first test, detonated on August 29, 1949. For the residents of those settlements born in 1935, the dose estimates calculated according to the analytical method, are compared to those derived from the thermoluminescence measurements in bricks and electron paramagnetic resonance measurements in teeth. The methods described in this paper were used for external dose assessment for the cohort members at an initial stage of an ongoing epidemiological study conducted by the U.S. National Cancer Institute in the Republic of Kazakhstan. Recently revised methods and estimates of external exposure for that cohort are given in another paper (Simon et al.) in this conference. C1 Minist Publ Hlth & Social Dev, Inst Biophys, State Res Ctr, Moscow 123182, Russia. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. Hiroshima Univ, Res Inst Radiat Biol & Med, Minami Ku, Hiroshima 7348557, Japan. RP Shinkarev, S (reprint author), Minist Publ Hlth & Social Dev, Inst Biophys, State Res Ctr, 46 Zhivopisnaya St, Moscow 123182, Russia. EM sshinkarev@atom.ru RI Shinkarev, Sergey /B-3254-2017 NR 24 TC 19 Z9 20 U1 0 U2 1 PU JAPAN RADIATION RESEARCH SOC PI CHIBA PA C/O NAT INST RADIOLOGICAL SCI 9-1 ANAGAWA-4-CHOME INAGE-KU, CHIBA, 263, JAPAN SN 0449-3060 J9 J RADIAT RES JI J. Radiat. Res. PD FEB PY 2006 VL 47 SU A BP A129 EP A136 DI 10.1269/jrr.47.A129 PG 8 WC Biology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA 043KL UT WOS:000237599800018 PM 16571927 ER PT J AU Simon, SL Beck, HL Gordeev, K Bouville, A Anspaugh, LR Land, CE Luckyanov, N Shinkarev, S AF Simon, SL Beck, HL Gordeev, K Bouville, A Anspaugh, LR Land, CE Luckyanov, N Shinkarev, S TI External dose estimates for Dolon village: Application of the US/Russian joint methodology SO JOURNAL OF RADIATION RESEARCH LA English DT Article; Proceedings Paper CT 3rd Dosimetry Workshop on the Semipalatinsk Nuclear Test Site Area CY MAR 09-11, 2005 CL Hiroshima Univ, Hiroshima, JAPAN HO Hiroshima Univ ID FALLOUT AB Methods to estimate external dose from radioactive fallout from nuclear tests have for many years depended on two types of data: measurements of exposure rate in air and an empirically derived power function to describe the change in exposure rate with time, Over the last four years, a working group with American and Russian participation has developed a bi-national joint methodology that offers an improved capability for estimating external dose. In this method, external dose is estimated using exposure rate functions derived from data from American nuclear tests similar in construction to SNTS (Semipalatinsk Nuclear Test Site) devices. For example, in this paper, we derive doses for test #1 (August 29, 1949) at the SNTS using an exposure rate function for the U.S. TRINITY test. For the case of test #1, the average external dose for a person in Dolon is estimated to have been about 0.5 Gy compared to 1 to 2 Gy estimated in other work. This prediction agrees better with reported EPR measurements in teeth from village residents and with measurements of TL signals in bricks from Dolon buildings. This report presents the basic elements of the joint methodology model for estimation of external dose received from SNTS fallout. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. US DOE, Environm Measurements Lab, New York, NY 10014 USA. Univ Utah, Salt Lake City, UT USA. Minist Publ Hlth Russia, Inst Biophys, Moscow, Russia. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov RI Shinkarev, Sergey /B-3254-2017 FU Intramural NIH HHS NR 16 TC 14 Z9 14 U1 0 U2 2 PU JAPAN RADIATION RESEARCH SOC PI CHIBA PA C/O NAT INST RADIOLOGICAL SCI 9-1 ANAGAWA-4-CHOME INAGE-KU, CHIBA, 263, JAPAN SN 0449-3060 J9 J RADIAT RES JI J. Radiat. Res. PD FEB PY 2006 VL 47 SU A BP A143 EP A147 DI 10.1269/jrr.47.A143 PG 5 WC Biology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA 043KL UT WOS:000237599800020 PM 16571929 ER PT J AU Stepanenko, VF Hoshi, M Bailiff, IK Ivannikov, AI Toyoda, S Yamamoto, M Simon, SL Matsuo, M Kawano, N Zhumadilov, Z Sasaki, MS Rosenson, RI Apsalikov, KN AF Stepanenko, Valeriy F. Hoshi, Masaharu Bailiff, Ian K. Ivannikov, Alexander I. Toyoda, Shin Yamamoto, Masayoshi Simon, Steven L. Matsuo, Masatsugu Kawano, Noriyuki Zhumadilov, Zhaxybay Sasaki, Masao S. Rosenson, Rafail I. Apsalikov, Kazbek N. TI Around Semipalatinsk nuclear test site: Progress of dose estimations relevant to the consequences of nuclear tests - (A summary of 3rd Dosimetry Workshop on the Semipalatinsk Nuclear Test Site Area, RIRBM, Hiroshima University, Hiroshima, 9-11 of March, 2005) SO JOURNAL OF RADIATION RESEARCH LA English DT Article; Proceedings Paper CT 3rd Dosimetry Workshop on the Semipalatinsk Nuclear Test Site Area CY MAR 09-11, 2005 CL Hiroshima Univ, Hiroshima, JAPAN HO Hiroshima Univ DE retrospective dosimetry; Semipanalatinsk; nuclear tests; health consequences of irradiation AB The paper is an analytical overview of the main results presented at the 3(rd) Dosimetry Workshop in Hiroshima (9-11 of March 2005), where different aspects of the dose reconstruction around the Semipalatinsk nuclear test site (SNTS) were discussed and summarized. The results of the international intercomparison of the retrospective luminescence dosimetry (RLD) method for Dolon' village (Kazakhstan) were presented at the Workshop and good concurrence between dose estimations by different laboratories from 6 countries (Japan, Russia, USA, Germany, Finland and UK) was pointed out. The accumulated dose values in brick for a common depth of 10 mm depth obtained independently by all participating laboratories were in good agreement for all four brick samples from Dolon' village, Kazakhstan, with the average value of the local gamma dose due to fallout (near the sampling locations) being about 220 mGy (background dose has been subtracted). Furthermore, using a conversion factor of about 2 to obtain the free-in-air dose, a value of local dose similar to 440 mGy is obtained, which supports the results of external dose calculations for Dolon': recently published soil contamination data, archive information and new models were used for refining dose calculations and the external dose in air for Dolon village was estimated to be about 500 mGy. The results of electron spin resonance (ESR) dosimetry with tooth enamel have demonstrated the notable progress in application of ESR dosimetry to the problems of dose reconstruction around the Semipalatinsk nuclear test site. At the present moment, dose estimates by the ESR method have become more consistent with calculated values and with retrospective luminescence dosimetry data, but differences between ESR dose estimates and RLD/calculation data were noted. For example mean ESR dose for eligible tooth samples from Dolon' village was estimated to be about 140 mGy (above background dose), which is less than dose values obtained by RLD and calculations. A possible explanation of the differences between ESR and RLD/calculations doses is the following: for interpretation of ESR data the "shielding and behaviour" factors for investigated persons should be taken into account. The "upper level" of the combination of "shielding and behaviour" factors of dose reduction for inhabitants of Dolon' village of about 0.28 was obtained by comparing the individual ESR tooth enamel dose estimates with the calculated mean dose for this settlement. The biological dosimetry data related to the settlements near SNTS were presented at the Workshop. A higher incidence of unstable chromosome aberrations, micronucleus in lymphocytes, nuclear abnormalities of thyroid follicular cells, T-cell receptor mutations in peripheral blood were found for exposed areas (Dolon', Sarjal) in comparison with unexposed ones (Kokpekty). The significant greater frequency of stable translocations (results of analyses of chromosome aberrations in lymphocytes by the FISH technique) was demonstrated for Dolon' village in comparison with Chekoman (unexposed village). The elevated level of stable translocations in Dolon' corresponds to a dose of about 180 mSv, which is close to the results of ESR dosimetry for this village. The importance of investigating specific morphological types of thyroid nodules for thyroid dosimetry studies was pointed out. In general the 3(rd) Dosimetry Workshop has demonstrated remarkable progress in developing an international level of common approaches for retrospective dose estimations around the SNTS and in understanding the tasks for the future joint work in this direction. In the framework of a special session the problems of developing a database and registry in order to support epidemiological studies around SNTS were discussed. The results of investigation of psychological consequences of nuclear tests, which are expressed in the form of verbal behaviour, were presented at this session as well. C1 Hiroshima Univ, RIRBM, Minami Ku, Hiroshima 7348553, Japan. RAMS, MRRC, Obninsk 249036, Russia. Univ Durham, Environm Res Ctr, Luminescence Lab, Durham DH1 3LE, England. Okayama Univ, Dept Appl Phys, Okayama 7000005, Japan. Kanazawa Univ, Low Level Radioactiv Lab, Nomi, Ishikawa, Japan. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. Hiroshima Univ, Inst Peace Sci, Naka Ku, Hiroshima 7300053, Japan. Kyoto Univ, Kyoto, Japan. Semipalatinsk State Med Acad, Semipalatinsk, Kazakhstan. SRIRME, Semipalatinsk 490026, Kazakhstan. RP Stepanenko, VF (reprint author), Hiroshima Univ, RIRBM, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. EM mrrc@obninsk.ru RI Apsalikov, Kazbek/C-2974-2014 NR 44 TC 16 Z9 18 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0449-3060 EI 1349-9157 J9 J RADIAT RES JI J. Radiat. Res. PD FEB PY 2006 VL 47 SU A BP A1 EP A13 DI 10.1269/jrr.47.A1 PG 13 WC Biology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA 043KL UT WOS:000237599800002 PM 16571923 ER PT J AU Kelly, E Cai, YC McKenzie, T Chang, N Lim, S Harrison, H Hudson, T Cooper, G Greenwood, C Fortin, P Wither, J AF Kelly, E Cai, YC McKenzie, T Chang, N Lim, S Harrison, H Hudson, T Cooper, G Greenwood, C Fortin, P Wither, J TI Evidence for abnormal B and T cell activation in lupus patients but not their parents SO JOURNAL OF RHEUMATOLOGY LA English DT Meeting Abstract CT 1st Mexican-Canadian Congress of Rheumatology CY FEB 17-21, 2006 CL Acapulco, MEXICO C1 Univ Western Ontario, Toronto, ON, Canada. Univ Toronto, Hlth Network, Toronto, ON, Canada. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. McGill Univ, Montreal, PQ H3A 2T5, Canada. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD FEB PY 2006 VL 33 IS 2 BP 392 EP 393 PG 2 WC Rheumatology SC Rheumatology GA 010GD UT WOS:000235174200114 ER PT J AU Whipple, B Komisaruk, BR AF Whipple, B Komisaruk, BR TI Where in the brain is a woman's sexual response? Laboratory studies including brain imaging during orgasm SO JOURNAL OF SEX RESEARCH LA English DT Meeting Abstract C1 State Univ New Jersey, New Brunswick, NJ USA. Natl Inst Gen Med Sci, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 4 PU SOC SCIENTIFIC STUDY SEX INC PI MT VERNON PA PO BOX 208, MT VERNON, IA 52314 USA SN 0022-4499 J9 J SEX RES JI J. Sex Res. PD FEB PY 2006 VL 43 IS 1 BP 29 EP 29 PG 1 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA 015AZ UT WOS:000235525600091 ER PT J AU Fischer, TB Holmes, JB Miller, IR Parsons, JR Tung, L Hu, JC Tsai, J AF Fischer, TB Holmes, JB Miller, IR Parsons, JR Tung, L Hu, JC Tsai, J TI Assessing methods for identifying pair-wise atomic contacts across binding interfaces SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE protein-protein interactions; Voronoi polyhedra; binding interface; solvent accessible surface area; radial cutoff; protein packing ID PROTEIN-PROTEIN INTERFACES; PLACENTAL RIBONUCLEASE INHIBITOR; ANTILYSOZYME ANTIBODY HYHEL-63; DOUBLE MUTANT CYCLES; SHAPE COMPLEMENTARITY; CRYSTAL-STRUCTURE; VORONOI PROCEDURE; PACKING DENSITY; DOCKING; COMPLEX AB An essential step in understanding the molecular basis of protein-protein interactions is the accurate identification of inter-protein contacts. We evaluate a number of common methods used in analyzing protein-protein interfaces: a Voronoi polyhedra-based approach, changes in solvent accessible surface area (Delta SASA) and various radial cutoffs (closest atom, C beta, and centroid). First, we compared the Voronoi polyhedra-based analysis to the Delta SASA and show that using Voronoi polyhedra finds knob-in-hole contacts. To assess the accuracy between the Voronoi polyhedra-based approach and the various radial cutoff methods, two sets of data were used: a small set of 75 experimental mutants and a larger one of 592 structures of protein-protein interfaces. In an assessment using the small set, the Voronoi polyhedra-based methods, a solvent accessible surface area method, and the closest atom radial method identified 100%, of the direct contacts defined by mutagenesis data, but only the Voronoi polyhedra-based method found no false positives. The other radial methods were not able to find all of the direct contacts even using a cutoff of 9 angstrom. With the larger set or structures, we compared the overall number contacts using the Voronoi polyhedra-based method as a standard. All the radial methods using a 6-angstrom cutoff identified more interactions, but these putative contacts included many false positives as well as missed many false negatives. While radial cutoffs are quicker to calculate as well as to implement, this result highlights why radial cutoff methods do not have the proper resolution to detail the non-homogeneous packing within protein interfaces, and suggests an inappropriate bias in pair-wise contact potentials. Of the radial cutoff methods, using the closest atom approach exhibits the best approximation to the more intensive Voronoi calculation. Our version of the Voronoi polyhedra-based method QContacts is available at http://tsailab.tamu.edu/Qcons. (C) 2005 Elsevier Inc. All rights reserved. C1 Texas A&M Univ, Texas Agr Expt Stn, Dept Biochem & Biophys, College Stn, TX 77843 USA. NICHD, NIH, Bethesda, MD USA. Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92103 USA. Texas A&M Univ, Texas Agr Expt Stn, Ctr Adv Biomol Res, College Stn, TX 77843 USA. Texas A&M Univ, Texas Agr Expt Stn, Ctr Struct Biol, College Stn, TX 77843 USA. RP Tsai, J (reprint author), Texas A&M Univ, Texas Agr Expt Stn, Dept Biochem & Biophys, 2128 TAMU,Room 111, College Stn, TX 77843 USA. EM JerryTsai@tamu.edu OI Parsons, Jerod/0000-0002-4184-343X FU PHS HHS [NIGMS452791] NR 50 TC 18 Z9 18 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD FEB PY 2006 VL 153 IS 2 BP 103 EP 112 DI 10.1016/j.jsb.2005.11.005 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 013DJ UT WOS:000235389500001 PM 16377205 ER PT J AU Zimmerman, SB AF Zimmerman, SB TI Cooperative transitions of isolated Escherichia coli nucleoids: Implications for the nucleoid as a cellular phase SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE chloroamphenicol DNA; H protein; polyethylene glycol; polylysine; spermidine; RNase; trypsin; urea ID HISTONE-LIKE PROTEINS; DNA-BINDING PROTEINS; ATOMIC-FORCE MICROSCOPY; COIL-GLOBULE TRANSITION; DOUBLE-STRANDED DNA; SPERMIDINE NUCLEOIDS; FOLDED CHROMOSOME; H-NS; MEDIATED COMPACTION; GENOME STRUCTURE AB The genomic DNA of Escherichia coli occurs in compact bodies known as nucleoids. Organization and Structure of nucleoids lire poorly understood. Compact, characteristically shaped. nucleoids isolated by the polysine spermidine procedure were visualized by DNA fluorescence microscopy. Treatment with urea or trypsin converted compact nucleoids to partially expanded forms. The transition in urea solutions was accompanied by release of most DNA-associated proteins the transition point between compact and partially expanded forms was not changed by the loss of the proteins nor was it changed in nucleoids isolated from cells after exposure to chloramphenicol or from cells in which Dps, Fis, or H-NS and StpA had been deleted. Partially expanded forms became dispersed upon RNase exposure, indicating a role of RNA in maintaining the partial expansion. Partially expanded forms that had been stripped of most DNA-associated proteins were recompacted by polyethylene glycol 8000, a macromolecular crowding agent, in a cooperative transition. DNA-associated proteins are suggested to have relatively little effect on the phase-like behavior of the cellular nucleoid, Changes in the urea transition indicate that a previously described procedure for compaction of polylysine spermidine nucleoids may have an artifactual basis, and raise questions about reports of repetitive local structures involving the DNA of lysed (C) 2005 Elsevier Inc. All rights reserved. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zimmerman, SB (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 96 TC 34 Z9 35 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD FEB PY 2006 VL 153 IS 2 BP 160 EP 175 DI 10.1016/j.jsb.2005.10.011 PG 16 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 013DJ UT WOS:000235389500006 PM 16384714 ER PT J AU Jacob, SE Cowen, EW Goldbach-Mansky, R Kastner, D Turner, ML AF Jacob, SE Cowen, EW Goldbach-Mansky, R Kastner, D Turner, ML TI A recurrent rash with fever and arthropathy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material C1 NCI, Dermatol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NIAMSD, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Canc Res Ctr, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2006 VL 54 IS 2 BP 318 EP 321 DI 10.1016/j.jaad.2005.07.007 PG 4 WC Dermatology SC Dermatology GA 008VL UT WOS:000235068700015 PM 16443062 ER PT J AU Xu, JH Toptygin, D Graver, KJ Albertini, RA Savtchenko, RS Meadow, ND Roseman, S Callis, PR Brand, L Knutson, JR AF Xu, JH Toptygin, D Graver, KJ Albertini, RA Savtchenko, RS Meadow, ND Roseman, S Callis, PR Brand, L Knutson, JR TI Ultrafast fluorescence dynamics of tryptophan in the proteins monellin and IIA(Glc) SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TIME-RESOLVED FLUORESCENCE; SIGNAL-TRANSDUCING PROTEIN; LIFETIME DISTRIBUTIONS; ESCHERICHIA-COLI; EXCITED-STATE; FEMTOSECOND RESOLUTION; SOLVENT RELAXATION; WATER; DECAY; SOLVATION AB The complete time-resolved fluorescence of tryptophan in the proteins monellin and IIA(Glc) has been investigated, using both an upconversion spectrophotofluorometer with 150 fs time resolution and a time-correlated single photon counting apparatus on the 100 ps to 20 ns time scale. In monellin, the fluorescence decay displays multiexponential character with decay times of 1.2 and 16 ps, and 0.6, 2.2, and 4.2 ns. In contrast, IIA(Glc) exhibited no component between 1.2 ps and 0.1 ns. For monellin, surprisingly, the 16 ps fluorescence component was found to have positive amplitude even at longer wavelengths (e.g., 400 nm). In conjunction with quantum mechanical simulation of tryptophan in monellin, the experimental decay associated spectra (DAS) and time-resolved emission spectra (TRES) indicate that this fluorescence decay time should be ascribed to a highly quenched conformer. Recent models (Peon, J.; et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 10964) invoked exchange-coupled relaxation of protein water to explain the fluorescence decay of monellin. C1 NHLBI, Opt Spect Sect, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. RP Knutson, JR (reprint author), NHLBI, Opt Spect Sect, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. EM jaysan@helix.nih.gov FU Intramural NIH HHS; NIGMS NIH HHS [GM-38759] NR 48 TC 39 Z9 40 U1 3 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 1 PY 2006 VL 128 IS 4 BP 1214 EP 1221 DI 10.1021/ja055746h PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 007BA UT WOS:000234941100046 PM 16433538 ER PT J AU Dye, BA Morin, NM Robinson, V AF Dye, BA Morin, NM Robinson, V TI The relationship between cigarette smoking and perceived dental treatment needs in the United States, 1988-1994 SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE perceived dental treatment needs; tobacco use; NHANES III ID QUALITY-OF-LIFE; ORAL-HEALTH; PERIODONTAL-DISEASE; NATIONAL-HEALTH; OLDER ADULTS; TOBACCO USE; NHANES-III; CANCER; RISK; EPIDEMIOLOGY AB Background. Although factors affecting perceived dental treatment needs have been investigated, the effect of smoking status on perceptions of dental needs has not been examined. Methods. The authors examined data on 13,227 dentate people aged 20 to 79 years from the Third National Health and Nutrition Examination Survey (NHANES III). Information was collected information on sociodemographic characteristics, cigarette smoking, perceived dental treatment needs and other factors during a home interview, and clinical oral health information was collected at a mobile examination center. Results. In univariate analyses, current smokers were more likely than nonsmokers to perceive dental needs in all categories, except for the need for a dental cleaning. Multivariate regression results indicate that current smokers were more likely to report a need for periodontal treatment and dental extractions compared with nonsmokers (odds ratio [OR] = 1.40; 95 percent confidence interval [CI] = 1.05-1.87 and OR = 1.61; 95 percent CI = 1.22-2.14, respectively). The authors found an interaction between smoking and race/ethnicity in models describing the need for teeth to be filled/replaced and for orthodontic/cosmetic work. Conclusions. Current smokers were more likely to have more perceived dental needs compared with nonsmokers. Practice Implications. These results may be important for the advancement of efforts directed toward tobacco-use cessation programs and to understand factors that could affect dental care utilization. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, NHANES Program, Hyattsville, MD 20782 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. Ctr Dis Control & Prevent, Div Oral Hlth, Atlanta, GA USA. RP Dye, BA (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, NHANES Program, 3311 Toledo Rd,Room 4416, Hyattsville, MD 20782 USA. EM bfd1@cdc.gov NR 47 TC 18 Z9 19 U1 0 U2 2 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD FEB PY 2006 VL 137 IS 2 BP 224 EP 234 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 013QI UT WOS:000235423800023 PM 16521389 ER PT J AU Gray, SL LaCroix, AZ Hanlon, JT Penninx, BWJH Blough, DK Leveille, SG Artz, MB Guralnik, JM Buchner, DM AF Gray, SL LaCroix, AZ Hanlon, JT Penninx, BWJH Blough, DK Leveille, SG Artz, MB Guralnik, JM Buchner, DM TI Benzodiazepine use and physical disability in community-dwelling older adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE benzodiazepines; activities of daily living; disability; adverse drug event ID ELIMINATION HALF-LIFE; MEDICATION USE; RISK-FACTORS; ESTABLISHED POPULATIONS; DEPRESSIVE SYMPTOMS; FUNCTIONAL STATUS; CONSENSUS PANEL; ELDERLY-PEOPLE; HIP FRACTURE; DRUG-USE AB OBJECTIVES: To determine whether benzodiazepine use is associated with incident disability in mobility and activities of daily living (ADLs) in older individuals. DESIGN: A prospective cohort study. SETTING: Four sites of the Established Populations for Epidemiologic Studies of the Elderly. PARTICIPANTS: This study included 9,093 subjects (aged >= 65) who were not disabled in mobility or ADLs at baseline. MEASUREMENTS: Mobility disability was defined as inability to walk half a mile or climb one flight of stairs. ADL disability was defined as inability to perform one or more basic ADLs (bathing, eating, dressing, transferring from a bed to a chair, using the toilet, or walking across a small room). Trained interviewers assessed outcomes annually. RESULTS: At baseline, 5.5% of subjects reported benzodiazepine use. In multivariable models, benzodiazepine users were 1.23 times as likely as nonusers (95% confidence interval (CI)=1.09-1.39) to develop mobility disability and 1.28 times as likely (95% CI=1.09-1.52) to develop ADL disability. Risk for incident mobility was increased with short- (hazard ratio (HR)=1.27, 95% CI=1.08-1.50) and long-acting benzodiazepines (HR=1.20, 95% CI=1.03-1.39) and no use. Risk for ADL disability was greater with short- (HR=1.58, 95% CI=1.25-2.01) but not long-acting (HR=1.11, 95% CI=0.89-1.39) agents than for no use. CONCLUSION: Older adults taking benzodiazepines have a greater risk for incident mobility and ADL disability. Use of short-acting agents does not appear to confer any safety benefits over long-acting agents. C1 Univ Washington, Sch Pharm, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat Clin Coordinating Ctr, Seattle, WA 98104 USA. Grp Hlth Cooperat Puget Sound, Seattle, WA 98121 USA. Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr Med, Pittsburgh, PA USA. Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. Vet Adm Pittsburgh Hlth Care Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. Vrije Univ Amsterdam, Ctr Med, Dept Psychiat, NL-1081 HV Amsterdam, Netherlands. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. NIA, Epidemiol & Demog Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Phys Act & Hlth Branch, Atlanta, GA USA. RP Gray, SL (reprint author), Univ Washington, Sch Pharm, Bpx 357630, Seattle, WA 98195 USA. EM slgray@u.washington.edu FU NIA NIH HHS [K08AG00808-01, P01 AG004390, P01 AG004390-21A10016] NR 42 TC 67 Z9 68 U1 1 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2006 VL 54 IS 2 BP 224 EP 230 DI 10.1111/j.1532-5415.2005.00571.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 009FZ UT WOS:000235098300004 PM 16460372 ER PT J AU Hoenig, H Ganesh, SP Taylor, DH Pieper, C Guralnik, J Fried, LP AF Hoenig, H Ganesh, SP Taylor, DH Pieper, C Guralnik, J Fried, LP TI Lower extremity physical performance and use of compensatory strategies for mobility SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT 66th Annual Assembly of the American-Academy-for-Physical-Medicine-and-Rehabilitation CY OCT 27-30, 2005 CL Philadelphia, PA SP Amer Acad Phys Med & Rehabilitat DE disability measurement; mobility; assistive technology; history of medicine; activities of daily living ID ASSISTIVE TECHNOLOGY; SUBSEQUENT DISABILITY; PERSONAL ASSISTANCE; WHEELCHAIR USERS; OLDER WOMEN; COMMUNITY; CARE; REHABILITATION; BATTERY; TRIAL AB OBJECTIVES: To compare measured lower extremity physical performance in the clinic with the methods used to carry out mobility tasks at home and to identify key factors influencing day-to-day task performance. DESIGN: Cross-sectional analysis of the Women's Health and Aging Study I. SETTING: Community-dwelling female residents of Baltimore, Maryland. PARTICIPANTS: One thousand two cognitively intact women aged 65 and older with moderate to severe physical limitations. MEASUREMENTS: Compensatory strategies reportedly used for mobility in the home, distinguishing between use of no compensatory strategies, behavioral changes only, durable medical equipment (DME) with or without behavioral change, and human help; measured lower extremity (LE) physical performance (gait speed, timed chair stands, balance). RESULTS: There was a statistically significant difference in LE physical performance between women using the four types of compensatory strategy (P <.001). Women who used DME for mobility in the home had worse performance than those using human help who in turn had worse performance than those with behavioral changes only; women reporting no compensatory strategies for in-home mobility performed best. Sequential multivariate logistic regressions identified several factors other than LE physical performance that were associated with use of specific compensatory strategies. Medical conditions, education, and environmental barriers influenced whether compensatory strategies were used at all, whereas income, contact with health providers, and availability of help in the home influenced the type of compensatory strategy. CONCLUSION: Physical abilities are an important factor influencing use of compensatory strategies for mobility, but several other factors also influence the ways that women adapt to mobility limitations. C1 Duke Univ, Phys Med & Rehabil Serv, Durham, NC USA. Duke Univ, Div Geriatr, Durham, NC USA. Duke Univ, Med Ctr, Div Biostat & Bioinformat, Durham, NC USA. Duke Univ, Sch Med, Durham, NC USA. Duke Univ, Ctr Hlth Policy Law & Management, Durham, NC USA. NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Hlth Policy, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Nursing, Baltimore, MD 21205 USA. RP Hoenig, H (reprint author), Rehabil Serv, 508 Fulton St, Durham, NC 27705 USA. EM helen.hoenig@med.va.gov FU NIA NIH HHS [R37AG019905, 2P60AG11268]; PHS HHS [1A9-1-2112] NR 31 TC 16 Z9 16 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2006 VL 54 IS 2 BP 262 EP 269 DI 10.1111/j.1532-5415.2005.00588.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 009FZ UT WOS:000235098300009 PM 16460377 ER PT J AU Fox, CS Larson, MG Vasan, RS Guo, CY Parise, H Levy, D Leip, EP O'Donnell, CJ D'Agostino, RB Benjamin, EJ AF Fox, Caroline S. Larson, Martin G. Vasan, Ramachandran S. Guo, Chao-Yu Parise, Helen Levy, Daniel Leip, Eric P. O'Donnell, Christopher J. D'Agostino, Ralph B., Sr. Benjamin, Emelia J. TI Cross-sectional association of kidney function with valvular and annular calcification: The Framingham Heart Study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CARDIAC-VALVE CALCIFICATION; GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; ALL-CAUSE MORTALITY; CORONARY-ARTERY CALCIFICATION; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; SERUM CREATININE; CARDIOVASCULAR MORTALITY; ATRIAL-FIBRILLATION AB Valvular calcification is common in the setting of end-stage kidney disease and is associated with increased risks for cardiovascular disease events. It is unknown whether the prevalence of valvular calcification is increased in milder kidney disease after accounting for cardiovascular risk factors. Participants who attended the sixth examination of the Framingham Offspring Study (1995 to 1998) were eligible. Kidney function was estimated by GFR using the simplified Modification of Diet in Renal Disease Study equation. Mitral annular calcification (MAC), aortic sclerosis, and aortic annular calcification were assessed by two-dimensional echocardiography. Logistic regression was used to examine the odds of valvular calcification among participants with chronic kidney disease (CKD; GFR < 60 ml/min per 1.73 m(2)). A total of 3047 participants (52% women; mean age 59 +/- 10 yr) were available for analysis. CKD was present in 8.6% (n = 262) of the sample. Among participants with valve/annular calcification (n = 284; 9.3%), 20% had CKD, compared with 7% in patients without valvular calcification. After adjustment for age, gender, systolic and diastolic BP, hypertension treatment, total/HDL cholesterol, body mass index, diabetes, smoking status, and cardiovascular disease, participants with CKD had a 60% increased odds of MAC (odds ratio 1.6; 95% confidence interval 1.03 to 2.5). There was no significant association between CKD and either aortic sclerosis or aortic annular calcification (odds ratio 1.1 and 1.1, respectively). After age and gender adjustment, the combination of both CKD and MAC was associated with a three-fold increased risk for death compared with those with neither condition (P = 0.0004). In the community, CKD is associated with presence of MAC before the onset of ESRD. Further research is warranted to understand whether traditional and novel vascular risk factor burden, as well as metabolic derangements found in early kidney disease, can account for the CKD-MAC association. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [2K24-HL-04334, N01-HC-25195]; NINDS NIH HHS [6R01-NS-17950] NR 48 TC 62 Z9 66 U1 0 U2 1 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2006 VL 17 IS 2 BP 521 EP 527 DI 10.1681/ASN.2005060627 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 106SD UT WOS:000242120200027 PM 16382018 ER PT J AU Cheung, AK Rocco, MV Yan, GF Leypoldt, JK Levin, NW Greene, T Agodoa, L Bailey, J Beck, GJ Clark, W Levey, AS Ornt, DB Schulman, G Schwab, S Teehan, B Eknoyan, G AF Cheung, Alfred K. Rocco, Michael V. Yan, Guofen Leypoldt, John K. Levin, Nathan W. Greene, Tom Agodoa, Lawrence Bailey, James Beck, Gerald J. Clark, William Levey, Andrew S. Ornt, Daniel B. Schulman, Gerald Schwab, Steven Teehan, Brendan Eknoyan, Garabed CA HEMO Study Grp TI Serum beta-2 microglobulin levels predict mortality in dialysis patients: Results of the HEMO study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MAINTENANCE HEMODIALYSIS-PATIENTS; HIGH-FLUX HEMODIALYSIS; PERITONEAL-DIALYSIS; RENAL-FUNCTION; BETA(2)-MICROGLOBULIN; UREA; CLEARANCES; DISEASES; PROTEIN; TRIAL AB sIn the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta M-2) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta M-2 levels and the associations of serum beta M-2 levels or dialyzer beta M-2 clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta M-2 clearance were strong predictors of predialysis serum beta M-2 levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/- 0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/- 0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta M-2 levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta M-2 levels but not dialyzer beta M-2 clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta M-2 level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta M-2 as a marker to guide chronic hemodialysis therapy. C1 Univ Utah, Med Ctr, Dialysis Program, Dept Med, Salt Lake City, UT 84112 USA. VA Salt Lake City Healthcare Syst, Salt Lake City, UT USA. Wake Forest Univ, Dept Med, Winston Salem, NC USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Renal Res Inst, New York, NY USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Emory Univ, Dept Med, Atlanta, GA 30322 USA. Baxter Corp, McGaw Pk, IL USA. Tufts Univ, New England Med Ctr, Dept Med, Boston, MA 02111 USA. Univ Rochester, Dept Med, Rochester, NY USA. Vanderbilt Univ, Dept Med, Nashville, TN USA. Duke Univ, Dept Med, Durham, NC USA. Lankenau Hosp, Dept Med, Philadelphia, PA USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Cheung, AK (reprint author), Univ Utah, Med Ctr, Dialysis Program, Dept Med, 85 N Med Dr E,Room 201, Salt Lake City, UT 84112 USA. EM alfred.cheung@hsc.utah.edu NR 32 TC 221 Z9 231 U1 0 U2 7 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2006 VL 17 IS 2 BP 546 EP 555 DI 10.1681/ASN.2005020132 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 106SD UT WOS:000242120200030 PM 16382021 ER PT J AU Schrag, D Earle, C Xu, F Panageas, KS Yabroff, KR Bristow, RE Trimble, EL Warren, JL AF Schrag, D Earle, C Xu, F Panageas, KS Yabroff, KR Bristow, RE Trimble, EL Warren, JL TI Associations between hospital and surgeon procedure volumes and patient outcomes after ovarian cancer resection SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID OPERATIVE MORTALITY; UNITED-STATES; COLON-CANCER; HIGH-RISK; SURVIVAL; IMPACT; CARE AB Background. Strong associations between provider (i.e., hospital or surgeon) procedure volumes and patient outcomes have been demonstrated for many types of cancer operation. We performed a population-based cohort stud), to examine these associations for ovarian cancer resections. Method: We used the Surveillance, Epidemiology, and End Results (SEER)Medicare linked database to identify 2952 patients aged 65 years or older who had surgery for a primary ovarian cancer diagnosed from 1992 through 1999. Hospital- and surgeon-specific procedure volumes were ascertained based on the number of claims submitted during the 8-year study period. Primary outcome measures were mortality at 60 days and 2 years after surgery, and overall survival. Length of hospital stay was also examined. Patient age at diagnosis, race, marital status, comorbid illness, cancer stage, and median income and population density in the area of residence were used to adjust for differences in case mix. All P values are two-sided. Results: Neither hospital- nor surgeon-specific procedure volume was statistically significantly associated with 60-day mortality following primary ovarian cancer resection. However, differences by hospital volume were seen with 2-year mortality; patients treated at the low-, intermediate-, and high-volume hospitals had 2-year mortality rates of 45.2% (95%, confidence interval [CI] = 42.1% to 48.4%), 41.1% (95% Cl = 38.1% to 44.3%), and 40.4% (95% Cl = 37.4% to 43.4%), respectively. The inverse association between hospital procedure volume and 2-year mortality was statistically significant both before (P=.011) and after (P=.006) case-mix adjustment but not after adjustment for surgeon volume. Two-year mortality for patients treated by low-, intermediate-, and high-volume surgeons was 43.20%(95% CI=40.70% to 45.8%),42.9% (95% CI = 39.5% to 46.4%), and 39.5% (95% CI = 36.0% to 43.2%), respectively,; there was no association between 2-year mortality and surgeon procedure volume, with or without case-mix adjustment. After case-mix adjustment, neither hospital volume (P = .031) nor surgeon volume (P = .062) was strongly associated with overall survival. Conclusion: Hospital- and surgeon-specific procedure volumes are not strong predictors of survival outcomes following surgery for ovarian cancer among women aged 65 years or older. C1 Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. Johns Hopkins Med Inst, Dept Obstet & Gynecol, Baltimore, MD 21205 USA. Natl Canc Inst, Appl Res Program, Bethesda, MD USA. Natl Canc Inst, Canc Therapy & Evaluat Program, Bethesda, MD USA. RP Schrag, D (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Box 221,1275 York Ave, New York, NY 10021 USA. EM schragd@mskcc.org OI Yabroff, K. Robin/0000-0003-0644-5572 NR 27 TC 99 Z9 99 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 1 PY 2006 VL 98 IS 3 BP 163 EP 171 DI 10.1093/jnci/djj018 PG 9 WC Oncology SC Oncology GA 010SR UT WOS:000235218700008 PM 16449676 ER PT J AU Earle, CC Schrag, D Neville, BA Yabroff, KR Topor, M Fahey, A Trimble, EL Bodurka, DC Bristow, RE Carney, M Warren, JL AF Earle, CC Schrag, D Neville, BA Yabroff, KR Topor, M Fahey, A Trimble, EL Bodurka, DC Bristow, RE Carney, M Warren, JL TI Effect of surgeon specialty on processes of care and outcomes for ovarian cancer patients SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COMORBIDITY INDEX; UNITED-STATES; CHEMOTHERAPY; CARCINOMA; SURVIVAL; PATTERNS; IMPACT; WOMEN AB Background. For many diseases, specialized care (i.e., care rendered by a specialist) has been associated with superior-quality care (i.e., better outcomes). We examined associations between physician specialty and outcomes in a population-based cohort of elderly ovarian cancer surgery patients. Methods: We analyzed the Medicare claims, by physician specialty, of all women aged 65 years or older who,underwent surgery for pathologically confirmed invasive epithelial ovarian cancer between January 1, 1992, and December 31, 1999, while living in an area monitored by the Surveillance, Epidemiology, and End Results (SEER) program to assess important care processes (i.e., the appropriate extent of surgery and use of adjuvant chemotherapy) and outcomes (i.e., surgical complications, ostomy rates, and survival). All statistical tests were two-sided. Results: Among 3067 ovarian cancer patients who underwent surgery, 1017 patients (33%) were treated by a gynecologic oncologist, 1377 patients (45%) by a general gynecologist, and 673 patients (22%) by a general surgeon. Among patients with stage I or II disease, those treated by a gynecologic oncologist (60%) were more likely to undergo lymph node dissection than those treated by a general gynecologist (36%) or a general surgeon (16%). Patients with stage III or IV disease were more likely to undergo a debulking procedure if the initial surgery was performed by a gynecologic oncologist (58%) than by a general gynecologist (51 %) or a general surgeon (40%; P <.001) and were more likely to receive postoperative chemotherapy when operated on by a gynecologic oncologist (79%) or a general gynecologist (76%) than by a general surgeon (62%, P <.001). Survival among patients operated on by gynecologic oncologists (hazard ratio [HR] of death from any cause = 0.85, 95% confidence interval [CI] = 0.76 to 0.95) or general gynecologists (HR = 0.86, 95% CI = 0.78 to 0.96) was better than that among patients operated on by general surgeons. Conclusions: Ovarian cancer patients treated by gynecologic oncologists had marginally better outcomes than those treated by general gynecologists and clearly superior outcomes compared with patients treated by general surgeons. C1 Dana Farber Canc Ctr, Dept Med Oncol, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Natl Canc Inst, Appl Res Program, Bethesda, MD USA. Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. Informat Management Serv Inc, Rockville, MD USA. Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Univ Hawaii, Kapiolani Med Ctr, Dept Obstet Gynecol & Womens Hlth, Honolulu, HI 96822 USA. RP Earle, CC (reprint author), Dana Farber Canc Ctr, Dept Med Oncol, Ctr Outcomes & Policy Res, 44 Binney St, Boston, MA 02115 USA. EM craig_earle@dfci.harvard.edu OI Yabroff, K. Robin/0000-0003-0644-5572 NR 24 TC 208 Z9 210 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 1 PY 2006 VL 98 IS 3 BP 172 EP 180 DI 10.1093/jnci/djj019 PG 9 WC Oncology SC Oncology GA 010SR UT WOS:000235218700009 PM 16449677 ER PT J AU Khan, T Hixon, JA Stauffer, JK Lincoln, E Back, TC Brenner, J Lockett, S Nagashima, K Powell, D Wigginton, JM AF Khan, T Hixon, JA Stauffer, JK Lincoln, E Back, TC Brenner, J Lockett, S Nagashima, K Powell, D Wigginton, JM TI Therapeutic modulation of Akt activity and antitumor efficacy of interleukin-12 against orthotopic murine neuroblastoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TRAIL-INDUCED APOPTOSIS; CELL STIMULATORY FACTOR; PROTEIN-KINASE-B; FAS-MEDIATED APOPTOSIS; PHASE-I TRIAL; IFN-GAMMA; INTERFERON-GAMMA; T-CELLS; CASPASE-8 EXPRESSION; COMPLETE REGRESSION AB Background: Patients with advanced neuroblastoma have a poor prognosis. The antiapoptotic protein Akt has been implicated as a possible mediator of the resistance of human neuroblastoma cells to apoptosis; the proapoptotic protein Bid, is inhibited by activated Akt. Neuroblastoma has demonstrated responsiveness to immunotherapeutic approaches in preclinical studies, prompting investigation of new therapeutic strategies based on potentiation of the host immune response, including the use of systemic cytokines. Methods: We examined the antitumor efficacy and mechanisms of action of the central immunoregulatory cytokine interleukin-12 (IL-12) in mice bearing established orthotopic neuroblastoma tumors derived from murine TBJ and Neuro-2a cells. Cohorts of mice (10 mice/group) bearing established orthotopic neuroblastoma tumors were injected intraperitoneally with IL-12 or vehicle and monitored for survival. IL-12-induced apoptosis within the tumor microenvironment was investigated using ribonuclease protection assays, nuclear staining, and electron microscopy. Protein expression was determined via Western blot analysis and enzyme-linked immunosorbent assays. Confocal microscopy was used to examine the distribution of overexpressed Bid-enhanced green fluorescent protein fusion protein (Bid-EGFP) in TBJ cells. All statistical tests were two-sided. Results: IL-12 induced complete tumor regression and long-term survival of 8 (80%) of 10 mice bearing established neuroblastoma tumors compared with 1 (10%) of 10 control mice (P = .0055) and profound tumor cell apoptosis in vivo despite the fact that TBJ and Neuro-2a cells were resistant to receptor-mediated apoptosis in vitro. These cells expressed high levels of phosphorylated Akt, a key prosurvival molecule, and Akt inhibitors sensitized neuroblastoma cells to apoptosis mediated by IL-12-inducible cytokines including tumor necrosis factor-a and interferon-7 in vitro. IL-12 increased the expression of proapoptotic genes and decreased Akt phosphorylation within established TBJ tumors in conjunction with activation and subcellular translocation of Bid. Conclusions: Our results suggest that IL-12 overcomes a potentially critical mechanism of tumor self-defense in vivo by inhibiting Akt activity and imply that IL-12 may possess unique therapeutic activity against tumors that express high levels of activated Akt. C1 NCI, Pediat Oncol Branch, Canc Res Ctr, Ft Detrick, MD 21702 USA. NCI, Data Management Serv, Ft Detrick, MD 21702 USA. Natl Canc Inst, SAIC Frederick, Intramural Res Support Program, Frederick, MD USA. Natl Canc Inst, SAIC Frederick, Image Anal Lab, Frederick, MD USA. RP Wigginton, JM (reprint author), NCI, Pediat Oncol Branch, Canc Res Ctr, Bldg 560,Room 31-93, Ft Detrick, MD 21702 USA. EM jw12lb@nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 81 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 1 PY 2006 VL 98 IS 3 BP 190 EP 202 DI 10.1093/jnci/djj021 PG 13 WC Oncology SC Oncology GA 010SR UT WOS:000235218700011 PM 16449679 ER PT J AU Schonfeld, SJ Gilbert, ES Dores, GM Lynch, CF Hodgson, DC Hall, P Storm, H Andersen, A Pukkala, E Holowaty, E Kaijser, M Andersson, M Joensuu, H Fossa, SD Allan, JM Travis, LB AF Schonfeld, SJ Gilbert, ES Dores, GM Lynch, CF Hodgson, DC Hall, P Storm, H Andersen, A Pukkala, E Holowaty, E Kaijser, M Andersson, M Joensuu, H Fossa, SD Allan, JM Travis, LB TI Acute myeloid leukemia following Hodgkin lymphoma: A population-based study of 35511 patients SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID LONG-TERM SURVIVORS; 2ND CANCERS; ABVD CHEMOTHERAPY; ALKYLATING-AGENTS; DISEASE; RISK; ADOLESCENCE; MALIGNANCY; EXPERIENCE; THERAPY AB Treatments for Hodgkin lymphoma are associated with large relative risks of acute myeloid leukemia (AML), but there are few estimates of the excess absolute risk (EAR), a useful measure of disease burden. One-year Hodgkin lymphoma survivors (N = 35 511) were identified within 14 population-based cancer registries in Nordic countries and North America from January 1, 1970, through December 31, 2001. We used Poisson regression analysis to model the EAR of ANI L, per 10 000 person-years. A total of 217 Hodgkin lymphoma survivors were diagnosed with AML (10.8 expected; unadjusted EAR = 6.2; 95% confidence interval 5.4 to 7.1). Excess absolute risk for AML was highest during the first 10 years after Hodgkin lymphoma diagnosis but remained elevated thereafter. In subsequent analyses, adjusted for time since Hodgkin lymphoma diagnosis and presented for the 5-9 year interval, the EAR was statistically significantly (P <.001) larger in patients diagnosed with Hodgkin lymphoma at age 35 years and older than in those diagnosed before 35 years of age. The EAR of AML declined statistically significantly after 1984 (7.0 to 4.2 and 16.4 to 9.9 in the < 35 and >= 35 age groups, respectively), which may be associated with modifications in chemotherapy. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, DHHS, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA USA. Univ Toronto, Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. Karolinska Inst, Stockholm, Sweden. Danish Canc Soc, Copenhagen, Denmark. Canc Registry Norway, Oslo, Norway. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Canc Care Ontario, Toronto, ON, Canada. Univ Helsinki, Cent Hosp, Helsinki, Finland. Radiumhosp Trust, Oslo, Norway. Univ York, York YO10 5DD, N Yorkshire, England. RP Travis, LB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 7086,MSC 7238, Bethesda, MD 20892 USA. EM travisl@mail.nih.gov RI Allan, James/B-4448-2009; OI Storm, Hans/0000-0001-7223-8198 FU Intramural NIH HHS NR 27 TC 39 Z9 42 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 1 PY 2006 VL 98 IS 3 BP 215 EP 218 DI 10.1093/jnci/djj017 PG 4 WC Oncology SC Oncology GA 010SR UT WOS:000235218700013 PM 16449681 ER PT J AU Pearlman, DN Zierler, S Meersman, S Kim, HK Viner-Brown, SI Caron, C AF Pearlman, DN Zierler, S Meersman, S Kim, HK Viner-Brown, SI Caron, C TI Race disparities in childhood asthma: Does where you live matter? SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE children/adolescents; asthma; racial/ethnic disparities; socioeconomic inequalities ID NUTRITION EXAMINATION SURVEY; LONGITUDINAL DATA-ANALYSIS; HEALTH-CARE UTILIZATION; PUERTO-RICAN CHILDREN; 3RD NATIONAL-HEALTH; INNER-CITY CHILDREN; UNITED-STATES; SOCIOECONOMIC-STATUS; NEIGHBORHOOD ENVIRONMENT; MULTILEVEL ANALYSIS AB Objective: This study investigates whether racial/ethnic disparities in childhood asthma prevalence can be explained by differences in family and neighborhood socioeconomic position (SEP). Methods: Data were from the 2001 Rhode Island Health Interview Survey (RI HIS), a statewide representative sample of 2,600 Rhode Island households, and the 2000 U.S. Census. A series of weighted multivariate models were fitted using generalized estimating equations (GEE) for the logistic case to analyze the independent and joint effects of race/ethnicity and SEP on doctor-diagnosed asthma among 1,769 white, black and Hispanic children < 18 years old. Results: Compared with white children, black children were at increased odds for asthma and this effect persisted when measures of family and neighborhood SEP were included in multivariate models (AOR: 2.49; 95% Cl: 1.30-4.77). Block children living in poverty neighborhoods had substantially higher odds of asthma than Hispanic and white children in poverty areas and children in moderate- and high-income neighborhoods (AOR: 3,20; 95% Cl: 1.62-6.29). Conclusion: The high prevalence of asthma among black children in poor neighborhoods is consistent with previous research on higher-than-average prevalence of childhood asthma in poor urban minority communities. Changing neighborhood social structures that contribute to racial disparties in asthma prevalence remains a challenge. C1 Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. NCI, Div Canc Control & Populat Sci, Surveillance Res Branch, Bethesda, MD 20892 USA. Rhode Isl Dept Hlth, Div Family & Community Hlth, Providence, RI 02908 USA. Rhode Isl Dept Hlth, Div Dis Prevent & Control, Providence, RI 02908 USA. RP Pearlman, DN (reprint author), Brown Univ, Dept Community Hlth, Box G-ST 103, Providence, RI 02912 USA. EM deborah_pearlman@brown.edu RI Pearlman, Deborah/I-4438-2014 NR 68 TC 32 Z9 32 U1 5 U2 12 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD FEB PY 2006 VL 98 IS 2 BP 239 EP 247 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 017AA UT WOS:000235665300015 PM 16708510 ER PT J AU Armant, DR Kilburn, BA Kim, YM Nien, JK Romero, R Leach, RE AF Armant, DR Kilburn, BA Kim, YM Nien, JK Romero, R Leach, RE TI EGF family signaling capacity of human placentas is reduced in preeclampsia. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Detroit, MI USA. NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. Univ Illinois, Chicago, IL 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 44 BP 78A EP 78A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800045 ER PT J AU Kim, CJ Guice, E Kim, JS Jeanty, C Hotra, J Kilburn, B Armant, DR Romero, R AF Kim, CJ Guice, E Kim, JS Jeanty, C Hotra, J Kilburn, B Armant, DR Romero, R TI Nerve growth factor enhances invasiveness of human trophoblast cells. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHD, Perinatal Res Branch, NIH, DHHS, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 123 BP 104A EP 104A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800123 ER PT J AU Han, YM Romero, R Kim, YM Friel, L Kusanovic, JP Kim, SS Vitale, S Nien, JK Espinoza, J Kim, CJ AF Han, YM Romero, R Kim, YM Friel, L Kusanovic, JP Kim, SS Vitale, S Nien, JK Espinoza, J Kim, CJ TI Surfactant protein-A mRNA expression by human fetal membranes is increased in histologic chorioamnionitis but not in spontaneous labor at term. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 152 BP 113A EP 113A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800152 ER PT J AU Johnson, B AF Johnson, B TI The MFMU Cesarean Registry: Comparision of vertical and Pfannensteil skin incisions for emergency cesarean delivery. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHD, Maternal Fetal Med Units Network, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 169 BP 119A EP 119A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800169 ER PT J AU Mercer, BM AF Mercer, BM TI The MFMU Cesarean Registry: Does the number of prior successful VBACs affect subsequent VBAC attempt success and complications? SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHD, MFMU, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 182 BP 122A EP 122A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800181 ER PT J AU Gammill, HS Powers, RW AF Gammill, HS Powers, RW TI Does C-reactive protein predict recurrent preeclampsia? SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHD, MFMU, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 188 BP 124A EP 124A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800187 ER PT J AU Baird, DD Kesner, JS Dunson, DB AF Baird, DD Kesner, JS Dunson, DB TI Luteinizing hormone in premenopausal women may stimulate uterine leiomyomata development SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Article DE uterine leiomyome; uterine fibroids; luteinizing hormone; perinienopause ID HUMAN CHORIONIC-GONADOTROPIN; SMOOTH-MUSCLE-CELLS; RISK-FACTORS; RECEPTORS; FIBROIDS; UTERUS; PROFILES AB OBJECTIVE: Human chorionic gonadotropin (hCG) has proliferative effects on uterine smooth muscle and leiomyoma tissue in vitro. We hypothesized that luteinizing hormone (LH) would have the same effect by activating the LH/hCG receptor, and it would follow that premenopausal women with higher basal LH levels would be more likely to have leiomyomata. METHODS: Randomly selected women, aged 35 to 49 years, from a prepaid health plan were screened for leiomyomata with pelvic ultrasound. Urine samples collected during the first or last 5 days of the menstrual cycle were analyzed for LH by immunofluorometric assay, and concentrations were corrected for creatinine (n = 523). Logistic regression and Bayes analyses were used to evaluate the association of LH with presence and size of leiomyomata, adjusting for age, and other risk factors. RESULTS: Women with higher LH were more likely to have leiomyomata (adjusted odd ratios for second and third tertiles were 1.7 and 2.0 compared with lower tertile; 95% confidence intervals, 1.0 to 2.7 and 1.2 to 3.4, respectively). The association was stronger for large leiomyomata. Bayes analyses designed to estimate LH effects on tumor onset separately from tumor growth showed significantly accelerated tumor onset but little evidence of effects on tumor growth. Age, an independent risk factor for leiomyomata, was not affected by the inclusion of LH in the logistic models. CONCLUSIONS: As hypothesized, women with higher LH were more likely to have leiomyomata, but this did not explain the age-related increase in leiomyomata during perimenopausal ages. Determining whether LH is causal or a marker for susceptibility will require further research. C1 NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. NIOSH, Div Appl Res & Technol, Biomonitoring & Hlth Assessment Branch, Cincinnati, OH USA. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural NIH HHS NR 33 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 BP 130 EP 135 DI 10.1016/j.jsgi.2005.12.001 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KX UT WOS:000235693600010 PM 16443507 ER PT J AU Phillippe, M Sweet, LM Bradley, D Dorfman, R Romero, R AF Phillippe, M Sweet, LM Bradley, D Dorfman, R Romero, R TI Anticoagulant modulation of proinflammatory mediators involved in LPS-induced preterm delivery. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Univ Vermont, Coll Med, Dept Obstet & Gynecol, Burlington, VT 05405 USA. Haematol Technol Inc, Essex Jct, VT USA. NICHD, Perinatol Res Branch, Intramural Div, NIH,DHHS, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 231 BP 138A EP 138A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800230 ER PT J AU Wittenberger, M Catherino, W Armstrong, A AF Wittenberger, M Catherino, W Armstrong, A TI The role of embryo transfer in fellowship training SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHD, RBMB, NIH, Bethesda, MD USA. USUHS, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 281 BP 155A EP 155A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800280 ER PT J AU McGovern, P Legro, R Myers, E Barnhart, H Carson, S Diamond, M Carr, B Schlaff, W Coutifaris, C Guidice, L Steinkampf, M Nestler, J Gosman, G Leppert, P AF McGovern, P Legro, R Myers, E Barnhart, H Carson, S Diamond, M Carr, B Schlaff, W Coutifaris, C Guidice, L Steinkampf, M Nestler, J Gosman, G Leppert, P TI Utility of screening for other causes of infertility in women with "known" polycystic ovary syndrome: Results from subjects presenting for inclusion in the NICHD-reproductive medicine network 's "pregnancy in polycystic ovary syndrome " (PPCOS) trial. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. Penn State Univ, Hershey, PA USA. Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. Baylor Coll Med, Houston, TX 77030 USA. Wayne State Univ, Detroit, MI USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Colorado, Denver, CO 80202 USA. Univ Penn, Philadelphia, PA 19104 USA. Stanford Univ, Palo Alto, CA 94304 USA. Univ Alabama, Birmingham, AL USA. Virginia Commonwealth Univ, Dept Med, Sch Med, Richmond, VA 23298 USA. Univ Pittsburgh, Pittsburgh, PA USA. NICHHD, Reprod Sci Branch, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 282 BP 156A EP 156A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800281 ER PT J AU Wildman, D Santolaya-Forgas, J Erez, O Espinoza, J Goncalves, L Kim, YM Kim, CJ Romero, R AF Wildman, D Santolaya-Forgas, J Erez, O Espinoza, J Goncalves, L Kim, YM Kim, CJ Romero, R TI A novel method to detect cross-species microchimerism and the fate of transplanted cells. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 308 BP 164A EP 164A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800307 ER PT J AU Saxena, D Cracchiolo, BM Palumbo, P Wolff, EC Park, MH Hanauske-Abel, HM AF Saxena, D Cracchiolo, BM Palumbo, P Wolff, EC Park, MH Hanauske-Abel, HM TI A vaginal fungicide as a topical antiretroviral: Evidence from the knowledge-guided study of ciclopirox. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 UMDNJ, NJMS, Newark, NJ USA. NIDCR, Oral & Pharyngeal Canc Branch, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 345 BP 177A EP 178A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800344 ER PT J AU Erez, O Montenegro, D Wildman, DE Liu, GZ Espinoza, J Goodman, M Grossman, LI Romero, R AF Erez, O Montenegro, D Wildman, DE Liu, GZ Espinoza, J Goodman, M Grossman, LI Romero, R TI Phylogenetic association between matrix metalloproteinases and placentation type. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. NICHD, Perinatol Res Branch, NIH, DHHS, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 356 BP 181A EP 181A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800355 ER PT J AU Santolaya-Forgas, J Edwin, S Nien, JK Zeiter, K Espinoza, J Kusanovic, JP Van Hook, J Romero, R AF Santolaya-Forgas, J Edwin, S Nien, JK Zeiter, K Espinoza, J Kusanovic, JP Van Hook, J Romero, R TI Maternal and umbilical cord plasma soluble VEGF-receptors 1 and 2 at term in non-human primates. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Texas Tech Univ, Dept Obstet & Gynecol, Amarillo, TX USA. Womens Hlth Res Inst, Amarillo, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 400 BP 195A EP 196A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800399 ER PT J AU Toso, L Roberson, R Abebe, D Spong, CY AF Toso, L Roberson, R Abebe, D Spong, CY TI Prenatal alcohol exposure alters GABA-A-beta 3 expression: A mechanism of alcohol-induced cleft palate. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHD, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD USA. NIAAA, Unit Perinatal & Dev Neurobiol, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 410 BP 199A EP 199A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693800409 ER PT J AU Cushenberry, E Romero, R Richani, K Nien, JK Espinoza, J Kim, CJ AF Cushenberry, E Romero, R Richani, K Nien, JK Espinoza, J Kim, CJ TI The chorionic trophoblast cell mass in fetal membranes is a function of gestational age and does not change with labor, preterm premature rupture of membranes and chorioamnionitis. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 472 BP 219A EP 219A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801027 ER PT J AU Richani, K Romero, R Cushenberry, E Nien, JK Soto, E Kim, JS Kim, YM Espinoza, J Kim, CJ AF Richani, K Romero, R Cushenberry, E Nien, JK Soto, E Kim, JS Kim, YM Espinoza, J Kim, CJ TI Is there a difference between "random" and "nonrandom" sampling of the placenta in assessing the expression of angiogenic factors? SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 475 BP 220A EP 220A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801030 ER PT J AU Wildman, DE Chen, C Opazo, JC Uddin, M Santaloya, J Goodman, M Grossman, LI Romero, R AF Wildman, DE Chen, C Opazo, JC Uddin, M Santaloya, J Goodman, M Grossman, LI Romero, R TI Evolutionary history of the progesterone receptor in primates. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. RI Opazo, Juan/A-9363-2009 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 530 BP 238A EP 238A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801085 ER PT J AU Attardi, B Caritis, S Simhan, H Chiao, JP Zeleznik, T AF Attardi, B Caritis, S Simhan, H Chiao, JP Zeleznik, T TI Binding of 17alpha-hydroxyprogesterone caproate (17alpha-OHPC) and other progestins to rabbit uterine and recombinant human progesterone receptors. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Univ Pittsburgh, Pittsburgh, PA USA. Bioqual Inc, Mol Endocrinol, Rockville, MD USA. NICHD, Obstet Fetal Pharmacol Res Units, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 532 BP 239A EP 239A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801087 ER PT J AU Zeleznik, T Caritis, SN Simhan, HN Chiao, JP Attardi, B AF Zeleznik, T Caritis, SN Simhan, HN Chiao, JP Attardi, B TI Impact of 17-hydroxyprogesterone caproate (17-OHPC) and other progestins on gene transcription. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. BioQual Inc, Mol Endocrinol Lab, Rockville, MD USA. NICHD, Obstet Fetal Pharmacol Res Units, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S BP 239A EP 240A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801089 ER PT J AU Segars, JH Driggers, PH Tiulpakov, AN AF Segars, JH Driggers, PH Tiulpakov, AN TI Elucidation of the mechanism of ligand-dependent activation of the estrogen receptor by AKAP-Brx in Ishikawa cells. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHD, Reprod Biol & Med Branch, NIH, Bethesda, MD USA. USUHS, Dept Ob Gyn, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 602 BP 262A EP 262A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801157 ER PT J AU Legro, RS Myers, ER Barnhart, HX Carson, SA Diamond, MP Carr, BA Schlaff, WD Coutifaris, C McGovern, PG Cataldo, NA Steinkampf, MP Nestler, JE Gosman, G Giudice, LC Leppert, PC AF Legro, RS Myers, ER Barnhart, HX Carson, SA Diamond, MP Carr, BA Schlaff, WD Coutifaris, C McGovern, PG Cataldo, NA Steinkampf, MP Nestler, JE Gosman, G Giudice, LC Leppert, PC TI Pregnancy in polycystic ovary syndrome (PPCOS) baseline characteristics: Effect of race and ethnicity on the PCOS phenotype. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Penn State Univ, University Pk, PA 16802 USA. Duke Univ, Durham, NC 27706 USA. Baylor Univ, Waco, TX 76798 USA. Wayne State Univ, Detroit, MI 48202 USA. UT SW, Dallas, TX USA. Univ Colorado, Boulder, CO 80309 USA. Univ Penn, Philadelphia, PA 19104 USA. UMDNJ Newark, Newark, NJ USA. Stanford Univ, Stanford, CA 94305 USA. UAB Birmingham, Birmingham, AL USA. Virginia Commonwealth Univ, Richmond, VA 23284 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NICHD Reprod Med Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 620 BP 268A EP 269A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801175 ER PT J AU Barnhart, K Chung, K Lorch, S Frederick, M Huang, XK Zhang, J AF Barnhart, K Chung, K Lorch, S Frederick, M Huang, XK Zhang, J TI Surgical management of first trimester pregnancy failure is more effective and potentially less costly than medical management: A cost effectiveness analysis. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Univ Penn, Philadelphia, PA 19104 USA. USC, OBGYN, Los Angeles, CA USA. CHOP, Philadelphia, PA USA. Clin Trials & Surveys Corp, Baltimore, MD USA. 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 623 BP 269A EP 270A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801178 ER PT J AU Legro, RS Myers, ER Barnhart, HX Carson, SA Diamond, MP Carr, BA Schlaff, WD Coutifaris, C McGovern, PG Cataldo, NA Steinkampf, MP Nestler, JE Gosman, G Giudice, LC Leppert, PC AF Legro, RS Myers, ER Barnhart, HX Carson, SA Diamond, MP Carr, BA Schlaff, WD Coutifaris, C McGovern, PG Cataldo, NA Steinkampf, MP Nestler, JE Gosman, G Giudice, LC Leppert, PC TI Pregnancy in polycystic ovary syndrome (PPCOS): Study design and baseline characteristics of the randomized cohort. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Penn State Univ, University Pk, PA 16802 USA. Duke Univ, Durham, NC 27706 USA. Baylor Univ, Waco, TX 76798 USA. Wayne State Univ, Detroit, MI 48202 USA. UT SW, Dallas, TX USA. Univ Colorado, Boulder, CO 80309 USA. Univ Penn, Philadelphia, PA 19104 USA. IMNDJ Newark, Newark, NJ USA. Stanford Univ, Stanford, CA 94305 USA. UAB Birmingham, Birmingham, AL USA. Virginia Commonwealth Univ, Richmond, VA 23284 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NICHD Reprod Med Network, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 621 BP 269A EP 269A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801176 ER PT J AU Merideth, M Karp, B Bartrum, E Zimmer, C Stratton, P AF Merideth, M Karp, B Bartrum, E Zimmer, C Stratton, P TI Botulinum toxin in the treatment of chronic pelvic pain and endometriosis. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NINDS, Neurol Consult Serv, Bethesda, MD 20892 USA. NHGRI, Off Rare Dis, Bethesda, MD 20892 USA. NICHD, Dept Nursing, CC, NIH, Bethesda, MD USA. NICHD, Reprod Biol & Med Branch, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 644 BP 276A EP 276A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801199 ER PT J AU Sinaii, N Cleary, SD Ballweg, ML Knoff, D Stratton, P AF Sinaii, N Cleary, SD Ballweg, ML Knoff, D Stratton, P TI A cross-sectional survey of women with endometriosis: Experiences during the diagnostic process. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHD, Reprod Biol & Med Branch, NIH, Bethesda, MD USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. Endometriosis Assoc Int Headquarters, Milwaukee, WI 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 649 BP 278A EP 278A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801204 ER PT J AU Stegmann, BJ Sinaii, N Funk, MLJ Hartmann, KE Merino, M Segars, J Nieman, LK Stratton, P AF Stegmann, BJ Sinaii, N Funk, MLJ Hartmann, KE Merino, M Segars, J Nieman, LK Stratton, P TI A logistic regression model for the prediction of endometriosis. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 UNC Chapel Hill, Ctr Womens Hlth Res, Chapel Hill, NC USA. NICHD, RBMB, NIH, Bethesda, MD USA. NCI, Dept Surg Pathol, NIH, Bethesda, MD 20892 USA. RI Jonsson Funk, Michele/F-6885-2011 OI Jonsson Funk, Michele/0000-0002-3756-7540 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 650 BP 278A EP 279A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801205 ER PT J AU Payson, MD Segars, JI Catherino, WH AF Payson, MD Segars, JI Catherino, WH TI Changes in Jun expression between small and large leiomyoma. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 652 BP 279A EP 279A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801207 ER PT J AU Wang, HY Ogawa, M Wood, JR Sammel, M Romero, R Strauss, JF AF Wang, HY Ogawa, M Wood, JR Sammel, M Romero, R Strauss, JF TI Identification of a functionally significant polymorphism in the MMP1 promoter and its relationship to preterm premature rupture of the fetal membranes (PPROM) SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Univ Penn, CRRWH, Philadelphia, PA 19104 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. NICHD, Perinatol Res Branch, Hutzel Hosp, Detroit, MI USA. VCU, OB GYN, Richmond, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 661 BP 282A EP 282A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801216 ER PT J AU Santolaya-Forgas, J Uhlmann, RA Hanif, F Goncalves, L Soto, E Richani, K Romero, R AF Santolaya-Forgas, J Uhlmann, RA Hanif, F Goncalves, L Soto, E Richani, K Romero, R TI Incorporation of a graphic visual model into current reporting systems to aid end-users in the interpretation of pathological relationships of comprehensive fetal morphometric and Doppler evaluations throughout pregnancy. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 744 BP 310A EP 311A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801299 ER PT J AU Santolaya-Forgas, J De Leon, J Nien, JK Kusanovic, JP Gooch, J Van Hook, J Mari, G Romero, R AF Santolaya-Forgas, J De Leon, J Nien, JK Kusanovic, JP Gooch, J Van Hook, J Mari, G Romero, R TI Embryonic heart rate response to celocentesis at 40 days of development in the baboon model. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Texas Tech Univ, Dept Obstet & Gynecol, Amarillo, TX USA. Womens Hlth Res Inst, Amarillo, TX USA. NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 743 BP 310A EP 310A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801298 ER PT J AU Santolaya-Forgas, J Van Hook, J Edwin, S Nien, JK Goncalves, L Espinoza, J Erez, O Kusanovic, JP Soto, E Richani, K Romero, R AF Santolaya-Forgas, J Van Hook, J Edwin, S Nien, JK Goncalves, L Espinoza, J Erez, O Kusanovic, JP Soto, E Richani, K Romero, R TI Maternal plasma and celomic fluid concentration of TNF alpha, TNFR-1, TNFr-2 and RANTES in extra-embryonic celomic fluid in pregnant baboons. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Texas Tech Univ, Dept Obstet & Gynecol, Amarillo, TX USA. Womens Hlth Res Inst, Amarillo, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 742 BP 310A EP 310A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801297 ER PT J AU Kim, JS Romero, R Kim, YM Cushenberry, E Montenegro, D Erez, O Nien, JK Kim, CJ AF Kim, JS Romero, R Kim, YM Cushenberry, E Montenegro, D Erez, O Nien, JK Kim, CJ TI A systematic study of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 766 BP 318A EP 318A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801320 ER PT J AU Ho, M AF Ho, M TI Clinical markers of adverse perinatal outcomes in women with chronic hypertension. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 NICHHD, Maternal Fetal Med Units Network, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 794 BP 327A EP 327A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801348 ER PT J AU Klebanoff, MA AF Klebanoff, MA TI Salivary progesterone and estriol concentrations at 16-20 weeks and risk of preterm birth. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 825 BP 337A EP 337A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801379 ER PT J AU Lin, MG Andrews, WW Klebanoff, MA Schwebke, JR Zhang, J Cliver, SP Nansel, TR Yu, KF AF Lin, MG Andrews, WW Klebanoff, MA Schwebke, JR Zhang, J Cliver, SP Nansel, TR Yu, KF TI Longitudinal study of vaginal flora: Obesity is significantly associated with bacterial vaginosis (BV). SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecolog Investigation C1 Univ Alabama, Birmingham, AL USA. NIH, 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2006 VL 13 IS 2 SU S MA 861 BP 349A EP 349A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 017KZ UT WOS:000235693801415 ER PT J AU Kassis, ES Zhao, M Hong, JA Chen, GA Nguyen, DM Schrump, DS AF Kassis, ES Zhao, M Hong, JA Chen, GA Nguyen, DM Schrump, DS TI Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 85th Annual Meeting of the American-Association-for-Thoracic-Surgery CY APR 10-13, 2005 CL San Francisco, CA SP Amer Assoc Thorac Surg ID GENE-EXPRESSION; HISTONE MODIFICATIONS; METHYLATION; TRANSCRIPTION; DNMT3B; TRANSFORMATION; DEMETHYLATION; KNOCKDOWN; INDUCTION AB Objective: DNA methyltransferase (DNMT) 1, DNMT3b, or both, facilitate malignant transformation through chromatin remodeling mechanisms. The present study was undertaken to examine the effects of antisense-mediated inhibition of DNMT expression in cultured thoracic malignancies. Methods: CALU-6 and A549 lung cancer, SKGT5 and BIC esophageal adenocarcinoma, and H2373 and H2052 malignant pleural mesothelioma (MPM) cells, as well as normal human bronchial epithelial (NHBE) cells, were transfected with phosphorothioate-modified antisense oligos targeting DNMT1, DNMT3b, or both, or mismatch oligos. Quantitative reverse transcription-polymerase chain reaction, Western blotting, trypan blue exclusion, and ApoBrdU techniques were used to evaluate DNMT expression, proliferation, and apoptosis after antisense oligo transfections. Gene expression profiles were assessed by using long-oligo array techniques. Results: Antisense oligos mediated specific and dose-dependent depletion of DNMT1 and DNMT3b, resulting in pronounced inhibition of proliferation of all thoracic cancer lines, but not NHBE cells. Depletion of DNMT1 or DNMT3b coincided with dramatic, caspase-dependent, p53-independent apoptosis in 4 of the 6 thoracic cancer lines. The antiproliferative effects of the antisense oligos were not attributable to induction of RASSF1A, p16, or p21 tumor suppressor genes, and did not coincide with demethylation of genes encoding cancer-testis antigens. DNA methyltransferase knockdown mediated induction of numerous genes regulating response to genotoxic stress. Gene expression profiles after DNMT1, DNMT3b, or combined DNMT1/3b depletion were remarkably similar, yet distinctly different from expression profiles mediated by 5 aza 2' deoxycytidine. Conclusions: Antisense oligos targeting DNMT1 and DNMT3b induce genomic stress, and mediate potent growth inhibition in lung and esophageal cancer and MPM cells. These findings support further evaluation of DNMT knockdown strategies for cancer therapy. C1 NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bldg 10,Room 4-3942,10 Ctr Dr MSC 1201, Bethesda, MD 20892 USA. EM david_schrump@nih.gov NR 30 TC 39 Z9 46 U1 0 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD FEB PY 2006 VL 131 IS 2 BP 298 EP 306 DI 10.1016/j.jtcvs.2005.05.022 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 010MK UT WOS:000235198600008 PM 16434257 ER PT J AU Heeb, MJ Schuck, P Xu, X AF Heeb, MJ Schuck, P Xu, X TI Protein S multimers and monomers each have direct anticoagulant activity SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE analytical ultracentrifugation; anticoagulant activity; multimeric protein; protein S; prothrombinase ID ORAL-CONTRACEPTIVES; SELF-ASSOCIATION; FACTOR VA; DEFICIENCY; PLASMA; COMPLEX; PROTHROMBINASE; INHIBITION; BINDING; THROMBOEMBOLISM AB Background and Objectives: Plasma protein S (PS) is an essential anticoagulant that has activated protein C-independent, direct anticoagulant activity (PS-direct). It was reported that monomeric purified PS has poor PS-direct and that a subpopulation of multimeric purified PS has high PS-direct and high affinity for phospholipids. We independently examined the relative PS-direct and affinity for phospholipids of monomeric and multimeric PS and we obtained contrasting results. Methods and Results: Unpurified recombinant protein S (rPS) was monomeric and had PS-direct potency similar to that of both PS in plasma and multimeric affinity-purified PS, as measured in plasma assays for PS-direct and in thrombin-generation assays. Multimers of unpurified rPS were not induced by ethylenediaminetetraacetic acid (EDTA), pH 2.5, NaSCN, or barium adsorption/elution. Multimers were induced by chromatography in the presence of EDTA and thus may be concentration-dependent. In contrast to a different report, monomers, dimers, trimers, and higher-order PS forms were clearly separated in sedimentation velocity experiments and multimers were not dissociated by adding Ca2+. Active plasma-derived and recombinant immunoaffinity-purified PS were fractionated into monomers and multimers. On a mass basis, monomers and multimers had similar specific PS-direct and ability to compete with prothrombinase components (factors Xa/Va) for limiting phospholipids. FXa ligand blotted to both monomers and multimers. Conclusions: Plasma PS-direct is similar to that of affinity-purified PS and unpurified rPS. Under our conditions, monomeric and multimeric PS have similar PS-direct and ability to compete for phospholipids. Discordant earlier findings are likely due to loss of PS-direct during conventional purification procedures. C1 Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. NIH, Div Bioengn & Phys Sci, ORS, OD, Bethesda, MD 20892 USA. RP Heeb, MJ (reprint author), Scripps Res Inst, Dept Mol & Expt Med, MEM180,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM heeb@scripps.edu OI Schuck, Peter/0000-0002-8859-6966 FU NCRR NIH HHS [M01 RR00833]; NHLBI NIH HHS [R01 HL70002] NR 35 TC 14 Z9 14 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD FEB PY 2006 VL 4 IS 2 BP 385 EP 391 DI 10.1111/j.1538-7836.2006.01743.x PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 005TR UT WOS:000234847200017 PM 16420570 ER PT J AU Propert, KJ McNaughton-Collins, M Leiby, BE O'Leary, MP Kusek, JW Litwin, MS AF Propert, KJ McNaughton-Collins, M Leiby, BE O'Leary, MP Kusek, JW Litwin, MS CA Chronic Prostatitis Collaborative TI A prospective study of symptoms and quality of life in men with chronic prostatitis/chronic pelvic pain syndrome: The National Institutes of Health Chronic Prostatitis Cohort Study SO JOURNAL OF UROLOGY LA English DT Article DE prostatitis; pelvic pain; cohort studies; prospective studies; quality of life ID TRIAL; INDEX AB Purpose: We present the results of 2 years of symptom and quality of life followup of men with CP/CPPS enrolled in the CPC. Materials and Methods: We followed 445 subjects from 6 clinical centers across North America for 2 years with outcome measures that included the NIH-CPSI, quality of life, and GRA. All subjects were treated according to usual care practices at each clinical site. Results: Of the 445 subjects 293 had complete data at 2 years. Withdrawals were younger, had been diagnosed more recently and had higher baseline symptoms. Among the 293 men the mean improvement at 2 years was 5 points on the 43-point NIH-CPSI total score. Most of the observed improvement occurred in the first 3 months of followup. Among all 445 subjects, retaining withdrawals in the denominator, 31% considered themselves moderately or markedly improved at :2 years. Although group mean symptom scores were stable and improved slightly over time, some individual subjects reported large fluctuations. No baseline demographic or clinical factors significantly predicted changes in symptom scores over time. Conclusions: CP/CPPS is a chronic disease characterized by substantial variation in symptoms within and among subjects. There is no evidence that the disorder worsens significantly during 2 years of followup, and for about a third of men with long-standing symptoms there may be moderate to marked improvement during this period. C1 Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Hlth Serv, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. RP Propert, KJ (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, Blockey Hall,6th Floor,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kpropert@cceb.upenn.edu FU NIDDK NIH HHS [U01 DK53736, U01 DK53730, U01 DK53732, U01 DK53734, U01 DK53738, U01 DK53752, T32 DK060455, U01 DK53746] NR 13 TC 28 Z9 31 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2006 VL 175 IS 2 BP 619 EP 623 DI 10.1016/S0022-5347(05)00233-8 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 001XO UT WOS:000234576200056 PM 16407009 ER PT J AU Brown, DB Cardella, JF Sacks, D Goldberg, SN Gervais, DA Rajan, D Vedantham, S Miller, DL Brountzos, EN Grassi, CJ Towbin, RB AF Brown, DB Cardella, JF Sacks, D Goldberg, SN Gervais, DA Rajan, D Vedantham, S Miller, DL Brountzos, EN Grassi, CJ Towbin, RB TI Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID UNRESECTABLE HEPATOCELLULAR-CARCINOMA; TRANSCATHETER OILY CHEMOEMBOLIZATION; RANDOMIZED CONTROLLED TRIAL; RADIOFREQUENCY THERMAL ABLATION; METASTATIC COLORECTAL-CARCINOMA; INFERIOR PHRENIC ARTERY; LIVER-DISEASE MELD; PHASE-II TRIAL; TRANSARTERIAL CHEMOEMBOLIZATION; LIPIODOL CHEMOEMBOLIZATION C1 Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Siteman Canc Ctr, St Louis, MO 63110 USA. Univ Colorado, Hlth Sci Ctr, Dept Radiol, Denver, CO 80262 USA. Reading Hosp Med Ctr, Dept Radiol, W Reading, PA USA. Childrens Hosp Philadelphia, Dept Radiol, Philadelphia, PA 19104 USA. Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Radiol, Gastrointestinal Genitourinary Div, Boston, MA 02114 USA. Lahey Clin Med Ctr, Dept Radiol, Burlington, MA 01803 USA. Univ Toronto, Div Intervent Radiol, Dept Med Imaging, Toronto, ON, Canada. Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, F Edward Hebert Sch Med,NCI, Med Oncol Clin Res Unit,Ctr Canc Res, Bethesda, MD 20814 USA. Univ Athens, Dept Radiol, Athens, Greece. RP Brown, DB (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Siteman Canc Ctr, 510 S Kingshighway Blvd,Box 8131, St Louis, MO 63110 USA. EM brownda@mir.wustl.edu NR 71 TC 66 Z9 73 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2006 VL 17 IS 2 BP 225 EP 232 DI 10.1097/01.RVI.0000195330.47954.48 PN 1 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 020ZN UT WOS:000235952100004 PM 16517768 ER PT J AU Fu, W Dang, Q Nagashima, K Freed, EO Pathak, VK Hu, WS AF Fu, W Dang, Q Nagashima, K Freed, EO Pathak, VK Hu, WS TI Effects of Gag mutation and processing on retroviral dimeric RNA maturation SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; MAJOR HOMOLOGY REGION; HIV-1 CAPSID PROTEIN; PARTICLE FORMATION; REVERSE-TRANSCRIPTASE; VIRION MORPHOGENESIS; VIRAL REPLICATION; TERMINAL DOMAIN; INFECTED-CELLS AB After their release from host cells, most retroviral particles undergo a maturation process, which includes viral protein cleavage, core condensation, and increased stability of the viral RNA dimer. Inactivating the viral protease prevents protein cleavage; the resulting virions lack condensed cores and contain fragile RNA dimers. Therefore, protein cleavage is linked to virion morphological change and increased stability of the RNA dimer. However, it is unclear whether protein cleavage is sufficient for mediating virus RNA maturation. We have observed a novel phenotype in a murine leukemia virus capsid mutant, which has normal virion production, viral protein cleavage, and RNA packaging. However, this mutant also has immature virion morphology and contains a fragile RNA dimer, which is reminiscent of protease-deficient mutants. To our knowledge, this mutant provides the first evidence that Gag cleavage alone is not sufficient to promote RNA dimer maturation. To extend our study further, we examined a well-defined human immunodeficiency virus type 1 (HIV-1) Gag mutant that lacks a functional PTAP motif and produces immature virions without major defects in viral protein cleavage. We found that the viral RNA dimer in the PTAP mutant is more fragile and unstable compared with those from wild-type HIV-1. Based on the results of experiments using two different Gag mutants from two distinct retroviruses, we conclude that Gag cleavage is not sufficient for promoting RNA dimer maturation, and we propose that there is a link between the maturation of virion morphology and the viral RNA dimer. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. W Virginia Univ, Sch Med, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26505 USA. SAIC Frederick, Frederick, MD 21702 USA. RP Hu, WS (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 535,Room 336, Frederick, MD 21702 USA. EM whu@ncifcrf.gov FU Intramural NIH HHS NR 64 TC 21 Z9 21 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2006 VL 80 IS 3 BP 1242 EP 1249 DI 10.1128/JVI.80.3.1242-1249.2006 PG 8 WC Virology SC Virology GA 006BZ UT WOS:000234871400018 PM 16415001 ER PT J AU Davis, CW Nguyen, HY Hanna, SL Sanchez, MD Doms, RW Pierson, TC AF Davis, CW Nguyen, HY Hanna, SL Sanchez, MD Doms, RW Pierson, TC TI West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BORNE ENCEPHALITIS-VIRUS; HEPATITIS-C VIRUS; ENVELOPE PROTEIN GLYCOSYLATION; N-LINKED GLYCOSYLATION; HUMAN DENDRITIC CELLS; ENDOTHELIAL-CELLS; DENGUE-VIRUS; IN-VITRO; STRUCTURAL BASIS AB The C-type lectins DC-SIGN and DC-SIGNR bind mannose-rich glycans with high affinity. In vitro, cells expressing these attachment factors efficiently capture, and are infected by, a diverse array of appropriately glycosylated pathogens, including dengue virus. In this study, we investigated whether these lectins could enhance cellular infection by West Nile virus (WNV), a mosquito-borne flavivirus related to dengue virus. We discovered that DC-SIGNR promoted WNV infection much more efficiently than did DC-SIGN, particularly when the virus was grown in human cell types. The presence of a single N-linked glycosylation site on either the prM or E glycoprotein of WNV was sufficient to allow DC-SIGNR-mediated infection, demonstrating that uncleaved prM protein present on a flavivirus virion can influence viral tropism under certain circumstances. Preferential utilization of DC-SIGNR was a specific property conferred by the WNV envelope glycoproteins. Chimeras between DC-SIGN and DC-SIGNR demonstrated that the ability of DC-SIGNR to promote WNV infection maps to its carbohydrate recognition domain. WNV virions and subviral particles bound to DC-SIGNR with much greater affinity than DC-SIGN. We believe this is the first report of a pathogen interacting more efficiently with DC-SIGNR than with DC-SIGN. Our results should lead to the discovery of new mechanisms by which these well-studied lectins discriminate among ligands. C1 NIH, Viral Dis Lab, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA USA. RP Pierson, TC (reprint author), NIH, Viral Dis Lab, 4 Ctr Dr,Bldg 4,Room 216, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU NCRR NIH HHS [F31 RR 05074, F31 RR005074]; NIAID NIH HHS [U54 AI057168, AI 50469, R01 AI050469, T32 AI 07324-13, T32 AI 07632, T32 AI007324, T32 AI007632, U54 AI 57168]; NIGMS NIH HHS [T32 GM 007229, T32 GM007229] NR 92 TC 163 Z9 176 U1 2 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2006 VL 80 IS 3 BP 1290 EP 1301 DI 10.1128/JVI.80.3.1290-1301.2006 PG 12 WC Virology SC Virology GA 006BZ UT WOS:000234871400023 PM 16415006 ER PT J AU Hu, ZY Zhang, ZS Kim, JW Huang, Y Liang, TJ AF Hu, ZY Zhang, ZS Kim, JW Huang, Y Liang, TJ TI Altered proteolysis and global gene expression in hepatitis B virus X transgenic mouse liver SO JOURNAL OF VIROLOGY LA English DT Article ID FACTOR-BINDING-PROTEINS; HBX PROTEIN; TRANSCRIPTION FACTORS; PROTEASOME COMPLEX; DNA-BINDING; IN-VIVO; TRANSACTIVATION; REPLICATION; CANCER; MICE AB Hepatitis B virus X (HBX) is essential for the productive infection of hepatitis B virus (HBV) in vivo and has a pleiotropic effect on host cells. We have previously demonstrated that the proteasome complex is a cellular target of HBX, that HBX alters the proteolytic activity of proteasome in vitro, and that inhibition of proteasome leads to enhanced viral replication, suggesting that HBX and proteasome interaction plays a crucial role in the life cycle and pathogenesis of HBV. In the present study, we tested the effect of HBX on the proteasome activities in vivo in a transgenic mouse model in which HBX expression is developmentally regulated by the mouse major urinary promoter in the liver. In addition, microarray analysis was performed to examine the effect of HBX expression on the global gene expression profile of the liver. The results showed that the peptidase activities of the proteasome were reduced in the HBX transgenic mouse liver, whereas the activity of another cellular protease was elevated, suggesting a compensatory mechanism in protein degradation. In the microarray analysis, diverse genes were altered in the HBX mouse livers and the number of genes with significant changes increased progressively with age. Functional clustering showed that a number of genes involved in transcription and cell growth were significantly affected in the HBX mice, possibly accounting for the observed pleiotropic effect of HBX. In particular, insulin-like growth factor-binding protein I was down-regulated in the HBX mouse liver. The down-regulation was similarly observed during acute woodchuck hepatitis virus infection. Other changes including up-regulation of proteolysis-related genes may also contribute to the profound alterations of liver functions in HBV infection. C1 NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Rm 9B16, Bethesda, MD 20892 USA. EM jakel@intra.niddk.nih.gov FU Intramural NIH HHS NR 39 TC 20 Z9 20 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2006 VL 80 IS 3 BP 1405 EP 1413 DI 10.1128/JVI.80.3.1405-1413.2006 PG 9 WC Virology SC Virology GA 006BZ UT WOS:000234871400035 PM 16415018 ER PT J AU Li, Y Svehla, K Mathy, NL Voss, G Mascola, JR Wyatt, R AF Li, Y Svehla, K Mathy, NL Voss, G Mascola, JR Wyatt, R TI Characterization of antibody responses elicited by human immunodeficiency virus type 1 primary isolate trimeric and monomeric envelope glycoproteins in selected adjuvants SO JOURNAL OF VIROLOGY LA English DT Article ID FUSION INHIBITOR T-20; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; T-CELLS; OLIGOMERIC STRUCTURE; PARTIAL DELETION; MALARIA VACCINE; AIDS PATIENTS; CD4 BINDING; HIV-1 ENTRY AB We previously reported that soluble, stable YU2 gp140 trimeric human immunodeficiency virus type I (HIV-1) envelope glycoprotein immunogens could elicit improved breadth of neutralization against HIV-1 isolates compared to monomeric YU2 gp120 proteins. In this guinea pig immunization study, we sought to extend these data and determine if adjuvant could quantitatively or qualitatively alter the neutralizing response elicited by trimeric or monomeric immunogens. Consistent with our earlier studies, the YU2 gp140 immunogens elicited higher-titer neutralizing antibodies against homologous and heterologous isolates than those elicited by monomeric YU2 gp120. Additionally, the GlaxoSmithKline family of adjuvants AS01B, AS02A, and AS03 induced higher levels of neutralizing antibodies compared to emulsification of the same immunogens in Ribi adjuvant. Further analysis of vaccine sera indicated that homologous virus neutralization was not mediated by antibodies to the V3 loop, although V3 loop-directed neutralization could be detected for some heterologous isolates. In most gp120-inoculated animals, the homologous YU2 neutralization activity was inhibited by a peptide derived from the YU2 V1 loop, whereas the neutralizing activity elicited by YU2 gp140 trimers was much less sensitive to V1 peptide inhibition. Consistent with a less VI-focused antibody response, sera from the gp140-immunized animals more efficiently neutralized heterologous HIV-1 isolates, as determined by two distinct neutralization formats. Thus, there appear to be qualitative differences in the neutralizing antibody response elicited by YU2 gp140 compared to YU2 monomeric gp120. Further mapping analysis of more conserved regions of gp120/gp41 may be required to determine the neutralizing specificity elicited by the trimeric immunogens. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. GlaxoSmithKline Inc, Rixensart, Belgium. RP Wyatt, R (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Rm 4512, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov FU Intramural NIH HHS NR 62 TC 114 Z9 117 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2006 VL 80 IS 3 BP 1414 EP 1426 DI 10.1128/JVI.80.3.1414-1426.2006 PG 13 WC Virology SC Virology GA 006BZ UT WOS:000234871400036 PM 16415019 ER PT J AU Rumyantsev, AA Murphy, BR Pletnev, AG AF Rumyantsev, AA Murphy, BR Pletnev, AG TI A tick-borne Langat virus mutant that is temperature sensitive and host range restricted in neuroblastoma cells and lacks neuroinvasiveness for immunodeficient mice SO JOURNAL OF VIROLOGY LA English DT Article ID INFECTIOUS CDNA-CLONE; HUMAN NEURO-BLASTOMA; GROUP B ARBOVIRUSES; ENCEPHALITIS-VIRUS; ATTENUATION PHENOTYPES; VACCINE CANDIDATE; CRYSTAL-STRUCTURE; SERINE-PROTEASE; POWASSAN VIRUS; FLAVIVIRUSES AB Langat virus (LGT), the naturally attenuated member of the tick-borne encephalitis virus (TBEV) complex, was tested extensively in clinical trials as a live TBEV vaccine and was found to induce a protective, durable immune response; however, it retained a low residual neuroinvasiveness in mice and humans. In order to ablate or reduce this property, LGT mutants that produced a small plaque size or temperature-sensitive (ts) phenotype in Vero cells were generated using 5-fluorouracil. One of these ts mutants, clone E5-104, exhibited a more than 10(3)-fold reduction in replication at the permissive temperature in both mouse and human neuroblastoma cells and lacked detectable neuroinvasiveness for highly sensitive immunodeficient mice. The E5-104 mutant possessed five amino acid substitutions in the structural protein E and one change in each of the nonstructural proteins NS3 and NS5. Using reverse genetics, we demonstrated that a Lys(46)-> Glu substitution in NS3 as well as a single Lys(315)-> Glu change in E significantly impaired the growth of LGT in neuroblastoma cells and reduced its peripheral neurovirulence for SCID mice. This study and our previous experience with chimeric flaviviruses indicated that a decrease in viral replication in neuroblastoma cells might serve as a predictor of in vivo attenuation of the neurotropic flaviviruses. The combination of seven mutations identified in the nonneuroinvasive E5-104 mutant provided a useful foundation for further development of a live attenuated TBEV vaccine. An evaluation of the complete sequence of virus recovered from brain of SCID mice inoculated with LGT mutants identified sites in the LGT genome that promoted neurovirulence/neuroinvasiveness. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, 12735 Twinbrook Pkwy,Twinbrook 3,Room 3W13,MSC 81, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov FU Intramural NIH HHS NR 43 TC 25 Z9 25 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2006 VL 80 IS 3 BP 1427 EP 1439 DI 10.1128/JVI.80.3.1427-1439.2006 PG 13 WC Virology SC Virology GA 006BZ UT WOS:000234871400037 PM 16415020 ER PT J AU Kuwata, T Dehghani, H Brown, CR Plishka, R Buckler-White, A Igarashi, T Mattapallil, J Roederer, M Hirsch, VM AF Kuwata, T Dehghani, H Brown, CR Plishka, R Buckler-White, A Igarashi, T Mattapallil, J Roederer, M Hirsch, VM TI Infectious molecular clones from a simian immunodeficiency virus-infected rapid-progressor (RP) macaque: Evidence of differential selection of RP-specific envelope mutations in vitro an in vivo SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; END-STAGE DISEASE; VIRAL REPLICATION; RHESUS MACAQUES; MACROPHAGE TROPISM; SIV INFECTION; V3 DOMAIN; HIV-1; TYPE-1; GP120 AB A minor fraction of simian immunodeficiency virus (SIV)-infected macaques progress rapidly to AIDS in the absence of SIV-specific immune responses. Common mutations in conserved residues of env in three SIVsmE543-3-infected rapid-progressor (RP) macaques suggest the evolution of a common viral variant in R-P macaques. The goal of the present study was to analyze the biological properties of these variants in vitro and in vivo through the derivation of infectious molecular clones. Virus isolated from a SIVsm E543-3-infected RP macaque, H445 was used to inoculate six naive rhesus macaques. Although RP-specific mutations dominated in H445 tissues, they represented only 10% of the population of the virus stock, suggesting a selective disadvantage in vitro. Only one of these macaques (11635) progressed rapidly to AIDS. Plasma virus during primary infection of H635 was similar to the inoculum. However, RP-specific mutations were apparently rapidly reselected by 4 to 9 weeks postinfection. Terminal plasma from H635 was used as a source of viral RNA to generate seven full-length, infectious molecular clones. With the exception of one clone, which was similar to SIVsmE543-3, clones with RP-specific mutations replicated with delayed kinetics in rhesus peripheral blood mononuclear cells and human T-cell lines. None of the clones replicated in monocyte-derived or alveolar macrophages, and all used CCR5 as their major coreceptor. RP variants appear to be well adapted to replicate in vivo in R-P macaques but are at a disadvantage in tissue culture compared to their parent, SIVsmE543-3. Therefore, tissue culture may not provide a good surrogate for replication of RP variants in macaques. These infectious clones will provide a valuable reagent to study the roles of specific viral variants in rapid progression in vivo. C1 NIAID, LMM, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hirsch, VM (reprint author), NIAID, LMM, NIH, Bldg 4,Rm B1-33,4 Ctr Dr, Bethesda, MD 20892 USA. EM vhirsch@nih.gov RI Roederer, Mario/G-1887-2011; Kuwata, Takeo/F-5809-2013 FU Intramural NIH HHS NR 59 TC 18 Z9 18 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2006 VL 80 IS 3 BP 1463 EP 1475 DI 10.1128/JVI.80.3.1463-1475.2006 PG 13 WC Virology SC Virology GA 006BZ UT WOS:000234871400040 PM 16415023 ER PT J AU Urabe, M Nakakura, T Xin, KQ Obara, Y Mizukami, H Kume, A Kotin, RM Ozawa, K AF Urabe, M Nakakura, T Xin, KQ Obara, Y Mizukami, H Kume, A Kotin, RM Ozawa, K TI Scalable generation of high-titer recombinant adeno-associated virus type 5 in insect cells SO JOURNAL OF VIROLOGY LA English DT Article ID PHOSPHOLIPASE A(2); EFFICIENT TRANSDUCTION; VIRAL VECTORS; REP; PROTEIN; TRANSCRIPTION; TRANSLATION; SPECIFICITY; EXPRESSION; GENOMES AB We established a method for production of recombinant adeno-associated virus type 5 (rAAV5) in insect cells by use of baculovirus expression vectors. One baculovirus harbors a transgene between the inverted terminal repeat sequences of type 5, and the second expresses Rep78 and Rep52. Interestingly, the replacement of type 5 Rep52 with type 1 Rep52 generated four times more rAAV5 particles. We replaced the N-terminal portion of type 5 VP1 with the equivalent portion of type 2 to generate infectious AAV5 particles. The rAAV5 with the modified VP1 required alpha 2-3 sialic acid for transduction, as revealed by a competition experiment with an analog of alpha 2-3 sialic acid. rAAV5-GFP/Neo with a 4.4-kb vector genome produced in HEK293 cells or Sf9 cells transduced COS cells with similar efficiencies. Surprisingly, Sf9-produced humanized Renilla green fluorescent protein (hGFP) vector with a 2.4-kb vector genome induced stronger GFP expression than the 293-produced one. Transduction of murine skeletal muscles with Sf9-generated rAAV5 with a 3.4-kb vector genome carrying a human secreted alkaline phosphatase (SEAP) expression cassette induced levels of SEAP more than 30 times higher than those for 293-produced vector 1 week after injection. Analysis of virion DNA revealed that in addition to a 2.4- or 3.4-kb single-stranded vector genome, Sf9-rAAV5 had more-abundant forms of approximately 4.7 kb, which appeared to correspond to the monomer duplex form of hGFP vector or truncated monomer duplex SEAP vector DNA. These results indicated that rAAV5 can be generated in insect cells, although the difference in incorporated virion DNA may induce different expression patterns of the transgene. C1 Jichi Med Sch, Div Genet Therapeut, Tochigi 3290498, Japan. Yokohama City Univ, Grad Sch Med, Dept Mol Biodef Res, Yokohama, Kanagawa 2360004, Japan. Natl Heart Lung & Blood Inst, Lab Biochem Genet, NIH, Bethesda, MD USA. RP Urabe, M (reprint author), Jichi Med Sch, Div Genet Therapeut, 3311-1 Yakushiji, Tochigi 3290498, Japan. EM murabe@jichi.ac.jp RI kotin, robert/B-8954-2008; Mizukami, Hiroaki/D-7674-2013 OI Mizukami, Hiroaki/0000-0001-8954-874X FU Intramural NIH HHS NR 37 TC 35 Z9 35 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2006 VL 80 IS 4 BP 1874 EP 1885 DI 10.1128/JVI.80.4.1874-1885.2006 PG 12 WC Virology SC Virology GA 011DQ UT WOS:000235248500026 PM 16439543 ER PT J AU Maggio, M Ble, A Ceda, GP Metter, EJ AF Maggio, M Ble, A Ceda, GP Metter, EJ TI Decline in insulin-like growth factor-I levels across adult life span in two large population studies SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Letter ID RANCHO-BERNARDO; SERUM-LEVELS; IGF-I; WOMEN; MORTALITY; MEN C1 NIA, NIH, Harbor Hosp, Baltimore, MD 21225 USA. RP Maggio, M (reprint author), NIA, NIH, Harbor Hosp, 3001 S Hanover St, Baltimore, MD 21225 USA. EM maggiom@grc.nia.nih.gov OI Ceda, Gian Paolo/0000-0002-9648-8295 FU Intramural NIH HHS NR 8 TC 16 Z9 16 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2006 VL 61 IS 2 BP 182 EP 183 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 018TB UT WOS:000235786600010 PM 16510863 ER PT J AU McArdle, PF Pollin, TI O'Connell, JR Sorkin, JD Agarwala, R Schaffer, AA Streeten, EA King, TM Shuldiner, AR Mitchell, BD AF McArdle, PF Pollin, TI O'Connell, JR Sorkin, JD Agarwala, R Schaffer, AA Streeten, EA King, TM Shuldiner, AR Mitchell, BD TI Does having children extend life span? A genealogical study of parity and longevity in the Amish SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID OLD ORDER AMISH; REPRODUCTION; POPULATION; HERITABILITY; FERTILITY; PEDIGREES; EVOLUTION; NUMBER; TRAIT; RISK AB Background. The relationship between parity and life span is uncertain, with evidence of both positive and negative relationships being reported previously. We evaluated this issue by using genealogical data from an Old Order Amish community in Lancaster, Pennsylvania, a population characterized by large nuclear families, homogeneous lifestyle, and extensive genealogical records. Methods. The analysis was restricted to the set of 2015 individuals who had children, were born between 1749 and 1912. and survived until at least age 50 years. Pedigree structures and birth and death dates were extracted from Amish genealogies, and the relationship between parity and longevity was examined using a variance component framework. Results. Life span of fathers increased in linear fashion with increasing number of children (0.23 years per additional child; p =.01), while life span of mothers increased linearly up to 14 children (0.32 years per additional child; p =.004) but decreased with each additional child beyond 14 (p =.0004). Among women, but not men, a later age at last birth was associated with longer life span (p =.00 1). Adjusting for age at last birth obliterated the correlation between maternal life span and number of children, except among mothers with ultrahigh (> 14 children) parity. Conclusions. We conclude that high parity among men and later menopause among women may be markers for increased life span. Understanding the biological and/or social factors mediating these relationships may provide insights into mechanisms underlying successful aging. C1 Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. Natl Inst Hlth, Dept Hlth & Human Serv, Informat Engn Branch, Bethesda, MD USA. Natl Inst Hlth, Dept Hlth & Human Serv, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD USA. Univ Texas, Dept Internal Med, Div Geriatr Med, Houston, TX USA. Vet Adm Hosp, Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD USA. RP Mitchell, BD (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. EM bmitchel@medicine.umaryland.edu RI Schaffer, Alejandro/F-2902-2012; OI Mitchell, Braxton/0000-0003-4920-4744 NR 31 TC 37 Z9 41 U1 5 U2 16 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2006 VL 61 IS 2 BP 190 EP 195 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 018TB UT WOS:000235786600012 PM 16510865 ER PT J AU Wigglesworth, C AF Wigglesworth, Carol TI A word from OLAW SO LAB ANIMAL LA English DT Editorial Material C1 NIH, Off Lab Anim Welf, OER, OD,HHS, Bethesda, MD 20892 USA. RP Wigglesworth, C (reprint author), NIH, Off Lab Anim Welf, OER, OD,HHS, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD FEB PY 2006 VL 35 IS 2 BP 18 EP 18 DI 10.1038/laban0206-18 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 070TA UT WOS:000239545800005 PM 16446731 ER PT J AU Friedman, B Berman, JJ AF Friedman, B Berman, JJ TI Reinventing pathology: Enhancing the clinical laboratory and pathology report SO LABMEDICINE LA English DT Editorial Material C1 Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. NCI, Canc Diag Program, Bethesda, MD 20892 USA. RP Friedman, B (reprint author), Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0007-5027 J9 LABMEDICINE JI Labmedicine PD FEB PY 2006 VL 37 IS 2 BP 121 EP 122 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 006RF UT WOS:000234913900018 ER PT J AU Qi, CF Xiang, S Shin, MS Hao, XP Lee, CH Zhou, JX Torrey, TA Hartley, JW Fredrickson, TN Morse, HC AF Qi, CF Xiang, S Shin, MS Hao, XP Lee, CH Zhou, JX Torrey, TA Hartley, JW Fredrickson, TN Morse, HC TI Expression of the cyclin-dependent kinase inhibitor p27 and its deregulation in mouse B cell lymphomas SO LEUKEMIA RESEARCH LA English DT Article DE p27; mouse B cell lymphoma; cell-cycle regulation ID MARGINAL ZONE LYMPHOMAS; PROGNOSTIC IMPLICATIONS; MULTIPLE-MYELOMA; MALIGNANT-LYMPHOMAS; P27(KIP1) PROTEIN; BURKITT-LYMPHOMA; BREAST-CANCER; IN-VIVO; MICE; DEGRADATION AB CDKN1B (p27) regulates cell-cycle progression at the G1-S transition by suppressing the cyclin E/CDK2 kinase complex. In normal lymphocytes and most human B cell non-Hodgkin lymphomas (NHL), there is an inverse correlation between proliferative activity and expression of p27; however, a subset of NHL with high mitotic indices expresses p27, which is inactive due to sequestration in nuclear protein complexes or due to cytoplasmic retention. Our studies of mouse B cell NHL also identified cases with high proliferative activity and high levels of p27 at a surprisingly high frequency. Here, p27 was complexed with D-type cyclins 1 and 3 and with the COPS9 protein, JAB 1. In addition, we found cytoplasmic sequestration following phosphorylation by activated AKT. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Morse, HC (reprint author), NIAID, Immunopathol Lab, NIH, Twinbrook 1,Room 1421, Rockville, MD 20852 USA. EM hmorse@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 NR 52 TC 22 Z9 23 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD FEB PY 2006 VL 30 IS 2 BP 153 EP 163 DI 10.1016/j.leukres.2005.06.025 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 004UC UT WOS:000234776800004 PM 16122798 ER PT J AU Koon, HB Severy, P Hagg, DS Butler, K Hill, T Jones, AG Waldmann, TA Junghans, RP AF Koon, HB Severy, P Hagg, DS Butler, K Hill, T Jones, AG Waldmann, TA Junghans, RP TI Antileukemic effect of daclizumab in CD25 high-expressing leukemias and impact of tumor burden on antibody dosing SO LEUKEMIA RESEARCH LA English DT Article DE HAT; humanized; Tac; antibody ID T-CELL LEUKEMIA; INTERLEUKIN-2 RECEPTOR; HUMANIZED ANTIBODY; MONOCLONAL-ANTIBODIES; RENAL-TRANSPLANTATION; TAC-H; RADIOIMMUNOTHERAPY; IMMUNOTHERAPIES; BIOACTIVITY; SURVIVAL AB Humanized anti-CD25 antibody, daclizumab, was applied in a pilot study of 10 patients with CD25(+) leukemias and pharmacokinetic/pharmacodynamic properties were characterized. Two widely held concepts - tumor sink accelerating pharmacokinetics and higher antigen expression correlating with target cell clearance - were supported by this first systematic evaluation of these questions with actual human clinical data. A flexi-closing regimen was validated for maintaining target drug levels in vivo with a wide range of tumor burdens. Daclizumab induced clearance of peripheral leukemic cells when highly positive for CD25, but durable responses were not obtained. If daclizumab will have a role in antileukemic therapy, it may be in minimal disease settings or as a component of a combination regimen, but only when CD25 expression is high. (c) 2005 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Nucl Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Nucl Med, Boston, MA 02115 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Junghans, RP (reprint author), Roger Williams Canc Med Ctr, Dept Surg, 825 Chalkstone Ave, Providence, RI 02908 USA. EM rjunghans@rwmc.org NR 26 TC 21 Z9 25 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD FEB PY 2006 VL 30 IS 2 BP 190 EP 203 DI 10.1016/j.leukres.2005.06.007 PG 14 WC Oncology; Hematology SC Oncology; Hematology GA 004UC UT WOS:000234776800009 PM 16165209 ER PT J AU Shapiro, EM Sharer, K Skrtic, S Koretsky, AP AF Shapiro, EM Sharer, K Skrtic, S Koretsky, AP TI In vivo detection of single cells by MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; iron oxide; cells; contrast agents; liver ID STATIC DEPHASING REGIME; IRON-OXIDE PARTICLES; STEM-CELLS; MAMMALIAN-CELLS; TAT PEPTIDE; TRANSPLANTATION; NANOPARTICLES; PROGENITOR; MIGRATION; TRACKING AB The use of high-relaxivity, intracellular contrast agents has enabled MRI monitoring of cell migration through and homing to various tissues, such as brain, spinal cord, heart, and muscle. Here it is shown that MRI can detect single cells in vivo, homing to tissue, following cell labeling and transplantation. Primary mouse hepatocytes were double-labeled with green fluorescent 1.63-mu m iron oxide particles and red fluorescent endosomal labeling dye, and injected into the spleens of recipient mice. This is a common hepatocyte transplantation paradigm in rodents whereby hepatocytes migrate from the spleen to the liver as single cells. One month later the animals underwent in vivo MRI and punctuated, dark contrast regions were detected scattered through the livers. MRI of perfused, fixed samples and labeled hepatocyte phantoms in combination with histological evaluation confirmed the presence of dispersed single hepatocytes grafted into the livers. Appropriate controls were used to determine whether the observed contrast could have been due to dead cells or free particles, and the results confirmed that the contrast was due to disperse, single cells. Detecting single cells in vivo opens the door to a number of experiments, such as monitoring rare cellular events, assessing the kinetics of stem cell homing, and achieving early detection of metastases. C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Shapiro, EM (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM ShapiroE@ninds.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Skrtic, Stanko/0000-0002-1950-5418 FU Intramural NIH HHS [Z01 NS003047-01] NR 30 TC 256 Z9 272 U1 4 U2 26 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2006 VL 55 IS 2 BP 242 EP 249 DI 10.1002/mrm.20718 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 012GO UT WOS:000235326500003 PM 16416426 ER PT J AU Keilholz, SD Silva, AC Raman, M Merkle, H Koretsky, AP AF Keilholz, SD Silva, AC Raman, M Merkle, H Koretsky, AP TI BOLD and CBV-weighted functional magnetic resonance imaging of the rat somatosensory system SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE fMRI; BOLD; cerebral blood volume; somatosensory stimulation; 11.7 Tesla MRI ID CEREBRAL BLOOD-VOLUME; FOREPAW STIMULATION; CONTRAST AGENT; GRADIENT-ECHO; BRAIN; MRI; OXYGENATION; PERFUSION; TESLA; FMRI AB A multislice spin echo EPI sequence was used to obtain functional MR images of the entire rat brain with blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) contrast at 11.7 T. Maps of activation incidence were created by warping each image to the Paxinos rat brain atlas and marking the extent of the activated area. Incidence maps for BOLD and CBV were similar, but activation in draining veins was more prominent in the BOLD images than in the CBV images. Cerebellar activation was observed along the surface in BOLD images, but in deeper regions in the CBV images. Both effects may be explained by increased signal dropout and distortion in the EPI images after administration of the ferumoxtran-10 contrast agent for CBV fMRI. CBV-weighted incidence maps were also created for 10, 20, and 30 mg Fe/kg doses of ferumoxtran-10. The magnitude of the average percentage change during stimulation increased from 4.9% with the 10 mg Fe/kg dose to 8.7% with the 30-mg Fe/kg dose. Incidence of activation followed a similar trend. C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Emory Univ, Atlanta, GA 30322 USA. Stanford Univ, Palo Alto, CA 94304 USA. RP Koretsky, AP (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,10 B1D728,MSC 1065, Bethesda, MD 20892 USA. EM KoretskyA@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08] NR 31 TC 45 Z9 47 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2006 VL 55 IS 2 BP 316 EP 324 DI 10.1002/mrm.20744 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 012GO UT WOS:000235326500013 PM 16372281 ER PT J AU Li, TQ Takahashi, A Wang, Y Mathews, V Glover, GH AF Li, TQ Takahashi, A Wang, Y Mathews, V Glover, GH TI Dual-echo spiral in/in acquisition method for reducing magnetic susceptibility artifacts in blood-oxygen-level-dependent functional magnetic resonance imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article; Proceedings Paper CT 11th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine CY JUL 10-16, 2003 CL TORONTO, CANADA SP Int Soc Magnet Resonance Med DE BOLD fMRI; susceptibility artifact; spiral trajectory; dual-echo spiral in/in; effective TE ID TAILORED RF PULSES; BOLD FMRI; SELECTIVE EXCITATION; FOURIER INVERSION; GRADIENT-ECHO; COMPENSATION; REDUCTION; MRI; ALGORITHM AB MRI signal dropout in gradient recalled echo acquisitions limits the capability of blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) to study activation tasks that involve the orbitofrontal, temporal, and basal areas of the brain where significant macroscopic magnetic susceptibility differences exist. Among the various approaches aimed to address this issue, the acquisition method based on spiral in/out trajectories is one of the most time-efficient and effective techniques. In this study, we extended further the spiral in/out approach into 3D acquisition and compared the effectiveness of the different spiral in/out trajectory combinations in reducing signal dropout. The activation results from whole brain fMRI studies using complex finger tapping and breath-holding tasks demonstrate that the acquisition method based on dual-echo spiral in/in (DSPIN) trajectories is the most favorable. The DSPIN acquisition method has the following advantages: (1) It reduces most effectively signal dropout in the brain where magnetic susceptibility inhomogeneity is problematic and significantly improves the sensitivity to detect functional activations in those regions. (2) It significantly improves SNR in the whole brain by dual echo averaging without compromising functional contrast. (3) There is no reduction in time-efficiency and spatial resolution. C1 NINDS, NIH, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. GE Healthcare, Global Appl Sci Lab, Menlo Pk, CA USA. Indiana Univ, Sch Med, Dept Radiol, Indianapolis, IN 46204 USA. Stanford Univ, Dept Radiol, Radiol Sci Lab, Stanford, CA 94305 USA. RP Li, TQ (reprint author), NINDS, NIH, Lab Funct & Mol Imaging, 10 Ctr Dr,Room 10-B1D720, Bethesda, MD 20892 USA. EM litie@ninds.nih.gov OI Li, Tieqiang/0000-0002-6636-8938; Li, Tie-Qiang/0000-0002-4866-5904 FU NIMH NIH HHS [MH063455-01A1R01] NR 24 TC 13 Z9 13 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2006 VL 55 IS 2 BP 325 EP 334 DI 10.1002/mrm.20783 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 012GO UT WOS:000235326500014 PM 16408267 ER PT J AU Hakami, RM Hou, L Baxter, LL Loftus, SK Southard-Smith, EM Incao, A Cheng, J Pavan, WJ AF Hakami, RM Hou, L Baxter, LL Loftus, SK Southard-Smith, EM Incao, A Cheng, J Pavan, WJ TI Genetic evidence does not support direct regulation of EDNRB by SOX10 in migratory neural crest and the melanocyte lineage SO MECHANISMS OF DEVELOPMENT LA English DT Article DE neural crest; SOX10; melanocyte; Waardenburg syndrome; Hirschsprung disease; transcription factor; endothelin; genetics; transgenic mouse ID ENDOTHELIN RECEPTOR-B; WAARDENBURG-SYNDROME TYPE-4; TRANSCRIPTION FACTOR SOX10; DOPACHROME-TAUTOMERASE; MOUSE MODEL; HIRSCHSPRUNG-DISEASE; MITF; EXPRESSION; CELLS; MUTATION AB Mutations in the transcription factor Sox10 or Endothelin Receptor B (Ednrb) result in Waardenburg Syndrome Type IV (WS-IV), which presents with deficiencies of neural crest derived melanocytes (hypopigmentation) and enteric ganglia (hypoganglionosis). As Sox.10 and Ednrb are expressed in mouse migratory neural crest cells and melanoblasts, we investigated the possibility that SOX10 and EDNRB function through a hierarchical relationship during melanocyte development. However, our results support a distinct rather than hierarchical relationship. First, SOX10 expression continues in Ednrb null melanoblasts, demonstrating that SOX10 expression is not dependent on EDNRB function. Second, Ednrb expression persists in E10.5 Sox10null embryos, demonstrating that Ednrb is not dependent on SOX10 for expression in migratory neural crest cells. Third, over-expression of SOX10 in melanoblasts of mice that harbor null or hypomorphic Ednrb alleles does not rescue hypopigmentation, suggesting that SOX10 overexpression can neither complement a lack of EDNRB function nor increase Ednrb expression. Fourth, mice that are double heterozygous for loss-of-function mutations in Sox10 and Ednrb do not demonstrate synergistically increased hypopigmentation compared to mice that are single heterozygotes for either mutation alone, suggesting a lack of direct genetic interaction between these genes. Our results suggest that SOX10 does not directly activate Ednrb transcription in the melanocyte lineage. Given that SOX10 directly activates Ednrb in the enteric nervous system, our results suggest that SOX10 may differentially activate target genes based on the particular cellular context. Published by Elsevier Ireland Ltd. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Med, Div Med Genet, Nashville, TN 37232 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov RI Southard-Smith, Michelle/C-3488-2012; OI Hou, Ling/0000-0003-0705-8099 FU Intramural NIH HHS; NHGRI NIH HHS [Z01 HG000070-10, Z01 HG000136-07] NR 40 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD FEB PY 2006 VL 123 IS 2 BP 124 EP 134 DI 10.1016/j.mod.2005.11.004 PG 11 WC Developmental Biology SC Developmental Biology GA 021VP UT WOS:000236014300003 PM 16412618 ER PT J AU Berman, JD AF Berman, JD TI Development of miltefosine for the leishmaniases SO MINI-REVIEWS IN MEDICINAL CHEMISTRY LA English DT Review DE miltefosine; visceral leishmaniasis; cutaneous leishmaniasis; efficacy; tolerance ID INDIAN VISCERAL LEISHMANIASIS; ORAL MILTEFOSINE; DONOVANI PROMASTIGOTES; HEXADECYLPHOSPHOCHOLINE MILTEFOSINE; PHOSPHATIDYLCHOLINE SYNTHESIS; LYSOPHOSPHOLIPID ANALOGS; CUTANEOUS LEISHMANIASIS; ETHER LYSOPHOSPHOLIPIDS; TRYPANOSOMA-CRUZI; TOPICAL TREATMENT AB The leishmaniases consist of visceral and cutaneous syndromes present in > 30 endemic regions of the world. Miltefosine (hexadecylephosphocholine) is the first oral agent that is effective and tolerated for both visceral and cutaneous disease in several endemic regions, and represents a major advance in the treatment of these diseases. C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Berman, JD (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM Bermanjo@mail.nih.gov NR 36 TC 20 Z9 21 U1 2 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-5575 J9 MINI-REV MED CHEM JI Mini-Rev. Med. Chem. PD FEB PY 2006 VL 6 IS 2 BP 145 EP 151 DI 10.2174/138955706775475993 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 012GW UT WOS:000235327300004 PM 16472183 ER PT J AU Colson, AO Gershengorn, MC AF Colson, AO Gershengorn, MC TI Thyrotropin-releasing hormone analogs SO MINI-REVIEWS IN MEDICINAL CHEMISTRY LA English DT Review DE TRH; TRH receptor; hormone; neuropeptide; analogs ID CENTRAL-NERVOUS-SYSTEM; TRH ANALOGS; BINDING-SITES; BIOLOGICAL-ACTIVITIES; DOPAMINE RELEASE; PITUITARY-CELLS; FRONTAL-CORTEX; RAT-BRAIN; RECEPTOR; BENZODIAZEPINES AB Thyrotropin releasing hormone (TRH: pyroglutamic acid-histidine-prolineamide) regulates the activity of cells in the anterior pituitary and within the central and peripheral nervous systems. TRH, which has been the subject of much research over the past three decades, exerts its effects by acting through class A G-protein coupled receptors. The recent discovery of a second receptor subtype has generated an interest in the discovery of receptor subtype-selective TRH analogs. In this review, we describe advances in the development of TRH analogs and in the understanding of their mechanism of interaction with TRH receptors. We also describe the recent breakthrough in the identification of analogs that bind selectively at TRH-R2. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Computat Chem Sect, Chem Biol Core Facil, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Clin Endocrinol Branch, NIH, 50 S Dr,Bldg 50-4134, Bethesda, MD 20892 USA. EM MarvinG@intra.niddk.nih.gov NR 75 TC 9 Z9 9 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-5575 J9 MINI-REV MED CHEM JI Mini-Rev. Med. Chem. PD FEB PY 2006 VL 6 IS 2 BP 221 EP 226 DI 10.2174/138955706775476019 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 012GW UT WOS:000235327300010 PM 16472189 ER PT J AU Gaur, D Furuya, T Mu, JB Jiang, LB Su, XZ Miller, LH AF Gaur, D Furuya, T Mu, JB Jiang, LB Su, XZ Miller, LH TI Upregulation of expression of the reticulocyte homology gene 4 in the Plasmodium falciparum clone Dd2 is associated with a switch in the erythrocyte invasion pathway SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Plasmodium falciparum; transcription; erythrocyte invasion; sialic acids; switch in invasion ID YOELII ADHESIVE PROTEINS; MALARIA PARASITES; ANTISENSE TRANSCRIPTS; INVADE ERYTHROCYTES; GLYCOPHORIN-B; RECEPTOR HETEROGENEITY; MEROZOITE PROTEINS; HOST-CELL; VIVAX; STRAIN AB The Plasmodium falciparum clone, Dd2, that requires sialic acid for invasion can switch to a sialic acid independent pathway, Dd2(NM). To elucidate the molecular basis of the switch in invasion phenotype of Dd2 to Dd2(NM), we performed expression profiling of the parasites using an oligonucleotide microarray and real-time RT-PCR. We found that four genes were upregulated in Dd2(NM) by microarray analysis, only two of which could be confirmed by real time RT-PCR. One gene, PfRH4, is a member of the reticulocyte homology family and the other, PEBL, is a pseudogene of the Duffy binding-like family. The two genes are contiguous but transcribed in opposite directions. The DNA sequence of these ORFs, their 5'-intergenic region and a 1.1kb region 3' to each ORF are identical between Dd2 and Dd2(NM), suggesting that their transcription upregulation relates to transactivating factors. The transcription upregulation of PfRH4 was reflected at the protein level as PfRH4 protein expression was detected in Dd2(NM) and not in Dd2. Other sialic acid independent and dependent clones of P. falciparum showed variable transcript levels of PfRH4 and PEBL, unrelated to their dependence on sialic acid for invasion, suggesting that different P. falciparum clones use different receptors for sialic acid independent invasion. As Dd2(NM) is a selected subclone of Dd2, the marked upregulation of PfRH4 expression in Dd2(NM) suggests its role in erythrocyte invasion through the sialic acid independent pathway of Dd2(NM). (c) 2005 Elsevier B.V. All rights reserved. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Bldg Twinbrook 3,Room 3E-32D, Bethesda, MD 20892 USA. EM lmiller@niaid.nih.gov RI Furuya, Tetsuya/J-5916-2013; Furuya, Tetsuya/H-2412-2013; OI Furuya, Tetsuya/0000-0003-3979-7072; Su, Xinzhuan/0000-0003-3246-3248 NR 48 TC 52 Z9 54 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD FEB PY 2006 VL 145 IS 2 BP 205 EP 215 DI 10.1016/j.molbiopara.2005.10.004 PG 11 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 010XE UT WOS:000235230400007 PM 16289357 ER PT J AU Yang, HS Matthews, CP Clair, T Wang, Q Baker, AR Li, CCH Tan, TH Colburn, NH AF Yang, HS Matthews, CP Clair, T Wang, Q Baker, AR Li, CCH Tan, TH Colburn, NH TI Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HEMATOPOIETIC PROGENITOR KINASE; N-TERMINAL KINASE; C-JUN; TRANSFORMATION SUPPRESSOR; ADAPTER PROTEINS; TRANSCRIPTIONAL REGULATION; MATRIX METALLOPROTEINASES; SIGNALING PATHWAY; TUMOR-SUPPRESSOR; CANCER-CELLS AB Programmed cell death 4 (Pdcd4) suppresses neoplastic transformation by inhibiting the activation of c-Jun and consequently AP-1-dependent transcription. We report that Pdcd4 blocks c-Jun activation by inhibiting the expression of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1)/hematopoietic progenitor kinase 1, a kinase upstream of Jun N-terminal kinase (JNK). cDNA microarray analysis of Pdcd4-overexpressing RKO human colon carcinoma cells revealed MAP4K1 as the sole target of Pdcd4 on the JNK activation pathway. Cotransfection of a MAP4K1 promoter-reporter with Pdcd4 demonstrated inhibition of transcription from the MANK1 promoter. Ectopic expression of Pdcd4 in metastatic RKO cells suppressed invasion. MAP4K1 activity is functionally significant in invasion, as overexpression of a dominant negative MAP4K1 (dnMAP4KI) mutant in RKO cells inhibited not only c-Jun activation but also invasion. Overexpression of a MAP4K1 cDNA in Pdcd4-transfected cells rescued the kinase activity of JNK. Thus, Pdcd4 suppresses tumor progression in human colon carcinoma cells by the novel mechanism of down-regulating MAP4K1 transcription, with consequent inhibition of c-Jun activation and AP-1-dependent transcription. C1 NCI, Canc Res Ctr, Lab Canc Prevent, Ft Detrick, MD 21702 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. Bayer Coll Med, Dept Immunol, Houston, TX 77030 USA. RP Yang, HS (reprint author), Univ Kentucky, Coll Med, Grad Ctr Toxicol, Lexington, KY 40536 USA. EM hyang3@uky.edu; colburn@mail.ncifcrf.gov RI Yang, Hsin-Sheng/A-6419-2008; Tan, Tse-Hua/E-3983-2010 OI Tan, Tse-Hua/0000-0003-4969-3170 FU Intramural NIH HHS NR 51 TC 133 Z9 144 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2006 VL 26 IS 4 BP 1297 EP 1306 DI 10.1128/MCB.26.4.1297-1306.2006 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013VN UT WOS:000235438200012 PM 16449643 ER PT J AU Jivotovskaya, AV Valasek, L Hinnebusch, AG Nielsen, KH AF Jivotovskaya, AV Valasek, L Hinnebusch, AG Nielsen, KH TI Eukaryotic translation initiation factor 3 (eIF3) and eIF2 can promote mRNA binding to 40S subunits independently of eIF4G in yeast SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EUKARYOTIC TRANSLATION INITIATION; FACTOR 4G EIF4G; MAMMALIAN PROTEIN-SYNTHESIS; C-TERMINAL DOMAIN; SACCHAROMYCES-CEREVISIAE; IN-VIVO; PREINITIATION COMPLEX; MULTIFACTOR COMPLEX; DEPENDENT TRANSLATION; RABBIT RETICULOCYTES AB Recruitment of the eukaryotic translation initiation factor 2 (eIF2)-GTP-Met-tRNA(i)(Met) ternary complex to the 40S ribosome is stimulated by multiple initiation factors in vitro, including eIF3, eIF1, eIF5, and eIF1A. Recruitment of mRNA is thought to require the functions of eIF4F and eIF3, with the latter serving as an adaptor between the ribosome and the 4G subunit of eIF4F. To define the factor requirements for these reactions in vivo, we examined the effects of depleting eIF2, eIF3, eIF5, or eIF4G in Saccharomyces cerevisiae cells on binding of the ternary complex, other initiation factors, and RPL41A mRNA to native 43S and 48S preinitiation complexes. Depleting eIF2, eIF3, or eIF5 reduced 40S binding of all constituents of the multifactor complex (MFC), comprised of these three factors and eIF1, supporting a mechanism of coupled 40S binding by MFC components. 40S-bound mRNA strongly accumulated in eIF5-depleted cells, even though MFC binding to 40S subunits was reduced by eIF5 depletion. Hence, stimulation of the GTPase activity of the ternary complex, a prerequisite for 60S subunit joining in vitro, is likely the rate-limiting function of eIF5 in vivo. Depleting eIF2 or eIF3 impaired mRNA binding to free 40S subunits, but depleting eIF4G led unexpectedly to accumulation of mRNA on 40S subunits. Thus, it appears that eIF3 and eIF2 are more critically required than eIF4G for stable binding of at least some mRNAs to native preinitiation complexes and that eIF4G has a rate-limiting function at a step downstream of 48S complex assembly in vivo. C1 NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP NIH, Bldg 6A,Room B1A13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI Valasek, Leos/I-5743-2014 FU Intramural NIH HHS NR 64 TC 66 Z9 69 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2006 VL 26 IS 4 BP 1355 EP 1372 DI 10.1128/MCB.26.4.1355-1372.2006 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013VN UT WOS:000235438200017 PM 16449648 ER PT J AU Motegi, A Kuntz, K Majeed, A Smith, S Myung, K AF Motegi, A Kuntz, K Majeed, A Smith, S Myung, K TI Regulation of gross chromosomal rearrangements by ubiquitin and SUMO ligases in Saccharomyces cerevisiae SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DAMAGE-INDUCED MUTAGENESIS; SPONTANEOUS DNA-DAMAGE; GENOME INSTABILITY; S-PHASE; POSTREPLICATION REPAIR; ELEVATED RECOMBINATION; XERODERMA-PIGMENTOSUM; CONJUGATING ACTIVITY; SRS2 SUPPRESSOR; REQUIRES SRS2 AB Gross chromosomal rearrangements (GCRs) are frequently observed in many cancers. Previously, we showed that inactivation of Rad5 or Rad18, ubiquitin ligases (E3) targeting for proliferating cell nuclear antigen (PCNA), increases the de novo telomere addition type of GCR (S. Smith, J. Y. Hwang, S. Banerjee, A. Majeed, A. Gupta, and K. Myung, Proc. Nad. Acad. Sci. USA 101:9039-9044, 2004). GCR suppression by Rad5 and Rad18 appears to be exerted by the RAD5-dependent error-free mode of bypass DNA repair. In contrast, Siz1 SUMO ligase and another ubiquitin ligase, Bre1, which target for PCNA and histone H2B, respectively, have GCR-supporting activities. Inactivation of homologous recombination (HR) proteins or the helicase Srs2 reduces GCR rates elevated by the rad5 or rad18 mutation. GCRs are therefore likely to be produced through the restrained recruitment of an HR pathway to stalled DNA replication forks. Since this HR pathway is compatible with Srs2, it is not a conventional form of recombinational pathway. Lastly, we demonstrate that selection of proper DNA repair pathways to stalled DNA replication forks is controlled by the Mec1-dependent checkpoint and is executed by cooperative functions of Siz1 and Srs2. We propose a mechanism for how defects in these proteins could lead to diverse outcomes (proper repair or GCR formation) through different regulation of DNA repair machinery. C1 NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, K (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bldg 49,Room 4A22,49 Convent Dr, Bethesda, MD 20892 USA. EM kmyung@nhgri.nih.gov FU Intramural NIH HHS NR 73 TC 41 Z9 42 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2006 VL 26 IS 4 BP 1424 EP 1433 DI 10.1128/MCB.26.4.1424-1433.2006 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013VN UT WOS:000235438200022 PM 16449653 ER PT J AU Park, JM Kohn, MJ Bruinsma, MW Vech, C Intine, RV Fuhrmann, S Grinberg, A Mukherjee, I Love, PE Ko, MS DePamphilis, ML Maraia, RJ AF Park, JM Kohn, MJ Bruinsma, MW Vech, C Intine, RV Fuhrmann, S Grinberg, A Mukherjee, I Love, PE Ko, MS DePamphilis, ML Maraia, RJ TI The multifunctional RNA-binding protein La is required for mouse development and for the establishment of embryonic stem cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POLYMERASE-III TRANSCRIPTS; METHIONYL-TRANSFER-RNA; SACCHAROMYCES-CEREVISIAE; SS-B; DROSOPHILA-MELANOGASTER; ANTIGEN; MATURATION; AUTOANTIGEN; ANTIBODIES; NUCLEAR AB The La protein is a target of autoantibodies in patients suffering from Sjogren's syndrome, systemic lupus erythematosus, and neonatal lupus. Ubiquitous in eukaryotes, La functions as a RNA-binding protein that promotes the maturation of tRNA precursors and other nascent transcripts synthesized by RNA polymerase III as well as other noncoding RNAs. La also associates with a class of mRNAs that encode ribosome subunits and precursors to snoRNAs involved in ribosome biogenesis. Thus, it was surprising that La is dispensable in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the organisms from which it has been characterized most extensively. To determine whether La is essential in mammals and if so, at which developmental stage it is required, mice were created with a disrupted La gene, and the offspring from La+/- intercrosses were analyzed. La-/- offspring were detected at the expected frequency among blastocysts prior. to implantation, whereas no nullizygotes were detected after implantation, indicating that La is required early in development. Blastocysts derived from La+/- intercrosses yielded 38 La+/+ and La+/- embryonic stem (ES) cell lines but no La-/- ES cell lines, suggesting that La contributes a critical function toward the establishment or survival of ES cells. Consistent with this, La-/- blastocyst outgrowths revealed loss of the inner cell mass (ICM). The results indicate that in contrast to the situation in yeasts, La is essential in mammals and is one of a limited number of genes required as early as the development of the ICM. C1 NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. NIA, Genet Lab, Baltimore, MD 21224 USA. RP Maraia, RJ (reprint author), NICHHD, Lab Mol Growth Regulat, 31 Ctr Dr,Bldg 31,Rm 2A25, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS NR 35 TC 26 Z9 29 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2006 VL 26 IS 4 BP 1445 EP 1451 DI 10.1128/MCB.26.4.1445-1451.2006 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013VN UT WOS:000235438200024 PM 16449655 ER PT J AU Pramatarova, A Ochalski, PG Lee, CH Howell, BW AF Pramatarova, A Ochalski, PG Lee, CH Howell, BW TI Mouse disabled 1 regulates the nuclear position of neurons in a Drosophila eye model SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; REELIN-STIMULATED NEURONS; BRAIN-DEVELOPMENT; AXONAL-TRANSPORT; TYROSINE PHOSPHORYLATION; TAU PHOSPHORYLATION; CYTOPLASMIC DYNEIN; BINDING-PROTEIN; MIGRATION; LIS1 AB Nucleokinesis has recently been suggested as a critical regulator of neuronal migration. Here we show that Disabled 1 (Dab1), which is required for neuronal positioning in mammals, regulates the nuclear position of postmitotic neurons in a phosphorylation-site dependent manner. Dab1 expression in the Drosophila visual system partially rescues nuclear position defects caused by a mutation in the Dynactin subunit Glued. Furthermore, we observed that a loss-of-function allele of amyloid precursor protein (APP)-like, a kinesin cargo receptor, enhanced the severity of a Dab1 overexpression phenotype characterized by misplaced nuclei in the adult retina. In mammalian neurons, overexpression of APP reduced the ability of Reelin to induce Dab1. tyrosine phosphorylation, suggesting an antagonistic relationship between APP family members and Dab1 function. This is the first evidence that signaling which regulates Dab1 tyrosine phosphorylation determines nuclear positioning through Dab1-mediated influences on microtubule motor proteins in a subset of neurons. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Unit Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Howell, BW (reprint author), NINDS, Neurogenet Branch, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM howellb@ninds.nih.gov RI Lee, Chi-Hon/G-9190-2012; OI Howell, Brian/0000-0002-0204-0773 FU Intramural NIH HHS NR 56 TC 14 Z9 16 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2006 VL 26 IS 4 BP 1510 EP 1517 DI 10.1128/MCB.26.4.1510-1517.2006 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013VN UT WOS:000235438200029 PM 16449660 ER PT J AU Rarnkissoon, SH Mainwaring, LA Sloand, EM Young, NS Kajigaya, S AF Rarnkissoon, SH Mainwaring, LA Sloand, EM Young, NS Kajigaya, S TI Nonisotopic detection of microRNA using digoxigenin labeled RNA probes SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE microRNA; RNA oligonucleotide probe; northern analysis; DIG ID CANCERS; GENES; DNA AB MicroRNAs (miRNAs) are an important class of endogenously derived, small similar to 22 nucleotide noncoding regulatory RNAs that have recently become implicated in development, cell regulation and cancers of various tissues. Here we report a nonisotopic Northern analysis method for miRNA detection using 3 '-diaoxi-enin (DIG)-labeled RNA oligo probes. Northern blot analysis was performed using miRNA or total RNA fractions extracted from human leukemic cell lines, and blots were hybridized with either P-32- or DIG-labeled RNA probe for miR-181, miR-155 or miR-16. A labeled probe for U6 small nuclear RNA served as an internal control. The use of DIG-labeled RNA probes was equally sensitive compared to P-32-labeled probes in detecting miRNA quantities as low as 50 ng. The ability to use nonisotopic methods and yet obtain sensitive and reliable results offers an advantage to investigators who prefer to avoid isotopes. Published by Elsevier Ltd. C1 Natl Heart Lung & Blood Inst, Hematol Branch, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Grad Sch Biomed Sci, Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD USA. RP Kajigaya, S (reprint author), Natl Heart Lung & Blood Inst, Hematol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kajiaays@mail.nih.gov NR 10 TC 1 Z9 2 U1 1 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD FEB PY 2006 VL 20 IS 1 BP 1 EP 4 DI 10.1016/j.mcp.2005.07.004 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 022JU UT WOS:000236052700001 ER PT J AU Niemela, JE Hsu, AP Fleisher, TA Puck, JM AF Niemela, JE Hsu, AP Fleisher, TA Puck, JM TI Single nucleotide polymorphisms in the apoptosis receptor gene TNFRSF6 SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE autoimmune lymphoproliferative syndrome (ALPS); DNA mutation; loss of heterozygosity; lymphocyte homeostasis; immune regulation; linkage disequilibrium; haplotype ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; SYSTEMIC-LUPUS-ERYTHEMATOSUS; SOMATIC FAS MUTATIONS; LINKAGE DISEQUILIBRIUM; PROMOTER REGION; DISEASE; PATHOGENESIS; ASSOCIATION; ANTIGEN; LIGAND AB The homotrimeric Fas receptor, an inducer of lymphocyte apoptosis, plays a critical role in cellular pathways of immune homeostasis and immunologic tolerance. Inherited and acquired defects in the Fas gene, TNFRSF6 (tumor necrosis factor receptor superfamily member 6) have been associated with human autoimmune lymphoproliferative syndrome (ALPS) and a spectrum of other complex autoimmune diseases and malignancies. In addition to over 60 deleterious mutations associated with dominant inhibitory defects or null mutations of TNFRSF6, several sequence variants have been noted. To facilitate interpretation of genotypes of this important locus, we sequenced DNA from unrelated, healthy Caucasians and African Americans. Two new and 12 previously recorded SNPs were confirmed, and their allele frequencies were determined. We also investigated haplotype frequencies and linkage disequilibrium (LD) coefficients for these SNPs in Caucasians. Four TNFRSF6 SNP pairs were found to be in strong LD. The TNRFSF6 SNPs are useful for linkage and loss of heterozygosity studies probing the role of Fas-mediated apoptosis in autoimmune diseases and malignancies. Published by Elsevier Ltd. C1 NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Dept Lab Med, NIH, Bethesda, MD USA. RP Puck, JM (reprint author), NHGRI, Genet & Mol Biol Branch, 49 Convent Dr,NIH Bldg 49, Bethesda, MD 20892 USA. EM jniemela@cc.nih.gov; twins@mail.nih.gov; tfleishe@mail.cc.nih.gov; jpuck@mail.nih.gov OI Niemela, Julie/0000-0003-4197-3792 FU Intramural NIH HHS NR 38 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD FEB PY 2006 VL 20 IS 1 BP 21 EP 26 DI 10.1016/j.mcp.2005.05.004 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 022JU UT WOS:000236052700005 PM 16271851 ER PT J AU Prunuske, AJ Liu, J Elgort, S Joseph, J Dasso, M Ullman, KS AF Prunuske, AJ Liu, J Elgort, S Joseph, J Dasso, M Ullman, KS TI Nuclear envelope breakdown is coordinated by both Nup358/RanBP2 and Nup153, two nucleoporins with zinc finger modules SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PORE COMPLEX STRUCTURE; UBIQUITIN INTERACTIONS; PROTEIN; DOMAIN; ASSOCIATION; TRANSPORT; MITOSIS; EXPORT; MEMBRANES; BINDING AB When higher eukaryotic cells transition into mitosis, the nuclear envelope, nuclear pore complexes, and nuclear lamina are coordinately disassembled. The COPI coatomer complex, which plays a major role in membrane remodeling at the Golgi, has been implicated in the process of nuclear envelope breakdown and requires interactions at the nuclear pore complex for recruitment to this new site of action at mitosis. Nup153, a resident of the nuclear pore basket, was found to be involved in COPI recruitment, but the molecular nature of the interface between COPI and the nuclear pore has not been fully elucidated. To better understand what occurs at the nuclear pore at this juncture, we have probed the role of the nucleoporin Nup358/RanBP2. Nup358 contains a repetitive zinc finger domain with overall organization similar to a region within Nup153 that is critical to COPI association, yet inspection of these two zinc finger domains reveals features that also clearly distinguish them. Here, we found that the Nup358 zinc finger domain, but not a zinc finger domain from an unrelated protein, binds to COPI and dominantly inhibits progression of nuclear envelope breakdown in an assay that robustly recapitulates this process in vitro. Moreover, the Nup358 zinc finger domain interferes with COPI recruitment to the nuclear rim. Consistent with a role for this pore protein in coordinating nuclear envelope breakdown, Nup358-specific antibodies impair nuclear disassembly. Significantly, targeting either Nup153 or Nup358 for inhibition perturbs nuclear envelope breakdown, supporting a model in which these nucleoporins play nonredundant roles, perhaps contributing to COPI recruitment platforms on both the nuclear and cytoplasmic faces of the pore. We found that an individual zinc finger is the minimal interface for COPI association, although tandem zinc fingers are optimal. These results provide new information about the critical components of nuclear membrane remodeling and lay the foundation for a better understanding of how this process is regulated. C1 Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Ullman, KS (reprint author), Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. EM katharine.ullman@hci.utah.edu OI Dasso, Mary/0000-0002-5410-1371 FU Intramural NIH HHS [Z01 HD008740-06]; NCI NIH HHS [P30CA42014, P30 CA042014]; NIGMS NIH HHS [R01 GM061275-07, GM61275, R01 GM061275] NR 37 TC 29 Z9 29 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2006 VL 17 IS 2 BP 760 EP 769 DI 10.1091/mbc.E05-06-0485 PG 10 WC Cell Biology SC Cell Biology GA 009MX UT WOS:000235117300019 PM 16314393 ER PT J AU Kim, T Loh, YP AF Kim, T Loh, YP TI Protease nexin-1 promotes secretory granule biogenesis by preventing granule protein degradation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TYROSINE-HYDROXYLASE GENE; ADRENAL CHROMAFFIN CELLS; CHROMOGRANIN-A; PHEOCHROMOCYTOMA CELLS; SITE-1 PROTEASE; ON/OFF SWITCH; BREFELDIN-A; PC12 CELLS; EXPRESSION; TRANSCRIPTION AB Dense-core secretory granule (DCG) biogenesis is a prerequisite step for the sorting, processing, and secretion of neuropeptides and hormones in (neuro)endocrine cells. Previously, chromogranin A (CgA) has been shown to play a key role in the regulation of DCG biogenesis in vitro and in vivo. However, the underlying mechanism of CgA-mediated DCG biogenesis has not been explored. In this study, we have uncovered a novel mechanism for the regulation of CgA-mediated DCG biogenesis. Transfection of CgA into endocrine 6T3 cells lacking CgA and DCGs not only recovered DCG formation and regulated secretion but also prevented granule protein degradation. Genetic profiling of CgA-expressing 6T3 versus CgA- and DCG-deficient 6T3 cells, followed by real-time reverse transcription-polymerase chain reaction and Western blotting analyses, revealed that a serine protease inhibitor, protease nexin-1 (PN-1), was significantly up-regulated in CgA-expressing 6T3 cells. Overexpression of PN-1 in CgA-deficient 6T3 cells prevented degradation of DCG proteins at the Golgi apparatus, enhanced DCG biogenesis, and recovered regulated secretion. Moreover, depletion of PN-1 by antisense RNAs in CgA-expressing 6T3 cells resulted in the specific degradation of DCG proteins. We conclude that CgA increases DCG biogenesis in endocrine cells by up-regulating PN-1 expression to stabilize granule proteins against degradation. C1 NICHHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), NICHHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Intramural NIH HHS NR 41 TC 31 Z9 32 U1 4 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2006 VL 17 IS 2 BP 789 EP 798 DI 10.1091/mbc.E05-08-0755 PG 10 WC Cell Biology SC Cell Biology GA 009MX UT WOS:000235117300022 PM 16319172 ER PT J AU Nishiyama, A Dey, A Miyazaki, J Ozato, K AF Nishiyama, A Dey, A Miyazaki, J Ozato, K TI Brd4 is required for recovery from antimicrotubule drug-induced mitotic arrest: Preservation of acetylated chromatin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SPINDLE ASSEMBLY CHECKPOINT; BROMODOMAIN PROTEIN BRD4; DEPENDENT TRANSCRIPTION; GENE-EXPRESSION; CELL-DIVISION; LIVING CELLS; MITOSIS; CHROMOSOMES; METAPHASE; KINASE AB The mammalian bromodomain protein Brd4 interacts with mitotic chromosomes by binding to acetylated histone H3 and H4 and is thought to play a role in epigenetic memory. Mitotic cells are susceptible to antimicrotubule drugs. These drugs activate multiple response pathways and arrest cells at mitosis. We found that Brd4 was rapidly released from chromosomes upon treatment with antimicrotubule drugs, including the reversible agent nocodazole. Yet, when nocodazole was withdrawn, Brd4 was reloaded onto chromosomes, and cells proceeded to complete cell division. However, cells in which a Brd4 allele was disrupted (Brd4+/-), and expressing only half of the normal Brd4 levels, were defective in reloading Brd4 onto chromosomes. Consequently, Brd4+/- cells were impaired in their ability to recover from nocodazole-induced mitotic arrest: a large fraction of +/- cells failed to reach anaphase after drug withdrawal, and those that entered anaphase showed an increased frequency of abnormal chromosomal segregation. The reloading defect observed in Brd4+/- cells coincided with selective hypoacetylation of lysine residues on H3 and H4. The histone deacetylase inhibitor trichostatin A increased global histone acetylation and perturbed nocodazole-induced Brd4 unloading. Brd4 plays an integral part in a cellular response to drug-induced mitotic stress by preserving a properly acetylated chromatin status. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Osaka Univ, Med Sch G6, Div Stem Cell Regulat Res, Suita, Osaka 5650871, Japan. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov RI Miyazaki, Jun-ichi/N-1976-2015 OI Miyazaki, Jun-ichi/0000-0003-2475-589X FU Intramural NIH HHS NR 42 TC 40 Z9 42 U1 0 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2006 VL 17 IS 2 BP 814 EP 823 DI 10.1091/mbc.E05-08-0729 PG 10 WC Cell Biology SC Cell Biology GA 009MX UT WOS:000235117300024 PM 16339075 ER PT J AU Altan-Bonnet, N Sougrat, R Liu, W Snapp, EL Ward, T Lippincott-Schwartz, J AF Altan-Bonnet, N Sougrat, R Liu, W Snapp, EL Ward, T Lippincott-Schwartz, J TI Golgi inheritance in mammalian cells is mediated through endoplasmic reticulum export activities SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID VESICULAR STOMATITIS-VIRUS; MATRIX PROTEIN GM130; DE-NOVO FORMATION; MITOTIC GOLGI; LIVING CELLS; BREFELDIN-A; HELA-CELLS; PLASMA-MEMBRANE; PICHIA-PASTORIS; QUALITY-CONTROL AB Golgi inheritance during mammalian cell division occurs through the disassembly, partitioning, and reassembly of Golgi membranes. The mechanisms responsible for these processes are poorly understood. To address these mechanisms, we have examined the identity and dynamics of Golgi proteins within mitotic membranes using live cell imaging and electron microscopy techniques. Mitotic Golgi fragments, seen in prometaphase and telophase, were found to localize adjacent to endoplasmic reticulum (ER) export domains, and resident Golgi transmembrane proteins cycled rapidly into and out of these fragments. Golgi proteins within mitotic Golgi haze-seen during metaphase-were found to redistribute with ER markers into fragments when the ER was fragmented by ionomycin treatment. The temperature-sensitive misfolding mutant ts045VSVG protein, when localized to the Golgi at the start of mitosis, became trapped in the ER at the end of mitosis in cells shifted to 40 degrees C. Finally, reporters for Arf1 and Sar1 activity revealed that Arf1 and Sar1 undergo sequential inactivation during mitotic Golgi breakdown and sequential reactivation upon Golgi reassembly at the end of mitosis. Together, these findings support a model of mitotic Golgi inheritance that involves inhibition and subsequent reactivation of cellular activities controlling the cycling of Golgi components into and out of the ER. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov RI Ward, Theresa/E-9650-2013 OI Sougrat, Rachid/0000-0001-6476-1886; Ward, Theresa/0000-0002-9881-8649 FU Medical Research Council [G0400373]; NIDDK NIH HHS [R21 DK074650, R21 DK074650-02] NR 66 TC 73 Z9 76 U1 1 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2006 VL 17 IS 2 BP 990 EP 1005 DI 10.1091/mbc.E05-02-0155 PG 16 WC Cell Biology SC Cell Biology GA 009MX UT WOS:000235117300039 PM 16314396 ER PT J AU Marchand, C Antony, S Kohn, KW Cushman, M Ioanoviciu, A Staker, BL Burgin, AB Stewart, L Pommier, Y AF Marchand, C Antony, S Kohn, KW Cushman, M Ioanoviciu, A Staker, BL Burgin, AB Stewart, L Pommier, Y TI A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CRYSTAL-STRUCTURE; CAMPTOTHECIN RESISTANCE; BIOLOGICAL EVALUATION; CLEAVAGE COMPLEXES; HUMAN CALCINEURIN; ELECTRON-DENSITY; PROTEIN CLAMP; STRAND BREAKS; BINDING-SITE; MECHANISM AB We show that five topoisomerase I inhibitors (two indenoisoquinolines, two camptothecins, and one indolocarbazole) each intercalate between the base pairs flanking the cleavage site generated during the topoisomerase I catalytic cycle and are further stabilized by a network of hydrogen bonds with topoisomerase I. The interfacial inhibition paradigm described for topoisomerase I inhibitors can be generalized to a variety of natural products that trap macromolecular complexes as they undergo catalytic conformational changes that create hotspots for drug binding. Stabilization of such conformational states results in uncompetitive inhibition and exemplifies the relevance of screening for ligands and drugs that stabilize ("trap") these macromolecular complexes. C1 NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Purdue Univ, Sch Pharm & Pharmaceut Sci, Purdue Canc Ctr, W Lafayette, IN 47907 USA. Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. deCODE Biostruct Inc, Bainbridhe Isl, WA USA. RP Pommier, Y (reprint author), NCI, Ctr Canc Res, Mol Pharmacol Lab, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Marchand, Christophe/D-8559-2016 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [U01 CA89566] NR 65 TC 112 Z9 113 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2006 VL 5 IS 2 BP 287 EP 295 DI 10.1158/1535-7163.MCT-05-0456 PG 9 WC Oncology SC Oncology GA 017VM UT WOS:000235721400012 PM 16505102 ER PT J AU Li, PK Pandit, B Sackett, DL Hu, ZG Zink, J Zhi, JD Freeman, D Robey, RW Werbovetz, K Lewis, A Li, CL AF Li, PK Pandit, B Sackett, DL Hu, ZG Zink, J Zhi, JD Freeman, D Robey, RW Werbovetz, K Lewis, A Li, CL TI A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubule-stabilizing activities SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID BIOLOGICAL RESPONSE MODIFIERS; TNF-ALPHA PRODUCTION; LOW-DOSE THALIDOMIDE; PHASE-II TRIAL; TUBULIN-POLYMERIZATION; RHEUMATOID-ARTHRITIS; MULTIDRUG-RESISTANCE; INHIBITORY-ACTIVITY; POTENT INHIBITORS; MULTIPLE-MYELOMA AB We discovered a thalidomide analogue [5-hydroxy-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33)] with antiproliferative activity against nine cancer cell lines in vitro. Flow cytometric analyses showed that the compound caused G(2)-M arrest, which occurred mainly at the mitotic phase. In addition, immunofluorescence microscopy and in vitro tubulin polymerization studies showed that 5HPP-33 has antimicrotubule activity with a paclitaxel-like mode of action. It is effective against four different paclitaxel-resistant cell lines. Thus, 5HPP-33 represents a potential antitumor agent. C1 Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. NICHHD, Lab Integrat & Med Biophys, NCI, NIH, Bethesda, MD 20892 USA. RP Li, PK (reprint author), Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, 338 Parks Hall,500 W 12th Ave, Columbus, OH 43210 USA. EM li.27@osu.edu RI Li, Chenglong/E-7182-2010; Werbovetz, Karl/E-4290-2011 OI Li, Chenglong/0000-0003-3174-8719; FU Intramural NIH HHS NR 44 TC 25 Z9 25 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2006 VL 5 IS 2 BP 450 EP 456 DI 10.1158/1535-7163.MCT-05-0254 PG 7 WC Oncology SC Oncology GA 017VM UT WOS:000235721400030 PM 16505120 ER PT J AU Mahadevan, B Arora, V Schild, LJ Keshava, C Cate, ML Iversen, PL Poirier, MC Weston, A Pereira, C Baird, WM AF Mahadevan, B Arora, V Schild, LJ Keshava, C Cate, ML Iversen, PL Poirier, MC Weston, A Pereira, C Baird, WM TI Reduction in tamoxifen-induced CYP3A2 expression and DNA adducts using antisense technology SO MOLECULAR CARCINOGENESIS LA English DT Article DE DNA adducts; cytochrome P450; CYP3A2; antisense; microarray ID BREAST-CANCER; DRUG-METABOLISM; C-MYC; ALPHA-ACETOXYTAMOXIFEN; CYTOCHROME-P450 3A2; RAT HEPATOCYTES; IN-VIVO; IDENTIFICATION; LIVER; OLIGOMERS AB Tamoxifen (TAM) is widely used in the treatment and prevention of breast cancer. There is clear evidence that cytochrome P450 (CYP) 3A enzymes play an important role in TAM metabolism, resulting in metabolites that lead to formation of TAM-DNA adducts. We have investigated the effect of CYP3A2 antisense (AVI-4472) exposure on CYP3A2 transcription, enzyme activity, translation, and TAM-DNA adducts, in livers of rats administered TAM (50 mg/kg body weight [bw]/day) for 7 days. The study design Included administration of 0, 0.5, 2.5, or 12.5 mg AVI-4472/kg bw/day for 8 days, beginning 1 day before TAM exposure. The specific activity of CYP3A2 was increased after TAM administration, and decreased significantly (similar to 70%) in the presence of 12.5 mg AVI-4472. CYP3A2 protein levels, determined by immunoblot analysis, showed a similar pattern. Hepatic TAM-DNA adduct levels were measurable in all TAM-exposed groups. However, when rats were co-treated with 2.5 and 12.5 mg AVI-4472/kg bw/day, statistically significant (similar to 50%) reductions in TAM-DNA adduct levels (2.0-2.8 adducts/10(8) nucleotides) were observed compared to rats treated with TAM alone (5.1 adducts/10(8) nucleotides). Rat toxicology U34 arrays (Affymetrix) were used to investigate the modulation of gene expression patterns on co-administration of TAM with AVI-4472. Results indicated that several CYP genes were down regulated although no significant induction of CYP3A2 was observed in the TAM-exposed rats co-treated with AVI-4472. Overall the data suggest the utility of antisense technology in the redirection of TAM metabolism thereby lowering TAM genotoxicity in rat liver. Published 2005 Wiley-Liss, Inc. C1 Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. AVI BioPharma, Res & Dev, Corvallis, OR USA. NCI, Canc Res Ctr, Carcinogen DNA Interact Sect, NIH, Bethesda, MD 20892 USA. NIOSH, Toxicol & Mol Biol Branch, CDC, Morgantown, WV USA. Oregon State Univ, Dept Stat, Corvallis, OR 97331 USA. RP Baird, WM (reprint author), Oregon State Univ, Dept Environm & Mol Toxicol, 1007, Corvallis, OR 97331 USA. FU NIEHS NIH HHS [5T32 ES07060-23, P30 ES00210] NR 46 TC 5 Z9 6 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2006 VL 45 IS 2 BP 118 EP 125 DI 10.1002/mc.20143 PG 8 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 009MU UT WOS:000235116900006 PM 16329150 ER PT J AU Dang, H Trempus, C Malarkey, DE Wei, SJ Humble, M Morris, RJ Tennant, RW AF Dang, H Trempus, C Malarkey, DE Wei, SJ Humble, M Morris, RJ Tennant, RW TI Identification of genes and gene ontology processes critical to skin papilloma development in Tg.AC transgenic mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE epidermal; wound healing; gene ontology; neoplastic processes; DNA microarray ID EPIDERMAL DIFFERENTIATION COMPLEX; CYSTEINE PROTEINASE-INHIBITORS; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; MOUSE SKIN; CYSTATIN-C; EXPRESSION; RAS; CARCINOGENESIS; APOPTOSIS AB This study analyzes gene expression associated with papilloma development in Tg.AC v-Ha-ras transgenic mice and identifies novel genes and biological processes that may be critical to skin carcinogenesis in these mice. Epidermal abrasion was used to synchronously induce epidermal regeneration in FVB/N wild type and transgenic Tg.AC mice. Skin papillomagenesis was uniquely induced in Tg.AC mice, and gene expression profiling was carried out using a 22 000 element mouse DNA microarray. Histological analysis showed that papillomas developed at a high rate by d 30 after abrasion in transgenic animals, while no papilloma developed in wild type mice. Transgene-specific differentially expressed genes were identified at d 30 postabrasion and these genes were annotated using EASE software and literature mining. Annotated and non-annotated genes associated with papilloma development were identified and clustering analysis revealed groups of genes that are coordinately expressed. A number of genes associated with differentiation and development were also physically clustered on Mouse chromosome 16, including 16B3 that contains several Stefins and stefin-like genes, and 16A1 containing a number of keratin associated protein genes. Additional analyses presented here yield novel insights into the genes and processes involved in papilloma development in Tg.AC mice. Published 2005 Wiley-Liss, Inc. C1 NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. Alpha Gamma Technol Inc, Raleigh, NC USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY USA. RP Tennant, RW (reprint author), NIEHS, Natl Ctr Toxicogenom, POB 12233,MD 12233,MD F1-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 38 TC 5 Z9 5 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2006 VL 45 IS 2 BP 126 EP 140 DI 10.1002/mc.20154 PG 15 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 009MU UT WOS:000235116900007 PM 16329151 ER PT J AU Gagnon, SJ Turner, RV Shiue, MG Damirjian, M Biddison, WE AF Gagnon, SJ Turner, RV Shiue, MG Damirjian, M Biddison, WE TI Extensive T cell receptor cross-reactivity on structurally diverse haptenated peptides presented by HLA-A2 SO MOLECULAR IMMUNOLOGY LA English DT Article DE T cell receptors; cytotoxic T lymphocytes; cross-reactivity ID CONFORMATIONAL DIVERSITY; ANTIGEN RECOGNITION; MOLECULAR MIMICRY; SEQUENCE HOMOLOGY; TCR BINDING; HTLV-1 TAX; MHC; COMPLEX; IDENTIFICATION; ANTIBODY AB Previous studies have shown that individual TCRs are able to effectively recognize multiple peptide/MHC complexes that have varying degrees of structural diversity. These TCR cross-reactivities have usually been demonstrated by using peptides that have different amino acid sequences. To further examine the extent to which TCRs can accommodate structurally diverse ligands, we analyzed human TCR cross-reactivity to eight structurally distinct haptens that are coupled to the HLA-A2-binding Tax peptide with a lysine substitution at position 5 (Tax-5K, LLFG[K-hapten]PVYV). The results demonstrate that 71% percent of the haptenated-peptide-induced CTL lines could cross-react on at least one other hapten. We compared the effects of HLA-A2 mutants with substitutions at known TCR contact sites for recognition by hapten-cross-reactive CTL. Recognition of the A2 mutants was remarkably similar whether they were presenting the immunizing or the cross-reactive peptide, indicating that similar amino acid contacts are made by the TCR during recognition of both complexes. Thus, hapten cross-reactivity is apparently accomplished without major adjustments to the interaction between the TCR and the surface of the HLA-A2 molecule. Collectively, these results suggest that TCRs possess the molecular flexibility to accommodate very structurally diverse ligands while retaining conserved interactions with the surface of the MHC molecule. Published by Elsevier Ltd. C1 NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Princeton BioMol Corp, Langhorne, PA 19047 USA. RP Gagnon, SJ (reprint author), NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16, Bethesda, MD 20892 USA. EM gagnons@ninds.nih.gov NR 41 TC 7 Z9 7 U1 0 U2 2 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 FEB PY 2006 VL 43 IS 4 BP 346 EP 356 DI 10.1016/j.molimm.2005.02.011 PG 11 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 002UB UT WOS:000234635900006 PM 16310048 ER PT J AU Schmid, T Young, MR AF Schmid, T Young, MR TI Lights on for low oxygen: A noninvasive mouse model useful for sensing oxygen deficiency SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID HYPOXIA-INDUCIBLE FACTOR; CANCER-THERAPY; FACTOR-I; HIF; PROLYL; HYDROXYLASES; INVOLVEMENT; INHIBITION; PROTEIN; FAMILY C1 NCI, Lab Canc Prevent, Frederick, MD 21702 USA. RP Schmid, T (reprint author), NCI, Lab Canc Prevent, Frederick, MD 21702 USA. EM Tschmid@ncifcrf.gov; Youngm@ncifcrf.gov FU Intramural NIH HHS NR 20 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD FEB PY 2006 VL 6 IS 1 BP 20 EP 22 DI 10.1124/mi.6.1.4 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 022OT UT WOS:000236066100003 PM 16507746 ER PT J AU Pham, PT Zhao, W Schaaper, RM AF Pham, PT Zhao, W Schaaper, RM TI Mutator mutants of Escherichia coli carrying a defect in the DNA polymerase III tau subunit SO MOLECULAR MICROBIOLOGY LA English DT Article ID CHROMOSOMAL REPLICATION MACHINE; ONE HOLOENZYME PARTICLE; GAMMA-SUBUNIT; MISMATCH REPAIR; NUCLEOTIDE MISINCORPORATION; MUTATIONAL SPECIFICITY; RESISTANCE ELEMENTS; ANTIMUTATOR ALLELES; BASE SUBSTITUTION; BINDING DOMAIN AB To investigate the possible role of accessory subunits of Escherichia coli DNA polymerase III holoenzyme (HE) in determining chromosomal replication fidelity, we have investigated the role of the dnaX gene. This gene encodes both the tau and gamma subunits of HE, which play a central role in the organization and functioning of HE at the replication fork. We find that a classical, temperature-sensitive dnaX allele, dnaX36, displays a pronounced mutator effect, characterized by an unusual specificity: preferential enhancement of transversions and -1 frameshifts. The latter occur predominantly at non-run sequences. The dnaX36 defect does not affect the gamma subunit, but produces a tau subunit carrying a missense substitution (E601K) in its C-terminal domain (domain V) that is involved in interaction with the Pol III alpha subunit. A search for new mutators in the dnaX region of the chromosome yielded six additional dnaX mutators, all carrying a specific tau subunit defect. The new mutators displayed phenotypes similar to dnaX36: strong enhancement of transversions and frameshifts and only weak enhancement for transitions. The combined findings suggest that the tau subunit of HE plays an important role in determining the fidelity of the chromosomal replication, specifically in the avoidance of transversions and frameshift mutations. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov NR 65 TC 16 Z9 16 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2006 VL 59 IS 4 BP 1149 EP 1161 DI 10.1111/j.1365-2958.2005.05011.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 005CQ UT WOS:000234800600006 PM 16430690 ER PT J AU Hartz, AMS Bauer, B Fricker, G Miller, DS AF Hartz, AMS Bauer, B Fricker, G Miller, DS TI Rapid modulation of p-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide SO MOLECULAR PHARMACOLOGY LA English DT Article ID RESISTANCE PROTEIN; RAT-BRAIN; ABC TRANSPORTERS; CNS INFLAMMATION; INNATE IMMUNITY; UP-REGULATION; IN-VIVO; EXPRESSION; ENDOTHELIN; DRUGS AB At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain parenchyma, impeding pharmacotherapy of a number of central nervous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ET B receptor, NO synthase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain's innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), activated a TNF-R1 receptor, released ET-1, activated ET B receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain's innate immune response, reduced P-glycoprotein activity through TNF-alpha release, ET-1 release, and ET B receptor signaling. TNF-alpha and LPS effects had a rapid onset (minutes), were reversible, and did not involve changes in tight junctional permeability. These findings define a signaling pathway through which P-glycoprotein activity is acutely modulated. They show that this key component of the selective/active blood-brain barrier is an early target of cytokine signaling during the innate immune response and suggest ways to manipulate the barrier for improved CNS pharmacotherapy. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Univ Heidelberg, Inst Pharm & Mol Biotechnol, Heidelberg, Germany. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov FU Intramural NIH HHS NR 29 TC 106 Z9 111 U1 1 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2006 VL 69 IS 2 BP 462 EP 470 DI 10.1124/mol.105.017954 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 003JQ UT WOS:000234678300007 PM 16278373 ER PT J AU Townsend, DM Findlay, VJ Fazilev, F Ogle, M Fraser, J Saavedra, JE Ji, XH Keefer, LK Tew, KD AF Townsend, DM Findlay, VJ Fazilev, F Ogle, M Fraser, J Saavedra, JE Ji, XH Keefer, LK Tew, KD TI A glutathione S-transferase pi-activated prodrug causes kinase activation concurrent with S-glutathionylation of proteins SO MOLECULAR PHARMACOLOGY LA English DT Article ID NITRIC-OXIDE; PARKINSONS-DISEASE; OXIDATIVE STRESS; THIOL PROTEINS; CELLS; APOPTOSIS; ACTIN AB Nitric oxide (NO) is an endogenous, diffusible, transcellular messenger shown to affect regulatory and signaling pathways with impact on cell survival. Exposure to NO can impart direct post-translational modifications on target proteins such as nitration and/or nitrosylation. As an alternative, after interaction with oxygen, superoxide, glutathione, or certain metals, NO can lead to S-glutathionylation, a post-translational modification potentially critical to signaling pathways. A novel glutathione S-transferase pi (GST pi)-activated pro-drug, O-2-{2,4-dinitro-5[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), liberates NO and elicits toxicity in vitro and in vivo. We now show that PABA/NO induces nitrosative stress, resulting in undetectable nitrosylation, limited nitration, and high levels of S-glutathionylation. After a single pharmacologically relevant dose of PABA/NO, S-glutathionylation occurs rapidly (< 5 min) and is sustained for similar to 7 h, implying a half-life for the deglutathionylation process of approximately 3 h. Two-dimensional SDS-polyacrylamide gel electrophoresis and immunoblotting with a monoclonal antibody to S-glutathionylated residues indicated that numerous proteins were S-glutathionylated. Subsequent matrix-assisted laser desorption ionization/time of flight analysis identified 10 proteins, including beta-lactate dehydrogenase, Rho GDP dissociation inhibitor beta, ATP synthase, elongation factor 2, protein disulfide isomerase, nucleophosmin-1, chaperonin, actin, protein tyrosine phosphatase 1B (PTP1B), and glucosidase II. In addition, we showed that sustained S-glutathionylation was temporally concurrent with drug-induced activation of the stress kinases, known to be linked with cell death pathways. This is consistent with the fact that PABA/NO induces S-glutathionylation and inactivation of PTP1B, one phosphatase that can participate in deactivation of kinases. These effects were consistent with the presence of intracellular PABA/NO or metabolites, because cells overexpressing MRP1 were less sensitive to the drug and had reduced levels of S-glutathionylated proteins. C1 Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pharmaceut Sci, Charleston, SC 29425 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. RP Med Univ S Carolina, Dept Cell & Mol Pharmacol, 173 Ashley Ave,POB 250505, Charleston, SC 29425 USA. EM tewk@musc.edu RI Ji, Xinhua/C-9664-2012; Keefer, Larry/N-3247-2014 OI Ji, Xinhua/0000-0001-6942-1514; Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS; NCI NIH HHS [1-CO-12400, CA53783] NR 30 TC 62 Z9 65 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2006 VL 69 IS 2 BP 501 EP 508 DI 10.1124/mol.105.018523 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 003JQ UT WOS:000234678300011 PM 16288082 ER PT J AU Tliba, O Cidlowski, JA Amrani, Y AF Tliba, O Cidlowski, JA Amrani, Y TI CD38 expression is insensitive to steroid action in cells treated with tumor necrosis factor-alpha and interferon-gamma by a mechanism involving the up-regulation of the glucocorticoid receptor beta isoform SO MOLECULAR PHARMACOLOGY LA English DT Article ID AIRWAY SMOOTH-MUSCLE; MESSENGER-RNA; IFN-GAMMA; TNF-ALPHA; ACTIVATION; RESISTANCE; CORTICOSTEROIDS; PROLIFERATION; NEUTROPHILS; INHIBITION AB Evidence shows that the CD38 molecule, recently involved in the two main features of asthma, bronchial hyper-responsiveness and airway inflammation, could represent a new potential therapeutic target for asthma. In this study, we investigated whether glucocorticoid ( GC), the most effective treatment for lung diseases, can affect CD38 expression in human airway smooth muscle (ASM) cells treated with different pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF alpha) and interferons ( IFNs). We found that CD38 expression induced by TNF alpha alone was completely abrogated by fluticasone ( 100 nM), dexamethasone ( 1 mu M), or budesonide ( 100 nM). In contrast, the synergistic induction of CD38 by the combination of TNF alpha with IFN gamma or IFN beta, but not with IL-1 beta or IL-13, was completely insensitive to the GC inhibitory effects. We also found that TNF alpha and IFN gamma impaired GC responsiveness by inhibiting steroid induced both 1) GR alpha-DNA binding activity and 2) GC-responsive element-( GRE)-dependent gene transcription. Although levels of the GC receptor ( GR) alpha isoform remained unchanged, expression of GR beta, the dominant-negative GR isoform, was synergistically increased by TNF alpha and IFN gamma with a GR alpha/GR beta ratio of 1 to 3. More importantly, fluticasone failed to induce GRE-dependent gene transcription and to suppress TNF alpha-induced CD38 expression in ASM cells transfected with constitutively active GR beta. We conclude that, upon pro-inflammatory cytokine stimulation, CD38 expression becomes insensitive to GC action by a mechanism involving the up-regulation of GR beta isoform, thus providing a novel in vitro cellular model to dissect GC resistance in primary cells. C1 Univ Penn, Ctr Med, Dept Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. Natl Inst Hlth, Natl Inst Environm Hlth Sci, Lab Signal Trasduct, Mol Endocrinol Grp, Res Triangle Pk, NC USA. RP Tliba, O (reprint author), Univ Penn, Ctr Med, Dept Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. EM omartlib@mail.med.upenn.edu RI Amrani, Yassine/A-1826-2013 FU NHLBI NIH HHS [HL64063] NR 47 TC 69 Z9 78 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2006 VL 69 IS 2 BP 588 EP 596 DI 10.1124/mol.105.019679 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 003JQ UT WOS:000234678300020 PM 16291871 ER PT J AU Leslie, EM Liu, J Klaassen, CD Waalkes, MP AF Leslie, EM Liu, J Klaassen, CD Waalkes, MP TI Acquired cadmium resistance in metallothionein-I/II(-/-) knockout cells: Role of the T-type calcium channel Cacn alpha(1G) in cadmium uptake SO MOLECULAR PHARMACOLOGY LA English DT Article ID DIVALENT METAL TRANSPORTER-1; NULL-CELLS; MESSENGER-RNA; CA2+ CHANNELS; BRUSH-BORDER; RAT; ZINC; COPPER; LOCALIZATION; ALPHA(1G) AB Metallothioneins (MTs) are cytoplasmic proteins that sequester certain divalent cations and are considered a primary cellular defense against the toxic transition metal cadmium (Cd2+). MT-I/II(-/-) knockout [MT(-/-)] cells are available and serve as an excellent tool to study non-MT-related mechanisms in metal tolerance. In the current study, Cd2+-resistant MT(-/-) (CdR) and CdR revertant (CdR-rev) cell lines were developed and characterized to investigate non-MT-mediated cellular protection mechanisms. Resistance to Cd2+ was approximately 70-fold higher in CdR than the parental MT(-/-) cell line (IC50 = 20 versus 0.3 mu M, respectively) and was stable in the absence of Cd2+ for 35 days. Accumulation of Cd2+ by the CdR cell line was reduced by approximately 95% compared with parental cells, primarily because of a decreased Cd2+ uptake. Cd2+ uptake by the MT(-/- ) parental cell line was independent of sodium, energy, and electrogenic potential. Uptake was saturable ( K-m = 65 nM; V-max = 4.9 pmol/mg/min) and pH-dependent ( maximal at pH 6.5-7). Potent inhibitors of Cd2+ uptake included Zn2+ ( IC50 = 7 mu M), Mn2+ (IC50 = 0.4 mu M), and the T-type Ca2+ channel antagonist mibefradil (IC50 = 5 mu M), whereas other metals ( including Fe2+) and L- type Ca2+ channel antagonists had little effect. Immunoblot and real- time reverse transcription-polymerase chain reaction analysis indicated that the Cacn alpha(1G) T-type Ca2+ channel was expressed at a reduced level in CdR compared with the parental MT(-/-) cell line, suggesting it is important for Cd2+ uptake. The CdR1-rev cell line was found to have a Cd2+ uptake and sensitivity level in between that of the CdR1 and MT(-/-) cell lines. Consistent with this was an intermediate expression of Cacn alpha(1G) in the CdR-rev cell line. These data suggest that decreased expression of Cacn alpha(1G) protects cells from Cd2+ exposure by limiting Cd2+ uptake. C1 NCI, Lab Comparat Carcinogenesis, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ Kansas, Ctr Med, Dept Pharmcol Toxicol & Therpeut, Kansas City, KS USA. RP Waalkes, MP (reprint author), NCI, Lab Comparat Carcinogenesis, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC USA. EM waalkes@niehs.nih.gov FU Intramural NIH HHS NR 45 TC 31 Z9 32 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2006 VL 69 IS 2 BP 629 EP 639 DI 10.1124/mol.105.014241 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 003JQ UT WOS:000234678300024 PM 16282520 ER PT J AU Tunbridge, EM Weinberger, DR Harrison, PJ AF Tunbridge, EM Weinberger, DR Harrison, PJ TI A novel protein isoform of catechol O-methyltransferase (COMT): brain expression analysis in schizophrenia and bipolar disorder and effect of Val(158)Met genotype SO MOLECULAR PSYCHIATRY LA English DT Letter ID DORSOLATERAL PREFRONTAL CORTEX; GENETIC-VARIATION; MESSENGER-RNA; NEUROPATHOLOGY C1 Univ Oxford, Dept Psychiat, Oxford, England. NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Tunbridge, EM (reprint author), Univ Oxford, Dept Psychiat, Oxford, England. EM elizabeth.tunbridge@psych.ox.ac.uk OI Tunbridge, Elizabeth/0000-0002-2966-2281 NR 12 TC 22 Z9 23 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2006 VL 11 IS 2 BP 116 EP 117 DI 10.1038/sj.mp.4001767 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 007FJ UT WOS:000234953700001 PM 16247488 ER PT J AU McQuillan, A Bass, NJ Kalsi, G Lawrence, J Puri, V Choudhury, K Detera-Wadleigh, SD Curtis, D Gurling, HMD AF McQuillan, A Bass, NJ Kalsi, G Lawrence, J Puri, V Choudhury, K Detera-Wadleigh, SD Curtis, D Gurling, HMD TI Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3 SO MOLECULAR PSYCHIATRY LA English DT Article DE chromosome 21; manic depression; linkage disequilibrium; genetic susceptibility ID DROSOPHILA WHITE GENE; MUTATION ANALYSIS; LINKAGE ANALYSIS; HUMAN HOMOLOG; SUPPORTS; POLYMORPHISMS; PEDIGREE; SEARCH; SCAN AB Linkage analyses of bipolar families have confirmed that there is a susceptibility locus near the telomere on chromosome 21q. To fine map this locus we carried out tests of allelic association using 30 genetic markers near the telomere at 21q22.3 in 600 bipolar research subjects and 450 ancestrally matched supernormal control subjects. We found significant allelic association with the microsatellite markers D21S171 (P=0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P=0.008) and rs1785467 (P=0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P=0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P=0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P=0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. These changes need further investigation to establish any aetiological role in bipolar disorder. C1 UCL Royal Free & UCL Med Sch, Windeyer Inst Med Sci, Dept Mental Hlth Sci, Mol Psychiat Lab, London W1T 4JF, England. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Royal London Hosp, St Bartholomews & Royal London Sch Med & Dent, Dept Psychol Med, London E1 1BB, England. RP Gurling, HMD (reprint author), UCL Royal Free & UCL Med Sch, Windeyer Inst Med Sci, Dept Mental Hlth Sci, Mol Psychiat Lab, 3rd Floor,46 Cleveland St, London W1T 4JF, England. EM h.gurling@ucl.ac.uk RI Gurling, Hugh/A-5029-2010; McQuillin, Andrew/C-1623-2008 OI McQuillin, Andrew/0000-0003-1567-2240 NR 32 TC 52 Z9 54 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2006 VL 11 IS 2 BP 134 EP 142 DI 10.1038/sj.mp.4001759 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 007FJ UT WOS:000234953700007 PM 16205735 ER PT J AU Richardson, SP Mari, Z Matsuhashi, M Hallett, M AF Richardson, SP Mari, Z Matsuhashi, M Hallett, M TI Psychogenic palatal tremor SO MOVEMENT DISORDERS LA English DT Article DE palatal tremor; psychogenic movement disorders; movement-related cortical potentials ID TICS AB We describe a case of psychogenic palatal tremor. The diagnosis was supported by clinical criteria and neurophysiological testing, including frequency analysis and jerk-locked back-averaging. We discuss the differential diagnosis of palatal tremor as well as the role of neurophysiological testing in the diagnosis of psychogenic movement disorders. (C) 2005 Movement Disorder Society. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 12 TC 9 Z9 9 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2006 VL 21 IS 2 BP 274 EP 276 DI 10.1002/mds.20731 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 016DW UT WOS:000235601900025 ER PT J AU Eblan, MJ Nguyen, J Ziegler, SG Lwin, A Hanson, M Gallardo, M Weiser, R De Lucca, M Singleton, A Sidransky, E AF Eblan, MJ Nguyen, J Ziegler, SG Lwin, A Hanson, M Gallardo, M Weiser, R De Lucca, M Singleton, A Sidransky, E TI Glucocerebrosidase mutations are also found in subjects with early-onset parkinsonism from Venezuela SO MOVEMENT DISORDERS LA English DT Letter ID GAUCHER-DISEASE; ASHKENAZI-JEWS; GENE C1 NIMH, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIA, Mol Genet Unit, NIH, Bethesda, MD 20892 USA. Univ Hosp, Dept Neurol, Movement Disorders Unit, Caracas, Venezuela. Inst Estudios Avanzados, Caracas, Venezuela. RP Sidransky, E (reprint author), NIMH, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. EM sidranse@irp.nimh.nih.gov RI Singleton, Andrew/C-3010-2009 NR 11 TC 45 Z9 47 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2006 VL 21 IS 2 BP 282 EP 283 DI 10.1002/mds.20766 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 016DW UT WOS:000235601900028 PM 16261622 ER PT J AU Jankowski, JA Hawk, ET AF Jankowski, JA Hawk, ET TI A methodologic analysis of chemoprevention and cancer prevention strategies for gastrointestinal cancer SO NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY LA English DT Review DE cancer; chemoprevention; clinical trials; drugs; gastroenterology ID HELICOBACTER-PYLORI ERADICATION; COLORECTAL-CANCER; RANDOMIZED-TRIAL; GASTRIC-CANCER; CLINICAL-TRIALS; DIETARY FIBER; ASPIRIN; RISK; NUTRITION; ADENOMAS AB Gastroenterology lags behind other specialties such as cardiology in the quality of its evidence base for clinical practice. One area where this is particularly evident is in cancer prevention, despite developments in chemoprevention strategies for high-risk patients. For chemoprevention strategies to be successful, we need appropriate clinical networks and translational science infrastructures, model chemoprevention agents and Multiple, large, flexible and randomized clinical trials. Translational science must also be embedded into large-scale, long-term, randomized clinical trials that have hard endpoints, so that irrefutable evidence of the longevity of treatment efficacy can be gathered. We also need to be able to identify an individual's cancer risk using valid global patient populations, so that medical benefits can be applied to all, regardless of ethnicity, sex, economic status, age and comorbidities. The future success of gastrointestinal chemoprevention relies on fostering a closer link between basic pharmaceutical research and clinical applications, in a 'bench to bedside and back' manner. In this review we systematically assess the evidence for various cancer prevention strategies, especially chemoprevention, and highlight the obstacles to further exploitation of this knowledge base. C1 Univ Oxford, Radcliffe Infirm, Dept Clin Pharmacol, Oxford OX2 6HE, England. Canc Res UK, London Res Inst, London, England. Leicester Royal Infirm, Leicester, Leics, England. NCI, Sect Director Canc Prevent, Div Canc Prevent, Bethesda, MD 20892 USA. RP Jankowski, JA (reprint author), Univ Oxford, Dept Clin Pharmacol, Woodstock Rd, Oxford OX2 6HE, England. EM janusz.jankowski@clinpharm.ox.ac.uk RI Jankowski, Janusz/H-2706-2012 OI Jankowski, Janusz/0000-0003-2130-9181 FU Cancer Research UK [4584] NR 47 TC 21 Z9 21 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4378 J9 NAT CLIN PRACT GASTR JI Nat. Clin. Pract. Gastroenterol. Hepatol. PD FEB PY 2006 VL 3 IS 2 BP 101 EP 111 DI 10.1038/ncpgasthep0412 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 012MG UT WOS:000235342700011 PM 16456576 ER PT J AU Bugge, TH Leppla, SH AF Bugge, TH Leppla, SH TI Anthrax target in macrophages unveiled SO NATURE GENETICS LA English DT Editorial Material ID LETHAL FACTOR; TOXIN; SUSCEPTIBILITY; INFLAMMATION; PROTEIN; NALPS C1 NIDCR, Proteases & Tissue Remodeling Unit, NIH, Bethesda, MD 20892 USA. NIAID, Bacterial Toxins & Therapeut Sect, NIH, Bethesda, MD 20892 USA. RP Bugge, TH (reprint author), NIDCR, Proteases & Tissue Remodeling Unit, NIH, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov NR 14 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2006 VL 38 IS 2 BP 137 EP 138 DI 10.1038/ng0206-137 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 007FE UT WOS:000234953200003 PM 16444249 ER PT J AU Drake, JA Bird, C Nemesh, J Thomas, DJ Newton-Cheh, C Reymond, A Excoffier, L Attar, H Antonarakis, SE Dermitzakis, ET Hirschhorn, JN AF Drake, JA Bird, C Nemesh, J Thomas, DJ Newton-Cheh, C Reymond, A Excoffier, L Attar, H Antonarakis, SE Dermitzakis, ET Hirschhorn, JN TI Conserved noncoding sequences are selectively constrained and not mutation cold spots SO NATURE GENETICS LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; NON-GENIC SEQUENCES; HUMAN GENOME; NONGENIC SEQUENCES; REGIONS; MAMMALS; DISEASE; IDENTIFICATION; POPULATION; DELETIONS AB Noncoding genetic variants are likely to influence human biology and disease, but recognizing functional noncoding variants is difficult. Approximately 3% of noncoding sequence is conserved among distantly related mammals(1-4), suggesting that these evolutionarily conserved noncoding regions (CNCs) are selectively constrained and contain functional variation. However, CNCs could also merely represent regions with lower local mutation rates. Here we address this issue and show that CNCs are selectively constrained in humans by analyzing HapMap genotype data. Specifically, new ( derived) alleles of SNPs within CNCs are rarer than new alleles in nonconserved regions (P = 3 x 10(-18)), indicating that evolutionary pressure has suppressed CNC-derived allele frequencies. Intronic CNCs and CNCs near genes show greater allele frequency shifts, with magnitudes comparable to those for missense variants. Thus, conserved noncoding variants are more likely to be functional. Allele frequency distributions highlight selectively constrained genomic regions that should be intensively surveyed for functionally important variation. C1 Childrens Hosp, Program Genom, Boston, MA 02115 USA. Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02139 USA. MIT, Cambridge, MA 02139 USA. Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. Univ Bern, Inst Zool, CH-3012 Bern, Switzerland. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Hirschhorn, JN (reprint author), Childrens Hosp, Program Genom, 300 Longwood Ave, Boston, MA 02115 USA. EM md4@sanger.ac.uk; joelh@broad.mit.edu RI Dermitzakis, Emmanouil/B-7687-2013; Excoffier, Laurent/D-3498-2013; Antonarakis, Stylianos/N-8866-2014 OI Excoffier, Laurent/0000-0002-7507-6494; Antonarakis, Stylianos/0000-0001-8907-5823 FU Wellcome Trust NR 30 TC 150 Z9 155 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2006 VL 38 IS 2 BP 223 EP 227 DI 10.1038/ng1710 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 007FE UT WOS:000234953200019 PM 16380714 ER PT J AU Hickman-Miller, HD Yewdell, JW AF Hickman-Miller, HD Yewdell, JW TI Youth has its privileges: maturation inhibits DC cross-priming SO NATURE IMMUNOLOGY LA English DT Editorial Material ID CELLS IN-VIVO; DENDRITIC CELLS; ANTIGEN PRESENTATION AB Naive CD8(+) T cells can be activated via dendritic cell 'cross-priming' of antigens obtained exogenously. Dendritic cells cannot cross-prime, however, after systemic activation in vivo, potentially contributing to immunosuppression associated with severe infections. C1 NIAID, Lab Viral Dis, Bethesda, MD 20892 USA. RP Hickman-Miller, HD (reprint author), NIAID, Lab Viral Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 8 TC 7 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2006 VL 7 IS 2 BP 125 EP 126 DI 10.1038/ni0206-125 PG 2 WC Immunology SC Immunology GA 005DB UT WOS:000234801700005 PM 16424887 ER PT J AU Frahm, N Kiepiela, P Adams, S Linde, CH Hewitt, HS Sango, K Feeney, ME Addo, MM Lichterfeld, M Lahaie, MP Pae, E Wurcel, AG Roach, T St John, MA Altfeld, M Marincola, FM Moore, C Mallal, S Carrington, M Heckerman, D Allen, TM Mullins, JI Korber, BT Goulder, PJR Walker, BD Brander, C AF Frahm, N Kiepiela, P Adams, S Linde, CH Hewitt, HS Sango, K Feeney, ME Addo, MM Lichterfeld, M Lahaie, MP Pae, E Wurcel, AG Roach, T St John, MA Altfeld, M Marincola, FM Moore, C Mallal, S Carrington, M Heckerman, D Allen, TM Mullins, JI Korber, BT Goulder, PJR Walker, BD Brander, C TI Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes SO NATURE IMMUNOLOGY LA English DT Article ID HLA-B; IMMUNE ESCAPE; HIV; RESPONSES; AIDS; TRANSMISSION; PROGRESSION; VACCINE; ADAPTATION; MUTATIONS AB Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div AIDS, Boston, MA 02115 USA. Univ KwaZulu Natal, ZA-4015 Durban, South Africa. Clin Ctr Natl Inst Hlth, Bethesda, MD 20892 USA. Fenway Community Hlth Ctr, Boston, MA 02115 USA. Lemuel Shattuck Hosp, Boston, MA 02115 USA. Queen Elizabeth Hosp, Bridgetown, Barbados. Royal Perth Hosp, Ctr Clin Immunol & Biomed Stat, Murdoch, WA 6000, Australia. Murdoch Univ, Murdoch, WA 6150, Australia. NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Basic Res Program, Frederick, MD 21702 USA. Microsoft Corp, Redmond, WA 98052 USA. Univ Washington, Seattle, WA 98195 USA. Santa Fe Inst, Santa Fe, NM 87501 USA. Los Alamos Natl Lab, Los Alamos, NM 87545 USA. Univ Oxford, Oxford OX1 3SY, England. Howard Hughes Med Inst, Chevy Chase, MD 20185 USA. RP Brander, C (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02115 USA. EM cbrander@partners.org RI Allen, Todd/F-5473-2011; OI Brander, Christian/0000-0002-0548-5778; Korber, Bette/0000-0002-2026-5757 FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [N01-AI-15422, R01-AI-067077] NR 32 TC 163 Z9 168 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2006 VL 7 IS 2 BP 173 EP 178 DI 10.1038/ni1281 PG 6 WC Immunology SC Immunology GA 005DB UT WOS:000234801700018 PM 16369537 ER PT J AU Ramirez, DC Mejiba, SEG Mason, RP AF Ramirez, DC Mejiba, SEG Mason, RP TI Immuno-spin trapping of DNA radicals SO NATURE METHODS LA English DT Article ID HYDROGEN-PEROXIDE; OXIDATIVE DAMAGE; COPPER; ION; 8-HYDROXY-2'-DEOXYGUANOSINE; DEGRADATION; METALS; BASES; RAT; RNA AB The detection of DNA radicals by immuno-spin trapping (IST) is based on the trapping of radicals with 5,5-dimethyl-1-pyffoline N-oxide (DMPO), forming stable nitrone adducts that are then detected using an anti-DMPO serum. DNA radicals are very reactive species, and because they are paramagnetic they have previously been detected only by electron spin resonance (ESR) with or without spin trapping, which is not available in most bioresearch laboratories. IST combines the simplicity, reliability, specificity and sensitivity of spin trapping with heterogeneous immunoassays for the detection of DNA radicals, and complements existing methods for the measurement of oxidatively generated DNA damage. Here we have used IST to demonstrate that DMPO traps Cu(II)-H2O2-induced DNA radicals in situ and in real time, forming DMPO-DNA nitrone adducts, but preventing both 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) formation and DNA fragmentation. We also applied IST to detect DNA radicals in rat hepatocytes exposed to Cu(II) and H2O2 under nonlethal conditions. C1 Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Ramirez, DC (reprint author), Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM ramirez1@niehs.nih.gov RI RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 FU Intramural NIH HHS NR 30 TC 44 Z9 44 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD FEB PY 2006 VL 3 IS 2 BP 123 EP 127 DI 10.1038/NMETH852 PG 5 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 007HQ UT WOS:000234960000016 PM 16432522 ER PT J AU Gerfen, CR AF Gerfen, CR TI Indirect-pathway neurons lose their spines in Parkinson disease SO NATURE NEUROSCIENCE LA English DT Editorial Material ID BASAL GANGLIA; GENE-EXPRESSION; DISORDERS; LESIONS C1 NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Gerfen, CR (reprint author), NIMH, Lab Syst Neurosci, 35 Convent Dr,3A-1000, Bethesda, MD 20892 USA. EM gerfenc@mail.nih.gov NR 14 TC 27 Z9 29 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2006 VL 9 IS 2 BP 157 EP 158 DI 10.1038/nn0206-157 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 007SN UT WOS:000234990100004 PM 16439979 ER PT J AU Hunter, K AF Hunter, K TI Opinion - Host genetics influence tumour metastasis SO NATURE REVIEWS CANCER LA English DT Article ID BREAST-CANCER METASTASIS; MICROARRAY PLATFORMS; TRANSGENIC MICE; ETHICAL-ISSUES; GENES; PROGRESSION; CARCINOMAS; MOUSE; IDENTIFICATION; SIGNATURE AB The complexity of the metastatic process has made it difficult to gain a full understanding of the origins of this most lethal aspect of cancer. Many factors probably have an important role, including somatic mutation, epigenetic modulations, interactions with normal stroma, and environmental stimuli. Additionally, recent evidence implies a significant role for germline polymorphisms in cancer progression. The existence of inherited metastasis risk factors ( or prospective metastatic biomarkers) has potentially significant implications for our models of metastasis, clinical prognosis and the development of tailored treatment. Further investigations into the inherited components of metastasis might help resolve many of the questions that remain about tumour progression. C1 NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hunter, K (reprint author), NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bldg 41,Room D702,41 Lib Dr, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU Intramural NIH HHS NR 38 TC 79 Z9 89 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD FEB PY 2006 VL 6 IS 2 BP 141 EP 146 DI 10.1038/nrc1803 PG 6 WC Oncology SC Oncology GA 005SL UT WOS:000234844000012 PM 16491073 ER PT J AU Schiffmann, R Ries, M Timmons, M Flaherty, JT Brady, RO AF Schiffmann, R Ries, M Timmons, M Flaherty, JT Brady, RO TI Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE chronic renal disease; enzyme replacement therapy; Fabry disease; genetic disease; glomerular filtration rate; renal dysfunction ID ENZYME REPLACEMENT THERAPY; CLINICAL MANIFESTATIONS; GALACTOSIDASE; PHENOTYPE; REVERSAL; IMPACT; COHORT AB Background. Fabry disease is an X-linked disorder of glycosphingolipid catabolism that is the result of an intracellular deficiency in the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). This enzymatic defect results in the accumulation of globotriaosylceramide (Gb(3)) within cells and causes progressive neurological, cardiovascular and renal dysfunction. Our objective is to describe the safety and renal effects of long-term enzyme replacement therapy. Methods. This was a single centre, prospective open-label treatment trial in 25 adult male Fabry patients who had completed a 6-month randomized placebo-controlled study and subsequently enrolled in an open-label extension study. Patients were treated every other week with agalsidase alfa (0.2 mg/kg) infused intravenously over 40 min. The main outcome measures were safety, antibody response and renal glomerular filtration rate (GFR). Results. During the 4-4.5 years of enzyme replacement therapy, all eligible subjects were able to transition to home therapy. Eight patients developed persistent IgG antibodies to agalsidase alfa, but IgE antibodies were not detected in any patient. The development of IgG antibodies appeared not to affect any clinical end points. Estimated GFR remained stable in subgroups of patients with Stage I (GFR > 90 ml/min) or Stage II (GFR 60-89 ml/min) chronic kidney disease at baseline. In contrast, in the subgroup of patients with Stage III chronic kidney disease (GFR 30-59 ml/min), the slope of the decline in GFR was reduced compared with comparable historical controls, suggesting that enzyme replacement therapy was slowing the decline of renal function in this susceptible population. Conclusions. Long-term enzyme replacement therapy with agalsidase alfa is safe and may slow the progressive decline in renal function that was commonly observed in adult males with Fabry disease. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Transkaryot Therapies Inc, Cambridge, MA USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rs4e@nih.gov OI Ries, Markus/0000-0002-5054-5741 FU NINDS NIH HHS [NS002984-05] NR 31 TC 180 Z9 184 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD FEB PY 2006 VL 21 IS 2 BP 345 EP 354 DI 10.1093/ndt/gfi152 PG 10 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 004WI UT WOS:000234782900016 PM 16204287 ER PT J AU Yucesoy, B Peila, R White, LR Wu, KM Johnson, VJ Kashon, ML Luster, MI Launer, LJ AF Yucesoy, B Peila, R White, LR Wu, KM Johnson, VJ Kashon, ML Luster, MI Launer, LJ TI Association of interleukin-1 gene polymorphisms with dementia in a community-based sample: The Honolulu-Asia Aging Study SO NEUROBIOLOGY OF AGING LA English DT Article DE interleukin-1 cytokine family; polymorphisms; Alzheimer disease; vascular dementia; neurodegenerative diseases ID ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; ANTIINFLAMMATORY CYTOKINES; VASCULAR DEMENTIA; SEVERITY FACTOR; BLOOD-PRESSURE; MESSENGER-RNA; APOE GENE; ONSET; RISK AB The interleukin I (IL-1) pro-inflammatory cytokine family participates in inflammatory processes and vessel damage involved in neurodegeneration. Recent studies suggest that Alzheimer's disease (AD) and vascular dementia (VaD) may share genetic risk factors. In this study, the frequency of polymorphisms in the genes coding for interleukin (IL)-1 alpha IL-1 beta and the IL-1 receptor antagonist (RN) and their genotype associations with late-onset AD and VaD were determined in a Japanese-American cohort of men (n=931) participating in the Honolulu-Asia Aging Study (HAAS). A significant association was found between the IL-1 beta (-511) and IL-1RN (+2018) polymorphisms and AD. suggesting that these variants confer an increased risk. Possessing the IL-1 beta (-511) T/T genotype was also associated with VaD. There was no difference in the IL-1 beta (+3953) frequency among the groups. Our results support the hypothesis that certain genetic variations contained within the IL-1 gene family contribute to the pathogenesis of dementia. (C) 2005 Elsevier Inc. All rights reserved. C1 NIOSH, Toxicol & Mol Biol Branch, Biostat Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI USA. RP Yucesoy, B (reprint author), NIOSH, Toxicol & Mol Biol Branch, Biostat Branch, Hlth Effects Lab Div, 1095 Willowdale Rd, Morgantown, WV 26505 USA. EM byucesoy@cdc.gov RI Johnson, Victor/A-7910-2009; Yucesoy, Berran/B-4497-2009 FU Intramural NIH HHS; NHLBI NIH HHS [N01-HC-0-5102]; NIA NIH HHS [R01-AG-0-7155-06A1, UO1-AG-0-19349-03, N01-AG-4-2149] NR 55 TC 33 Z9 34 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2006 VL 27 IS 2 BP 211 EP 217 DI 10.1016/j.neurobiolaging.2005.01.013 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 004WD UT WOS:000234782400003 PM 16226351 ER PT J AU Tanaka, Y Igarashi, S Nakamura, M Gafni, J Torcassi, C Schilling, G Crippen, D Wood, JD Sawa, A Jenkins, NA Copeland, NG Borchelt, DR Ross, CA Ellerby, LM AF Tanaka, Y Igarashi, S Nakamura, M Gafni, J Torcassi, C Schilling, G Crippen, D Wood, JD Sawa, A Jenkins, NA Copeland, NG Borchelt, DR Ross, CA Ellerby, LM TI Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin SO NEUROBIOLOGY OF DISEASE LA English DT Article ID NEURONAL INTRANUCLEAR INCLUSIONS; CREB-BINDING PROTEIN; KNOCK-IN MICE; MEDIATED TRANSCRIPTION; TRINUCLEOTIDE REPEAT; POLYGLUTAMINE TRACT; CASPASE CLEAVAGE; DEPENDENT PROTEOLYSIS; AGGREGATE FORMATION; CELLULAR TOXICITY AB Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized behaviorally by chorea, incoordination, and shortened lifespan and neuropathologically by huntingtin inclusions and neuronal degeneration. In order to facilitate studies of pathogenesis and therapeutics, we have generated a new inducible mouse model of HD expressing full-length huntingtin (Htt) using a tetracycline-regulated promoter. In double transgenic mice Htt was expressed widely in the brain under the control of the tet-transactivator (tTA) driven by the prion promoter PrP (in the absence of doxycycline). Mice expressing full-length mutant Htt, but not full-length normal Htt, displayed a progressive behavioral phenotype, consisting of slowed and irregular voluntary movements, gait ataxia, tremor and jerky movements, incoordination, and weight loss, with a shortened lifespan. Neuropathology included prominent intranuclear inclusions in cortex and striatum as well as cytoplasmic aggregates. This phenotype is very similar to the phenotypes of previous transgenic mice expressing N-terminal fragments of mutant Htt. The current HD-transgenic mice bad nuclear accumulation of Htt, particularly an approximately 60-kDa fragment, which appears to represent an N-terminal cleavage product. This fragment is smaller than calpain or caspase-derived cleavage products of Htt, but it is comparable to a product, termed cp-A, which accumulates in nuclei of cells in a previously described cell model. This new mouse model may be useful in the future for pathogenic and preclinical therapeutic studies related to HD. The data suggest that proteolytic processing could be a part of the pathogenesis of HD, potentially representing an attractive therapeutic target. (c) 2005 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, Baltimore, MD 21287 USA. Buck Inst Age Res, Novato, CA 94945 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Ellerby, LM (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, CMSC 8-121,600 N Wolfe St, Baltimore, MD 21287 USA. EM caross@jhu.edu; lellerby@buckinstitute.org RI Wood, Jonathan/A-5060-2009; Ross, Christopher/H-8395-2013 FU NINDS NIH HHS [NS16375, F32 NS043937, NS34172, NS38144, NS40251A] NR 62 TC 39 Z9 39 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2006 VL 21 IS 2 BP 381 EP 391 DI 10.1016/j.nbd.2005.07.014 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 008KW UT WOS:000235040600012 PM 16150600 ER PT J AU Jacobowitz, DM AF Jacobowitz, DM TI The birth of neurochemical maps - Miklos Palkovits SO NEUROCHEMICAL RESEARCH LA English DT Biographical-Item C1 Natl Inst Hlth, Clin Sci Lab, Bethesda, MD 20892 USA. RP Jacobowitz, DM (reprint author), Natl Inst Hlth, Clin Sci Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD FEB PY 2006 VL 31 IS 2 BP 125 EP 126 DI 10.1007/s11064-005-9002-x PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 039RW UT WOS:000237325500003 PM 16673172 ER PT J AU Mezey, E Brownstein, M AF Mezey, E Brownstein, M TI Lessons learned from Miki - Miklos Palkovits SO NEUROCHEMICAL RESEARCH LA English DT Biographical-Item C1 NIH, Bethesda, MD 20892 USA. RP Mezey, E (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Brownstein, Michael/B-8609-2009 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 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD FEB PY 2006 VL 31 IS 2 BP 127 EP 129 DI 10.1007/s11064-005-9003-9 PG 3 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 039RW UT WOS:000237325500004 PM 16673173 ER PT J AU Mutsuga, N Gainer, H AF Mutsuga, N Gainer, H TI Molecular analysis of the magnocellular neuroendocrine phenotype: From the micropunch to laser microdissection SO NEUROCHEMICAL RESEARCH LA English DT Article DE vasopressin; oxytocin; C1q domain; microarray; hypothalamus; gene expression ID LEUKEMIA INHIBITORY FACTOR; RAT SUPRAOPTIC NUCLEUS; MESSENGER RIBONUCLEIC-ACIDS; CAPTURE MICRODISSECTION; GENE-EXPRESSION; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; MICROARRAY ANALYSIS; MICROGLIAL CELLS; ADULT-RAT; NEURONS AB Microdissection of selected regions of central nervous system (CNS) has provided the basis of modern chemoarchitectonics. Laser microdissection is a modern variant of the "Palkovits punch" technique and used together with gene array analysis has revolutionalized CNS molecular analysis. Here we describe the use of such an approach to elucidate molecules selectively expressed in magnocellular neuroendocrine cells (MCNs) in the supraoptic nucleus (SON). We found 123 genes that are preferentially expressed in the SON, and of these, 89 were substantially osmoregulated in their expression. One of these, C1q domain containing 1, is a novel gene that is osmoregulated much more than even vasopressin itself. C1 NINDS, Mol Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Mol Neurosci Sect, NIH, Bldg 49,Rm 5A78, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov FU Intramural NIH HHS NR 43 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 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD FEB PY 2006 VL 31 IS 2 BP 189 EP 199 DI 10.1007/s11064-005-9008-4 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 039RW UT WOS:000237325500011 PM 16572260 ER PT J AU Dobolyi, A Irwin, S Wang, J Usdin, TB AF Dobolyi, A Irwin, S Wang, J Usdin, TB TI The distribution and neurochemistry of the parathyroid hormone 2 receptor in the rat hypothalamus SO NEUROCHEMICAL RESEARCH LA English DT Article DE parathyroid; hormone; PTH2R; receptor; ligand; tuberoinfundibular; peptide; TIP39; neuropeptide; hypothalamus; distribution; immunoreactivity; fluorescent; amplification; immunocytochemistry; immunolabeling; secretion; somatostatin; growth hormone releasing hormone; gonadotropin releasing hormone; corticotropin releasing hormone; arginine vasopressin; anatomical; double-labeling; release; fiber terminals; vesicular glutamate transporter; excitatory; median eminence; paraventricular; periventricular; arcuate; nucleus; preoptic; pituitary ID TUBEROINFUNDIBULAR PEPTIDE; 39 RESIDUES; PARATHYROID-HORMONE; PTH2 RECEPTOR; NERVOUS-SYSTEM; EXPRESSION; ACID; IMMUNOREACTIVITY; IDENTIFICATION; DECARBOXYLASE AB This study reports the distribution of parathyroid hormone 2 receptor (PTH2R)-immunoreactive fibers in the hypothalamus using fluorescent amplification immunocytochemistry. The pattern of immunolabeling is strikingly similar to that of tuberoinfundibular peptide of 39 residues (TIP39), a peptide recently purified from bovine hypothalamus and proposed to be a ligand of the PTH2R based on pharmacological data. To investigate the anatomical basis of suggestions that TIP39 affects the secretion of several hypophysiotropic hormones we performed double-labeling studies and found that only somatostatin fibers contain PTH2R in the median eminence, which suggests that somatostatin release could be directly regulated via the PTH2R. However, several hypothalamic nuclei projecting to the median eminence contain a high density of both TIP39 and PTH2R fibers and terminals. We report here, that the PTH2R terminals also contain vesicular glutamate transporter-2, and suggest that TIP39 terminals are ideally positioned to modulate glutamatergic influences on hypophysiotropic neurons. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Genet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov RI Dobolyi, Arpad/B-9089-2008 FU Intramural NIH HHS NR 28 TC 16 Z9 16 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD FEB PY 2006 VL 31 IS 2 BP 227 EP 236 DI 10.1007/s11064-005-9011-9 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 039RW UT WOS:000237325500015 PM 16570212 ER PT J AU Tosun, D Rettmann, ME Naiman, DQ Resnick, SM Kraut, MA Prince, JL AF Tosun, D Rettmann, ME Naiman, DQ Resnick, SM Kraut, MA Prince, JL TI Cortical reconstruction using implicit surface evolution: Accuracy and precision analysis SO NEUROIMAGE LA English DT Article DE cerebral cortex; magnetic resonance; T1-weighted MR brain images; cortical reconstruction; human brain mapping; accuracy analysis; precision analysis; ANOVA; MANOVA ID MAGNETIC-RESONANCE IMAGES; HUMAN CEREBRAL-CORTEX; PARCELLATION METHOD; COORDINATE SYSTEM; SULCAL REGIONS; HUMAN BRAIN; THICKNESS; SEGMENTATION; MRI; ALGORITHM AB Two different studies were conducted to assess the accuracy and precision of an algorithm developed for automatic reconstruction of the cerebral cortex from T1-weighted magnetic resonance (MR) brain images. Repeated scans of three different brains were used to quantify the precision of the algorithm, and manually selected landmarks on different sulcal regions throughout the cortex were used to analyze the accuracy of the three reconstructed surfaces: inner, central, and pial. We conclude that the algorithm can find these surfaces in a robust fashion and with subvoxel accuracy, typically with an accuracy of one third of a voxel, although this varies with brain region and cortical geometry. Parameters were adjusted on the basis of this analysis in order to improve the algorithm's overall performance. (c) 2005 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. NIA, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Appl Math & Stat, Baltimore, MD 21218 USA. Johns Hopkins Univ Hosp, Dept Radiol, Div Neuroradiol, Baltimore, MD 21287 USA. RP Johns Hopkins Univ, Dept Elect & Comp Engn, 3400 N Charles St, Baltimore, MD 21218 USA. EM prince@jhu.edu RI Prince, Jerry/A-3281-2010 OI Prince, Jerry/0000-0002-6553-0876 FU NINDS NIH HHS [R01 NS037747, R01NS37747] NR 48 TC 17 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2006 VL 29 IS 3 BP 838 EP 852 DI 10.1016/j.neuroimage.2005.08.061 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 010WA UT WOS:000235227400016 PM 16269250 ER PT J AU Zapata, A Gonzales, RA Shippenberg, TS AF Zapata, A Gonzales, RA Shippenberg, TS TI Repeated ethanol intoxication induces behavioral sensitization in the absence of a sensitized accumbens dopamine response in C57BL/6J and DBA/2J mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE inbred strains; microdialysis; ventral striatum; chronic ethanol; addiction; alcohol ID SUBSEQUENT WITHDRAWAL SEIZURES; VENTRAL TEGMENTAL AREA; RAT NUCLEUS-ACCUMBENS; LOCOMOTOR-ACTIVITY; EXTRACELLULAR DOPAMINE; IN-VIVO; GLUTAMATERGIC TRANSMISSION; INCENTIVE-SENSITIZATION; DIFFERENTIAL CHANGES; PYRAZOLE TREATMENT AB Repeated exposure to drugs of abuse results in an increased sensitivity to their behavioral effects, a phenomena referred to as behavioral sensitization. It has been suggested that the same neuroadaptations underlying behavioral sensitization contribute to the maintenance and reinstatement of addiction. Dysregulation of dopamine (DA) neurotransmission in the mesoaccumbens system is one neuroadaptation that is thought to lead to the compulsive drug-seeking that characterizes addiction. Evidence that sensitization to psychostimulants and opiates is associated with an enhancement of drug-evoked DA levels in the nucleus accumbens has also been obtained. Like other drugs of abuse, the acute administration of ethanol (ETOH) stimulates DA release in this brain region. Moreover, repeated ETOH experience results in an enhanced behavioral response to a subsequent ethanol challenge. Data regarding the influence of repeated ethanol intoxication and withdrawal upon mesoaccumbal DA neurotransmission is limited. Studies examining ETOH-evoked alterations in mesoaccumbal DA neurotransmission as a function of withdrawal duration are lacking. The present experiments quantified basal and ethanol-evoked DA levels 14 days and 24 h following the cessation of a repeated ETOH intoxication protocol, which results in sensitization to the locomotor activating effects of ethanol. Locomotor activity was assessed in parallel groups of animals. Studies were conducted in two mouse strains, C57BL/6J and DBA/2J, which differ in their behavioral responses to ETOH. The results indicate the development of transient tolerance to both ETOH-induced behavioral activation and evoked accumbens DA release at early withdrawal. Moreover, no enhanced DA response to a subsequent ETOH challenge could be demonstrated in ETOH experienced animals 2 weeks after withdrawal, in spite of the observation of clear behavioral sensitization at this time point. These results suggest that, at least in the case of ethanol, sensitization of the DA mesolimbic system may not be necessary for the development of behavioral sensitization. C1 NIDA, Integrat Neurosci Sect, Behav Neurosci Branch, IRP, Baltimore, MD 21224 USA. Univ Texas, Coll Pharm, Austin, TX 78712 USA. RP Zapata, A (reprint author), NIDA, Integrat Neurosci Sect, Behav Neurosci Branch, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Azapata@intra.nida.nih.gov FU Intramural NIH HHS; NIAAA NIH HHS [AA U01 13486]; NIDA NIH HHS [Z01 DA000398-10] NR 57 TC 61 Z9 61 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2006 VL 31 IS 2 BP 396 EP 405 DI 10.1038/sj.npp.1300833 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 023MY UT WOS:000236132100014 PM 16034441 ER PT J AU Gilbert, DL Ridel, KR Sallee, FR Zhang, J Lipps, TD Wassermann, EM AF Gilbert, DL Ridel, KR Sallee, FR Zhang, J Lipps, TD Wassermann, EM TI Comparison of the inhibitory and excitatory effects of ADHD medications methylphenidate and atomoxetine on motor cortex SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE attention deficit hyperactivity disorder; neurophysiology; transcranial magnetic stimulation; methylphenidate; atomoxetine; catecholamine ID TRANSCRANIAL MAGNETIC STIMULATION; DEFICIT-HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; NOREPINEPHRINE-REUPTAKE INHIBITOR; INTRACORTICAL INHIBITION; TYROSINE-HYDROXYLASE; PREFRONTAL CORTEX; TOURETTE-SYNDROME; DOPAMINE; CHILDREN AB Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory ( 3 ms) and facilitatory ( 10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology. C1 Univ Cincinnati, Childrens Hosp, Med Ctr, Div Neurol, Cincinnati, OH 45229 USA. Univ Cincinnati, Sch Med, Cincinnati, OH USA. Univ Cincinnati, Div Psychiat, Cincinnati, OH USA. Natl Inst Neurol Disorders & Stroke, Brain Stimulat Unit, Bethesda, MD USA. RP Gilbert, DL (reprint author), Univ Cincinnati, Childrens Hosp, Med Ctr, Div Neurol, ML 2015,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM d.gilbert@cchmc.org RI Gilbert, Donald/D-6443-2016 OI Gilbert, Donald/0000-0002-9245-6878 FU NINDS NIH HHS [K23 NS41920] NR 56 TC 47 Z9 48 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2006 VL 31 IS 2 BP 442 EP 449 DI 10.1038/sj.npp.1300806 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 023MY UT WOS:000236132100019 PM 16034446 ER PT J AU Schellinger, PD Latour, LL Wu, CS Chalela, JA Warach, S AF Schellinger, PD Latour, LL Wu, CS Chalela, JA Warach, S TI The association between neurological deficit in acute ischemic stroke and mean transit time - Comparison of four different perfusion MRI algorithms SO NEURORADIOLOGY LA English DT Article DE perfusion MRI; mean transit time; acute stroke ID HYPERACUTE CEREBRAL-ISCHEMIA; THROMBOLYTIC THERAPY; DWI/PWI MISMATCH; WEIGHTED MRI; DIFFUSION; PENUMBRA; TISSUE; THRESHOLDS; PARAMETERS; SCALE AB The purpose of our study was to identify the perfusion MRI (pMRI) algorithm which yields a volume of hypoperfused tissue that best correlates with the acute clinical deficit as quantified by the NIH Stroke Scale (NIHSS) and therefore reflects critically hypoperfused tissue. A group of 20 patients with a first acute stroke and stroke MRI within 24 h of symptom onset were retrospectively analyzed. Perfusion maps were derived using four different algorithms to estimate relative mean transit time (rMTT): (1) cerebral blood flow (CBF) arterial input function (AIF)/singular voxel decomposition (SVD); (2) area peak; (3) time to peak (TTP); and (4) first moment method. Lesion volumes based on five different MTT thresholds relative to contralateral brain were compared with each other and correlated with NIHSS score. The first moment method had the highest correlation with NIHSS (r=0.79, P < 0.001) followed by the AIF/SVD method, both of which did not differ significantly from each other with regard to lesion volumes. TTP and area peak derived both volumes, which correlated poorly or only moderately with NIHSS scores. Data from our pilot study suggest that the first moment and the AIF/SVD method have advantages over the other algorithms in identifying the pMRI lesion volume that best reflects clinical severity. At present there seems to be no need for extensive postprocessing and arbitrarily defined delay thresholds in pMRI as the simple qualitative approach with a first moment algorithm is equally accurate. Larger sample sizes which allow comparison between imaging and clinical outcomes are needed to refine the choice of best perfusion parameter in pMRI. C1 Univ Heidelberg, Dept Neurol, Kopfklin, D-69120 Heidelberg, Germany. NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Durham, NC 27708 USA. RP Schellinger, PD (reprint author), Univ Heidelberg, Dept Neurol, Kopfklin, Neuenheimer Feld 400, D-69120 Heidelberg, Germany. EM Peter_Schellinger@med.uni-heidelberg.de NR 30 TC 20 Z9 20 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0028-3940 J9 NEURORADIOLOGY JI Neuroradiology PD FEB PY 2006 VL 48 IS 2 BP 69 EP 77 DI 10.1007/s00234-005-0012-9 PG 9 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 010SV UT WOS:000235219100001 PM 16315062 ER PT J AU Woo, NH Lu, B AF Woo, NH Lu, B TI Regulation of cortical interneurons by neurotrophins: From development to cognitive disorders SO NEUROSCIENTIST LA English DT Review DE Parvalbumin; basket cells; chandelier cells; axo-axonic; epilepsy; schizophrenia; GABA; BDNF ID CULTURED HIPPOCAMPAL-NEURONS; RAT VISUAL-CORTEX; SPONTANEOUS CORRELATED ACTIVITY; MESSENGER-RNA EXPRESSION; PREFRONTAL CORTEX; INHIBITORY SYNAPSES; WORKING-MEMORY; DEVELOPING NETWORKS; GABAERGIC SYNAPSES; PYRAMIDAL CELLS AB Parvalbumin-positive interneurons, which include basket and chandelier cells, represent a unique class of interneurons. By innervating the soma and the axonal initial segment of pyramidal cells, these interneurons can elicit powerful control on the output of pyramidal cells and consequently are important for a number of physiological processes in the mammalian brain. Recent evidence indicates that neurotrophins regulate the development and functions of parvalbumin-positive interneurons. Disruption of neurotrophin-mediated regulation of interneurons is thought to contribute to the pathological processes underlying CNS dysfunction. This review brings together recently described roles of neurotrophins in migration, differentiation, synaptogenesis during development, and acute effects of neurotrophins in transmission at inhibitory synapses, Cl- homeostasis, and network activity of cortical interneurons. The authors also discuss the importance of neurotrophin regulation of GABAergic neurons in schizophrenia and epilepsy. C1 NICHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. NICHD, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Lu, B (reprint author), NICHD, Sect Neural Dev & Plast, NIH, Bldg 35,Rm 1C1004,35 Convent Dr,MSC 3714, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012 FU Intramural NIH HHS NR 107 TC 82 Z9 85 U1 3 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD FEB PY 2006 VL 12 IS 1 BP 43 EP 56 DI 10.1177/1073858405284360 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 005DT UT WOS:000234803500012 PM 16394192 ER PT J AU Munoz, RF Lenert, LL Delucchi, K Stoddard, J Perez, JE Penilla, C Perez-Stable, EJ AF Munoz, RF Lenert, LL Delucchi, K Stoddard, J Perez, JE Penilla, C Perez-Stable, EJ TI Toward evidence-based Internet interventions: A Spanish/English Web site for international smoking cessation trials SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID DEPRESSION; NICOTINE; PROGRAM; SPANISH; RATES AB The Internet provides a medium to administer and evaluate evidence-based interventions for highly prevalent public health problems worldwide. The authors report a series of four Internet smoking cessation studies conducted in English and Spanish. These studies examined both outcome (self-reported 7-day abstinence) and mechanisms related to outcome (the impact of major depressive episodes [MDEs] on the likelihood of quitting). Over 4,000 smokers from 74 countries entered the studies. Studies 1 and 2 evaluated a standard smoking cessation guide (the "Guia''). Studies 3 and 4 were randomized trials comparing the Guia+ITEMs (individually timed educational messages) to the Guia+ITEMs+a mood management course. ITEMs were E-mails inviting participants back to the site at specific times. Online follow-up assessments resulted in completion rates of 44%-54% at 1 month and 26%-30% at 6 months in studies 1 and 2. Incentives and follow-up phone calls increased these rates to 70%,66%,65%, and 62% at 1, 3, 6, and 12 months in study 4. At 6 months, self-reported 7-day abstinence rates using missing=smoking data were 6% in studies 1 and 2, 10%-14% in study 3, and 20%-26% in study 4. The Guia+ITEMs condition tended to have higher quit rates, which reached significance at the 12-month follow-up in study 3 and at the 3-month follow-up in study 4. Smokers with past (but not current) MDEs tended to be the most likely to abstain and those with current MDEs the least likely. This trend reached significance in studies 1 and 4. C1 Univ Calif San Francisco, San Francisco, CA 94110 USA. NCI, Bethesda, MD 20892 USA. Univ Massachusetts, Boston, MA 02125 USA. RP Munoz, RF (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, 1001 Potrero Ave,Suite 7M, San Francisco, CA 94110 USA. EM munoz@itsa.ucsf.edu FU FIC NIH HHS [TW05935]; NIDA NIH HHS [T32 DA07250]; NIMH NIH HHS [F32 MH065777] NR 35 TC 102 Z9 104 U1 1 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2006 VL 8 IS 1 BP 77 EP 87 DI 10.1080/14622200500431940 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 032VM UT WOS:000236804000009 PM 16497602 ER PT J AU Aoki, I Yoshiyuki, T Chuang, KH Silva, AC Igarashi, T Tanaka, C Childs, RW Koretsky, AP AF Aoki, I Yoshiyuki, T Chuang, KH Silva, AC Igarashi, T Tanaka, C Childs, RW Koretsky, AP TI Cell labeling for magnetic resonance imaging with the T-1 agent manganese chloride SO NMR IN BIOMEDICINE LA English DT Article DE manganese; cell labeling; cytotoxic T cells; NK cells; manganese-enhanced magnetic resonance imaging; apoptosis; lymphocyte ID RECEPTOR-MEDIATED ENDOCYTOSIS; MR CONTRAST AGENTS; T-CELLS; IRON-OXIDE; ENHANCED MRI; PC12 CELLS; PARTICLES; TRACKING; REJECTION; APOPTOSIS AB There is growing interest in using MRI to track cellular migration. To date, most work in this area has been performed using ultra-small particles of iron oxide. Immune cells are difficult to label with iron oxide particles. The ability of adoptively infused tumor specific T cells and N cells to traffic to the tumor microenvironment may be a critical determinant of their therapeutic efficacy. We tested the hypothesis that lymphocytes and B cells would label with MnCl2 to a level that would allow their detection by T-1-weighted MRI. Significant signal enhancement was observed in human lymphocytes after a 1 h incubation with 0.05-1.0mM MnCl2. A flow cytometry-based evaluation using propidium iodide and Annexin V staining showed that lymphocytes did not undergo apoptosis or necrosis immediately after and 24h following a 1 h incubation with up to 1.0 mM MnCl2. Importantly, NK cells and cytotoxic T cells maintained their ill vitro killing capacity after being incubated with up to 0.5 mM MnCl2. This is the first report to describe the use of MnCl2 to label lymphocytes. Our data suggests MnCl2 might be an alternative to iron oxide cell labeling for MRI-based cell migration studies. Copyright (c) 2006 John Wiley & Sons, Ltd. C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Meiji Univ Oriental Med, Dept Med Informat, Kyoto 6290392, Japan. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM korestskya@ninds.nih.gov RI Aoki, Ichio/G-2529-2011; Silva, Afonso/A-7129-2009; Takahashi, Yoshiyuki/I-1929-2012; Koretsky, Alan/C-7940-2015; OI Aoki, Ichio/0000-0002-4429-5053; Koretsky, Alan/0000-0002-8085-4756; Igarashi, Takehito/0000-0001-9422-7131; Chuang, Kai-Hsiang/0000-0002-8356-0657 FU Intramural NIH HHS [Z01 NS003047-01] NR 44 TC 53 Z9 55 U1 1 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD FEB PY 2006 VL 19 IS 1 BP 50 EP 59 DI 10.1002/nbm.1000 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 017EX UT WOS:000235678000006 PM 16411253 ER PT J AU Donato, KA AF Donato, KA TI National health education programs to promote healthy eating and physical activity SO NUTRITION REVIEWS LA English DT Article; Proceedings Paper CT 5th Nestle Nutrition Conference CY OCT 07-08, 2004 CL Mexico City, MEXICO DE national education program; communications campaign; childhood obesity; Obesity Education Initiative; five-a-day; VERB AB The national education programs and campaigns described here are examples of the man), unique kinds of federal efforts under way to promote the pillars of healthy eating and increased physical activity included in the "Healthier US Initiative." They are similar in that: 1) they are based on the best available science that a health problem exists, and 2) that healthy eating and physical active behaviors will improve health status. They are unique in their implementation, for example, in private/public partnerships, coordinating committees of professional associations, and congressionally mandated interventions. Most importantly, they provide the impetus to get a particular health issue on the public agenda. C1 NHLBI, Obes Educ Initiat, Bethesda, MD 20816 USA. RP Donato, KA (reprint author), NHLBI, Obes Educ Initiat, Bldg 31,Room 4A10,31 Ctr Dr,MSC 2480, Bethesda, MD 20816 USA. EM donatok@nih.gov NR 17 TC 1 Z9 1 U1 0 U2 2 PU INT LIFE SCIENCES INST NORTH AMERICA PI WASHINGTON PA ONE THOMAS CIRCLE, N W, 9TH FLOOR, WASHINGTON, DC 20005 USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD FEB PY 2006 VL 64 IS 2 SU S BP S65 EP S70 DI 10.1301/nr.2006.feb.S65-S70 PN 2 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 020KR UT WOS:000235908400010 PM 16532902 ER PT J AU Szymanski, LM Little, R Matthews, DC Stratton, P AF Szymanski, Linda M. Little, Richard Matthews, Douglas C. Stratton, Pamela TI Post-loop electrosurgical excision procedure sepsis in a human immunodeficiency virus-infected woman SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID WOMEN AB BACKGROUND: Squamous intraepithelial lesions are more prevalent in women infected with the human immunodeficiency virus (HIV) compared with immunocompetent women. Loop electrosurgical excision procedure (LEEP) is commonly used to treat squamous intraepithelial lesions because it may be performed as an outpatient procedure with minimal blood loss and a low complication rate. CASE: We report a major infectious post-LEEP complication in an HIV-infected female who had an uneventful LEEP in which a cellulose hemostatic agent was used. Despite the severity of the infection, she was successfully treated with a minor surgical procedure along with broad antibiotic coverage. CONCLUSION: Although a cellulose hemostatic agent contaminated with perineal secretions may have served as a nidus for infection, use of perioperative antibiotics or cervical cleansing should be considered to prevent sepsis in immunocompromised hosts. C1 NICHHD, Gynecol Consult Serv, Pediat & Reprod Endocrinol Branch, NIH,CRC, Bethesda, MD 20892 USA. NCI, AIDS Malignancy Clin Res Sect, Med Oncol Clin Res Unit, NIH, Bethesda, MD 20892 USA. RP Stratton, P (reprint author), NICHHD, Gynecol Consult Serv, Pediat & Reprod Endocrinol Branch, NIH,CRC, Bldg 10,Room 1-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM strattop@ccl.nichd.nih.gov NR 8 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2006 VL 107 IS 2 BP 496 EP 498 DI 10.1097/01.AOG.0000171107.88468.29 PN 2 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 095GG UT WOS:000241295600024 PM 16449162 ER PT J AU Dana, R Nussenblatt, R Gordon, L AF Dana, R Nussenblatt, R Gordon, L TI Advances in immunology: From bench to bedside - A symposium at the 2005 Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS), Boston, MA, USA SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Review DE innate immunity; adaptive immunity; immune regulation; animal models ID HERPES-SIMPLEX-VIRUS; AUTOIMMUNE UVEITIS; KERATITIS; ANTIGENS; RECEPTOR; MIMICRY; CELLS AB The American Uveitis Society sponsored a symposium at the recent 2005 Annual FOCIS meeting in Boston, MA, USA, that was organized by the authors of this report. The symposium was designed to bring together several leaders in the broad field of immunology and investigators in ocular immunology to discuss three interrelated areas of interest: (i) animal models of ocular inflammation; (ii) interface of innate and adaptive immunity; and (iii) immune regulation. A brief summary of the salient points of the symposium is given. C1 Harvard Univ, Dept Ophthalmol, Boston, MA USA. NEI, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. RP Dana, R (reprint author), 20 Stanford St, Boston, MA 02114 USA. NR 12 TC 2 Z9 2 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD FEB PY 2006 VL 14 IS 1 BP 1 EP 6 DI 10.1080/09273940500545635 PG 6 WC Ophthalmology SC Ophthalmology GA 017KL UT WOS:000235692400001 PM 16507484 ER PT J AU Niiya, F Tatsumoto, T Lee, KS Miki, T AF Niiya, F Tatsumoto, T Lee, KS Miki, T TI Phosphorylation of the cytokinesis regulator ECT2 at G2/M phase stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA SO ONCOGENE LA English DT Article DE protooncogene; Rho GTPase; exchange factor; polo-box domain; interacting protein ID POLO-BOX DOMAIN; CELL-DIVISION; EXCHANGE FACTOR; FAMILY GTPASES; SPINDLE; EXPRESSION; PROTEINS; SRF AB The epithelial cell transforming gene 2 (ECT2) proto-oncogene encodes a Rho exchange factor, and regulates cytokinesis. ECT2 is phosphorylated in G2/M phases, but its role in the biological function is not known. Here we show that two mitotic kinases, Cdk1 and polo-like kinase 1 (Plk1), phosphorylate ECT2 in vitro. We identified an in vitro Cdk1 phosphorylation site (T412) in ECT2, which comprises a consensus phosphospecific-binding module for the Plk1 polo-box domain (PBD). Endogenous ECT2 in mitotic cells strongly associated with Plk1 PBD, and this binding was inhibited by phosphatase treatment. A phosphorylation-deficient mutant form of ECT2, T412A, did not exhibit strong association with Plk1 PBD compared with wild-type (WT) ECT2. Moreover, ECT2 T412A, but not phosphomimic T412D, displayed a diminished accumulation of GTP-bound RhoA compared with WT ECT2, suggesting that phosphorylation of Thr-412 is critical for the catalytic activity of ECT2. Moreover, while overexpression of WT ECT2 or the T412D mutant caused cortical hyperactivity in U2OS cells during cell division, this activity was not observed in cells expressing ECT2 T412A. These results suggest that ECT2 is regulated by Cdk1 and Plk1 in concert. C1 NCI, Mol Tumor Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Miki, T (reprint author), NCI, Mol Tumor Biol Sect, Cell Biol Lab, NIH, Bldg 37 Rm 2144,37 Convent Dr, Bethesda, MD 20892 USA. EM toru@helix.nih.gov FU Intramural NIH HHS NR 29 TC 61 Z9 63 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB PY 2006 VL 25 IS 6 BP 827 EP 837 DI 10.1038/sj.onc.1209124 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 010RK UT WOS:000235212700002 PM 16247472 ER PT J AU Imanguli, MM Pavletic, SZ Guadagnini, JP Brahim, JS Atkinson, JC AF Imanguli, MM Pavletic, SZ Guadagnini, JP Brahim, JS Atkinson, JC TI Chronic graft versus host disease of oral mucosa: Review of available therapies SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID STEM-CELL TRANSPLANTATION; LOW-DOSE METHOTREXATE; TERM-FOLLOW-UP; TOPICAL CYCLOSPORINE; BONE-MARROW; MYCOPHENOLATE-MOFETIL; RANDOMIZED TRIAL; EXTRACORPOREAL PHOTOCHEMOTHERAPY; MONOCLONAL-ANTIBODY; SALVAGE THERAPY AB The use of hematopoetic stem cell transplantation (HSCT) has greatly expanded in the recent years for many neoplastic and hematological disorders. Chronic graft versus host disease (cGVHD) is a major complication of allogeneic HSCT and a major cause of morbidity and mortality. Oral mucosal involvement is frequent in cGVHD and contributes significantly to the overall burden of the condition. Oral medicine professionals should be familiar with various treatment options for oral cGVHD. This review discusses treatment modalities available for the management of oral mucosal manifestations of cGVHD. Available evidence for efficacy and safety of various systemic and topical agents, including corticosteroids, calcineurin antagonists, mycophenolate mofetil, and extracorporeal photopheresis, is reviewed. C1 NCI, Graft Versus Host Dis Sect, NIH, Bethesda, MD 20892 USA. NIDCR, Dent Consult Serv, NIH, Bethesda, MD USA. RP Imanguli, MM (reprint author), 10 Ctr Dr,Bldg 1,Room 1N-118, Bethesda, MD 20892 USA. EM mimanguli@mail.nih.gov NR 78 TC 0 Z9 0 U1 0 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD FEB PY 2006 VL 101 IS 2 BP 177 EP 185 DI 10.1016/j.tripleo.2005.08.028 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 011WL UT WOS:000235299200008 ER PT J AU Mauck, RL Yuan, X Tuan, RS AF Mauck, RL Yuan, X Tuan, RS TI Chondrogenic differentiation and functional maturation of bovine mesenchymal stem cells in long-term agarose culture SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE mesenchymal stem cells; agarose; mechanical properties; chondrogenesis; chondrocyte; cartilage ID TISSUE-ENGINEERED CARTILAGE; MARROW STROMAL CELLS; EXTRACELLULAR-MATRIX PRODUCTION; BONE MORPHOGENETIC PROTEIN-2; IN-VITRO CHONDROGENESIS; ARTICULAR-CARTILAGE; SEEDING DENSITY; GROWTH-FACTORS; CHONDROCYTES; SCAFFOLDS AB Background. The developmental history of the chondrocyte results in a cell whose biosynthetic activities are optimized to maintain the concentration and organization of a mechanically functional cartilaginous extracellular matrix. While useful for cartilage tissue engineering studies, the limited supply of healthy autologous chondrocytes may preclude their clinical use. Consequently, multipotential mesenchymal stem cells (MSCs) have been proposed as an alternative cell source. Objective: While MSCs undergo chondrogenesis, few studies have assessed the mechanical integrity of their forming matrix. Furthermore, efficiency of matrix formation must be determined in comparison to healthy chondrocytes from the same donor. Given the scarcity of healthy human tissue, this study determined the feasibility of isolating bovine chondrocytes and MSCs, and examined their long-term maturation in three-dimensional agarose culture. Experimental design: Bovine MSCs were seeded in agarose and induced to undergo chondrogenesis. Mechanical and biochemical properties of MSC-laden constructs were monitored over a 10-week period and compared to those of chondrocytes derived from the same group of animals maintained similarly. Results: Our results show that while chondrogenesis does occur in MSC-laden hydrogels, the amount of the forming matrix and measures of its mechanical properties are lower than that produced by chondrocytes under the same conditions. Furthermore, some important properties, particularly glycosaminoglycan content and equilibrium modulus, plateau with time in MSC-laden constructs, suggesting that diminished capacity is not the result of delayed differentiation. Conclusions: These findings suggest that while MSCs do generate constructs with substantial cartilaginous properties, further optimization must be done to achieve levels similar to those produced by chondrocytes. Published by Elsevier Ltd on behalf of OsteoArthritis Research Society International. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, 50 S Dr,MSC 8022,Bldg 50,Room 1503, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU NIAMS NIH HHS [Z01 AR41131] NR 65 TC 304 Z9 317 U1 3 U2 53 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD FEB PY 2006 VL 14 IS 2 BP 179 EP 189 DI 10.1016/j.joca.2005.09.002 PG 11 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 011AM UT WOS:000235240000011 PM 16257243 ER PT J AU Vesikari, T Karvonen, A Forrest, BD Hoshino, Y Chanock, RM Kapikian, AZ AF Vesikari, T Karvonen, A Forrest, BD Hoshino, Y Chanock, RM Kapikian, AZ TI Neonata administration of rhesus rotavirus tetravalent vaccine SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE rotavirus; rhesus rotavirus; rotavirus vaccine; neonates ID REASSORTANT VACCINES; YOUNG-CHILDREN; EFFICACY; INFANTS; SAFETY; TRIAL; IMMUNOGENICITY; INTUSSUSCEPTION; PREVENTION; AGE AB Background and Aims: Administration of the first dose of rhesus rotavirus-based tetravalent (RRV-TV) vaccine is followed by a transient febrile reaction at 3-4 days postvaccination in about one-third of vaccinees. We hypothesized that giving the first dose of RRV-TV vaccine during the neonatal period might reduce the reactogenicity of RRV-TV vaccine without compromising the utilization of the vaccine. Methods: A double blind placebo-controlled safety and immunogenicity trial of 90 infants who received RRV-TV vaccine at 0-4-6, 0-2-4 or 2-4-6 months of age was conducted. Reactions were evaluated for I week after each vaccination and, in addition, serum specimens were collected before vaccination and at 5 and 7 months of age. Results: Febrile reactions were not observed in 62 infants receiving the first dose of RRV-TV vaccine during the neonatal period. Five of the 28 (18%) infants receiving the first dose at 2 months were febrile on 1 or more days, whereas none of the 30 infants who had received a neonatal dose developed a fever when vaccinated again at 2 months of age. An enzyme-linked immunosorbent assay IgA antibody response after 3 doses was observed significantly less frequently (77%) in infants who had received a neonatal dose, a second dose at 2 months of age, and a third dose at 4 months of age compared with those who received their first dose at 2 months and a second dose at 4 months (100%, P < 0.02). Also, the frequency of a neutralizing antibody response to RRV and human rotavirus serotypes G1-4 tended to be lower in the group that had received the vaccine at 0-2-4 months compared with those who received it at 2-4-6 months. When the 2 tests were combined, the frequency of a seroresponse following the 0-2-4 month schedule (94%) was comparable with that following the 2-4-6 month schedule (100%). Conclusion: Infants who received the first dose of RRV-TV vaccine during the neonatal period did not develop a febrile reaction. The immune response in a 3-dose schedule initiated in the neonatal period is somewhat dampened but still acceptable. Neonatal immunization might also reduce the very small risk of intussusception, which has been associated with administration of RRV-TV vaccine to older infants. C1 Univ Tampere, Sch Med, Tampere 33520, Finland. Wyeth Vaccines Res, Henrietta, NY USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Vesikari, T (reprint author), Univ Tampere, Sch Med, Biokatu 10, Tampere 33520, Finland. EM timo.vesikari@uta.fi NR 27 TC 21 Z9 23 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2006 VL 25 IS 2 BP 118 EP 122 DI 10.1097/01.inf.0000199288.98370.71 PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 015QY UT WOS:000235567100004 PM 16462287 ER PT J AU Raju, TNK AF Raju, TNK TI Hot brains: Manipulating body heat to save the brain SO PEDIATRICS LA English DT Editorial Material C1 NICHHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. RP Raju, TNK (reprint author), NICHHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Execut Blvd,Room 4B03,MS 7510, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 5 TC 3 Z9 3 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2006 VL 117 IS 2 BP E320 EP E321 DI 10.1542/peds.2005-1934 PG 2 WC Pediatrics SC Pediatrics GA 014PC UT WOS:000235491100074 PM 16452338 ER PT J AU Bartold, PM Shi, ST Gronthos, S AF Bartold, PM Shi, ST Gronthos, S TI Stem cells and periodontal regeneration SO PERIODONTOLOGY 2000 LA English DT Article ID HUMAN-BONE-MARROW; HUMAN DENTAL-PULP; GROWTH-FACTOR; STROMAL CELLS; IN-VITRO; TELOMERASE EXPRESSION; TISSUE REGENERATION; MATRIX PROTEIN; LIGAMENT CELLS; HUMAN CEMENTUM C1 Univ Adelaide, Sch Dent, Colgate Australian Clin Dent Resource Ctr, Adelaide, SA, Australia. NIDCR, NIH, Bethesda, MD USA. Inst Med & Vet Sci, Div Haematol, Mesenchymal Stem Cell Grp, Adelaide, SA 5000, Australia. RP Bartold, PM (reprint author), Univ Adelaide, Sch Dent, Colgate Australian Clin Dent Resource Ctr, Adelaide, SA, Australia. OI Bartold, Peter/0000-0002-5695-3877 NR 75 TC 100 Z9 108 U1 3 U2 17 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0906-6713 J9 PERIODONTOL 2000 JI Periodontol. 2000 PD FEB PY 2006 VL 40 BP 164 EP 172 DI 10.1111/j.1600-0757.2005.00139.x PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 999TU UT WOS:000234414200011 PM 16398692 ER PT J AU Wellner, RB Redman, RS Swaim, WD Baum, BJ AF Wellner, RB Redman, RS Swaim, WD Baum, BJ TI Further evidence for AQP8 expression in the myoepithelium of rat submandibular and parotid glands SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE AQP8; salivary gland AQP; salivary myoepithelium ID SALIVARY-GLANDS; AQUAPORIN; MEMBRANE AB Previously (Wellner et al., P. ugers Arch 441: 49 - 56, 2000) we suggested that the localization of the aquaporins (AQPs) AQP5 and AQP8 in the apical and basolateral membranes of rat submandibular gland (SMG) acinar cells, respectively, provides for transcellular water flow during saliva formation. While the localization of AQP5 in this gland has been verified in several laboratories, there have been differing reports regarding AQP8 localization. Other investigators subsequently reported that AQP8 is not expressed in the acinar or ductal cells of the major salivary glands of the rat, but in the myoepithelium of each gland. Thus, we have carried out additional studies: ( 1) to reassess the localization of AQP8 in the rat SMG and ( 2) to assess the localization of AQP8 in the rat parotid gland ( PG). Initially, we compared the localizations of AQP8 with recognized basolateral markers in acinar cells [ the Na+, K+- ATPase and the Na+ - K+ - 2Cl(-) cotransporter (NKCC1)]. Our results indicated that Na+, K+- ATPase localized in both the basal and lateral membranes of rat SMG acinar cells, whereas AQP8 was detected only in the basal regions of the acini. In the rat PG, AQP8 was invested near intercalated ducts and adjacent acini, whereas NKCC1 localized in the basolateral membranes of acinar cells. As these results were suggestive of myoepithelial localization in both glands, we compared AQP8 localization with the localization of smooth muscle actin, a myoepithelial marker. We found that AQP8 and smooth muscle actin colocalized in both the rat SMG and PG, providing additional strong support for a myoepithelial localization of AQP8. Thus, in agreement with an earlier report by other investigators (Elkjaer et al., Am J Physiol Renal Physiol 281: F1047 - F1057, 2001), we report that AQP8 is expressed in the myoepithelial cells, but not in the acinar cells, of both the rat SMG and PG. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, Bethesda, MD 20892 USA. Dept Vet Affairs Med Ctr, Oral Pathol Res Lab, Washington, DC 20422 USA. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, 10 Ctr Dr,Bldg 10,Rm 1N113,MSC 1190, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov NR 8 TC 15 Z9 17 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD FEB PY 2006 VL 451 IS 5 BP 642 EP 645 DI 10.1007/s00424-005-1489-0 PG 4 WC Physiology SC Physiology GA 999NV UT WOS:000234397200006 PM 16311720 ER PT J AU Petermann, T De Los Rios, P AF Petermann, T De Los Rios, P TI Physical realizability of small-world networks SO PHYSICAL REVIEW E LA English DT Article ID OPTIMIZATION; PERCOLATION; CROSSOVER; SYSTEMS; MODELS AB Supplementing a lattice with long-range connections effectively models small-world networks characterized by a high local and global interconnectedness observed in systems ranging from society to the brain. If the links have a wiring cost associated with their length l, the corresponding distribution q(l) plays a crucial role. Uniform length distributions have received the most attention despite indications that q(l)similar to l(-alpha) exists-e.g., for integrated circuits, the Internet, and cortical networks. While length distributions of this type were previously examined in the context of navigability, we here discuss for such systems the emergence and physical realizability of small-world topology. Our simple argument allows us to understand under which condition and at what expense a small world results. C1 Ecole Polytech Fed Lausanne, Inst Theoret Phys, LBS, CH-1015 Lausanne, Switzerland. RP Petermann, T (reprint author), NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bethesda, MD 20892 USA. EM Thomas.Petermann@alumni.ethz.ch RI De Los Rios, Paolo/B-2456-2010; EPFL, LBS/B-3567-2010 OI De Los Rios, Paolo/0000-0002-5394-5062; NR 38 TC 28 Z9 28 U1 0 U2 0 PU AMERICAN 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 FEB PY 2006 VL 73 IS 2 AR 026114 DI 10.1103/PhysRevE.73.026114 PN 2 PG 4 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 017AY UT WOS:000235667700028 PM 16605405 ER PT J AU Frontera, WR Fuhrer, MJ Jette, AM Chan, L Cooper, RA Duncan, PW Kemp, JD Ottenbacher, KJ Peckham, PH Roth, EJ Tate, DG AF Frontera, WR Fuhrer, MJ Jette, AM Chan, L Cooper, RA Duncan, PW Kemp, JD Ottenbacher, KJ Peckham, PH Roth, EJ Tate, DG TI Rehabilitation Medicine Summit: Building Research Capacity - Executive summary SO PHYSICAL THERAPY LA English DT Article AB The general objective of the Rehabilitation Medicine Summit: Building Research Capacity was to advance and promote research in medical rehabilitation by making recommendations to expand research capacity. The 5 elements of research capacity that guided the discussions were: (1) researchers, (2) research environment, infrastructure, and culture, (3) funding, (4) partnerships, and (5) metrics. The [approximately] 100 participants included representatives of professional organizations, consumer groups, academic departments, researchers, governmental funding agencies, and the private sector. The small-group discussions and plenary sessions generated an array of problems, possible solutions, and recommended actions. A post-Summit, multi-organizational initiative is called to pursue the agendas outlined in this report. C1 Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Boston, MA 02114 USA. NIH, Bethesda, MD 20892 USA. Boston Univ, Boston, MA 02215 USA. Univ Washington, Seattle, WA 98195 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Florida, Gainesville, FL USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Rehabil Inst Chicago, Chicago, IL 60611 USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Frontera, WR (reprint author), Harvard Univ, Sch Med, Spaulding Rehabil Hosp, 125 Nashua St, Boston, MA 02114 USA. EM wfrontera@partners.org NR 3 TC 2 Z9 2 U1 0 U2 1 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD FEB PY 2006 VL 86 IS 2 BP 285 EP 298 PG 14 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 010PZ UT WOS:000235207900013 PM 16445342 ER PT J AU Wendler, D Kington, R Madans, J Van Wye, G Christ-Schmidt, H Pratt, LA Brawley, OW Gross, CP Emanuel, E AF Wendler, D Kington, R Madans, J Van Wye, G Christ-Schmidt, H Pratt, LA Brawley, OW Gross, CP Emanuel, E TI Are racial and ethnic minorities less willing to participate in health research? SO PLOS MEDICINE LA English DT Article ID NONRANDOMIZED CLINICAL-TRIALS; AFRICAN-AMERICANS; RANDOMIZED PATIENTS; ONCOLOGY PROGRAM; MEDICAL-RESEARCH; WOMEN; RECRUITMENT; REPRESENTATION; SELECTION; REVASCULARIZATION AB Background It is widely claimed that racial and ethnic minorities, especially in the US, are less willing than non-minority individuals to participate in health research. Yet, there is a paucity of empirical data to substantiate this claim. Methods and Findings We performed a comprehensive literature search to identify all published health research studies that report consent rates by race or ethnicity. We found 20 health research studies that reported consent rates by race or ethnicity. These 20 studies reported the enrollment decisions of over 70,000 individuals for a broad range of research, from interviews to drug treatment to surgical trials. Eighteen of the twenty studies were single-site studies conducted exclusively in the US or multi-site studies where the majority of sites (i.e., at least 2/3) were in the US. Of the remaining two studies, the Concorde study was conducted at 74 sites in the United Kingdom, Ireland, and France, while the Delta study was conducted at 152 sites in Europe and 23 sites in Australia and New Zealand. For the three interview or non-intervention studies, African-Americans had a nonsignificantly lower overall consent rate than non-Hispanic whites (82.2% versus 83.5%; odds ratio [OR] = 0.92; 95% confidence interval [CI] 0.84-1.02). For these same three studies, Hispanics had a nonsignificantly higher overall consent rate than non-Hispanic whites (86.1% versus 83.5%; OR = 1.37; 95% CI 0.94-1.98). For the ten clinical intervention studies, African-Americans' overall consent rate was nonsignificantly higher than that of non-Hispanic whites (45.3% versus 41.8%; OR = 1.06; 95% CI 0.78-1.45). For these same ten studies, Hispanics had a statistically significant higher overall consent rate than non-Hispanic whites (55.9% versus 41.8%; OR = 1.33; 95% CI 1.08-1.65). For the seven surgery trials, which report all minority groups together, minorities as a group had a nonsignificantly higher overall consent rate than non-Hispanic whites (65.8% versus 47.8%; OR = 1.26; 95% CI 0.89-1.77). Given the preponderance of US sites, the vast majority of these individuals from minority groups were African-Americans or Hispanics from the US. Conclusions We found very small differences in the willingness of minorities, most of whom were African-Americans and Hispanics in the US, to participate in health research compared to non-Hispanic whites. These findings, based on the research enrollment decisions of over 70,000 individuals, the vast majority from the US, suggest that racial and ethnic minorities in the US are as willing as non-Hispanic whites to participate in health research. Hence, efforts to increase minority participation in health research should focus on ensuring access to health research for all groups, rather than changing minority attitudes. C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. NIH, Off Behav & Social Sci Res, Bethesda, MD USA. Natl Ctr Hlth Stat, Ctr Dis Control & Prevent, Hyattsville, MD 20782 USA. Yale Univ, Sch Med, Dept Epidemiol, New Haven, CT USA. Stat Collaborat, Washington, DC USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. Yale Univ, Sch Med, Gen Internal Med Sect, New Haven, CT 06520 USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 64 TC 285 Z9 285 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD FEB PY 2006 VL 3 IS 2 BP 201 EP 210 AR e19 DI 10.1371/journal.pmed.0030019 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 034OC UT WOS:000236937300013 PM 16318411 ER PT J AU Boyer, PL Sarafianos, SG Clark, PK Arnold, E Hughes, SH AF Boyer, Paul L. Sarafianos, Stefan G. Clark, Patrick K. Arnold, Eddy Hughes, Stephen H. TI Why do HIV-1 and HIV-2 use different pathways to develop AZT resistance? SO PLOS PATHOGENS LA English DT Article AB The human immunodeficiency virus type 1 (HIV-1) develops resistance to all available drugs, including the nucleoside analog reverse transcriptase inhibitors (NRTIs) such as AZT. ATP-mediated excision underlies the most common form of HIV-1 resistance to AZT. However, clinical data suggest that when HIV-2 is challenged with AZT, it usually accumulates resistance mutations that cause AZT resistance by reduced incorporation of AZTTP rather than selective excision of AZTMP. We compared the properties of HIV-1 and HIV-2 reverse transcriptase (RT) in vitro. Although both RTs have similar levels of polymerase activity, HIV-1 RT more readily incorporates, and is more susceptible to, inhibition by AZTTP than is HIV-2 RT. Differences in the region around the polymerase active site could explain why HIV-2 RT incorporates AZTTP less efficiently than HIV-1 RT. HIV-1 RT is markedly more efficient at carrying out the excision reaction with ATP as the pyrophosphate donor than is HIV-2 RT. This suggests that HIV-1 RT has a better nascent ATP binding site than HIV-2 RT, making it easier for HIV-1 RT to develop a more effective ATP binding site by mutation. A comparison of HIV-1 and HIV-2 RT shows that there are numerous differences in the putative ATP binding sites that could explain why HIV-1 RT binds ATP more effectively. HIV-1 RT incorporates AZTTP more efficiently than does HIV-2 RT. However, HIV-1 RT is more efficient at ATP-mediated excision of AZTMP than is HIV-2 RT. Mutations in HIV-1 RT conferring AZT resistance tend to increase the efficiency of the ATP-mediated excision pathway, while mutations in HIV-2 RT conferring AZT resistance tend to increase the level of AZTTP exclusion from the polymerase active site. Thus, each RT usually chooses the pathway best suited to extend the properties of the respective wild-type enzymes. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ USA. Rutgers State Univ, Dept Chem & Biol Chem, Piscataway, NJ USA. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21701 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM hughes@ncifcrf.gov OI Sarafianos, Stefan G/0000-0002-5840-154X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 0 TC 44 Z9 45 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2006 VL 2 IS 2 BP 101 EP 111 AR e10 DI 10.1371/journal.ppat0020010 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA V42VE UT WOS:000202894200005 PM 16485036 ER PT J AU Burke, RE AF Burke, Robert E. TI John Eccles' pioneering role in understanding central synaptic transmission SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE central nervous system; spinal cord; motoneurons; intracellular recording ID CAT SPINAL MOTONEURONES; MEMBRANE TIME CONSTANT; CENTRAL NERVOUS SYSTEM; INPUT-OUTPUT RELATIONS; GROUP-IA SYNAPSES; RENSHAW CELLS; HORSERADISH-PEROXIDASE; PRESYNAPTIC INHIBITION; RECURRENT INHIBITION; ANION PERMEABILITY AB This chapter deals with the central role that Sir John Eccles played in the elucidation of the mechanisms of synaptic transmission within the central nervous system during the three decades between the late 1930s and 1966. His seminal discoveries involved studies of synaptic input to spinal motoneurons using intracellular recording via glass micropipettes after their introduction in the late 1940s. After defending the hypothesis that electrical currents alone explained central synaptic events, his observations of reversal potentials and sensitivity to ion injections instantly converted Eccles to the idea that central synapses generate postsynaptic potentials, designated IPSPs and EPSPs, by liberating chemical transmitters. He and his collaborators used pharmacological manipulations of recurrent inhibition to support the idea that a given neuron liberates the same chemical transmitter substance at all of its synapses, which he called "Dale's Principle". His team worked out the mechanisms and spinal circuits underlying disynaptic and recurrent inhibition, as well as those of presynaptic inhibition. Not content with the view that central synapses were static entities, Eccles also made seminal observations on synaptic plasticity induced by alterations in use and disuse. Although his firmly held belief that the extensive dendritic trees of motoneurons were essentially irrelevant to synaptic events at the soma was later refuted by others in the mid-1960s, Eccles stands as a towering figure in the history of neuroscience. His prodigious energy and commanding intellect gave the field of central synaptic transmission the conceptual bases that have guided it for over 40 years. Published by Elsevier Ltd. C1 NINDS, Neural Control Lab, NIH, Bethesda, MD 20895 USA. RP Burke, RE (reprint author), POB 1722, El Prado, NM 87529 USA. EM reburke@taosnet.com NR 157 TC 16 Z9 16 U1 3 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD FEB-APR PY 2006 VL 78 IS 3-5 SI SI BP 173 EP 188 DI 10.1016/j.pneurobio.2006.02.002 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 062AM UT WOS:000238916700004 PM 16647800 ER PT J AU Shoemaker, BA Panchenko, AR Bryant, SH AF Shoemaker, BA Panchenko, AR Bryant, SH TI Finding biologically relevant protein domain interactions: Conserved binding mode analysis SO PROTEIN SCIENCE LA English DT Article DE protein-protein interactions; conserved binding modes; homology modeling; protein structure; protein domain families ID CRYSTAL CONTACTS; DATABASE; INTERFACES; SEQUENCE; YEAST; CDD AB Proteins evolved through the shuffling of functional domains, and therefore, the same domain can be found in different proteins and species. Interactions between such conserved domains often involve specific, well-determined binding surfaces reflecting their important biological role in a cell. To find biologically relevant interactions we developed a method of systematically comparing and classifying protein domain interactions from the structural data. As a result, a set of conserved binding modes (CBMs) was created using the atomic detail of structure alignment data and the protein domain classification of the Conserved Domain Database. A conserved binding mode is inferred when different members of interacting domain families dock in the same way, such that their structural complexes superimpose well. Such domain interactions with recurring structural themes have greater significance to be biologically relevant, unlike spurious crystal packing interactions. Consequently, this study gives lower and upper bounds on the number of different types of interacting domain pairs in the structure database on the order of 1000-2000. We use CBMs to create domain interaction networks, which highlight functionally significant connections by avoiding many infrequent links between highly connected nodes. The CBMs also constitute a library of docking templates that may be. just as used in molecular modeling to infer the characteristics of an unknown binding surface. ' conserved domains may be used to infer the structure of an unknown protein. The method's ability to sort through and classify large numbers of putative interacting domain pairs is demonstrated on the oligomeric interactions of globins. C1 Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bethesda, MD 20894 USA. RP Shoemaker, BA (reprint author), Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bldg 38A, Bethesda, MD 20894 USA. EM shoemake@mail.nih.gov FU Intramural NIH HHS; NLM NIH HHS [Z01 LM000057-12] NR 34 TC 47 Z9 52 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2006 VL 15 IS 2 BP 352 EP 361 DI 10.1110/ps.051760806 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 009FJ UT WOS:000235096600015 PM 16385001 ER PT J AU Chung, JY Braunschweig, T Baibakov, G Galperin, M Ramesh, A Skacel, M Gannot, G Knezevic, V Hewitt, SM AF Chung, JY Braunschweig, T Baibakov, G Galperin, M Ramesh, A Skacel, M Gannot, G Knezevic, V Hewitt, SM TI Transfer and multiplex immunoblotting of a paraffin embedded tissue SO PROTEOMICS LA English DT Article DE formalin fixed tissue; immunodetection; paraffin embedded tissue; pathological proteomics ID LASER CAPTURE MICRODISSECTION; GENE-EXPRESSION; MICROARRAYS; PROTEINS; CANCER; ELECTROPHORESIS AB As we transition from genomics to the challenges of the functional proteome, new tools to explore the expression of proteins within tissue are essential. We have developed a method of transferring proteins from a formalin fixed, paraffin embedded tissues section to a stack of membranes which is then probed with antibodies for detection of individual epitopes. This method converts a traditional tissue section into a multiplex platform for expression profiling. A single tissue section can be transferred to up to ten membranes, each of which is probed with different antibodies, and detected with fluorescent secondary antibodies, and quantified by a microarray scanner. Total protein can be determined on each membrane, hence each antibody has its own normalization. This method works with phospho-specific antibodies as well as antibodies that do not readily work well with paraffin embedded tissue. This novel technique enables archival paraffin embedded tissue to be molecularly profiled in a rapid and quantifiable manner, and reduces the tissue microarray to a form of protein array. This method is a new tool for exploration of the vast archive of formalin fixed, paraffin embedded tissue, as well as a tool for translational medicine. C1 NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD USA. 20 20 GeneSyst Inc, Rockville, MD USA. Inje Univ, Coll Med, PharmacoGenom Res Ctr, Pusan, South Korea. Inje Univ, Coll Med, Mol Cell Physiol Res Grp, Pusan, South Korea. Cleveland Clin Fdn, Dept Anat Pathol, Cleveland, OH 44195 USA. NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hewitt, SM (reprint author), Ctr Adv Technol, TARP Lab, MSC 4605, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 NR 25 TC 31 Z9 32 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD FEB PY 2006 VL 6 IS 3 BP 767 EP 774 DI 10.1002/pmic.200401343 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 013MY UT WOS:000235414600004 PM 16400680 ER PT J AU Kim, BJ Hood, BL Aragon, RA Hardwick Jr Conrads, TR Veenstra, TD Song, BJ AF Kim, BJ Hood, BL Aragon, RA Hardwick, JR Conrads, TR Veenstra, TD Song, BJ TI Increased oxidation and degradation of cytosolic proteins in alcohol-exposed mouse liver and hepatoma cells SO PROTEOMICS LA English DT Article DE alcoholism; CYP2E1; oxidative stress; protein oxidation; protein degradation; peroxiredoxin ID CYTOCHROME P-4502E1; NITRIC-OXIDE; RAT-LIVER; OXIDIZED PROTEINS; INDUCED APOPTOSIS; IN-VITRO; ETHANOL; INJURY; DISEASE; STRESS AB We recently developed a sensitive method using biotin-N-maleimide (biotin-NM) as a probe to positively identify oxidized mitochondrial proteins. In this study, biotin-NM was used to identify oxidized cytosolic proteins in alcohol-fed mouse livers. Alcohol treatment for 6 wk elevated the levels of CYP2E1 and nitrotyrosine, a marker of oxidative stress. Markedly increased levels of oxidized proteins were detected in alcohol-fed mouse livers compared to pair-fed controls. The biotin-NM-labeled oxidized proteins from alcohol-exposed mouse livers were subsequently purified with streptavidin-agarose and resolved on 2-DE. More than 90 silver-stained protein spots that displayed differential intensities on 2-D gels were identified by MS. Peptide sequence analysis revealed that many enzymes or proteins involved in stress response, chaperone activity, intermediary metabolism, and antioxidant defense systems such as peroxiredoxin were oxidized after alcohol treatment. Smaller fragments of many proteins were repeatedly detected only in alcohol-fed mice, indicating that many oxidized proteins after alcohol exposure were degraded. Immunoblot results showed that the level of oxidized peroxiredoxin (inactivated) was markedly increased in the alcohol-exposed mouse livers and ethanol-sensitive hepatoma cells compared to the corresponding controls. Our results may explain the underlying mechanism for cellular dysfunction and increased susceptibility to other toxic agents following alcohol-mediated oxidative stress. C1 NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD USA. Northeastern Ohio Univ Coll Med & Pharm, Dept Biochem, Rootstown, OH USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bjs@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAAA NIH HHS [Z01 AA000036-19] NR 62 TC 47 Z9 47 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD FEB PY 2006 VL 6 IS 4 BP 1250 EP 1260 DI 10.1002/pmic.200500447 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 018HZ UT WOS:000235756400019 PM 16408314 ER PT J AU Arora, NK Bellizzi, KM Rowland, JH Potosky, A Aziz, N Hamilton, A AF Arora, NK Bellizzi, KM Rowland, JH Potosky, A Aziz, N Hamilton, A TI Health-related quality of life of survivors of non-Hodgkin's lymphoma: Results from the Experience of Care and Health Outcomes of Survivors of NHL (ECHOS-NHL) study SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD FEB PY 2006 VL 15 IS 1 SU S BP S22 EP S23 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 016XZ UT WOS:000235659000039 ER PT J AU Bellizzi, KM Miller, MF Arora, NK Rowland, JH AF Bellizzi, KM Miller, MF Arora, NK Rowland, JH TI Positive and negative life changes experienced by survivors of non-Hodgkin's lymphoma: Results from the Experience of Care and Health Outcomes of Survivors of NHL (ECHOS-NHL) study SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Control & Populat Sci, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD FEB PY 2006 VL 15 IS 1 SU S BP S37 EP S37 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 016XZ UT WOS:000235659000066 ER PT J AU Hadley, J AF Hadley, J TI NCI's office of liaison activities: A portal for cancer advocates SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD FEB PY 2006 VL 15 IS 1 SU S BP S63 EP S63 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 016XZ UT WOS:000235659000118 ER PT J AU Owen, JE Boxley, L Goldstein, M Lee, J Breen, N Rowland, J AF Owen, JE Boxley, L Goldstein, M Lee, J Breen, N Rowland, J TI A population-based analysis of support group utilization in cancer survivors: A report from the California Health Survey SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 Loma Linda Univ, Loma Linda, CA 92350 USA. Univ Calif Los Angeles, Los Angeles, CA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD FEB PY 2006 VL 15 IS 1 SU S BP S22 EP S22 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 016XZ UT WOS:000235659000038 ER PT J AU Rutten, LJF Moser, R Hesse, B AF Rutten, LJF Moser, R Hesse, B TI Trends in cancer information seeking: Sources, barriers and efficacy SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 SAIC Frederick Inc, Frederick, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD FEB PY 2006 VL 15 IS 1 SU S BP S62 EP S63 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 016XZ UT WOS:000235659000117 ER PT J AU Bornstein, MH Hahn, CS Bell, C Haynes, OM Slater, A Golding, J Wolke, D AF Bornstein, MH Hahn, CS Bell, C Haynes, OM Slater, A Golding, J Wolke, D CA ALSPAC Study Team TI Stability in cognition across early childhood - A developmental cascade SO PSYCHOLOGICAL SCIENCE LA English DT Article ID INFANT HABITUATION; VISUAL FIXATION; INTELLIGENCE; REVISION; CHILDREN; MEMORY; HOME AB Children confront the formidable task of assimilating information in the environment and accommodating their cognitive structures to that information. Developmental science is concerned equally with two distinctive features of these processes: children's group mean level of performance through time and the standing of individual children through time. Prevailing opinion since the inception of the mental-measurement movement has been that individual development is unstable-that individual children change unpredictably in their abilities. We report results of a large-scale controlled, multivariate, prospective, microgenetic, 4-year longitudinal study that reveals a statistically significant cascade of species-typical cognitive abilities from infancy to childhood. Infancy is a recognizable starting point of life; we find that to a small but significant degree, infancy also represents a setting point in the life of the individual. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Univ Bristol, Bristol BS8 1TH, Avon, England. Univ Exeter, Sch Psychol, Washington Singer Labs, Exeter EX4 4QJ, Devon, England. Jacobs Fdn, Zurich, Switzerland. RP Bornstein, MH (reprint author), Rockledge 1,Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov RI Wolke, Dieter/C-5372-2008 OI Wolke, Dieter/0000-0003-0304-268X FU Intramural NIH HHS; Medical Research Council [G9815508] NR 40 TC 31 Z9 31 U1 1 U2 12 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD FEB PY 2006 VL 17 IS 2 BP 151 EP 158 DI 10.1111/j.1467-9280.2006.01678.x PG 8 WC Psychology, Multidisciplinary SC Psychology GA 005CU UT WOS:000234801000010 PM 16466423 ER PT J AU Le Foll, B Goldberg, SR AF Le Foll, B Goldberg, SR TI Nicotine as a typical drug of abuse in experimental animals and humans SO PSYCHOPHARMACOLOGY LA English DT Review ID DOPAMINE D-3 RECEPTOR; CONDITIONED PLACE PREFERENCES; SELF-ADMINISTERED COCAINE; SUSTAINED-RELEASE BUPROPION; BRAIN REWARD FUNCTION; DISCRIMINATIVE-STIMULUS; SMOKING-CESSATION; INTRAVENOUS NICOTINE; SQUIRREL-MONKEYS; SEEKING BEHAVIOR AB Rationale and background: Tobacco use through cigarette smoking is the leading preventable cause of death in the developed world. Nicotine, a psychoactive component of tobacco, appears to play a major role in tobacco dependence, but reinforcing effects of nicotine often are difficult to demonstrate directly in controlled laboratory studies with animal or human subjects. Objective: To review the major findings obtained with various procedures developed to study dependence-related behavioral effects of nicotine in experimental animals and humans, i.e., drug self-administration, conditioned place preference, subjective reports of nicotine effects and nicotine discrimination, withdrawal signs, and ratings of drug withdrawal. Results: Nicotine can function as an effective reinforcer of drug-seeking and drug-taking behavior both in experimental animals and humans under appropriate conditions. Interruption of chronic nicotine exposure produces withdrawal symptoms that may contribute to relapse. Difficulties encountered in demonstrating reinforcing effects of nicotine under some conditions, relative to other drugs of abuse, may be due to weaker primary reinforcing effects of nicotine or to a more critical contribution of environmental stimuli to the maintenance of drug-seeking and drug-taking behavior with nicotine than with other drugs of abuse. Further experiments are also needed to delineate the role other chemical substances inhaled along with nicotine in tobacco smoke play in sustaining smoking behavior. Conclusions: Nicotine acts as a typical drug of abuse in experimental animals and humans. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Le Foll, B (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM blefoll@intra.nida.nih.gov; sgoldber@intra.nida.nih.gov RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 NR 202 TC 75 Z9 75 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2006 VL 184 IS 3-4 BP 367 EP 381 DI 10.1007/s00213-005-0155-8 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 013ZE UT WOS:000235447700013 PM 16205918 ER PT J AU Tycko, R AF Tycko, Robert TI Molecular structure of amyloid fibrils: insights from solid-state NMR SO QUARTERLY REVIEWS OF BIOPHYSICS LA English DT Review ID NUCLEAR-MAGNETIC-RESONANCE; ANGLE-SPINNING NMR; BETA-SHEET STRUCTURE; CHEMICAL-SHIFT ANISOTROPIES; PROTEIN SECONDARY STRUCTURE; URE2P PRION FILAMENTS; MAGIC-ANGLE; ALZHEIMERS-DISEASE; ROTATIONAL-RESONANCE; IN-VITRO AB Solid-state nuclear magnetic resonance (NMR) measurements have made major contributions to our understanding of the molecular structures of amyloid fibrils, including fibrils formed by the beta-amyloid peptide associated with Alzheimer's disease, by proteins associated with fungal prions, and by a variety of other polypeptides. Because solid-state NMR techniques can be used to determine interatomic distances (both intramolecular and intermolecular), place constraints on backbone and side-chain torsion angles, and identify tertiary and quaternary contacts, full molecular models for amyloid fibrils can be developed from solid-state NMR data, especially when supplemented by lower-resolution structural constraints from electron microscopy and other sources. In addition, solid-state NMR data can be used as experimental tests of various proposals and hypotheses regarding the mechanisms of amyloid formation, the nature of intermediate structures, and the common structural features within amyloid fibrils. This review introduces the basic experimental and conceptual principles behind solid-state NMR methods that are applicable to amyloid fibrils, reviews the information about amyloid structures that has been obtained to date with these methods, and discusses how solid-state NMR data provide insights into the molecular interactions that stabilize amyloid structures, the generic propensity of polypeptide chains to form amyloid fibrils, and a number of related issues that are of current interest in the amyloid field. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural NIH HHS NR 222 TC 319 Z9 325 U1 8 U2 105 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-5835 J9 Q REV BIOPHYS JI Q. Rev. Biophys. PD FEB PY 2006 VL 39 IS 1 BP 1 EP 55 DI 10.1017/S0033583506004173 PG 55 WC Biophysics SC Biophysics GA 097LW UT WOS:000241450300001 PM 16772049 ER PT J AU Okazaki, R Moon, Y Norimura, T Eling, T AF Okazaki, R Moon, Y Norimura, T Eling, T TI Ionizing radiation enhances the expression of the nonsteroidal anti-inflammatory drug-activated gene (NAG1) by increasing the expression of TP53 in human colon cancer cells SO RADIATION RESEARCH LA English DT Article ID TGF-BETA SUPERFAMILY; GROWTH-FACTOR-BETA; WILD-TYPE P53; P53-DEPENDENT MECHANISM; MORPHOGENETIC PROTEIN; MEMBER; APOPTOSIS; OVEREXPRESSION; INHIBITION; CYTOKINE-1 AB The induction of apoptosis in cells of human colon cancer cell lines after gamma irradiation was investigated to determine whether apoptosis was mediated by TP53 and the subsequent expression of its downstream target, the NSAID-activated gene (NAG1). HCT116 (TP53(+/+)), HCT15 (TP53 mutant) and TP53 null HCT116 (TP53(-/-)) cells were irradiated with gamma rays, and apoptosis was measured at various times after irradiation. In HCT116 TP53(+/+) cells, apoptosis was increased after irradiation; the increase was dependent on the time after treatment and the dose of gamma rays. However, in HCT15 TP53 mutant cells and HCT116 TP53(-/-) cells, there were no remarkable changes in apoptosis. The expression of TP53 protein in HCT116 cells was increased after irradiation and was followed by an increase in the expression of NAG1 protein. In contrast, the expression of NAG1 protein in TP53 mutant cells and TP53(-/-) cells was not increased by the radiation treatment, suggesting that NAG1 was required for apoptosis. The expression of NAG1 increased apoptosis in HCT116 cells, but radiation treatment did not further increase apoptosis. The transfection of a NAG1 siRNA into HCT116 cells suppressed radiation-induced apoptosis and inhibited the induction A NAG1 protein without altering the expression of TP53. a NAG1 luciferase promoter construct that included both of the TP53 binding sites, was activated by radiation in dose-dependent manner, while the promoters lacking one or both of the TP53 binding sites in the NAG1 promoter activity either was less responsive or did not respond. The findings reported here indicate that gamma radiation activates the TP53 tumor suppressor, which then increases the expression of NAG1. NAG1 mediates the induction of apoptosis in human colorectal cells. (c) 2006 by Radiation Research Society. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Univ Occupat & Environm Hlth, Sch Med, Dept Radiat Biol & Hlth, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. RP Eling, T (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM Eling@niehs.nih.gov NR 33 TC 17 Z9 17 U1 0 U2 1 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2006 VL 165 IS 2 BP 125 EP 130 DI 10.1667/RR3492.1 PG 6 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 005BG UT WOS:000234796500001 PM 16435911 ER PT J AU Liu, WM Ding, I Chen, KQ Olschowka, J Xu, JH Hu, DP Morrow, GR Okunieff, P AF Liu, WM Ding, I Chen, KQ Olschowka, J Xu, JH Hu, DP Morrow, GR Okunieff, P TI Interleukin 1 beta (IL1B) signaling is a critical component of radiation-induced skin fibrosis SO RADIATION RESEARCH LA English DT Article ID HUMAN DERMAL FIBROBLASTS; CHRONIC RADIOTHERAPY DAMAGE; NECROSIS-FACTOR-ALPHA; MATRIX METALLOPROTEINASES; BREAST-CANCER; CULTURED FIBROBLASTS; SUPEROXIDE-DISMUTASE; THERAPEUTIC TARGET; PHENOTYPIC CHANGES; GENE-EXPRESSION AB Interleukin 1 beta (IL1B), a potent pro-inflammatory cytokine, is directly up-regulated by radiation and is known to regulate other inflammation-related molecules, such as the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs). However, the nature of the interaction of IL1B with MMPs and TIMPs in radiation-induced skin fibrosis is unknown. We examined the response of primary dermal keratinocytes, fibroblasts and endothelial cells to single-fraction radiation (10 Gy) and compared the results to a temporal sequence of histology from irradiated C57BL/6 and IL1R1 knockout mice. These studies showed that keratinocytes are the major IL1-producing cells in vitro and that radiation induces an immediate and chronic elevation in the expression of IL1B mRNA in the skin of C57BL/6 mice. This elevation was principally early and was less pronounced in the IL1R1 knockout strain, which also demonstrated reduced late radiation fibrosis. Radiation also increased expression of MMP mRNA in C57BL/6 mice. Finally, exogenous IL1B protein induced robust endogenous IL1B mRNA expression, along with a brisk increase in MMPs and collagen III, but only in the C57BL/6 mice. In conclusion, these data suggest that IL1B plays a critical role in radiation-induced fibrosis and that the increased MMPs fail to block the IL1-related collagen accumulation. (c) 2006 by Radiation Research Society. C1 Univ Rochester, Med Ctr, Dept Radiat Oncol, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. NCI, Organ Syst Branch, Rockville, MD 20852 USA. Univ Rochester, Med Ctr, Dept Neurobiol & Anat, Rochester, NY 14642 USA. RP Okunieff, P (reprint author), Univ Rochester, Med Ctr, Dept Radiat Oncol, James P Wilmot Canc Ctr, 601 Elmwood Ave,Box 647, Rochester, NY 14642 USA. EM paul_okunieff@urmc.rochester.edu FU NCI NIH HHS [CA11051-30] NR 51 TC 44 Z9 46 U1 1 U2 6 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2006 VL 165 IS 2 BP 181 EP 191 DI 10.1667/RR3478.1 PG 11 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 005BG UT WOS:000234796500007 PM 16435917 ER PT J AU Simon, SL Anspaugh, LR Hoffman, FO Scholl, AE Stone, MB Thomas, BA Lyon, JL AF Simon, SL Anspaugh, LR Hoffman, FO Scholl, AE Stone, MB Thomas, BA Lyon, JL TI 2004 Update of dosimetry for the Utah Thyroid Cohort Study SO RADIATION RESEARCH LA English DT Article ID NEVADA TEST-SITE; EXTERNAL GAMMA-EXPOSURE; NUCLEAR BOMB TESTS; FOOD-CHAIN MODEL; RADIONUCLIDE INGESTION; RADIATION EXPOSURES; CHERNOBYL ACCIDENT; CANCER INCIDENCE; HARDTACK-II; TEST SERIES AB In the 1980s, individual thyroid doses and uncertainties were estimated for members of a cohort of children identified in 1965 in Utah and Nevada who had potentially been exposed to fallout from the Nevada Test Site. That reconstruction represented the first comprehensive assessment of doses received by the cohort and was the first large effort to assess the uncertainty of dose on an individual person basis. The data on dose and thyroid disease prevalence during different periods were subsequently used in an analysis to determine risks of radiogenic thyroid disease. This cohort has received periodic medical follow-up to observe changes in disease frequency and to reassess the previously reported radiation-related risks, most recently after a Congressional mandate in 1998. In a recent effort to restore the databases and computer codes used to estimate doses in the 1980s, various deficiencies were found in the estimated doses due to improperly operating computer codes, corruption of secondary data files, and lack of quality control procedures. From 2001 through 2004, the dosimetry system was restored and corrected and all doses were recalculated. In addition, two parameter values were updated. While the mean of all doses has not changed significantly, many individual doses have changed by more than an order of magnitude. (c) 2006 by Radiation Research Society. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Utah, Div Radiobiol, Salt Lake City, UT 84112 USA. Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. SENES Oak Ridge Inc, Oak Ridge, TN USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Ececut Blvd,Room 7100 Execut Plaza S, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov FU PHS HHS [U50/CCU816245] NR 79 TC 17 Z9 17 U1 1 U2 1 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2006 VL 165 IS 2 BP 208 EP 222 DI 10.1667/RR3483.1 PG 15 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 005BG UT WOS:000234796500010 PM 16435919 ER PT J AU Aletaha, D Smolen, JS AF Aletaha, D Smolen, JS TI The definition and measurement of disease modification in inflammatory rheumatic diseases SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Review ID HEALTH-ASSESSMENT QUESTIONNAIRE; COLLEGE-OF-RHEUMATOLOGY; ARTHRITIS CLINICAL-TRIALS; IMPACT MEASUREMENT SCALES; ERYTHROCYTE SEDIMENTATION-RATE; SPONDYLITIS FUNCTIONAL INDEX; MCGILL PAIN QUESTIONNAIRE; ANTITUMOR NECROSIS FACTOR; LONG-TERM OUTCOMES; C-REACTIVE PROTEIN AB This article focuses on measures that are used to evaluate disease activity, damage, and function in three major inflammatory musculoskeletal disorders. The instruments used in rheumatoid arthritis, where most of the methodologic work has been done, are extensively discussed and instruments for the respective domains in psoriatic arthritis and ankylosing spondylitis are likewise presented. C1 Univ Vienna, Dept Rheumatol, A-1090 Vienna, Austria. NIAMSD, NIH, Bethesda, MD 20892 USA. Lainz Hosp, Dept Med 2, Vienna, Austria. RP Aletaha, D (reprint author), Univ Vienna, Dept Rheumatol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM daniel.aletaha@meduniwien.ac.at NR 190 TC 74 Z9 79 U1 6 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-857X J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD FEB PY 2006 VL 32 IS 1 BP 9 EP + DI 10.1016/j.rdc.2005.09.005 PG 37 WC Rheumatology SC Rheumatology GA 025ZV UT WOS:000236307400003 PM 16504819 ER PT J AU Collins, FS AF Collins, FS TI Delivering on the dream: Biomedical research in the Genome era SO SCIENTIST LA English DT Editorial Material C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM fcollins@the-scientist.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD FEB PY 2006 VL 20 IS 2 BP 46 EP 46 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 005RA UT WOS:000234840300018 ER PT J AU Baird, AE Wright, VL AF Baird, AE Wright, VL TI Vascular biology: Cellular and molecular profiling SO SEMINARS IN NEUROLOGY LA English DT Article DE endothelium; peripheral blood; lymphocyte; gene expression ID C-REACTIVE PROTEIN; INTERCELLULAR-ADHESION MOLECULE-1; CAROTID ATHEROSCLEROTIC PLAQUE; GENE-EXPRESSION PROFILES; ISCHEMIC-STROKE; T-CELLS; MYOCARDIAL-INFARCTION; INDEPENDENT PREDICTOR; CEREBRAL-ISCHEMIA; DNA MICROARRAY AB Our understanding of the mechanisms underlying cerebrovascular atherosclerosis has improved in recent years, but significant gaps remain. New insights into the vascular biological processes that result in ischemic stroke may come from cellular and molecular profiling studies of the peripheral blood. In recent cellular profiling studies, increased levels of a proinflammatory T-cell subset (CD4(+)CD28(-)) have been associated with stroke recurrence and death. Expansion of this T-cell subset may occur after ischemic stroke and be a pathogenic mechanism leading to recurrent stroke and death. Increases in certain phenotypes of endothelial cell microparticles have been found in stroke patients relative to controls, possibly indicating a state of increased vascular risk. Molecular profiling approaches include gene expression profiling and proteomic methods that permit large-scale analyses of the transcriptome and the proteome, respectively. Ultimately panels of genes and proteins may be identified that are predictive of stroke risk. Cellular and molecular profiling studies of the peripheral blood and of atherosclerotic plaques may also pave the way for the development of therapeutic agents for primary and secondary stroke prevention. C1 NINDS, Stroke Neurosci Unit, NIH, Bethesda, MD 20814 USA. RP Baird, AE (reprint author), NINDS, Stroke Neurosci Unit, NIH, 10 Ctr Dr,MSC1294,Room 3N258, Bethesda, MD 20814 USA. NR 60 TC 2 Z9 2 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PD FEB PY 2006 VL 26 IS 1 BP 65 EP 74 DI 10.1055/s-2006-933310 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 042VK UT WOS:000237558500009 PM 16479445 ER PT J AU Tycko, R AF Tycko, R TI Special issue in honor of Alex Pines - Foreword SO SOLID STATE NUCLEAR MAGNETIC RESONANCE LA English DT Editorial Material C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0926-2040 J9 SOLID STATE NUCL MAG JI Solid State Nucl. Magn. Reson. PD FEB PY 2006 VL 29 IS 1-3 BP 1 EP 1 DI 10.1016/j.ssnmr.2005.10.008 PG 1 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Physics, Condensed Matter; Spectroscopy SC Chemistry; Physics; Spectroscopy GA 999VA UT WOS:000234417500001 ER PT J AU Greco, NJ Seetharaman, S Kurtz, J Lee, WR Moroff, G AF Greco, NJ Seetharaman, S Kurtz, J Lee, WR Moroff, G TI Evaluation of the reactivity of apoptosis markers before and after cryopreservation in cord blood CD34(+) cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID PROGENITOR CELLS; STEM-CELLS; TRANSPLANTATION; PROLIFERATION; POPULATIONS; ENGRAFTMENT; INHIBITION; EXPRESSION; PROTEINS; LIGAND AB Umbilical cord blood (CB) CD34(+) cells, on the basis of flow cytometry analysis, are comprised of multiple populations. In in vitro assays, only CD34(regular) FSChigh cells are functional and low percentages of nonfunctional CD34(regular) FSClow cells were determined to be present in liquid-stored CB. Liquid-stored CD34(regular) FSChigh cells prior to cryopreservation were judged to be functional by the formation of erythroid and myeloid colonies and transmigration assays. We have further evaluated the occurrence of apoptosis in CB CD34(+) cells using various apoptotic markers to understand better the influence of storage conditions that could be utilized with transplantation of CB. Of the CD34(regular) FSClow cells shown in the present study, 20-45% were labeled with the apoptotic reagents annexin-V, fluorescent caspase peptide substrates, and the anti-mitochondrial antibody APO2.7, but these cells were minimally stained with 7-aminoactinomycin- D (7-AAD). These apoptotic reagents identify different cellular targets, indicating the initiation of the apoptotic cascade prior to cryopreservation/ thawing. Following cryopreservation and thawing, the apoptotic markers SYTO-16, tetramethyl rhodamine ethyl ester (TMRE), and 7-AAD showed the presence of apoptotic cells. After cryopreservation/ thawing, enumeration of CB CD34(+) cells was reduced 10-65% when excluding cells positive for apoptotic markers. We attempted to limit the progression of apoptosis observed after cryopreservation/ thawing by the addition of anti-apoptotic reagents z-VAD-fmk ( 100 mu M) and Q-VD-OPH (100 mu M) ( peptide inhibitors of caspases) without or with the inclusion of survival reagents for CD34(+) cells-stromal-derived factor-1 (SDF-1), stem cell factor (SCF), thrombopoietin, and diprotin A, an inhibitor of CD26 prior to cryopreservation. The expression of apoptosis markers was minimally affected even when using combinations of caspase inhibitors/CD34(+) cell survival cytokines in an attempt to block apoptosis caused by cryopreservation/ thawing. Decreases in apoptosis marker reactivity following cryopreservation were not observed except for a reduced expression of APO2.7 reactivity with z-VAD-fmk and Q-VD-OPH caspase inhibitors. The ability of the inhibitors of apoptosis of CD34(+) cells to generate CFU-GM, CFU-MK, or BFUE colonies was also unaffected except with z-VAD-fmk (100 mu M) and Q-VD-OPH (100 mu M). The occurrence of apoptosis, as measured by flow cytometry with selected apoptotic markers, suggests a reduction in the number of viable CD34(+) cells. C1 Case Western Reserve Univ, Dept Med, Div Cardiol, Cleveland, OH 44106 USA. Amer Red Cross, Blood & Cell Therapy Dev Dept, Jerome H Holland Lab Biomed Sci, Rockville, MD 20855 USA. Amer Red Cross, Jerome H Holland Lab Biomed Sci, Blood Components Dept, Rockville, MD 20855 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Greco, NJ (reprint author), Case Western Reserve Univ, Dept Med, Div Cardiol, 2103 Cornell Rd, Cleveland, OH 44106 USA. EM njg7@case.edu NR 34 TC 14 Z9 15 U1 1 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD FEB PY 2006 VL 15 IS 1 BP 124 EP 135 DI 10.1089/scd.2006.15.124 PG 12 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 026RE UT WOS:000236359000014 PM 16522170 ER PT J AU Chamorro, A Hallenbeck, J AF Chamorro, A Hallenbeck, J TI The harms and benefits of inflammatory and immune responses in vascular disease SO STROKE LA English DT Editorial Material DE inflammation ID C-REACTIVE PROTEIN; ISCHEMIC-STROKE; TISSUE FACTOR; ACTIVATION; MARKERS; ATHEROSCLEROSIS; NEUROPROTECTION; ATHEROGENESIS; INHIBITION; INFARCTION C1 Hosp Clin Barcelona, Inst Clin Neurosci, Stroke Unit, E-08036 Barcelona, Spain. Natl Inst Neurol Disorders & Stroke, Stroke Branch, NIH, Bethesda, MD USA. RP Chamorro, A (reprint author), Hosp Clin Barcelona, Inst Clin Neurosci, Stroke Unit, 170 Villarroel, E-08036 Barcelona, Spain. EM achamorro@ub.edu FU Intramural NIH HHS [Z99 NS999999] NR 32 TC 122 Z9 131 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 291 EP 293 DI 10.1161/01.STR.0000200561.69611.f8 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800007 PM 16410468 ER PT J AU Warach, S Wardlaw, J AF Warach, S Wardlaw, J TI Advances in imaging 2005 SO STROKE LA English DT Editorial Material DE CT; imaging; MRI ID ACUTE ISCHEMIC-STROKE; POSITRON-EMISSION-TOMOGRAPHY; COMPUTED-TOMOGRAPHY; DIFFUSION; MISMATCH; MRI; THROMBOLYSIS; PATTERNS; INFARCT; LESION C1 Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. NIH, Bethesda, MD 20892 USA. RP Wardlaw, J (reprint author), Western Gen Hosp, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland. EM dcn.stroke.journal@ed.ac.uk NR 12 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 297 EP 298 DI 10.1161/01.STR.0000200980.55215.7f PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800009 PM 16410467 ER PT J AU Fullerton, H Lynch, JK deVeber, G AF Fullerton, H Lynch, JK deVeber, G TI The call for multicenter studies of pediatric stroke SO STROKE LA English DT Letter ID CHILDREN C1 Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Natl Inst Neurol Disorders & Stroke, Neuroepidemiol Branch, Bethesda, MD USA. Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada. RP Fullerton, H (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. NR 5 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 330 EP 331 DI 10.1161/01.STR.0000199630.48970.f7 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800022 PM 16373629 ER PT J AU Johnston, KC Wagner, DP Newman, GC Thijs, V Sen, S Warach, S AF Johnston, KC Wagner, DP Newman, GC Thijs, V Sen, S Warach, S CA GAIN Citicoline Investigators TI An improved prediction model for acute ischemic stroke SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Univ Virginia, Charlottesville, VA USA. Univ Wisconsin, Madison, WI USA. Univ Hosp Leuven, Louvain, Belgium. NINDS, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. RI Thijs, Vincent/C-3647-2009 OI Thijs, Vincent/0000-0002-6614-8417 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 627 EP 627 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800128 ER PT J AU Mlynash, M Hsia, AW Finley-Caulfield, AC Eyngorn, I Bammer, R Moseley, M Wijman, CA AF Mlynash, M Hsia, AW Finley-Caulfield, AC Eyngorn, I Bammer, R Moseley, M Wijman, CA TI The utility of diffusion-weighted imaging to predict neurologic outcome in comatose patients after cardiac arrest SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Stanford Univ, Stanford Stroke Ctr, Palo Alto, CA 94304 USA. NINDS, Stroke Branch, Bethesda, MD 20892 USA. Stanford Univ, Lucas MRS Ctr 1, Palo Alto, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 644 EP 644 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800212 ER PT J AU Emr, M Warren, M AF Emr, M Warren, M TI Know Stroke in the Community: A grassroots Outreach model for the dissemination of stroke prevention information SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 666 EP 666 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800315 ER PT J AU Elkins, JS Longstreth, WT Manolio, TA Newman, AB Bhadelia, RA Johnston, SC AF Elkins, JS Longstreth, WT Manolio, TA Newman, AB Bhadelia, RA Johnston, SC TI Education level modifies cognitive decline associated with incident cerebral infarction SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Univ Washington, Seattle, WA 98195 USA. UCSF, San Francisco, CA USA. NHLBI, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. Tufts New England Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 667 EP 667 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800319 ER PT J AU Wadley, VG McClure, LA Howard, VM Unverzagt, FW Go, RC Moy, CS Crowther, MR Gomez, CR Howard, G AF Wadley, VG McClure, LA Howard, VM Unverzagt, FW Go, RC Moy, CS Crowther, MR Gomez, CR Howard, G TI Impaired cognitive screening status is associated with stroke symptom reports and modifiable health-related behaviors after controlling for age, education, ethnicity, and regional variation in stroke risk SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Univ Alabama, Birmingham, AL USA. Indiana Univ, Sch Med, Indianapolis, IN USA. NINDS, Rockville, MD USA. Alabama Neurol Inst, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 673 EP 673 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800347 ER PT J AU Foroud, T Potter, OL Woo, D Sauerbeck, L Bailey-Wilson, J Hornung, R Wiebers, D Connolly, ES Anderson, C Rouleau, G Deka, R Meissner, I Huston, J Brown, RD Broderick, JP AF Foroud, T Potter, OL Woo, D Sauerbeck, L Bailey-Wilson, J Hornung, R Wiebers, D Connolly, ES Anderson, C Rouleau, G Deka, R Meissner, I Huston, J Brown, RD Broderick, JP CA FIA Investigators TI Genomewide screen for intracranial aneurysm susceptibility genes SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Indiana Univ, Indianapolis, IN 46204 USA. Univ Cincinnati, Cincinnati, OH USA. NHGRI, NIH, Baltimore, MD USA. Mayo Clin, Rochester, MN USA. Columbia Univ, New York, NY USA. Univ Sydney, Sydney, NSW 2006, Australia. Univ Montreal, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 677 EP 677 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800368 ER PT J AU Yilmaz, G Arumugam, TV Stokes, KY Granger, DN AF Yilmaz, G Arumugam, TV Stokes, KY Granger, DN TI Role of T-lymphocytes and interferon-gamma in the inflammatory response and tissue injury associated with ischemic stroke SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA 71105 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011 NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 680 EP 680 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800382 ER PT J AU Merino, JG Luby, M Jothen, J Warach, S AF Merino, JG Luby, M Jothen, J Warach, S TI Pretreatment lesions or mismatched volumes are not independent predictors of clinical outcome after standard treatment with tissue plasminogen activator SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 NINDS, Intramural Acute Stroke Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 701 EP 701 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800492 ER PT J AU Tanne, D Macko, RF Lin, H Tilley, BC Levine, SR AF Tanne, D Macko, RF Lin, H Tilley, BC Levine, SR CA NINDS rt-PA Stroke Study Grp TI Effect of elevated hemostatic markers on outcome after rt-PA therapy for acute ischemic stroke: Results from the NINDS rt-PA stroke trial SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Mt Sinai Sch Med, New York, NY USA. NINDS, RTPA Stroke Study Grp, Bethesda, MD USA. RI Tanne, David/F-2560-2010 OI Tanne, David/0000-0002-6699-2220 NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 704 EP 704 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800504 ER PT J AU Arumugam, TV Chan, SL Tang, SC Jo, DG Gleichmann, M Magnus, T Mattson, MP AF Arumugam, TV Chan, SL Tang, SC Jo, DG Gleichmann, M Magnus, T Mattson, MP TI Involvement of gamma-secretase activity in focal ischemia-reperfusion induced brain injury and hypoxic cell death SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 16-18, 2006 CL Kissimmee, FL SP Amer Stroke Assoc C1 Natl Inst Aging Intramural Res Program, Neurosci Lab, Baltimore, MD USA. RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2006 VL 37 IS 2 BP 727 EP 727 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 005NJ UT WOS:000234829800621 ER PT J AU Agniswamy, J Nagiec, MJ Liu, MY Schuck, P Musser, JM Sun, PD AF Agniswamy, J Nagiec, MJ Liu, MY Schuck, P Musser, JM Sun, PD TI Crystal structure of group A Streptococcus Mac-1: Insight into dimer-mediated specificity for recognition of human IgG SO STRUCTURE LA English DT Article ID CYSTEINE PROTEASE; IMMUNOGLOBULIN-G; STRICT SPECIFICITY; BINDING; RECEPTOR; OPSONOPHAGOCYTOSIS; IDENTIFICATION; ENDOPEPTIDASE; INTEGRINS; PROTEINS AB Group A Streptococcus secretes cysteine proteases named Mac-1 and Mac-2 that mediate host immune evasion by targeting both IgG and Fc receptors. Here, we report the crystal structures of Mac-1 and its catalytically inactive C94A mutant in two different crystal forms. Despite the lack of sequence homology, Mac-1 adopts the canonical papain fold. Alanine mutations at the active site confirmed the critical residues involved in a papain-like catalytic mechanism. Mac-1 forms a symmetric dimer in both crystal forms and displays the unique dimer interface among papain superfamily members. Mutations at the dimer interface resulted in a significant reduction in IgG binding and catalysis, suggesting that the dimer contributes to both IgG specificity and enzyme cooperativity. A tunnel observed at the dimer interface constitutes a target for designing potential Mac-l-specific antimicrobial agents. The structures also offer insight into the functional difference between Mac-1 and Mac-2. C1 NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis Res, Houston, TX 77030 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM psun@nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural NIH HHS NR 43 TC 18 Z9 18 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD FEB PY 2006 VL 14 IS 2 BP 225 EP 235 DI 10.1016/j.str.2005.10.012 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 013TF UT WOS:000235431700010 PM 16472742 ER PT J AU Garcia-Alai, MM Gallo, M Salame, M Wetzler, DE McBride, AA Paci, M Cicero, DO de Prat-Gay, G AF Garcia-Alai, MM Gallo, M Salame, M Wetzler, DE McBride, AA Paci, M Cicero, DO de Prat-Gay, G TI Molecular basis for phosphorylation-dependent, PEST-mediated protein turnover SO STRUCTURE LA English DT Article ID BACKBONE CONFORMATION; CIRCULAR-DICHROISM; CHEMICAL-SHIFTS; POLYPROLINE-II; COPY NUMBER; DEGRADATION; PAPILLOMAVIRUS; NMR; PEPTIDES; HELIX AB Proteasomal-mediated rapid turnover of proteins is often modulated by phosphorylation of PEST sequences. The E2 protein from papillomavirus participates in gene transcription, DNA replication, and episomal genome maintenance. Phosphorylation of a PEST sequence located in a flexible region accelerates its degradation. NMR analysis of a 29 amino acid peptide fragment derived from this region shows pH-dependent polyproline 11 and alpha helix structures, connected by a turn. Phosphorylation, in particular that at serine 301, disrupts the overall structure, and point mutations have either stabilizing or destabilizing effects. There is an excellent correlation between the thermodynamic stability of different peptides and the half-life of E2 proteins containing the same mutations in vivo. The structure around the PEST region appears to have evolved a marginal stability that is finely tunable by phosphorylation. Thus, conformational stability, rather than recognition of a phosphate modification, modulates the degradation of this PEST sequence by the proteasome machinery. C1 Inst Leloir, RA-1405 Buenos Aires, DF, Argentina. Univ Roma Tor Vergata, I-00133 Rome, Italy. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP de Prat-Gay, G (reprint author), Inst Leloir, Patricias Argentinas 435, RA-1405 Buenos Aires, DF, Argentina. EM gpratgay@leloir.org.ar OI McBride, Alison/0000-0001-5607-5157 FU Wellcome Trust [U41 RG27994] NR 45 TC 41 Z9 41 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD FEB PY 2006 VL 14 IS 2 BP 309 EP 319 DI 10.1016/j.str.2005.11.012 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 013TF UT WOS:000235431700018 PM 16472750 ER PT J AU Li, JZ Li, HW Hankins, GR Lieu, AS Noh, E Jacobson, L Pittman, DD Chiorini, JA Helm, GA AF Li, JZ Li, HW Hankins, GR Lieu, AS Noh, E Jacobson, L Pittman, DD Chiorini, JA Helm, GA TI Different osteogenic potentials of recombinant human BMP-6 adeno-associated virus and adenovirus in two rat strains SO TISSUE ENGINEERING LA English DT Article; Proceedings Paper CT 7th Annual Meeting of the American-Society-of-Gene-Therapy CY JUN 02-06, 2004 CL Minneapolis, MN SP Amer Soc Gene Therapy ID BONE MORPHOGENETIC PROTEIN-2; INNATE IMMUNE-RESPONSES; GENE-THERAPY; IN-VIVO; T-CELL; TRANSGENE EXPRESSION; LONG-TERM; FACTOR-IX; VECTORS; MICE AB The osteogenic potential of AAV5hBMP6 was compared with that of ADhBMP6 in immunodeficient and immunocompetent rats. AAV5hBMP6 (2.3 x 10(12) particles) and ADhBMP6 ( 5 x 10(7) PFU) elicited viral antibody production in immunocompetent rats. Among rats that received AAV5hBMP6, the earliest time points at which the bone was visible under CT scanner were 30 days in 2-month-old Sprague-Dawley (SD) rats and 60 days in 18-month-old SD rats. The mean volumes of ectopic bone 90 days after viral injection were 0.31 +/- 0.14 cm(3) in athymic nude rats, 0.64 +/- 0.12 cm(3) in 2-month-old SD rats, and 0.21 +/- 0.10 cm(3) in 18-month-old SD rats. In contrast, among rats that received ADhBMP6, the earliest time points to observe the bone formation by CT scan were 15 days in 2-month-old rats and no bone formation in 18-month-old SD rats. The mean volumes of ectopic bone were 4.17 +/- 0.05 cm(3) in athymic nude rats and 0.06 +/- 0.03 cm(3) in 2-month-old SD rats. Although both types of viruses induced an immune response in immunocompetent animals, this response played different roles in the process of bone formation induced by the BMP6 vectors. C1 Univ Virginia Hlth Syst, Dept Neurol Surg, Charlottesville, VA 22908 USA. Univ Virginia Hlth Syst, Dept Biomed Engn, Charlottesville, VA USA. Genet Inst Inc, Andover, MA USA. Natl Inst Dent & Craniofacial Res, Gene Therapeut Branch, Bethesda, MD USA. RP Li, JZ (reprint author), Univ Virginia Hlth Syst, Dept Neurol Surg, POB 800420, Charlottesville, VA 22908 USA. EM jl9v@virginia.edu FU NIAMS NIH HHS [R01 AR46488-01A2] NR 51 TC 9 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD FEB PY 2006 VL 12 IS 2 BP 209 EP 219 DI 10.1089/ten.2006.12.209 PG 11 WC Cell & Tissue Engineering SC Cell Biology GA 027FZ UT WOS:000236401100001 PM 16548680 ER PT J AU Shen, J Wanibuchi, H Waalkes, MP Salim, EI Kinoshita, A Yoshida, K Endo, G Fukushima, S AF Shen, J Wanibuchi, H Waalkes, MP Salim, EI Kinoshita, A Yoshida, K Endo, G Fukushima, S TI A comparative study of the sub-chronic toxic effects of three organic arsenical compounds on the urothelium in F344 rats; gender-based differences in response SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE arsenic; dimethylarsinic acid; monomethylarsonic acid; trimethylarsine oxide; toxicity; urinary bladder; F344 rat; necrosis ID URINARY-BLADDER CARCINOGENESIS; MONOMETHYLARSONOUS ACID MMA(III); DIMETHYLARSINIC ACID; DRINKING-WATER; METHYLATED ARSENICALS; METABOLITES; REGENERATION; INDUCTION; TRIVALENT; LESIONS AB Epidemiological studies indicated that human arsenic exposure can induce urinary bladder cancer. Methylation of inorganic arsenic can generate more reactive and toxic organic arsenical species. In this regard, it was recently reported that the methylated arsenical metabolite, dimethylarsinic acid [DMA(V)], induced urinary bladder tumors in rats. However, other methylated metabolites, like monomethylarsonic acid [MMA(V)] and trimethylarsine oxide (TMAO) were not carcinogenic to the urinary bladder. In order to compare the early effects of DMA(V), MMA(V), and TMAO on the urinary bladder transitional cell epithelium at the scanning electron microscope (SEM) level, we investigated the sub-chronic (13 weeks) toxicological effects of MMA(V) (187 ppm), DMA(V) (184 ppm), TMAO (182 ppm) given in the drinking water to male and female F344 rats with a focus on the urinary bladder in this study. Obvious pathological changes, including ropy microridges, pitting, increased separation of epithelial cells, exfoliation, and necrosis, were found in the urinary bladders of both sexes, but particularly in females receiving carcinogenic doses of DMA(V). Urine arsenical metabolic differences were found between males and females, with levels of NINIA(III), a potential genotoxic form, higher in females treated with DMA(V) than in males. Thus, this study provides clear evidence that DMA(V) is more toxic to the female urinary bladder, in accord with sensitivity to carcinogenesis. Important gender-related metabolic differences including enhanced presentation of MMA(Ill) to the urothelial cells might possibly account for heightened sensitivity in females. However, the potential carcinogenic effects of MMA(III) need to be further elucidated. (c) 2005 Elsevier Inc. All rights reserved. C1 Osaka City Univ, Sch Med, Dept Pathol, Abeno Ku, Osaka 5458585, Japan. NIEHS, Comparat Carcinogenesis Lab, NCI, NIH, Res Triangle Pk, NC 27709 USA. Osaka City Univ, Sch Med, Dept Prevent Med & Environm Hlth, Osaka 5458585, Japan. RP Fukushima, S (reprint author), Osaka City Univ, Sch Med, Dept Pathol, Abeno Ku, 1-4-3 Asahi Machi, Osaka 5458585, Japan. EM fukuchan@med.osaka-cu.ac.jp NR 50 TC 27 Z9 30 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD FEB 1 PY 2006 VL 210 IS 3 BP 171 EP 180 DI 10.1016/j.taap.2005.04.018 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 013MR UT WOS:000235413900001 PM 15950995 ER PT J AU Stoszek, SK Engle, RE Abdel-Hamida, M Mikhail, N Abdel-Aziz, F Medhat, A Fix, AD Emerson, SU Purcell, RH Strickland, GT AF Stoszek, SK Engle, RE Abdel-Hamida, M Mikhail, N Abdel-Aziz, F Medhat, A Fix, AD Emerson, SU Purcell, RH Strickland, GT TI Hepatitis E antibody seroconversion without disease in highly endemic rural Egyptian communities SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE hepatitis E virus; HEV; incidence; epidemiology; Eqypt ID E VIRUS; NILE DELTA; VIRAL-HEPATITIS; HEV INFECTION; EPIDEMIC; PREVALENCE; PAKISTAN; COUNTRIES; SWINE AB Hepatitis E virus (HEV) is enterically transmitted and causes self-limiting acute viral hepatitis (AVH) primarily in Less developed countries. A prospective cohort study to assess incidence of, and risk factors for, seroconversion to HEV (anti-HEV) was conducted in two Egyptian villages with a 67.7% anti-HEV prevalence. Nine hundred and nineteen villagers who were initially anti -HEV-negative were followed for 10.7 months. Thirty-four (3.7%) had strong anti-HEV serologic responses at follow-up giving an estimated anti-HEV incidence of 41.6/ 1000 person-years. No significant associations were found between anti-HEV seroincidence and demographic and socioeconomic factors, source of water, household plumbing or sanitation, hand and vegetable washing, ownership of animals, jaundice and many other variables. None of the seroconverting subjects gave a history compatible with AVH during the interval. We hypothesize that both zoonotic and anthroponotic transmission of avirulent (possibly genotype-3) HEV is occurring extensively in these rural villages. An alternative explanation for the lack of morbidity among anti-HEV incident cases could be initial asymptomatic infections occur during early childhood with subsequent antibody titer boosting without illness upon re-exposure to the virus. (C) 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. C1 Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Int Hlth Div, Baltimore, MD 20201 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Natl Hepatol & Trop Med Res Inst, Cairo, Egypt. Assiut Univ, Fac Med, Assiut, Egypt. Ctr Field & Appl Res, Qualibya, Egypt. RP Strickland, GT (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Int Hlth Div, 660 W Redwood St, Baltimore, MD 20201 USA. EM tstrick@epi.umaryland.edu FU NICHD NIH HHS [1U01HD39164] NR 24 TC 45 Z9 45 U1 0 U2 4 PU ROYAL SOC TROPICAL MEDICINE PI LONDON PA MANSON HOUSE 26 PORTLAND PLACE, LONDON W1N 1EY, ENGLAND SN 0035-9203 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD FEB PY 2006 VL 100 IS 2 BP 89 EP 94 DI 10.1016/j.trstmh.2005.05.019 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 002RA UT WOS:000234627700001 PM 16257427 ER PT J AU Stoszek, SK Abdel-Hamid, M Saleh, DA El Kafrawy, S Narooz, S Hawash, Y Shebl, FM El Daly, M Said, A Kassem, E Mikhail, N Engle, RE Sayed, M Sharaf, S Fix, AD Emerson, SU Purcell, RH Strickland, GT AF Stoszek, SK Abdel-Hamid, M Saleh, DA El Kafrawy, S Narooz, S Hawash, Y Shebl, FM El Daly, M Said, A Kassem, E Mikhail, N Engle, RE Sayed, M Sharaf, S Fix, AD Emerson, SU Purcell, RH Strickland, GT TI High prevalence of hepatitis E antibodies in pregnant Egyptian women SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE hepatitis E virus; HEV; prevalence; epidemiology; pregnancy; Egypt ID NON-B HEPATITIS; E VIRUS; VIRAL-HEPATITIS; UNITED-STATES; NILE DELTA; SPORADIC ACUTE; HEV INFECTION; E EPIDEMIC; NON-A; SWINE AB The epidemiology of hepatitis E virus (HEV), an enterically-transmitted cause of acute viral hepatitis (AVH), is not fully understood. During outbreaks on the Indian subcontinent and elsewhere, HEV causes severe AVH with mortality rates around 20% during pregnancy. In Egypt, where prevalence of HEV antibodies (anti-HEV) in rural communities is very high, severe HEV-caused AVH in pregnant women has not been reported. This study examined a cohort of 2428 pregnant women in the Nile Delta to assess prevalence of, and risk factors for, anti-HEV and correlated these with history of liver disease. Anti-HEV prevalence was 84.3%. Several risk factors associated with anti-HEV included older age, many siblings, not using soap to wash produce and frequent contact with cats. History of jaundice and liver disease was rare and not increased in those having anti-HEV. Our results confirm Egypt's high HEV endemicity and show that almost at[ women of childbearing age in these communities had prior HEV exposures without a history of liver disease. Reasons for the tack of clinical hepatitis remain unclear but could be the result of early childhood HEV exposures, producing long-tasting immunity and/or modify subsequent responses to exposure. Alternatively, the pm dominant HEV strain(s) in Egypt are less virulent than those in South Asia. (C) 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. C1 Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Int Hlth Div, Baltimore, MD 20201 USA. Natl Hepatol & Trop Med Res Inst, Cairo, Egypt. Menoufia Univ, Natl Liver Inst, Shibin El Kom, Egypt. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Strickland, GT (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Int Hlth Div, 660 W Redwood St, Baltimore, MD 20201 USA. EM tstrick@epi.umaryland.edu RI Huang, Linlu/H-3410-2011; El-Daly, Mai/C-4704-2013 FU NICHD NIH HHS [1U01HD39164] NR 32 TC 56 Z9 59 U1 1 U2 5 PU ROYAL SOC TROPICAL MEDICINE PI LONDON PA MANSON HOUSE 26 PORTLAND PLACE, LONDON W1N 1EY, ENGLAND SN 0035-9203 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD FEB PY 2006 VL 100 IS 2 BP 95 EP 101 DI 10.1016/j.trstmh.2004.12.005 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 002RA UT WOS:000234627700002 PM 16257426 ER PT J AU Ryan, PE Davies, GC Nau, MM Lipkowitz, S AF Ryan, PE Davies, GC Nau, MM Lipkowitz, S TI Regulating the regulator: negative regulation of Cbl ubiquitin ligases SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; RECEPTOR DOWN-REGULATION; COLONY-STIMULATING FACTOR; FACTOR-I RECEPTOR; C-CBL; TYROSINE PHOSPHORYLATION; EGF RECEPTOR; V-CBL; SUSCEPTIBILITY GENE; PROTEIN LIGASES AB Cbl proteins are regulators of signal transduction through many pathways and, consequently, regulate cell function and development. They are ubiquitin ligases that ubiquitinate and target many signaling molecules for degradation. The Cbl proteins themselves are regulated by an increasingly complex network of interactions that fine-tune the effects that Cbl proteins have on signaling. The negative regulation of Cbl protein function can occur via cis-acting structural elements that prevent inappropriate ubiquitin ligase activity, degradation of the Cbl proteins, inhibition without degradation owing to interaction with other signaling proteins, deubiquitination of Cbl substrates, and regulation of assembly of the endosomal ESCRT-I complex. Defects in the regulatory mechanisms that control Cbl function are implicated in the development of immunological and malignant diseases. C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. George Washington Univ, Inst Biomed Sci, Washington, DC 20037 USA. RP Lipkowitz, S (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM lipkowis@mail.nih.gov FU Intramural NIH HHS NR 101 TC 58 Z9 60 U1 0 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD FEB PY 2006 VL 31 IS 2 BP 79 EP 88 DI 10.1016/j.tibs.2005.12.004 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 024KE UT WOS:000236193100003 PM 16406635 ER PT J AU Muraro, PA Douek, DC AF Muraro, PA Douek, DC TI Renewing the T cell repertoire to arrest autoimmune aggression SO TRENDS IN IMMUNOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; MULTIPLE-SCLEROSIS; IMMUNE RECONSTITUTION; THYMIC FUNCTION; HOMEOSTATIC PROLIFERATION; REPLICATIVE SENESCENCE; INTENSIVE CHEMOTHERAPY; LYMPHOPENIC HOSTS; TCR REPERTOIRE; HIV-INFECTION AB There is now evidence that high-dose immune ablation and autologous hematopoietic stem cell transplantation in humans triggers a reconstitution program that leads to the comprehensive renewal of the T cell repertoire. We argue here that several features of this program help to explain how autologous hematopoietic stem cell transplantation can induce long-term clinical remission from organ-specific-, as well as systemic, autoimmune diseases. We propose a model envisioning a coordinated sequence of events, rebuilding an immune system that is competent against infection but that is substantially reconfigured in a way that is less likely to redevelop autoimmunity. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Muraro, PA (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Dr,MSC1400, Bethesda, MD 20892 USA. EM murarop@ninds.nih.gov OI Muraro, Paolo/0000-0002-3822-1218 FU Intramural NIH HHS NR 55 TC 44 Z9 45 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD FEB PY 2006 VL 27 IS 2 BP 61 EP 67 DI 10.1016/j.it.2005.12.003 PG 7 WC Immunology SC Immunology GA 020LX UT WOS:000235912000003 PM 16406806 ER PT J AU Abath, FGC Morais, CNL Montenegro, CEL Wynn, TA Montenegro, SML AF Abath, FGC Morais, CNL Montenegro, CEL Wynn, TA Montenegro, SML TI Immunopathogenic mechanisms in schistosomiasis: what can be learnt from human studies? SO TRENDS IN PARASITOLOGY LA English DT Review ID BLOOD MONONUCLEAR-CELLS; REGULATORY T-CELLS; INTERFERON-GAMMA; MANSONI INFECTION; MURINE SCHISTOSOMIASIS; CYTOKINE PRODUCTION; IMMUNE-RESPONSE; PORTAL FIBROSIS; EGG ANTIGEN; IFN-GAMMA AB Studies in mice indicate that schistosome egg-induced granuloma formation and hepatic fibrosis depend markedly on cytokine regulation, with interleukin 10 having a central role. There is no clear consensus about the pattern of cytokine production and regulation that causes a minority of chronically exposed patients to develop severe hepatosplenic (HS) disease, which is characterized by periportal fibrosis and portal hypertension. HS disease and the progression of hepatic fibrosis are associated with the production of profibrotic type 2 cytokines in the early stages of infection with Schistosoma mansoni. However, other studies indicate that HIS disease is characterized by a predominant T helper 1 profile. Until new tools and approaches are developed to study human disease in endemic areas, investigators must either speculate about indirect evidence from human studies or rely more heavily on findings generated from experimental models of the disease. C1 Fdn Oswaldo Cruz, Dept Imunol, Ctr Pesquisas Aggeu Magalhaes, BR-50670420 Recife, PE, Brazil. Univ Fed Pernambuco, Fac Med, BR-50100130 Recife, PE, Brazil. NIAID, Immunopathogenesis Sect Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Abath, FGC (reprint author), Fdn Oswaldo Cruz, Dept Imunol, Ctr Pesquisas Aggeu Magalhaes, Ave Prof Moraes Rego S-N,Cidade Univ, BR-50670420 Recife, PE, Brazil. EM fabath@cpqam.fiocruz.br RI Wynn, Thomas/C-2797-2011 NR 60 TC 58 Z9 61 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD FEB PY 2006 VL 22 IS 2 BP 85 EP 91 DI 10.1016/j.pt.2005.12.004 PG 7 WC Parasitology SC Parasitology GA 015TY UT WOS:000235575100011 PM 16380294 ER PT J AU Luke, B Brown, MB Hediger, ML Misiunas, RB Anderson, E AF Luke, B Brown, MB Hediger, ML Misiunas, RB Anderson, E TI Perinatal and early childhood outcomes of twins versus triplets SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Article ID LOW-BIRTH-WEIGHT; IN-VITRO FERTILIZATION; UNITED-STATES; MULTIFETAL REDUCTION; EMBRYO REDUCTION; GROWTH; AGE; INFANTS; PREGNANCIES; TERM AB The purpose of this prospective cohort study of twins and triplets was to evaluate perinatal and early childhood outcomes through 18 months of age. The study population included 141 twin pregnancies (282 twin children) and 8 triplet pregnancies (24 triplet children) recruited between May, 1996 and June, 2001. Mothers of triplets versus twins were significantly more likely to have infertility treatments, to be overweight or obese before conception, to be admitted antenatally, and to deliver by cesarean section. Length of gestation for triplets was significantly shorter (-2.31 weeks, p <.0001), and more likely to be less than 35 weeks (Adjusted Odds Ratio [AOR] 9.38, 95% confidence interval [CI] 3.22-27.29). Average birthweight for triplets was significantly lighter (-495 grams, p <.0001), and more likely to be low birthweight (AOR 11.38, 95% Cl 3.11-41.61). Triplets were also more likely to be admitted to neonatal intensive care (AOR 7.97, 95% Cl 2.13-29.77), to require mechanical ventilation AOR 5.67, 95% Cl 2.05-15.65), to develop respiratory distress syndrome (AOR 12.50, 95% Cl 3.89-40.20), or a major morbidity (retinopathy of prematurity, necrotizing enterocolitis, ventilator support, or grade III or IV intraventricular hemorrhage, AOR 5.67, 95% Cl 2.05-15.65). Weight, length, and head circumference was significantly smaller at birth for triplets compared to twins, and these differences remained through 18 months of age, along with lower mental developmental scores at the oldest age. Compared to twins, triplets have greater neonatal morbidity, and through 18 months of age lower mental and motor scores, slower postnatal growth and more residual stunting, particularly of length and head circumference. C1 Univ Miami, Sch Nursing & Hlth Studies, Coral Gables, FL 33143 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,US Dept HHS, Bethesda, MD USA. Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. RP Luke, B (reprint author), Univ Miami, Sch Nursing & Hlth Studies, 5801 Red Rd, Coral Gables, FL 33143 USA. EM b.luke@miami.edu NR 43 TC 17 Z9 19 U1 0 U2 1 PU AUSTRALIAN ACAD PRESS PI BOWEN HILLS PA 32 JEAYS ST, BOWEN HILLS, QLD 4006, AUSTRALIA SN 1832-4274 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD FEB PY 2006 VL 9 IS 1 BP 81 EP 88 DI 10.1375/183242706776403064 PG 8 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 035MY UT WOS:000237006600012 PM 16611472 ER PT J AU Ortner, ER Hayes, RB Weissfeld, J Gelmann, EP AF Ortner, ER Hayes, RB Weissfeld, J Gelmann, EP TI Effect of homeodomain protein NKX3.1 R52C polymorphism on prostate gland size SO UROLOGY LA English DT Article ID DIGITAL RECTAL EXAMINATION; CANCER; HYPERPLASIA; GENE; VOLUME; MEN; AGE; DIFFERENTIATION; HOMOLOG; HEIGHT AB Objectives. To determine the association between prostatic enlargement and a cytosine for thymine genetic polymorphism at nucleotide 154 (C154T) of the NKX3.1 prostate homeobox gene. The polymorphism, found in 10% of the population, affects the NKX3.1 protein by replacing a cysteine for arginine at amino acid 52 and alters protein phosphorylation and DNA binding. Methods. A study group of men without prostate cancer from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was identified who had had at least three annual serial digital rectal examinations by a single examiner. The cohort of 772 men consisted of the lowest and highest tertiles of the entire study group as defined by two-dimensional measurements at digital rectal examination. The TaqMan allelic discrimination assay was used to genotype NKX3.1 for the nucleotide 154 polymorphism. Results. The men in the lower tertile (n=413) had a mean age of 60.8 years, mean prostate-specific antigen level of 1.2 ng/mL, and mean prostate volume of 37.9 +/- 4.5 cm(3). The men in the upper tertile (n=359) had a mean age of 61.6 years, mean prostate-specific antigen level of 2.1 ng/mL, and mean prostate volume of 61 +/- 6.3 cm(3). The men in the upper tertile had a greater likelihood of having a clinical history of benign prostatic hyperplasia and more frequent nocturia. The presence of one or two polymorphic NKX3.1 alleles conferred a risk of 1.6 (95% confidence interval 1.0 to 2.6) for an enlarged prostate (highest tertile). Conclusions. The NKX3.1 nucleotide 154 C/T or T/T genotype increases the relative odds for prostatic enlargement. The group with prostatic enlargement also had increased clinical benign prostatic hyperplasia and nocturia. C1 Georgetown Univ, Dept Oncol, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Georgetown Univ, Dept Med, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Univ Pittsburgh, Med Ctr, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Gelmann, EP (reprint author), Georgetown Univ, Dept Oncol, Vincent T Lombardi Canc Res Ctr, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM Gelmanne@georgetown.edu OI Hayes, Richard/0000-0002-0918-661X NR 23 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD FEB PY 2006 VL 67 IS 2 BP 311 EP 315 DI 10.1016/j.urology.2005.08.021 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 024EO UT WOS:000236178500017 ER PT J AU Lu, XF Li, L Wu, R Feng, XH Li, ZM Yang, HY Wang, CH Guo, H Galkin, A Herzberg, O Mariano, PS Martin, BM Dunaway-Mariano, D AF Lu, XF Li, L Wu, R Feng, XH Li, ZM Yang, HY Wang, CH Guo, H Galkin, A Herzberg, O Mariano, PS Martin, BM Dunaway-Mariano, D TI Kinetic analysis of Pseudomonas aeruginosa arginine deiminase mutants and alternate substrates provides insight into structural determinants of function SO BIOCHEMISTRY LA English DT Article ID DIMETHYLARGININE DIMETHYLAMINOHYDROLASE; ESCHERICHIA-COLI; IDENTIFICATION; PATHWAY; ENZYMES; GENES; HYDROLYSIS; EXPRESSION; CATALYSIS; DYNAMICS AB L-Arginine deiminase from Pseudomonas aeruginosa (PaADI) catalyzes the hydrolysis of arginine to citrulline and ammonia. PaADI belongs to the guanidino group-modifying enzyme superfamily (GMSF), which conserves backbone fold and a Cys-, His-, and Asp-based catalytic core. In this paper the contributions made by the PaADI core residues Cys406, His278, and Asp166 and the contribution from the neighboring Asp280 (conserved in most but not all GMSF members) to catalysis of the formation and hydrolysis of the Cys406-alkyluronium intermediate were accessed by kinetic analysis of site-directed mutants. In addition, solution hydrolysis in a chemical model of the S-alkylthiouronium intermediate was examined to reveal the importance of general base catalysis in the enzymatic reaction. Substitutions of the active site gating residue Arg401, the L-arginine C alpha NH3+(COO-) binding residues, Arg185, Arg243, and Asn160, or the His278 hydrogen bond partner, Glu224, were found to cause dramatic reductions in the enzyme turnover rate. These results are interpreted to suggest that electrostatic interactions play a dominant role in PaADI catalysis. Structural variations observed in P. aeruginosa GMSF enzymes PaADI, agmatine deiminase (PaAgDl), and N-omega,N-omega-dimethylarginine dimethylaminohydrolase (PaDDAH) indicate an early divergence of the encoding genes. Arginine analogues that are known substrates for PaAgDI and PaDDAH were tested with PaADI to define clear boundaries of biochemical function in the three hydrolases. The conservation of a catalytic core associated with the common chemical function and the divergence of substrate-binding residues (as well as one key catalytic residue) to expand the substrate range provide insight into the evolution of the catalysts that form the GMSF. C1 Univ New Mexico, Dept Chem, Albuquerque, NM 87131 USA. Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. NIMH, Mol Struct Unit, Lab Neurotoxicol, Bethesda, MD 20892 USA. RP Dunaway-Mariano, D (reprint author), Univ New Mexico, Dept Chem, Albuquerque, NM 87131 USA. EM dd39@unm.edu RI Wu, Rui/E-3728-2010; Li, Zhimin/A-9671-2011; Guo, Hua/J-2685-2014 OI Li, Zhimin/0000-0001-7036-9282; Guo, Hua/0000-0001-9901-053X FU Intramural NIH HHS; NIAID NIH HHS [AI59733]; NIGMS NIH HHS [GM28688, GM57890] NR 27 TC 43 Z9 43 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 31 PY 2006 VL 45 IS 4 BP 1162 EP 1172 DI 10.1021/bi051591e PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 008XH UT WOS:000235073500010 PM 16430212 ER PT J AU Glazko, GV Babenko, VN Koonin, EV Rogozin, IB AF Glazko, Galina V. Babenko, Vladimir N. Koonin, Eugene V. Rogozin, Igor B. TI Mutational hotspots in the TP53 gene and, possibly, other tumor suppressors evolve by positive selection SO BIOLOGY DIRECT LA English DT Article ID GAIN-OF-FUNCTION; LI-FRAUMENI-SYNDROME; EVOLUTIONARY CONSERVATION; LUNG CANCERS; P53 GENE; TRANSVERSIONS; ACTIVATION; EXPRESSION; DATABASE; MUTANTS AB Background: The mutation spectra of the TP53 gene and other tumor suppressors contain multiple hotspots, i.e., sites of non-random, frequent mutation in tumors and/or the germline. The origin of the hotspots remains unclear, the general view being that they represent highly mutable nucleotide contexts which likely reflect effects of different endogenous and exogenous factors shaping the mutation process in specific tissues. The origin of hotspots is of major importance because it has been suggested that mutable contexts could be used to infer mechanisms of mutagenesis contributing to tumorigenesis. Results: Here we apply three independent tests, accounting for non-uniform base compositions in synonymous and non-synonymous sites, to test whether the hotspots emerge via selection or due to mutational bias. All three tests consistently indicate that the hotspots in the TP53 gene evolve, primarily, via positive selection. The results were robust to the elimination of the highly mutable CpG dinucleotides. By contrast, only one, the least conservative test reveals the signature of positive selection in BRCA1, BRCA2, and p16. Elucidation of the origin of the hotspots in these genes requires more data on somatic mutations in tumors. Conclusion: The results of this analysis seem to indicate that positive selection for gain-of-function in tumor suppressor genes is an important aspect of tumorigenesis, blurring the distinction between tumor suppressors and oncogenes. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Univ Rochester, Med Ctr, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. RP Rogozin, IB (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM Galina_Glazko@URMC.Rochester.edu; babenko@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov; rogozin@ncbi.nlm.nih.gov RI Babenko, Vladimir/K-5609-2014; OI Babenko, Vladimir/0000-0002-3077-9559 NR 27 TC 5 Z9 6 U1 0 U2 2 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 JAN 31 PY 2006 VL 1 AR 4 DI 10.1186/1745-6150-1-4 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 133FD UT WOS:000243997300004 PM 16542006 ER PT J AU Koonin, EV Landweber, LF Lipman, DJ AF Koonin, Eugene V. Landweber, Laura F. Lipman, David J. TI A community experiment with fully open and published peer review SO BIOLOGY DIRECT LA English DT Editorial Material C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov; lfl@princeton.edu; lipman@ncbi.nlm.nih.gov NR 0 TC 18 Z9 18 U1 0 U2 3 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 JAN 31 PY 2006 VL 1 AR 1 DI 10.1186/1745-6150-1-1 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 133FD UT WOS:000243997300001 PM 16542032 ER PT J AU Hager, S Mahrholdt, H Goldfarb, LG Goebel, HH Sechtem, U AF Hager, S Mahrholdt, H Goldfarb, LG Goebel, HH Sechtem, U TI Giant right atrium in the setting of desmin-related restrictive cardiomyopathy SO CIRCULATION LA English DT Editorial Material C1 Robert Bosch Med Ctr, Dept Cardiol, D-70376 Stuttgart, Germany. NIH, Bethesda, MD 20892 USA. Univ Mainz, Dept Neuropathol, D-6500 Mainz, Germany. RP Sechtem, U (reprint author), Robert Bosch Med Ctr, Dept Cardiol, Auerbachstr 110, D-70376 Stuttgart, Germany. EM Udo.Sechtem@rbk.de NR 0 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 31 PY 2006 VL 113 IS 4 BP E53 EP E55 DI 10.1161/CIRCULATIONAHA.105.502575 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 008HU UT WOS:000235031600023 PM 16449718 ER PT J AU Elango, N Thomas, JW Yi, SV AF Elango, N Thomas, JW Yi, SV CA NISC Comparative Sequencing Progra TI Variable molecular clocks in hominoids SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE comparative genomics; generation time; hominoid evolution; primate genomics ID HUMAN GENOME; CHIMPANZEE GENOME; NUCLEOTIDE SUBSTITUTION; DNA-SEQUENCES; LIFE-HISTORY; EVOLUTION; HUMANS; RATES; RECOMBINATION; DIVERGENCE AB Generation time is an important determinant of a neutral molecular clock. There are several human-specific life history traits that led to a substantially longer generation time in humans than in other hominoids. Indeed, a long generation time is considered an important trait that distinguishes humans from their closest relatives. Therefore, humans may exhibit a significantly slower molecular clock as compared to other hominoids. To investigate this hypothesis, we performed a large-scale analysis of lineage-specific rates of single-nucleotide substitutions among hominoids. We found that humans indeed exhibit a significant slowdown of molecular evolution compared to chimpanzees and other hominoids. However, the amount of fixed differences between humans and chimpanzees appears extremely small, suggesting a very recent evolution of human-specific life history traits. Notably, chimpanzees also exhibit a slower rate of molecular evolution compared to gorillas and orangutans in the regions analyzed. C1 Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. NHGRI, Gen Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Yi, SV (reprint author), Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. EM soojinyi@gatech.edu NR 54 TC 64 Z9 67 U1 2 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 JAN 31 PY 2006 VL 103 IS 5 BP 1370 EP 1375 DI 10.1073/pnas.0510716103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 009EO UT WOS:000235094300040 PM 16432233 ER PT J AU Menendez, D Krysiak, O Inga, A Krysiak, B Resnick, MA Schonfelder, G AF Menendez, D Krysiak, O Inga, A Krysiak, B Resnick, MA Schonfelder, G TI A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE single-nucleotide polymorphism; genotoxic stress; VEGF receptor 1; cancer cells ID ENDOTHELIAL GROWTH-FACTOR; FACTOR RECEPTOR-1; PLASMINOGEN-ACTIVATOR; TYROSINE KINASE; CANCER-CELLS; IN-VIVO; ANGIOGENESIS; EXPRESSION; MIGRATION; BINDING AB The VEGF system is essential for angiogenesis. VEGF overexpression frequently correlates with increased microvascularity and metastasis and decreased spontaneous apoptosis. Although a precise mechanism has not been established, studies suggest that VEGF expression is negatively regulated by p53, a master regulator and tumor suppressor. There are no reports of additional components of the VEGF signal transduction pathway being part of the p53 transcriptional network. A target of VEGF, the VEGF receptor 1/flt-1, can regulate growth and migration of endothelial cells and modulate angiogenesis. VEGF appears to be up-regulated in various cancers in which flt-1 may have a role in tumor progression and metastasis. We identified a C-to-T SNP upstream of the transcriptional start site in approximate to 6% of the people examined. The SNP is located within a putative p53 response element. Only the promoter with the T SNP (FLT1-T) was responsive to p53 when examined with reporter assays or by endogenous gene expression analysis in cell lines with different SNP status. In response to doxorubicin-induced DNA damage, there was clear allele discrimination based on p53 binding at the FLT1-T but not FLT1-C promoters as well as p53-dependent induction of flt-1 mRNA, which required the presence of FLT1-T. Our results establish that p53 can differentially stimulate transcription at a polymorphic variant of the flt-1 promoter and directly places the VEGF system in the p53 stress-response network via fit-1 in a significant fraction of the human population. We suggest that the p53-VEGF-flt-1 interaction is relevant to risks in angiogenesis-associated diseases, including cancer. C1 Natl Inst Environm Hlth Sci, Chromosome Stabil Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Charite Univ Med Berlin, Inst Clin Pharmacol & Toxicol, D-14195 Berlin, Germany. Natl Inst Canc Res, Ist Sci Tumori, Lab Expt Oncol B, I-16132 Genoa, Italy. RP Resnick, MA (reprint author), Natl Inst Environm Hlth Sci, Chromosome Stabil Sect, Mol Genet Lab, NIH, MD3-01,111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov; gilbert.schoenfelder@charite.de OI Schonfelder, Gilbert/0000-0001-6134-1990 NR 40 TC 58 Z9 59 U1 1 U2 4 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 JAN 31 PY 2006 VL 103 IS 5 BP 1406 EP 1411 DI 10.1073/pnas.0508103103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 009EO UT WOS:000235094300046 PM 16432214 ER PT J AU Roper, RJ Baxter, LL Saran, NG Klinedinst, DK Beachy, PA Reeves, RH AF Roper, RJ Baxter, LL Saran, NG Klinedinst, DK Beachy, PA Reeves, RH TI Defective cerebellar response to mitogenic Hedgehog signaling in Down's syndrome mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aneuploicly; neuronal deficit; sonic hedgehog; trisomy 21 ID TS65DN MICE; SONIC HEDGEHOG; MOUSE MODEL; CELL-PROLIFERATION; PHENOTYPES; ABNORMALITIES; NUMBER; VOLUME AB Trisomy 21 is the cause of Down's syndrome (DS) which is characterized by a number of phenotypes, including a brain which is small and hypocellular compared to that of euploid individuals. The cerebellum is disproportionately reduced. Ts65Dn mice are trisomic for orthologs of about half of the genes on human chromosome 21 and provide a genetic model for DS. These mice display a number of developmental anomalies analogous to those in DS, including a small cerebellum with a significantly decreased number of both granule and Purkinje cell neurons. Here we trace the origin of the granule cell deficit to precursors in early postnatal development, which show a substantially reduced mitogenic response to Hedgehog protein signaling. Purified cultures of trisomic granule cell precursors show a reduced but dose-dependent response to the Sonic hedgehog protein signal in vitro, demonstrating that this is a cell-autonomous deficit. Systemic treatment of newborn trisomic mice with a small molecule agonist of Hedgehog pathway activity increases mitosis and restores granule cell precursor populations in vivo. These results demonstrate a basis for and a potential therapeutic approach to a fundamental aspect of CNS pathology in DS. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Beachy, PA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pbeachy@jhmi.edu; rreeves@jhmi.edu FU NICHD NIH HHS [F32 HD043614, HD 38384, HD 43614, R01 HD038384] NR 36 TC 110 Z9 111 U1 1 U2 4 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 JAN 31 PY 2006 VL 103 IS 5 BP 1452 EP 1456 DI 10.1073/pnas.0510750103 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 009EO UT WOS:000235094300054 PM 16432181 ER PT J AU Buck, CB Day, PM Thompson, CD Lubkowski, J Lu, WY Lowy, DR Schiller, JT AF Buck, CB Day, PM Thompson, CD Lubkowski, J Lu, WY Lowy, DR Schiller, JT TI Human alpha-defensins block papillomavirus infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cathelicidin; hCAP18; lactoferrin; LL-37; microbicide ID ANTIMICROBIAL PEPTIDES; IN-VITRO; HUMAN ALPHA-DEFENSIN-1; CHLAMYDIA-TRACHOMATIS; ADENOVIRAL INFECTION; DIRECT INACTIVATION; REPRODUCTIVE-TRACT; GENE-EXPRESSION; INNATE IMMUNITY; CAPSID PROTEIN AB Sexually transmitted human papillomaviruses (HPVs) are the primary cause of cervical cancer. Recent advances in techniques for production of papillomaviral vectors [known as pseudoviruses (PsVs)] have made it possible to perform high-throughput screens for compounds that might block the initial stages of papillomavirus infection. We have used PsVs to screen a variety of compounds that might function as inhibitors of HPV infection, with emphasis on human peptides previously implicated in innate antimicrobial immunity. Little is known about the possible activity of these peptides against nonenveloped viruses, such as HPVs. Our screen revealed that human alpha-defensins 1-3 [known as human neutrophil peptides (HNPs) 1-3] and human alpha-defensin 5 (HD-5) are potent antagonists of infection by both cutaneous and mucosal papillomavirus types. In contrast, human beta-defensins 1 and 2 displayed little or no anti-HPV activity. HD-5 was particularly active against sexually transmitted HPV types, with 50% inhibitory doses in the high ng/ml range. Microscopic studies of PsV inhibition by the alpha-defensins revealed that they block virion escape from endocytic vesicles but not virion binding or internalization. Consistent with this finding, PsVs remained susceptible to inhibition by alpha-defensins for many hours after initial binding to cells. HNPs 1-3 and HD-5 have been reported to be present in the female genital tract at levels that overlap those that inhibit HPVs in vitro, suggesting that they could present a natural barrier to the sexual transmission of HPV and could serve as the basis of a broad-spectrum topical microbicide. C1 NCI, Cellular Oncol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Macromol Assembly Struct & Cell Signaling Sect, Ft Detrick, MD 21702 USA. Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. EM schillej@dc37a.nci.nih.gov RI Lu, Wuyuan/B-2268-2010; OI Buck, Christopher/0000-0003-3165-8094 FU Intramural NIH HHS NR 69 TC 140 Z9 156 U1 4 U2 10 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 JAN 31 PY 2006 VL 103 IS 5 BP 1516 EP 1521 DI 10.1073/pnas.0508033103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 009EO UT WOS:000235094300065 PM 16432216 ER PT J AU Richards, RM Lowy, DR Schiller, JT Day, PM AF Richards, RM Lowy, DR Schiller, JT Day, PM TI Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE proprotein convertase ID TOXIN PROTECTIVE ANTIGEN; IN-VITRO; PROTEOLYTIC ACTIVATION; PRECURSOR PROTEINS; BACTERIAL TOXINS; CELLS; PATHWAY; LOCALIZATION; EXPRESSION; PROTEASES AB Papillomaviruses (PV) comprise a large family of nonenveloped DNA viruses that include the oncogenic PV types that are the causative agents of human cervical cancer. As is true of many animal DNA viruses, PV are taken into the cell by endocytosis and must escape from the endosomal compartment to the cytoplasm to initiate infection. Here we show that this step depends on the site-specific enzymatic cleavage of the PV minor virion protein L2 at a consensus furin recognition site. Cleavage by furin, a cell-encoded proprotein convertase, is known to be required for endosome escape by many bacterial toxins. However, to our knowledge, furin has not been previously implicated in the viral entry process. This step is potentially a target for PV inhibition. C1 NCI, Cellular Oncol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Day, PM (reprint author), NCI, Cellular Oncol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM pmd@nih.gov FU Intramural NIH HHS NR 41 TC 146 Z9 153 U1 0 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 JAN 31 PY 2006 VL 103 IS 5 BP 1522 EP 1527 DI 10.1073/pnas.0508815103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 009EO UT WOS:000235094300066 PM 16432208 ER PT J AU Jiang, ZG Lu, XCM Nelson, V Yang, XF Pan, WY Chen, RW Lebowitz, MS Almassian, B Tortella, FC Brady, RO Ghanbari, HA AF Jiang, ZG Lu, XCM Nelson, V Yang, XF Pan, WY Chen, RW Lebowitz, MS Almassian, B Tortella, FC Brady, RO Ghanbari, HA TI A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hypoglycemia/hypoxia; neuroprotection; PAN-811/Triapine; oxidative; calcium ID RIBONUCLEOTIDE REDUCTASE INHIBITOR; TRANSIENT FOCAL ISCHEMIA; CEREBRAL-ISCHEMIA; IN-VITRO; NEUROPROTECTIVE EFFICACY; MOLECULAR DIVERSITY; NEURONAL DEATH; CA2+ CHANNELS; RAT MODEL; PHASE-I AB Cellular and molecular pathways underlying ischemic neurotoxicity are multifaceted and complex. Although many potentially neuroprotective agents have been investigated, the simplicity of their protective mechanisms has often resulted in insufficient clinical utility. We describe a previously uncharacterized class of potent neuroprotective compounds, represented by PAN-811, that effectively block both ischemic and hypoxic neurotoxicity. PAN-811 disrupts neurotoxic pathways by at least two modes of action. It causes a reduction of intracellular-free calcium as well as free radical scavenging resulting in a significant decrease in necrotic and apoptotic cell death. in a rat model of ischemic stroke, administration of PAN-811 i.c.v. 1 h after middle cerebral artery occlusion resulted in a 59% reduction in the volume of infarction. Human trials of PAN-811 for an unrelated indication have established a favorable safety and pharmacodynamic profile within the dose range required for neuroprotection warranting its clinical trial as a neuroprotective drug. C1 Panacea Pharmaceut Inc, Gaithersburg, MD 20877 USA. Walter Reed Army Inst Res, Div Neurosci, Dept Appl Neurobiol, Silver Spring, MD 20910 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Jiang, ZG (reprint author), Panacea Pharmaceut Inc, Gaithersburg, MD 20877 USA. EM zgjiang@panaceapharma.com FU NINDS NIH HHS [R43 NS048694-01, R43 NS048694, 1R43 NS 048694-01] NR 29 TC 22 Z9 23 U1 0 U2 2 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 JAN 31 PY 2006 VL 103 IS 5 BP 1581 EP 1586 DI 10.1073/pnas.0510573103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 009EO UT WOS:000235094300076 PM 16423893 ER PT J AU Yin, HH Knowlton, BJ Balleine, BW AF Yin, HH Knowlton, BJ Balleine, BW TI Inactivation of dorsolateral striatum enhances sensitivity to changes in the action-outcome contingency in instrumental conditioning SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE basal ganglia; compulsive behavior; striatum; instrumental conditioning; operant learning; procedural learning; habit; omission ID LATERAL CAUDATE-PUTAMEN; BASAL GANGLIA CIRCUITS; DORSOMEDIAL STRIATUM; DORSAL STRIATUM; HABIT FORMATION; NUCLEUS; LESIONS; PLACE; RAT; REINFORCEMENT AB Actions become compulsive when they are no longer controlled by their consequences. Compulsivity can be assessed using the omission procedure in which animals are required to withhold a previously reinforced action to earn reward. The current study tested the hypothesis that inactivation of the dorsolateral striatum (DLS), a structure implicated in habitual behavior, can enhance sensitivity to changes in the action-outcome contingency during omission training, thus leading to a reduction in compulsive responding. Over 10 days rats were trained to press a freely available lever for sucrose reward delivered on interval schedules of reinforcement. After teaming to press the lever at a stable and high rate, rats in the omission group received a session in which the rewards were now delayed by pressing the lever; i.e. withholding lever pressing resulted in increased access to reward. A control group was yoked to the omission group and received the same number and pattern of reward delivery but without the omission contingency. Half the rats in each group received infusions of vehicle into the DLS prior to this training whereas the remainder received an infusion of the GABA-A receptor agonist muscimol. On the next day, the effect of these treatments was assessed on a probe test in which the tendency of the various groups to press the lever was assessed in extinction and without drug infusion. Rats that received vehicle infusions prior to the omission session showed complete insensitivity to the newly imposed omission contingency. In contrast, rats given the infusion of muscimol selectively reduced lever pressing compared to yoked controls. Thus, extended training with interval schedules resulted in compulsive lever pressing that prevented the learning of the omission contingency, whereas inactivation of the DLS appeared to enhance the rats' sensitivity to this change in the action-outcome contingency. (c) 2005 Elsevier B.V. All rights reserved. C1 NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA USA. RP Yin, HH (reprint author), NIAAA, Lab Integrat Neurosci, NIH, 5625 Fishers Lane,Room TS-13, Rockville, MD 20852 USA. EM yinh@mail.nih.gov FU NIMH NIH HHS [MH 56446] NR 46 TC 199 Z9 201 U1 3 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 30 PY 2006 VL 166 IS 2 BP 189 EP 196 DI 10.1016/j.bbr.2005.07.012 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 002WU UT WOS:000234643600001 PM 16153716 ER PT J AU Gourlaouen, C Piquemal, JP Saue, T Parisel, O AF Gourlaouen, C Piquemal, JP Saue, T Parisel, O TI Revisiting the geometry of nd(10) (n+1)s(0) [M(H2O)](P+) complexes using four-component relativistic DFT calculations and scalar relativistic correlated CSOV energy decompositions (MP+=Cu+, Zn2+, Ag+, Cd2+, Au+, Hg2+) SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Review DE relativistic effects; four-component relativistic calculations; CSOV decomposition analysis; scalar relativistic pseudopotentials ID DENSITY-FUNCTIONAL THEORY; COLLISION-INDUCED DISSOCIATION; CATIONIC GOLD(I) COMPLEXES; SPIN-ORBIT OPERATORS; SMALL ORGANIC-MOLECULES; BINDING-ENERGIES; AB-INITIO; GAS-PHASE; ELECTRONIC-STRUCTURE; EFFECTIVE POTENTIALS AB Hartree-Fock and DFT (B3LYP) nonrelativistic (scalar relativistic pseudopotentials for the metallic cation) and relativistic (molecular four-component approach coupled to an all-electron basis set) calculations are performed on a series of six nd(10) (n + 1)s(0) [M(H2O)](p+) complexes to investigate their geometry, either planar C-2v or nonplanar C-s. These complexes are, formally, entities originating from the complexation of a water molecule to a metallic cation: in the present study, no internal reorganization has been found, which ensures that the complexes can be regarded as a water molecule interacting with a metallic cation. For [Au(H2O)](+) and [Hg(H2O)](2+), it is observed that both electronic correlation and relativistic effects are required to recover the C, structures predicted by the four-component relativistic all-electron DFT calculations. However, including the zero-point energy corrections makes these shallow C, minima vanish and the systems become floppy. In all other systems, namely [Cu(H2O)](+), [Zn(H2O)](2+), [Ag(H2O)](+), and [Cd(H2O)](2+), all calculations predict a C-2v geometry arising from especially flat potential energy surfaces related to the out-of-plane wagging vibration mode. In all cases, our computations point to the quasi-perfect transferability of the atomic pseudopotentials considered toward the molecular species investigated. A rationalization of the shape of the wagging potential energy surfaces (i.e., single well vs. double well) is proposed based on the Constrained Space Orbital Variation decompositions of the complexation energies. Any way of stabilizing the lowest unoccupied orbital of the metallic cation is expected to favor charge-transfer (from the highest occupied orbital(s) of the water ligand), covalence, and, consequently, C, structures. The CSOV complexation energy decompositions unambiguously reveal that such stabilizations are achieved by means of relativistic effects for [Au(H2O)](+), and, to a lesser extent, for [Hg(H2O)](2+). Such analyses allow to numerically quantify the rule of thumb known for Au+ which, once again, appears as a better archetype of a relativistic cation than Hg2+. This observation is reinforced due to the especially high contribution of the nonadditive correlation/relativity terms to the total complexation energy of [Au(H2O)](+). (c) 2005 Wiley Periodicals, Inc. C1 Univ Paris 06, Chim Theor Lab, UMR 7616, CNRS, F-75252 Paris, France. Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ Strasbourg 1, Lab Chim Quant & Modelisat Mol, UMR 7551, CNRS, F-67000 Strasbourg, France. RP Parisel, O (reprint author), Univ Paris 06, Chim Theor Lab, UMR 7616, CNRS, Case Courier 137,4,Pl Jussieu, F-75252 Paris, France. EM parisel@lct.jussieu.fr RI Piquemal, Jean-Philip/B-9901-2009 OI Piquemal, Jean-Philip/0000-0001-6615-9426 FU Intramural NIH HHS NR 111 TC 31 Z9 31 U1 0 U2 13 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JAN 30 PY 2006 VL 27 IS 2 BP 142 EP 156 DI 10.1002/jcc.20329 PG 15 WC Chemistry, Multidisciplinary SC Chemistry GA 999IG UT WOS:000234382400003 PM 16312018 ER PT J AU Francis, HW Rivas, A Lehar, M Saito, Y Mouton, PR Ryugo, DK AF Francis, HW Rivas, A Lehar, M Saito, Y Mouton, PR Ryugo, DK TI Efficient quantification of afferent cochlear ultrastructure using design-based stereology SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article; Proceedings Paper CT 28th Midwinter Meeting of the Association-of-Research-in-Otolaryngology CY FEB, 2005 CL New Orleans, LA SP Assoc Res Otolaryngol DE cochlea; inner hair cell; afferent innervation; synapse; nerve terminal; ultrastructure; stereology; disector principle ID INNER HAIR-CELLS; AUDITORY-NERVE; QUANTITATIVE-ANALYSIS; ARBITRARY PARTICLES; SYNAPTIC PLASTICITY; CAT COCHLEA; MOUSE; PATHOLOGY; FIBERS; TERMINALS AB The afferent synapse between the auditory nerve fiber and the inner hair cell (IHC) represents a critical junction for hearing. Elucidation of the structure at this site will help establish the substrate for normal sound encoding as well as pathologic processes associated with hearing dysfunction. Previous applications of unbiased (design-based) stereological principles have expanded our knowledge of neuro-morphological changes evident with the light microscope. Applying these principles at the level of the synapse is a promising morphometric approach for the efficient sampling of large reference spaces with electron microscopy. This study tests the accuracy of using ultra-thin sections at a fixed interval, known as disector pairs, to quantify afferent innervation density. We analyzed the total numbers of afferent terminals, synaptic thickenings, and synaptic bodies associated with each IHC in the C57BL/6J mouse cochlea, and confirmed the accuracy of the stereological approach in comparison to three-dimensional reconstructions of serial alternate sections. The higher sampling efficiency of the disector pair method rapidly increases precision while also reducing the largest source of variability, inter-animal differences. We conclude that ultrastructural quantification of afferent innervation can be accomplished in the cochlea using efficient design-based stereology. (c) 2005 Published by Elsevier B.V. C1 Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. NIA, Dept Genontol Res Ctr, NIH, Baltimore, MD 21224 USA. Dept Stereol Resource Ctr, Baltimore, MD USA. RP Francis, HW (reprint author), Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, 601 N Caroline St,JHOC 6th Floor, Baltimore, MD 21205 USA. EM hfrancis@jhmi.edu FU NIDCD NIH HHS [DC05211, DC000143, DC05909, DC00232] NR 35 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JAN 30 PY 2006 VL 150 IS 2 BP 150 EP 158 DI 10.1016/j.jneumeth.2005.06.020 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 013OG UT WOS:000235418000002 PM 16115689 ER PT J AU Pogribny, IP Ross, SA Wise, C Pogribna, M Jones, EA Tryndyak, VP James, SJ Dragan, YP Poirier, LA AF Pogribny, IP Ross, SA Wise, C Pogribna, M Jones, EA Tryndyak, VP James, SJ Dragan, YP Poirier, LA TI Irreversible global DNA hypomethylation as a key step in hepatocarcinogenesis induced by dietary methyl deficiency SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE methyl-deficient diet; methyl-adequate diet; DNA hypomethylation; rat hepatocarcinogenesis ID RAT-LIVER; HEPATOCELLULAR CARCINOMAS; S-ADENOSYLHOMOCYSTEINE; CELL-PROLIFERATION; TUMOR PROGRESSION; C-MYC; CARCINOGENESIS; CHOLINE; CANCER; PATTERNS AB Dietary methyl group deprivation is now well recognized as a model of hepatocarcinogenesis in rodents. In the present study, we examined the effects of feeding a methyl-deficient diet followed by a methyl-adequate diet on the extent of methylation of liver DNA and on the formation and evolution of altered hepatic foci. Male F344 rats were fed a methyl-deficient diet for 9 18, 24, and 36 weeks, followed by re-feeding a methyl-adequate diet for a total of 54 weeks. Similar to previous findings, the methy I-deficient diet resulted in decreased levels of S-adenosylmethionine (SAM), SAM/SAH ratios, and global DNA hypomethylation. Feeding the rnethyl-adequate diet restored the liver SAM levels and SAM/SAH ratios to control levels in all experimental groups. In contrast, re-feeding the complete diet restored DNA methylation to normal level only in the group that had been fed the methyl-deficient diet for 9 weeks in animals exposed to methyl deprivation longer, the methyl-adequate diet failed to reverse the hypomethylation of DNA. Liver tissue of rats exposed to methyl deficiency for 9, 18, 24, or 36 weeks was characterized by the persistent presence of placental isoform of glutathione-S-transferase (GST pi)-positive lesions despite re-feeding the methyl-adequate diet. The persistence of altered hepatic foci in liver after withdrawal of methyl-deficient diet serves as an indication of the carcinogenic potential of a methyl-deficient diet. Substitution of the methyl-deficient diet with complete diet failed to prevent the expansion of initiated foci and restore DNA methylation in animals exposed to deficiency for 18, 24, or 36 weeks. The association between DNA hypomethylation and expansion of foci suggests that stable DNA hypomethylation is a promoting factor for clonal expansion of initiated cells. These results provide an experimental evidence and a mechanistic basis by which epigenetic alterations may contribute to the initiation and promotion steps of carcinogenesis. Published by Elsevier B.V. C1 Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NCI, Bethesda, MD USA. Univ Arkansas Med Sci, Little Rock, AR USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Dr, Jefferson, AR 72079 USA. EM ipogribny@nctr.fda.gov NR 35 TC 99 Z9 103 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JAN 29 PY 2006 VL 593 IS 1-2 BP 80 EP 87 DI 10.1016/j.mrfmmm.2005.06.028 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 011MI UT WOS:000235272000008 PM 16144704 ER PT J AU Podgornik, R French, RH Parsegian, VA AF Podgornik, R French, RH Parsegian, VA TI Nonadditivity in van der Waals interactions within multilayers SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID SYSTEMS; FORCES; FILMS AB Working at the macroscopic continuum level, we investigate effective van der Waals interactions between two layers within a multilayer assembly. By comparing the pair interactions between two layers with effective pair interactions within an assembly we assess the significant consequences of nonadditivity of van der Waals interactions. This allows us to evaluate the best numerical estimate to date for the Hamaker coefficient of van der Waals interactions in lipid-water multilamellar systems. (c) 2006 American Institute of Physics. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Fac Math & Phys, Ljubljana 1000, Slovenia. Jozef Stefan Inst, Dept Theoret Phys, Ljubljana 1000, Slovenia. DuPont Co Inc, Cent Res, Wilmington, DE 19880 USA. Univ Penn, Dept Mat Sci, Philadelphia, PA 19104 USA. RP Podgornik, R (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bldg 9 Room 1E116, Bethesda, MD 20892 USA. EM rudi@helix.nih.gov RI French, Roger/E-1986-2011; Podgornik, Rudolf/C-6209-2008 OI French, Roger/0000-0002-6162-0532; Podgornik, Rudolf/0000-0002-3855-4637 NR 17 TC 42 Z9 42 U1 4 U2 15 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 JAN 28 PY 2006 VL 124 IS 4 AR 044709 DI 10.1063/1.2150825 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 007OP UT WOS:000234979300061 PM 16460202 ER PT J AU Tsurutani, J Ballas, M Steinberg, SM Egilsson, V Dennis, PA AF Tsurutani, J Ballas, M Steinberg, SM Egilsson, V Dennis, PA TI Gefitinib for refractory advanced non-small-cell lung cancer SO LANCET LA English DT Letter ID ERLOTINIB C1 NCI, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20889 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20889 USA. Natl Univ Hosp Reykjavik, Dept Pathol, Reykjavik, Iceland. RP Dennis, PA (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20889 USA. EM dennisp@mail.nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JAN 28 PY 2006 VL 367 IS 9507 BP 300 EP 300 DI 10.1016/S0140-6736(06)68064-1 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 009AX UT WOS:000235084600021 PM 16443034 ER PT J AU Liu, XH Yu, EZ Li, YY Rollwagen, FM Kagan, E AF Liu, XH Yu, EZ Li, YY Rollwagen, FM Kagan, E TI RNA interference targeting Akt promotes apoptosis in hypoxia-exposed human neuroblastoma cells SO BRAIN RESEARCH LA English DT Article DE anoxia; apoptosis; neuroblastoma; RNAi; Akt ID ENDOTHELIAL GROWTH-FACTOR; PANCREATIC-CANCER CELLS; GENE-EXPRESSION; TUMOR ANGIOGENESIS; SIGNALING PATHWAY; SURVIVAL PATHWAY; KAPPA-B; ACTIVATION; PTEN; TRANSCRIPTION AB Overactivation of the PI3 kinase/Akt pathway plays an essential role in the development and progression of various tumors. Akt is a key component of this pathway and hyperactivated in different tumors including neuroblastoma and glioma. In the present study, we tested the therapeutic efficacy of siRNA targeting Akt in inducing apoptotic cell death in NBFL cells (a human neuroblastoma cell line) subjected to anoxia/reoxygenation (A/R), a process that has been shown to modulate growth and progression of malignant tumors. We observed that siRNA targeting Akt effectively induced apoptotic cell death in NBFL cells (as determined by TUNEL assay and activated caspase-3 immunoreactivity) under normoxic conditions, an effect that was greatly enhanced under conditions of A/R. These findings underscore the importance of Akt signaling in promoting survival of neuroblastoma cells and may have potential therapeutic applications. Published by Elsevier B.V. C1 Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Liu, XH (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. EM liuxiuhuai@mail.nih.gov FU NIAID NIH HHS [AI-55592] NR 42 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 27 PY 2006 VL 1070 IS 1 BP 24 EP 30 DI 10.1016/j.brainres.2005.11.041 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 023BB UT WOS:000236099000003 PM 16405925 ER PT J AU Mostoslavsky, R Chua, KF Lombard, DB Pang, WW Fischer, MR Gellon, L Liu, PF Mostoslavsky, G Franco, S Murphy, MM Mills, KD Patel, P Hsu, JT Hong, AL Ford, E Cheng, HL Kennedy, C Nunez, N Bronson, R Frendewey, D Auerbach, W Valenzuela, D Karow, M Hottiger, MO Hursting, S Barrett, JC Guarente, L Mulligan, R Demple, B Yancopoulos, GD Alt, FW AF Mostoslavsky, R Chua, KF Lombard, DB Pang, WW Fischer, MR Gellon, L Liu, PF Mostoslavsky, G Franco, S Murphy, MM Mills, KD Patel, P Hsu, JT Hong, AL Ford, E Cheng, HL Kennedy, C Nunez, N Bronson, R Frendewey, D Auerbach, W Valenzuela, D Karow, M Hottiger, MO Hursting, S Barrett, JC Guarente, L Mulligan, R Demple, B Yancopoulos, GD Alt, FW TI Genomic instability and aging-like phenotype in the absence of mammalian SIRT6 SO CELL LA English DT Article ID BASE-EXCISION-REPAIR; DNA-REPAIR; CALORIE RESTRICTION; LIFE-SPAN; SACCHAROMYCES-CEREVISIAE; ADP-RIBOSYLTRANSFERASE; PROTEIN DEACETYLASES; IONIZING-RADIATION; OXIDATIVE STRESS; B-CELLS AB The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,CB Inst Biomed Res, Boston, MA 02115 USA. Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Zurich, Inst Vet Biochem & Mol Biol, CH-8057 Zurich, Switzerland. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,CB Inst Biomed Res, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI Hottiger, Michael/J-7747-2013; OI Hottiger, Michael/0000-0002-7323-2270; Frendewey, David/0000-0003-2305-3490 FU PHS HHS [K08] NR 76 TC 652 Z9 687 U1 3 U2 52 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 27 PY 2006 VL 124 IS 2 BP 315 EP 329 DI 10.1016/j.cell.2005.11.044 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 008VJ UT WOS:000235068500020 PM 16439206 ER PT J AU Garcia-Diaz, M Bebenek, K Krahn, JM Pedersen, LC Kunkel, TA AF Garcia-Diaz, M Bebenek, K Krahn, JM Pedersen, LC Kunkel, TA TI Structural analysis of strand misalignment during DNA synthesis by a human DNA polymerase SO CELL LA English DT Article ID BASE EXCISION-REPAIR; MICROSATELLITE INSTABILITY; FRAMESHIFT MUTATIONS; CRYSTAL-STRUCTURE; REPLICATION FIDELITY; MISMATCH REPAIR; ERROR-PRONE; POL LAMBDA; FAMILY; MECHANISM AB Insertions and deletions in coding sequences can alter the reading frame of genes and have profound biological consequences. In 1966, Streisinger proposed that these mutations result from strand slippage, which in repetitive sequences generates misaligned intermediates stabilized by correct base pairing that support polymerization. We report here crystal structures of human DNA polymerase lambda, which frequently generates deletion mutations, bound to such intermediates. Each contains an extra-helical template nucleotide upstream of the active site. Surprisingly, the extra nucleotide, even when combined with an adjacent mismatch, does not perturb polymerase active site geometry, which is indistinguishable from that for correctly aligned strands. These structures reveal how pol lambda can polymerize on substrates with minimal homology during repair of double-strand breaks and represent strand-slippage intermediates consistent with Streisinger's classical hypothesis. They are thus relevant to the origin of single-base deletions, a class of mutations that can confer strong biological phenotypes. C1 NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Struct Biol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Intramural NIH HHS NR 60 TC 76 Z9 76 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 27 PY 2006 VL 124 IS 2 BP 331 EP 342 DI 10.1016/j.cell.2005.10.039 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 008VJ UT WOS:000235068500021 PM 16439207 ER PT J AU Gan, JH Tropea, JE Austin, BP Court, DL Waugh, DS Ji, XH AF Gan, JH Tropea, JE Austin, BP Court, DL Waugh, DS Ji, XH TI Structural insight into the mechanism of double-stranded RNA processing by ribonuclease III SO CELL LA English DT Article ID ESCHERICHIA-COLI; BINDING DOMAIN; DSRNA-BINDING; SUBSTRATE RECOGNITION; BACTERIOPHAGE-LAMBDA; GENE-EXPRESSION; NUCLEASE DOMAIN; PROTEIN; CLEAVAGE; INTERFERENCE AB Members of the ribonuclease III (RNase III) family are double-stranded RNA (dsRNA) specific endoribonucleases characterized by a signature motif in their active centers and a two-base 3' overhang in their products. While Dicer, which produces small interfering RNAs, is currently the focus of intense interest, the structurally simpler bacterial RNase III serves as a paradigm for the entire family. Here, we present the crystal structure of an RNase III-product complex, the first catalytic complex observed for the family. A 7 residue linker within the protein facilitates induced fit in protein-RNA recognition. A pattern of protein-RNA interactions, defined by four RNA binding motifs in RNase III and three protein-interacting boxes in dsRNA, is responsible for substrate specificity, while conserved amino acid residues and divalent cations are responsible for scissile-bond cleavage. The structure reveals a wealth of information about the mechanism of RNA hydrolysis that can be extrapolated to other RNase III family members. C1 NCI, Canc Res Ctr, NIH, Ft Detrick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Canc Res Ctr, NIH, Ft Detrick, MD 21702 USA. EM jix@ncifcrf.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU Intramural NIH HHS NR 54 TC 134 Z9 138 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 27 PY 2006 VL 124 IS 2 BP 355 EP 366 DI 10.1016/j.cell.2005.11.034 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 008VJ UT WOS:000235068500023 PM 16439209 ER PT J AU Calvo, E Mans, BJ Andersen, JF Ribeiro, JMC AF Calvo, E Mans, BJ Andersen, JF Ribeiro, JMC TI Function and evolution of a mosquito salivary protein family SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADULT FEMALE MOSQUITO; VECTOR ANOPHELES-GAMBIAE; BLOOD-FEEDING INSECT; AEDES-AEGYPTI; RHODNIUS-PROLIXUS; BINDING PROTEIN; GLAND; NITROPHORIN-2; TRANSCRIPTOME; SEROTONIN AB Saliva of blood-sucking arthropods contains a complex and diverse mixture of antihemostatic, antiinflammatory, and immunomodulatory compounds. The D7 salivary family of proteins is abundantly expressed in blood-feeding Diptera and is distantly related to the odorant-binding protein superfamily. In mosquitoes, two subfamilies exist, the long and short D7 proteins. Ticks and kissing bugs evolved salivary lipocalins that act as efficient scavengers of biogenic amines, and a similar function was postulated for the D7 proteins. Accordingly, we expressed the five members of the small D7 family of the African malaria vector Anopheles gambiae and a D7 long form from Aedes aegypti and showed by isothermal microcalorimetry, a modified and very sensitive non-equilibrium chromatography/ spectrum distortion method, and by smooth muscle bioassay that four of these five short D7 proteins and the D7 long form bind serotonin with high affinity, as well as histamine and norepinephrine. The nonbinding D7 protein is poorly expressed in the salivary glands and appears to be on the path to becoming a pseudogene. Scavenging of host amines would antagonize their vasoconstrictor, platelet-aggregating, and pain-inducing properties. It appears that counteracting biogenic amines is of strong adaptive value in the convergent evolution of arthropods to hematophagy. This adaptation has been solved independently in ticks, bugs, and mosquitoes by co-option of either member of the lipocalin or, as shown here, by the odorant-binding protein families. C1 NIAID, LMVR, Sect Vector Biol, NIH, Rockville, MD 20852 USA. RP Ribeiro, JMC (reprint author), NIAID, LMVR, Sect Vector Biol, NIH, 12735 Twinbrook Pkwy,Rm 2E32D, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov OI Mans, Ben/0000-0002-0177-0029; Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 NR 45 TC 107 Z9 116 U1 5 U2 30 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 27 PY 2006 VL 281 IS 4 BP 1935 EP 1942 DI 10.1074/jbc.M510359200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 004NV UT WOS:000234760400012 PM 16301315 ER PT J AU Henry, LK Field, JR Adkins, EM Parnas, ML Vaughan, RA Zou, MF Newman, AH Blakely, RD AF Henry, LK Field, JR Adkins, EM Parnas, ML Vaughan, RA Zou, MF Newman, AH Blakely, RD TI Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SPECIES-SCANNING MUTAGENESIS; DOPAMINE TRANSPORTER; DOMAIN-I; NEUROTRANSMITTER TRANSPORTERS; BINDING-SITE; CITALOPRAM; SUBSTRATE; ACID; ESCITALOPRAM; EXPRESSION AB In previous studies examining the structural determinants of antidepressant and substrate recognition by serotonin transporters (SERTs), we identified Tyr-95 in transmembrane segment 1 (TM1) of human SERT as a major determinant of binding for several antagonists, including racemic citalopram ((RS)-CIT). Here we described a separate site in hSERT TM3 (Ile-172) that impacts (RS)-CIT recognition when switched to the corresponding Drosophila SERT residue (I172M). The hSERT I172M mutant displays a marked loss of inhibitor potency for multiple inhibitors such as (RS)-CIT, clomipramine, RTI-55, fluoxetine, cocaine, nisoxetine, mazindol, and nomifensine, whereas recognition of substrates, including serotonin and 3,4-methylenedioxymethamphetamine, is unaffected. Selectivity for antagonist interactions is evident with this substitution because the potencies of the antidepressants tianeptine and paroxetine are unchanged. Reduced cocaine analog recognition was verified in photoaffinity labeling studies using [I-125] MFZ 2-24. In contrast to the I172M substitution, other substitutions at this position significantly affected substrate recognition and/or transport activity. Additionally, the mouse mutation (mSERT I172M) exhibits similar selective changes in inhibitor potency. Unlike hSERT or mSERT, analogous substitutions in mouse dopamine transporter (V152M) or human norepinephrine transporter (V148M) result in transporters that bind substrate but are deficient in the subsequent translocation of the substrate. A double mutant hSERT Y95F/ I172M had a synergistic impact on ( RS)-CIT recognition (similar to 10,000-fold decrease in ( RS)-CIT potency) in the context of normal serotonin recognition. The less active enantiomer (R)-CIT responded to the I172M substitution like (S)-CIT but was relatively insensitive to the Y95F substitution and did not display a synergistic loss at Y95F/ I172M. An hSERT mutant with single cysteine substitutions in TM1 and TM3 resulted in formation of a high affinity cadmium metal coordination site, suggesting proximity of these domains in the tertiary structure of SERT. These studies provided evidence for distinct binding sites coordinating SERT antagonists and revealed a close interaction between TM1 and TM3 differentially targeted by stereoisomers of CIT. C1 Vanderbilt Univ, Ctr Med, Ctr Mol Neurosci, Nashville, TN 37232 USA. Vanderbilt Univ, Ctr Med, Dept Pharmacol, Nashville, TN 37232 USA. Univ Utah, Ctr Med, Dept Pathol, Salt Lake City, UT 84112 USA. Univ N Dakota, Dept Biochem & Mol Biol, Grand Forks, ND 58203 USA. NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Blakely, RD (reprint author), Vanderbilt Univ, Ctr Med, Ctr Mol Neurosci, Ste 7140 MRBIII, Nashville, TN 37232 USA. EM randy.blakely@vanderbilt.edu FU NIDA NIH HHS [DA 07390, DA 15175] NR 36 TC 112 Z9 113 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 27 PY 2006 VL 281 IS 4 BP 2012 EP 2023 DI 10.1074/jbc.M505055200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 004NV UT WOS:000234760400022 PM 16272152 ER PT J AU Pandhare, J Cooper, SK Phang, JM AF Pandhare, J Cooper, SK Phang, JM TI Proline oxidase, a proapoptotic gene, is induced by troglitazone - Evidence for both peroxisome proliferator-activated receptor gamma-dependent and -independent mechanisms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLON-CANCER CELLS; LIGAND-INDUCED APOPTOSIS; PPAR-GAMMA; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; INHIBIT GROWTH; IN-VITRO; PATHWAY; OXYGEN; DIFFERENTIATION AB Proline oxidase ( POX) is a redox enzyme localized in the mitochondrial inner membrane. We and others have shown that POX is a p53-induced gene that can mediate apoptosis through generation of reactive oxygen species (ROS). The peroxisome proliferator-activated receptor gamma(PPAR gamma) ligand troglitazone was found to activate the POX promoter in colon cancer cells. PPAR gamma ligands have been reported to induce apoptosis in a variety of cancer cells. In HCT116 cells expressing a wild-type PPAR gamma, troglitazone enhanced the binding of PPAR gamma to PPAR-responsive element in the POX promoter and increased endogenous POX expression. Blocking of PPAR gamma activation either by antagonist GW9662 or deletion of PPAR-responsive element in the POX promoter only partially decreased the POX promoter activation in response to troglitazone, indicating also the involvement of PPAR gamma-independent mechanisms. Further, troglitazone also induced p53 protein expression in HCT116 cells, which may be the possible mechanism for PPAR gamma-independent POX activation, since POX has been shown to be a downstream mediator in p53-induced apoptosis. In HCT15 cells, with both mutant p53 and mutant PPAR gamma, there was no effect of troglitazone on POX activation, whereas in HT29 cells, with a mutant p53 and wild type PPAR gamma, increased activation was observed by ligand stimulation, indicating that both PPAR gamma-dependent and gamma-independent mechanisms are involved in the troglitazone-induced POX expression. A time- and dose-dependent increase in POX catalytic activity was obtained in HCT116 cells treated with troglitazone with a concomitant increase in the production of intracellular ROS. Our results suggest that the induction of apoptosis by troglitazone may, at least in part, be mediated by targeting POX gene expression for generation of ROS by POX both by PPAR gamma-dependent and gamma-independent mechanisms. C1 NCI, NIH, Metab & Canc Susceptibil Sect, Lab Comparat Carcinogenesis,Ctr Canc Res, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. RP Phang, JM (reprint author), NCI, NIH, Metab & Canc Susceptibil Sect, Lab Comparat Carcinogenesis,Ctr Canc Res, Bldg 538,Rm 144, Ft Detrick, MD 21702 USA. EM phang@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01 CO 12400] NR 48 TC 64 Z9 67 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 27 PY 2006 VL 281 IS 4 BP 2044 EP 2052 DI 10.1074/jbc.M507867200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 004NV UT WOS:000234760400025 PM 16303758 ER PT J AU Naylor, K Ingerman, E Okreglak, V Marino, M Hinshaw, JE Jodi, N AF Naylor, K Ingerman, E Okreglak, V Marino, M Hinshaw, JE Jodi, N TI Mdv1 interacts with assembled Dnm1 to promote mitochondrial division SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DYNAMIN-RELATED GTPASE; RED FLUORESCENT PROTEIN; WD REPEAT PROTEIN; SACCHAROMYCES-CEREVISIAE; FISSION; YEAST; FUSION; SEGREGATION; MORPHOLOGY; LIBRARIES AB The dynamin-related GTPase, Dnm1, self-assembles into punctate structures that are targeted to the outer mitochondrial membrane where they mediate mitochondrial division. Post-targeting, Dnm1-dependent division is controlled by the actions of the WD repeat protein, Mdv1, and the mitochondrial tetratricopeptide repeat-like outer membrane protein, Fis1. Our previous studies suggest a model where at this step Mdv1 functions as an adaptor linking Fis1 with Dnm1. To gain insight into the exact role of the Fis1 center dot Mdv1 center dot Dnm1 complex in mitochondrial division, we performed a structure-function analysis of the Mdv1 adaptor. Our analysis suggests that dynamic interactions between Mdv1 and Dnm1 play a key role in division by regulating Dnm1 self-assembly. C1 Univ Calif Davis, Sect Mol & Cellular Biol, Davis, CA 95616 USA. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Jodi, N (reprint author), Univ Calif Davis, Sect Mol & Cellular Biol, Davis, CA 95616 USA. EM jmnunnari@ucdavis.edu FU NEI NIH HHS [1R01 EY 015294]; NIGMS NIH HHS [5R01 GM 062942] NR 33 TC 84 Z9 88 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 27 PY 2006 VL 281 IS 4 BP 2177 EP 2183 DI 10.1074/jbc.M507943200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 004NV UT WOS:000234760400041 PM 16272155 ER PT J AU Heimlich, G Cidlowski, JA AF Heimlich, G Cidlowski, JA TI Selective role of intracellular chloride in the regulation of the intrinsic but not extrinsic pathway of apoptosis in Jurkat T-cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAS-INDUCED APOPTOSIS; N-TERMINAL KINASE; SIGNAL-TRANSDUCTION; VOLUME DECREASE; JNK ACTIVATION; JUN KINASE; CL-CHANNEL; DEATH; K+; POTASSIUM AB Apoptosis is a genetic program for the removal of unwanted cells from an organism, which is distinct from necrosis by its characteristic volume loss or apoptotic volume decrease. This cell shrinkage is the result of ion redistribution that is crucial for both the activation and execution of apoptosis. Here we report that UV-C but not Fas ligand treatment results in a significant decrease in intracellular chloride that can be abolished by modulation of chloride flux using either the chloride channel inhibitor SITS or medium with a reduced chloride concentration. Accordingly, downstream events are diminished during UV-C-induced apoptosis following chloride flux modulation, whereas Fas ligand-induced apoptotic characteristics are not affected. Moreover, the activation of the mitogen-activated protein kinase signal transduction pathway early in the apoptotic signaling cascade was affected by chloride flux in Jurkat T-cells. Thus, an alteration of intracellular chloride plays an important role in the activation of signaling molecules upstream of the mitochondria, specifically impairing the intrinsic but not extrinsic apoptotic pathway. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov NR 45 TC 35 Z9 38 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 27 PY 2006 VL 281 IS 4 BP 2232 EP 2241 DI 10.1074/jbc.M507367200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 004NV UT WOS:000234760400047 PM 16299378 ER PT J AU Kullman, L Gurnev, PA Winterhalter, M Bezrukov, SM AF Kullman, L Gurnev, PA Winterhalter, M Bezrukov, SM TI Functional subconformations in protein folding: Evidence from single-channel experiments SO PHYSICAL REVIEW LETTERS LA English DT Article ID INDIVIDUAL MOLECULES; SUGAR TRANSLOCATION; ESCHERICHIA-COLI; OUTER-MEMBRANE; TRANSPORT; MALTOPORIN; ENERGY; HETEROGENEITY; FLUCTUATIONS; PERMEABILITY AB We study fluctuations in ion conductance and enzymatic rates of the sugar-specific channel-forming membrane protein, Maltoporin, at the single-molecule level. Specifically, we analyze time-persistent deviations in the transport parameters of individual channels from the multichannel averages and discuss our findings in the context of static disorder in protein folding. We show that the disorder responsible for variations in ion conductance does not affect sugar binding, suggesting that Maltoporin can exist in a wide set of fully functional, yet distinctly different, subconformations. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Uppsala, Dept Med Cell Biol, S-75123 Uppsala, Sweden. Int Univ Bremen, D-28725 Bremen, Germany. RP Kullman, L (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 28 TC 19 Z9 19 U1 0 U2 3 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JAN 27 PY 2006 VL 96 IS 3 AR 038101 DI 10.1103/PhysRevLett.96.038101 PG 4 WC Physics, Multidisciplinary SC Physics GA 007LA UT WOS:000234969300109 PM 16486775 ER PT J AU Watkins, JD Lancelot, S Campbell, GR Esquieu, D de Mareuil, J Opi, S Annappa, S Salles, JP Loret, EP AF Watkins, Jennifer D Lancelot, Sophie Campbell, Grant R. Esquieu, Didier de Mareuil, Jean Opi, Sandrine Annappa, Sylvie Salles, Jean-Pierre Loret, Erwann P. TI Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine SO RETROVIROLOGY LA English DT Article ID RHESUS MACAQUES; STRUCTURAL CHARACTERIZATION; CYNOMOLGUS MONKEYS; VIRAL LOAD; PROTEIN; REPLICATION; INDIVIDUALS; INFECTION; APOPTOSIS; AIDS AB Background: Extra-cellular roles of Tat might be the main cause of maintenance of HIV-I infected CD4 T cells or reservoir cells. We developed a synthetic vaccine based on a Tat variant of 101 residues called Tat Oyi, which was identified in HIV infected patients in Africa who did not progress to AIDS. We compared, using rabbits, different adjuvants authorized for human use to test on ELISA the recognition of Tat variants from the five main HIV-I subtypes. A formulation was tested on macaques followed by a SHIV challenge with a European strain. Results: Tat Oyi with Montanide or Calcium Phosphate gave rabbit sera able to recognize all Tat variants. Five on seven Tat Oyi vaccinated macaques showed a better control of viremia compared to control macaques and an increase of CD8 T cells was observed only on Tat Oyi vaccinated macaques. Reservoir cells were not detectable at 56 days post-challenge in all Tat Oyi vaccinated macaques but not in the controls. Conclusion: The Tat Oyi vaccine should be efficient worldwide. No toxicity was observed on rabbits and macaques. We show in vivo that antibodies against Tat could restore the cellular immunity and make it possible the elimination of reservoir cells. C1 Univ Aix Marseille 2, Fac Pharm, CNRS, UMR Univ Med,FRE 2737, F-13385 Marseille, France. SynProsis, Hotel Technol, F-13013 Marseille, France. Univ Calif San Diego, Dept Pediat, Div Infect Dis, La Jolla, CA 92093 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Loret, EP (reprint author), Univ Aix Marseille 2, Fac Pharm, CNRS, UMR Univ Med,FRE 2737, 27 Bd Jean Moulin, F-13385 Marseille, France. EM jennifer.watkins@pharmacie.univ-mrs.fr; sophie.lancelot@pharmacie.univ-mrs.fr; gcampbell@ucsd.edu; desquieu@synprosis.com; jean.boulademareuil@pharmacie.univ-mrs.fr; sopi@niaid.nih.gov; sannappa@synprosis.com; jpsalles@synprosis.com; erwann.loret@pharmacie.univ-mrs.fr OI Campbell, Grant/0000-0003-3927-1994 NR 45 TC 18 Z9 19 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JAN 27 PY 2006 VL 3 AR 8 DI 10.1186/1742-4690-3-8 PG 10 WC Virology SC Virology GA 067OC UT WOS:000239311500001 PM 16441880 ER PT J AU Stuelten, CH Buck, MB Dippon, J Roberts, AB Fritz, P Knabbe, C AF Stuelten, CH Buck, MB Dippon, J Roberts, AB Fritz, P Knabbe, C TI Smad4-expression is decreased in breast cancer tissues: a retrospective study SO BMC CANCER LA English DT Article ID GROWTH-FACTOR-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1 TGF-BETA-1; TUMOR-SUPPRESSOR SMAD4; CELL-LINES; ENHANCES TUMORIGENESIS; DPC4 INACTIVATION; METASTASIS; PROTEIN; GENE; PROGRESSION AB Background: Although transforming growth factor beta (TGF-beta) typically inhibits proliferation of epithelial cells, consistent with a tumor suppressor activity, it paradoxically also exhibits prometastatic activity in the later stages of carcinogenesis. Since tumors often display altered TGF-beta signaling, particularly involving the Smad-pathway, we investigated the role of Smad4-expression in breast cancer. Methods: Smad4 expression was investigated by immunohistochemistry in formalin-fixed, paraffin-embedded tissue from 197 samples of primary breast cancer obtained between 1986 and 1998. The prognostic value of Smad4-expression was analyzed. Results: Smad4 expression was found to be reduced in lobular and ductal breast carcinoma as compared to surrounding uninvolved lobular and ductal breast epithelia (p < 0.001, n = 50). Smad4-expression correlated positively with expression of TGF-beta-receptor I (p < 0.001, n = 197) and TGF-beta-receptor II (p < 0.001, n = 197), but showed no significant correlation with tumor size, metastases, nodal status, histological grade, histological type, or estrogen receptor expression. While not achieving statistical significance, there was a trend towards longer survival times in patients with Smad4 negative tumors. Conclusion: According to the suggested role of Smad4 as a tumor suppressor we observed that expression of Smad4 is lower in human breast cancer than in surrounding breast epithelium. However, we also observed a trend towards longer survival times in Smad4-negative patients, indicating the complex role of TGF-beta signaling in tumor progression. C1 Robert Bosch Krankenhaus, Dept Clin Chem, Stuttgart, Germany. Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. Univ Stuttgart, Dept Math, D-7000 Stuttgart, Germany. NCI, NIH, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Stuelten, CH (reprint author), Robert Bosch Krankenhaus, Dept Clin Chem, Stuttgart, Germany. EM chrisstu@mail.nih.gov; miriam.buck@ikp-stuttgart.de; dippon@mathematik.uni-stuttgart.de; Robertsa@mail.nih.gov; peter.fritz@rbk.de; cornelius.knabbe@rbk.de NR 45 TC 24 Z9 27 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JAN 26 PY 2006 VL 6 AR 25 DI 10.1186/1471-2407-6-25 PG 10 WC Oncology SC Oncology GA 025OR UT WOS:000236276400001 PM 16438724 ER PT J AU Atwood, LD Heard-Costa, NL Fox, CS Jaquish, CE Cupples, LA AF Atwood, LD Heard-Costa, NL Fox, CS Jaquish, CE Cupples, LA TI Sex and age specific effects of chromosomal regions linked to body mass index in the Framingham Study SO BMC GENETICS LA English DT Article ID TRAIT LINKAGE ANALYSIS; HUMAN OBESITY; VARIANCE-COMPONENTS; LOCUS; PEDIGREES; BIAS AB Background: Previously, we reported significant linkage of body mass index (BMI) to chromosomes 6 and 11 across six examinations, covering 28 years, of the Framingham Heart Study. These results were on all individuals available at each exam, thus the sample size varied from exam to exam. To remove any effect of sample size variation we have now constructed six subsets; for each exam individuals were only included if they were measured at every exam, i.e. for each exam, included individuals comprise the intersection of the original six exams. This strategy preferentially removed older individuals who died before reaching the sixth exam, thus the intersection datasets are smaller ( n = 1114) and significantly younger than the full datasets. We performed variance components linkage analysis on these intersection datasets and on their sex-specific subsets. Results: Results from the sex-specific genome scans revealed 11 regions in which a sex-specific maximum lodscore was at least 2.0 for at least one dataset. Randomization tests indicated that all 11 regions had significant ( p < 0.05) differences in sex-specific maximum lodscores for at least three datasets. The strongest sex-specific linkage was for men on chromosome 16 with maximum lodscores 2.70, 3.00, 3.42, 3.61, 2.56 and 1.93 for datasets 1 - 6 respectively. Results from the full genome scans revealed that linked regions on chromosomes 6 and 11 remained significantly and consistently linked in the intersection datasets. Surprisingly, the maximum lodscore on chromosome 10 for dataset 1 increased from 0.97 in the older original dataset to 4.23 in the younger smaller intersection dataset. This difference in maximum lodscores was highly significant ( p < 0.0001), implying that the effect of this chromosome may vary with age. Age effects may also exist for the linked regions on chromosomes 6 and 11. Conclusion: Sex specific effects of chromosomal regions on BMI are common in the Framingham study. Some evidence also exists for age-specific effects of chromosomal regions. C1 Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Atwood, LD (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. EM lda@bu.edu; nheard@bu.edu; foxc@nhlbi.nih.gov; jaquishc@nhlbi.nih.gov; adrienne@bu.edu OI Heard-Costa, Nancy/0000-0001-9730-0306; Cupples, L. Adrienne/0000-0003-0273-7965 FU NHLBI NIH HHS [HC-25195, N01HC25195]; NIDDK NIH HHS [R01 DK066241] NR 19 TC 12 Z9 13 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD JAN 26 PY 2006 VL 7 AR 7 DI 10.1186/1471-2156-7-7 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 017TB UT WOS:000235715100001 PM 16438729 ER PT J AU Nussenzweig, A Paull, T AF Nussenzweig, A Paull, T TI DNA repair - Tails of histones lost SO NATURE LA English DT Editorial Material ID DOUBLE-STRAND BREAK; H2AX PHOSPHORYLATION; INO80 C1 NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. Univ Texas, Dept Mol Genet & Microbiol, Austin, TX 78712 USA. RP Nussenzweig, A (reprint author), NIH, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov; tpaull@icmb.utexas.edu NR 13 TC 14 Z9 14 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 26 PY 2006 VL 439 IS 7075 BP 406 EP 407 DI 10.1038/439406a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 005XH UT WOS:000234859200030 PM 16437102 ER PT J AU Zhu, HM Geiman, TM Xi, SC Jiang, Q Schmidtmann, A Chen, TP Li, E Muegge, K AF Zhu, HM Geiman, TM Xi, SC Jiang, Q Schmidtmann, A Chen, TP Li, E Muegge, K TI Lsh is involved in de novo methylation of DNA SO EMBO JOURNAL LA English DT Article DE chromatin; DNA methylation; Dnmt3; epigenetic; Lsh ID MAMMALIAN DEVELOPMENT; GENE-EXPRESSION; FAMILY-MEMBER; SNF2 FAMILY; METHYLTRANSFERASES; DNMT3A; CANCER; MICE; MAINTENANCE; PATTERNS AB Deletion of Lsh perturbs DNA methylation patterns in mice yet it is unknown whether Lsh plays a direct role in the methylation process. Two types of methylation pathways have been distinguished: maintenance methylation by Dnmt1 occurring at the replication fork, and de novo methylation established by the methyltransferases Dnmt3a and Dnmt3b. Using an episomal vector in Lsh-/- embryonic fibroblasts, we demonstrate that the acquisition of DNA methylation depends on the presence of Lsh. In contrast, maintenance of previously methylated episomes does not require Lsh, implying a functional role for Lsh in the establishment of novel methylation patterns. Lsh affects Dnmt3a as well as Dnmt3b directed methylation suggesting that Lsh can cooperate with both enzymatic activities. Furthermore, we demonstrate that embryonic stem cells with reduced Lsh protein levels show a decreased ability to silence retroviral vector or to methylate endogenous genes. Finally, we demonstrate that Lsh associates with Dnmt3a or Dnmt3b but not with Dnmt1 in embryonic cells. These results suggest that the epigenetic regulator, Lsh, is directly involved in the control of de novo methylation of DNA. C1 NCI, Mol Immunoregulat Lab, SAIC, Frederick, MD 21701 USA. NCI, Lab Canc Prevent, SAIC FCRDC, Basic Res Program, Frederick, MD 21701 USA. Novartis Inst Biomed Res Inc, Epigenet Program, Cambridge, MA USA. RP Muegge, K (reprint author), NCI, Mol Immunoregulat Lab, SAIC, Bldg 469,Room 243, Frederick, MD 21701 USA. EM muegge@ncifcrf.gov FU PHS HHS [N01-C0-12400] NR 48 TC 88 Z9 96 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 25 PY 2006 VL 25 IS 2 BP 335 EP 345 DI 10.1038/sj.emboj.7600925 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 007EX UT WOS:000234952500007 PM 16395332 ER PT J AU Cutler, JA Thom, TJ Roccella, E AF Cutler, JA Thom, TJ Roccella, E TI Leading causes of death in the United States SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TRENDS C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Cutler, JA (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM thomas.thom@nih.hhs.gov NR 4 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 25 PY 2006 VL 295 IS 4 BP 383 EP 384 DI 10.1001/jama.295.4.383-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 005QJ UT WOS:000234838600011 PM 16434623 ER PT J AU Ward, SDC Hamdan, FF Bloodworth, LM Siddiqui, NA Li, JH Wess, J AF Ward, SDC Hamdan, FF Bloodworth, LM Siddiqui, NA Li, JH Wess, J TI Use of an in situ disulfide cross-linking strategy to study the dynamic properties of the cytoplasmic end of transmembrane domain VI of the M-3 muscarinic acetylcholine receptor SO BIOCHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; CONFORMATIONAL-CHANGES; RHODOPSIN STRUCTURE; AGONIST ACTIVATION; HORMONE RECEPTOR; IDENTIFICATION; MECHANISMS; HELICES; SURFACE; BRIDGES AB The ligand-induced activation of G protein-coupled receptors (GPCRs) is predicted to involve pronounced conformational changes on the intracellular surface or the receptor proteins. A reorientation of the cytoplasmic end of transmembrane domain VI (TM VI) is thought to play a key role in GPCR activation and productive receptor/G protein coupling. Disulfide cross-linking studies with solubilized, Cys-substituted mutant versions of bovine rhodopsin and the M-3 muscarinic acetylcholine receptor suggested that the cytoplasmic end of TM VI is conformationally highly flexible, even in the absence of activating ligands (Farrens, D. L., et al. (1996) Science 274, 768-770; Zeng, F. Y., et al. (1999) J. Biol. Chem. 274, 16629-16640). To test the hypothesis that the promiscuous disulfide cross-linking pattern observed in these studies was caused by the use of solubilized receptor proteins endowed with increased conformational flexibility, we employed a recently developed in situ disulfilde cross-linking strategy that allows the detection of disulfide bonds in Cys-substituted mutant M3 muscarinic receptors present in their native membrane environment. Specifically, we used membranes prepared from transfected COS-7 cells to analyze a series of double Cys mutant M-3 receptors containing one Cys residue within the sequence K484(6.29) to S493(6.38) at the cytoplasmic end of TM VI and a second Cys residue at the cytoplasmic end of TM III (1169C(3.54)). This analysis revealed a disulfide cross-linking pattern that was strikingly more restricted than that observed previously with solubilized receptor proteins, both in the absence and in the presence of the muscarinic agonist, carbachol. Carbachol stimulated the formation of disulfide bonds in only two of the 10 analyzed mutant muscarinic receptors, I169C(3.54)/K484C(6.29) and I169C(3.54)/A488C(6.33), consistent with an agonist-induced rotation of the cytoplasmic end of TM VI. These findings underline the usefulness of analyzing the structural and dynamic properties of GPCRs in their native lipid environment. C1 NIDDK, Mol Signal Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signal Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Li, Jianhua/B-7671-2011 OI Li, Jianhua/0000-0002-5744-3182 FU Intramural NIH HHS NR 46 TC 24 Z9 25 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 24 PY 2006 VL 45 IS 3 BP 676 EP 685 DI 10.1021/bi051503q PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 007RZ UT WOS:000234988600003 PM 16411743 ER PT J AU Sharpe, S Yau, WM Tycko, R AF Sharpe, S Yau, WM Tycko, R TI Structure and dynamics of the HIV-1 Vpu transmembrane domain revealed by solid-state NMR with magic-angle spinning SO BIOCHEMISTRY LA English DT Review ID VIRUS TYPE-1 VPU; PROTEIN-U VPU; NUCLEAR-MAGNETIC-RESONANCE; ION-CHANNEL ACTIVITY; INTEGRAL MEMBRANE-PROTEIN; VIRAL PARTICLE RELEASE; HEPATITIS-C VIRUS; INFLUENZA-A VIRUS; CYTOPLASMIC DOMAIN; CHEMICAL-SHIFTS AB We report solid-state nuclear magnetic resonance (NMR) measurements on the peptide Vpu(1-40), comprising residues 1-40 of the 81-residue type 1 integral membrane protein Vpu encoded by the HIV-1 genome. On the basis of a combination of C-13 and N-15 NMR chemical shifts under magic-angle spinning (MAS), effects of local mobility on NMR signal intensities, site-specific MAS NMR line widths, and NMR-detected hydrogen-deuterium exchange, we develop a model for the structure and dynamics of the Vpu(1-40) monomer in phospholipid bilayer membranes. Our data are largely consistent with earlier structural studies of Vpu peptides by Opella and co-workers, in which solution NMR and solid-state NMR without MAS were used, but our data provide new information about local variations in the degree of mobility and structural order. In addition, our data indicate that the transmembrane a-helix of Vpu(1-40) extends beyond the hydrophobic core of the bilayer. We find no evidence for heterogeneity in the conformation and intermolecular contacts of the transmembrane alpha-helix, with the exception of two distinct chemical shifts observed for the C alpha and C beta atoms of A18 that may reflect distinct modes of helix-helix interaction. These results have possible implications for the supramolecular structure of Vpu oligomers that form cation-selective ion channels. C1 Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Phys Chem Lab, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Phys Chem Lab, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural NIH HHS NR 102 TC 54 Z9 55 U1 3 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 24 PY 2006 VL 45 IS 3 BP 918 EP 933 DI 10.1021/bi051766k PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 007RZ UT WOS:000234988600028 PM 16411768 ER PT J AU Nie, ZZ Hirsch, DS Luo, RB Jian, XY Stauffer, S Cremesti, A Andrade, J Lebowitz, J Marino, M Ahvazi, B Hinshaw, JE Randazzo, PA AF Nie, ZZ Hirsch, DS Luo, RB Jian, XY Stauffer, S Cremesti, A Andrade, J Lebowitz, J Marino, M Ahvazi, B Hinshaw, JE Randazzo, PA TI A BAR domain in the N terminus of the Arf GAP ASAP1 affects membrane structure and trafficking of epidermal growth factor receptor SO CURRENT BIOLOGY LA English DT Article ID GTPASE-ACTIVATING PROTEIN; ADP-RIBOSYLATION FACTOR; DOWNSTREAM EFFECTOR; PHOSPHOLIPASE-D; COMPLEX; GOLGI; CELL; TRANSPORT; AGAP1; COAT AB Background: Arf GAPs are multidomain proteins that function in membrane traffic by inactivating the GTP binding protein Arf1. Numerous Arf GAPs contain a BAR domain, a protein structural element that contributes to membrane traffic by either inducing or sensing membrane curvature. We have examined the role of a putative BAR domain in the function of the Arf GAP ASAP1. Results: ASAP1's N terminus, containing the putative BAR domain together with a PH domain, dimerized to form an extended structure that bound to large unilamellar vesicles containing acidic phospholipids, properties that define a BAR domain. A recombinant protein containing the BAR domain of ASAP1, together with the PH and Arf GAP domains, efficiently bent the surface of large unilamellar vesicles, resulting in the formation of tubular structures. This activity was regulated by Arf1 center dot GTP binding to the Arf GAP domain. In vivo, the tubular structures induced by ASAP1 mutants contained epidermal growth factor receptor (EGFR) and Rab11, and ASAP1 colocalized in tubular structures with EGFR during recycling of receptor. Expression of ASAP1 accelerated EGFR trafficking and slowed cell spreading. An ASAP1 mutant lacking the BAR domain had no effect. Conclusions: The N-terminal BAR domain of ASAP1 mediates membrane bending and is necessary for ASAP1 function. The Arf dependence of the bending activity is consistent with ASAP1 functioning as an Arf effector. C1 NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Virginia, Ctr Cell Signaling, Charlottesville, VA 22908 USA. NIDDK, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov FU Intramural NIH HHS NR 42 TC 59 Z9 59 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 24 PY 2006 VL 16 IS 2 BP 130 EP 139 DI 10.1016/j.cub.2005.11.069 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 009IT UT WOS:000235105900017 PM 16431365 ER PT J AU Pavlov, YI Frahm, C McElhinny, SAN Niimi, A Suzuki, M Kunkel, TA AF Pavlov, YI Frahm, C McElhinny, SAN Niimi, A Suzuki, M Kunkel, TA TI Evidence that errors made by DNA polymerase alpha are corrected by DNA polymerase delta SO CURRENT BIOLOGY LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; MUTATION AVOIDANCE; REVERSE-TRANSCRIPTASE; REPLICATION FIDELITY; MISMATCH REPAIR; LIGATABLE NICK; MUTANTS; EXONUCLEASE; ETA; 6-N-HYDROXYLAMINOPURINE AB Eukaryotic replication [1, 2] begins at origins and on the lagging strand with RNA-primed DNA synthesis of a few nucleotides by polymerase alpha, which lacks proofreading activity. A polymerase switch then allows chain elongation by proofreading-proficient pol delta and pol epsilon. Pol delta and pol epsilon are essential, but their roles in replication are not yet completely defined [3]. Here, we investigate their roles by using yeast pol alpha with a Leu868Met substitution [4]. L868M pol alpha copies DNA in vitro with normal activity and processivity but with reduced fidelity. In vivo, the pol1-L868M allele confers a mutator phenotype. This mutator phenotype is strongly increased upon inactivation of the 3' exonuclease of pol delta but not that of pol epsilon. Several nonexclusive explanations are considered, including the hypothesis that the 3' exonuclease of pol delta proofreads errors generated by pol alpha during initiation of Okazaki fragments. Given that eukaryotes encode specialized, proofreading-deficient polymerases with even lower fidelity than pol alpha [5], such intermolecular proofreading could be relevant to several DNA transactions that control genome stability. C1 Natl Inst Environm Hlth Sci, Lab Struct Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. Nagoya Univ, Grad Sch Med, Div Mol Carcinogenesis, Ctr Neural Dis & Canc, Nagoya, Aichi 4668550, Japan. RP Kunkel, TA (reprint author), Natl Inst Environm Hlth Sci, Lab Struct Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Suzuki, Motoshi/I-7246-2014 OI Suzuki, Motoshi/0000-0003-0682-5006 FU Intramural NIH HHS NR 33 TC 94 Z9 96 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 24 PY 2006 VL 16 IS 2 BP 202 EP 207 DI 10.1016/j.cub.2005.12.002 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 009IT UT WOS:000235105900026 PM 16431373 ER PT J AU Rossi, L Moharram, R Martin, BM White, RL Panelli, MC AF Rossi, L Moharram, R Martin, BM White, RL Panelli, MC TI Detection of human MCP-4/CCL13 isoforms by SELDI immunoaffinity capture SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID MONOCYTE CHEMOTACTIC PROTEIN-4; CC-CHEMOKINE; MCP-4; EXPRESSION; INFLAMMATION; (MCP)-4; EOTAXIN; SIGNALS; ASTHMA; CELLS AB Monocyte Chemoattractant Proteins 4 (MCP-4/CCL13)is a member of a distinct, structurally-related subclass of CC chemokines mainly involved in recruitment of eosinphils to inflammatory sites. Recent evidence demonstrates that serum level of this protein strongly increases following high dose IL-2 immunotherapy. The physiological form of human MCP-4/CCL13 has yet to be purified. Therefore, the primary structure of the biologically relevant (mature) form has not been established. By using SELDI immunoaffinity capture technology we describe two mature isoforms both present in serum before and after high-dose IL-2 immunotherapy. C1 Univ Pisa, Dept Human Morphol & Appl Biol, I-56126 Pisa, Italy. NIMH, NIH, Bethesda, MD 20892 USA. Carolinas Med Ctr, Blumenthal Canc Ctr, Charlotte, NC 28232 USA. NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Rossi, L (reprint author), Univ Pisa, Dept Human Morphol & Appl Biol, I-56126 Pisa, Italy. EM leoros@biomed.unipi.it; moharrar@mail.nih.gov; BrianMartin@mail.nih.gov; Richard.White@carolinashealthcare.org; mpanelli@mail.cc.nih.gov NR 14 TC 6 Z9 6 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 24 PY 2006 VL 4 AR 5 DI 10.1186/1479-5876-4-5 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 020VZ UT WOS:000235942400001 PM 16433902 ER PT J AU Hoskins, JR Wickner, S AF Hoskins, JR Wickner, S TI Two peptide sequences can function cooperatively to facilitate binding and unfolding by ClpA and degradation by ClpAP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AAA(+) ATPases; adaptor proteins; ATP-dependent proteolysis; Hsp100; molecular chaperones ID ESCHERICHIA-COLI; SUBSTRATE RECOGNITION; REPLICATION PROTEIN; PROTEASES DEGRADE; CHAPERONE CLPA; TAGGING SYSTEM; DNAJ; TRANSLOCATION; REGULATOR; PROTEOLYSIS AB Clp/Hsp100 proteins comprise a large family of AAA(+) ATPases. Some Clp proteins function alone as molecular chaperones, whereas others act in conjunction with peptidases, forming ATP-dependent proteasome-like compartmentalized proteases. Protein degradation by Clp proteases is regulated primarily by substrate recognition by the Clp ATPase component. The ClpA and ClpX ATPases of Escherichia coli generally recognize short amino acid sequences that are located near the N or C terminus of a substrate. However, both ClpAP and ClpXP are able to degrade proteins in which the end containing the recognition signal is fused to GFP such that the signal is in the interior of the primary sequence of the substrate. Here, we tested whether the internal ClpA recognition signal was the sole element required for targeting the substrate to ClpA. The results show that, in the absence of a high-affinity peptide recognition signal at the terminus, two elements are important for recognition of GFP-RepA fusion proteins by ClpA. One element is the natural ClpA recognition signal located at the junction of GFP and RepA in the fusion protein. The second element is the C-terminal peptide of the fusion protein. Together, these two elements facilitate binding and unfolding by ClpA and degradation by ClpAP. The internal site appears to function similarly to Clp adaptor proteins but, in this case, is covalently attached to the polypeptide containing the terminal tag and both the "adaptor" and "substrate" modules are degraded. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 5144,37 Convent Dr, Bethesda, MD 20892 USA. EM suewick@helix.nih.gov FU Intramural NIH HHS NR 37 TC 25 Z9 25 U1 0 U2 1 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 JAN 24 PY 2006 VL 103 IS 4 BP 909 EP 914 DI 10.1073/pnas.0509154103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AC UT WOS:000234938300015 PM 16410355 ER PT J AU Yao, ZJ Cui, YZ Watford, WT Bream, JH Yamaoka, K Hissong, BD Li, D Durum, SK Jiang, QO Bhandoola, A Hennighausen, L O'Shea, JJ AF Yao, ZJ Cui, YZ Watford, WT Bream, JH Yamaoka, K Hissong, BD Li, D Durum, SK Jiang, QO Bhandoola, A Hennighausen, L O'Shea, JJ TI Stat5a/b are essential for normal lymphoid development and differentiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytokine; jak; lymphocyte; severe combined immunodeficiency; interleukin ID RECEPTOR-GAMMA CHAIN; T-CELL HOMEOSTASIS; MICE LACKING JAK3; SEVERE COMBINED IMMUNODEFICIENCY; INTERLEUKIN-7 RECEPTOR; LOCUS ACCESSIBILITY; TH2 DIFFERENTIATION; GENE REARRANGEMENT; IN-VIVO; ACTIVATION AB Cytokines that use the common gamma chain gamma c are critical for lymphoid development and function. Mutations of the IL-7 receptor, gamma c, or its associated kinase, Jak3, are the major cause of human severe combined immunodeficiency. Although activated by IL-7, Stat5a/b (Stat, signal transducer and activator of transcription) have been thought to play limited roles in lymphoid development. However, we now show that mice completely deficient in Stat5a/b have severely impaired lymphoid development and differentiation. Absence of Stat5 also abrogates T cell receptor gamma rearrangement and survival of peripheral CD8(+) T cells. Thus, deficiency of Stat5 results in severe combined immunodeficiency, similar in many respects to deficiency of IL-7R, gamma c, and Jak3. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N262,10 Ctr Dr,MSC-1820, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov FU Intramural NIH HHS NR 50 TC 204 Z9 209 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 JAN 24 PY 2006 VL 103 IS 4 BP 1000 EP 1005 DI 10.1073/pnas.0507350103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AC UT WOS:000234938300031 PM 16418296 ER PT J AU Zhang, YQ Lee, FY Barrera, G Lee, H Vales, C Gonzalez, FJ Willson, TM Edwards, PA AF Zhang, YQ Lee, FY Barrera, G Lee, H Vales, C Gonzalez, FJ Willson, TM Edwards, PA TI Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glucose; GW4064; farnesoid x receptor-VP16; triglyceride; cholesterol ID GLYCOGEN-SYNTHASE KINASE-3; FARNESOID-X-RECEPTOR; BILE-ACID BIOSYNTHESIS; INSULIN-RESISTANCE; GENE-EXPRESSION; CARBOHYDRATE-METABOLISM; MYOCARDIAL-INFARCTION; TRIGLYCERIDE LEVELS; LIPID HOMEOSTASIS; PROTEIN-KINASE AB Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus. C1 Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. NCI, Met Lab, NIH, Bethesda, MD 20892 USA. GlaxoSmithKline Inc, Discovery Res, Res Triangle Pk, NC 27709 USA. RP Edwards, PA (reprint author), Univ Calif Los Angeles, Dept Biol Chem, CHS 33-257,10833 Le Conet Ave, Los Angeles, CA 90095 USA. EM pedwards@mednet.ucla.edu FU GAS NIH HHS [GW07185]; NHLBI NIH HHS [HL68445, HL30568, P01 HL030568, R01 HL068445] NR 47 TC 370 Z9 394 U1 3 U2 30 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 JAN 24 PY 2006 VL 103 IS 4 BP 1006 EP 1011 DI 10.1073/pnas.0506982103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AC UT WOS:000234938300032 PM 16410358 ER PT J AU Lee, S Chen, JJ Zhou, GL Shi, RZ Bouffard, GG Kocherginsky, M Ge, XJ Sun, M Jayathilaka, N Kim, YC Emmanuel, N Bohlander, SK Minden, M Kline, J Ozer, O Larson, RA LeBeau, MM Green, ED Trent, J Karrison, T Liu, PP Wang, SM Rowley, JD AF Lee, S Chen, JJ Zhou, GL Shi, RZ Bouffard, GG Kocherginsky, M Ge, XJ Sun, M Jayathilaka, N Kim, YC Emmanuel, N Bohlander, SK Minden, M Kline, J Ozer, O Larson, RA LeBeau, MM Green, ED Trent, J Karrison, T Liu, PP Wang, SM Rowley, JD TI Gene expression profiles in acute myeloid leukemia with common translocations using SAGE SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hematopoietic cell differention; diagnostic microarray ID ACUTE MYELOGENOUS LEUKEMIA; GENOME-WIDE ANALYSIS; PROTHYMOSIN-ALPHA; IN-VIVO; DISTINCT; REVEALS; PATTERN; CELLS; DIFFERENTIATION; CLASSIFICATION AB Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15(+) myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15(+) cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy. C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Dept Hlth Sci, Chicago, IL 60637 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Northwestern Univ, ENH Res Inst, Evanston, IL 60208 USA. Univ Munich, Dept Med 3, D-80539 Munich, Germany. GSF, Natl Res Ctr Environm & Hlth, Clin Cooperat Grp Leukemia, D-80539 Munich, Germany. Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON M5G 2M9, Canada. RP Wang, SM (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM swang1@northwestern.edu; jrowley@medicine.bsd.uchicago.edu RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; Ge, Steven/0000-0001-7406-3782; Bohlander, Stefan/0000-0002-2202-9088; Larson, Richard/0000-0001-9168-3203 FU Intramural NIH HHS; NCI NIH HHS [CA40046, CA84405, P01 CA040046, R01 CA084405]; NHGRI NIH HHS [R01 HG002600] NR 44 TC 27 Z9 27 U1 0 U2 0 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 JAN 24 PY 2006 VL 103 IS 4 BP 1030 EP 1035 DI 10.1073/pnas.0509878103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AC UT WOS:000234938300036 PM 16418266 ER PT J AU Oliveira, JG Colf, LA McBride, AA AF Oliveira, JG Colf, LA McBride, AA TI Variations in the association of papillomavirus E2 proteins with mitotic chromosomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE human papillomavirus; mitosis; replication; segregation ID EPISOMAL MAINTENANCE; BROMODOMAIN PROTEIN; NUCLEOTIDE-SEQUENCE; ORAL PAPILLOMAVIRUS; HUMAN KERATINOCYTES; MOLECULAR-CLONING; GENOMIC SEQUENCE; VIRAL-DNA; BRD4; PHOSPHORYLATION AB The E2 protein segregates episomal bovine papillomavirus (BPV) genomes to daughter cells by tethering them to mitotic chromosomes, thus ensuring equal distribution and retention of viral DNA. To date, only the BPV1 E2 protein has been shown to bind to mitotic chromosomes. We assessed the localization of 13 different animal and human E2 proteins from seven papillomavirus genera, and we show that most of them are stably bound to chromosomes throughout mitosis. Furthermore, in contrast to the random association of BPV1 E2 with mitotic chromosomes, several of these proteins appear to bind to more specific regions of mitotic chromosomes. Using human papillomavirus (HPV) type 8 E2, we show that this region is adjacent to centromeres/kinetochores. Therefore, E2 proteins from both HPV and animal papillomavirus bind to mitotic chromosomes, and there are variations in the specificity of this binding. Only the a-papillomavirus E2 proteins do not stably associate with mitotic chromatin throughout mitosis. These proteins closely associate with prophase chromosomes and bind to chromosomes in telophase but not in metaphase. However, extraction of mitotic cells before fixation results in alpha-E2 proteins binding to the pericentromeric region of metaphase chromosomes, as observed for HPV8 E2. We postulate that this is the authentic target of these E2 proteins but that additional factors or a specialized cellular environment is required to stabilize this association. Thus, E2-mediated tethering of viral genomes to mitotic chromosomes is a common strategy of papillomaviruses, but different viruses have evolved different variations of this theme. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU Intramural NIH HHS NR 31 TC 63 Z9 64 U1 0 U2 1 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 JAN 24 PY 2006 VL 103 IS 4 BP 1047 EP 1052 DI 10.1073/pnas.0507624103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AC UT WOS:000234938300039 PM 16415162 ER PT J AU Furey, ML Tanskanen, T Beauchamp, MS Avikainen, S Uutela, K Hari, R Haxby, JV AF Furey, ML Tanskanen, T Beauchamp, MS Avikainen, S Uutela, K Hari, R Haxby, JV TI Dissociation of face-selective cortical responses by attention SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE functional MRI; human; magnetoencephalography; visual ID HUMAN EXTRASTRIATE CORTEX; HUMAN FUSIFORM GYRUS; BRAIN POTENTIALS; VISUAL-ATTENTION; PERCEPTION; RECOGNITION; FMRI; AREA; OBJECTS; REPRESENTATION AB We studied attentional modulation of cortical processing of faces and houses with functional MRI and magnetoencephalography (MEG). MEG detected an early, transient face-selective response. Directing attention to houses in "double-exposure" pictures of superimposed faces and houses strongly suppressed the characteristic, face-selective functional MRI response in the fusiform gyrus. By contrast, attention had no effect on the M170, the early, face-selective response detected with MEG. Late (> 190 ms) category-related MEG responses elicited by faces and houses, however, were strongly modulated by attention. These results indicate that hemodynamic and electrophysiological measures of face-selective cortical processing complement each other. The hemodynamic signals reflect primarily late responses that can be modulated by feedback connections. By contrast, the early, face-specific M170 that was not modulated by attention likely reflects a rapid, feed-forward phase of face-selective processing. C1 NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Helsinki Univ Technol, Brain Res Unit, Low Temp Lab, FIN-02015 Espoo, Finland. Univ Helsinki, Dept Clin Neurophysiol, FIN-02015 Helsinki, Finland. Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. RP Hari, R (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, Bldg 15K,Room 114, Bethesda, MD 20892 USA. EM hari@neuro.hut.fi RI Tanskanen, Topi/A-6123-2011; Furey, Maura/H-5273-2013; Hari, Riitta/J-1880-2012; OI Hari, Riitta/0000-0002-3142-2703; Beauchamp, Michael/0000-0002-7599-9934 NR 37 TC 77 Z9 78 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 JAN 24 PY 2006 VL 103 IS 4 BP 1065 EP 1070 DI 10.1073/pnas.0510124103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AC UT WOS:000234938300042 PM 16415158 ER PT J AU Sumner, AE AF Sumner, AE TI Why the plasma TG/HDL-C concentration ratio does not predict insulin resistance in African Americans - Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID LIPOPROTEIN-LIPASE; TRIGLYCERIDE; MARKERS C1 NIDDK, Clin Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), NIDDK, Clin Epidemiol Branch, NIH, 9000 Rockville Pk,Bldg 10-CRC,Room 6W-5940, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 23 PY 2006 VL 166 IS 2 BP 249 EP 250 DI 10.1001/archinte.166.2.249-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 004RH UT WOS:000234769400023 ER PT J AU Glass, WG McDermott, DH Lim, JK Lekhong, S Yu, SF Frank, WA Pape, J Cheshier, RC Murphy, PM AF Glass, WG McDermott, DH Lim, JK Lekhong, S Yu, SF Frank, WA Pape, J Cheshier, RC Murphy, PM TI CCR5 deficiency increases risk of symptomatic West Nile virus infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NEW-YORK; UNITED-STATES; ENCEPHALITIS; OUTBREAK; RESISTANCE; DISEASE AB West Nile virus (WNV) is a reemerging pathogen that causes fatal encephalitis in several species, including mouse and human. Recently, we showed that the chemokine receptor CCR5 is critical for survival of mice infected with WNV, acting at the level of leukocyte trafficking to the brain. To test whether this receptor is also protective in man, we determined the frequency of CCR5 Delta 32, a defective CCR5 allele found predominantly in Caucasians, in two independent cohorts of patients, one from Arizona and the other from Colorado, who had laboratory-confirmed, symptomatic WNV infection. The distribution of CCR5 Delta 32 in a control population of healthy United States Caucasian random blood donors was in Hardy-Weinberg equilibrium and CCR5 Delta 32 homozygotes represented 1.0% of the total group (n = 1,318). In contrast, CCR5 Delta 32 homozygotes represented 4.2% of Caucasians in the Arizona cohort (odds ratios [OR] = 4.4 [95% confidence interval [CI], 1.6-11.8], P = 0.0013) and 8.3% of Caucasians in the Colorado cohort (OR = 9.1 [95% CI, 3.4-24.8], P < 0.0001). CCR5 Delta 32 homozygosity was significantly associated with fatal outcome in the Arizona cohort (OR = 13.2 [95% CI, 1.9-89.9], P = 0.03). We conclude that CCR5 mediates resistance to symptomatic WNV infection. Because CCR5 is also the major HIV coreceptor, these findings have important implications for the safety of CCR5-blocking agents under development for HIV/AIDS. C1 NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Arizona Dept Hlth Serv, Bur State Lab Serv, Phoenix, AZ 85007 USA. Arizona Dept Hlth Serv, Bur Epidemiol & Dis Control Serv, Phoenix, AZ 85007 USA. Colorado Dept Publ Hlth & Environm, Denver, CO 80246 USA. RP Murphy, PM (reprint author), NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov OI McDermott, David/0000-0001-6978-0867 FU Intramural NIH HHS NR 21 TC 273 Z9 290 U1 3 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 JAN 23 PY 2006 VL 203 IS 1 BP 35 EP 40 DI 10.1084/jem.20051970 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 007XB UT WOS:000235003600006 PM 16418398 ER PT J AU Peng, G Lei, KJ Jin, WW Greenwell-Wild, T Wahl, SM AF Peng, G Lei, KJ Jin, WW Greenwell-Wild, T Wahl, SM TI Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti-HIV-1 activity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RESTRICTS HIV-1 INFECTION; CYTIDINE DEAMINASE; GENE-EXPRESSION; ANTIRETROVIRAL THERAPY; ALPHA-INTERFERON; VIF PROTEIN; IFN-ALPHA; MACROPHAGES; HYPERMUTATION AB Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G), a cytidine deaminase, is a recently recognized innate intracellular protein with lethal activity against human immunodeficiency virus (HIV). Packaged into progeny virions, APOBEC3G enzymatic activity leads to HIV DNA degradation. As a counterattack, HIV virion infectivity factor (Vif) targets APOBEC3G for proteasomal proteolysis to exclude it from budding virions. Based on the ability of APOBEC3G to antagonize HIV infection, considerable interest hinges on elucidating its mechanism(s) of regulation. In this study, we provide the first evidence that an innate, endogenous host defense factor has the potential to promote APOBEC3G and rebuke the virus-mediated attempt to control its cellular host. We identify interferon (IFN)-alpha as a potent inducer of APOBEC3G to override HIV Vif neutralization of APOBEC3 proteins that pose a threat to efficient macrophage HIV replication. Our data provide a new dimension by which IFN-alpha mediates its antiviral activity and suggest a means to render the host nonpermissive for viral replication. C1 Natl Inst Dental & Craniofacial Res, Oral Infect & Immunity Branch, NIH, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), Natl Inst Dental & Craniofacial Res, Oral Infect & Immunity Branch, NIH, Bethesda, MD 20892 USA. EM smwahl@dir.nidcr.nih.gov FU Intramural NIH HHS NR 30 TC 187 Z9 199 U1 0 U2 5 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 JAN 23 PY 2006 VL 203 IS 1 BP 41 EP 46 DI 10.1084/jem.20051512 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 007XB UT WOS:000235003600007 PM 16418394 ER PT J AU Hayes, SM Love, PE AF Hayes, SM Love, PE TI Stoichiometry of the murine gamma delta T cell receptor SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ALPHA-BETA; ANTIGEN RECEPTOR; MULTIVALENT STRUCTURE; CD3-EPSILON CHAINS; TCR/CD3 COMPLEX; TCR COMPLEX; CD3; LINEAGES; ASSOCIATION; DEFICIENCY AB The T cell receptor for antigen (TCR) complex is organized into two functional domains: the antigen-binding clonotypic heterodimer and the signal-transducing invariant CD3 and TCR zeta chains. In most vertebrates, there are two different clonotypic heterodimers (TCR alpha beta and TCR gamma delta) that define the alpha beta and gamma delta T cell lineages, respectively. alpha beta- and gamma delta TCRs also differ in their invariant chain subunit composition, in that alpha beta TCRs contain CD3 gamma epsilon and CD3 delta epsilon dimers, whereas gamma delta TCRs contain only CD3 gamma epsilon dimers. This difference in subunit composition of the alpha beta- and gamma delta TCRs raises the question of whether the stoichiometries of these receptor complexes are different. As the stoichiometry of the murine gamma delta TCR has not been previously investigated, we used two quantitative immunofluorescent approaches to determine the valency of TCR gamma delta heterodimers and CD3 gamma epsilon dimers in surface murine gamma delta TCR complexes. Our results support a model of murine gamma delta TCR stoichiometry in which there are two CD3 gamma epsilon dimers for every TCR gamma epsilon heterodimer. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Hayes, SM (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. EM hayessa@upstate.edu NR 26 TC 18 Z9 20 U1 0 U2 0 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 JAN 23 PY 2006 VL 203 IS 1 BP 47 EP 52 DI 10.1084/jem.20051886 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 007XB UT WOS:000235003600008 PM 16418397 ER PT J AU Lee, CH Melchers, M Wang, HS Torrey, TA Slota, R Qi, CF Kim, JY Lugar, P Kong, HJ Farrington, L van der Zouwen, B Zhou, JX Lougaris, V Lipsky, PE Grammer, AC Morse, HC AF Lee, CH Melchers, M Wang, HS Torrey, TA Slota, R Qi, CF Kim, JY Lugar, P Kong, HJ Farrington, L van der Zouwen, B Zhou, JX Lougaris, V Lipsky, PE Grammer, AC Morse, HC TI Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CYTIDINE DEAMINASE AID; PLASMA-CELL DIFFERENTIATION; MYELOID PROGENITOR CELLS; CENTER B-CELLS; TRANSCRIPTION FACTOR; FACTOR FAMILY; IN-VIVO; EXPRESSION; ACTIVATION; ICSBP AB Interferon (IFN) consensus sequence-binding protein/IFN regulatory factor 8 (IRF8) is a transcription factor that regulates the differentiation and function of macrophages, granulocytes, and dendritic cells through activation or repression of target genes. Although IRF8 is also expressed in lymphocytes, its roles in B cell and T cell maturation or function are ill defined, and few transcriptional targets are known. Gene expression profiling of human tonsillar B cells and mouse B cell lymphomas showed that IRF8 transcripts were expressed at highest levels in centroblasts, either from secondary lymphoid tissue or transformed cells. In addition, staining for IRF8 was most intense in tonsillar germinal center (GC) darkzone centroblasts. To discover B cell genes regulated by IRF8, we transfected purified primary tonsillar B cells with enhanced green fluorescent protein-tagged IRF8, generated small interfering RNA knockdowns of IRF8 expression in a mouse B cell lymphoma cell line, and examined the effects of a null mutation of IRF8 on B cells. Each approach identified activation-induced cytidine deaminase (AICDA) and BCL6 as targets of transcriptional activation. Chromatin immunoprecipitation studies demonstrated in vivo occupancy of 5' sequences of both genes by IRF8 protein. These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6. C1 NIAMSD, B Cell Biol Grp, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, Bethesda, MD 20892 USA. NIAMSD, Automimmun Branch, Bethesda, MD 20892 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Grammer, AC (reprint author), NIAMSD, B Cell Biol Grp, Bethesda, MD 20892 USA. EM grammera@mail.nih.gov; hmorse@niaid.nih.gov RI Melchers, Mark/C-1438-2008; OI Morse, Herbert/0000-0002-9331-3705 FU Intramural NIH HHS NR 63 TC 106 Z9 107 U1 1 U2 4 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 JAN 23 PY 2006 VL 203 IS 1 BP 63 EP 72 DI 10.1084/jem.20051450 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 007XB UT WOS:000235003600010 PM 16380510 ER PT J AU Yu, Q Park, JH Doan, LL Erman, B Feigenbaum, L Singer, A AF Yu, Q Park, JH Doan, LL Erman, B Feigenbaum, L Singer, A TI Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID RECEPTOR-DEFICIENT MICE; T-CELL DEVELOPMENT; INTERLEUKIN-7 RECEPTOR; IL-7 RECEPTOR; GAMMA CHAIN; NEGATIVE REGULATORS; EXPRESSION; DIFFERENTIATION; BCL-2; TRANSCRIPTION AB Death by neglect requires that CD4(+)8(+) double-positive (DP) thymocytes avoid cytokine-mediated survival signals, which is presumably why DP thymocytes normally extinguish IL-7R gene expression. We report that DP thymocytes before positive selection (preselection DP thymocytes) fail to transduce IL-7 signals even when they express high levels of transgenic IL-7R on their surface, because IL-7R signal transduction is actively suppressed in preselection DP thymocytes by suppressor of cytokine signaling (SOCS)-1. SOCS-1 is highly expressed in preselection DP thymocytes, but it is down-regulated by T cell receptor mediated positive selection signals. Interestingly, we found that the uniquely small cell volume of DP thymocytes is largely the result of absent IL-7 signaling in preselection DP thymocytes. We also report that, contrary to current concepts, preselection DP thymocytes express high levels of endogenously encoded IL-4Rs. However, their ability to transduce cytokine signals is similarly suppressed by SOCS-1. Thus, despite high surface expression of transgenic or endogenous cytokine receptors, cytokine signal transduction is actively suppressed in preselection DP thymocytes until it is restored by positive selection. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Sabanci Univ, Fac Engn & Nat Sci, TR-34956 Istanbul, Turkey. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. EM singera@nih.gov FU Intramural NIH HHS NR 36 TC 56 Z9 61 U1 0 U2 0 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 JAN 23 PY 2006 VL 203 IS 1 BP 165 EP 175 DI 10.1084/jem.20051836 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 007XB UT WOS:000235003600019 PM 16390939 ER PT J AU Woelbing, F Kostka, SL Moelle, K Belkaid, Y Sunderkoetter, C Verbeek, S Waisman, A Nigg, AP Knop, J Udey, MC von Stebut, E AF Woelbing, F Kostka, SL Moelle, K Belkaid, Y Sunderkoetter, C Verbeek, S Waisman, A Nigg, AP Knop, J Udey, MC von Stebut, E TI Uptake of Leishmania major by dendritic cells is mediated by Fc gamma receptors and facilitates acquisition of protective immunity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID EPIDERMAL LANGERHANS CELLS; EXPERIMENTAL CUTANEOUS LEISHMANIASIS; SUSCEPTIBLE BALB/C MICE; B-CELLS; ANTIGEN PRESENTATION; DISEASE PROGRESSION; CROSS-PRESENTATION; CANDIDA-ALBICANS; RESISTANT MICE; DEFICIENT MICE AB Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4(+) and CD8(+) T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3-dependent phagocytosis of L. major by macrophages (M Phi) leads exclusively to MHC class II-restricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig) G and involved Fc gamma RI and Fc gamma RIII. In vivo, DC infiltration of L. major-infected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cell-deficient mice and Fc gamma(-/-) mice contained fewer parasite-infected DCs in vivo. Infected B cell-deficient mice as well as Fc gamma(-/-) mice (all on the C57BL/6 background) showed similarly increased disease susceptibility as assessed by lesion volumes and parasite burdens. The B cell-deficient mice displayed impaired T cell priming and dramatically reduced IFN gamma production, and these deficits were normalized by infection with IgG-opsonized parasites. These data demonstrate that DC and M Phi use different receptors to recognize and ingest L. major with different outcomes, and indicate that B cell-derived, parasite-reactive IgG and DC Fc gamma RI and Fc gamma RIII are essential for optimal development of protective immunity. C1 Univ Mainz, Dept Internal Med 1, Dept Dermatol, D-55131 Mainz, Germany. Univ Mainz, Dept Internal Med 1, Sect Pathophysiol, D-55131 Mainz, Germany. NCI, NIAID, Parasit Dis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Munster, Dept Dermatol, D-48129 Munster, Germany. Leiden Univ, Med Ctr, Dept Human & Clin Genet, NL-2300 Leiden, Netherlands. RP von Stebut, E (reprint author), Univ Mainz, Dept Internal Med 1, Dept Dermatol, D-55131 Mainz, Germany. EM vonstebu@mail.uni-mainz.de RI Waisman, Ari/C-7383-2015 OI Waisman, Ari/0000-0003-4304-8234 FU Intramural NIH HHS NR 61 TC 121 Z9 126 U1 0 U2 4 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 JAN 23 PY 2006 VL 203 IS 1 BP 177 EP 188 DI 10.1084/jem.20052288 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 007XB UT WOS:000235003600020 PM 16418399 ER PT J AU Lee, HJ Mayette, J Rapoport, SI Bazinet, RP AF Lee, Ho-Joo Mayette, Jana Rapoport, Stanley I. Bazinet, Richard P. TI Selective remodeling of cardiolipin fatty acids in the aged rat heart SO LIPIDS IN HEALTH AND DISEASE LA English DT Article ID LIVER MITOCHONDRIA; LIPID-COMPOSITION; ACYL COMPOSITION; BRAIN; PHOSPHATIDYLGLYCEROL; PHOSPHOLIPIDS; BIOSYNTHESIS; PURIFICATION; TISSUES; PROFILE AB Background: The heart is rich in cardiolipin, a phospholipid acylated in four sites, predominately with linoleic acid. Whether or not aging alters the composition of cardiolipin acyl chains is controversial. We therefore measured the fatty acid concentration of cardiolipin in hearts of 4, 12 and 24 month old rats that consumed one diet, adequate in fatty acids for the duration of their life. Results: The concentration (nmol/g) of linoleic acid was decreased in 24 month old rats (3965 +/- 617, mean +/- SD) vs 4 month old rats (5525 +/- 656), while the concentrations of arachidonic and docosahexaenoic acid were increased in 24 month old rats (79 +/- 9 vs 178 +/- 27 and 104 +/- 16 vs 307 +/- 68 for arachidonic and docosahexaenoic acids, 4 months vs 24 months, respectively). Similar changes were not observed in ethanolamine glycerophospholipids or plasma unesterified fatty acids, suggesting specificity of these effects to cardiolipin. Conclusion: These results demonstrate that cardiolipin remodeling occurs with aging, specifically an increase in highly unsaturated fatty acids. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bazinet, RP (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM hojoolee@mail.nih.gov; jana_mayette@yahoo.com; sir@helix.nih.gov; rbazinet@mail.nih.gov FU Intramural NIH HHS NR 29 TC 38 Z9 39 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD JAN 23 PY 2006 VL 5 AR 2 DI 10.1186/1476-511X-5-2 PG 4 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 181TY UT WOS:000247460200002 PM 16430781 ER PT J AU John-Aryankalayil, M Dushku, N Jaworski, CJ Cox, CA Schultz, G Smith, JA Ramsey, KE Stephan, DA Freedman, KA Reid, TW Carper, DA AF John-Aryankalayil, M Dushku, N Jaworski, CJ Cox, CA Schultz, G Smith, JA Ramsey, KE Stephan, DA Freedman, KA Reid, TW Carper, DA TI Microarray and protein analysis of human pterygium SO MOLECULAR VISION LA English DT Article ID PROSTAGLANDIN-D SYNTHASE; GELATINASE-ASSOCIATED LIPOCALIN; EXTRACELLULAR-MATRIX PROTEINS; HUMAN NEUTROPHIL GELATINASE; HUMAN-PAPILLOMAVIRUS; EPITHELIAL-CELLS; P53 EXPRESSION; BETA-TRACE; MICROSATELLITE INSTABILITY; ABNORMAL EXPRESSION AB PURPOSE: Pterygium is a sunlight-related, ocular-surface lesion that can obscure vision. In order to identify specific genes that may play a role in pterygium pathogenesis, we analyzed the global gene expression profile of pterygium in relation to autologous conjunctiva. METHODS: Oligonucleotide microarray hybridization was used to compare the gene expression profile between human whole pterygium and autologous conjunctiva. Selected genes were further characterized by RT-PCR, western blot, and immunohistochemistry, and comparisons were made with limbal and corneal tissues. RESULTS: Thirty-four genes exhibited a 2 fold or greater difference in expression between human whole pterygium and autologous conjunctiva. Twenty-nine transcripts were increased and five transcripts were decreased in pterygium. Fibronectin, macrophage-inflammatory protein-4 (MIP-4), and lipocalin 2 (oncogene 24p3; NGAL) were increased 9, 5, and 2.4 fold, respectively, while Per1 and Ephrin-A1 were decreased 2 fold in pterygium. Western blots showed that fibronectin and MIP-4 were increased in pterygium compared to limbus, cornea, and conjunctiva. Immunohistochemical analysis showed fibronectin in the stroma; lipocalin 2 in the basal epithelial cells, basement membrane, and extracellular stroma; and MIP-4 in all areas of the pterygium. CONCLUSIONS: These data show both novel and previously identified extracellular-matrix-related, proinflammatory, angiogenic, fibrogenic, and oncogenic genes expressed in human pterygium. Comparisons of selected genes with limbal and corneal tissues gave results similar to comparisons between pterygium and normal conjunctiva. The increased expression of lipocalin 2, which activates matrix metalloproteinases (MMP), is consistent with our previous findings that MMP-9 and other MMPs are highly expressed in pterygium basal epithelium. C1 NEI, NIH, Bethesda, MD 20892 USA. Kaiser Permanente Med Ctr, Sacramento, CA USA. Univ Florida, Dept Obstet & Gynecol, Gainesville, FL 32611 USA. Translat Genom Res Inst, Phoenix, AZ USA. Texas Tech Univ, Hlth Sci Ctr, Dept Ophthalmol & Visual Sci, Lubbock, TX 79430 USA. RP Carper, DA (reprint author), NEI, NIH, 31 Ctr Dr,MSC 2510,Bldg 31,Room 6A03, Bethesda, MD 20892 USA. EM carperd@nei.nih.gov FU Intramural NIH HHS NR 72 TC 33 Z9 34 U1 0 U2 4 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JAN 23 PY 2006 VL 12 IS 6 BP 55 EP 64 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 007OO UT WOS:000234979200001 PM 16446702 ER PT J AU Deary, IJ Hayward, C Permana, PA Nair, S Whalley, LJ Starr, JM Chapman, KE Walker, BR Seckl, JR AF Deary, IJ Hayward, C Permana, PA Nair, S Whalley, LJ Starr, JM Chapman, KE Walker, BR Seckl, JR TI Polymorphisms in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD 11B1) and lifetime cognitive change SO NEUROSCIENCE LETTERS LA English DT Article DE 11B-hydroxysteroid dehydrogenase type 1; HSD11B1; cognitive ageing; IQ; verbal reasoning ID PITUITARY-ADRENAL ACTIVITY; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; GLUCOCORTICOID ACTION; PIMA-INDIANS; HIPPOCAMPUS; IMPAIRMENTS; METABOLISM; EXPRESSION; CORTISOL; MEMORY AB A rare polymorphism in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1: rs846911-C/A) has been associated with an increased risk of Alzheimer's disease. We tested the hypothesis that this and 2 other HSD11B1 polymorphisms (rs 12086634-G/T and rs846910-A/G) were associated with lifetime cognitive change in humans. Subjects were 194 participants of the Scottish Mental Survey of 1932 who took the same well-validated mental test at age 11 and age 79. The subjects represented the highest and lowest quintiles with respect to cognitive decline between ages 11 and 79. Despite having non-significantly different IQs at age 11, by age 79 the groups had mean (S.D.) IQs of 80.3 (14.1) and 109.6 (9.1), respectively (p < .001). The polymorphism rs846911-C/A was absent from both groups. There were no significant differences in the frequency of polymorphisms of rs12086634-G/T (p = .91) and rs846910-A/G (p = .90) between the groups. We conclude that these variants in HSD11B1 are not significant contributors to the range of cognitive ageing examined here. (C) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. Carl T Hayden VAMC, Phoenix, AZ USA. NIDDKD, NIH, Phoenix, AZ USA. Univ Aberdeen, Dept Mental Hlth, Aberdeen, Scotland. Univ Edinburgh, Dept Geriatr Med, Edinburgh, Midlothian, Scotland. Univ Edinburgh, Sch Mol & Clin Med, Endocrinol Unit, Edinburgh, Midlothian, Scotland. RP Deary, IJ (reprint author), Univ Edinburgh, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. EM I.Deary@ed.ac.uk RI Starr, John/C-8951-2011; whalley, lawrence/E-9019-2011; Deary, Ian/C-6297-2009; Seckl, Jonathan/C-3555-2013; Hayward, Caroline/M-8818-2016; OI Hayward, Caroline/0000-0002-9405-9550; Chapman, Karen/0000-0001-7777-6817 NR 24 TC 8 Z9 9 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 23 PY 2006 VL 393 IS 1 BP 74 EP 77 DI 10.1016/j.neulet.2005.09.047 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 997XI UT WOS:000234281800016 PM 16236446 ER PT J AU Toyooka, N Dejun, Z Nemoto, H Garraffo, HM Spande, TF Daly, JW AF Toyooka, N Dejun, Z Nemoto, H Garraffo, HM Spande, TF Daly, JW TI The enantioselective synthesis of poison-frog alkaloids (-)-203A, (-)-209B, (-)-231C, (-)-233D, and (-)-235B" SO TETRAHEDRON LETTERS LA English DT Article ID ASYMMETRIC TOTAL-SYNTHESIS; NICOTINIC ACETYLCHOLINE-RECEPTORS; DESS-MARTIN PERIODINANE; QUINOLIZIDINE ALKALOIDS; (-)-INDOLIZIDINE 209B; DENDROBATID ALKALOIDS; SECONDARY ALCOHOLS; AMPHIBIAN SKIN; INDOLIZIDINE; PIPERIDINES AB The enantioselective synthesis of indolizidines (-)-203A, (-)-209B, (-)-231C, (-)-233D, and (-)-235B" has been achieved and the absolute stereochemistry of both indolizidines 203A and 233D was established as 5S,8R,9S. The relative stereochemistry of natural 231C was established by the present asymmetric synthesis. (c) 2005 Elsevier Ltd. All rights reserved. C1 Toyama Univ, Fac Pharmaceut Sci, Toyama 9300194, Japan. NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Toyooka, N (reprint author), Toyama Univ, Fac Pharmaceut Sci, Sugitani 2630, Toyama 9300194, Japan. EM toyooka@ms.toyama-mpu.ac.jp NR 54 TC 17 Z9 17 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JAN 23 PY 2006 VL 47 IS 4 BP 577 EP 580 DI 10.1016/j.tetlet.2005.11.047 PG 4 WC Chemistry, Organic SC Chemistry GA 002PW UT WOS:000234624600040 ER PT J AU Toyooka, N Dejun, Z Nemoto, H Garraffo, HM Spande, TF Daly, JW AF Toyooka, N Dejun, Z Nemoto, H Garraffo, HM Spande, TF Daly, JW TI Enantioselective syntheses of poison-frog alkaloids: 219F and 221I and an epimer of 193E SO TETRAHEDRON LETTERS LA English DT Article AB Enantioselective syntheses of indolizidines (-)-219F and (-)-221l have been achieved and the relative stereochemistries 14 of natural 219F and 2211 were determined by the present synthesis. A levorotatory indolizidine, corresponding to one proposed structure for 193E, was also synthesized, but was found to differ from 193E. It seems likely that natural 193E is the 8-epimer of the synthesized indolizidine. (c) 2005 Elsevier Ltd. All rights reserved. C1 Toyama Univ, Fac Pharmaceut Sci, Toyama 9300194, Japan. NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Toyooka, N (reprint author), Toyama Univ, Fac Pharmaceut Sci, Sugitani 2630, Toyama 9300194, Japan. EM toyooka@ms.toyama-mpu.ac.jp NR 8 TC 11 Z9 11 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JAN 23 PY 2006 VL 47 IS 4 BP 581 EP 582 DI 10.1016/j.tetlet.2005.11.046 PG 2 WC Chemistry, Organic SC Chemistry GA 002PW UT WOS:000234624600041 ER PT J AU Lodmell, DL Ewalt, LC Parnell, MJ Rupprecht, CE Hanlon, CA AF Lodmell, DL Ewalt, LC Parnell, MJ Rupprecht, CE Hanlon, CA TI One-time intradermal DNA vaccination in ear pinnae one year prior to infection protects dogs against rabies virus SO VACCINE LA English DT Article DE rabies; dogs; one-time DNA vaccination; 100% long-term protection; ear pinna ID NEUTRALIZING ANTIBODY; IMMUNE-RESPONSES; IMMUNIZATION; VACCINES; MICE AB Rabid dog exposures result in > 99% of human rabies deaths worldwide. Ninety-eight percent of these cases occur in developing countries. Thus, the best protection against human rabies would be prevention through adequate vaccination of the reservoir population. The difficulty in re-locating ownerless, freely roaming dogs for booster vaccinations, in addition to poor coverage with inadequate vaccines, suggests that a potentially inexpensive vaccine that elicits long-term protection after a single-dose could improve control of canine rabies in developing countries. One solution could be a DNA vaccine. We have previously determined that dogs vaccinated intradermally (i.d.) in ear pinnae with a rabies DNA vaccine expressing a rabies virus glycoprotein (G) produce high levels of neutralizing antibody that persist for at least 6 months. In the present study, we determined whether a one-time W. rabies DNA vaccination into ear pinnae 1 year before viral challenge would protect dogs against rabies virus. The dogs did not receive a booster vaccination. All dogs (100%) vaccinated W. in each ear pinna with 50 mu g of rabies DNA vaccine, or intramuscular (i.m.) with a commercial canine rabies vaccine survived a lethal dose of rabies vir-us. In contrast, 100% of dogs vaccinated i.m. with 100 mu g of rabies DNA developed rabies, as did 100% of negative control dogs that were vaccinated W. in each ear pinna or i.m. with DNA that did not express the rabies virus G. The data suggest that a one-time W. rabies DNA vaccination into ear pinnae offers a new approach to facilitate control of endemic canine rabies in developing countries. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. Ctr Dis Control, Natl Ctr Infect Dis, Rabies Sect, Viral & Rickettsial Zoonoses Branch,Div Viral & R, Atlanta, GA 30333 USA. RP Lodmell, DL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM dlodmell@nih.gov NR 18 TC 22 Z9 24 U1 0 U2 5 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 JAN 23 PY 2006 VL 24 IS 4 BP 412 EP 416 DI 10.1016/j.vaccine.2005.08.003 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 008OZ UT WOS:000235051600003 PM 16153757 ER PT J AU Simonsen, L Taylor, R Viboud, C Dushoff, J Miller, M AF Simonsen, L Taylor, R Viboud, C Dushoff, J Miller, M TI US flu mortality estimates are based on solid science SO BRITISH MEDICAL JOURNAL LA English DT Letter ID UNITED-STATES; INFLUENZA; IMPACT C1 NIH, Div Epidemiol & Int Populat Studies, Bethesda, MD 20892 USA. RP Simonsen, L (reprint author), NIH, Div Epidemiol & Int Populat Studies, Bldg 10, Bethesda, MD 20892 USA. EM L.Simonsen@niaid.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 NR 5 TC 11 Z9 14 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD JAN 21 PY 2006 VL 332 IS 7534 BP 177 EP 178 DI 10.1136/bmj.332.7534.177-a PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 006OC UT WOS:000234905800034 PM 16424502 ER PT J AU Berezhkovskii, AM Monine, MI Muratov, CB Shvartsman, SY AF Berezhkovskii, AM Monine, MI Muratov, CB Shvartsman, SY TI Homogenization of boundary conditions for surfaces with regular arrays of traps SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CONTROLLED LIGAND-BINDING; DIFFUSION-CONTROLLED RATE; CHRONOAMPEROMETRIC CURRENT; RECEPTORS; MICROELECTRODES; AUTOCRINE C1 Princeton Univ, Dept Chem Engn, Princeton, NJ 08540 USA. Princeton Univ, Lewis Sigler Inst Integrat Genom, Carl Icahn Lab, Princeton, NJ 08544 USA. NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. N Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA. New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. Karpov Inst Phys Chem, Moscow, Russia. RP Berezhkovskii, AM (reprint author), Princeton Univ, Dept Chem Engn, Princeton, NJ 08540 USA. FU Intramural NIH HHS NR 23 TC 29 Z9 29 U1 0 U2 2 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 JAN 21 PY 2006 VL 124 IS 3 AR 036103 DI 10.1063/1.2161196 PG 3 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 004MR UT WOS:000234757400057 PM 16438616 ER PT J AU Rintelman, JM Gordon, MS Fletcher, GD Ivanic, J AF Rintelman, JM Gordon, MS Fletcher, GD Ivanic, J TI A systematic multireference perturbation-theory study of the low-lying states of SiC3 SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CORRELATED MOLECULAR CALCULATIONS; FIELD REFERENCE FUNCTIONS; GAUSSIAN-BASIS SETS; RHOMBOIDAL SIC3; PHOTOELECTRON-SPECTROSCOPY; WAVE-FUNCTIONS; ENERGIES; CLUSTERS; ANIONS; IDENTIFICATION AB The three known lowest-energy isomers of SiC3, two cyclic singlets (2s and 3s) and a linear triplet (1t), have been reinvestigated using multireference second-order perturbation theory (MRPT2). The dependence of the relative energies of the isomers upon the quality of the basis sets and the sizes of the reference active spaces is explored. When using a complete-active-space self-consistent-field reference wave function with 12 electrons in 11 orbitals [CASSCF (12, 11)] together with basis sets that increase in size up to the correlation-consistent polarized core-valence quadruple zeta basis set (cc-pCVQZ), the MRPT2 method consistently predicts the linear triplet to be the most stable isomer. A new parallel direct determinant MRPT2 code has been used to systematically explore reference spaces that vary in size from CASSCF (8,8) to full optimized reaction space [FORS or CASSCF (16,16)] with the cc-pCVQZ basis. It is found that the relative energies of the isomers change substantially as the active space is increased. At the best level of theory, MRPT2 with a full valence FORS reference, the 2s isomer is predicted to be more stable than 3s and 1t by 4.7 and 2.2 kcal/mol, respectively. C1 Iowa State Univ, Dept Chem, Ames, IA 50011 USA. Ames Lab, Ames, IA 50011 USA. Eloret Corp, Sunnyvale, CA 94086 USA. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Rintelman, JM (reprint author), Iowa State Univ, Dept Chem, Ames, IA 50011 USA. EM jivanic@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 44 TC 13 Z9 13 U1 2 U2 5 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 JAN 21 PY 2006 VL 124 IS 3 AR 034303 DI 10.1063/1.2140687 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 004MR UT WOS:000234757400020 PM 16438579 ER PT J AU Wu, LT AF Wu, LT TI Structure and functional characterization of single-strand DNA binding protein SSDP1: Carboxyl-terminal of SSDP1 has transcription activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE SSDP1; transcription factor; nuclear localization ID LDB1; GENE AB LIM-homeodomain transcription factors control a wide range of developmental processes, such as early patterning of the embryonic development, organ formations of brain, limbs, and eyes. Molecular mechanisms of the underlying processes involve complicated multiple protein complexes that direct transcription activation of target genes, protein-protein interactions, and transcriptional regulations. Among those molecules, cofactor Ldb1, interacting with LIM/homeobox family transcription factor, defines a tetrameric protein complex in controlling downstream genes of transcriptional regulation. In addition, SSDP specifically involves this complex supported by showing that both SSDP1 and SSDP2 bind to Ldb1 in vivo. Here it has been found that SSDP1 itself is a transcription factor that has transcription activity independently. Furthermore, C-terminal of SSDP1 possessing an entire transcription activity in vivo, confirmed in both yeast and mammalian cells, has been defined. Interestingly, the transcriptional function of SSDP1 was not required for the interaction with Ldb1. Thus, biochemical data of SSDP1 presented by this study provides biochemical evidence for a better understanding of transcriptional regulation. (c) 2005 Elsevier Inc. All rights reserved. C1 NICHHD, Lab Mammalian Genet & Gene Express, NIH, Bethesda, MD 20892 USA. RP Wu, LT (reprint author), NICHHD, Lab Mammalian Genet & Gene Express, NIH, Bethesda, MD 20892 USA. EM wuliangt@mail.nih.gov FU Intramural NIH HHS NR 10 TC 11 Z9 11 U1 0 U2 0 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 JAN 20 PY 2006 VL 339 IS 3 BP 977 EP 984 DI 10.1016/j.bbrc.2005.11.098 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 000CT UT WOS:000234439200036 PM 16325762 ER PT J AU Kawaguchi, Y Ito, A Appella, E Yao, TP AF Kawaguchi, Y Ito, A Appella, E Yao, TP TI Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RING-FINGER DOMAIN; TETRAMERIZATION DOMAIN; TUMOR-SUPPRESSOR; ACETYLATION; MDM2; EXPORT; PHOSPHORYLATION; UBIQUITINATION; DEACETYLATION; LOCALIZATION AB The basal level of the tumor suppressor p53 is regulated by MDM2-mediated ubiquitination at specific lysines, which leads to p53 nuclear export and degradation. Upon p53 activation, however, these lysines become acetylated by p300/CREB-binding protein. Here we have reported an unexpected finding that p300-mediated acetylation also regulates p53 subcellular localization and can promote cytoplasmic localization of p53. This activity is independent of MDM2 but requires a p53 nuclear export signal and acetylation of multiple lysines by p300. Mechanistically, we showed that conversion of a minimal four of these lysines to alanines but not arginines mimics p300-mediated p53 nuclear export, and these lysine-neutralizing mutations effectively prevent p53 tetramerization, thus exposing the oligomerization-regulated nuclear export signal. Our study suggested a threshold mechanism whereby the degree of acetylation regulates p53 nucleus-cytoplasm trafficking by neutralizing a lysine-dependent charge patch, which in turn, controls oligomerization-dependent p53 nuclear export. C1 Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yao, TP (reprint author), Duke Univ, Dept Pharmacol & Canc Biol, C327,LSRC, Durham, NC 27710 USA. EM yao00001@mc.duke.edu RI Ito, Akihiro/A-6100-2015 FU NCI NIH HHS [CA85676] NR 23 TC 41 Z9 42 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 20 PY 2006 VL 281 IS 3 BP 1394 EP 1400 DI 10.1074/jbc.M505772200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 002ZS UT WOS:000234652000015 PM 16291740 ER PT J AU El Omari, K Ren, J Bird, LE Bona, MK Klarmann, G LeGrice, SFJ Stammers, DK AF El Omari, K Ren, J Bird, LE Bona, MK Klarmann, G LeGrice, SFJ Stammers, DK TI Molecular architecture and ligand recognition determinants for T4 RNA ligase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BACTERIOPHAGE-T4 ANTICODON NUCLEASE; ELECTRON-DENSITY MAPS; CRYSTAL-STRUCTURE; DNA-LIGASE; NUCLEOTIDYL TRANSFER; CAPPING ENZYME; PROTEIN; MECHANISM; PURIFICATION; SUPERFAMILY AB RNA ligase type 1 from bacteriophage T4 ( Rnl1) is involved in countering a host defense mechanism by repairing 5'-PO4 and 3'-OH groups in tRNALys. Rnl1 is widely used as a reagent in molecular biology. Although many structures for DNA ligases are available, only fragments of RNA ligases such as Rnl2 are known. We report the first crystal structure of a complete RNA ligase, Rnl1, in complex with adenosine 5'-(alpha,beta-methylenetriphosphate) (AMPcPP). The N- terminal domain is related to the equivalent region of DNA ligases and Rnl2 and binds AMPcPP but with further interactions from the additional N- terminal 70 amino acids in Rnl1 (via Tyr37 and Arg54) and the C-terminal domain (Gly269 and Asp272). The active site contains two metal ions, consistent with the two-magnesium ion catalytic mechanism. The C-terminal domain represents a new all alpha-helical fold and has a charge distribution and architecture for helix-nucleic acid groove interaction compatible with tRNA binding. C1 Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford OX3 7BN, England. Sci Appl Int Co, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Stammers, DK (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Roosevelt Dr, Oxford OX3 7BN, England. EM daves@strubi.ox.ac.uk OI Bird, Louise/0000-0002-9846-5716; El Omari, Kamel/0000-0003-3506-6045 FU NCI NIH HHS [N01-CO-12400] NR 32 TC 39 Z9 40 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 20 PY 2006 VL 281 IS 3 BP 1573 EP 1579 DI 10.1074/jbc.M509658200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 002ZS UT WOS:000234652000035 PM 16263720 ER PT J AU Bassal, M Mertens, AC Taylor, L Neglia, JP Greffe, BS Hammond, S Ronckers, CM Friedman, DL Stovall, M Yasui, YY Robison, LL Meadows, AT Kadan-Lottick, NS AF Bassal, M Mertens, AC Taylor, L Neglia, JP Greffe, BS Hammond, S Ronckers, CM Friedman, DL Stovall, M Yasui, YY Robison, LL Meadows, AT Kadan-Lottick, NS TI Risk of selected subsequent carcinomas in survivors of childhood cancer: A report from the childhood cancer survivor study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 05-08, 2004 CL New Orleans, LA SP Amer Soc Clin Oncol ID 2ND MALIGNANT NEOPLASMS; RENAL-CELL CARCINOMA; SALIVARY-GLAND TUMORS; LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; HODGKINS-DISEASE; BREAST-CANCER; 5-YEAR SURVIVORS; LATE MORTALITY AB Purpose To determine the risk of subsequent carcinomas other than breast, thyroid, and skin, and to identify factors that influence the risk among survivors of childhood cancer. Patients and Methods Subsequent malignant neoplasm history was determined in 13,136 participants (surviving ! 5 years postmalignancy, diagnosed from 1970 to 1986 at age < 21 years) of the Childhood Cancer Survivor Study to calculate standardized incidence ratios (SIRs), using Surveillance, Epidemiology, and End Results data. Results In 71 individuals, 71 carcinomas were diagnosed at a median age of 27 years and a median elapsed time of 15 years in the genitourinary system (35%), head and neck area (32%), gastrointestinal tract (23%), and other sites (10%). Fifty-nine patients (83%) had received radiotherapy, and 42 (59%) developed a second malignant neoplasm in a previous radiotherapy field. Risk was significantly elevated following all childhood diagnoses except CNS neoplasms, and was highest following neuroblastoma (SIR = 24.2) and soft tissue sarcoma (SIR = 6.2). Survivors of neuroblastoma had a 329-fold increased risk of renal cell carcinomas; survivors of Hodgkin's lymphoma had a 4.5-fold increased risk of gastrointestinal carcinomas. Significantly elevated risk of head and neck carcinoma occurred in survivors of soft tissue sarcoma (SIR = 22.6), neuroblastoma (SIR = 20.9), and leukemia (SIR = 20.9). Conclusion Young survivors of childhood cancers are at increased risk of developing subsequent carcinomas typical of later adulthood, underscoring the importance of long-term follow-up and risk-based screening. Follow-up of the cohort is ongoing to determine lifetime risk and delineate individual characteristics that contribute to risk. C1 Yale Univ, Sch Med, Dept Pediat, Sect Pediat Hematol Oncol, New Haven, CT 06520 USA. Univ Colorado, Div Pediat Hematol Oncol BMT, Hlth Sci Ctr, Denver, CO 80202 USA. Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98104 USA. Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Pediat, Seattle, WA 98195 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Alberta, Dept Publ Hlth Sci, Edmonton, AB, Canada. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. RP Kadan-Lottick, NS (reprint author), Yale Univ, Sch Med, Dept Pediat, Sect Pediat Hematol Oncol, 333 Cedar St,LMP 2073,POB 208064, New Haven, CT 06520 USA. EM nina.kadan-lottick@yale.edu FU NCI NIH HHS [U24-CA55727]; NCRR NIH HHS [K12RR17594] NR 43 TC 146 Z9 151 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2006 VL 24 IS 3 BP 476 EP 483 DI 10.1200/JCO.2005.02.7235 PG 8 WC Oncology SC Oncology GA 004TX UT WOS:000234776300025 PM 16421424 ER PT J AU Widemann, BC Salzer, WL Arceci, RJ Blaney, SM Fox, E End, D Gillespie, A Whitcomb, P Palumbo, JS Pitney, A Jayaprakash, N Zannikos, P Balis, FM AF Widemann, BC Salzer, WL Arceci, RJ Blaney, SM Fox, E End, D Gillespie, A Whitcomb, P Palumbo, JS Pitney, A Jayaprakash, N Zannikos, P Balis, FM TI Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROTEIN TRANSFERASE INHIBITOR; ADVANCED CANCER; HEMATOLOGIC MALIGNANCIES; R115777; COMBINATION; THERAPY; GEMCITABINE AB Purpose This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1)-related plexiform neurofibromas. Patients and Methods Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m(2)/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m(2)/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation. Results Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m(2)/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m(2)/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m(2)/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs. Conclusion Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m(2)/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Hosp & Med Ctr, Cincinnati, OH USA. Texas Childrens Canc Ctr, Houston, TX USA. Janssen Res Fdn, B-2340 Beerse, Belgium. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Room 1-5750,MSC 1101, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov FU Intramural NIH HHS NR 28 TC 85 Z9 88 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2006 VL 24 IS 3 BP 507 EP 516 DI 10.1200/JCO.2005.03.8638 PG 10 WC Oncology SC Oncology GA 004TX UT WOS:000234776300029 PM 16421428 ER PT J AU Gomez-Roman, VR Florese, RH Patterson, LJ Peng, B Venzon, D Aldrich, K Robert-Guroff, M AF Gomez-Roman, VR Florese, RH Patterson, LJ Peng, B Venzon, D Aldrich, K Robert-Guroff, M TI A simplified method for the rapid fluorometric assessment of antibody-dependent cell-mediated cytotoxicity SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE ADCC; FATAL; HIV vaccine; flow cytometry; PKH-26; CFSE ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOMETRY-BASED ASSAY; HERPES-SIMPLEX-VIRUS; RHESUS MACAQUES; PROTECTIVE IMMUNITY; INFECTED-CELLS; CYTO-TOXICITY; KILLER-CELLS; GP120; GLYCOPROTEIN AB We demonstrate that the FATAL cytolysis assay can be adapted into a rapid and fluorometric antibody-dependent cellular cytotoxicity assay (RFADCC). The RFADCC relies on double-staining target cells with a membrane dye (PKH-26) and a viability dye (CFSE) prior to the addition of antibody and effector cells. We used the RFADCC to assess dose-dependent and envelope-specific anti-human immunodeficiency virus (HIV) ADCC responses mediated by monoclonal antibody-2GI2 and human sera. Using the assay, we also detected early anti-simian immunodeficiency virus (SIV) ADCC responses in rhesus macaques infected with pathogenic SIVmac251. Importantly, the RFADCC was further useful in monitoring anti-HIV and anti-SIV ADCC responses elicited by immunizing chimpanzees and rhesus macaques with replicating adenovirus-based AIDS vaccine candidates. In comparison to the standard chromium release assay, the RFADCC provides a higher cell killing readout and is advantageous in allowing use of viably frozen as well as fresh effector cells, thus facilitating assay standardization. The RFADCC is therefore a simple, reliable, and highly sensitive method that can be applied to assess the ADCC activity of monoclonal antibodies as well as ADCC responses elicited by HIV or SIV infection or by AIDS vaccine candidates. (c) 2005 Elsevier B.V. All rights reserved. C1 NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, 41 Medlars Dr,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Venzon, David/B-3078-2008 FU Intramural NIH HHS NR 38 TC 103 Z9 107 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JAN 20 PY 2006 VL 308 IS 1-2 BP 53 EP 67 DI 10.1016/j.jim.2005.09.018 PG 15 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 011RL UT WOS:000235285700006 PM 16343526 ER PT J AU Goth, SR Chu, RA Pessah, IN AF Goth, SR Chu, RA Pessah, IN TI Oxygen tension regulates the in vitro maturation of GM-CSF expanded murine bone marrow dendritic cells by modulating class II MHC expression SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE dendritic cell; bone marrow; mycloid; oxygen tension; class II MHC; 2-mercaptoethanol ID GENERATION AB Conventional culture conditions for GM-CSF expanded murine bone marrow derived dendritic cells (BMDCs) uses ambient (hyperoxic) oxygen pressure (20% v/v, 152 Torr) and medium supplemented with the thiol 2-mercaptoethanol (2-Me). Given the redox activities of O-2 and 2-Me, the effects of 2%, 5%, 10%, and 20% v/v 02 atmospheres and omitting 2-Me from the medium were tested upon the generation of GM-CSF expanded BMDCs. DC yield, phenotype and function were compared to BMDCs grown using conventional conditions. All cultures yielded DC subsets with CD11c(+) MHC IINEG, CD11c(+) MHC IIINT, CD11c(+) MHC IIHI. expression phenotypes, classed as precursor, immature, and mature DCs (IDC, MDC). Low 02 tensions generated significantly fewer precursor DCs, and more lDCs and MDCs. Cytometer sorted precursor DCs expressed surface class 11 MHC after transfer to low, but not high O-2 atmospheres. Expression of myeloid markers was similar between BMDC cultures generated in 5% O-2 or conventional conditions, and MDCs from low O-2 cultures had the morphology typical of mature myeloid DCs. lDCs and MDCs from low O-2 and conventional culture conditions were similarly potent allostimulatory APCs. The O-2 tension (but not 2-Me addition) in vitro significantly influences overall DC subset frequencies and yield, and governs DC maturation by regulating the surface class 11 MHC expression of GM-CSF expanded BMDC cultures. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Calif Davis, Ctr Childrens Environm Hlth, NIEHS, Davis, CA 95616 USA. Univ Calif Davis, Sch Vet Med Mol Biosci, Davis, CA 95616 USA. Univ Calif Davis, MIND Inst, Sacramento, CA 95817 USA. RP Goth, SR (reprint author), Univ Calif Davis, Ctr Childrens Environm Hlth, NIEHS, Davis, CA 95616 USA. EM srgoth@ucdavis.edu FU NIEHS NIH HHS [P01 ES11269] NR 10 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JAN 20 PY 2006 VL 308 IS 1-2 BP 179 EP 191 DI 10.1016/j.jim.2005.10.012 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 011RL UT WOS:000235285700017 PM 16406060 ER PT J AU Harris, A Belnap, DM Watts, NR Conway, JF Cheng, N Stahl, SJ Vethanayagam, JG Wingfield, PT Steven, AC AF Harris, A Belnap, DM Watts, NR Conway, JF Cheng, N Stahl, SJ Vethanayagam, JG Wingfield, PT Steven, AC TI Epitope diversity of hepatitis B virus capsids: Quasi-equivalent variations in spike epitopes and binding of different antibodies to the same epitope SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE antibody-antigen interaction; quasi-equivalence; conformational epitope; discontinuous epitope; cryo-electron microscopy ID X-RAY CRYSTALLOGRAPHY; CORE ANTIGEN; CRYOELECTRON MICROSCOPY; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; DENSITY MAPS; ELECTRON-MICROSCOPY; C-TERMINUS; PROTEIN AB To investigate the range of antigenic variation of HBV capsids, we have characterized the epitopes for two anti-capsid antibodies by cryo-electron microscopy and image reconstruction of Fab-labeled capsids to similar to 10 angstrom resolution followed by molecular modeling. Both antibodies engage residues on the protruding spikes but their epitopes and binding orientations differ. Steric interference effects limit maximum binding to similar to 50% average occupancy in each case. However, the occupancies of the two copies of a given epitope that are present on a single spike differ, reflecting subtle distinctions in structure and hence, binding affinity, arising from quasi-equivalence. The epitope for mAb88 is conformational but continuous, consisting of a loop-helix motif (residues 77-87) on one of the two polypeptide chains in the spike. In contrast, the epitope for mAb842, like most conformational epitopes, is discontinuous, consisting of a loop on one polypeptide chain (residues 74-78) combined with a loop-helix element (residues 78-83) on the other. The epitope of mAb842 is essentially identical with that previously mapped for mAb F11A4, although the binding orientations of the two monoclonal antibodies (mAbs) differ, as do their affinities measured by surface plasmon resonance. From the number of monoclonals (six) whose binding had to be characterized to give the first duplicate epitope, we estimate the total number of core antigen (cAg) epitopes to be of the order of 20. Given that different antibodies may share the same epitope, the potential number of distinct anti-cAg clones should be considerably higher. The observation that the large majority of cAg epitopes are conformational reflects the relative dimensions of a Fab (large) and the small size and close packing of the motifs that are exposed and accessible on the capsid surface. Published by Elsevier Ltd. C1 NIH, Struct Biol Lab, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. Inst Biol Struct JP Ebel, Lab Microscopie Electron, F-38027 Grenoble, France. RP Steven, AC (reprint author), NIH, Struct Biol Lab, Bethesda, MD 20892 USA. EM alasdair_steven@nih.gov RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 FU Intramural NIH HHS NR 66 TC 22 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 20 PY 2006 VL 355 IS 3 BP 562 EP 576 DI 10.1016/j.jmb.2005.10.035 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 002KF UT WOS:000234609600018 PM 16309704 ER PT J AU Maraia, RJ Bayfield, MA AF Maraia, RJ Bayfield, MA TI The La protein-RNA complex surfaces - Minireview SO MOLECULAR CELL LA English DT Review ID POLYMERASE-III; BINDING; RECOGNITION; DOMAIN; MOTIF; ANTIGEN; RNPS; RO AB A recent issue of Molecular Cell reported that the typical nucleic acid binding surfaces of the FIRM and winged-helix motifs, although present in the RNA binding protein La, are not used to engage its best-characterized ligand, 3' UUU-OH. Instead, La uses edgewise and backsides of these motifs for UUU-OH recognition, leaving open their typical surfaces for other potential interactions. These observations provide a framework for appreciating the various activities attributed to this ubiquitous nuclear phosphoprotein, which include its principal function, snRNA 3' end protection, in addition to mRNA-related and RNA chaperone-like activities, as well as DNA and chromatin-associated activity. C1 NICHHD, NIH, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. RP Maraia, RJ (reprint author), NICHHD, NIH, Lab Mol Growth Regulat, 31 Ctr Dr,2A25, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov NR 20 TC 39 Z9 39 U1 2 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 20 PY 2006 VL 21 IS 2 BP 149 EP 152 DI 10.1016/j.molcel.2006.01.004 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 007BR UT WOS:000234943000004 PM 16427005 ER PT J AU Lou, ZK Minter-Dykhouse, K Franco, S Gostissa, M Rivera, MA Celeste, A Manis, JP van Deursen, J Nussenzweig, A Paull, TT Alt, FW Chen, JJ AF Lou, ZK Minter-Dykhouse, K Franco, S Gostissa, M Rivera, MA Celeste, A Manis, JP van Deursen, J Nussenzweig, A Paull, TT Alt, FW Chen, JJ TI MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals SO MOLECULAR CELL LA English DT Article ID DOUBLE-STRAND BREAKS; HISTONE H2AX PHOSPHORYLATION; CLASS-SWITCH RECOMBINATION; IONIZING-RADIATION; ATAXIA-TELANGIECTASIA; RESPONSE PATHWAYS; DEFICIENT MICE; REPAIR FACTORS; ACTIVATION; 53BP1 AB MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1(-/-) mice recapitulated many phenotypes of H2AX(-/-) mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability. C1 Mayo Clin, Dept Oncol, Rochester, MN 55905 USA. Mayo Clin, Dept Pediat & Adolescent Med, Rochester, MN 55905 USA. Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med Inst,Dept Genet, Boston, MA 02115 USA. CBR Inst Biomed Res, Boston, MA 02115 USA. Univ Texas, Dept Mol Genet & Microbiol, Inst Cellular & Mol Biol, Austin, TX 78712 USA. NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Chen, JJ (reprint author), Mayo Clin, Dept Oncol, Rochester, MN 55905 USA. EM chen.junjie@mayo.edu RI Minter Dykhouse, Katherine/L-4573-2013 OI Minter Dykhouse, Katherine/0000-0003-4363-5826 FU NCI NIH HHS [CA92312, R01 CA89239] NR 44 TC 350 Z9 374 U1 2 U2 20 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 20 PY 2006 VL 21 IS 2 BP 187 EP 200 DI 10.1016/j.molcel.2005.11.025 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 007BR UT WOS:000234943000008 PM 16427009 ER PT J AU Galanis, J Harries, D Sackett, DL Losert, W Nossal, R AF Galanis, J Harries, D Sackett, DL Losert, W Nossal, R TI Spontaneous patterning of confined granular rods SO PHYSICAL REVIEW LETTERS LA English DT Article ID ISOTROPIC-NEMATIC TRANSITION; LIQUID-CRYSTALS; SUSPENSIONS AB Vertically vibrated rod-shaped granular materials confined to quasi-2D containers self-organize into distinct patterns. We find, consistent with theory and simulation, a density dependent isotropic-nematic transition. Along the walls, rods interact sterically to form a wetting layer. For high rod densities, complex patterns emerge as a result of competition between bulk and boundary alignment. A continuum elastic energy accounting for nematic distortion and local wall anchoring reproduces the structures seen experimentally. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Phys, IPST, College Pk, MD 20742 USA. Univ Maryland, Dept Phys, IREAP, College Pk, MD 20742 USA. RP Galanis, J (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. RI Harries, Daniel/F-7016-2012 OI Harries, Daniel/0000-0002-3057-9485 FU Intramural NIH HHS NR 22 TC 56 Z9 57 U1 0 U2 14 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JAN 20 PY 2006 VL 96 IS 2 AR 028002 DI 10.1103/PhysRevLett.96.028002 PG 4 WC Physics, Multidisciplinary SC Physics GA 004MY UT WOS:000234758100102 PM 16486645 ER PT J AU Wu, XL Luke, BT Burgess, SM AF Wu, XL Luke, BT Burgess, SM TI Redefining the common insertion site SO VIROLOGY LA English DT Article DE insertion site; gene; tumorigenesis ID CANCER; GENES; IDENTIFICATION; GENOME; LEUKEMIA; MICE AB Retroviral mutagenesis has been used as a powerful tool to discover genes involved in oncogenesis through a technique called Common Insertion Site (CIS) analysis where tumors are induced by proviral integrations and the genomic loci of the proviruses are identified. A fundamental assumption made in this analysis is that multiple proviral insertions in close proximity occurring more frequently than would be predicted randomly provides evidence that the genes near the integrations are involved in the formation of the tumors. We demonstrate here using data derived from MLV integrations not put under selection for tumor induction that CIS analysis as currently defined is often not a sufficient argument for a gene's significance in tumorigenesis. (C) 2005 Elsevier Inc. All rights reserved. C1 NHGRI, Dev Genom Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Mol Technol, Sci Applicat Int Corp Frederick, NIH, Frederick, MD 21701 USA. NCI, Adv Biomed Comp Ctr, Sci Applicat Int Corp Frederick, NIH, Frederick, MD 21701 USA. RP Burgess, SM (reprint author), NHGRI, Dev Genom Sect, Genome Technol Branch, NIH, Bldg 50,Rm 5537,MSC 8004,50 South Dr, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI Burgess, Shawn/0000-0003-1147-0596 FU NCI NIH HHS [N01-CO-12400] NR 11 TC 46 Z9 47 U1 0 U2 0 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 JAN 20 PY 2006 VL 344 IS 2 BP 292 EP 295 DI 10.1016/j.virol.2005.08.047 PG 4 WC Virology SC Virology GA 004UD UT WOS:000234776900005 PM 16271739 ER PT J AU Teterina, NL Gorbalenya, AE Egger, D Bienz, K Rinaudo, MS Ehrenfeld, E AF Teterina, NL Gorbalenya, AE Egger, D Bienz, K Rinaudo, MS Ehrenfeld, E TI Testing the modularity of the N-terminal amphipathic helix conserved in picornavirus 2C proteins and hepatitis CNS5A protein SO VIROLOGY LA English DT Article DE poliovirus; hepatitis C virus; chimera; protein 2C; amphipathic helix; membrane anchor; polyprotein processing; replication complex ID RIBOSOMAL ENTRY SITE; VIRUS NONSTRUCTURAL PROTEINS; MULTIPLE SEQUENCE ALIGNMENT; VIRAL REPLICATION COMPLEX; STRAND RNA-SYNTHESIS; DOUBLE-MEMBRANE VESICLES; C VIRUS; ENDOPLASMIC-RETICULUM; POLIOVIRUS 2C; INTRACELLULAR MEMBRANE AB The N-terminal region of the picornaviral 2C protein is predicted to fold into an amphipathic a-helix that is responsible for the protein's association with membranes in the viral RNA replication complex. We have identified a similar sequence in the N-terminal region of NS5A of hepaciviruses that was recently shown to form an amphipathic a-helix. The conservation of the N-terminal region in two apparently unrelated proteins of two different RNA virus families suggested that this helix might represent an independent module. To test this hypothesis, we constructed chimeric poliovirus (PV) genomes in which the sequence encoding the N-terminal 2C amphipathic helix was replaced by orthologous sequences from other picornaviral genomes or a similar sequence from NS5A of HCV. Effects of the mutations were assessed by measuring the accumulation of viable virus and viral RNA in HeLa cells after transfection, examining membrane morphology in cells expressing chimeric proteins and by in vitro analysis of RNA translation, protein processing and negative strand RNA synthesis in HeLa cell extracts. The chimeras manifested a wide range of growth and RNA synthesis phenotypes. The results are compatible with our hypothesis, although they demonstrate that helix exchangeability may be restricted due to requirements for interactions with other viral components involved in virus replication. Published by Elsevier Inc. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Leiden Univ, Med Ctr, Dept Med Microbiol, NL-2300 RA Leiden, Netherlands. Univ Basel, Inst Med Microbiol, Basel, Switzerland. RP Teterina, NL (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6122,50 South Dr, Bethesda, MD 20892 USA. EM nteterina@niaid.nih.gov RI Gorbalenya, Alexander/J-4818-2012 OI Gorbalenya, Alexander/0000-0002-4967-7341 FU Intramural NIH HHS NR 71 TC 28 Z9 28 U1 0 U2 0 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 JAN 20 PY 2006 VL 344 IS 2 BP 453 EP 467 DI 10.1016/j.virol.2005.08.044 PG 15 WC Virology SC Virology GA 004UD UT WOS:000234776900020 PM 16226781 ER PT J AU Yi, M Horton, JD Cohen, JC Hobbs, HH Stephens, RM AF Yi, M Horton, JD Cohen, JC Hobbs, HH Stephens, RM TI WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data SO BMC BIOINFORMATICS LA English DT Article ID BILIARY CHOLESTEROL SECRETION; GENE-EXPRESSION PATTERNS; DIETARY-CHOLESTEROL; NETWORKS; CANCER; DISCOVERY; DIFFERENTIATION; ACCUMULATION; MICROARRAYS; DATABASES AB Background: Analysis of High Throughput (HTP) Data such as microarray and proteomics data has provided a powerful methodology to study patterns of gene regulation at genome scale. A major unresolved problem in the post-genomic era is to assemble the large amounts of data generated into a meaningful biological context. We have developed a comprehensive software tool, WholePathwayScope (WPS), for deriving biological insights from analysis of HTP data. Result: WPS extracts gene lists with shared biological themes through color cue templates. WPS statistically evaluates global functional category enrichment of gene lists and pathway-level pattern enrichment of data. WPS incorporates well-known biological pathways from KEGG (Kyoto Encyclopedia of Genes and Genomes) and Biocarta, GO (Gene Ontology) terms as well as user-defined pathways or relevant gene clusters or groups, and explores gene-term relationships within the derived gene-term association networks (GTANs). WPS simultaneously compares multiple datasets within biological contexts either as pathways or as association networks. WPS also integrates Genetic Association Database and Partial MedGene Database for disease-association information. We have used this program to analyze and compare microarray and proteomics datasets derived from a variety of biological systems. Application examples demonstrated the capacity of WPS to significantly facilitate the analysis of HTP data for integrative discovery. Conclusion: This tool represents a pathway-based platform for discovery integration to maximize analysis power. The tool is freely available at http://www.abcc.ncifcrf.gov/wps/wps index.php. C1 NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21702 USA. Univ Texas, SW Med Ctr, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Mol Genet, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA. RP Stephens, RM (reprint author), NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21702 USA. EM myi@ncifcrf.gov; Jay.Horton@utsouthwestern.edu; Jonathan.Cohen@utsouthwestern.edu; Helen.Hobbs@utsouthwestern.edu; bobs@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NHLBI NIH HHS [R01 HL72304, UO1 HL66880, R01 HL072304, U01 HL066880] NR 49 TC 134 Z9 141 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JAN 19 PY 2006 VL 7 AR 30 DI 10.1186/1471-2105-7-30 PG 24 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 019GX UT WOS:000235824700001 PM 16423281 ER PT J AU Cisneros, GA Wang, M Silinski, P Fitzgerald, MC Yang, WT AF Cisneros, GA Wang, M Silinski, P Fitzgerald, MC Yang, WT TI Theoretical and experimental determination on two substrates turned over by 4-oxalocrotonate tautomerase SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID MINIMUM-ENERGY PATHS; ELASTIC BAND METHOD; STRUCTURAL BASIS; PERTURBED PK(A); MUTATIONS; RESIDUES; CATALYSIS; ENZYMES; PROTEIN; VALUES AB Quantum mechanical/molecular mechanical (QM/MM) calculations and experimental kinetic studies have been performed on 4-oxalocrotonate tautomerase (4OT) for two different substrates, 2-hydroxymuconate (2HM) and 2-oxo-4-hexenedioate (2o4hex). Potential (Delta E) and free energy (Delta G) paths for both steps of the reaction using both substrates were calculated to determine the free energy barriers and compared to the experimental values obtained from the kinetic studies via the transition state theory. In the first step, a proton from the hydroxyl oxygen on the second carbon of 2HM, or from the third carbon of 2o4hex, is abstracted by Pro-1. In the second step, the proton is transferred to the fifth carbon of the substrate to form the product, 2-oxo-3-hexenedioate (2o3hex). For both substrates we obtain a calculated Delta G of approximate to 13 kcal/mol, in agreement with experimental determinations. The calculated free energy barrier difference Delta G(2o4hex) -Delta G(2HM) (Delta Delta G) is 0.87 kcal/mol. We obtained an experimental AAG of 0.85 kcal/mol. These results suggest that 2HM is turned over faster than 2o4hex by 4OT. However, these energy differences are so small that both 2HM and 2o4hex need to be taken into account in considering the mechanism of catalysis of 4OT. C1 Duke Univ, Dept Chem, Durham, NC 27708 USA. Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27707 USA. RP Cisneros, GA (reprint author), Duke Univ, Dept Chem, Box 90346, Durham, NC 27708 USA. RI Yang, Weitao/C-1109-2008; Cisneros, Gerardo/B-3128-2010; Fitzgerald, Michael/E-3392-2010 NR 31 TC 15 Z9 15 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD JAN 19 PY 2006 VL 110 IS 2 BP 700 EP 708 DI 10.1021/jp0543328 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 003RJ UT WOS:000234699000039 PM 16405343 ER PT J AU Li, X Wang, E Zhao, YD Ren, JQ Jin, P Yao, KT Marincola, FM AF Li, X Wang, E Zhao, YD Ren, JQ Jin, P Yao, KT Marincola, FM TI Chromosomal imbalances in nasopharyngeal carcinoma: a meta-analysis of comparative genomic hybridization results SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID DIFFERENTIALLY EXPRESSED GENES; SQUAMOUS-CELL CARCINOMA; PROMOTER HYPERMETHYLATION; TUMOR PROGRESSION; C-MYC; CANCER; ARRAY; LINES; 3Q; IDENTIFICATION AB Nasopharyngeal carcinoma (NPC) is a highly prevalent disease in Southeast Asia and its prevalence is clearly affected by genetic background. Various theories have been suggested for its high incidence in this geographical region but to these days no conclusive explanation has been identified. Chromosomal imbalances identifiable through comparative genomic hybridization may shed some light on common genetic alterations that may be of relevance to the onset and progression of NPC. Review of the literature, however, reveals contradictory results among reported findings possibly related to factors associated with patient selection, stage of disease, differences in methodological details etc. To increase the power of the analysis and attempt to identify commonalities among the reported findings, we performed a meta-analysis of results described in NPC tissues based on chromosomal comparative genomic hybridization (CGH). This meta-analysis revealed consistent patters in chromosomal abnormalities that appeared to cluster in specific "hot spots" along the genome following a stage-dependent progression. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. So Med Univ, Coll Basic Med, Dept Pathol, Guangzhou 510515, Guangdong, Peoples R China. So Med Univ, Coll Basic Med, Canc Res Inst, Guangzhou 510515, Guangdong, Peoples R China. NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM lixin2@cc.nih.gov; Ewang@cc.nih.gov; Zhaoy@mail.nih.gov; renj@cc.nih.gov; pingj@cc.nih.gov; ktyao@fimmu.com; FMarincola@cc.nih.gov NR 51 TC 56 Z9 58 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 19 PY 2006 VL 4 AR 4 DI 10.1186/1479-5876-4-4 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 023KI UT WOS:000236125200001 PM 16423296 ER PT J AU Nusbaum, C Mikkelsen, TS Zody, MC Asakawa, S Taudien, S Garber, M Kodira, CD Schueler, MG Shimizu, A Whittaker, CA Chang, JL Cuomo, CA Dewar, K FitzGerald, MG Yang, XP Allen, NR Anderson, S Asakawa, T Blechschmidt, K Bloom, T Borowsky, ML Butler, J Cook, A Corum, B DeArellano, K DeCaprio, D Dooley, KT Dorris, L Engels, R Glockner, G Hafez, N Hagopian, DS Hall, JL Ishikawa, SK Jaffe, DB Kamat, A Kudoh, J Lehmann, R Lokitsang, T Macdonald, P Major, JE Matthews, CD Mauceli, E Menzel, U Mihalev, AH Minoshima, S Murayama, Y Naylor, JW Nicol, R Nguyen, C O'Leary, SB O'Neill, K Parker, SCJ Polley, A Raymond, CK Reichwald, K Rodriguez, J Sasaki, T Schilhabel, M Siddiqui, R Smith, CL Sneddon, TP Talamas, JA Tenzin, P Topham, K Venkataraman, V Wen, GP Yamazaki, S Young, SK Zeng, QD Zimmer, AR Rosenthal, A Birren, BW Platzer, M Shimizu, N Lander, ES AF Nusbaum, C Mikkelsen, TS Zody, MC Asakawa, S Taudien, S Garber, M Kodira, CD Schueler, MG Shimizu, A Whittaker, CA Chang, JL Cuomo, CA Dewar, K FitzGerald, MG Yang, XP Allen, NR Anderson, S Asakawa, T Blechschmidt, K Bloom, T Borowsky, ML Butler, J Cook, A Corum, B DeArellano, K DeCaprio, D Dooley, KT Dorris, L Engels, R Glockner, G Hafez, N Hagopian, DS Hall, JL Ishikawa, SK Jaffe, DB Kamat, A Kudoh, J Lehmann, R Lokitsang, T Macdonald, P Major, JE Matthews, CD Mauceli, E Menzel, U Mihalev, AH Minoshima, S Murayama, Y Naylor, JW Nicol, R Nguyen, C O'Leary, SB O'Neill, K Parker, SCJ Polley, A Raymond, CK Reichwald, K Rodriguez, J Sasaki, T Schilhabel, M Siddiqui, R Smith, CL Sneddon, TP Talamas, JA Tenzin, P Topham, K Venkataraman, V Wen, GP Yamazaki, S Young, SK Zeng, QD Zimmer, AR Rosenthal, A Birren, BW Platzer, M Shimizu, N Lander, ES TI DNA sequence and analysis of human chromosome 8 SO NATURE LA English DT Article ID HUMAN GENOME; BRAIN SIZE; CHROMOSOME; DEFENSINS; MICROCEPHALIN; ANNOTATION; MUTATION; DATABASE; HISTORY; GENES AB The International Human Genome Sequencing Consortium (IHGSC) recently completed a sequence of the human genome(1). As part of this project, we have focused on chromosome 8. Although some chromosomes exhibit extreme characteristics in terms of length, gene content, repeat content and fraction segmentally duplicated, chromosome 8 is distinctly typical in character, being very close to the genome median in each of these aspects. This work describes a finished sequence and gene catalogue for the chromosome, which represents just over 5% of the euchromatic human genome. A unique feature of the chromosome is a vast region of similar to 15 megabases on distal 8p that appears to have a strikingly high mutation rate, which has accelerated in the hominids relative to other sequenced mammals. This fast-evolving region contains a number of genes related to innate immunity and the nervous system, including loci that appear to be under positive selection(2)-these include the major defensin (DEF) gene cluster(3,4) and MCPH1(5,6), a gene that may have contributed to the evolution of expanded brain size in the great apes. The data from chromosome 8 should allow a better understanding of both normal and disease biology and genome evolution. C1 MIT, Broad Inst, Cambridge, MA 02141 USA. Harvard Univ, Cambridge, MA 02141 USA. Keio Univ, Sch Med, Dept Mol Biol, Shinjuku Ku, Tokyo 1608582, Japan. Inst Mol Biotechnol, D-07745 Jena, Germany. NHGRI, NIH, Bethesda, MD 20982 USA. UCL, Dept Biol, Galton Lab, HGNC, London NW1 2HE, England. RP Nusbaum, C (reprint author), MIT, Broad Inst, 320 Charles St, Cambridge, MA 02141 USA. EM chad@broad.mit.edu; shimizu@dmb.med.keio.ac.jp RI Mikkelsen, Tarjei/A-1306-2007; Glockner, Gernot/A-7800-2010; OI Mikkelsen, Tarjei/0000-0002-8133-3135; Glockner, Gernot/0000-0002-9061-1061; Sneddon, Tam Paterson/0000-0003-1137-8992; Engels, Reinhard/0000-0003-0921-0736; Cuomo, Christina/0000-0002-5778-960X FU Medical Research Council [G0000107] NR 32 TC 59 Z9 450 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 19 PY 2006 VL 439 IS 7074 BP 331 EP 335 DI 10.1038/nature04406 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 003LA UT WOS:000234682100044 PM 16421571 ER PT J AU Hartman, JM Berger, A Baker, K Bolle, J Handel, D Mannes, A Pereira, D St Germain, D Ronsaville, D Sonbolian, N Torvik, S Calis, KA Phillips, TM Cizza, G AF Hartman, Jill M. Berger, Ann Baker, Karen Bolle, Jacques Handel, Daniel Mannes, Andrew Pereira, Donna St Germain, Diane Ronsaville, Donna Sonbolian, Nina Torvik, Sara Calis, Karim A. Phillips, Terry M. Cizza, Giovanni CA POWER Study Grp TI Quality of life and pain in premenopausal women with major depressive disorder: The POWER Study SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article ID CHRONIC-FATIGUE-SYNDROME; SERUM-LEVELS; SF-36; RISK; EPIDEMIOLOGY; FIBROMYALGIA; ILLNESS AB Background: Whereas it is established that organic pain may induce depression, it is unclear whether pain is more common in healthy subjects with depression. We assessed the prevalence of pain in premenopausal women with major depression (MDD). Subjects were 21- to 45-year-old premenopausal women with MDD (N = 70; age: 35.4 +/- 6.6; mean +/- SD) and healthy matched controls (N = 36; age 35.4 +/- 6.4) participating in a study of bone turnover, the P.O.W.E.R. (Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression) Study. Methods: Patients received a clinical assessment by a pain specialist, which included the administration of two standardized forms for pain, the Brief Pain Inventory - Short Form, and the Initial Pain Assessment Tool, and two scales of everyday stressors, the Hassles and Uplifts Scales. In addition, a quality-of-life instrument, the SF-36, was used. The diagnosis of MDD was established by a semi-structured interview, according to the DSM-IV criteria. Substance P (SP) and calcitonin-gene-related-peptide (CGRP), neuropeptides which are known mediators of pain, were measured every hour for 24 h in a subgroup of patients (N = 17) and controls (N = 14). Results: Approximately one-half of the women with depression reported pain of mild intensity. Pain intensity was significantly correlated with the severity of depression (r(2) = 0.076; P = 0.04) and tended to be correlated with the severity of anxiety, (r(2) = 0.065; P = 0.07), and the number of depressive episodes (r(2) = 0.072; P = 0.09). Women with MDD complained of fatigue, insomnia, and memory problems and experienced everyday negative stressors more frequently than controls. Quality of life was decreased in women with depression, as indicated by lower scores in the emotional and social well-being domains of the SF-36. SP (P < 0.0003) and CGRP ( P < 0.0001) were higher in depressed subjects. Conclusion: Women with depression experienced pain more frequently than controls, had a lower quality of life, and complained more of daily stressors. Assessment of pain may be important in the clinical evaluation of women with MDD. SP and CGRP may be useful biological markers in women with MDD. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. NIDKD, NIH, Bethesda, MD USA. NIH, Off Res Serv, Div Bioengn & Phys Sci, Ultramicro Analyt Immunochem Resource, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM swimfinz@usa.net; aberger@mail.nih.gov; kbaker@mail.nih.gov; jbolle@mail.nih.gov; dhandel@mail.nih.gov; amannes@mail.nih.gov; dpereira@mail.nih.gov; dstgermain@mail.nih.gov; ronsavid@mail.nih.gov; ninas@niddk.nih.gov; storvik@niddk.nih.gov; kcalis@mail.cc.nih.gov; phillipt@ors.od.nih.gov; cizzag@intra.niddk.nih.gov FU Intramural NIH HHS NR 29 TC 22 Z9 23 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD JAN 18 PY 2006 VL 4 AR 2 DI 10.1186/1477-7525-4-2 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 091KS UT WOS:000241027100001 PM 16420706 ER PT J AU Ikemoto, S Qin, M Liu, ZH AF Ikemoto, S Qin, M Liu, ZH TI Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area SO JOURNAL OF NEUROSCIENCE LA English DT Article DE nicotinic cholinergic receptor; supramammillary nucleus; central linear nucleus raphe; caudal linear nucleus raphe; reward; intracranial self-administration ID NUCLEUS-ACCUMBENS; SUPRAMAMMILLARY NUCLEUS; OLFACTORY TUBERCLE; ADJACENT REGIONS; DOPAMINE; RAT; REWARD; SYSTEM; PROJECTIONS; RECEPTORS AB Nicotine is thought to be the key substance responsible for tobacco-smoking habits and appears to trigger reinforcement via the ventral tegmental area (VTA). Recently, multiple anatomical substrates for drug reinforcement have been identified in the vicinity of the ventral midbrain. In addition to the posterior portion of the VTA, the central linear nucleus raphe and the supramammillary nucleus of the posterior hypothalamus mediate drug reinforcement. Using intracranial self-administration procedures, we examined whether these regions mediate the reinforcing effects of nicotine. Rats learned to lever press for self-administration of nicotine into the posterior VTA, central linear nucleus, and supramammillary nucleus, suggesting a reinforcing action of nicotine in these regions. The rats did not self-administer nicotine into surrounding regions including the anterior VTA, substantia nigra, the region just dorsal to the posterior VTA, interpeduncular nucleus, or medial mammillary nucleus. The reinforcing effects of nicotine into the three brain regions were further confirmed by a two-lever discrimination procedure, in which rats learned to selectively respond between active and inactive levers. The reinforcing effects of nicotine administration into the posterior VTA, central linear nucleus, and supramammillary nucleus were blocked by coadministration of the nicotine receptor antagonist mecamylamine. The reinforcing effects of nicotine into the posterior VTA or central linear nucleus were attenuated by coadministration of the D-2 receptor agonist quinpirole. These findings demonstrate that nicotine reinforcement involves multiple regions both inside and outside the VTA. C1 NIDA, Behav Neurosci Branch, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, NIH, US Dept HHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sikemoto@intra.nida.nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU Intramural NIH HHS; NIDA NIH HHS [Z01 DA000439-06] NR 38 TC 89 Z9 91 U1 0 U2 1 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 JAN 18 PY 2006 VL 26 IS 3 BP 723 EP 730 DI 10.1523/JNEUROSCI.4542-05.2006 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 003XG UT WOS:000234715000003 PM 16421292 ER PT J AU Iwahara, J Clore, GM AF Iwahara, J Clore, GM TI Direct observation of enhanced translocation of a homeodomain between DNA cognate sites by NMR exchange spectroscopy SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HETERONUCLEAR CORRELATION; PROTEIN DYNAMICS; RATES C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 FU Intramural NIH HHS NR 13 TC 55 Z9 58 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JAN 18 PY 2006 VL 128 IS 2 BP 404 EP 405 DI 10.1021/ja056786o PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 005ID UT WOS:000234814900012 PM 16402815 ER PT J AU Kulasingam, SL Kim, JJ Lawrence, WF Mandelblatt, JS Myers, ER Schiffman, M Solomon, D Goldie, SJ AF Kulasingam, SL Kim, JJ Lawrence, WF Mandelblatt, JS Myers, ER Schiffman, M Solomon, D Goldie, SJ CA ALTS Grp TI Cost-effectiveness analysis based on the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion triage study (ALTS) SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID 2001 CONSENSUS GUIDELINES; ASCUS-LSIL TRIAGE; RANDOMIZED-TRIAL; CERVICAL NEOPLASIA; MANAGEMENT; CANCER; STRATEGIES; WOMEN AB Background: The ALTS (atypical squamous cells of undetermined significance [ASCUS] and low-grade squamous intraepithelial lesion [LSIL] Triage Study) suggests that, for women diagnosed with ASCUS, human papillornavirus (HPV) DNA testing followed by referral to colposcopy of only those women with oncogenic HPV (i.e., HPV DNA testing) is as effective at detecting cervical intraepithelial neoplasia (CIN) 3 or cancer (CIN3+) as referring all women with ASCUS for immediate colposcopy. We conducted a cost-effectiveness analysis of the ALTS trial to determine whether HPV DNA testing is a cost-effective alternative to immediate colposcopy or conservative management with up to three cytology examinations. Methods: Data from the ALTS trial were used in conjunction with medical care costs in a short-term decision model. The model compared the incrementa costs per case of CIN3+ detected as measured by the incremental cost-effectiveness ratio (ICER) for the following management strategies for women with ASCUS: immediate colposcopy, HPV DNA testing, and conservative management with up to three cytology examinations. Results: The least costly and least sensitive strategy was conservative management with one repeat cytology examination using a threshold of high-grade squamous intraepithelial lesion (HSIL) for referral to colposcopy. Compared with this strategy, triage to colposcopy based on a positive HPV DNA test result had an ICER of $3517 per case of CIN3+ detected. Immediate colposcopy and conservative management with up to three repeat cytology visits detected fewer cases of CIN3+ and were more costly than HPV DNA testing. Immediate colposcopy became cost-effective at $20370 compared with HPV DNA testing only if colposcopy and biopsy were assumed to be 100% sensitive. Conclusions: HPV DNA testing is an economically viable strategy for triage of ASCUS cytology. The less than perfect sensitivity of colposcopy and biopsy needs to be accounted for in future clinical guidelines and policy analyses. C1 Duke Univ, Ctr Clin Hlth Policy Res, Dept Obstet & Gynecol, Durham, NC 27705 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Harvard Ctr Risk Anal, Boston, MA 02115 USA. Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. Lombardi Comprehens Canc Ctr, Canc Clin & Econ Outcomes Core, Washington, DC USA. NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Rockville, MD USA. NCI, Div Canc Prevent, US Dept HHS, NIH, Rockville, MD USA. RP Kulasingam, SL (reprint author), Duke Univ, Ctr Clin Hlth Policy Res, Dept Obstet & Gynecol, 2200 W Main St,Ste 220, Durham, NC 27705 USA. EM kulas002@mc.duke.edu FU NCI NIH HHS [CN-55158, CN-55157, CN-55105, CN-55155, CN-55156, CN-55153, CN-55159, CN-55154] NR 19 TC 61 Z9 65 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 18 PY 2006 VL 98 IS 2 BP 92 EP 100 DI 10.1093/jnci/djj009 PG 9 WC Oncology SC Oncology GA 008JH UT WOS:000235036100007 PM 16418511 ER PT J AU Beattie, MS Costantino, JP Cummings, SR Wickerham, DL Vogel, VG Dowsett, M Folkerd, EJ Willett, WC Wolmark, N Hankinson, SE AF Beattie, MS Costantino, JP Cummings, SR Wickerham, DL Vogel, VG Dowsett, M Folkerd, EJ Willett, WC Wolmark, N Hankinson, SE TI Endogenous sex hormones, breast cancer risk, and tamoxifen response: An ancillary study in the NSABP Breast Cancer Prevention Trial (P-1) SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SURGICAL ADJUVANT BREAST; BOWEL PROJECT P-1; POSTMENOPAUSAL WOMEN; ESTROGEN-RECEPTOR; SERUM ESTRADIOL; PREMENOPAUSAL; TESTOSTERONE; RALOXIFENE; TISSUE AB Background. Prospective studies have shown an association between increased serum levels of estradiol and testosterone and breast cancer risk in postmenopausal women. Raloxifene has been shown to reduce breast cancer risk more in women with high estradiol levels than in those with lower levels. The purpose of this study was to determine whether sex hormone levels were associated with breast cancer risk and with response to tamoxifen in a high-risk population. Methods: Using a case-cohort design, we studied 135 women with postmenopausal breast cancer and 275 postmenopausal women without breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project Cancer Prevention Trial (P-1) and who had been treated with tarnoxifen or placebo for 69 months. We measured estradiol, testosterone, and sex hormone-binding globulin by using radioimmunoassay in baseline plasma samples. Relative risks (RRs) and 95% confidence intervals (CIs) for invasive breast cancer were estimated for each quartile of sex hormone level using Cox proportional hazards models. All statistical tests were two-sided. Results: Median plasma levels of estradiol, testosterone, and sex hormone-binding globulin were similar between the case and cohort groups. The relative risk of breast cancer for. women in the placebo group was not associated with sex hormone levels (risk of estrogen receptor-positive breast cancer in women by quartile of estradiol: Q1 [lowest], RR = 1.0; Q2, RR = 1.16, 95% CI = 0.49 to 2.7; Q3, RR = 1.08, 95% CI = 0.45 to 2.61; and Q4, RR = 1.29, 95% C1 = 0.59 to 2.82). The reduced risk of invasive breast cancer in tamoxifen-treated women compared with placebo-treated women was not associated with sex hormone levels. Conclusions: These data do not support the use of endogenous sex hormone levels to identify women who are at particularly high risk of breast cancer and who are most likely to benefit from chernoprevention with tamoxifen. C1 Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. Univ Pittsburgh, Dept Med, Div Oncol, Pittsburgh, PA 15260 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Royal Marsden Hosp, Acad Dept Biochem, London SW3 6JJ, England. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Calif Pacific Med Ctr, San Francisco, CA 94115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Beattie, MS (reprint author), 1635 Divisadero St,Ste 600, San Francisco, CA 94115 USA. EM mary.beattie@ucsfmedctr.org FU NCI NIH HHS [U10-CA-69974, U10-CA-37377] NR 25 TC 42 Z9 44 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 18 PY 2006 VL 98 IS 2 BP 110 EP 115 DI 10.1093/jnci/djj011 PG 6 WC Oncology SC Oncology GA 008JH UT WOS:000235036100009 PM 16418513 ER PT J AU Landi, MT Kanetsky, P Goldstein, A Pfeiffer, R AF Landi, MT Kanetsky, P Goldstein, A Pfeiffer, R TI Re: MC1R, ASIP, and DNA repair in sporadic and familial melanoma in a Mediterranean population - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID ASSOCIATION; RISK; ENVIRONMENT; VARIANTS C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, 6120 Execut Blvd,EPS 7114, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 NR 6 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 18 PY 2006 VL 98 IS 2 BP 145 EP 146 DI 10.1093/jnci/djj026 PG 2 WC Oncology SC Oncology GA 008JH UT WOS:000235036100015 ER PT J AU Petkova, AT Yau, WM Tycko, R AF Petkova, AT Yau, WM Tycko, R TI Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils SO BIOCHEMISTRY LA English DT Article ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; MOLECULAR-DYNAMICS SIMULATIONS; PROBING SOLVENT ACCESSIBILITY; PRION PROTEIN-FRAGMENT; ANGLE-SPINNING NMR; SECONDARY STRUCTURE; HYDROGEN-EXCHANGE; SHEET STRUCTURE; H/D-EXCHANGE AB We describe solid-state nuclear magnetic resonance (NMR) measurements on fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (A beta(1-40)) that place constraints on the identity and symmetry of contacts between in-register, parallel beta-sheets in the fibrils. We refer to these contacts as internal and external quaternary contacts, depending on whether they are within a single molecular layer or between molecular layers. The data include (1) two-dimensional C-13-C-13 NMR spectra that indicate internal quaternary contacts between side chains of L17 and F19 and side chains of 132, L34, and V36, as well as external quaternary contacts between side chains of 131 and G37; (2) two-dimensional N-15-C-13 NMR spectra that indicate external quaternary contacts between the side chain of M35 and the peptide backbone at G33; (3) measurements of magnetic dipole-dipole couplings between the side chain carboxylate group of D23 and the side chain amine group of K28 that indicate salt bridge interactions. Isotopic dilution experiments allow us to make distinctions between intramolecular and intermolecular contacts. On the basis of these data and previously determined structural constraints from solid-state NMR and electron microscopy, we construct full molecular models using restrained molecular dynamics simulations and restrained energy minimization. These models apply to A beta(1-40) fibrils grown with gentle agitation. We also present evidence for different internal quaternary contacts in A beta(1-40) fibrils grown without agitation, which are morphologically distinct. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK029029-09] NR 91 TC 686 Z9 693 U1 8 U2 154 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 17 PY 2006 VL 45 IS 2 BP 498 EP 512 DI 10.1021/bi051952q PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003BN UT WOS:000234656700016 PM 16401079 ER PT J AU Zarin, DA AF Zarin, DA CA Clinical Trials govteam TI Clarifying a misunderstanding on clinical trial registry SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Letter ID MEDICAL JOURNAL EDITORS; INTERNATIONAL COMMITTEE; STATEMENT C1 Natl Lib Med, Clin Trials Gov Team, NIH, Bethesda, MD 20894 USA. RP Zarin, DA (reprint author), Natl Lib Med, Clin Trials Gov Team, NIH, Bethesda, MD 20894 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU CMA MEDIA INC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JAN 17 PY 2006 VL 174 IS 2 BP 203 EP 206 DI 10.1503/cmaj.1050201 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 007OH UT WOS:000234978500022 PM 16415468 ER PT J AU Normanno, N De Luca, A Bianco, C Strizzi, L Mancino, M Maiello, MR Carotenuto, A De Feo, G Caponigro, F Salomon, DS AF Normanno, N De Luca, A Bianco, C Strizzi, L Mancino, M Maiello, MR Carotenuto, A De Feo, G Caponigro, F Salomon, DS TI Epidermal growth factor receptor (EGFR) signaling in cancer SO GENE LA English DT Review DE ErbB; EGF; growth factors; signal transduction ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITOR; HUMAN BREAST-CANCER; MAMMARY-GLAND DEVELOPMENT; ERBB-FAMILY RECEPTORS; FACTOR-ALPHA CDNA; GENE COPY NUMBER; TRANSGENIC MICE; TGF-ALPHA; EXTRACELLULAR DOMAIN AB The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTK). These trams-membrane proteins are activated following binding with peptide growth factors of the EGF-family of proteins. Evidence suggests that the EGFR is involved in the pathogenesis and progression of different carcinoma types. The EGFR and EGF-like peptides are often over-expressed in human carcinomas, and in vivo and in vitro studies have shown that these proteins are able to induce cell transformation. Amplification of the EGFR gene and mutations of the EGFR tyrosine kinase domain have been recently demonstrated to occur in carcinoma patients. Interestingly, both these genetic alterations of the EGFR are correlated with high probability to respond to anti-EGFR agents. However, ErbB proteins and their ligands form a complex system in which the interactions occurring between receptors and ligands affect the type and the duration of the intracellular signals that derive from receptor activation. In fact, proteins of the ErbB family form either home- or hetero-dimers following ligand binding, each dimer showing different affinity for ligands and different signaling properties. In this regard, evidence suggests that cooperation of multiple ErbB receptors and cognate ligands is necessary to induce cell transformation. In particular, the growth and the survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. This phenomenon is also important for therapeutic approaches, since the response to anti-EGFR agents might depend on the total level of expression of ErbB receptors and ligands in tumor cells. Published by Elsevier B.V. C1 INT Fdn Pascale, Cell Biol & Preclin Models Unit, I-80131 Naples, Italy. NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. INT, Fdn Pascale, Med Oncol B Unit, I-80131 Naples, Italy. RP Normanno, N (reprint author), INT Fdn Pascale, Cell Biol & Preclin Models Unit, I-80131 Naples, Italy. EM nicnorm@yahoo.com RI De Luca, Antonella/J-8737-2016; ionna, Franco/K-4564-2016; OI De Luca, Antonella/0000-0001-5762-447X; ionna, Franco/0000-0002-0512-274X; Normanno, Nicola/0000-0002-7158-2605 NR 179 TC 751 Z9 791 U1 38 U2 180 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 17 PY 2006 VL 366 IS 1 BP 2 EP 16 DI 10.1016/j.gene.2005.10.018 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 026TL UT WOS:000236365100002 PM 16377102 ER PT J AU Gauss, KA Bunger, PL Crawford, MA McDermott, BE Swearingen, R Nelson-Overton, LK Siemsen, DW Kobayashi, SD DeLeo, FR Quinn, MT AF Gauss, KA Bunger, PL Crawford, MA McDermott, BE Swearingen, R Nelson-Overton, LK Siemsen, DW Kobayashi, SD DeLeo, FR Quinn, MT TI Variants of the 5 '-untranslated region of human NCF2: Expression and translational efficiency SO GENE LA English DT Article DE NADPH oxidase; superoxide anion; gene expression regulation; promoter; alternative splicing; phagocytes ID CHRONIC GRANULOMATOUS-DISEASE; RESPIRATORY BURST OXIDASE; NADPH OXIDASE; MESSENGER-RNA; ANGIOTENSIN-II; POLYMORPHONUCLEAR LEUKOCYTES; HL-60 CELLS; P67(PHOX); NEUTROPHILS; COMPONENTS AB The NCF2 gene encodes p67(phox), an essential component of the multi-protein NADPH oxidase enzyme in phagocytic leukocytes, as well as in certain non-phagocytic cells. In humans, the NCF2 gene is expressed as multiple NCF2 variants that differ in the 5'-untranslated region (5'-UTR). Previously, we reported the presence of four NCF2 5'-UTR mRNA variants (designated as NCF2 exon 1, intron la, intron 1b and intron 1c). As each of the gene variants encodes an identical p67(phax) protein, the functional significance of these message variants was not apparent. In this study, we investigated the relative expression levels and tissue-specificity of NCF2 5'-UTR variant mRNAs and their translation efficiency and stability. NCF2 5'-UTR variant transcripts were differentially expressed in various cell lines and human tissues. In vitro translation assays indicated that the NCF2 5'-UTR variants also differed in their effects on the translation of a luciferase reporter mRNA and NCF2 mRNA. Notably, NCF2 intron 1 5'-UTR variants, which are the predominantly expressed variants found in vivo, strongly inhibited translation when compared to the NCF2 exon 1 5'-UTR variant. In contrast, RNA decay assays demonstrated that there was no significant difference between stability of NCF2 intron 1 transcripts and the exon 1 5'-UTR variant in HL-60, MonoMac 6, and 0937 cells. Moreover, expression of the variant transcripts remained unchanged after neutrophil phagocytosis, and was similar in normal neutrophils and neutrophils from a patient with X-linked chronic granulomatous disease. These studies suggest that expression of p67(phox) is regulated through mechanisms that include modulation of transcription and translation. (c) 2005 Elsevier B.V. All rights reserved. C1 Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Quinn, MT (reprint author), Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. EM mquinn@montana.edu OI DeLeo, Frank/0000-0003-3150-2516 FU NCRR NIH HHS [RR020185]; NHLBI NIH HHS [HL66575]; NIAMS NIH HHS [AR42426] NR 41 TC 15 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 17 PY 2006 VL 366 IS 1 BP 169 EP 179 DI 10.1016/j.gene.2005.09.012 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 026TL UT WOS:000236365100019 PM 16310324 ER PT J AU Jin, C Felsenfeld, G AF Jin, C Felsenfeld, G TI Distribution of histone H3.3 in hematopoietic cell lineages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE folate receptor; vascular endothelial growth factor D; globin; chromatin ID BETA-GLOBIN LOCUS; ACTIVE CHROMATIN; VARIANT H3.3; GENES; TRANSCRIPTION; DEPOSITION; PROMOTERS; GENOME AB We have introduced the histone variant H3.3 into chicken erythroid cell lines and examined its distribution in the neighborhood of the folate receptor (FR) and beta-globin genes by using high-resolution chromatin immunoprecipitation (ChIP). Marked incorporation of tagged H3.3 into the FR gene is confined to its upstream regulatory region and is observed whether or not the gene is transcriptionally active. Incorporation is also observed over locus control regulatory elements in the absence of transcription of genes regulated by these elements, suggesting that gene activity per se is not necessarily required to replace H3 with H3.3. Other active genes display various behaviors, either incorporating H3.3 over both the coding region and upstream regulatory region or over upstream sequences only. There is, however, no straightforward correlation between sites of H3.3 incorporation and regions of enrichment in H3 acetylation and lysine-4 methylation. In the case of FIR and VEGF-D, in which incorporation is confined to upstream regions, the presence of exogenous H3 results in reduced expression, whereas H3.3 stimulates expression. This finding suggests that these histone variants can be active rather than passive participants in regulation of expression. C1 NIDDKD, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Lab Mol Biol, NIH, Bldg 5,Room 212,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU Intramural NIH HHS NR 18 TC 51 Z9 53 U1 0 U2 1 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 JAN 17 PY 2006 VL 103 IS 3 BP 574 EP 579 DI 10.1073/pnas.0509974103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 004BU UT WOS:000234727800015 PM 16407103 ER PT J AU Gegonne, A Weissman, JD Zhou, MS Brady, JN Singer, DS AF Gegonne, A Weissman, JD Zhou, MS Brady, JN Singer, DS TI TAF7: A possible transcription initiation check-point regulator SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MHC class; regulation; preinitiation complex; TFIID ID RNA-POLYMERASE-II; CARBOXYL-TERMINAL DOMAIN; PROMOTER SELECTIVITY; TFIID SUBUNIT; ACETYLTRANSFERASE ACTIVITY; BINDING PROTEIN; HEAT-SHOCK; IN-VIVO; COMPLEX; TAF(II)250 AB Transcription consists of a series of highly regulated steps: assembly of a preinitiation complex (PIC) at the promoter nucleated by THID, followed by initiation, elongation, and termination. The present study has focused on the role of the TFIID component, TAF7 in regulating transcription initiation. In THID, TAF7 binds to TAF1 and inhibits its intrinsic acetyl transferase activity. We now report that although TAF7 remains bound to TAF1 and associated with THID during the formation of the PIC, TAF7 dissociates from the PIC upon transcription initiation. Entry of polymerase II into the assembling PIC is associated with TAF1 and TAF7 phosphorylation, coincident with TAF7 release. We propose that the TFIID composition is dynamic and that TAF7 functions as a check-point regulator suppressing premature transcription initiation until PIC assembly is complete. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Virus Tumor Biol Sect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM dinah.singer@nih.gov FU Intramural NIH HHS NR 41 TC 20 Z9 20 U1 0 U2 2 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 JAN 17 PY 2006 VL 103 IS 3 BP 602 EP 607 DI 10.1073/pnas.0510031103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 004BU UT WOS:000234727800020 PM 16407123 ER PT J AU Pareek, TK Keller, J Kesavapany, S Pant, HC Iadarola, MJ Brady, RO Kulkarni, AB AF Pareek, TK Keller, J Kesavapany, S Pant, HC Iadarola, MJ Brady, RO Kulkarni, AB TI Cyclin-dependent kinase 5 activity regulates pain signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nociception; inflammation; dorsal root ganglia; trigeminal ganglia; spinal cord ID CDC2-RELATED PROTEIN-KINASE; FOS-LIKE PROTEIN; SPINAL-CORD; NOXIOUS-STIMULATION; PARKINSONS-DISEASE; NMDA RECEPTORS; CDK5 ACTIVITY; P35; PHOSPHORYLATION; HYPERALGESIA AB Several molecules and cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase implicated in the development and disease of the mammalian nervous system. The precise role of this kinase in sensory pathways has not been well characterized. Here we report a molecular role for Cdk5 in nociception. We identified the expression of Cdk5 and its activator p35 in nociceptive neurons, which is modulated during a peripheral inflammatory response. Increased calpain activity in sensory neurons after inflammation resulted in the cleavage of p35 to p25, which forms a more stable complex with Cdk5 and, consequently, leads to elevation of Cdk5 activity. p35 knockout mice (p35(-/-)), which exhibit significantly decreased Cdk5 activity, showed delayed responses to painful thermal stimulation compared with WT controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, were more sensitive to painful thermal stimuli than were controls. In conclusion, our data demonstrate a role for Cdk5/p35 activity in primary afferent nociceptive signaling, suggesting that Cdk5/p35 may be a target for the development of analgesic drugs. C1 Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cytoskeletal Prot Regulat Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. EM rb57v@nih.gov; akulkarn@mail.nih.gov OI Pareek, Tej/0000-0001-5134-1647 FU Intramural NIH HHS NR 46 TC 62 Z9 68 U1 0 U2 0 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 JAN 17 PY 2006 VL 103 IS 3 BP 791 EP 796 DI 10.1073/pnas.0510405103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 004BU UT WOS:000234727800052 PM 16407116 ER PT J AU Abrami, L Leppla, SH van der Goot, FG AF Abrami, L Leppla, SH van der Goot, FG TI Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PLASMA-MEMBRANE; PROTEIN PALMITOYLATION; PROTECTIVE ANTIGEN; LIPID RAFTS; LOCALIZATION; DEGRADATION; INHIBITION; ACTIVATION; TRANSPORT; ACYLATION AB The anthrax toxin is composed of three independent polypeptide chains. Successful intoxication only occurs when heptamerization of the receptor-binding polypeptide, the protective antigen (PA), allows binding of the two enzymatic subunits before endocytosis. We show that this tailored behavior is caused by two counteracting posttranslational modifications in the cytoplasmic tail of PA receptors. The receptor is palmitoylated, and this unexpectedly prevents its association with lipid rafts and, thus, its premature ubiquitination. This second modi. cation, which is mediated by the E3 ubiquitin ligase Cbl, only occurs in rafts and is required for rapid endocytosis of the receptor. As a consequence, cells expressing palmitoylation-defective mutant receptors are less sensitive to anthrax toxin because of a lower number of surface receptors as well as premature internalization of PA without a requirement for heptamerization. C1 Univ Geneva, Dept Microbiol & Mol Med, CH-1211 Geneva 4, Switzerland. NIAID, Microbial Pathogenesis Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP van der Goot, FG (reprint author), Univ Geneva, Dept Microbiol & Mol Med, CH-1211 Geneva 4, Switzerland. EM vandergoot@medecine.unige.ch RI van der Goot, Francoise/B-2279-2012; OI van der Goot, Gisou/0000-0002-8522-274X FU NIAID NIH HHS [AI053270-01, R21 AI053270] NR 39 TC 109 Z9 109 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 16 PY 2006 VL 172 IS 2 BP 309 EP 320 DI 10.1083/jcb.200507067 PG 12 WC Cell Biology SC Cell Biology GA 003JR UT WOS:000234678500015 PM 16401723 ER PT J AU Stein, DM Robbin, J Miller, MA Lin, FYC Schneerson, R AF Stein, DM Robbin, J Miller, MA Lin, FYC Schneerson, R TI Are antibodies to the capsular polysaccharide of Neisseria meningitidis group B and Escherichia coli K1 associated with immunopathology?. SO VACCINE LA English DT Review DE vaccine; autoimmunity; polysialic acid (poly alpha(2 -> 8) N-acetylneuraminic acid) ID CELL-ADHESION MOLECULES; HUMAN MONOCLONAL MACROGLOBULIN; GUINEA-PIG MODEL; MENINGOCOCCAL DISEASE; COLI K1; POLYSIALIC ACID; SEROGROUP-B; N-CAM; BACTERICIDAL ANTIBODIES; PASTEURELLA-HAEMOLYTICA AB As polysialic acid (PSA), the capsule of Group B meningococcus (GBM) and Escherichia coli K1, is a component of mammalian glycopeptides, there is concern that vaccines against PSA could induce immunopathology. Purified PSA is not immunogenic; however, as a component of bacteria or bound to proteins, it induces protective antibodies. In this review, we did not unearth data indicating an association of IgG anti-PSA with immunopathology in experimental animals or humans. We found no increased incidence of autoimmunity from GBM infections in our review of the natural history/sequellae of Neisseria meningitis infections. Accordingly, we propose that clinical trials of PSA conjugate vaccines, be considered. Published by Elsevier Ltd. C1 NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. NICHHD, Dev & Mol Immun Lab, Bethesda, MD 20892 USA. RP Miller, MA (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr,Room 308, Bethesda, MD 20892 USA. EM millermark@nih.gov RI Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 NR 102 TC 31 Z9 31 U1 0 U2 5 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 JAN 16 PY 2006 VL 24 IS 3 BP 221 EP 228 DI 10.1016/j.vaccine.2005.07.084 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 006ZJ UT WOS:000234936300001 PM 16125824 ER PT J AU Prater, MR Johnson, VJ Germolec, DR Luster, MI Holladay, SD AF Prater, MR Johnson, VJ Germolec, DR Luster, MI Holladay, SD TI Maternal treatment with a high dose of CpG ODN during gestation alters fetal craniofacial and distal limb development in C57BL/6 mice SO VACCINE LA English DT Article DE CpG ODN; immunostiniulatory DNA; fetal malformation; craniofacial and distal limb development; abortion; Th1 cytokine shift ID TOLL-LIKE RECEPTOR-9; IMMUNE-RESPONSES; CUTTING EDGE; MURINE MODEL; GENE-EXPRESSION; BACTERIAL-DNA; PREGNANT MICE; TNF-ALPHA; VACCINE; OLIGODEOXYNUCLEOTIDES AB Synthetic oligodeoxynucleotides (ODN) containing CpG motifs, characteristic of bacterial DNA, are currently being evaluated as vaccine adjuvants for inducing protective immunity. Recently, there is increasing pressure to vaccinate pregnant women against maternally transmitted diseases including AIDS and tetanus, as well as against potential bio-weapons such as anthrax. CpG vaccines are effective because they trigger transient increases in T(H)1 cytokine production. Recent literature suggests, however, that a shift toward a T(H)1 cytokine profile during pregnancy may increase the risk of fetal morphologic defects. On this basis, we hypothesized that exposure to CpG motifs during pregnancy could result in T(H)1 inflammation leading to adverse effects on fetal development. To address this hypothesis, pregnant C57BL/6 mice were injected with CpG ODN (0-300 mu g/dam) and maternal and fetal outcomes were determined. Injection of darns with the highest dose of CpG ODN resulted in markedly increased fetal resorptions and craniofacial/limb defects. while lower doses had little, if any effects. Histological examination of placentas revealed cellular necrosis with mixed inflammation and calcification in the spongiotrophoblast layer and dysregulation of labyrinthine vascular development. Concomitant elevations in maternal serum cytokine levels were observed including interleukin (IL)-2, IL-10 and IL-12. Treatment with 300 mu g of non-CpG ODN did not cause any adverse effects. The 300 mu g dose of CpG ODN used in the present study is 30-fold higher than the highest dose that has been administered to humans during clinical trials. These results suggest that the induction of T(H)1 cytokines during pregnancy by CpG motifs may potentially increase the risk of fetal loss and morphologic defects in mice, at least at high doses, and support the need for further investigation of teratogenesis that may result from exposure to vaccine adjuvants designed to produce T(H)1 cytokine profile shifts. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA. Edward Via Virginia Coll Osteopath Med, Dept Biomed Sci, Blacksburg, VA 24060 USA. Virginia Tech, Virginia Maryland Reg Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24061 USA. NIEHS, Mol Toxicol Lab, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Johnson, VJ (reprint author), NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, 1095 Willow Rd, Morgantown, WV 26505 USA. EM vjohnson3@cdc.gov RI Johnson, Victor/A-7910-2009 FU NIEHS NIH HHS [Y1-ES0001-06] NR 46 TC 17 Z9 22 U1 0 U2 1 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 JAN 16 PY 2006 VL 24 IS 3 BP 263 EP 271 DI 10.1016/j.vaccine.2005.07.105 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 006ZJ UT WOS:000234936300006 PM 16143434 ER PT J AU Rao, SS Gomez, P Mascola, JR Dang, V Krivulka, GR Yu, F Lord, CI Shen, L Bailer, R Nabel, GJ Letvin, NL AF Rao, SS Gomez, P Mascola, JR Dang, V Krivulka, GR Yu, F Lord, CI Shen, L Bailer, R Nabel, GJ Letvin, NL TI Comparative evaluation of three different intramuscular delivery methods for DNA immunization in a nonhuman primate animal model SO VACCINE LA English DT Article DE nonhuman primate; DNA vaccination; AIDS vaccine; delivery methods; i.m. injection ID T-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS; GENE-GUN; PLASMID DNA; IMMUNE-RESPONSES; LISTERIA-MONOCYTOGENES; MUCOSAL IMMUNIZATION; ANTIBODY-RESPONSES; DENDRITIC CELLS; VACCINE VECTOR AB Although plasmid DNA vaccines induce potent cell-mediated immune responses and prime for antibody responses in experimental laboratory animals, their immunogenicity in humans has been less remarkable. A number of strategies have been proposed to improve the immunogenicity of these vaccines, including using novel means of vaccine delivery. In the present study, the immunogenicity of three different methods of intramuscular plasmid DNA administration was compared in cynomolgus monkeys: needle and syringe, Biojector (R) 2000, and Mini-Ject (TM). The elicited cellular and humoral immune responses were comparable in monkeys immunized using these different delivery techniques, suggesting that the needle-free approaches to vaccine administration do not significantly improve the immunogenicity of the plasmid DNA vaccine used in the study. (c) 2005 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Letvin, NL (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. EM nletvin@bidmc.harvard.edu NR 43 TC 29 Z9 29 U1 0 U2 0 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 JAN 16 PY 2006 VL 24 IS 3 BP 367 EP 373 DI 10.1016/j.vaccine.2005.07.072 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 006ZJ UT WOS:000234936300017 PM 16194587 ER PT J AU Oliveira, F Kamhawi, S Seitz, AE Pham, VM Guigal, PM Fischer, L Ward, J Valenzuela, JG AF Oliveira, F Kamhawi, S Seitz, AE Pham, VM Guigal, PM Fischer, L Ward, J Valenzuela, JG TI From transcriptome to immunome: Identification of DTH inducing proteins from a Phlebotomus ariasi salivary gland cDNA library SO VACCINE LA English DT Article DE cellular immune responses; DNA vaccine; delayed-type hypersensitivity; Phlebotomus; reverse antigen screening; sand fly saliva; sand fly transcripts ID FLY LUTZOMYIA-LONGIPALPIS; LEISHMANIA-MAJOR; MICE; INFECTION; ENHANCEMENT; RESISTANCE; DATABASE; APYRASE; FAMILY AB Delayed-type hypersensitivity (DTH) response to arthropod vector salivary proteins is associated with protection against pathogen transmission. Massive cDNA sequencing, high-throughput DNA plasmid construction and DNA immunisation were used to identify twelve DTH inducing proteins isolated from a Phlebotomus ariasi salivary gland cDNA library. Additionally, nine R ariasi DNA plasmids produced specific anti-saliva antibodies, four of these showed a Th1 immune response while the other two exhibited a Th2 profile as determined by IgG2a and IgG1 isotype switching, respectively. In order to validate the specificity of sand fly DNA plasmids, mice previously exposed to sand fly saliva were intradermally injected once with selected P ariasi plasmids and a specific DTH response consisting of infiltration of mononuclear cells in varying proportions was observed at 24 and 48 h. This approach can help to identify DTH inducing proteins that may be related to host protection against vector-borne diseases or other disease agents where cellular immune response is protective. Published by Elsevier Ltd. C1 NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Univ Fed Bahia, Ctr Pesquisa Goncalo Moniz, Fundacao Oswaldo Cruz, Salvador, BA, Brazil. Univ Fed Bahia, Fac Med, Salvador, BA, Brazil. NIAID, Parasit Dis Lab, NIH, Rockville, MD 20852 USA. Merial SAS, Biol Discovery Res, Lyon, France. NIAID, Comparat Med Branch, NIH, Rockville, MD 20852 USA. RP Valenzuela, JG (reprint author), NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Room 2E-22C, Rockville, MD 20852 USA. EM jvalenzuela@niaid.nih.gov RI Oliveira, Fabiano/B-4251-2009 OI Oliveira, Fabiano/0000-0002-7924-8038 NR 27 TC 70 Z9 71 U1 0 U2 6 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 JAN 16 PY 2006 VL 24 IS 3 BP 374 EP 390 DI 10.1016/j.vaccine.2005.07.085 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 006ZJ UT WOS:000234936300018 PM 16154670 ER PT J AU Naqvi, TZ Padmanabhan, S Rafii, F Hyuhn, HK Mirocha, J AF Naqvi, TZ Padmanabhan, S Rafii, F Hyuhn, HK Mirocha, J TI Comparison of usefulness of left ventricular diastolic versus systolic function as a predictor of outcome following primary percutaneous coronary angioplasty for acute myocardial infarction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CAPILLARY WEDGE PRESSURE; MODE DOPPLER-ECHOCARDIOGRAPHY; TISSUE DOPPLER; NONINVASIVE ESTIMATION; FILLING PRESSURES; VELOCITY; FLOW; REGURGITATION; INDEX AB Left ventricular (LV) diastolic function is an important predictor of morbidity and mortality after acute myocardial infarction (AMI). We evaluated the role of diastolic function in predicting in-hospital events and LV ejection fraction (EF) 6 months after a first AMI that was treated with primary percutaneous coronary intervention (PCI). We prospectively enrolled 59 consecutive patients who were 60 +/- 15 years of age (48 men), presented at our institution with their first AMI, and were treated with primary PCI. Patients underwent 2-dimensional and Doppler echocardiography, including tissue Doppler imaging of 6 basal mitral annular regions within 24 hours after primary PCI and were followed until discharge. Clinical and echocardiographic variables at index AMI were compared with a combined end point of cardiac death, ventricular tachycardia, congestive heart failure, or emergency in-hospital surgical revascularization. Follow-up echocardiographic assessment was performed at 6 months in 24 patients. During hospitalization, 3 patients died, 7 developed congestive heart failure, 4 had ventricular tachycardia, and 1 required emergency surgical revascularization. Stepwise logistic regression analysis showed the ratio of early mitral inflow diastolic filling wave (E) to peak early diastolic velocity of non-infarct-related mitral annulus (p < 0.01) (E) and mitral inflow E-wave deceleration time (p < 0.02) to be independent predictors of in-hospital cardiac events (generalized R-2 = 0.66). In a stepwise multiple linear regression model, independent predictors of follow-up LVEF were mitral inflow deceleration time (R-2 = 0.39, p = 0.002), baseline LVEF (R-2 = 0.54, p < 0.02), and mitral inflow peak early velocity/mitral annular peak early velocity (or E/E') of infarct annulus (R-2 = 0.66, p = 0.02). In conclusion, in patients who are treated with primary PCI for a first AMI, E/E' velocity ratio and mitral inflow E-wave deceleration time are strong predictors of in-hospital cardiac events and of LVEF at 6-month follow-up. (C) 2006 Elsevier Inc. All rights reserved. C1 Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Los Angeles, CA 90048 USA. Keck Sch Med, Los Angeles, CA USA. NIH, Bethesda, MD 20892 USA. RP Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Los Angeles, CA 90048 USA. EM tasneem.naqvi@cshs.org NR 23 TC 36 Z9 36 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2006 VL 97 IS 2 BP 160 EP 166 DI 10.1016/j.amjcard.2005.08.022 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 005VC UT WOS:000234851100002 PM 16442355 ER PT J AU Dushoff, J Plotkin, JB Viboud, C Earn, DJD Simonsen, L AF Dushoff, J Plotkin, JB Viboud, C Earn, DJD Simonsen, L TI Mortality due to influenza in the United States - an annualized regression approach using multiple-cause mortality data SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cause of death; influenza; linear regression; mortality; seasons; temperature; time series; United States ID RESPIRATORY SYNCYTIAL VIRUS; EXCESS WINTER MORTALITY; AIR-POLLUTION; VACCINATION; DEATHS; INFECTIONS; DISEASE; IMPACT; RISK; ASSOCIATION AB Influenza is an important cause of mortality in temperate countries, but there is substantial controversy as to the total direct and indirect mortality burden imposed by influenza viruses. The authors have extracted multiple-cause death data from public-use data files for the United States from 1979 to 2001. The current research reevaluates attribution of deaths to influenza, by use of an annualized regression approach: comparing measures of excess deaths with measures of influenza virus prevalence by subtype over entire influenza seasons and attributing deaths to influenza by a regression model. This approach is more conservative in its assumptions than is earlier work, which used weekly regression models, or models based on fitting baselines, but it produces results consistent with these other methods, supporting the conclusion that influenza is an important cause of seasonal excess deaths. The regression model attributes an annual average of 41,400 (95% confidence interval: 27,100, 55,700) deaths to influenza over the period 1979-2001. The study also uses regional death data to investigate the effects of cold weather on annualized excess deaths. C1 Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Harvard Univ, Cambridge, MA 02138 USA. McMaster Univ, Dept Math & Stat, Hamilton, ON, Canada. NIAID, NIH, Bethesda, MD 20892 USA. RP Dushoff, J (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Guyot Hall, Princeton, NJ 08544 USA. EM dushoff@eno.princeton.edu RI Plotkin, Joshua/E-6947-2013; OI Earn, David/0000-0002-7562-1341; Simonsen, Lone/0000-0003-1535-8526 NR 33 TC 150 Z9 157 U1 0 U2 9 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 JAN 15 PY 2006 VL 163 IS 2 BP 181 EP 187 DI 10.1093/aje/kwj024 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 000AY UT WOS:000234434500010 PM 16319291 ER PT J AU McDonnell, NB Gorman, BL Mandel, KW Schurman, SH Assanah-Carroll, A Mayer, SA Najjar, SS Francomano, CA AF McDonnell, NB Gorman, BL Mandel, KW Schurman, SH Assanah-Carroll, A Mayer, SA Najjar, SS Francomano, CA TI Echocardiographic findings in classical and hypermobile Ehlers-Danlos syndromes SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Ehlers-Danlos syndromes; aorta; echocardiography; impaired left ventricular relaxation ID MITRAL-VALVE PROLAPSE; PRESERVE; FEATURES; COLLAGEN; IV AB Structural cardiovascular alterations in the classical and hypermobile forms of Ehlers-Danlos syndrome(EDS) warrant investigation. We have examined a cohort of 38 patients with hypermobile and classical EDSs using two-dimensional echocardiography. The cohort includes 7 males and 31 females, With an aloe range from 12-60 years. Altered echocardiographic parameters were seen in the initial crosssectional data analysis in 24/38 patients. Five of the 38 participants had mildly dilated aortic root (AR) or sinuses of Valsalva (SV), and an additional 7 patients had an abnormal pouching of the SV, although the absolute dimensions did not exceed the normal range. Ten patients had mild mitral, tricuspid, or aortic regurgitation, and only one patient had mitral valve prolapse (MVP). Three patients had low normal systolic function; three had evidence of mildly elevated pulmonary pressures, and two patients had mild concentric left ventricular hypertrophy (LVH). Five patients had evidence of impaired left ventricular relaxation (LVR) based on mitral valve E to A velocity ratio. Interestingly, 26/38 subjects demonstrated a prominent right coronary (RCA) easily visualized by trans-thoracic echocardiography, and 10/38 had in elongated cardiac Silhouette on the 4-chamber apical views. The "pouching" shape of the SV was more common in hypermobile type than in the classical type of EDS. The study is ongoing and will accrue longitudinal data on 100 subjects with classical and hypermobile EDSs at 2-year intervals. Published 2005 Wiley-Liss. Inc. C1 NIA, Human Genet & Integrat Med Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. NIA, Clin Res Branch, NIA ASTRA Unit, NIH, Baltimore, MD 21224 USA. Johns Hopkins Sch Med, Johns Hopkins Bayview Med Ctr, Dept Med, Div Cardiol, Baltimore, MD USA. NIA, Human Cardiovasc Studies Unit, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP McDonnell, NB (reprint author), NIA, Human Genet & Integrat Med Sect, Genet Lab, NIH, 5600 Nathan Shock Dr,Room 3101, Baltimore, MD 21224 USA. EM mcdonnellna@mail.nih.gov OI Schurman, Shepherd/0000-0002-9133-7906 FU Intramural NIH HHS NR 19 TC 35 Z9 36 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN 15 PY 2006 VL 140A IS 2 BP 129 EP 136 DI 10.1002/ajmg.a.31035 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 000VX UT WOS:000234491600004 PM 16353246 ER PT J AU Morgulis, A Gertz, EM Schaffer, AA Agarwala, R AF Morgulis, A Gertz, EM Schaffer, AA Agarwala, R TI WindowMasker: window-based masker for sequenced genomes SO BIOINFORMATICS LA English DT Article ID DE-NOVO IDENTIFICATION; REPETITIVE SEQUENCES; TANDEM REPEATS; DNA-SEQUENCES; SEARCH; ALGORITHM; DATABASE; PROGRAM; PROTEIN; UPDATE AB Motivation: Matches to repetitive sequences are usually undesirable in the output of DNA database searches. Repetitive sequences need not be matched to a query, if they can be masked in the database. RepeatMasker/Maskeraid (RM), currently the most widely used software for DNA sequence masking, is slow and requires a library of repetitive template sequences, such as a manually curated RepBase library, that may not exist for newly sequenced genomes. Results: We have developed a software tool called WindowMasker (WM) that identifies and masks highly repetitive DNA sequences in a genome, using only the sequence of the genome itself. WM is orders of magnitude faster than RM because WM uses a few linear-time scans of the genome sequence, rather than local alignment methods that compare each library sequence with each piece of the genome. We validate WM by comparing BLAST outputs from large sets of queries applied to two versions of the same genome, one masked by WM, and the other masked by RM. Even for genomes such as the human genome, where a good RepBase library is available, searching the database as masked with WM yields more matches that are apparently non-repetitive and fewer matches to repetitive sequences. We show that these results hold for transcribed regions as well. WM also performs well on genomes for which much of the sequence was in draft form at the time of the analysis. C1 Natl Ctr Biotechnol Informat, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Agarwala, R (reprint author), Natl Ctr Biotechnol Informat, Natl Inst Hlth, Dept Hlth & Human Serv, Bldg 38A,Room 1003N,8600 Rockville Pike, Bethesda, MD 20894 USA. EM richa@helix.nih.gov RI Schaffer, Alejandro/F-2902-2012; OI Gertz, E. Michael/0000-0001-8390-4387 NR 27 TC 78 Z9 78 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JAN 15 PY 2006 VL 22 IS 2 BP 134 EP 141 DI 10.1093/bioinformatics/bit774 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 010ST UT WOS:000235218900003 PM 16287941 ER PT J AU Crawford, JH Isbell, TS Huang, Z Shiva, S Chacko, BK Schechter, AN Darley-Usmar, VM Kerby, JD Lang, JD Kraus, D Ho, C Gladwin, MT Patel, RP AF Crawford, JH Isbell, TS Huang, Z Shiva, S Chacko, BK Schechter, AN Darley-Usmar, VM Kerby, JD Lang, JD Kraus, D Ho, C Gladwin, MT Patel, RP TI Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation SO BLOOD LA English DT Article ID OXIDE SYNTHASE ACTIVITY; S-NITROSOHEMOGLOBIN; OXYGEN DELIVERY; FLOW REGULATION; BIOCHEMICAL-CHARACTERIZATION; GUANYLATE-CYCLASE; HUMAN-HEMOGLOBIN; SODIUM-NITRITE; OXIDATION; ATP AB Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase activity of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal activity observed at 50% hemoglobin oxygenation (P-50). Concomitantly, vasodilation is initiated at the P-50, suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved beta 93cys residue decreases the heme redox potential (ie, decreases E-1/2), an effect that increases nitrite reductase activity and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose "enzyme activity" couples hypoxia to increased NO-dependent blood flow. C1 Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. Univ Alabama, Dept Anesthesiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Biol, Birmingham, AL 35294 USA. Univ Alabama, Ctr Free Rad Biol, Birmingham, AL 35294 USA. NIDDK, Vasc Med Branch, NHLBI, Mol Med Branch, Bethesda, MD USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Patel, RP (reprint author), Univ Alabama, Dept Pathol, BMR 2,Rm 307,901 19th St S, Birmingham, AL 35294 USA. EM patel@path.uab.edu RI Darley-Usmar, Victor/F-7656-2010; Ho, Chien/O-6112-2016; OI Ho, Chien/0000-0002-4094-9232; Schechter, Alan N/0000-0002-5235-9408; Patel, Rakesh/0000-0002-1526-4303 FU Intramural NIH HHS; NHLBI NIH HHS [HL70146, HL-24525]; NIGMS NIH HHS [T32 GM08361] NR 56 TC 286 Z9 295 U1 6 U2 36 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2006 VL 107 IS 2 BP 566 EP 574 DI 10.1182/blood-2005-07-2668 PG 9 WC Hematology SC Hematology GA 001PR UT WOS:000234549300031 PM 16195332 ER PT J AU Qiao, HH Andrade, MV Lisboa, FA Morgan, K Beaven, MA AF Qiao, HH Andrade, MV Lisboa, FA Morgan, K Beaven, MA TI Fc epsilon R1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells SO BLOOD LA English DT Article ID NECROSIS-FACTOR-ALPHA; RESPIRATORY SYNCYTIAL VIRUS; ACTIVATED T-CELLS; N-TERMINAL KINASE; INNATE IMMUNITY; KAPPA-B; PHOSPHATIDYLINOSITOL 3-KINASE; ARACHIDONIC-ACID; GENE-EXPRESSION; CUTTING EDGE AB Mast cells mediate both IgE-dependent allergic reactions and protective responses against acute infections, possibly through the activation of Toll-like receptors (TLRs). We find that antigen interacts synergistically with TLR2 and TLR4 ligands to markedly enhance production of cytokines in murine mast cell lines. However, the TLR ligands neither stimulated degranulation and release of arachidonic acid nor influenced such responses to antigen, probably because these ligands failed to generate a necessary calcium signal. The enhanced cytokine production could be attributed to synergistic activation of mitogen-activated protein kinases in addition to the engagement of a more effective repertoire of transcription factors for cytokine gene transcription. The synergistic interactions of TLR ligands and antigen might have relevance to the exacerbation of IgE-mediated allergic diseases by infectious agents. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Beaven, MA (reprint author), NHLBI, Lab Mol Immunol, NIH, Rm 8N109,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM beavenm@nhlbi.nih.gov RI ANDRADE, MARCUS/A-4764-2008 OI ANDRADE, MARCUS/0000-0002-3716-0919 FU FIC NIH HHS [R01 TW006612-01, R01 TW006612-04, R01 TW006612-02, 1 R01 TW006612-01, R01 TW006612-05, R01 TW006612-03]; Intramural NIH HHS NR 66 TC 121 Z9 127 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2006 VL 107 IS 2 BP 610 EP 618 DI 10.1182/blood-2005-06-2271 PG 9 WC Hematology SC Hematology GA 001PR UT WOS:000234549300037 PM 16174756 ER PT J AU Boyd, KE Xiao, YY Fan, K Poholek, A Copeland, NG Jenkins, NA Perkins, AS AF Boyd, KE Xiao, YY Fan, K Poholek, A Copeland, NG Jenkins, NA Perkins, AS TI Sox4 cooperates with Evi1 in AKXD-23 myeloid tumors via transactivation of proviral LTR SO BLOOD LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIAS; COLONY-STIMULATING FACTOR; DNA-BINDING ACTIVITY; ZINC FINGER PROTEIN; TRANSFORMING GENE; CELL-LINES; GRANULOCYTIC DIFFERENTIATION; INTEGRATION SITE; RAT1 FIBROBLASTS; CO-REPRESSOR AB Myeloid leukemias in AKXD23 mice contain proviral insertions at Evil, resulting in transcriptional activation. Although Evil is clearly involved in leukemia, gene transfer studies in mice with Evil fail to cause leukemia, arguing that cooperating events are necessary. We reanalyzed AKXD-23 tumors for cooperating proviral insertion and found that each tumor had a proviral insertion in Sox4, which encodes an HMG-box transcription factor. RNA analysis revealed these insertions cause increased Sox4 expression. Overexpression of Sox4 in 32Dcl3 cells markedly inhibited cytokine-induced granulocyte maturation, as documented by morphologic and mRNA analysis. Sox4-expressing cells had higher levels of transcripts associated with proliferation, including Evil. Conversely, in leukemic cells that express Sox4 and bear provirally activated Evil, suppression of Sox4 with short hairpin RNAs resulted in down-regulation of both Sox4 and Evil. By cotransfection studies, Sox4 is able to transactivate the AKV long terminal repeat, which likely explains how Sox4 transcriptionally up-regulates provirally activated Evil; however, Sox4 does not appear to regulate the native Evil promoter. We propose that Sox4 proviral activation is selected for in the setting of prior proviral activation of Evil, because it transactivates the relatively weak LTR of AKV leading to higher Evil expression and consequent block to differentiation. C1 Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. Natl Canc Inst, Mouse Canc Genet Program, Frederick, MD USA. RP Perkins, AS (reprint author), Yale Univ, Sch Med, Dept Pathol, POB 208023, New Haven, CT 06520 USA. EM archibald.perkins@yale.edu FU NCI NIH HHS [R01 CA81216, 1F32CA88467-01] NR 58 TC 34 Z9 34 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2006 VL 107 IS 2 BP 733 EP 741 DI 10.1182/blood-2003-05-1626 PG 9 WC Hematology SC Hematology GA 001PR UT WOS:000234549300052 PM 16204320 ER PT J AU Knutsen, T Vakulchuk, A Mosijczuk, AD Gabrea, A Ried, T Tretyak, N AF Knutsen, T Vakulchuk, A Mosijczuk, AD Gabrea, A Ried, T Tretyak, N TI Complex rearrangements involving der(8)t(8;20) and der(14)t(8;14)t(11;14), CCND1, and duplication of IgH constant region in acute plasmablastic leukemia SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID PLASMA-CELL LEUKEMIA; IN-SITU HYBRIDIZATION; MULTIPLE-MYELOMA; ABERRATIONS; INTERPHASE AB We report on a rapidly fatal case of acute plasmablastic leukemia in a 72-year-old male from The Ukraine, who was 70 km away from Chernobyl at the time of the atomic accident in 1986. Spectral karyotyping and fluorescence in situ hybridization (FISH) studies of a bone marrow sample obtained at diagnosis revealed a hypodiploid karyotype with 45 chromosomes and two novel complex rearrangements, der(8)t(8;20)(p11.2;p?12) and der(14)t(8;14)(p?;p11.2)t(11;14)(q13;q32), with juxtaposition of CH (constant region of IgH) sequences to the oncogene CCND1 (translocated to 14q32). FISH analysis demonstrated that the CH on the der(14) was duplicated. (c) 2006 Elsevier Inc. All rights reserved. C1 NCI, Genet Branch, Clin Res Ctr, Bethesda, MD 20892 USA. Inst Hematol & Transfus Med, UA-84060 Kiev, Ukraine. Walter Reed Army Med Ctr, Pediat Hematol Oncol Serv, Washington, DC 20307 USA. Ukraine Acad Med Sci, UA-84060 Kiev, Ukraine. RP Knutsen, T (reprint author), NCI, Genet Branch, Clin Res Ctr, 50 S Dr,Room 1408, Bethesda, MD 20892 USA. EM knutsent@mail.nih.gov NR 14 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JAN 15 PY 2006 VL 164 IS 2 BP 137 EP 141 DI 10.1016/j.cancergencyto.2005.08.027 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 011FU UT WOS:000235254300007 PM 16434317 ER PT J AU Nummela, P Yin, M Kielosto, M Leaner, V Birrer, MJ Holtta, E AF Nummela, P Yin, M Kielosto, M Leaner, V Birrer, MJ Holtta, E TI Thymosin beta 4 is a determinant of the transformed phenotype and invasiveness of S-adenosylmethionine decarboxylase-transfected fibroblasts SO CANCER RESEARCH LA English DT Article ID ACTIN-SEQUESTERING PEPTIDE; C-HA-RAS; ORNITHINE-DECARBOXYLASE; HEPATOCELLULAR-CARCINOMA; ENDOTHELIAL-CELLS; GENE-EXPRESSION; RETINOIC ACID; LIVING CELLS; CANCER CELLS; IN-VIVO AB S-adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the synthesis of polyamines essential for cell growth and proliferation. Its overexpression induces the transformation of murine fibroblasts in both sense and antisense orientations, yielding highly invasive tumors in nude mice. These cell lines hence provide a good model to study cell invasion. Here, the gene expression profiles of these cells were compared with their normal counterpart by microarray analyses (Incyte Genomics, Palo Alto, CA, and Affymetrix, Santa Clara, CA). Up-regulation of the actin sequestering molecule thymosin 4 was the most prominent change in both cell lines. Tetracycline-inducible expression of thymosin beta 4 antisense RNA caused a partial reversal of the transformed phenotype. Further, reversal of transformation by dominant-negative mutant of c-Jun (TAM67) caused reduction in thymosin beta 4 mRNA. Interestingly, a sponge toxin, latrunculin A, which inhibits the binding of thymosin beta 4 to actin, was found to profoundly affect the morphology and proliferation of the AdoMetDC transformants and to block their invasion in three-dimensional Matrigel. Thus, thymosin beta 4 is a determinant of AdoMetDC-induced transformed phenotype and invasiveness. Up-regulation of thymosin beta 4 was also found in ras-transformed fibroblasts and metastatic human melanoma cells. These data encourage testing latrunculin A-like and other agents interfering with thymosin beta 4 for treatment of thymosin beta 4-overexpressing tumors with high invasive and metastatic potential. C1 Univ Helsinki, Dept Pathol, Haartman Inst, FIN-00014 Helsinki, Finland. Univ Helsinki, Dept Pathol, Helsinki Univ Cent Hosp, FIN-00014 Helsinki, Finland. NCI, Cell & Canc Biol Dept, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. RP Holtta, E (reprint author), Univ Helsinki, Dept Pathol, Haartman Inst, POB 21, FIN-00014 Helsinki, Finland. EM erkk.holtta@helsinki.fi NR 65 TC 21 Z9 21 U1 0 U2 0 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 JAN 15 PY 2006 VL 66 IS 2 BP 701 EP 712 DI 10.1158/0008-5472.CAN-05-2421 PG 12 WC Oncology SC Oncology GA 006RQ UT WOS:000234915100017 PM 16423999 ER PT J AU Mononen, N Seppala, EH Duggal, P Autio, V Ikonen, T Ellonen, P Saharinen, J Saarela, J Vihinen, M Tammela, TLJ Kallioniemi, O Bailey-Wilson, JE Schleutker, J AF Mononen, N Seppala, EH Duggal, P Autio, V Ikonen, T Ellonen, P Saharinen, J Saarela, J Vihinen, M Tammela, TLJ Kallioniemi, O Bailey-Wilson, JE Schleutker, J TI Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors SO CANCER RESEARCH LA English DT Article ID MISSENSE SUBSTITUTION; SECONDARY STRUCTURE; RECEPTOR GENE; PREDICTION; REDUCTASE; ASSOCIATION; POPULATION; HEREDITARY; CARCINOMA; VARIANTS AB Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T-1-T-2) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T > C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A > G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1. may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology. C1 Univ Tampere, Canc Genet Lab, Inst Med Technol, FIN-33014 Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Div Urol, Tampere, Finland. Tampere Univ Hosp, Res Unit, Tampere, Finland. Univ Tampere, Inst Med Technol, FIN-33101 Tampere, Finland. NHGRI, NIH, Baltimore, MD USA. Natl Publ Hlth Inst, Dept Mol Med, Helsinki, Finland. VTT Tech Res Ctr, Turku, Finland. Univ Turku, Turku, Finland. RP Schleutker, J (reprint author), Univ Tampere, Canc Genet Lab, Inst Med Technol, FIN-33014 Tampere, Finland. EM Johanna.Schleutker@uta.fi RI Kallioniemi, Olli/H-5111-2011; Vihinen, Mauno/A-8452-2012; Kallioniemi, Olli/H-4738-2012; Saarela, Janna/E-5369-2014; OI Kallioniemi, Olli/0000-0002-3231-0332; Vihinen, Mauno/0000-0002-9614-7976; Kallioniemi, Olli/0000-0002-3231-0332; Saarela, Janna/0000-0002-0853-6219; Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural NIH HHS NR 30 TC 45 Z9 45 U1 0 U2 2 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 JAN 15 PY 2006 VL 66 IS 2 BP 743 EP 747 DI 10.1158/0008-5472.CAN-05-1723 PG 5 WC Oncology SC Oncology GA 006RQ UT WOS:000234915100022 PM 16424004 ER PT J AU Lu, X de la Pena, L Barker, C Camphausen, K Tofilon, PJ AF Lu, X de la Pena, L Barker, C Camphausen, K Tofilon, PJ TI Radiation-induced changes in gene expression involve recruitment of existing messenger RNAs to and away from polysomes. SO CANCER RESEARCH LA English DT Article ID IONIZING-RADIATION; MICROARRAY ANALYSIS; CANCER CELLS; TRANSLATION; PROTEIN; RESPONSES; INITIATION; PATTERNS; EXPOSURE; IDENTIFY AB Although ionizing radiation has been shown to influence gene transcription, little is known about the effects of radiation on gene translational efficiency. To obtain a genome-wide perspective of the effects of radiation on gene translation, microarray analysis was done on polysome-bound RNA isolated from irradiated human brain tumor cells; to allow for a comparison with the effects of radiation on transcription, microarray analysis was also done using total RNA. The number of genes whose translational activity was modified by radiation was similar to 10-fold greater than those whose transcription was affected. The radiation-induced change in a gene's translational activity was shown to involve the recruitment of existing mRNAs to and away from polysomes. Moreover, the change in a gene's translational activity after irradiation correlated with changes in the level of its corresponding protein. These data suggest that radiation modifies gene expression primarily at the level of translation. In contrast to transcriptional changes, there was considerable overlap in the genes affected at the translational level among brain tumor cell lines and normal astrocytes. Thus, the radiation-induced translational control of a subset of mRNAs seems to be a fundamental component of cellular radioresponse. C1 NCI, Mol Radiat Therapeut Branch, Bethesda, MD USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), Mol Radiat Therapeut Branch, Radiat Res Program, EPN-6015A,6130 Execut Blvd,MSC 7440, Bethesda, MD 20892 USA. EM tofilonp@mail.nih.gov RI Barker, Christopher/I-9477-2012 NR 30 TC 75 Z9 77 U1 1 U2 5 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 JAN 15 PY 2006 VL 66 IS 2 BP 1052 EP 1061 DI 10.1158/0008-5472.CAN-05-3459 PG 10 WC Oncology SC Oncology GA 006RQ UT WOS:000234915100059 PM 16424041 ER PT J AU Guo, ZS Hong, JA Irvine, KR Chen, GA Spiess, PJ Liu, Y Zeng, G Wunderlich, JR Nguyen, DM Restifo, NP Schrump, DS AF Guo, ZS Hong, JA Irvine, KR Chen, GA Spiess, PJ Liu, Y Zeng, G Wunderlich, JR Nguyen, DM Restifo, NP Schrump, DS TI De novo induction of a cancer/testis antigen by 5-aza-2 '-deoxycytidine augments adoptive immunotherapy in a murine tumor model SO CANCER RESEARCH LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; MOUSE GENE P1A; CANCER-IMMUNOTHERAPY; LUNG-CANCER; DNA METHYLATION; CPG-ISLANDS; ISCOMATRIX ADJUVANT; VACCINE DEVELOPMENT; REJECTION ANTIGEN; NY-ESO-1 PROTEIN AB Recent studies suggest that immunotherapy targeting specific tumor-associated antigens (TAAs) may be beneficial in cancer patients. However, most of these TAAs are tumor type specific and heterogeneous among patients, thus limiting their applications. Here, we describe the de novo induction of a cancer/testis antigen (CTA) for immunotherapy of tumors of various histologies. The murine CTA PIA, normally expressed only in a few tumor lines, could be induced de novo in all P1A-negative cancer lines of eight histologic origins in vitro and in various murine xenografts by systemic administration of 5-aza-2'-deoxycytidine. The induction of PIA expression correlated strongly with demethylation of the CpG island in the promoter region of this gene. The induced antigen was processed and presented properly for recognition by H-2L(d)- restricted PIA-specific CTLs. The combination of a demethylating agent and adoptive transfer of PIA-specific CTL effectively treated lung metastases in syngeneic mice challenged with PIA-negative 4T1 mammary carcinoma cells. These data show a novel strategy of combined chemoimmunotherapy of cancer targeting a CTA induced de novo in A broad range of tumor histologies, and support further evaluation of chromatin-remodeling agents for human cancer therapy. C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. NCI, Thorac Oncol Sect, NIH, Bethesda, MD USA. NCI, Tumor Immunol Sect, Surg Branch, NIH, Bethesda, MD USA. Ohio State Univ, Med Ctr, Dept Pathol, Columbus, OH USA. Ohio State Univ, Med Ctr, Ctr Comprehens Canc, Columbus, OH USA. RP Guo, ZS (reprint author), Univ Pittsburgh, Inst Canc, UPCI Res Pavil 1-46,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM guozs@upmc.edu RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 56 TC 96 Z9 101 U1 0 U2 3 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 JAN 15 PY 2006 VL 66 IS 2 BP 1105 EP 1113 DI 10.1158/0008-5472.CAN-05-3020 PG 9 WC Oncology SC Oncology GA 006RQ UT WOS:000234915100065 PM 16424047 ER PT J AU Hwang, LN Yu, ZY Palmer, DC Restifo, NP AF Hwang, LN Yu, ZY Palmer, DC Restifo, NP TI The in vivo expansion on rate of properly stimulated transferred CD8(+) T cells exceeds that of an aggressive growing mouse tumor SO CANCER RESEARCH LA English DT Article ID ADOPTIVE IMMUNOTHERAPY; TRANSFER THERAPY; ANTIGEN; CANCER; REJECTION; NAIVE; REGRESSION; RESPONSES; GROWTH; AUTOIMMUNITY AB It has been hypothesized that rapidly dividing tumor cells can outpace adoptively transferred antitumor lymphocytes when tumors are large. However, this hypothesis is at odds with clinical observations indicating that bulky tumors can be destroyed by small numbers of adoptively transferred antitumor T cells. We sought to measure the relative growth rates of T cells and tumor cells in a model using transgenic CD8(+) T cells specific for the gp100(25-33) H-2D(b) epitope (called pmel-1) to treat large, well-established s.c. B16 melanoma. We tested the effect of the immunization using an altered peptide ligand vaccine alone or in combination with interleukin-2 (IL-2) by analyzing the kinetics of T-cell expansion using direct enumeration. We found that pmel-1 T cells proliferated explosively during a 5-day period following transfer. Calculations from net changes in population suggest that, at the peak of cell division, pmel-1 T cells divide at a rate of 5.3 hours per cell division, which was much faster than B16 tumor cells during optimal growth (24.9 hours per cell division). These results clearly indicate that the notion of a kinetic "race" between the tumor and the lymphocyte is no contest when adoptively transferred cells are stimulated with immunization and IL-2. When appropriately stimulated, tumor-reactive T-cell expansion can far exceed the growth of even an aggressively growing mouse tumor. C1 NCI, Clin Res Ctr, NIH, Bethesda, MD 20892 USA. RP Yu, ZY (reprint author), NCI, Clin Res Ctr, NIH, Bldg CRC,Room 3W-5316, Bethesda, MD 20892 USA. EM zhiya_yu@nih.gov RI Restifo, Nicholas/A-5713-2008; Palmer, Douglas/B-9454-2008 OI Palmer, Douglas/0000-0001-5018-5734 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010763-01] NR 29 TC 27 Z9 29 U1 0 U2 0 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 JAN 15 PY 2006 VL 66 IS 2 BP 1132 EP 1138 DI 10.1158/0008-5472.CAN-05-1679 PG 7 WC Oncology SC Oncology GA 006RQ UT WOS:000234915100068 PM 16424050 ER PT J AU Castle, PE Jeronimo, J Schiffman, M Herrero, R Rodriguez, AC Bratti, MC Hildesheim, A Wacholder, S Long, LR Neve, L Pfeiffer, R Burk, RD AF Castle, PE Jeronimo, J Schiffman, M Herrero, R Rodriguez, AC Bratti, MC Hildesheim, A Wacholder, S Long, LR Neve, L Pfeiffer, R Burk, RD TI Age-related changes of the cervix influence human papillomavirus type distribution SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; POLYMERASE-CHAIN-REACTION; UTERINE CERVIX; UNITED-STATES; RISK-FACTORS; E5 PROTEIN; INFECTION; CANCER; WORLDWIDE; WOMEN AB Approximately 15 human papillomavirus (HPV) types cause virtually all cervical cancer whereas other HPV types are unrelated to cancer. We were interested in whether some noncarcinogenic types differ from carcinogenic in their affinity for the cervical transformation zone, where nearly all HPV-induced cancers occur. To examine this possibility, we tested cervical specimens from 8,374 women without cervical precancer and cancer participating in a population-based study in Guanacaste for > 40 HPV types using PCR. We compared age-group specific prevalences of HPV types of the alpha 9 species, which are mainly carcinogenic and include HPV16, to the genetically distinct types of the alpha 3/alpha 15 species (e.g., HPV71), which are noncarcinogenic and common in vaginal specimens from hysterectomized women. We related HPV detection of each group to the location of the junction between the squamous epithelium of the ectocervix and vagina and the columnar epithelium of the endocervical canal. Models evaluated the independent effects of amount of exposed columnar epithelium (ectopy) and age on the presence of alpha 9 or alpha 3/alpha 15 types. Prevalence of alpha 9 types (7.6%) peaked in the youngest women, declined in middle-aged women, and then increased slightly in older women. By contrast, prevalence of alpha 3/alpha 15 types (7.6%) tended to remain invariant or to increase with increasing age. Detection of alpha 9 infections increased (P-trend < 0.0005) but alpha 3/alpha 15 infections decreased (Ptrend < 0.0005) with increasing exposure of the columnar epithelia. Older age and decreasing cervical ectopy were independently positively associated with having an alpha 3/alpha 15 infection compared with having an alpha 9 infection. These patterns need to be confirmed in other studies and populations. We suggest that these genetically distinct groups of HPV types may differ in tissue preferences, which may contribute to their differences in carcinogenic potential. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Natl Lib Med, Commun Engn Branch, NIH, Bethesda, MD 20892 USA. Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. Albert Einstein Coll Med, New York, NY USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, Room 7074,6120 Execut Blvd,EPS MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU NCI NIH HHS [N01 CP 21081, N01 CP 31061, CA 78527, N01 CP 33061, N01 CP 40542, N01 CP 50535, N01 CP 81023] NR 33 TC 68 Z9 71 U1 0 U2 2 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 JAN 15 PY 2006 VL 66 IS 2 BP 1218 EP 1224 DI 10.1158/0008-5472.CAN-05-3066 PG 7 WC Oncology SC Oncology GA 006RQ UT WOS:000234915100079 PM 16424061 ER PT J AU Yuan, BB Xu, Y Woo, JH Wang, YY Bae, YK Yoon, DS Wersto, RP Tully, E Wilsbach, K Gabrielson, E AF Yuan, BB Xu, Y Woo, JH Wang, YY Bae, YK Yoon, DS Wersto, RP Tully, E Wilsbach, K Gabrielson, E TI Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability SO CLINICAL CANCER RESEARCH LA English DT Article ID MUTATION ANALYSIS; DEFECTS; ROLES; BUBR1; HBUB1; BUB1B; LUNG AB Purpose: Most breast cancers have chromosomal instability that seems related to defective mitotic spindle checkpoints. Because the molecular basis of this defect is unknown, we evaluated breast cancer cell lines and tissues for possible defects involving the major mitotic checkpoint genes responsible for maintaining chromosomal stability. Experimental Design: We analyzed sequences and expression levels (RNA and protein) of eight major spindle checkpoint genes (MAD10, MAD20, MAD2L2, BUB1, BUB18, BUB3, CDC20, and TTK) in a panel of 12 breast cancer cell lines, most with established genetic instability and defective spindle damage checkpoint response. mRNA levels of these genes were also measured in primary tumor samples, and immunohistochemical staining was used to evaluate BUB1B protein levels in a panel of 270 additional cases of breast cancer. Results: No functionally significant sequence variations were found for any of the eight genes in the breast cancer cell lines with chromosomal instability. More surprisingly, the m RNA and protein levels for these checkpoint genes are significantly higher in the genetically unstable breast cancer cell lines and in high-grade primary breast cancer tissues than in the stable (and checkpoint proficient) MCF-10A and normal mammary epithelial cells, or in normal breast tissues. In fact, overexpression of the BUB1B protein is a marker that recognizes nearly 80% of breast cancers in paraffin-embedded tissues. Conclusions: Defective mitotic spindle checkpoints in breast cancer are most likely not caused by low expression or mutations of these eight checkpoint genes. High levels of these particular transcripts could represent a cellular compensation for defects in other molecular components of the mitotic spindle damage checkpoint, and increased expression of these genes might be markers of breast cancers with chromosomal instability. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Yeungnam Univ, Sch Med, Taegu, South Korea. Konyang Univ, Sch Med, Taegu, South Korea. RP Gabrielson, E (reprint author), Johns Hopkins Canc Ctr, 417 N Caroline St, Baltimore, MD 21231 USA. EM egabriel@jhmi.edu FU NCI NIH HHS [P50 CA 88846-04] NR 22 TC 137 Z9 151 U1 0 U2 3 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 JAN 15 PY 2006 VL 12 IS 2 BP 405 EP 410 DI 10.1158/1078-0432.CCR-05-0903 PG 6 WC Oncology SC Oncology GA 004ZL UT WOS:000234791300013 PM 16428479 ER PT J AU Ye, B Skates, S Mok, SC Horick, NK Rosenberg, HF Vitonis, A Edwards, D Sluss, P Han, WK Berkowitz, RS Cramer, DW AF Ye, B Skates, S Mok, SC Horick, NK Rosenberg, HF Vitonis, A Edwards, D Sluss, P Han, WK Berkowitz, RS Cramer, DW TI Proteomic-based discovery and characterization of glycosylated eosinophil-derived neurotoxin and COOH-terminal osteopontin fragments for ovarian cancer in urine SO CLINICAL CANCER RESEARCH LA English DT Article ID MASS-SPECTROMETRY; 2-DIMENSIONAL ELECTROPHORESIS; NONSECRETORY RIBONUCLEASE; PREGNANT-WOMEN; PROTEINS; CARCINOMA; INFLAMMATION; BIOMARKER; PLASMA; BLOOD AB Purpose: The objective was to identify and characterize low molecular weight proteins/peptides in urine and their posttranslational modifications that might be used as a screening tool for ovarian cancer. Experimental Design: Urine samples collected preoperatively from postmenopausal women with ovarian cancer and benign conditions and from nonsurgical controls were analyzed by surface-enhanced laser desorption/ionization mass spectrometry and two-dimensional gel electrophoresis. Selected proteins from mass profiles were purified by chromatography and followed by liquid chromatography-tandem mass spectrometry sequence analysis. Specific antibodies were generated for further characterization, including immunoprecipitation and glycosylation. Quantitative and semiquantitative ELISAs were developed for preliminary validation in patients of 128 ovarian cancer, 52 benign conditions, 44 other cancers, and 188 healthy controls. Results: A protein (m/z similar to 17,400) with higher peak intensities in cancer patients than in benign conditions and controls was identified and subsequently defined as eosinophil-derived neurotoxin (EDN). A glycosylated form of EDN was specifically elevated in ovarian cancer patients. A cluster of COOH-terminal osteopontin was identified from two-dimensional gels of urine from cancer patients. Modified forms EDN and osteopontin fragments were elevated in early-stage ovarian cancers and a combination of both resulted to 93% specificity and 72% sensitivity. Conclusions: Specific elevated posttranslationally modified urinary EDN and osteopontin COOH-terminal fragments in ovarian cancer might lead to potential noninvasive screening tests for early diagnosis. Urine with less complexity than serum and relatively high thermodynamic stability of peptides or metabolites is a promising study medium for discovery of the novel biomarkers which may present in many nonurinary tract neoplastic diseases. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med,Dana Farber Canc Ctr,Lab Gynecol Oncol, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med,Dana Farber Canc Ctr, Renal & Pathol Div, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Reprod Endocrine Unit Lab, Boston, MA 02114 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Ye, B (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med,Dana Farber Canc Ctr,Lab Gynecol Oncol, Dept Obstet Gynecol & Reprod Biol, 221 Longwood Ave,LMRC 610B, Boston, MA 02115 USA. EM Bye@partners.org FU NCI NIH HHS [1P50 CA 105009, R21 CA 111949-01, U01 CA 86381] NR 48 TC 97 Z9 108 U1 2 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 JAN 15 PY 2006 VL 12 IS 2 BP 432 EP 441 DI 10.1158/1078-0432.CCR-05-0461 PG 10 WC Oncology SC Oncology GA 004ZL UT WOS:000234791300017 PM 16428483 ER PT J AU Hassan, R Remaley, AT Sampson, ML Zhang, JL Cox, DD Pingpank, J Alexander, R Willingham, M Pastan, I Onda, M AF Hassan, R Remaley, AT Sampson, ML Zhang, JL Cox, DD Pingpank, J Alexander, R Willingham, M Pastan, I Onda, M TI Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CARCINOEMBRYONIC ANTIGEN; MOLECULAR-CLONING; PHOSPHOLIPASE-C; EXPRESSION; DIAGNOSIS; ANTIBODY; CELLS; IDENTIFICATION; CARCINOMA; RESPONSES AB Purpose: To determine whether mesothelin, a cell surface protein highly expressed in mesothelioma and ovarian cancer, is shed into serum and if so to accurately measure it. Experimental Design: We developed a sandwich ELISA using antibodies reacting with two different epitopes on human mesothelin. To quantitate serum mesothelin levels, a standard curve was generated using a mesothelin-Fc fusion protein. Sera from 24 healthy volunteers, 95 random hospital patients, 56 patients with mesothelioma, and 21 patients with ovarian cancer were analyzed. Serum mesothelin levels were also measured before and after surgical cytoreduction in six patients with peritoneal mesothelioma. Results: Elevated serum mesothelin levels were noted in 40 of 56 (71%) patients with mesothelioma and in 14 of 21 (67%) patients with ovarian cancer. Serum mesothelin levels were increased in 80% and 75% of the cases of mesothelioma and ovarian cancer, respectively, in which the tumors expressed mesothelin by immunohistochemistry. Out of the six patients with peritoneal mesothelioma who underwent surgery, four had elevated serum mesothelin levels before surgery. Out of these four patients, three had cytoreductive surgery and the serum mesothelin level decreased by 71% on postoperative day 1 and was undetectable by postoperative day 7. Conclusions: We developed a serum mesothelin assay that shows that mesothelin is elevated in patients with mesothelioma and ovarian cancer. The rapid decrease in mesothelin levels after surgery in patients with peritoneal mesothelioma suggests that serum mesothelin may be a useful test to monitor treatment response in mesothelin-expressing cancers. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Dept Lab Med, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Winston Salem, NC 27103 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU Intramural NIH HHS NR 30 TC 155 Z9 164 U1 1 U2 8 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 JAN 15 PY 2006 VL 12 IS 2 BP 447 EP 453 DI 10.1158/1078-0432.CCR-05-1477 PG 7 WC Oncology SC Oncology GA 004ZL UT WOS:000234791300019 PM 16428485 ER PT J AU Spacek, LA Shihab, HM Kamya, MR Mwesigire, D Ronald, A Mayanja, H Moore, RD Bates, M Quinn, TC AF Spacek, LA Shihab, HM Kamya, MR Mwesigire, D Ronald, A Mayanja, H Moore, RD Bates, M Quinn, TC TI Response to antiretroviral therapy in HIV-infected patients attending a public, urban clinic in Kampala, Uganda SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID DRUG-RESISTANCE; HIGH PREVALENCE; SOUTH-AFRICA; ADHERENCE; NEVIRAPINE; FAILURE AB Background. Access to antiretroviral therapy and human immunodeficiency virus (HIV) care is increasing in resource-limited settings. We evaluated clinical, behavioral, and demographic risk factors associated with virologic suppression in a public, urban clinic in Kampala, Uganda. Methods. We conducted a cross-sectional, observational study of 137 HIV-infected patients who were receiving antiretroviral therapy at the infectious diseases clinic at Mulago Hospital (Kampala). We measured the prevalence of viral suppression, evaluated risk factors associated with virologic failure, and documented phenotypic resistance patterns and genotypic mutations. Results. A total of 91 (66%) of 137 participants had an undetectable viral load (< 400 copies/mL) after a median duration of 38 weeks (interquartile range, 24-62 weeks) of antiretroviral therapy. Median CD4 cell count was 163 cells/mm(3) (interquartile range, 95-260 cells/mm(3)). The majority of the patients (91%) were treated with nonnucleoside reverse-transcriptase inhibitor-based 3-drug regimens. In multivariate analysis, treatment with the first antiretroviral regimen was associated with viral suppression (odds ratio, 2.6; 95% confidence interval, 1.1-6.1). In contrast, a history of unplanned treatment interruption was associated with virologic treatment failure (odds ratio, 0.2; 95% confidence interval, 0.1-0.6). Of 124 participants treated with nonnucleoside reverse-transcriptase inhibitors, 27 (22%) were documented to have experienced virologic treatment failure. The most common mutation detected was K103N (found in 14 of 27 patients with virologic treatment failure). Conclusions. Although many HIV-infected people treated in Kampala, Uganda, have advanced HIV disease, the majority of patients who received antiretroviral therapy experienced viral suppression and clinical benefit. Because of the frequent use of nonnucleoside reverse-transcriptase inhibitor-based therapy, the majority of resistance was against this drug class. In resource-limited settings, initiation of therapy with a potent, durable regimen, accompanied by stable drug supplies, will optimize the likelihood of viral suppression. C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. Monogram Biosci, San Francisco, CA USA. Acad Alliance AIDS Care & Prevent, Kampala, Uganda. Makerere Univ, Kampala, Uganda. Univ Manitoba, Winnipeg, MB, Canada. RP Spacek, LA (reprint author), Johns Hopkins Sch Med, 1830 E Monument St,Rm 456, Baltimore, MD 21287 USA. EM lspacek@jhmi.edu OI Ronald, Allan/0000-0002-5746-3490 FU NIAID NIH HHS [P30 AI42855, AI060384-01] NR 22 TC 67 Z9 70 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2006 VL 42 IS 2 BP 252 EP 259 DI 10.1086/499044 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 993UW UT WOS:000233981800015 PM 16355337 ER PT J AU Choo, D Ward, J Reece, A Dou, HW Lin, ZS Greinwald, J AF Choo, D Ward, J Reece, A Dou, HW Lin, ZS Greinwald, J TI Molecular mechanisms underlying inner ear patterning defects in kreisler mutants SO DEVELOPMENTAL BIOLOGY LA English DT Article DE inner ear; kreisler; MafB; endolymphatic sac; Wnt2b; Otx2; Dlx5; Gbx2; mouse ID MID/HINDBRAIN ORGANIZER; TRANSCRIPTION FACTOR; SEGMENTATION MUTANT; GENE-EXPRESSION; SENSORY ORGANS; MOUSE; GBX2; HINDBRAIN; OTX2; INDUCTION AB Prior studies have shown that kreisler mutants display early inner ear defects that are related to abnormal hindbrain development and signaling. These defects in kreisler mice have been linked to mutation of the kr/mafB gene. To investigate potential relevance of kr/mafB and abnormal hindbrain development in inner ear patterning, we analyzed the car morphogenesis in kreisler mice using a paint-fill technique. We also examined the expression patterns of a battery of genes important for normal inner ear patterning and development. Our results indicate that the loss of dorsal otic structures such as the endolymphatic duct and sac is attributable to the downregulation of Gbx2, Dlx5 and Wnt2b in the dorsal region of the otocyst. In contrast, the expanded expression domain of Otx2 in the ventral otic region likely contributes to the cochlear phenotype seen in kreisler mutants. Sensory organ development is also markedly disrupted in kreisler mutants. This pattern of defects and gene expression changes is remarkably similar to that observed in Gbx2 mutants. Taken together, the data show an important role for hindbrain cues, and indirectly, kr/mafB, in guiding inner ear morphogenesis. The data also identify Gbx2, Dlx5, Wnt2b and Otx2 as key otic genes ultimately affected by perturbation of the kr/mafB-hindbrain pathway. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Cincinnati, Coll Med, Dept Otolaryngol Head & Neck Surg,Med Ctr, Ctr Hearing & Deafness Res,Cincinnati Childrens H, Cincinnati, OH 45229 USA. Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, Rockville, MD 20850 USA. RP Choo, D (reprint author), Univ Cincinnati, Coll Med, Dept Otolaryngol Head & Neck Surg,Med Ctr, Ctr Hearing & Deafness Res,Cincinnati Childrens H, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM daniel.choo@cchmc.org NR 44 TC 34 Z9 36 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JAN 15 PY 2006 VL 289 IS 2 BP 308 EP 317 DI 10.1016/j.ydbio.2005.10.007 PG 10 WC Developmental Biology SC Developmental Biology GA 008WP UT WOS:000235071700004 PM 16325169 ER PT J AU Matsumoto, S Banine, F Struve, J Xing, RB Adams, C Liu, Y Metzger, D Chambon, P Rao, MS Sherman, LS AF Matsumoto, S Banine, F Struve, J Xing, RB Adams, C Liu, Y Metzger, D Chambon, P Rao, MS Sherman, LS TI Brg1 is required for murine neural stem cell maintenance and gliogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE neural stem cells; Brg1; chromatin remodeling; astrocytes; neurons; oligodendrocytes ID SWI/SNF COMPLEXES; CD44 EXPRESSION; CYCLE ARREST; N-COR; CHROMATIN; PROTEIN; GENE; DIFFERENTIATION; NEUROGENESIS; MUTATION AB Epigenetic alterations in cell-type-specific gene expression control the transition of neural stem cells (NSCs) from predominantly neurogenic to predominantly gliogenic phases of differentiation, but how this switch occurs is unclear. Here, we show that brahma-related gene 1 (Brg1), an ATP-dependent chromatin remodeling factor, is required for the repression of neuronal commitment and the maintenance of NSCs in a state that permits them to respond to gliogenic signals. Loss of Brg1 in NSCs in conditional brg1 mutant mice results in precocious neuronal differentiation, such that cells in the ventricular zone differentiate into post-mitotic neurons before the onset of gliogenesis. As a result, there is a dramatic failure of astrocyte and oligodendrocyte differentiation in these animals. The ablation of brg1 in gliogenic progenitors in vitro also prevents growth-factor-induced astrocyte differentiation. Furthermore, proteins implicated in the maintenance of stem cells, including Sox1, Pax6 and Musashi-1, are dramatically reduced in the ventricular zones of brg1 mutant mice. We conclude that Brg1 is required to repress neuronal differentiation in NSCs as a means of permitting glial cell differentiation in response to gliogenic signals, suggesting that Brg1 regulates the switch from neurogenesis to gliogenesis. (c) 2005 Elsevier Inc. All rights reserved. C1 Oregon Hlth & Sci Univ, Div Neurosci, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. Oregon Hlth & Sci Univ, Sch Dent, Integrat Biosci Dept, Portland, OR 97239 USA. NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Univ Strasbourg 1, Coll France, Inst Genet & Biol Mol & Cellulaire, CNRS,INSERM, Illkirch Graffenstaden, France. Inst Clin Souris, Illkirch Graffenstaden, France. RP Sherman, LS (reprint author), Oregon Hlth & Sci Univ, Div Neurosci, Oregon Natl Primate Res Ctr, 505 NW 185th Ave, Beaverton, OR 97006 USA. EM sherman1@ohsu.edu FU NCRR NIH HHS [RR00163]; NINDS NIH HHS [NS39550] NR 35 TC 72 Z9 72 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JAN 15 PY 2006 VL 289 IS 2 BP 372 EP 383 DI 10.1016/j.ydbio.2005.10.044 PG 12 WC Developmental Biology SC Developmental Biology GA 008WP UT WOS:000235071700010 PM 16330018 ER PT J AU Kleinbongard, P Dejam, A Lauer, T Jax, T Kerber, S Gharini, P Balzer, J Zotz, RB Scharf, RE Willers, R Schechter, AN Feelisch, M Kelm, M AF Kleinbongard, P Dejam, A Lauer, T Jax, T Kerber, S Gharini, P Balzer, J Zotz, RB Scharf, RE Willers, R Schechter, AN Feelisch, M Kelm, M TI Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE free radicals ID PROTEIN-CONTAINING SAMPLES; CORONARY-ARTERY-DISEASE; OXIDE SYNTHASE ACTIVITY; CIRCULATING NITRITE; BIOLOGICAL TISSUES; CIGARETTE-SMOKING; GRIESS METHOD; HUMAN BLOOD; RISK; NO AB A reduced nitric oxide availability is a hallmark of endothelial dysfunction occurring early in atherosclerosis. Recently, we have shown that plasma nitrite mirrors acute changes in endothelial nitric oxide synthase activity in various mammals, including humans. Here, we examined the hypothesis that plasma nitrite levels are reduced in humans with endothelial dysfunction and the decrease is correlated with increasing numbers of cardiovascular risk factors (RF). Plasma nitrite concentrations were quantified by flow-injection analysis. The coefficient of variation for repeated measurements of plasma nitrite was < 8%, and heart rate and blood pressure at the time of blood sampling had no significant effect on nitrite values measured (n = 10). Baseline levels of plasma nitrite followed a normal distribution in each group studied and decreased progressively with increasing numbers of cardiovascular risk factors (n = 35 1, p < 0.001): 351 +/- 13 (0 RF), 261 +/- 10 (1 RF), 253 +/- 11 (2 RF), 222 +/- 18 (3 RF), and 171 +/- 29 nmol/L (4 1117). Intima media thickness (IMT) and flow-mediated dilation (FMD) were determined via ultrasound. Plasma nitrite and FMD levels were lower, whereas IMT was greater in individuals with endothelial dysfunction (n = 12) compared to healthy volunteers (n = 12). Nitrite correlated significantly with FMD (r = 0.56, p < 0.001) and inversely with IMT (r = -0.49, p < 0.01). Plasma nitrite levels are reliably measurable in humans, indicate endothelial dysfunction, and correlate with cardiovascular risk factors. Future studies are necessary to identify the prognostic relevance of plasma nitrite determination ill patients suffering from cardiovascular disease. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Hosp RWTH Aachen, Med Clin 1, D-52074 Aachen, Germany. NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. Univ Dusseldorf, Inst Hemostasis & Transfus Med, D-40225 Dusseldorf, Germany. Univ Dusseldorf, Dept Stat Computat, D-40225 Dusseldorf, Germany. Boston Univ, Sch Med, Whitaker Cardiovasc Res Inst, Boston, MA 02118 USA. Univ Dusseldorf, Dept Med, Div Cardiol Pulm Dis & Angiol, D-40225 Dusseldorf, Germany. RP Kelm, M (reprint author), Univ Hosp RWTH Aachen, Med Clin 1, D-52074 Aachen, Germany. EM mkelm@ukaachen.de RI Feelisch, Martin/C-3042-2008; OI Feelisch, Martin/0000-0003-2320-1158; Schechter, Alan N/0000-0002-5235-9408 FU NHLBI NIH HHS [HL 69029] NR 47 TC 181 Z9 186 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2006 VL 40 IS 2 BP 295 EP 302 DI 10.1016/j.freeadbiomed.2005.08.025 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 009NP UT WOS:000235119100012 PM 16413411 ER PT J AU Antonellis, A Bennett, WR Prasad, AB Lee-Lin, SQ Green, ED Paisley, D Kelsh, RN Pavan, WJ Ward, A AF Antonellis, A Bennett, WR Prasad, AB Lee-Lin, SQ Green, ED Paisley, D Kelsh, RN Pavan, WJ Ward, A CA NUSC Comparative Sequencing TI Deletion of long-range sequences at Sox10 compromises developmental expression in a mouse model of Waardenburg-Shah (WS4) syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSCRIPTION FACTOR SOX10; NEURAL CREST DEVELOPMENT; AUTOSOMAL SEX REVERSAL; GENOMIC DNA-SEQUENCES; SRY-RELATED GENE; HIRSCHSPRUNG-DISEASE; CAMPOMELIC DYSPLASIA; FUGU-RUBRIPES; MUTATIONS; DIFFERENTIATION AB The transcription factor SOX10 is mutated in the human neurocristopathy Waardenburg-Shah syndrome (WS4), which is characterized by enteric aganglionosis and pigmentation defects. SOX10 directly regulates genes expressed in neural crest lineages, including the enteric ganglia and melanocytes. Although some SOX10 target genes have been reported, the mechanisms by which SOX10 expression is regulated remain elusive. Here, we describe a transgene-insertion mutant mouse line (Hry) that displays partial enteric aganglionosis, a loss of melanocytes, and decreased Sox10 expression in homozygous embryos. Mutation analysis of Sox10 coding sequences was negative, suggesting that non-coding regulatory sequences are disrupted. To isolate the Hry molecular defect, Sox10 genomic sequences were collected from multiple species, comparative sequence analysis was performed and software was designed EXACTPLUS to identify identical sequences shared among species. Mutation analysis of conserved sequences revealed a 15.9 kb deletion located 47.3 kb upstream of Sox10 in Hry mice. EXACTPLUS revealed three clusters of highly conserved sequences within the deletion, one of which shows strong enhancer potential in cultured melanocytes. These studies: (i) present a novel hypomorphic Sox10 mutation that results in a WS4-like phenotype in mice; (ii) demonstrate that a 15.9 kb deletion underlies the observed phenotype and likely removes sequences essential for Sox10 expression; (iii) combine a novel in silico method for comparative sequence analysis with in vitro functional assays to identify candidate regulatory sequences deleted in this strain. These studies will direct further analyses of Sox10 regulation and provide candidate sequences for mutation detection in WS4 patients lacking a SOX10-coding mutation. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. Univ Bath, Dept Biol & Biochem, Dev Biol Programme, Bath BA2 7AY, Avon, England. Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath BA2 7AY, Avon, England. George Washington Univ, Grad Program Genet, Washington, DC 20052 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr,Bldg 49,Room 4A82, Bethesda, MD 20892 USA. EM bpavan@nhgri.nih.gov RI Kelsh, Robert/B-6445-2008; Prasad, Arjun/C-6736-2008; Bennett, William/A-4039-2010; Menheniott, Treve/D-7964-2015 OI Kelsh, Robert/0000-0002-9381-0066; Bennett, William/0000-0002-1559-3027; Menheniott, Treve/0000-0003-2349-8238 FU Intramural NIH HHS; Medical Research Council [G0300415] NR 43 TC 42 Z9 42 U1 0 U2 2 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 JAN 15 PY 2006 VL 15 IS 2 BP 259 EP 271 DI 10.1093/hmg/ddi442 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 002RZ UT WOS:000234630400008 PM 16330480 ER PT J AU Huang, KM Wu, JH Duncan, MK Moy, C Dutra, A Favor, J Da, T Stambolian, D AF Huang, KM Wu, JH Duncan, MK Moy, C Dutra, A Favor, J Da, T Stambolian, D TI Xcat, a novel mouse model for Nance-Horan syndrome inhibits expression of the cytoplasmic-targeted Nhs1 isoform SO HUMAN MOLECULAR GENETICS LA English DT Article ID X-LINKED CATARACT; CONGENITAL CATARACT; CANDIDATE GENES; FAMILY; HYBRIDIZATION; CHROMOSOME; MUTATIONS; PROTEINS; REGION; LOCUS AB Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features and mental retardation. A recent report suggests that the novel gene NHS1 is involved in this disorder due to the presence of point mutations in NHS patients. A possible mouse model for NHS, Xcat, was mapped to a 2.11 Mb interval on the X-chromosome. Sequence and FISH analysis of the X-chromosome region containing the Xcat mutation reveal a large insertion between exons 1 and 2 of the mouse Nhs1 gene. The insertion inhibits the expression of the Nhs1 isoform containing exon 1 and results in exclusive expression of the alternative isoform containing exon 1A. Quantitative RT-PCR of Xcat cDNA shows reduced levels of Nhs1 transcripts. The Nhs1 protein is strongly expressed within the cytoplasm of elongating lens fiber cells from wild-type neonate lens, but is significantly reduced within the Xcat lens. Transient transfection studies of CHO cells with Nhs1-GFP fusion proteins were done to determine whether the amino acids encoded by exon 1 were critical for protein localization. We found the presence of Nhs1 exon 1 critical for localization of the fusion protein to the cytoplasm, whereas fusion proteins lacking Nhs1 exon 1 are predominantly nuclear. These results indicate that the first exon of Nhs1 contains crucial information required for the proper expression and localization of Nhs1 protein. Inhibition of expression of the exon 1 containing isoform results in the abnormal phenotype of Xcat. C1 Univ Penn, Sch Med, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA. Univ Delaware, Dept Biol Sci, Newark, DE USA. NHGRI, NIH, Bethesda, MD 20892 USA. GSF Natl Res Ctr Environm & Hlth, Inst Human Genet, Neuherberg, Germany. RP Stambolian, D (reprint author), Univ Penn, Sch Med, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Stellar Chance Bldg Room 313,422 Curie Blvd, Philadelphia, PA 19104 USA. EM stamboli@mail.med.upenn.edu OI Duncan, Melinda/0000-0003-1570-322X FU NCRR NIH HHS [P20 RR16472]; NEI NIH HHS [R01 EY15279, R01 EY13615] NR 20 TC 16 Z9 17 U1 0 U2 2 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 JAN 15 PY 2006 VL 15 IS 2 BP 319 EP 327 DI 10.1093/hmg/ddi449 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 002RZ UT WOS:000234630400013 PM 16357105 ER PT J AU Zhang, ZJ Lee, YC Kim, SJ Choi, MSS Tsai, PC Xu, Y Xiao, YJ Zhang, P Heffer, A Mukherjee, AB AF Zhang, ZJ Lee, YC Kim, SJ Choi, MSS Tsai, PC Xu, Y Xiao, YJ Zhang, P Heffer, A Mukherjee, AB TI Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL SO HUMAN MOLECULAR GENETICS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; NITRIC-OXIDE SYNTHASE; CEROID-LIPOFUSCINOSIS; FATTY ACYLATION; CASPASE-12; INITIATION-FACTOR-2; DEPHOSPHORYLATION; IDENTIFICATION; TRAFFICKING; HUNTINGTIN AB Numerous proteins undergo modification by palmitic acid (S-acylation) for their biological functions including signal transduction, vesicular transport and maintenance of cellular architecture. Although palmitoylation is an essential modification, these proteins must also undergo depalmitoylation for their degradation by lysosomal proteases. Palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme, cleaves thioester linkages in S-acylated proteins and removes palmitate residues facilitating the degradation of these proteins. Thus, inactivating mutations in the PPT1 gene cause infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disorder of childhood. Although rapidly progressing brain atrophy is the most dramatic pathological manifestation of INCL, the molecular mechanism(s) remains unclear. Using PPT1-knockout (PPT1-KO) mice that mimic human INCL, we report here that the endoplasmic reticulum (ER) in the brain cells of these mice is structurally abnormal. Further, we demonstrate that the level of growth-associated protein-43 (GAP-43), a palmitoylated neuronal protein, is elevated in the brains of PPT1-KO mice. Moreover, forced expression of GAP-43 in PPT1-deficient cells results in the abnormal accumulation of this protein in the ER. Consistent with these results, we found evidence for the activation of unfolded protein response (UPR) marked by elevated levels of phosphorylated translation initiation factor, eIF2 alpha, increased expression of chaperone proteins such as glucose-regulated protein-78 and activation of caspase-12, a cysteine proteinase in the ER, mediating caspase-3 activation and apoptosis. Our results, for the first time, link PPT1 deficiency with the activation of UPR, apoptosis and neurodegeneration in INCL and identify potential targets for therapeutic intervention in this uniformly fatal disease. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA. Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Intramural NIH HHS NR 48 TC 70 Z9 70 U1 1 U2 6 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 JAN 15 PY 2006 VL 15 IS 2 BP 337 EP 346 DI 10.1093/hmg/ddi451 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 002RZ UT WOS:000234630400015 PM 16368712 ER PT J AU Stuart, GR Santos, JH Strand, MK Van Houten, B Copeland, WC AF Stuart, GR Santos, JH Strand, MK Van Houten, B Copeland, WC TI Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase gamma associated with progressive external ophthalmoplegia SO HUMAN MOLECULAR GENETICS LA English DT Article ID ACCESSORY SUBUNIT; MULTIPLE DELETIONS; YEAST MITOCHONDRIA; CATALYTIC SUBUNIT; GENOME STABILITY; DAMAGE; REPAIR; MTDNA; POLG; GENE AB A number of nuclear mutations have been identified in a variety of mitochondrial diseases including progressive external ophthalmoplegia (PEO), Alpers syndrome and other neuromuscular and oxidative phosphorylation defects. More than 50 mutations have been identified in POLG, which encodes the human mitochondrial DNA (mtDNA) polymerase gamma, PEO and Alpers patients. To rapidly characterize the effects of these mutations, we have developed a versatile system that enables the consequences of homologous mutations, introduced in situ into the yeast mtDNA polymerase gene MIP1, to be evaluated in vivo in haploid and diploid cells. Overall, distinct phenotypes for expression of each of the mip1-PEO mutations were observed, including respiration-defective cells with decreased viability, dominant-negative mutant polymerases, elevated levels of mitochondrial and nuclear DNA damage and chromosomal mutations. Mutations in the polymerase domain caused the most severe phenotype accompanied by loss of mtDNA and cell viability, whereas the mutation in the exonuclease domain showed mild dominance with loss of mtDNA. Interestingly, the linker region mutation caused elevated mitochondrial and nuclear DNA damage. The cellular processes contributing to these observations in the mutant yeast cells are potentially relevant to understanding the pathologies observed in human mitochondrial disease patients. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. RP NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU Intramural NIH HHS NR 62 TC 46 Z9 47 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2006 VL 15 IS 2 BP 363 EP 374 DI 10.1093/hmg/ddi454 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 002RZ UT WOS:000234630400018 PM 16368709 ER PT J AU Walton, KLW He, JP Kelsall, BL Sartor, RB Fisher, NC AF Walton, KLW He, JP Kelsall, BL Sartor, RB Fisher, NC TI Dendritic cells in germ-free and specific pathogen-free mice have similar phenotypes and in vitro antigen presenting function SO IMMUNOLOGY LETTERS LA English DT Article DE germ-free mice; dendritic cells; commensal bacteria ID MESENTERIC LYMPH-NODES; T-CELL; PEYERS PATCH; MICROBIAL COLONIZATION; CONVENTIONAL MICE; IMMUNE-RESPONSES; DEFICIENT MICE; DIFFERENTIATION; MATURATION; BACTERIA AB Dendritic cells (DC) can direct downstream T-cell responses. Although bacterial adjuvants are strong activators of DC in vitro, the effects of normal enteric bacteria on DC in vivo are not well defined. We used germ-free (GF) mice to determine whether enteric bacteria alter DC phenotype and ability to stimulate naive T cells. Surface expression of CD11c, CD86, and MHCII was measured on splenic and mesenteric lymph node (MLN) DC. In addition, we tested the ability of T-cell depleted splenocytes from mice injected with LPS to stimulate allogeneic T cells, as determined by cell proliferation. The absolute numbers of CD11c+ DC were decreased in the MLN and spleen of GF mice. Freshly isolated CD11c+ DC from spleens or MLN of SPF and GF mice expressed similar levels of CD86 and MHCII by FACS analysis. Proportions of splenic DC expressing CD4 or CD8 were not different in GF versus SPF mice, although the percentage of CD8 alpha-/CD11b+ DC was higher in GF MLN. Intraperitoneal injection of LPS upregulated MHCII and CD86 to a similar extent on splenic DC from GF or SPF mice. Splenic antigen-presenting cells, as well as unseparated spleen or MLN cells, from GF or SPF mice also induced similar levels of T-cell proliferation in vitro. We conclude that commensal bacterial flora do not affect co-stimulatory molecule expression of DC in the spleen or MLN, which exhibit a predominantly immature phenotype. In addition, splenic APC from GF mice are fully competent to stimulate naive T-cell proliferation in vitro. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. Univ N Carolina, SPIRE Program, Chapel Hill, NC 27515 USA. Univ N Carolina, Ctr Gastrointestinal Dis, Chapel Hill, NC 27599 USA. Natl Inst Hlth, Immune Cell Interact Unit, Mucosal Immun Sect, Bethesda, MD USA. RP Walton, KLW (reprint author), Univ N Carolina, Dept Med, CB 7032,7317 MBRB, Chapel Hill, NC 27599 USA. EM kristen_williams@med.unc.edu FU NIDDK NIH HHS [P30 DK34987, R01 DK53347]; NIGMS NIH HHS [GM00678]; PHS HHS [A1041579] NR 54 TC 28 Z9 30 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD JAN 15 PY 2006 VL 102 IS 1 BP 16 EP 24 DI 10.1016/j.imlet.2005.07.001 PG 9 WC Immunology SC Immunology GA 004QX UT WOS:000234768400003 PM 16105690 ER PT J AU Zhao, FH Forman, MR Belinson, J Shen, YH Graubard, BI Patel, AC Rong, SD Pretorius, RG Qiao, Y AF Zhao, FH Forman, MR Belinson, J Shen, YH Graubard, BI Patel, AC Rong, SD Pretorius, RG Qiao, Y TI Risk factors for HPV infection and cervical cancer among unscreened women in a high-risk rural area of China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical cancer; human papillomavirus; tuberculosis; trichomoniasis ID HUMAN-PAPILLOMAVIRUS INFECTION; SEXUAL-BEHAVIOR; COSTA-RICA; POPULATION; NEOPLASIA; PREVALENCE; DETERMINANTS; CYTOLOGY; DNA AB We report a prevalence rate of 23.6% human papillomavirus (HPV) infection with oncogenic subtypes and 2.4% cervical intraepithelial neoplasia (CIN) III and cervical cancer (CC) in rural middle-aged women in 2 counties with the highest CC mortality in Shanxi Province, China. We examined the association of risk factors to HPV infection and to CIN III and CC in 8,798 unscreened women aged 35-50 years. Multivariate odds ratios (OR) and 95% confidence intervals (CI) for each endpoint were obtained for risk factors after adjustment for covariates. The OR of oncogenic HPV were: 1.41 (95% CI = 1.25-1.60) and 1.42 (95% CI = 1.24-1.61) for the participant and her husband having multiple sexual partners, respectively; 1.67 (95% CI = 1.37-2.04), 1.15 (95% CI = 1.04-1.26), and 0.82 (95% CI = 0.72-0.94) for ever (vs. never) diagnosed with tuberculosis, cervical inflammation and vaginal trichomoniasis, respectively; while bathing in a public (v. private) facility had an OR of 1.23 (95% CI = 1.11-1.35). Seasonal fluctuations in HPV infection, but not CC, appeared in Xiangyuan County, with OR of 1.23 (95% CI = 1.14-1.33) and 1.51 (95% CI = 1.35-1.67) in Spring and Winter compared to Summer, respectively. The OR of CIN III and CC in the HPV positives were: 2.03 (95% CI = 1.63-2.53) for ages >= 45 years (vs. <40); and 4.01 (95% CI = 1.46-11.0) for >= 3 (vs. no) home births. Public health interventions and control strategies for improving the reproductive health of women in these rural populations need to be developed to reduce risk of HPV and subsequent CC. (c) 2005 Wiley-Liss, Inc. C1 NCI, Ctr Canc Res, NIH, Lab Biosyst & Canc, Bethesda, MD 20892 USA. Chinese Acad Sci, Canc Inst Hosp, Dept Epidemiol, Beijing, Peoples R China. Cleveland Clin Fdn, Bethesda, MD USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship, Div Canc Prevent, CCR, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, CCR, Bethesda, MD 20892 USA. Kaiser Permanente, Dept Gynecol & Obstet, Fontana, CA USA. RP Forman, MR (reprint author), NCI, Ctr Canc Res, NIH, Lab Biosyst & Canc, 6116 Execut Blvd,Suite 702, Bethesda, MD 20892 USA. EM mf63p@nih.gov RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 45 TC 23 Z9 28 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2006 VL 118 IS 2 BP 442 EP 448 DI 10.1002/ijc.21327 PG 7 WC Oncology SC Oncology GA 992CN UT WOS:000233862100024 PM 16080192 ER PT J AU Landgren, O Bjorkholm, M Montgomery, SM Hjalgrim, H Sjoberg, J Goldin, LR Askling, J AF Landgren, O Bjorkholm, M Montgomery, SM Hjalgrim, H Sjoberg, J Goldin, LR Askling, J TI Personal and family history of autoimmune diabetes mellitus and susceptibility to young-adult-onset Hodgkin lymphoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Hodgkin lymphoma; susceptibility; etiology; pathogenetic; autoimmune; familial; diabetes ID EPSTEIN-BARR-VIRUS; RHEUMATOID-ARTHRITIS; MALIGNANT-LYMPHOMAS; CELL LYMPHOMA; BIRTH-ORDER; DISEASE; POPULATION; CANCER; RISK; CHILDHOOD AB Young-adult-onset (15-44 years of age) Hodgkin lymphoma (HL) is believed to arise as a consequence of late primary infection in susceptible individuals. The properties of this susceptibility remain little understood. We have previously reported an increased occurrence of HL in patients with rheumatoid arthritis and among their offspring, suggesting that susceptibility to autoimmunity might be of importance also in the pathogenesis of HL. To explore this hypothesis, we assessed the association of personal and family history of diabetes mellitus, with risk of subsequent HL in a population-based case-control study, including as cases all individuals diagnosed with HL above 15 years of age 1964-1999 (n = 6,873) in Sweden, and matched population controls (n = 12,565). First-degree relatives of cases and controls were identified through linkage with the Multi-generation Register. We identified discharges listing diabetes mellitus through linkage with the Inpatient Register (1964-2000). We used odds ratios (OR) as measures of relative risk. Cases with young-adult-onset HL were less likely to have a personal (OR=0.5, 95% CI 0.2-1.1) or family (OR=0.7, 95% CI 0.6-0.8) history of diabetes mellitus. In contrast, HL diagnosed at older ages was neither associated with a personal (OR=1.0) nor family (OR=1.0) history of diabetes mellitus. These findings suggests that characteristics of the immune system associated with conditions such as diabetes mellitus type I are of importance in the pathogenesis of young-adult-onset HL. (c) 2005 Wiley-Liss, Inc. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Hosp & Inst, Div Hematol, Stockholm, Sweden. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden. State Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. RP Landgren, O (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov OI Montgomery, Scott/0000-0001-6328-5494 NR 29 TC 8 Z9 8 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2006 VL 118 IS 2 BP 449 EP 452 DI 10.1002/ijc.21347 PG 4 WC Oncology SC Oncology GA 992CN UT WOS:000233862100025 PM 16049983 ER PT J AU Wessels, D Srikantha, T Yi, S Kuhl, S Aravind, L Soll, DR AF Wessels, D Srikantha, T Yi, S Kuhl, S Aravind, L Soll, DR TI The Shwachman-Bodian-Diamond syndrome gene encodes an RNA-binding protein that localizes to the pseudopod of Dictyostelium amoebae during chemotaxis SO JOURNAL OF CELL SCIENCE LA English DT Article DE computer-assisted motion analysis; SBDS gene; pseudopod localization; CAMP chemoattractant ID ACTIN MESSENGER-RNA; ARP2/3 COMPLEX; SACCHAROMYCES-CEREVISIAE; YEAST PROTEIN; BETA-ACTIN; TEMPORAL MECHANISM; CANDIDA-ALBICANS; DISCOIDEUM; CHEMOATTRACTANT; CELLS AB The Shwachman-Bodian-Diamond syndrome (SBDS) is an autosomal disorder with multisystem defects. The Shwachman-Bodian-Diamond syndrome gene (SBDS), which contains mutations in a majority of SBDS patients, encodes a protein of unknown function, although it has been strongly implicated in RNA metabolism. There is also some evidence that it interacts with molecules that regulate cytoskeletal organization. Recently, it has been demonstrated by computer-assisted methods that the single behavioral defect of polymorphonuclear leukocytes (PMNs) of SBDS patients is the incapacity to orient correctly in a spatial gradient of chemoattractant. We considered using the social amoeba Dictyostelium discoideum, a model for PMN chemotaxis, an excellent system for elucidating the function of the SBDS protein. We first identified the homolog of SBDS in D. discoideum and found that the amino acids that are altered in human disease were conserved. Given that several proteins involved in chemotactic orientation localize to the pseudopods of cells undergoing chemotaxis, we tested whether the SBDS gene product did the same. We produced an SBDS-GFP chimeric in-frame fusion gene, and generated transformants either with multiple ectopic insertions of the fusion gene or multiple copies of a non-integrated plasmid carrying the fusion gene. In both cases, the SBDS-GFP protein was dispersed equally through the cytoplasm and pseudopods of cells migrating in buffer. However, we observed differential enrichment of SBDS in the pseudopods of cells treated with the chemoattractant cAMP, suggesting that the SBDS protein may play a role in chemotaxis. In light of these results, we discuss how SBDS might function during chemotaxis. C1 Univ Iowa, WM Keck Dynam Image Anal Facil, Dept Biol Sci, Iowa City, IA 52242 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Computat Biol Branch, Bethesda, MD 20894 USA. RP Soll, DR (reprint author), Univ Iowa, WM Keck Dynam Image Anal Facil, Dept Biol Sci, Iowa City, IA 52242 USA. EM david-soll@uiowa.edu RI Yi, Song/L-7970-2013 FU NICHD NIH HHS [HD-18577] NR 91 TC 31 Z9 34 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JAN 15 PY 2006 VL 119 IS 2 BP 370 EP 379 DI 10.1242/jcs.02753 PG 10 WC Cell Biology SC Cell Biology GA 012HV UT WOS:000235330100017 PM 16410554 ER PT J AU Kramer, JM Yi, L Shen, F Maitra, A Jiao, XM Jin, T Gaffen, SL AF Kramer, JM Yi, L Shen, F Maitra, A Jiao, XM Jin, T Gaffen, SL TI Cutting edge: Evidence for ligand-independent multimerization of the IL-17 receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; ERYTHROPOIETIN RECEPTOR; RHEUMATOID-ARTHRITIS; SIGNAL-TRANSDUCTION; T-CELLS; INTERLEUKIN-17; INFLAMMATION; ACTIVATION; CYTOKINES; DOMAIN AB IL-17 and its receptor are founding members of a novel inflammatory cytokine family. To date, only one IL-17 receptor subunit has been identified, termed IL-17RA. All known cytokine receptors consist of a complex of multiple subunits. Although IL-17-family cytokines exist as homodimers, the configuration and stoichiometry of the IL-17P complex remain unknown. We used fluorescence resonance energy transfer (FRET) to determine whether IL-17RA subunits multimerize, and, if so, whether they are preassembled in the plasma membrane. HEK293 cells coexpressing IL-17RA fused to cyan or yellow fluorescent proteins (CFP or YFP) were used to evaluate FRET before and after IL-17A or IL-17F treatment. In the absence of ligand, IL-17RA molecules exhibited significant specific FRET efficiency, demonstrating that they exist in a multimeric, preformed receptor complex. Strikingly, treatment with IL-17A or IL-17F markedly reduced FRET efficiency, suggesting that IL-IM subunits within the IL-17R complex undergo a conformational change upon ligand binding. C1 SUNY Buffalo, Dept Oral Biol, Sch Dent Med, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med & Biomed Sci, Dept Microbiol & Immunol, Buffalo, NY 14214 USA. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Gaffen, SL (reprint author), SUNY Buffalo, Dept Oral Biol, Sch Dent Med, 3435 Main St, Buffalo, NY 14214 USA. EM tjin@niaid.nih.gov RI Gaffen, Sarah/B-1560-2009; OI Kramer, Jill/0000-0001-9828-8556 FU Intramural NIH HHS; NIAMS NIH HHS [R21 AR050458, AR050458]; NIDCR NIH HHS [DE014831, F30 DE014831, F30 DE014831-04] NR 38 TC 69 Z9 73 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2006 VL 176 IS 2 BP 711 EP 715 PG 5 WC Immunology SC Immunology GA 001RK UT WOS:000234553800005 PM 16393951 ER PT J AU Xu, H Dhanireddy, KK Kirk, AD AF Xu, H Dhanireddy, KK Kirk, AD TI Human monocytes as intermediaries between allogeneic endothelial cells and allospecific T cells: A role for direct scavenger receptor-mediated endothelial membrane uptake in the initiation of alloimmunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN RENAL-ALLOGRAFT; INNATE IMMUNE-SYSTEM; ANTIGEN PRESENTATION; IN-VITRO; TRANSPLANTATION; EXPRESSION; REJECTION; CD4(+); LEUKOCYTES; ADHESION AB Recipient monocytes, T cells, and donor endothelial cells (ECs) are recognized as critical components of allograft rejection. We have recently shown that human monocytes infiltrate vascularized allografts before clinical rejection and have thus hypothesized that monocytes, rather than costimulation-poor ECs, initiate an alloimmune response. However, the nature of the interactions between ECs, monocytes, and T cells has been incompletely defined. Specifically, it is not clear whether these cells interact in a hierarchical manner, nor is it apparent what constitutes an interaction. We therefore studied human ECs, monocytes, and T cells in various isolated in vitro combinations to define the salient features of their contact and to determine whether their interactions were sequential in nature. We find that T cells proliferate poorly to allogeneic ECs and autologous monocytes but well to autologous monocytes following allogeneic EC contact. We show that monocytes gain their stimulatory capacity by phagocytizing allogeneic but not autologous EC membranes in a process governed by scavenger receptors. This process facilitates the subsequent presentation of intact donor HLA molecules to T cells (semidirect presentation). Moreover, monocytes are receptive to T cell help only after exposure to ECs and require CD4(+) T cells to optimally express costimulatory molecules and foster Ag presentation. Our results indicate that monocytes engage allogeneic ECs through scavenger receptors and are then primed to facilitate T cell activation in a codependent manner. This reciprocal codependence allows for monocytes to serve as a regulated bridge between the allograft and T cells. C1 NIDDKD, Transplantat Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Xu, H (reprint author), Room 5-5832,Bldg 10 CRC,Ctr Dr, Bethesda, MD 20892 USA. EM hex@intra.niddk.nih.gov RI Kirk, Allan/B-6905-2012 FU Intramural NIH HHS NR 45 TC 28 Z9 32 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2006 VL 176 IS 2 BP 750 EP 761 PG 12 WC Immunology SC Immunology GA 001RK UT WOS:000234553800012 PM 16393958 ER PT J AU Kottilil, S Shin, K Jackson, JO Reitano, KN O'Shea, MA Yang, J Hallahan, CW Lempicki, R Arthos, J Fauci, AS AF Kottilil, S Shin, K Jackson, JO Reitano, KN O'Shea, MA Yang, J Hallahan, CW Lempicki, R Arthos, J Fauci, AS TI Innate immune dysfunction in HIV infection: Effect of HIV envelope-NK cell interactions SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NATURAL-KILLER-CELLS; BLOOD MONONUCLEAR-CELLS; FOCAL ADHESION KINASE; MACROPHAGE-TROPIC HIV; CD4(+) T-CELLS; CHEMOKINE RECEPTOR; GENE-EXPRESSION; PROTEIN; ACTIVATION AB We have previously described a number of NK cell dysfunctions in HIV-viremic individuals. In the present study, we performed DNA microarray analysis followed by phenotypic and functional characterization in an effort to investigate which HIV envelope glycoproteins (gp120) affect the physiologic functions of NK cells. Upon treatment of NK cells with HIV gp120, DNA microarray analyses indicated up-regulation of several categories of genes that are associated with apoptosis, suppression of both cellular proliferation and survival, as well as down-regulation of genes that play a vital role in cell proliferation, innate immune defense mechanism, and cell survival. Both subtypes of gp120 suppressed NK cell cytotoxicity, proliferation, and the ability to secrete IFN-gamma. NK cells exposed to X4-subtype HIV gp120 showed a significant decrease in the levels of CC chemokines, while exposure to R5-subtype HIV gp120 had minimal effect. Extended exposure to HIV gp120 resulted in apoptosis of NK cells, further validating the microarray data. Our data demonstrate that exposure of NK cells to HIV envelope proteins results in profound cellular abnormalities at the level of gene expression as well as generic cell functions. These findings are likely to be a consequence of a direct HIV gp120-mediated effect on NK cells. Identification of specific surface receptors on NK cells that interact with HIV envelope proteins might explain how HIV is capable of circumventing innate immune defense mechanisms and establishing infection in susceptible individuals. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp Frederick, NIH, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11N204,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Skottilil@naid.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 43 TC 46 Z9 49 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2006 VL 176 IS 2 BP 1107 EP 1114 PG 8 WC Immunology SC Immunology GA 001RK UT WOS:000234553800053 PM 16393999 ER PT J AU Talaat, KR Bonawitz, RE Domenech, P Nutman, TB AF Talaat, KR Bonawitz, RE Domenech, P Nutman, TB TI Preexposure to live Brugia malayi microfilariae alters the innate response of human dendritic cells to Mycobacterium tuberculosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene CY DEC 07, 2003 CL Philadelphia, PA SP Amer Soc Trop Med & Hygiene ID ANTIGEN-PRESENTING CELLS; DC-SIGN; T-CELLS; PULMONARY TUBERCULOSIS; ANNUAL RISK; IFN-GAMMA; INFECTION; RECEPTOR; ONCHOCERCIASIS; MACROPHAGES AB Background. Mycobacterium tuberculosis and helminth coinfection is highly prevalent, and the presence of helminths may modulate the Th1 response necessary for M. tuberculosis control. Methods. Elutriated human monocytes, differentiated into dendritic cells (DCs) and macrophages, were exposed in vitro to live microfilariae (mf). The influence that mf had on M. tuberculosis infectivity, expression of cell surface molecules, and production of cytokines was determined. Results. Compared with mf-unexposed, M. tuberculosis-infected cells, mf-exposed, M. tuberculosis - infected DCs had decreased expression of CD14, CD54, and human leukocyte antigen-DR, and mf-exposed, M. tuberculosis infected macrophages had decreased expression of CD40. DCs that were mf exposed and M. tuberculosis infected produced more interleukin (IL)-1b than did mf-unexposed, M. tuberculosis - infected DCs. Also, mf-exposed, M. tuberculosis-infected DCs and macrophages expressed less IL-10 and interferon (IFN)-alpha than did mf-unexposed, M. tuberculosis-infected cells. When they were cultured with autologous CD4(+) T cells, mf-exposed, M. tuberculosis infected DCs were less capable of stimulating the production of IFN-gamma than were other DCs. Exposure of DCs to mf decreased the surface expression of DC - specific intercellular adhesion molecule-3 grabbing nonintegrin, a receptor required by M. tuberculosis for entry into DCs. Conclusions. Exposure to mf reduces a key receptor on the DC surface, which perhaps renders these cells less susceptible to infection with M. tuberculosis. Exposure to mf changes the surface expression of adhesion and costimulatory molecules on DCs and macrophages and alters their expression of cytokines and chemokines in a way that renders them less capable of immunologic responses. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. RP Talaat, KR (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-B1-05, Bethesda, MD 20892 USA. EM ktalaat@niaid.nih.gov NR 48 TC 21 Z9 23 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2006 VL 193 IS 2 BP 196 EP 204 DI 10.1086/498912 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 996OJ UT WOS:000234183200005 PM 16362883 ER PT J AU Biggar, RJ Ng, J Kim, N Hisada, M Li, HC Cranston, B Hanchard, B Maloney, EM AF Biggar, RJ Ng, J Kim, N Hisada, M Li, HC Cranston, B Hanchard, B Maloney, EM TI Human leukocyte antigen concordance and the transmission risk via breast-feeding of human T cell lymphotropic virus type I SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CHILD TRANSMISSION; HIV TRANSMISSION; HTLV-I; LOAD; ALLELES; SUSCEPTIBILITY; CYTOTOXICITY; ASSOCIATION; ANTIBODIES; SPREAD AB Objective. We examined the association between mother-to-child human T cell lymphotropic virus type I (HTLV-I) transmission and human leukocyte antigen (HLA) class I types. Methods. In 1989, children born to HTLV-I-infected mothers in Jamaica were enrolled and prospectively evaluated for HTLV-I infection. HLA class I types in mothers and children were determined by DNA-based polymerase chain reaction methods. Associations between HLA class I types and transmission of HTLV-I were analyzed using proportional-hazards regression models adjusted for the duration of breast-feeding. Transmission risk in children still breast-feeding at 12 months was determined using actuarial methods. Results. Of 162 children, 28 (17%) became infected. After Bonferroni's adjustment for multiple comparisons, the transmission risk was not influenced by any specific HLA class type or the A2 supertype. However, compared with children who shared 3 HLA class I types with their mothers ( the minimum number possible), the transmission risk increased 1.8-fold with 4 shared types and 3.0-fold with 5 or 6 shared types (P-trend = .039; 1.75- fold increase for each additional concordant HLA type). This association was independent of maternal HTLV-I proviral level, antibody titer, and household income. Conclusions. We found a significant dose-response relationship between HTLV-I transmission via breast-feeding and mother-child HLA class I type concordance. Immunological interactions between a child's cells and maternal cells may influence the risk of HTLV-I infection by breast-feeding, perhaps because antigens on maternal cells are seen by the child as being "self." C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. Res Triangle Inst, Rockville, MD USA. Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. Univ W Indies, Kingston 7, Jamaica. RP Biggar, RJ (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Rm 8014, Rockville, MD 20852 USA. EM biggarb@mail.nih.gov FU NCI NIH HHS [N01-CP-40548] NR 26 TC 28 Z9 29 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2006 VL 193 IS 2 BP 277 EP 282 DI 10.1086/498910 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 996OJ UT WOS:000234183200014 PM 16362892 ER PT J AU Chou, J Harvey, BK Chang, CF Shen, H Morales, M Wang, Y AF Chou, J Harvey, BK Chang, CF Shen, H Morales, M Wang, Y TI Neuroregenerative effects of BMP7 after stroke in rats SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE stroke; growth factors; bone morphogenetic protein-7 ID BONE MORPHOGENETIC PROTEINS; INTRACISTERNAL OSTEOGENIC PROTEIN-1; FOCAL CEREBRAL-ISCHEMIA; DENTATE GYRUS; FUNCTIONAL RECOVERY; PROGENITOR CELLS; ADULT RATS; BRAIN; MODEL; PROLIFERATION AB Previous reports have indicated that the expression of bone morphogenetic protein-7 (BMP7) is enhanced after ischemic injury in brain. This upregulation may induce endogenous neurorepair in the ischemic brain. The purpose of this study was to examine neuroregenerative effects of BMP7 after ischemia-reperfusion injury. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. Right middle cerebral artery (MCA) was transiently ligated with 10-O suture for 1 h. One day after MCA occlusion, vehicle or BMP7 was infused to the contralateral cerebral ventricle. To identify possible neurogenesis, bromodeoxyurindine (BrdU) was systemically injected on the fourth and fifth days after MCA occlusion. Animals treated with BMP7 showed a rapid correction of body asymmetry and neurological deficits, suggesting BMP7 facilitates recovery after stroke. Animals were sacrificed at I month after stroke and brains were analyzed using immunohistological techniques. BMP7 treatment enhanced immunoreactivity of BrdU in the subventricular zone. lesioned cortex, and corpus callosum. These BrdU-positive cells co-labeled with nestin and NeuN. Our behavioral and anatomical data suggest that BMP7 promotes neuroregeneration in stroke animals, possibly through the proliferation of new neuronal precursors after ischemia. Published by Elsevier B.V. C1 NIDA, IRP, Baltimore, MD 21224 USA. Natl Def Med Ctr, Tri Serv Gen Hosp, Taipei, Taiwan. RP Wang, Y (reprint author), NIDA, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov RI Harvey, Brandon/A-5559-2010 NR 28 TC 52 Z9 58 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD JAN 15 PY 2006 VL 240 IS 1-2 BP 21 EP 29 DI 10.1016/j.jns.2005.08.015 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 003OU UT WOS:000234692300004 PM 16236321 ER PT J AU Fridman, EA Immisch, I Hanakawa, T Bohlhalter, S Waldvogel, D Kansaku, K Wheaton, L Wu, T Hallett, M AF Fridman, EA Immisch, I Hanakawa, T Bohlhalter, S Waldvogel, D Kansaku, K Wheaton, L Wu, T Hallett, M TI The role of the dorsal stream for gesture production SO NEUROIMAGE LA English DT Article DE transitive gesture; intransitive gesture; event-related fMRI; ventral premotor cortex (PMv); anterior intaparietal cortex (AIP); ideomotor apraxia ID POSITRON-EMISSION-TOMOGRAPHY; MOVEMENT-RELATED ACTIVITY; TOOL-USE GESTURES; PREMOTOR CORTEX; HUMAN BRAIN; PREFRONTAL CORTEX; PARIETAL CORTEX; FUNCTIONAL MRI; OPTIC ATAXIA; CORTICOSPINAL PROJECTIONS AB Skilled gestures require the integrity of the neural networks involved in storage, retrieval, and execution of motor programs. Premotor cortex and/or parietal cortex lesions frequently produce deficits during performance of gestures, transitive more than intransitive. The dorsal stream links object information with object action, suggesting that mechanical knowledge of tool use is stored focally in the brain. Using event-related fMRI, we explored activity during instructed-delay transitive and intransitive hand gestures. The comparison between planning-preparation and execution of gestures demonstrated a temporal rostral to caudal gradient of activation in the ventral premotor cortex (PMv) and inferior to superior gradient of activation in the posterior parietal cortex (PPc). Comparison between transitive and intransitive gestures established a functional specificity within the dorsal stream for mechanical knowledge. Results demonstrate that not only PPc but also the PMv acts in the processing of sensorimotor information during gestures. This might be the substrate underlying selective deficits in ideomotor apraxia patients. Published by Elsevier Inc. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Rm 5N226 10 Ctr Dr,MSC-1438, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Wheaton, Lewis /B-4482-2009; OI Wheaton, Lewis /0000-0003-0771-0294; Fridman, Esteban/0000-0001-7879-8874 NR 100 TC 82 Z9 83 U1 3 U2 8 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 JAN 15 PY 2006 VL 29 IS 2 BP 417 EP 428 DI 10.1016/j.neuroimage.2005.07.026 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005RJ UT WOS:000234841200007 PM 16154363 ER PT J AU Schaefer, M Flor, H Heinze, HJ Rotte, M AF Schaefer, M Flor, H Heinze, HJ Rotte, M TI Dynamic modulation of the primary somatosensory cortex during seeing and feeling a touched hand SO NEUROIMAGE LA English DT Article DE cross-modal; somatosensory cortex; touch; vision; multisensory; magnetoencephalography ID FUNCTIONAL-ORGANIZATION; TACTILE PERCEPTION; REPRESENTATION; HUMANS; ATTENTION; IMPROVES AB Previous work has demonstrated cross-modal links between vision and somatosensation at an early stage of sensory processing. Furthermore, recent behavioral studies have shown that viewing the stimulated body part can enhance tactile discrimination ability at the stimulated site. This study aims to investigate the role of the primary somatosensory cortex (SI) during visuotactile integration processes. Subjects looked at a hand in a video being touched on the first digit (D1) in synchrony with felt touches on their real hidden hand as compared with watching a video with asynchronous touches. During synchronous stimulation, subjects reported to feel the tactile sensation on the video hand, thus indicating that in this condition the subjects regarded the video hand as their own touched hand. This feeling disappeared in the asynchronous condition. Using neuromagnetic source imaging, we assessed the topography of the functional organization of SI related to tactile stimulation of D1. The cortical representation of D1 moved to a more inferior location during synchronous in comparison to asynchronous stimulation and rest. This modulation of the map in SI was significantly positively correlated with the feeling that the seen touch in the video represented the touch on the real hand. Thus, only if the seen touch is attributed to the own body, SI seems to be modulated. (c) 2005 Elsevier Inc. All rights reserved. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Otto Von Guericke Univ, Dept Neurol 2, D-39120 Magdeburg, Germany. Univ Heidelberg, Cent Inst Mental Hlth, Dept Clin & Cognit Neurosci, D-68159 Mannheim, Germany. RP Schaefer, M (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N-234, Bethesda, MD 20892 USA. EM schaefem@ninds.nih.gov OI Flor, Herta/0000-0003-4809-5398 NR 28 TC 51 Z9 51 U1 2 U2 9 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 JAN 15 PY 2006 VL 29 IS 2 BP 587 EP 592 DI 10.1016/j.neuroimage.2005.07.016 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005RJ UT WOS:000234841200024 PM 16099177 ER PT J AU Celnik, P Stefan, K Hummel, F Duque, J Classen, J Cohen, LG AF Celnik, P Stefan, K Hummel, F Duque, J Classen, J Cohen, LG TI Encoding a motor memory in the older adult by action observation SO NEUROIMAGE LA English DT Article DE aging; elementary motor memory; learning; action observation; plasticity; neurorehabilitation ID USE-DEPENDENT PLASTICITY; LONG-TERM POTENTIATION; VENTRAL PREMOTOR CORTEX; MIRROR-NEURON SYSTEM; MAGNETIC STIMULATION; FINGER MOVEMENTS; AGE-DIFFERENCES; D-AMPHETAMINE; HAND ACTIONS; LIFE-SPAN AB The ability of motor training to encode a motor memory is reduced in older adults. Here, we tested the hypothesis that training-dependent memory encoding, an issue of relevance in neuro-rehabilitation, is enhanced in elder individuals by action observation which alone can contribute to learning processes. A group of 11 healthy older adults participated in this study, which consisted of three randomized counterbalanced sessions on different days testing the effects of motor training (MT) alone, action observation (AO) alone, and a combination of both (MT + AO) on motor memory, encoding. The combination of MT + AO formed a motor memory in the primary motor cortex and differentially modulated motor cortical excitability in muscles that were agonist and antagonist with respect to the training task, but MT or AO alone did not. These results suggest that action observation can enhance the effects of motor training on memory encoding protocols in the older adult, possibly through Hebbian modulation of intracortical excitatory mechanisms. Published by Elsevier Inc. C1 NINDS, Human Cor Physiol Sect, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Neurol, Dept Phys Med & Rehabil, Baltimore, MD 21217 USA. Univ Wurzburg, Dept Neurol, D-97070 Wurzburg, Germany. RP Cohen, LG (reprint author), NINDS, Human Cor Physiol Sect, NIH, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [5K12HD001097] NR 64 TC 77 Z9 82 U1 0 U2 15 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 JAN 15 PY 2006 VL 29 IS 2 BP 677 EP 684 DI 10.1016/j.neuroimage.2005.07.039 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005RJ UT WOS:000234841200035 PM 16125417 ER PT J AU Newell, KA Larsen, CP Kirk, AD AF Newell, KA Larsen, CP Kirk, AD TI Transplant tolerance: Converging on a moving target SO TRANSPLANTATION LA English DT Review DE tolerance; transplantation; immunosuppression; regulation; deletion ID REGULATORY T-CELLS; ANTI-CD4 MONOCLONAL-ANTIBODY; IMMUNOLOGICAL SELF-TOLERANCE; BONE-MARROW-TRANSPLANTATION; CARDIAC ALLOGRAFT SURVIVAL; SECONDARY LYMPHOID ORGANS; INTESTINAL INFLAMMATION; COSTIMULATORY BLOCKADE; RENAL-TRANSPLANTATION; GALLIUM NITRATE AB Enthusiasm for tolerance induction has been tempered by the realization that it is more difficult to achieve clinically than was predicted by experimental models. Unlike the view that the immune response to an allograft is ordered and thus predictable, we view alloimmunity as highly plastic and molded by previous and ongoing experiences with allogeneic and environmental antigens. This implies that an individual's response to an allograft changes over time and that responses of seemingly similar individuals may vary greatly. This variability highlights the need to develop assays for monitoring the recipient immune response as well as individualized methods for therapeutic immune modulation. C1 Emory Univ, Emory Transplant Ctr, Atlanta, GA 30345 USA. NIDDKD, Transplantat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Newell, KA (reprint author), Emory Univ, Emory Transplant Ctr, Atlanta, GA 30345 USA. EM kenneth_newell@emoryhealthcare.org RI Kirk, Allan/B-6905-2012; Larsen, Christian/B-6906-2012 OI Larsen, Christian/0000-0001-6573-2649 NR 79 TC 26 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2006 VL 81 IS 1 BP 1 EP 6 DI 10.1097/01.tp.0000179149.12979.13 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 004WU UT WOS:000234784100001 PM 16421467 ER PT J AU Schiffman, M Castle, PE AF Schiffman, M Castle, PE TI When to test women for human papillomavirus - Cervical screening using HPV testing shows great promise but warrants caution SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID CANCER PREVENTION; RISK; DNA; MANAGEMENT; LESIONS C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM schiffmm@mail.nih.gov NR 12 TC 9 Z9 10 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD JAN 14 PY 2006 VL 332 IS 7533 BP 61 EP 62 DI 10.1136/bmj.332.7533.61 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 004UE UT WOS:000234777000001 PM 16410556 ER PT J AU Dosemeci, A Tao-Cheng, JW Vinade, L Jaffe, H AF Dosemeci, A Tao-Cheng, JW Vinade, L Jaffe, H TI Preparation of postsynaptic density fraction from hippocampal slices and proteomic analysis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE postsynaptic density; mass spectrometry; proteomics; hippocampal slices; PSD-95 ID DEPENDENT PROTEIN-KINASE; LONG-TERM POTENTIATION; MULTIDIMENSIONAL LIQUID-CHROMATOGRAPHY; TANDEM MASS-SPECTROMETRY; IDENTIFICATION; PHOSPHORYLATION; INDUCTION AB Hippocampal slices offer an excellent experimental system for the study of activity-induced changes in the postsynaptic density (PSD). While studies have documented electrophysiological and structural changes at synapses in response to precise manipulations of hippocampal slices, parallel biochemical and protcomic analyses were hampered by the lack of subcellular fractionation techniques applicable to starting tissue about three orders of magnitude smaller than that used in conventional protocols. Here, we describe a simple and convenient method for the preparation of PSD fractions from hippocampal slices and the identification of its components by proteomic techniques. The "micro PSD fraction" obtained following two consecutive extractions of a synaptosomal fraction with Triton X-100 shows a significant enrichment in the marker protein PSD-95. Thin section electron microscopy shows PSDs similar to those observed in situ. However, other particulate material, especially myelin, and membrane vesicles are also present. The composition of the PSD fraction from hippocampal slices was analyzed by 2D LC/MS/MS. The proteornic approach which utilizes as little as 10 mu g total protein allowed the identification of > 100 proteins. Many of the proteins detected in the fraction are the same as those identified in conventional PSD preparations including specialized PSD-scaffolding proteins, signaling molecules, cytoskeletal elements as well as certain contaminants. The results show the feasibility of the preparation of a PSD fraction from hippocampal slices of reasonable purity and of sufficient yield for proteomic analyses. In addition, we show that further purification of PSDs is possible using magnetic beads coated with a PSD-95 antibody.(c) 2005 Elsevier Inc. All rights reserved. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Electron Microscopy Facil, NIH, Bethesda, MD 20892 USA. NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM dosemeca@mail.nih.gov FU Intramural NIH HHS NR 22 TC 45 Z9 47 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 13 PY 2006 VL 339 IS 2 BP 687 EP 694 DI 10.1016/j.bbrc.2005.11.069 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 998OY UT WOS:000234329800034 PM 16332460 ER PT J AU Brooks, BP Meck, JM Haddad, BR Bendavid, C Blain, D Toretsky, JA AF Brooks, BP Meck, JM Haddad, BR Bendavid, C Blain, D Toretsky, JA TI Factor VII deficiency and developmental abnormalities in a patient with partial monosomy of 13q and trisomy of 16p: case report and review of the literature SO BMC MEDICAL GENETICS LA English DT Article ID COAGULATION FACTOR-VII; FACTOR-X; INSERTIONAL TRANSLOCATION; MENTAL-RETARDATION; DELETION SYNDROME; LIVEBORN INFANT; DUPLICATION 16P; CHROMOSOME-13; 13Q-SYNDROME; DISEASE AB Background: Unbalanced chromosomal translocations may present with a variety of clinical and laboratory findings and provide insight into the functions of genes on the involved chromosomal segments. Case Presentation: A 9 year-old boy presented to our clinic with Factor VII deficiency, microcephaly, a seizure disorder, multiple midline abnormalities ( agenesis of the corpus callosum, imperforate anus, bilateral optic nerve hypoplasia), developmental delay, hypopigmented macules, short 5(th) fingers, and sleep apnea due to enlarged tonsils. Cytogenetic and fluorescence in situ hybridization analyses revealed an unbalanced translocation involving the segment distal to 16p13 replacing the segment distal to 13q33 [ 46, XY, der( 13) t( 13; 16)( q33; p13.3)]. Specific BAC-probes were used to confirm the extent of the 13q deletion. Conclusion: This unique unbalanced chromosomal translocation may provide insights into genes important in midline development and underscores the previously-reported phenotype of Factor VII deficiency in 13q deletions. C1 NEI, NHGRI, Bethesda, MD 20892 USA. NHGRI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. Univ Rennes 1, CNRS,UMR Genet & Dev 6061, Fac Med, Grp Genet Humaine, Rennes, France. RP Brooks, BP (reprint author), NEI, NHGRI, Bldg 10,Room 10N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM brooksb@mail.nih.gov; meckj@gunet.georgetown.edu; haddadb1@georgetown.edu; claude.bendavid@univ-rennes1.fr; dblain@mail.nih.gov; jat42@georgetown.edu NR 39 TC 9 Z9 10 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JAN 13 PY 2006 VL 7 AR 2 DI 10.1186/1471-2350-7-2 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 014CN UT WOS:000235456400001 PM 16412230 ER PT J AU Oka, S Kato, J Moss, J AF Oka, S Kato, J Moss, J TI Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADP-RIBOSYLARGININE HYDROLASES; NUCLEOTIDE-BINDING PROTEIN; MODIFICATION SITE; DIPHTHERIA-TOXIN; SKELETAL-MUSCLE; RIBOSYLTRANSFERASE; RIBOSYLATION; ARGININE; RIBOSE; CLONING AB ADP-ribosylation is a post-translational modification resulting from transfer of the ADP-ribose moiety of NAD to protein. Mammalian cells contain mono-ADP-ribosyltransferases that catalyze the formation of ADP-ribose-(arginine) protein, which can be cleaved by a 39-kDa ADP-ribose-( arginine) protein hydrolase (ARH1), resulting in release of free ADP- ribose and regeneration of unmodified protein. Enzymes involved in poly( ADP- ribosylation) participate in several critical physiological processes, including DNA repair, cellular differentiation, and carcinogenesis. Multiple poly( ADP- ribose) polymerases have been identified in the human genome, but there is only one known poly( ADP- ribose) glycohydrolase (PARG), a 111-kDa protein that degrades the ( ADP- ribose) polymer to ADP- ribose. We report here the identification of an ARH1-like protein, termed poly( ADP- ribose) hydrolase or ARH3, which exhibited PARG activity, generating ADP- ribose from poly( ADP- ribose), but did not hydrolyze ADP-ribose- arginine, -cysteine, -diphthamide, or -asparagine bonds. The 39-kDa ARH3 shares amino acid sequence identity with both ARH1 and the catalytic domain of PARG. ARH3 activity, like that of ARH1, was enhanced by Mg2+. Critical vicinal acidic amino acids in ARH3, identified by mutagenesis (Asp(77) and Asp(78)), are located in a region similar to that required for activity in ARH1 but different from the location of the critical vicinal glutamates in the PARG catalytic site. All findings are consistent with the conclusion that ARH3 has PARG activity but is structurally unrelated to PARG. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Rm 6D05,Bldg 10,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU Intramural NIH HHS NR 47 TC 117 Z9 122 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 13 PY 2006 VL 281 IS 2 BP 705 EP 713 DI 10.1074/jbc.M510290200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 000FV UT WOS:000234447200006 PM 16278211 ER PT J AU Gatanaga, H Das, D Suzuki, Y Yeh, DD Hussain, KA Ghosh, AK Mitsuya, H AF Gatanaga, H Das, D Suzuki, Y Yeh, DD Hussain, KA Ghosh, AK Mitsuya, H TI Altered HIV-1 Gag protein interactions with cyclophilin A (CypA) on the acquisition of H219Q and H219P substitutions in the CypA binding loop SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 VARIANTS RESISTANT; POSTENTRY RESTRICTION; DRUG-RESISTANCE; CLEAVAGE SITES; CAPSID PROTEIN; SIMIAN CELLS; REPLICATION; INHIBITORS; GENE AB HIV-1 Gag protein interaction with cyclophilin A (CypA) is critical for viral fitness. Among the amino acid substitutions identified in Gag noncleavage sites in HIV-1 variants resistant to protease inhibitors, H219Q (Gatanaga, H., Suzuki, Y., Tsang, H., Yoshimura, K., Kavlick, M. F., Nagashima, K., Gorelick, R. J., Mardy, S., Tang, C., Summers, M. F., and Mitsuya, H. (2002) J. Biol. Chem. 277, 5952 5961) and H219P substitutions in the viral CypA binding loop confer the greatest replication advantage to HIV-1. These substitutions represent polymorphic amino acid residues. We found that the replication advantage conferred by these substitutions was far greater in CypA-rich MT-2 and H9 cells than in Jurkat cells and peripheral blood mononuclear cells (PBM), both of which contained less CypA. High intracellular CypA content in H9 and MT-2 cells, resulting in excessive CypA levels in virions, limited wild-type HIV-1 (HIV-1(WT)) replication and H219Q introduction into HIV-1 (HIV-1(H219Q)), reduced CypA incorporation of HIV-1, and potentiated viral replication. H219Q introduction also restored the otherwise compromised replication of HIV-1(P222A) in PBM, although the CypA content in HIV-1(H219Q/P222A) was comparable with that in HIV-1(P222A), suggesting that H219Q affected the conformation of the CypA-binding motif, rendering HIV-1 replicative in a low CypA environment. Structural modeling analyses revealed that although hydrogen bonds are lost with H219Q and H219P substitutions, no significant distortion of the CypA binding loop of Gag occurred. The loop conformation of HIV-1(P222A) was found highly distorted, although H219Q introduction to HIV-1(P222A) restored the conformation of the loop close to that of HIV-1WT. The present data suggested that the effect of CypA on HIV-1 replicative ability is bimodal (both high and low CypA content limits HIV-1 replication), that the conformation of the CypA binding region of Gag is important for viral fitness, and that the function of CypA is to maintain the conformation. C1 NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. Univ Illinois, Dept Chem, Chicago, IL 60607 USA. Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 860, Japan. Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 860, Japan. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Rm 5A11,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hmitsuya@helix.nih.gov FU NIGMS NIH HHS [GM 53386] NR 36 TC 33 Z9 34 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 13 PY 2006 VL 281 IS 2 BP 1241 EP 1250 DI 10.1074/jbc.M505920200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 000FV UT WOS:000234447200067 PM 16275650 ER PT J AU Smulevitch, S Bear, J Alicea, C Rosati, M Jalah, R Zolotukhin, AS Von Gegerfelt, A Michalowski, D Moroni, C Pavlakis, GN Felber, BK AF Smulevitch, Sergey Bear, Jenifer Alicea, Candido Rosati, Margherita Jalah, Rashmi Zolotukhin, Andrei S. Von Gegerfelt, Agneta Michalowski, Daniel Moroni, Christoph Pavlakis, George N. Felber, Barbara K. TI RTE and CTE mRNA export elements synergistically increase expression of unstable, rev-dependent HIV and SIV mRNAs SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CONSTITUTIVE TRANSPORT ELEMENT; SIMIAN RETROVIRUS TYPE-1; POSTTRANSCRIPTIONAL REGULATION; SECONDARY STRUCTURE; FUNCTIONAL-ANALYSIS; RESPONSIVE ELEMENT; GENE-EXPRESSION; NUCLEAR EXPORT; GAG EXPRESSION AB Studies of retroviral mRNA export identified two distinct RNA export elements utilizing conserved eukaryotic mRNA export mechanism(s), namely the Constitutive Transport Element (CTE) and the RNA Transport Element (RTE). Although RTE and CTE are potent in nucleocytoplasmic mRNA transport and expression, neither element is as powerful as the Rev-RRE posttranscriptional control. Here, we found that whereas CTE and the up-regulatory mutant RTEm26 alone increase expression from a subgenomic gag and env clones, the combination of these elements led to a several hundred-fold, synergistic increase. The use of the RTEm26-CTE combination is a simple way to increase expression of poorly expressed retroviral genes to levels otherwise only achieved via more cumbersome RNA optimization. The potent RTEm26-CTE element could be useful in lentiviral gene therapy vectors, DNA-based vaccine vectors, and gene transfer studies of other poorly expressed genes. C1 NCI, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. Univ Basel, Inst Med Mikrobiol, Basel, Switzerland. RP Felber, BK (reprint author), NCI, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. EM smulevit@hotmail.com; bear@ncifcrf.gov; calicea@ncifcrf.gov; rosati@ncifcrf.gov; rjalah@ncifcrf.gov; zolotukh@ncifcrf.gov; vongeger@ncifcrf.gov; michalowskid@missouri.edu; Christoph.Moroni@unibas.ch; pavlakis@ncifcrf.gov; felber@ncifcrf.gov FU Intramural NIH HHS NR 47 TC 17 Z9 17 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JAN 13 PY 2006 VL 3 AR 6 DI 10.1186/1742-4690-3-6 PG 9 WC Virology SC Virology GA 067OA UT WOS:000239311300002 PM 16412225 ER PT J AU Fishel, ML Rabik, CA Bleibel, WK Li, XM Moschel, RC Dolan, ME AF Fishel, ML Rabik, CA Bleibel, WK Li, XM Moschel, RC Dolan, ME TI Role of GADD34 in modulation of cisplatin cytotoxicity SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE microarray; cisplatin; modulation; chemotherapy; GADD34 ID ACQUIRED-RESISTANCE; MICROARRAY ANALYSIS; O-6-BENZYLGUANINE; CANCER; ALKYLTRANSFERASE; CHEMOTHERAPY; DERIVATIVES; STRESS AB Cisplatin and carboplatin are widely used clinical chemotherapeutic agents, especially against testicular, ovarian, and head and neck cancers. O-6-Benzylguanine (BG) has been shown to result in enhanced cytotoxicity, apoptosis, and DNA platination when used in conjunction with cisplatin and carboplatin in head and neck cancer cell lines. Microarray expression data indicated overexpression of 19 genes and underexpression of 22 genes specific to treatment with the combination of BG cisplatin compared to cisplatin alone treatment in SQ20b head and neck cancer cells (p < 0.05) using the Affymetrix HG-U133A GeneChip (R). Among the overexpressed probe sets were genes involved in DNA damage and apoptosis, including GADD34, DDIT4, ATF4, and PTHLH. A similarly structured analog, 9-CH3-BG, does not enhance cisplatin-induced cytotoxicity or apoptosis nor is there enhanced expression of GADD34 in cisplatin or 9-CH3-BG cisplatin-treated cells compared to control cells. Analysis of cells exposed to 9-CH3-BG cisplatin allowed us to focus our array list on 32 probe sets specific to BG +/- cisplatin versus cisplatin, ruling out differentially expressed probe sets common to 9-CH3-BG +/- cisplatin versus cisplatin. Similarly, 14 probe sets were specific to BG cisplatin versus BG, ruling out differentially expressed probe sets common to 9-CH3-BG cisplatin versus 9-CH3-BG. Quantitative real-time PCR demonstrated a dose dependent increase in GADD34 expression in cells exposed to BG cisplatin with levels approximately > 2-fold for cells exposed to BG +/- cisplatin compared to cisplatin alone. Levels of GADD34 transcripts were determined with both cisplatin and BG +/- cisplatin at several different time points concomitant with and following drug treatment. At all timepoints, GADD34 transcript levels are approximately two-fold elevated in cells treated with BG + cisplatin compared to cisplatin alone. Furthermore, significant changes in GADD34 expression levels in SQ20b, SCC3S, and SCC61 cells, with approximately three-fold, two-fold, and 3.5fold increases in expression, respectively, upon treatment with BG +/- cisplatin compared with control. Elucidation of these molecular pathways will aid in our goal of synthesizing more powerful modulators to increase efficacy of platinum agents. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA. Univ Chicago, Funct Genom Facil, Chicago, IL 60637 USA. NCI, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. Univ Chicago, Comm Canc Biol, Comm Clin Pharmacol & Pharmacogenet, Chicago, IL 60637 USA. Univ Chicago, Canc Res Ctr, Chicago, IL 60637 USA. RP Dolan, ME (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave,Box MC2115, Chicago, IL 60637 USA. EM edolan@medicine.bsd.uchicago.edu FU NCI NIH HHS [5T32 CA09594, CA81485]; NIGMS NIH HHS [5 T32 GM07281] NR 19 TC 8 Z9 9 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JAN 12 PY 2006 VL 71 IS 3 BP 239 EP 247 DI 10.1016/j.bcp.2005.10.039 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 001JP UT WOS:000234529700002 PM 16325149 ER PT J AU Codispoti, M Ferrari, V Bradley, MM AF Codispoti, M Ferrari, V Bradley, MM TI Repetitive picture processing: Autonomic and cortical correlates SO BRAIN RESEARCH LA English DT Article DE habituation; emotion; event-related potential; attention; autonomic nervous system ID HABITUATION; ATTENTION; REVEALS; NOVELTY; WORDS; P300; TASK AB Emotionally arousing pictures elicit larger late positive potentials (LPPs) than neutral pictures during passive viewing. Moreover, these cortical responses do not rely on voluntary evaluation of the hedonic content and are relatively unaffected by task demands. In this study, we examined modulation of the late positive potential as it varies with stimulus repetition. Three pictures (pleasant, neutral, unpleasant) were presented up to 60 times each. Although the amplitude of the late positive potential during picture viewing declined with stimulus repetition, affective modulation remained intact. On the other hand, autonomic responses (skin conductance and heart rate change) habituated rapidly with stimulus repetition. These findings suggest that while stimulus detection and categorization, reflected in the LPP, is mandatory, autonomic modulation reflects initial orienting responses that habituate rapidly. Published by Elsevier B.V. C1 Univ Bologna, Dept Psychol, Bologna, Italy. Univ Bologna, Dept Human & Gen Physiol, Bologna, Italy. Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL USA. RP Codispoti, M (reprint author), Univ Bologna, Dept Psychol, Bologna, Italy. EM maurizio.codispoti2@unibo.it RI Codispoti, Maurizio/B-7672-2008 OI Codispoti, Maurizio/0000-0002-7285-4342 NR 30 TC 117 Z9 122 U1 4 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 12 PY 2006 VL 1068 IS 1 BP 213 EP 220 DI 10.1016/j.brainres.2005.11.009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 013PA UT WOS:000235420100024 PM 16403475 ER PT J AU Somu, RV Boshoff, H Qiao, CH Bennett, EM Barry, CE Aldrich, CC AF Somu, RV Boshoff, H Qiao, CH Bennett, EM Barry, CE Aldrich, CC TI Rationally designed nucleoside antibiotics that inhibit siderophore biosynthesis of Mycobacterium tuberculosis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NONRIBOSOMAL PEPTIDE SYNTHETASES; TRANSFER-RNA SYNTHETASES; CRYSTAL-STRUCTURE; ANALOGS; MACROPHAGES; ADENYLATE; ASCAMYCIN; VIRULENCE; BACTERIA; DOMAINS AB A rationally designed nucleoside inhibitor of Mycobacterium tuberculosis growth (MIC99 = 0.19 mu M) that disrupts siderophore biosynthesis was identified. The activity is due to inhibition of the adenylate-forming enzyme MbtA which is involved in biosynthesis of the mycobactins. C1 Univ Minnesota, Ctr Drug Design, Acad Hlth Ctr, Minneapolis, MN 55455 USA. NIAID, Tuberculosis Res Sect, Rockville, MD 20852 USA. RP Aldrich, CC (reprint author), Univ Minnesota, Ctr Drug Design, Acad Hlth Ctr, Minneapolis, MN 55455 USA. EM aldri015@umn.edu RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000693-15] NR 27 TC 160 Z9 165 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 12 PY 2006 VL 49 IS 1 BP 31 EP 34 DI 10.1021/jm051060o PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 001XF UT WOS:000234575300004 PM 16392788 ER PT J AU Kim, P Zhang, YM Shenoy, G Nguyen, QA Boshoff, HI Manjunatha, UH Goodwin, MB Lonsdale, J Price, AC Miller, DJ Duncan, K White, SW Rock, CO Barry, CE Dowd, CS AF Kim, P Zhang, YM Shenoy, G Nguyen, QA Boshoff, HI Manjunatha, UH Goodwin, MB Lonsdale, J Price, AC Miller, DJ Duncan, K White, SW Rock, CO Barry, CE Dowd, CS TI Structure-activity relationships at the 5-position of thiolactomycin: An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACYL CARRIER PROTEIN; FATTY-ACID SYNTHASE; ABSOLUTE-CONFIGURATION; ASYMMETRIC-SYNTHESIS; NATURAL PRODUCT; ANALOGS; RESISTANCE; INHIBITION; SYSTEM; (5S)-THIOLACTOMYCIN AB Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC50 and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site. C1 NIAID, Tuberculosis Res Sect, NIH, Rockville, MD 20852 USA. St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA. GlaxoSmithKline Inc, Upper Providence, PA USA. RP Dowd, CS (reprint author), NIAID, Tuberculosis Res Sect, NIH, Rockville, MD 20852 USA. EM cdowd@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012; OI Shenoy, Gautham/0000-0002-1312-6257 FU Intramural NIH HHS; NCI NIH HHS [CA 21765, P30 CA021765]; NIAID NIH HHS [1 UC1 AI49520-01, UC1 AI049520, Z01 AI000693-13]; NIGMS NIH HHS [GM 34496, R01 GM034496, R37 GM034496] NR 57 TC 67 Z9 69 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 12 PY 2006 VL 49 IS 1 BP 159 EP 171 DI 10.1021/jm050825p PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 001XF UT WOS:000234575300016 PM 16392800 ER PT J AU Jeong, LS Lee, HW Jacobson, KA Kim, HO Shin, DH Lee, JA Gao, ZG Lu, CR Duong, HT Gunaga, P Lee, SK Jin, DZ Chun, MW Moon, HR AF Jeong, LS Lee, HW Jacobson, KA Kim, HO Shin, DH Lee, JA Gao, ZG Lu, CR Duong, HT Gunaga, P Lee, SK Jin, DZ Chun, MW Moon, HR TI Structure-activity relationships of 2-chloro-N-6-substituted-4 '-thioadenosine-5 '-uronamides as highly potent and selective agonists at the human A(3) adenosine receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MAST-CELLS; LIGANDS; DERIVATIVES; BINDING; DETERMINANTS; NUCLEOSIDES; ACTIVATION; EFFICACY; PURINE; SITE AB We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes.. and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N-6-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that. similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronarnide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups. maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR. C1 Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Pusan Natl Univ, Coll Pharm, Pusan 609753, South Korea. RP Jeong, LS (reprint author), Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Lu, Changrui/0000-0002-2171-9888 FU Intramural NIH HHS [Z01 DK031117-20] NR 26 TC 42 Z9 43 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 12 PY 2006 VL 49 IS 1 BP 273 EP 281 DI 10.1021/jm050595e PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 001XF UT WOS:000234575300028 PM 16392812 ER PT J AU Pang, ALY Johnson, W Ravindranath, N Dym, M Rennert, OM Chan, WY AF Pang, ALY Johnson, W Ravindranath, N Dym, M Rennert, OM Chan, WY TI Expression profiling of purified male germ cells: stage-specific expression patterns related to meiosis and postmeiotic development SO PHYSIOLOGICAL GENOMICS LA English DT Article DE gamete biology; testis; spermatogenesis; gametogenesis; developmental biology ID SPERMATOGONIAL STEM-CELLS; GENE-EXPRESSION; MOUSE SPERMATOGENESIS; MESSENGER-RNAS; PROTEIN GENE; RAT TESTIS; CLONING; MICE; TRANSCRIPTION; REQUIREMENT AB Gene expression profiling was performed using the National Institute on Aging 15,000-cDNA microarray to reveal the differential expression pattern of 160 genes between meiotic pachytene spermatocytes and postmeiotic round spermatids of the mouse. Our results indicate that more genes are expressed in spermatids than in spermatocytes. Genes participating in cell cycle regulation and chromatin structure and dynamics are preferentially expressed in spermatocytes, while genes for protein turnover, signal transduction, energy metabolism, and intracellular transport are prevalent in spermatids. This suggests that a switch of functional requirement occurs when meiotic germ cells differentiate into haploid spermatids. Concordant expression patterns were obtained when quantitative real-time polymerase chain reaction was performed to verify the microarray data. Interestingly, the majority of the differentially expressed genes were underrepresented in mitotic type A spermatogonia, and they were preferentially expressed in the testis. Our results suggest that an even higher proportion of the mouse genome is devoted to male gamete development from meiosis than was previously estimated. We also provide evidence that underscores the advantage of using purified germ cells over whole testes in profiling spermatogenic gene expression to identify transcripts that demonstrate stage-specific expression patterns. C1 NICHHD, Sect Dev Genom, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Washington, DC 20057 USA. RP Pang, ALY (reprint author), NICHHD, Sect Dev Genom, Lab Clin Genom, NIH, 49 Convent Dr,Rm 2C08,MSC 4429, Bethesda, MD 20892 USA. EM panga@mail.nih.gov RI Duello, Theresa/P-5752-2015 FU Intramural NIH HHS; NICHD NIH HHS [HD-36483, HD-33728] NR 54 TC 31 Z9 35 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JAN 12 PY 2006 VL 24 IS 2 BP 75 EP 85 DI 10.1152/physiolgenomics.00215.2004 PG 11 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 002CZ UT WOS:000234590300001 PM 16291737 ER PT J AU Huang, Y Yan, J Lubet, R Kensler, TW Sutter, TR AF Huang, Y Yan, J Lubet, R Kensler, TW Sutter, TR TI Identification of novel transcriptional networks in response to treatment with the anticarcinogen 3H-1,2-dithiole-3-thione SO PHYSIOLOGICAL GENOMICS LA English DT Article DE functional cluster scoring; gene ontology; ingenuity pathways knowledge database; canonical pathway; Nrf2 ID CANCER CHEMOPREVENTIVE DITHIOLETHIONES; HUMAN PREFRONTAL CORTEX; REGULATORY FACTOR-I; CD8(+) T-CELLS; GENE-EXPRESSION; FACTOR NRF2; TRYPTOPHAN-METABOLISM; CHEMOPROTECTIVE AGENT; HUMAN LIVER; RAT-LIVER AB 3H-1,2-dithiole-3thione (D3T), an inducer of antioxidant and phase 2 genes, is known to enhance the detoxification of environmental carcinogens, prevent neoplasia, and elicit other protective effects. However, a comprehensive view of the regulatory pathways induced by this compound has not yet been elaborated. Fischer F344 rats were gavaged daily for 5 days with vehicle or D3T (0.3 mmol/ kg). The global changes of gene expression in liver were measured with Affymetrix RG-U34A chips. With the use of functional class scoring, a semi-supervised method exploring both the expression pattern and the functional annotation of the genes, the Gene Ontology classes were ranked according to the significance of the impact of D3T treatment. Two unexpected functional classes were identified for the D3T treatment, cytosolic ribosome constituents with 90% of those genes increased, and cholesterol biosynthesis with 91% of the genes repressed. In another novel approach, the differentially expressed genes were evaluated by the Ingenuity computational pathway analysis tool to identify specific regulatory networks and canonical pathways responsive to D3T treatment. In addition to the known glutathione metabolism pathway (P = 0.0011), several other significant pathways were also revealed, including antigen presentation (P = 0.000476), androgen/ estrogen biosynthesis (P = 0.000551), fatty acid (P = 0.000216), and tryptophan metabolism (P = 0.000331) pathways. These findings showed a profound impact of D3T on lipid metabolism and anti-inflammatory/ immune-suppressive response, indicating a broader cytoprotective effect of this compound than previously expected. C1 Univ Memphis, W Harry Feinstone Ctr Genom Res, Memphis, TN 38152 USA. NCI, Div Canc Prevent, NIH, Rockville, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. RP Sutter, TR (reprint author), Univ Memphis, W Harry Feinstone Ctr Genom Res, 3774 Walker Ave, Memphis, TN 38152 USA. EM tsutter@memphis.edu RI Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NCI NIH HHS [R01-CA39416]; PHS HHS [N01-CW-95114] NR 56 TC 23 Z9 23 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JAN 12 PY 2006 VL 24 IS 2 BP 144 EP 153 DI 10.1152/physiolgenomics.00258.2005 PG 10 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 002CZ UT WOS:000234590300008 PM 16317079 ER PT J AU Ghorbel, MT Sharman, G Hindmarch, C Becker, KG Barrett, T Murphy, D AF Ghorbel, MT Sharman, G Hindmarch, C Becker, KG Barrett, T Murphy, D TI Microarray screening of suppression subtractive hybridization-PCR cDNA libraries identifies novel RNAs regulated by dehydration in the rat supraoptic nucleus SO PHYSIOLOGICAL GENOMICS LA English DT Article DE osmoregulation; functional plasticity; vasopressin; expressed sequence tags ID DIFFERENTIALLY EXPRESSED GENES; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; VASOPRESSIN NEURONS; MAGNOCELLULAR NEURONS; HYPOTHALAMIC NEURONS; LAMINA TERMINALIS; MESSENGER-RNA; PLASTICITY; OSMOREGULATION; SCHIZOPHRENIA AB The magnocellular neurons (MCNs) of the supraoptic nucleus ( SON) and paraventricular nucleus (PVN) of the hypothalamus are the principal site of biosynthesis of prepropeptide precursor of the antidiuretic hormone vasopressin (VP). This precursor is processed during anterograde axonal transportation to terminals in the posterior pituitary gland, where biologically active VP is stored until release into the general circulation in response to physiological activation of the SON by osmotic cues. By binding to V2-type receptors located in the kidney, VP decreases the amount of water lost in urine. Osmotic activation of the SON is accompanied by a dramatic morphological and functional remodeling. We have sought to understand the mechanistic basis of this plasticity in terms of the differential expression of genes. To identify such genes, we adopted an unbiased global approach based on suppressive subtractive hybridization-polymerase chain reaction (SSH-PCR) Using this method, we generated libraries of clones putatively differentially expressed in control vs. dehydrated SON. To rapidly screen these libraries, 1,152 clones were subjected to microarray analysis, resulting in the identification of 459 differentially expressed transcripts. cDNA clones corresponding to 56 of these RNAs were sequenced, revealing many of them to be novel expressed sequence tags (ESTs). Four transcripts were shown by in situ hybridization (ISH) to be significantly up- or downregulated in the SON after dehydration. These genes may represent novel effectors or mediators of SON physiological remodeling. C1 Univ Bristol, Henry Wellcome Lab Integrat Neurosci & Endocrinol, Mol Neuroendocrinol Res Grp, Bristol BS1 3NY, Avon, England. NIA, Gene Express & Genom Unit, NIH, Baltimore, MD USA. RP Murphy, D (reprint author), Univ Bristol, Henry Wellcome Lab Integrat Neurosci & Endocrinol, Mol Neuroendocrinol Res Grp, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England. EM d.murphy@bristol.ac.uk RI Murphy, David/C-3967-2012; Hindmarch, Charles/A-3077-2010; OI Murphy, David/0000-0003-2946-0353; Hindmarch, Charles/0000-0002-6036-1292; Becker, Kevin/0000-0002-6794-6656 FU Biotechnology and Biological Sciences Research Council [S18346]; Wellcome Trust NR 44 TC 13 Z9 13 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JAN 12 PY 2006 VL 24 IS 2 BP 163 EP 172 DI 10.1152/physiolgenomics.00229.2005 PG 10 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 002CZ UT WOS:000234590300010 PM 16249312 ER PT J AU Rurayantsev, AA Chanock, RM Murphy, BR Pletnev, AG AF Rurayantsev, AA Chanock, RM Murphy, BR Pletnev, AG TI Comparison of live and inactivated tick-borne encephalitis virus vaccines for safety, immunogenicity and efficacy in rhesus monkeys SO VACCINE LA English DT Article DE tick-borne encephalitis; live virus vaccine; monkey ID RUSSIAN-SPRING-SUMMER; WEST-NILE-VIRUS; ATTENUATED LANGAT-E5 VIRUS; DENGUE TYPE-4 VIRUSES; HUMAN NEURO-BLASTOMA; AMINO-ACID-SEQUENCE; JAPANESE ENCEPHALITIS; HETEROLOGOUS CHALLENGE; POWASSAN VIRUS; PROTECT MICE AB Three antigenic chimeric live attenuated tick-borne encephalitis virus (TBEV) vaccine candidates were compared for level of replication in murine and human neuroblastoma cells, for neurovirulence and neuroinvasiveness in mice, and for safety, immunogenicity and efficacy in rhesus monkeys. Two chimeric viruses were generated by replacing the membrane precursor and envelope protein genes of dengue type 4 virus (DEN4) with the corresponding genes of a Far Eastern TBEV, Sofjin strain, in the presence (TBEV/DEN4 Delta 30) or absence (TBEV/DEN4) of a 30 nucleotide deletion (Delta 30) in the 3' noncoding region of the DEN4 part of the chimeric genome. A third chimeric TBEV vaccine candidate was based on the antigenically distant, but naturally attenuated Langat virus (LGT). Chimerization of LGT with DEN4 resulted in decreased neurovirulence and neuroinvasiveness in mice and highly restricted viremia in rhesus monkeys. Also, the LGT/DEN4 chimera was highly restricted in replication in both murine and human neuroblastoma cells. In contrast, TBEV/DEN4 and TBEV/DEN4 Delta 30 were neither attenuated for neurovirulence in the mice nor restricted in replication in the neuroblastoma cells. However, both were highly attenuated for neuroinvasiveness in mice. TBEV/DEN4 replicated to moderately high titer in rhesus monkeys (mean peak viremia = 10(3.1) PFU/ml) indicating that the TBEV/DEN4 chimerization had only a modest, if any, attenuating effect in monkeys. However, the addition of the Delta 30 mutation to TBEV/DEN4 greatly attenuated the chimeric virus for rhesus monkeys (mean peak viremia = 10(0.7) PFU/ml) and induced a higher level of antibody against the TBEV than did LGT/DEN4. A single dose of either highly attenuated TBEV/DEN4 Delta 30 or LGT/DEN4 vaccine candidate or three doses of an inactivated TBEV vaccine were efficacious in monkeys against wild-type LGT challenge. These results indicate that both TBEV/DEN4 Delta 30 and LGT/DEN4 are safe and efficacious in rhesus monkeys and should be further evaluated as vaccine candidates for use in humans. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Twinbrook 3,12735 Twinbrook Pkwy,Room 3W13,MSC 81, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov NR 50 TC 0 Z9 0 U1 0 U2 3 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 JAN 12 PY 2006 VL 24 IS 2 BP 133 EP 143 DI 10.1016/j.vaccine.2005.07.067 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 004UM UT WOS:000234777800004 ER PT J AU Nitabach, MN Wu, Y Sheeba, V Lemon, WC Strumbos, J Zelensky, PK White, BH Holmes, TC AF Nitabach, MN Wu, Y Sheeba, V Lemon, WC Strumbos, J Zelensky, PK White, BH Holmes, TC TI Electrical hyperexcitation of lateral ventral pacemaker neurons desynchronizes downstream circadian oscillators in the fly circadian circuit and induces multiple behavioral periods SO JOURNAL OF NEUROSCIENCE LA English DT Article DE arrhythmia; behavior; circadian rhythms; desynchronization; Drosophila; sodium channel ID PIGMENT-DISPERSING FACTOR; COCKROACH LEUCOPHAEA-MADERAE; RAT SUPRACHIASMATIC NUCLEUS; DROSOPHILA-MELANOGASTER; LOCOMOTOR-ACTIVITY; ECLOSION HORMONE; ION CHANNELS; CLOCK GENE; RHYTHMS; EXPRESSION AB Coupling of autonomous cellular oscillators is an essential aspect of circadian clock function but little is known about its circuit requirements. Functional ablation of the pigment-dispersing factor-expressing lateral ventral subset (LNV) of Drosophila clock neurons abolishes circadian rhythms of locomotor activity. The hypothesis that LN(V)s synchronize oscillations in downstream clock neurons was tested by rendering the LNVs hyperexcitable via transgenic expression of a low activation threshold voltage-gated sodium channel. When the LNVs are made hyperexcitable, free-running behavioral rhythms decompose into multiple independent superimposed oscillations and the clock protein oscillations in the dorsal neuron 1 and 2 subgroups of clock neurons are phase-shifted. Thus, regulated electrical activity of the LNVs synchronize multiple oscillators in the fly circadian pacemaker circuit. C1 NYU, Dept Biol, Silver Ctr 1009, New York, NY 10003 USA. Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. NIMH, Unit Neural Funct, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Holmes, TC (reprint author), NYU, Dept Biol, Silver Ctr 1009, 100 Washington Sq E, New York, NY 10003 USA. EM todd.holmes@nyu.edu OI Lemon, William/0000-0003-4541-738X FU Intramural NIH HHS; NIDA NIH HHS [R21 DA016352-02, R21 DA016352]; NINDS NIH HHS [R01 NS046750, R01 NS046750-04, R01-NS046750] NR 56 TC 142 Z9 143 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 JAN 11 PY 2006 VL 26 IS 2 BP 479 EP 489 DI 10.1523/JNEUROSCI.3915-05.2006 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 001SI UT WOS:000234556200016 PM 16407545 ER PT J AU Jones, JM Montcouquiol, M Dabdoub, A Woods, C Kelley, MW AF Jones, JM Montcouquiol, M Dabdoub, A Woods, C Kelley, MW TI Inhibitors of differentiation and DNA binding (Ids) regulate Math1 and hair cell formation during the development of the organ of Corti SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cochlea; transcription factor; bHLH; hearing; ear; differentiation ID LOOP-HELIX PROTEIN; INNER-EAR; MAMMALIAN COCHLEA; T-CELL; TRANSCRIPTION FACTORS; EXPRESSION PATTERN; NEGATIVE REGULATOR; NERVOUS-SYSTEM; GENE; OVEREXPRESSION AB The basic helix-loop-helix (bHLH) transcription factor Math1 (also called Atoh1) is both necessary and sufficient for hair cell development in the mammalian cochlea (Bermingham et al., 1999; Zheng and Gao, 2000). Previous studies have demonstrated that a dynamic pattern of Math1 expression plays a key role in regulating the number and position of mechanosensory hair cells. However, the factors that regulate the temporal and spatial expression of Math1 within the cochlea are unknown. The bHLH-related inhibitors of differentiation and DNA binding (Id) proteins are known to negatively regulate many bHLH transcription factors, including Math1, in a number of different systems. Therefore, Id proteins are good candidates for regulating Math1 in the cochlea. Results from PCR and in situ hybridization indicate that Id1, Id2, and Id3 are expressed within the cochlear duct in a pattern that is consistent with a role in regulation of hair cell development. In particular, expression of Ids and Math1 overlapped in cochlear progenitor cells before cellular differentiation, but a specific downregulation of Id expression was observed in individual cells that differentiated as hair cells. In addition, progenitor cells in which the expression of Ids was maintained during the time period for hair cell differentiation were inhibited from developing as hair cells. These results indicate a key role for Ids in the regulation of expression of Math1 and hair cell differentiation in the developing cochlea. C1 NIDCD, NIH, Sect Dev Neurosci, Porter Neurosci Ctr, Bethesda, MD 20892 USA. RP Kelley, MW (reprint author), NIDCD, NIH, Sect Dev Neurosci, Porter Neurosci Ctr, 35 Convent Dr, Bethesda, MD 20892 USA. EM kelleymt@nidcd.nih.gov FU Intramural NIH HHS NR 55 TC 69 Z9 77 U1 0 U2 1 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 JAN 11 PY 2006 VL 26 IS 2 BP 550 EP 558 DI 10.1523/JNEUROSCI.3859-05.2006 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 001SI UT WOS:000234556200024 PM 16407553 ER PT J AU Luan, HJ Lemon, WC Peabody, NC Pohl, JB Zelensky, PK Wang, D Nitabach, MN Holmes, TC White, BH AF Luan, HJ Lemon, WC Peabody, NC Pohl, JB Zelensky, PK Wang, D Nitabach, MN Holmes, TC White, BH TI Functional dissection of a neuronal network required for cuticle tanning and wing expansion in Drosophila SO JOURNAL OF NEUROSCIENCE LA English DT Article DE excitability; network; circuit; hormone; neuropeptide; Drosophila ID MANDUCA-SEXTA; TOBACCO HORNWORM; CARDIOACCELERATORY PEPTIDE; SYNAPTIC-TRANSMISSION; TARGETED EXPRESSION; IMAGINAL ECDYSIS; ECLOSION HORMONE; BURSICON; PROTEIN; RECEPTOR AB A subset of Drosophila neurons that expresses crustacean cardioactive peptide (CCAP) has been shown previously to make the hormone bursicon, which is required for cuticle tanning and wing expansion after eclosion. Here we present evidence that CCAP-expressing neurons (N-CCAP) consist of two functionally distinct groups, one of which releases bursicon into the hemolymph and the other of which regulates its release. The first group, which we call N-CCAP-c929, includes 14 bursicon-expressing neurons of the abdominal ganglion that lie within the expression pattern of the enhancer-trap line c929-Gal4. We show that suppression of activity within this group blocks bursicon release into the hemolymph together with tanning and wing expansion. The second group, which we call N-CCAP-R, consists of N-CCAP neurons outside the c929-Gal4 pattern. Because suppression of synaptic transmission and protein kinase A (PKA) activity throughout N-CCAP, but not in N-CCAP-c929, also blocks tanning and wing expansion, we conclude that neurotransmission and PKA are required in N-CCAP-R to regulate bursicon secretion from N-CCAP-c929. Enhancement of electrical activity in N-CCAP-R by expression of the bacterial sodium channel NaChBac also blocks tanning and wing expansion and leads to depletion of bursicon from central processes. NaChBac expression in N-CCAP-c929 is without effect, suggesting that the abdominal bursicon-secreting neurons are likely to be silent until stimulated to release the hormone. Our results suggest that N-CCAP form an interacting neuronal network responsible for the regulation and release of bursicon and suggest a model in which PKA-mediated stimulation of inputs to normally quiescent bursicon-expressing neurons activates release of the hormone. C1 NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. NYU, Dept Biol, New York, NY 10003 USA. RP White, BH (reprint author), NIMH, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM benjaminwhite@mail.nih.gov OI Lemon, William/0000-0003-4541-738X FU Intramural NIH HHS; NIMH NIH HHS [Z01 MH002800-03]; NINDS NIH HHS [R01-NS046750, R01 NS046750] NR 44 TC 93 Z9 96 U1 0 U2 5 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 JAN 11 PY 2006 VL 26 IS 2 BP 573 EP 584 DI 10.1523/JNEUROSCI.3916-05.2006 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 001SI UT WOS:000234556200027 PM 16407556 ER PT J AU Ponomarenko, NA Vorobiev, II Alexandrova, ES Reshetnyak, AV Telegin, GB Khaidukov, SV Avalle, R Karavanov, A Morse, HC Thomas, D Friboulet, A Gabibov, AG AF Ponomarenko, NA Vorobiev, II Alexandrova, ES Reshetnyak, AV Telegin, GB Khaidukov, SV Avalle, R Karavanov, A Morse, HC Thomas, D Friboulet, A Gabibov, AG TI Induction of a protein-targeted catalytic response in autoimmune prone mice: Antibody-mediated cleavage of HIV-1 glycoprotein GP120 SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROTEOLYTIC ANTIBODIES; AUTOANTIBODIES; HYDROLYSIS; EXPRESSION; INFECTION; EPITOPES; DISEASE; ANALOG AB We have induced a polyclonal IgG that degrades the HIV-1 surface antigen, glycoprotein gp120, by taking advantage of the susceptibility of SJL mice to a peptide-induced autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). Specific pathogen-free SJL mice were immunized with structural fragments of gp120, fused in-frame with encephalitogenic peptide MBP85-101. It has resulted in a pronounced disease-associated immune response against antigens. A dramatic increase of gp120 degradation level by purified polyclonal IgG from immunized versus nonimmunized mice has been demonstrated by a newly developed fluorescence-based assay. This activity was inhibited by anti-mouse immunoglobulin antibodies as well as by Ser- and His-reactive covalent inhibitors. A dominant proteolysis site in recombinant gp120 incubated with purified polyclonal IgG from immunized mice was shown by SDS-PAGE. The SELDI-based mass spectrometry revealed that these antibodies exhibited significant specificity toward the Pro(484)-Leu(485) peptide bond. The sequence surrounding this site is present in nearly half of the HIV-1 variants. This novel strategy can be generalized for creating a catalytic vaccine against viral pathogens. C1 RAS, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow 117871, Russia. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 117984, Russia. Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. RAS, Puschino Branch Shemyakin & Ovchinnikov Inst Bioo, Pushchino 142290, Russia. Univ Technol Compiegne, CNRS, UMR 6022, F-60206 Compiegne, France. NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. Ciphergen Biosyst Inc, Fremont, CA 94555 USA. RP Gabibov, AG (reprint author), RAS, Shemyakin & Ovchinnikov Inst Bioorgan Chem, 16-10 Miklukho Maklaya Str, Moscow 117871, Russia. EM gabibov@ibch.ru OI Morse, Herbert/0000-0002-9331-3705; Ponomarenko, Natalia/0000-0003-3129-3515 FU Intramural NIH HHS NR 45 TC 12 Z9 13 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 10 PY 2006 VL 45 IS 1 BP 324 EP 330 DI 10.1021/bi050675k PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003PT UT WOS:000234694800035 PM 16388609 ER PT J AU Tsurutani, J Fukuoka, J Tsurutani, H Shih, JH Hewitt, SM Travis, WD Jen, J Dennis, PA AF Tsurutani, J Fukuoka, J Tsurutani, H Shih, JH Hewitt, SM Travis, WD Jen, J Dennis, PA TI Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; PROTEIN-KINASE; PHOSPHO-AKT; TREATED PATIENTS; PROSTATE-CANCER; PTEN EXPRESSION; SOLID TUMORS; GEFITINIB; TRIAL AB Purpose Akt is a serine/threonine kinase that has been implicated in lung tumorigenesis and lung cancer therapeutic resistance. Full activation of Akt requires two phosphorylation events, but only one site of phosphorylation (S473) has been evaluated thus far in clinical non-small-cell lung cancer (NSCLC) specimens, which has resulted in conflicting results regarding the prognostic significance of Akt activation in NSCLC. In this study, we sought to determine whether evaluation of Akt phosphorylation at T308 would improve prognostic accuracy. Patients and Methods Phosphospecific antibodies against T308 and S473 were validated and used in an immunohistochemical analysis of tissue microarray slides containing NSCLC specimens (n = 300) and surrounding lung tissue specimens (n = 100). Results Phosphorylation of either S473 or T308 was positive in most NSCSLC specimens, but was detected rarely in surrounding normal tissues. When Akt activation was defined by using both sites of phosphorylation, Akt activation was specific for NSCLC tumors versus surrounding tissue (73.4% v 0%; P < .05), was higher in adenocarcinoma than in squamous cell carcinoma (78.1% v 68.5%; P = .040), and was associated with shorter overall survival for all stages of disease (log-rank P = .041). In multivariate analyses, increased phosphorylation of T308 alone was a poor prognostic factor for stage I patients or for tumors < 5 cm (log-rank P = .011 and P = .015, respectively). Conclusion These results suggest that monitoring phosphorylation of Akt at T308 improves the assessment of Akt activation, and show that Akt activation is a poor prognostic factor for all stages of NSCLC. C1 NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Lab Pathol, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. RP Dennis, PA (reprint author), Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM pdennis@nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural NIH HHS NR 46 TC 95 Z9 103 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2006 VL 24 IS 2 BP 306 EP 314 DI 10.1200/JCO.2005.02.4133 PG 9 WC Oncology SC Oncology GA 004HD UT WOS:000234741700011 PM 16330671 ER PT J AU Yao, PJ Bushlin, I Petralia, RS AF Yao, PJ Bushlin, I Petralia, RS TI Partially overlapping distribution of Epsin1 and HIP1 at the synapse: Analysis by immunoelectron microscopy SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE clathrin adaptor; synaptic localization; hippocampus ID CLATHRIN ASSEMBLY PROTEIN; AMPA RECEPTOR TRAFFICKING; VESICLE ENDOCYTOSIS; COATED VESICLES; ALPHA-ADAPTIN; MEDIATED ENDOCYTOSIS; TRANSMITTER RELEASE; TERMINAL DOMAIN; BINDING; AP180 AB Synapses of neurons use clathrin-mediated endocytic pathways for recycling of synaptic vesicles and trafficking of neurotransmitter receptors. Epsin 1 and huntingtin-interacting protein 1 (HIP1) are endocytic accessory proteins. Both proteins interact with clathrin and the AP2 adaptor complex and also bind to the phosphoinositide-containing plasma membrane via an epsin/AP180 N-terminal homology (ENTH/ANTH) domain. Epsin1 and HIPI are found in neurons; however, their precise roles in synapses remain largely unknown. Using immunogold electron microscopy, we examine and compare the synaptic distribution of epsin1 and HIP1 in rat CA1 hippocampal synapse. We find that epsin1 is located across both sides of the synapse, whereas HIPI displays a preference for the postsynaptic compartment. Within the synaptic compartments, espin1 is distributed similarly throughout, whereas postsynaptic HIP1 is concentrated near the plasma membrane. Our results suggest a dual role for epsin1 and HIP1 in the synapse: as broadly required factors for promoting clathrin assembly and as adaptors for specific endocytic pathways. C1 NIA, Neurosci Lab, GRC, NIH, Baltimore, MD 21224 USA. Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, GRC, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov FU Intramural NIH HHS NR 69 TC 10 Z9 11 U1 2 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 10 PY 2006 VL 494 IS 2 BP 368 EP 379 DI 10.1002/cne.20810 PG 12 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 994JD UT WOS:000234026900012 PM 16320245 ER PT J AU Huey, ED Putnam, KT Grafman, J AF Huey, ED Putnam, KT Grafman, J TI A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia SO NEUROLOGY LA English DT Review ID MUSCARINIC ACETYLCHOLINE-RECEPTORS; EMISSION COMPUTED-TOMOGRAPHY; FRONTAL-LOBE DEMENTIA; PICKS-DISEASE; ALZHEIMERS-DISEASE; NEUROPSYCHIATRIC SYMPTOMS; EXECUTIVE DYSFUNCTION; CEREBROSPINAL-FLUID; GLUCOSE-METABOLISM; DEGENERATION AB Objective: To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD). Methods: The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD. Results: Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD. Conclusions: Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner. C1 NINDS, Cognit Neurosci Sect, CRC, Bethesda, MD 20892 USA. NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. RP Huey, ED (reprint author), NINDS, Cognit Neurosci Sect, CRC, Room 5C206, Bethesda, MD 20892 USA. EM hueye@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS [Z01 NS002792-19] NR 74 TC 124 Z9 130 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 10 PY 2006 VL 66 IS 1 BP 17 EP 22 DI 10.1212/01.wnl.0000191304.55196.4d PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 000VI UT WOS:000234490100006 PM 16401839 ER PT J AU Nath, A Venkataramana, A Reich, DS Cortese, I Major, EO AF Nath, A Venkataramana, A Reich, DS Cortese, I Major, EO TI Progression of progressive multifocal leukoencephalopathy despite treatment with beta-interferon SO NEUROLOGY LA English DT Editorial Material ID MULTIPLE-SCLEROSIS PATIENTS C1 Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD USA. RP Nath, A (reprint author), Johns Hopkins Univ, Dept Neurol, 600 N Wolfe St,Path 509, Baltimore, MD 21287 USA. EM anath1@jhmi.edu RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 9 TC 14 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 10 PY 2006 VL 66 IS 1 BP 149 EP 150 DI 10.1212/01.wnl.0000191322.93310.a1 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 000VI UT WOS:000234490100041 PM 16401874 ER PT J AU Ponomarenko, NA Durova, OM Vorobiev, II Belogurov, AA Kurkova, IN Petrenko, AG Telegin, GB Suchkov, SV Kiselev, SL Lagarkova, MA Govorun, VM Serebryakova, MV Avalle, R Tornatore, P Karavanov, A Morse, HC Thomas, D Friboulet, A Gabibov, AG AF Ponomarenko, NA Durova, OM Vorobiev, II Belogurov, AA Kurkova, IN Petrenko, AG Telegin, GB Suchkov, SV Kiselev, SL Lagarkova, MA Govorun, VM Serebryakova, MV Avalle, R Tornatore, P Karavanov, A Morse, HC Thomas, D Friboulet, A Gabibov, AG TI Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE catalytic antibodies; Copaxone; multiple sclerosis; surface enhanced laser desorption ionization; experimental allergic encephalomyelitis ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; ANTIBODIES; MICE; IMMUNOLOGY; EPITOPE; CELLS; DNA AB Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes "an antibody enzyme" (abzyme) contribution to the site-specific degradation of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced experimental allergic encephalomyelitis. Chromatography and zymography data demonstrated that the proteolytic activity of this preparation was exclusively associated with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage determined by mass spectrometry were localized within immunodominant regions of MBP. The abzymes could also cleave recombinant substrates containing encephalytogenic MBP85-101 peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibody-mediated degradation of MBP suggests a mechanistic explanation of the slow development of neurodegeneration associated with MS. C1 Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. Vladimirsky Moscow Reg Clin Inst, Minist Hlth, Moscow 129110, Russia. Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. Russian Acad Sci, Inst Gene Biol, Moscow 119334, Russia. Russian Acad Med Sci, Proteome Ctr, Moscow 119832, Russia. Univ Technol Compiegne, UMR 6022, CNRS, F-60205 Compiegne, France. Ciphergen Biosyst Inc, Fremont, CA 94555 USA. NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Gabibov, AG (reprint author), Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, 16-10 Miklukho Maklaya St, Moscow 117997, Russia. EM gabibov@ibch.ru RI Serebryakova, Marina/E-2986-2012; OI Morse, Herbert/0000-0002-9331-3705; kiselev, sergey/0000-0001-7921-6987; Ponomarenko, Natalia/0000-0003-3129-3515 FU Intramural NIH HHS NR 39 TC 98 Z9 111 U1 1 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 JAN 10 PY 2006 VL 103 IS 2 BP 281 EP 286 DI 10.1073/pnas.0509849103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002PR UT WOS:000234624100007 PM 16387849 ER PT J AU Kawasaki, BT Liao, YH Birnbaumer, L AF Kawasaki, BT Liao, YH Birnbaumer, L TI Role of Src in C3 transient receptor potential channel function and evidence for a heterogeneous makeup of receptor- and store-operated Ca2+ entry channels SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE G protein-coupled receptors; signal transduction; store depletion ID TYROSINE PHOSPHORYLATION; INOSITOL 1,4,5-TRISPHOSPHATE; MOLECULAR-CLONING; CATION CHANNELS; CALCIUM-ENTRY; MAST-CELLS; ACTIVATION; KINASE; INFLUX; TRP AB Receptor-operated Ca2+ entry (ROCE) and store-operated Ca2+ entry (SOCE) are known to be inhibited by tyrosine kinase inhibitors and activation of C-type transient receptor potential channel (TRPC) isoform 3 (TRPC3), a cation channel thought to be involved in SOCE and/or ROCE, was recently shown to depend on src tyrosine kinase activity. What is not known is the step at which src acts on TRPC3 and whether the role for tyrosine kinases in ROCE or SOCE is a general phenomenon. Using in vitro and in cell protein-protein interaction assays we now report that src phosphorylates TRPC3 at Y226 and that formation of phospho-Y226 is essential for TRPC3 activation. This requirement is unique for TRPC3 because (i) mutation of the cognate tyrosines of the closely related TRPC6 and TRPC7 had no effect; (ii) TRPC6 and TRPC7 were activated in src-, yes-, and fyn-deficient cells; and (iii) src, but not yes or fyn, rescued TRPC3 activation in src-, yes-, and fyn-deficient cells. The Src homology 2 domain of src was found to interact with either the IN or the C termini of all TRPCs, suggesting that other tyrosine kinases may play a role in ion fluxes mediated by TRPCs other than TRPC3. A side-by-side comparison of the effects of genistein (a general tyrosine kinase inhibitor) on endogenous ROCE and SOCE in mouse fibroblasts, HEK and COS-7 cells, and ROCE in HEK cells mediated by TRPC3, TRPC6, TRPC7, and TRPC5 showed differences that argue for ROCE and SOCE channels to be heterogeneous. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Birnbaumer, L (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov FU Intramural NIH HHS NR 25 TC 61 Z9 66 U1 0 U2 0 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 JAN 10 PY 2006 VL 103 IS 2 BP 335 EP 340 DI 10.1073/pnas.0508030102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002PR UT WOS:000234624100016 PM 16407161 ER PT J AU Chen, B Mariano, J Tsai, YC Chan, AH Cohen, M Weissman, AM AF Chen, B Mariano, J Tsai, YC Chan, AH Cohen, M Weissman, AM TI The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain,, RING finger, and an E2-binding site SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autocrine motility factor receptor; ubiquitin protein ligase; ubiquitin; unfolded protein response; MmUBC7 ID UBIQUITIN-PROTEIN LIGASE; ER-ASSOCIATED DEGRADATION; MOTILITY FACTOR-RECEPTOR; END RULE PATHWAY; MEMBRANE-PROTEIN; PROTEASOME PATHWAY; LUMINAL PROTEIN; QUALITY CONTROL; MAMMALIAN UBC7; COMPLEX AB Efficient targeting of proteins for degradation from the secretory pathway is essential to homeostasis. This occurs through endoplasmic reticulum (ER)-associated degradation (ERAD). In this study, we establish that a human ubiquitin ligase (E3), gp78, and a specific E2, Ube2g2, are both critically important for ERAD of multiple substrates. gp78 exhibits a complex domain structure that, in addition to the RING finger, includes a ubiquitin-binding Cue domain and a specific binding site for Ube2g2. Disruption of either of these domains abolishes gp78-mediated ubiquitylation and protein degradation, resulting in accumulation of substrates in their fully glycosylated forms in the ER. This suggests that gp78-mediated ubiquitylation is an early step in ERAD that precedes dislocation of substrates from the ER. The in vivo requirement for both an E2-bincling site distinct from the RING finger and a ubiquitin-binding domain intrinsic to an E3 suggests a previously unappreciated level of complexity in ubiquitin ligase function. These results also provide proof of principle that interrupting a specific E2-E3 interaction can selectively inhibit ERAD. C1 NCI, Lab Prot Dynam & Signaling, Canc Res Ctr, Frederick, MD 21702 USA. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signaling, Canc Res Ctr, Bldg 560,Room 22-103, Frederick, MD 21702 USA. EM amw@nih.gov RI Cohen, Mickael/F-4122-2011; OI Tsai, Yien Che/0000-0001-9624-1092 FU Intramural NIH HHS NR 38 TC 127 Z9 129 U1 1 U2 8 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 JAN 10 PY 2006 VL 103 IS 2 BP 341 EP 346 DI 10.1073/pnas.0506618103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002PR UT WOS:000234624100017 PM 16407162 ER PT J AU Morris, JC Janik, JE White, JD Fleisher, TA Brown, M Tsudo, M Goldman, CK Bryant, B Petrus, M Top, L Lee, CC Gao, W Waldmann, TA AF Morris, JC Janik, JE White, JD Fleisher, TA Brown, M Tsudo, M Goldman, CK Bryant, B Petrus, M Top, L Lee, CC Gao, W Waldmann, TA TI Preclinical and phase I clinical trial of blockade of IL-15 using Mik beta 1 monoclonal antibody in T cell large granular lymphocyte leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE IL-2/IL-15 beta receptor (CD122); natural killer cells; cytokine ID RECEPTOR-BETA-CHAIN; ANTIGRANULOCYTES LYMPHOCYTES; ALPHA-CHAIN; LYMPHOPROLIFERATIVE DISEASE; INTERLEUKIN-2 RECEPTOR; RHEUMATOID-ARTHRITIS; HUMANIZED ANTIBODY; P75 SUBUNIT; EXPRESSION; ACTIVATION AB Twelve patients with T cell large granular lymphocyte leukemia and associated hematocytopenia were treated in a phase 1 dosecscalation trial with the murine monoclonal antibody Mik beta 1. Mik beta 1 identifies CD122, the beta-subunit shared by the IL-2 and IL-15 receptors. At the doses administered in this study the antibody inhibited the actions of IL-15 on both natural killer and T cells and that of IL-2 when the intermediate-affinity IL-2 receptor was expressed. Mik beta 1 treatment was not associated with significant toxicity or with the development of an immune response to the infused monoclonal antibody. At these doses of Mik beta 1, > 95% saturation of the IL-2/IL-15 beta receptor (CD122) on the surfaces of the leukemic cells was achieved. Furthermore, in seven patients this led to the down-modulation of the receptor from the surfaces of the leukemic cells. Nevertheless, no patients manifested a reduction in peripheral leukemic cell count or an amelioration of their hematocytopenia. This latter observation may reflect the fact that the monoclonal T cell large granular lymphocyte leukemia leukemic cells of the patients did not produce IL-2 or IL-15 or require their actions for cell survival. In light of the lack of toxicity and lack of immunogenicity of the antibody observed in the present study and the role for IL-15 in the pathogenesis of autoimmune diseases, clinical trials should be performed using the humanized version of Miki beta 1 in groups of patients with human T cell lymphotropic virus I-associated myelopathy/tropical spastic paraparesis, rheumatoid arthritis, multiple sclerosis and refractory celiac disease. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Off Canc Complementary & Alternat Med, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Osaka Red Cross Hosp, Dept Internal Med 3, Osaka 5438555, Japan. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Room 4N115,10 Ctr Dr MSC 1374, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural NIH HHS NR 37 TC 42 Z9 44 U1 0 U2 1 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 JAN 10 PY 2006 VL 103 IS 2 BP 401 EP 406 DI 10.1073/pnas.0509575103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002PR UT WOS:000234624100028 PM 16387851 ER PT J AU Manjunatha, UH Boshoff, H Dowd, CS Zhang, L Albert, TJ Norton, JE Daniels, L Dickl, T Pang, SS Barry, CE AF Manjunatha, UH Boshoff, H Dowd, CS Zhang, L Albert, TJ Norton, JE Daniels, L Dickl, T Pang, SS Barry, CE TI Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE comparative genome sequencing; F-420; nitroimidazole ID COENZYME F-420; TRANSPOSON MUTAGENESIS; TRICHOMONAS-VAGINALIS; BOVIS BCG; METRONIDAZOLE; BIOSYNTHESIS; ACTIVATION; VIRULENCE; PROSPECTS; SYSTEM AB PA-824 is a promising new compound for the treatment of tuberculosis that is currently undergoing human trials. Like its progenitors metronidazole and CGI-17341, PA-824 is a prodrug of the nitroimidazole class, requiring bioreductive activation of an aromatic nitro group to exert an antitubercular effect. We have confirmed that resistance to PA-824 (a nitroimidazo-oxazine) and CGI-17341 (a nitroimidazo-oxazole) is most commonly mediated by loss of a specific glucose-6-phosphate dehydrogenase (FGD1) or its deazaflavin cofactor F-420, which together provide electrons for the reductive activation of this class of molecules. Although FGD1 and F-420 are necessary for sensitivity to these compounds, they are not sufficient and require additional accessory proteins that directly interact with the nitroimidazole. To understand more proximal events in the reductive activation of PA-824, we examined mutants that were wild-type for both FGD1 and F420 and found that, although these mutants had acquired high-level resistance to PA-824 (and another nitroimidazo-oxazine), they retained sensitivity to CGI-17341 (and a related nitroimidazo-oxazole). Microarray-based comparative genome sequencing of these mutants identified lesions in Rv3547, a conserved hypothetical protein with no known function. Complementation with intact Rv3547 fully restored sensitivity to nitroimidazo-oxazines and restored the ability of Mtb to metabolize PA-824. These results suggest that the sensitivity of Mtb to PA-824 and related compounds is mediated by a protein that is highly specific for subtle structural variations in these bicyclic nitroimidazoles. C1 NIAID, TB Res Sect, Rockville, MD 20852 USA. NimbleGen Syst Inc, Madison, WI 53711 USA. Univ Iowa, Dept Microbiol, Iowa City, IA 52241 USA. Novartis Inst Trop Dis, Singapore 138670, Singapore. RP Barry, CE (reprint author), NIAID, TB Res Sect, 12441 Parklawn Dr,Twinbrook 2, Rockville, MD 20852 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11] NR 31 TC 184 Z9 197 U1 2 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 JAN 10 PY 2006 VL 103 IS 2 BP 431 EP 436 DI 10.1073/pnas.0508392103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002PR UT WOS:000234624100033 PM 16387854 ER PT J AU Jackson, JB Parsons, T Musoke, P Nakabiito, C Donnell, D Fleming, T Mirochnick, M Mofenson, L Fowler, MG Mmiro, F Guay, L AF Jackson, JB Parsons, T Musoke, P Nakabiito, C Donnell, D Fleming, T Mirochnick, M Mofenson, L Fowler, MG Mmiro, F Guay, L TI Association of cord blood nevirapine concentration with reported timing of dose and HIV-1 transmission SO AIDS LA English DT Article DE HIV-1 perinatal transmission; nevirapine; cord blood; Uganda; HIVNET 012 ID TO-CHILD TRANSMISSION; IMMUNODEFICIENCY-VIRUS TYPE-1; INTRAPARTUM NEVIRAPINE; ANTIRETROVIRAL THERAPY; RANDOMIZED-TRIAL; UGANDAN WOMEN; ZIDOVUDINE; PHARMACOKINETICS; PREVENTION; KAMPALA AB Background: To correlate nevirapine presence and concentration in cord bloods of infants born to HIV-1 infected women with report of timing of dose and HIV-1 transmission at 6 weeks of age. Methods: All available cord blood samples from the infants of mothers enrolled in the HIVNET 012 trial who were randomly assigned to receive either nevirapine or zidovudine at the onset of labor were tested for a nevirapine concentration. Results: Nevirapine was detected in the cord blood of 244 of 259 (94%) infants whose mothers reported they took nevirapine in labor more than 1 h before delivery and in 12 of 13 (92%) infants whose mothers reported they took nevirapine less than I h before delivery. The median nevirapine cord blood concentration was 1238 ng/ml [interquartile range (IQR), 905-1474 ng/ml] and 122 ng/ml (IQR, 64-321 ng/ml) for women who reported taking nevirapine more or less than I h before delivery, respectively (P < 0.001). The median nevirapine cord blood concentration of infants who were HIV-1 negative at birth, but positive at 6-8 weeks of age (n = 11), was 916 mg/ml (IQR, 737-1245 ng/ml) compared with 1192 ng/ml (IQR, 875-1471 ng/ml) for uninfected infants (n = 236). Conclusions: Cord blood nevirapine concentration correlated well with report of nevirapine administration and timing of dose before delivery. The nevirapine cord blood concentration was modestly lower in infected infants, although the number of infants infected between birth and 6-8 weeks of age was small (n = 11). The high adherence rate in the HIVNET 012 study supports the efficacy, simplicity and deliverability of this regimen. (C) 2006 Lippincott Williams & Wilkins. C1 Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. Makerere Univ, Dept Pediat, Kampala, Uganda. Makerere Univ, Dept Obstet & Gynaecol, Kampala, Uganda. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. NICHD, NIH, Bethesda, MD USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Jackson, JB (reprint author), Johns Hopkins Univ, Carnegie 415,600 N Wolfe St, Baltimore, MD 21287 USA. EM bjackso@jhmi.edu OI Mofenson, Lynne/0000-0002-2818-9808; Donnell, Deborah/0000-0002-0587-7480 FU NIAID NIH HHS [U01-AI-46702, U01-AI-46745, U01-AI-48054] NR 13 TC 4 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 9 PY 2006 VL 20 IS 2 BP 217 EP 222 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 007PN UT WOS:000234981700009 PM 16511414 ER PT J AU Kuller, LH Arnold, AM Psaty, BM Robbins, JA O'Leary, DH Tracy, RP Burke, GL Manolio, TA Chaves, PHM AF Kuller, LH Arnold, AM Psaty, BM Robbins, JA O'Leary, DH Tracy, RP Burke, GL Manolio, TA Chaves, PHM TI 10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the cardiovascular health study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; MYOCARDIAL-INFARCTION; AFRICAN-AMERICANS; DIABETES-MELLITUS; ATHEROSCLEROSIS; PREDICTORS; ATORVASTATIN; INDIVIDUALS; ASSOCIATION AB Background: The incidence of coronary heart disease (CHD) is very high among individuals 65 years or older. Methods: We evaluated the relationships between measurements of subclinical disease at baseline (1989-1990) and at the third-year follow-up examination (1992-1993) and subsequent incidence of cardiovascular disease and total mortality as of June 2001. Approximately 61% of the participants without clinical cardiovascular disease at baseline had subclinical disease based on our previously described criteria from the Cardiovascular Health Study. Results: The incidence of CHD was substantially increased for participants with subclinical disease compared with those who had no subclinical disease: 30.5 per 1000 person-years with and 16.3 per 1000 person-years without for white individuals, and 31.2 per 1000 person-years with and 12.5 per 1000 person-years without for black individuals. The risk persisted over the entire follow-up period. Incidence rates were higher for men than for women with or without subclinical disease, but there was little difference in rates for black individuals and white individuals. Conclusions: In multivariable models, subclinical disease at baseline remained a significant predictor of CHD in both men and women; the hazard ratios (95% confidence intervals) of their relative risks were 1.64 (1.30-2.06) and 1.49 (1.21-1.84), respectively. The presence of subclinical disease substantially increased the risk of subsequent CHD for participants with hypertension, diabetes mellitus, or elevated C-reactive protein. In summary, subclinical disease is very prevalent among older individuals, is independently associated with risk of CHD even over a 10-year follow-up period, and substantially increases the risk of CHD among participants with hypertension or diabetes mellitus. C1 Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Calif Davis, Div Gen Med, Sacramento, CA 95817 USA. Tufts Univ, New England Med Ctr, Dept Radiol, Boston, MA 02111 USA. Univ Vermont, Dept Pathol, Colchester, VT USA. Univ Vermont, Dept Biochem, Colchester, VT USA. Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Kuller, LH (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 N Bellafield Ave,Room 550, Pittsburgh, PA 15213 USA. EM kullerl@edc.pitt.edu FU NHLBI NIH HHS [N01-HC-85086, N01-HC-15129, N01-HC-15103]; PHS HHS [N01-85079] NR 25 TC 53 Z9 54 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 9 PY 2006 VL 166 IS 1 BP 71 EP 78 DI 10.1001/archinte.166.1.71 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 001OD UT WOS:000234545300010 PM 16401813 ER PT J AU Riley, AM Deleu, S Qian, X Mitchell, J Chung, SK Adelt, S Vogel, G Potter, BVL Shears, SB AF Riley, AM Deleu, S Qian, X Mitchell, J Chung, SK Adelt, S Vogel, G Potter, BVL Shears, SB TI On the contribution of stereochemistry to human ITPK1 specificity: Ins(1,4,5,6)P-4 is not a physiologic substrate SO FEBS LETTERS LA English DT Article DE ITPK1; IPMK; inositol 3,4,5,6-terakisphosphate; inositol 1,4,5,6-tetrakisphosphate; stereoselective ID INOSITOL 1,3,4-TRISPHOSPHATE 5/6-KINASE; SCHIZOSACCHAROMYCES-POMBE; PHOSPHATE MULTIKINASE; HUMAN HOMOLOG; RAT-LIVER; 1,4,5,6-TETRAKISPHOSPHATE; TETRAKISPHOSPHATES; HEXAKISPHOSPHATE; 3-KINASE; PROTEIN AB Ins(1,4,5,6)P-4, a biologically active cell constituent, was recently advocated as a substrate of human Ins(3,4,5,6)P4 1-kinase (hITPK1), because stereochemical factors were believed relatively unimportant to specificity [Miller, G.J., Wilson, M.P., Majerus, P.W. and Hurley, J.H. (2005) Specificity determinants in inositol polyphosphate synthesis: crystal structure of inositol 1,3,4-triphosphate 5/6-kinase. Mol. Cell. 18, 201-212]. Contrarily, we provide three examples of hITPK1 stereospecificity. hITPK1 phosphorylates only the 1-hydroxyl of both Ins(3,5,6)P-3 and the meso-compound, Ins(4,5,6)P-3. Moreover, h1TPKI has > 13,000-fold preference for Ins(3,4,5,6)P4 over its enantiomer, Ins(1,4,5,6)P4. The biological significance of hITPK1 being stereospecific, and not physiologically phosphorylating Ins (1,4,5,6)P4, is reinforced by our demonstrating that Ins(1,4,5,6)P4 is phosphorylated (K-m = 0.18 mu M) by inositolphosphate-multikinase. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Lab Signal Transduct, Inositide Signaling Grp, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Univ Bath, Dept Pharm & Pharmacol, Wolfson Lab Med Chem, Bath BA2 7AY, Avon, England. Pohang Univ Sci & Technol, Dept Chem, Div Mol Life Sci, Pohang 790784, South Korea. Berg Univ Gesamthsch Wuppertal, Fachbereich Math & Nat Wissensch, D-42097 Wuppertal, Germany. RP Shears, SB (reprint author), Lab Signal Transduct, Inositide Signaling Grp, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov RI Potter, Barry/A-1845-2012 FU Intramural NIH HHS; Wellcome Trust NR 35 TC 5 Z9 6 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JAN 9 PY 2006 VL 580 IS 1 BP 324 EP 330 DI 10.1016/j.febslet.2005.12.016 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 002IN UT WOS:000234605100056 PM 16376887 ER PT J AU Mattay, VS Fera, F Tessitore, A Hariri, AR Berman, KF Das, S Meyer-Lindenberg, A Goldberg, TE Callicott, JH Weinberger, DR AF Mattay, VS Fera, F Tessitore, A Hariri, AR Berman, KF Das, S Meyer-Lindenberg, A Goldberg, TE Callicott, JH Weinberger, DR TI Neurophysiological correlates of age-related changes in working memory capacity SO NEUROSCIENCE LETTERS LA English DT Article DE aging; cognition; working memory; fMRI; prefrontal cortex ID DORSOLATERAL PREFRONTAL CORTEX; O-METHYLTRANSFERASE COMT; WHITE-MATTER CHANGES; INDIVIDUAL-DIFFERENCES; DOPAMINE TRANSPORTER; NEURAL ACTIVITY; HUMAN BRAIN; AGING MIND; BLOOD-FLOW; PET AB Cognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological, correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age = 29) and twelve older subjects (>55 years of age; mean age = 59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE = 24 ms, TR = 56 ms, FA = 60 degrees, voxel dimensions = 3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (I-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p = 0.4), but performed worse than the younger subjects at 2-Back (p < 0.01) and 3-Back (p = 0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p < 0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in I-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs. (C) 2005 Elsevier Ireland Ltd. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Mattay, VS (reprint author), Bldg 10,Ctr Dr,Rm 3C-108, Bethesda, MD 20982 USA. EM vsm@mail.nih.gov RI Hariri, Ahmad/D-5761-2011; Callicott, Joseph/C-9102-2009; OI Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 NR 51 TC 152 Z9 155 U1 4 U2 19 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 9 PY 2006 VL 392 IS 1-2 BP 32 EP 37 DI 10.1016/j.neulet.2005.09.025 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 997SP UT WOS:000234268400007 PM 16213083 ER PT J AU Cherif, H Landgren, A Konradsen, HB Kalin, M Bjorkholm, M AF Cherif, H Landgren, A Konradsen, HB Kalin, M Bjorkholm, M TI Poor antibody response to pneumococcal polysaccharide vaccination suggests increased susceptibility to pneumococcal infection in splenectomized patients with hematological diseases SO VACCINE LA English DT Article DE splenectomy; pneumococcal; vaccination; antibody response; hematological malignancy ID SICKLE-CELL-ANEMIA; HODGKINS-DISEASE; STREPTOCOCCUS-PNEUMONIAE; CAPSULAR POLYSACCHARIDE; DYSFUNCTIONAL SPLEEN; RENAL-TRANSPLANT; RANDOMIZED-TRIAL; ELDERLY ADULTS; ASPLENIC HOSTS; LYMPHOMA AB Patients with hematological diseases undergoing diagnostic or therapeutic splenectomy are at increased risk of pneumococcal infections. Vaccination is a straightforward option in preventing these infections. A well-defined cohort of splenectomized patients with hematological disorders was followed according to response to 23-valent pneumococcal capsular polysaccharide (Pneumovax N-(R)) vaccination. A total of 76 splenectomized patients (Hodgkin lymphoma, HL 26, non-Hodgkin lymphoma, NHL 19, immune-mediated cytopenias 28, and others 3) with a median age of 52 years (range 18-82 years) were included. Pneumococcal polysaccharide (PS) antibodies were determined using an enzyme-linked immunosorbent assay before vaccination, at peak, and follow-up. A poor response to vaccination was observed in 21 (28%) patients and a good response in 55 (72%), respectively. During the follow-up period of 7.5 years (range 3.5-10.5 years) after vaccination, and despite repeated revaccination in many cases, a total of five episodes (in three patients) of pneumococcal infections were reported, all confined to the poor responder group. Revaccination did not improve antibody levels in this group. The median age at vaccination was significantly higher in the group of poor responders (p = 0.0006). None of the following factors could predict a poor antibody response: gender, disease activity or aggressiveness in hematological malignancies, previous radiotherapy and/or chemotherapy, time between splenectomy and pneumococcal vaccination, time between chemotherapy/radiotherapy and study pneumococcal vaccination (1 year), or the presence of hypogammaglobulinemia. In conclusion, a substantial proportion of splenectomized patients with hematological diseases mounted a poor PS antibody response and remained at risk for pneumococcal infections despite vaccination. In the absence of apt indirect clinical predictors of antibody response, with the exception of age, measurement of antibody levels seems to be a feasible method for early identification of this patient subgroup. Poor responders do not benefit from revaccination, and should be offered other prophylactic measures. (c) 2005 Elsevier Ltd. Ail rights reserved. C1 Karolinska Univ Hosp & Inst, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. Natl Canc Inst, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. Statens Serum Inst, WHO Collaborating Ctr Res Pneumococci, DK-2300 Copenhagen, Denmark. Karolinska Univ Hosp & Inst, Div Infect Dis, Stockholm, Sweden. RP Cherif, H (reprint author), Karolinska Univ Hosp & Inst, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM honar.cherif@karolinska.se NR 53 TC 37 Z9 39 U1 0 U2 1 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 JAN 9 PY 2006 VL 24 IS 1 BP 75 EP 81 DI 10.1016/j.vaccine.2005.07.054 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 004UK UT WOS:000234777600009 PM 16107293 ER PT J AU Li, DK Willinger, M Petitti, DB Odouli, R Liu, LY Hoffman, HJ AF Li, DK Willinger, M Petitti, DB Odouli, R Liu, LY Hoffman, HJ TI Use of a dummy (pacifier) during sleep and risk of sudden infant death syndrome (SIDS): population based case-control study SO BRITISH MEDICAL JOURNAL LA English DT Article ID POSITION; COT AB Objectives To examine the association between use of a dummy (pacifier) during sleep and the risk of sudden infant death syndrome (STDS) in relation to other risk factors. Design Population based case-control study. Setting Eleven counties in California. Participants Mothers or carers of 185 infants whose deaths were attributed to SIDS and 312 randomly selected controls matched for race or ethnicity and age. Main outcome measure Use of a dummy during sleep determined through interviews. Results The adjusted odds ratio for SIDS associated with using a dummy during the last sleep was 0.08 (95% confidence interval 0.03 to 0.21). Use was associated with a reduction in risk in every category of sociodemographic characteristics and risk factors examined. The reduced risk associated with use seemed to be greater with adverse sleep conditions (such as sleeping prone or on side and sleeping with a mother who smoked), although the observed interactions were not significant. For example, infants who did not use a dummy and slept prone or on their sides (v on their back) had an increased risk of SIDS (2.61, 1.56 to 4.38). In infants who used dummies, there was no increased risk associated with sleeping position (0.66, 0.12 to 3.59). While cosleeping with a mother who smoked was also associated with increased risk of SIDS among infants who did not use a dummy (4.5, 1.3 to 15.1), there was no such association among those who did (1.1, 0.1 to 13.4). Conclusions Use of a dummy seems to reduce the risk of SIDS and possibly reduces the influence of known risk factors in the sleep environment. C1 Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. Kaiser Permanente So Calif, Res & Evaluat, Pasadena, CA 91188 USA. NICHHD, Prenancy & Perinatol Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Epidemiol & Biostat Program, Div Sci Programs, NIH, Bethesda, MD 20892 USA. RP Li, DK (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM dkl@dor.kaiser.org FU NICHD NIH HHS [N01-HD-5-3227] NR 9 TC 51 Z9 54 U1 0 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD JAN 7 PY 2006 VL 332 IS 7532 BP 18 EP 21 DI 10.1136/bmj.38671.640475.55 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 003LR UT WOS:000234684200015 PM 16339767 ER PT J AU Lee, H Gonzalez, FJ Yoon, M AF Lee, H Gonzalez, FJ Yoon, M TI Ginsenoside Rf, a component of ginseng, regulates lipoprotein metabolism through peroxisome proliferator-activated receptor alpha SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE ginseng; ginsenoside Rf; lipoprotein; PPAR alpha; Wy14,643 ID APOLIPOPROTEIN C-III; LIPID-METABOLISM; PANAX-GINSENG; GLUCOCORTICOID-RECEPTOR; GENE-EXPRESSION; NULL MICE; OBESITY; CELLS; DIFFERENTIATION; PHARMACOLOGY AB We investigated whether ginseng regulates lipoprotein metabolism by altering peroxisome proliferator-activated receptor alpha (PPAR alpha)mediated pathways, using a PPAR alpha-null mouse model. Administration of ginseng extract, ginsenosides, and ginsenoside Rf (Rf) to wildtype mice not only significantly increased basal levels of hepatic apolipoprotein (apo) A-I and C-III tnRNA compared with wild-type controls, but also substantially reversed the reductions in mRNA levels of apo A-I and C-III expected following treatment with the potent PPAR alpha ligand Wy14,643. In contrast, no effect was detected in the PPAR alpha-null mice. Testing of eight main ginsenosides on PPAR alpha reporter gene expression indicated that Rf was responsible for the effects of ginseng on lipoprotein metabolism. Furthermore, the inhibition of PPAR alpha-dependent transactivation by Rf seems to Occur at the level of DNA binding. These results demonstrate that ginseng component Rf regulates apo A-I and C-III mRNA and the actions of Rf on lipoprotein metabolism are mediated via interactions with PPAR alpha.. (c) 2005 Elsevier Inc. All rights reserved. C1 Mokwon Univ, Dept Life Sci, Taejon 302729, South Korea. NIH, Lab Metab, Div Basic Sci, Rockville, MD 20852 USA. RP Yoon, M (reprint author), Mokwon Univ, Dept Life Sci, Taejon 302729, South Korea. EM yoon60@mokwon.ac.kr NR 35 TC 15 Z9 15 U1 1 U2 5 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 JAN 6 PY 2006 VL 339 IS 1 BP 196 EP 203 DI 10.1016/j.bbrc.2005.10.197 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 993HF UT WOS:000233944500031 PM 16297877 ER PT J AU Helm, PA Younes, L Beg, MF Ennis, DB Leclercq, C Faris, OP McVeigh, E Kass, D Miller, MI Winslow, RL AF Helm, PA Younes, L Beg, MF Ennis, DB Leclercq, C Faris, OP McVeigh, E Kass, D Miller, MI Winslow, RL TI Evidence of structural remodeling in the dyssynchronous failing heart SO CIRCULATION RESEARCH LA English DT Article DE cardiac remodeling; computational anatomy; fiber architecture; dyssynchrony ID BUNDLE-BRANCH-BLOCK; CARDIAC RESYNCHRONIZATION THERAPY; CANINE LEFT VENTRICLE; DIFFUSION TENSOR; DILATED CARDIOMYOPATHY; FIBER-ORIENTATION; VOLUME-OVERLOAD; COMPUTATIONAL ANATOMY; LAMINAR STRUCTURE; FAILURE AB Ventricular remodeling of both geometry and fiber structure is a prominent feature of several cardiac pathologies. Advances in MRI and analytical methods now make it possible to measure changes of cardiac geometry, fiber, and sheet orientation at high spatial resolution. In this report, we use diffusion tensor imaging to measure the geometry, fiber, and sheet architecture of eight normal and five dyssynchronous failing canine hearts, which were explanted and fixed in an unloaded state. We apply novel computational methods to identify statistically significant changes of cardiac anatomic structure in the failing and control heart populations. The results demonstrate significant regional differences in geometric remodeling in the dyssynchronous failing heart versus control. Ventricular chamber dilatation and reduction in wall thickness in septal and some posterior and anterior regions are observed. Primary fiber orientation showed no significant change. However, this result coupled with the local wall thinning in the septum implies an altered transmural fiber gradient. Further, we observe that orientation of laminar sheets become more vertical in the early-activated septum, with no significant change of sheet orientation in the late-activated lateral wall. Measured changes in both fiber gradient and sheet structure will affect both the heterogeneity of passive myocardial properties as well as electrical activation of the ventricles. C1 Johns Hopkins Univ, Ctr Cardiovasc Bioinformat & Modeling, Baltimore, MD 21218 USA. Johns Hopkins Univ, Ctr Imaging Sci, Baltimore, MD 21218 USA. Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21218 USA. Simon Fraser Univ, Ctr Engn Sci, Burnaby, BC V5A 1S6, Canada. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Helm, PA (reprint author), Johns Hopkins Univ, Ctr Cardiovasc Bioinformat & Modeling, 202 Clark Hall,3400 N Charles St, Baltimore, MD 21218 USA. EM phelm@bme.jhu.edu RI Younes, E. Laurent/A-3349-2010; Miller, Michael I./A-3213-2010 FU Intramural NIH HHS; NHLBI NIH HHS [HL52307, HL70894] NR 55 TC 109 Z9 112 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 6 PY 2006 VL 98 IS 1 BP 125 EP 132 DI 10.1161/01.RES.0000199396.30688.eb PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 999VS UT WOS:000234419500019 PM 16339482 ER PT J AU Qian, SB Princiotta, MF Bennink, JR Yewdell, JW AF Qian, SB Princiotta, MF Bennink, JR Yewdell, JW TI Characterization of rapidly degraded polypeptides in mammalian cells reveals a novel layer of nascent protein quality control SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UBIQUITIN-ACTIVATING ENZYME; NEWLY SYNTHESIZED PROTEINS; OXIDIZED PROTEINS; IN-VIVO; MOLECULAR CHAPERONES; ANTIGEN PRESENTATION; PROTEOLYTIC PATHWAY; 26S PROTEASOME; DEGRADATION; CYCLE AB Approximately 30% of polypeptides synthesized by mammalian cells are degraded with a half-life of < 10 min by proteasomes. These rapidly degraded polypeptides ( RDPs) constitute the bulk of proteasome substrates and are the principal source of viral and self- peptide ligands for major histocompatibility complex class I molecules. Here we provide evidence that similar to 75% of RDPs are degraded by the standard ubiquitin 26 S proteasome system and that their degradation is regulated by modulating Hsc70 activity in cells. Surprisingly, the remaining similar to 25% of RDPs are degraded without ubiquitylation by 20 S proteasomes independently of 19 S regulators and in a manner that is largely unaffected by modulating Hsc70 activity. This latter pathway is utilized for generating an antigenic peptide from viral-defective ribosomal products. The dichotomy in the behavior of RDPs points to a novel quality control level for nascent proteins that is independent of the well established Hsc70-ubiquitin 26 S proteasome pathway. C1 NIAID, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), Rm 211,Bldg 4,4 Ctr Dr, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS NR 35 TC 73 Z9 75 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 6 PY 2006 VL 281 IS 1 BP 392 EP 400 DI 10.1074/jbc.M509126200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 998GS UT WOS:000234307200049 PM 16263705 ER PT J AU Zhao, P Caretti, G Mitchell, S McKeehan, WL Boskey, AL Pachman, LM Sartorelli, V Hoffman, EP AF Zhao, P Caretti, G Mitchell, S McKeehan, WL Boskey, AL Pachman, LM Sartorelli, V Hoffman, EP TI Fgfr4 is required for effective muscle regeneration in vivo - Delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTORS; CAT BINDING-FACTOR; HEAVY-CHAIN GENE; BILE-ACID SYNTHESIS; SKELETAL-MUSCLE; DNA-BINDING; EXPRESSION PATTERNS; CROUZON-SYNDROME; ENHANCER; DIFFERENTIATION AB Fgfr4 has been shown to be important for appropriate muscle development in chick limb buds; however, Fgfr4 null mice show no phenotype. Here, we show that staged induction of muscle regeneration in Fgfr4 null mice becomes highly abnormal at the time point when Fgfr4 is normally expressed. By 7 days of regeneration, differentiation of myotubes became poorly coordinated and delayed by both histology and embryonic myosin heavy chain staining. By 14 days much of the muscle was replaced by fat and calcifications. To begin to dissect the molecular pathways involving Fgfr4, we queried the promoter sequences for transcriptional factor binding sites and tested candidate regulators in a 27-time point regeneration series. The Fgfr4 promoter region contained a Tead protein binding site (M-CAT 5'-CATTCCT-3'), and Tead2 showed induction during regeneration commensurate with Fgfr4 regulation. Co-transfection of Tead2 and Fgfr4 promoter reporter constructs into C2C12 myotubes showed Tead2 to activate Fgfr4, and mutation of the M-CAT motif in the Fgfr4 promoter abolished these effects. Immunostaining for Tead2 showed timed expression in myotube nuclei consistent with the mRNA data. Query of the expression timing and genomic sequences of Tead2 suggested direct regulation by MyoD, and consistent with this, MyoD directly bound to two strong E-boxes in the first intron of Tead2 by chromatin immunoprecipitation assay. Moreover, co-transfection of MyoD and Tead2 intron reporter constructs into 10T1/2 cells activated reporter activity in a dose-dependent manner. This activation was greatly reduced when the two E-boxes were mutated. Our data suggest a novel MyoD-Tead2-Fgfr4 pathway important for effective muscle regeneration. C1 Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. NIAMS, NIH, Muscle Gene Express Grp, Lab Muscle Biol, Bethesda, MD 20892 USA. Texas A&M Univ, Ctr Canc Biol & Nutr, Inst Biosci & Technol, Syst Hlth Sci Ctr, Houston, TX 77030 USA. Hosp Special Surg, Mineralized Tissues Lab, New York, NY 10021 USA. Childrens Mem Res Ctr, Mol & Cellular Pathobiol Program, Chicago, IL 60614 USA. RP Hoffman, EP (reprint author), Childrens Natl Med Ctr, Res Ctr Genet Med, 111 Michigan Ave NW, Washington, DC 20010 USA. EM ehoffman@cnmcresearch.org OI Boskey, Adele/0000-0002-6181-2219 FU NCRR NIH HHS [P41 RR006009]; NIDDK NIH HHS [DK35310, R01 DK035310] NR 58 TC 46 Z9 50 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 6 PY 2006 VL 281 IS 1 BP 429 EP 438 DI 10.1074/jbc.M507440200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 998GS UT WOS:000234307200053 PM 16267055 ER PT J AU Johnson, AA Santos, W Pais, GCG Marchand, C Amin, R Burke, TR Verdine, G Pommier, Y AF Johnson, AA Santos, W Pais, GCG Marchand, C Amin, R Burke, TR Verdine, G Pommier, Y TI Integration requires a specific interaction of the donor DNA terminal 5 '-cytosine with glutamine 148 of the HIV-1 integrase flexible loop SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BETA-DIKETO ACIDS; ACTIVE-SITE; VIRAL-DNA; CATALYTIC DOMAIN; I INTEGRASE; CRYSTAL-STRUCTURE; STRAND TRANSFER; METAL-BINDING; CORE DOMAIN AB Integration is essential for retroviral replication and gene therapy using retroviral vectors. Human immunodeficiency virus, type 1 (HIV-1), integrase specifically recognizes the terminal sequences of each long terminal repeat ( LTR) and cleaves the 3'-end terminal dinucleotide 5'-GT. The exposed 3'-hydroxyl is then positioned for nucleophilic attack and subsequent strand transfer into another DNAduplex (target or chromosomal DNA). We report that both the terminal cytosine at the protruding 5'-end of the long terminal repeats (5'-C) and the integrase residue Gln-148 are critical for strand transfer. Proximity of the 5'-C and Gln-148 was demonstrated by disulfide cross-linking. Cross- linking is inhibited by the inhibitor 5CITEP 1-( 5- chloroindol- 3- yl)- 3- hydroxy- 3-(2H-tetrazol-5- yl)- propenone. We propose that strand transfer requires a conformational change of the integrase-viral (donor) DNA-complex with formation of an H-bond between the N-3 of the 5'-C and the amine group of Gln-148. These findings have implications for the molecular mechanisms coupling 3'-processing and strand transfer as well as for the molecular pharmacology of integrase inhibitors. C1 NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, NIH, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Burke, Terrence/N-2601-2014; Marchand, Christophe/D-8559-2016; OI Santos, Webster/0000-0002-4731-8548 FU Intramural NIH HHS; NIGMS NIH HHS [F32 GM067380, R01 GM044853] NR 45 TC 55 Z9 58 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 6 PY 2006 VL 281 IS 1 BP 461 EP 467 DI 10.1074/jbc.M511348200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 998GS UT WOS:000234307200057 PM 16257967 ER PT J AU Klase, Z Donio, MJ Blauvelt, A Marx, PA Jeang, KT Smith, SM AF Klase, Zachary Donio, Michael J. Blauvelt, Andrew Marx, Preston A. Jeang, Kuan-Teh Smith, Stephen M. TI A peptide-loaded dendritic cell based cytotoxic T-lymphocyte (CTL) vaccination strategy using peptides that span SIV Tat, Rev, and Env overlapping reading frames SO RETROVIROLOGY LA English DT Article ID INFECTION; SIVMAC239; VACCINES; EPITOPE; CANCER AB CTL based vaccine strategies in the macaque model of AIDS have shown promise in slowing the progression to disease. However, rapid CTL escape viruses can emerge rendering such vaccination useless. We hypothesized that such escape is made more difficult if the immunizing CTL epitope falls within a region of the virus that has a high density of overlapping reading frames which encode several viral proteins. To test this hypothesis, we immunized macaques using a peptide-loaded dendritic cell approach employing epitopes in the second coding exon of SIV Tat which spans reading frames for both Env and Rev. We report here that autologous dendritic cells, loaded with SIV peptides from Tat, Rev, and Env, induced a distinct cellular immune response measurable ex vivo. However, conclusive in vivo control of a challenge inoculation of SIVmac239 was not observed suggesting that CTL epitopes within densely overlapping reading frames are also subject to escape mutations. C1 St Michaels Hosp, Dept Infect Dis, Newark, NJ 07102 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Prevent Med & Community Hlth, Newark, NJ 07103 USA. Oregon Hlth Sci Univ, Dept Dermatol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. VA Med Ctr, Dermatol Serv, Portland, OR USA. Tulane Univ, Hlth Sci Ctr, Dept Trop Med, Natl Primate Res Ctr, Covington, LA USA. NIAID, Mol Virol Sect, Mol Med Lab, NIH, Bethesda, MD 20892 USA. RP Smith, SM (reprint author), St Michaels Hosp, Dept Infect Dis, 306 Dr ML King Jr Blvd, Newark, NJ 07102 USA. EM zklase@gwu.edu; mikedonio@aol.com; blauvela@ohsu.edu; pmarx@tulane.edu; KJEANG@niaid.nih.gov; ssmith1824@aol.com RI Jeang, Kuan-Teh/A-2424-2008 NR 13 TC 10 Z9 10 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JAN 6 PY 2006 VL 3 AR 1 DI 10.1186/1742-4690-3-1 PG 13 WC Virology SC Virology GA 067DR UT WOS:000239282400001 PM 16398928 ER PT J AU Ruijter, JM Thygesen, HH Schoneveld, OJLM Das, AT Berkhout, B Lamers, WH AF Ruijter, Jan M. Thygesen, Helene H. Schoneveld, Onard J. L. M. Das, Atze T. Berkhout, Ben Lamers, Wouter H. TI Factor correction as a tool to eliminate between-session variation in replicate experiments: application to molecular biology and retrovirology SO RETROVIROLOGY LA English DT Article AB Background: In experimental biology, including retrovirology and molecular biology, replicate measurement sessions very often show similar proportional differences between experimental conditions, but different absolute values, even though the measurements were presumably carried out under identical circumstances. Although statistical programs enable the analysis of condition effects despite this replication error, this approach is hardly ever used for this purpose. On the contrary, most researchers deal with such between-session variation by normalisation or standardisation of the data. In normalisation all values in a session are divided by the observed value of the 'control' condition, whereas in standardisation, the sessions' means and standard deviations are used to correct the data. Normalisation, however, adds variation because the control value is not without error, while standardisation is biased if the data set is incomplete. Results: In most cases, between-session variation is multiplicative and can, therefore, be removed by division of the data in each session with a session-specific correction factor. Assuming one level of multiplicative between-session error, unbiased session factors can be calculated from all available data through the generation of a between-session ratio matrix. Alternatively, these factors can be estimated with a maximum likelihood approach. The effectiveness of this correction method, dubbed "factor correction", is demonstrated with examples from the field of molecular biology and retrovirology. Especially when not all conditions are included in every measurement session, factor correction results in smaller residual error than normalisation and standardisation and therefore allows the detection of smaller treatment differences. Factor correction was implemented into an easy-to-use computer program that is available on request at: biolab-services@amc.uva.nl?subject=factor. Conclusion: Factor correction is an effective and efficient way to deal with between-session variation in multi-session experiments. C1 [Ruijter, Jan M.; Lamers, Wouter H.] Univ Amsterdam, Acad Med Ctr, Dept Anat & Embryol, NL-1105 AZ Amsterdam, Netherlands. [Thygesen, Helene H.] Dept Clin Epidemiol & Biostat, NL-1105 AZ Amsterdam, Netherlands. [Schoneveld, Onard J. L. M.; Lamers, Wouter H.] Univ Amsterdam, AMC Liver Ctr, NL-1105 BK Amsterdam, Netherlands. [Schoneveld, Onard J. L. M.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Das, Atze T.; Berkhout, Ben] Univ Amsterdam, Acad Med Ctr, Dept Human Retrovirol, NL-1105 AZ Amsterdam, Netherlands. RP Ruijter, JM (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Anat & Embryol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM j.m.ruijter@amc.uva.nl; h.h.thygesen@amc.uva.nl; schoneveldo@niehs.nih.gov; a.t.das@amc.uva.nl; b.berkhout@amc.uva.nl; w.h.lamers@amc.uva.nl NR 14 TC 70 Z9 70 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JAN 6 PY 2006 VL 3 AR 2 DI 10.1186/1742-4690-3-2 PG 8 WC Virology SC Virology GA V22YA UT WOS:000208309300001 PM 16398936 ER PT J AU Scarpa, T AF Scarpa, T TI Research funding - Peer review at NIH SO SCIENCE LA English DT Editorial Material C1 NIH, Ctr Sci Review, Bethesda, MD 20814 USA. RP Scarpa, T (reprint author), NIH, Ctr Sci Review, Bethesda, MD 20814 USA. EM scarpat@csr.nih.gov NR 3 TC 12 Z9 12 U1 0 U2 3 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 JAN 6 PY 2006 VL 311 IS 5757 BP 41 EP 41 DI 10.1126/science.1122796 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001ON UT WOS:000234546300022 PM 16400135 ER PT J AU Johnson, WE Eizirik, E Pecon-Slattery, J Murphy, WJ Antunes, A Teeling, E O'Brien, SJ AF Johnson, WE Eizirik, E Pecon-Slattery, J Murphy, WJ Antunes, A Teeling, E O'Brien, SJ TI The Late Miocene radiation of modern Felidae: A genetic assessment SO SCIENCE LA English DT Article ID MITOCHONDRIAL-DNA; CHRONOLOGY; PHYLOGENY; CARNIVORA; GENOME; CAT AB Modern fetid species descend from relatively recent (<11 million years ago) divergence and speciation events that produced successful predatory carnivores worldwide but that have confounded taxonomic classifications. A highly resolved molecular phylogeny with divergence dates for all living cat species, derived from autosomal, X-linked, Y-linked, and mitochondrial gene segments (22,789 base pairs) and 16 fossil calibrations define eight principal lineages produced through at least 10 intercontinental migrations facilitated by sea-level fluctuations. A ghost lineage analysis indicates that available fetid fossils underestimate (i.e., unrepresented basal branch length) first occurrence by an average of 76%, revealing a low representation of fetid lineages in paleontological remains. The phylogenetic performance of distinct gene classes showed that Y-chromosome segments are appreciably more informative than mitochondrial DNA, X-linked, or autosomal genes in resolving the rapid Felidae species radiation. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. Pontificia Univ Catolica Rio Grande do Sul, Fac Biociencias, Ctr Biol Genom & Mol, BR-90619900 Porto Alegre, RS, Brazil. Univ Porto, Fac Ciencias, Dept Quim, REQUIMTE, P-4167007 Oporto, Portugal. RP NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM johnsonw@ncifcrf.gov; obrien@ncifcrf.gov RI Eizirik, Eduardo/K-8034-2012; REQUIMTE, AL/H-9106-2013; Johnson, Warren/D-4149-2016 OI Eizirik, Eduardo/0000-0002-9658-0999; Johnson, Warren/0000-0002-5954-186X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 28 TC 314 Z9 338 U1 27 U2 219 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 6 PY 2006 VL 311 IS 5757 BP 73 EP 77 DI 10.1126/science.1122277 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001ON UT WOS:000234546300035 PM 16400146 ER PT J AU Hardy, J Scholz, S Evans, W Goldfarb, L Singleton, A AF Hardy, J Scholz, S Evans, W Goldfarb, L Singleton, A TI Prion genotypes in Central America suggest selection for the V129 allele SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE prion; genetics; cannibalism ID CREUTZFELDT-JAKOB-DISEASE; PROTEIN GENE; CANNIBALISM; POPULATIONS AB Using the well-characterized, human diversity sample series, we show that the V129 prion allele has a very high frequency in South American populations relative to the East Asian populations from which it arose. We suggest there has been selection at the prion locus, possibly mediated by Kuru-like diseases, which has influenced its allele frequency. (C) 2005 Wiley-Liss, Inc. C1 NIA, Neurogenet Lab, Bethesda, MD 20892 USA. NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, Porter Neurosci Bldg,35 Convent Dr, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Scholz, Sonja/0000-0002-6623-0429 FU Medical Research Council [G0701075] NR 14 TC 6 Z9 6 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN 5 PY 2006 VL 141B IS 1 BP 33 EP 35 DI 10.1002/ajmg.b.30248 PG 3 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 001DS UT WOS:000234514400006 PM 16287045 ER PT J AU Liu, QR Lu, L Zhu, XG Gong, JP Shaham, Y Uhl, GR AF Liu, QR Lu, L Zhu, XG Gong, JP Shaham, Y Uhl, GR TI Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine SO BRAIN RESEARCH LA English DT Article DE neurotrophin; gene regulation; addiction; dopamine; cocaine ID NEUROTROPHIC FACTOR GENE; FACTOR MESSENGER-RNA; ACTIVITY-DEPENDENT EXPRESSION; MEDIUM SPINY NEURONS; DOPAMINERGIC-NEURONS; HIPPOCAMPAL-NEURONS; TRANSCRIPTION FACTOR; SYNAPTIC SITES; MOUSE-BRAIN; IN-VIVO AB Results from studies using molecular and genetic methods in humans and rodents suggest that brain-derived neurotrophic factor (BDNF) is involved in the behavioral effects of abused drugs, making understanding of its genomic structure and regulation of substantial interest. Recently, we have reported that the human BDNF gene contains seven upstream exons that can each be spliced independently to the major BDNF coding exon to form diverse bipartite BDNF transcripts. We also identified a novel "BDNFOS" gene that is transcribed to produce alternatively spliced natural antisense transcripts (NATs); its fifth exon overlaps with the protein coding exon VIII of human BDNF. To better understand BDNF's genomic structure and differential regulation, we now describe the rodent BDNF gene and transcripts. This gene includes six bipartite transcripts that are generated by six independently transcribed exons, each of which is spliced to a major coding exon and a tripartite transcript that is composed of two upstream exons and one coding exon. In addition, we found no evidence for antisense, opposite strand BDNFOS gene transcripts in mice or rats. The BDNF rodent splice variants display specific patterns of differential expression in different brain regions and peripheral tissues. Acute cocaine administration increased striatal expression of a specific BDNF4 splice variant by up to 5-fold. Interestingly, however, neither experimenternor self-administered chronic cocaine administration enhanced striatal BDNF expression. These data suggest a role of specific BDNF promoter regions and regulatory sequences in stimulant-induced alterations in BDNF expression, and in the alterations that changed BDNF expression is likely to confer in the brain. Published by Elsevier B.V. C1 NIDA, IRP, Mol Neurobiol Branch, NIH,DHHS, Baltimore, MD 21224 USA. NIDA, IRP, Behav Neurosci Branch, NIH,DHHS, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, IRP, Mol Neurobiol Branch, NIH,DHHS, Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; Liu, Qing-Rong/A-3059-2012 OI Liu, Qing-Rong/0000-0001-8477-6452 NR 58 TC 177 Z9 182 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 5 PY 2006 VL 1067 IS 1 BP 1 EP 12 DI 10.1016/j.brainres.2005.10.004 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 012RI UT WOS:000235356500002 PM 16376315 ER PT J AU Narimatsu, S Takatsu, N Yamano, S Inoue, Y Hanioka, N Kiryu, K Naito, S Gonzalez, FJ Yamamoto, S AF Narimatsu, S Takatsu, N Yamano, S Inoue, Y Hanioka, N Kiryu, K Naito, S Gonzalez, FJ Yamamoto, S TI The effect of dimethyl sulfoxide on the function of cytochrome P450 2D6 in HepG2 cells upon the co-expression with NADPH-cytochrome P450 reductase SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE CYP2D6; HepG2 cell line; NADPH-cytochrome p450 reductase; dimethyl sulfoxide; bufuralol ID LIVER-MICROSOMES; SUBSTITUTION; METABOLISM; JAPANESE; ENZYMES; ALANINE; CYP2D6 AB HepG2 cells, a human hepatoma cell line, stably expressing NADPH-cytochrome P450 reductase (OR) and/or cytochrome P450 2D6 wild-type (CYP2D6-WT) or its variants (Pro34Ser, Gly42Arg, Arg296Cys and Ser486Thr) were established in the present study. The cultivation of HepG2 cells expressing CYP2D6-WT in the culture medium containing dimethyl sulfoxide (DMSO, 0.1% of final concentration) markedly increased the bufuralol (BF) 1 ''-hydroxylase activity compared with that of control cells when cultivated without DMSO. A similar effect was also observed in HepG2 cells stably expressing CYP2D6 and OR. The addition of hemin in place of DMSO to the culture medium resulted in no increase in the enzyme activity. Western blot analysis revealed that the levels of CYP2D6 protein were similar between DMSO-treated and non-treated HepG2 cells regardless of OR expression. Spectrophotometric analysis of reduced carbon monoxide-difference spectra of HepG2 cells expressing CYP2D6-WT and/or OR demonstrated that the addition of DMSO increased the peak height of functional CYP2D6 at 450 nm. These results suggest that the increase in CYP2D6 activity is attributable to the radical-scavenging effect of DMSO. The HepG2 cell lines stably expressing OR and CYP2D6 or its variants in combination with DMSO treatment may be useful for screening the cytotoxicity of chemical compounds which undergo oxidation by CYP2D6. (C) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Lab Hlth Chem, Okayama 7008530, Japan. Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Lab Biomol Sci, Okayama 7008530, Japan. Fukuoka Univ, Fac Pharmaceut Sci, Dept Hyg Chem, Jonan Ku, Fukuoka 8140180, Japan. Gunma Univ, Fac Engn, Dept Biol & Chem Engn, Gunma 3768515, Japan. Otsuka Pharmaceut Factory Inc, Div Pharmacol Drug Safety & Metab, Tokushima 7728601, Japan. NCI, NIH, Bethesda, MD 20892 USA. RP Narimatsu, S (reprint author), Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Lab Hlth Chem, 1-1-1 Tsushima Naka, Okayama 7008530, Japan. EM shizuo@pharm.okayama-u.ac.jp NR 19 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JAN 5 PY 2006 VL 159 IS 1 BP 47 EP 57 DI 10.1016/j.cbi.2005.09.001 PG 11 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 005AE UT WOS:000234793300003 PM 16214121 ER PT J AU Bishop, AJR Kosaras, B Hollander, MC Fornace, A Sidman, RL Schiestl, RH AF Bishop, AJR Kosaras, B Hollander, MC Fornace, A Sidman, RL Schiestl, RH TI p21 controls patterning but not homologous recombination in RPE development SO DNA REPAIR LA English DT Article DE p21; homologous recombination; eye development; retinal pigment epithelium; genetic instability ID RETINAL-PIGMENT EPITHELIUM; EYED UNSTABLE MUTATION; DEPENDENT KINASE INHIBITOR; SEQUENCE-SPECIFIC TRANSACTIVATION; II OCULOCUTANEOUS ALBINISM; CELL-CYCLE; INCREASED FREQUENCY; DNA DELETIONS; GROWTH ARREST; IN-VIVO AB p21/WAF1/CIP1/MDA6 is a key cell cycle regulator. Cell cycle regulation is an important part of development, differentiation, DNA repair and apoptosis. Following DNA damage, p53 dependent expression of p21 results in a rapid cell cycle arrest. p21 also appears to be important for the development of melanocytes, promoting their differentiation and melanogenesis. Here, we examine the effect of p21 deficiency on the development of another pigmented tissue, the retinal pigment epithelium. The murine mutation pink-eyed unstable (p(un)) spontaneously reverts to a wild-type allele by homologous recombination. In a retinal pigment epithelium cell this results in pigmentation, which can be observed in the adult eye. The clonal expansion of such cells during development has provided insight into the pattern of retinal pigment epithelium development. In contrast to previous results with Atm, p53 and Gadd45, p(un) reversion events in p21 deficient mice did not show any significant change. These results suggest that p21 does not play any role in maintaining overall genomic stability by regulating homologous recombination frequencies during development. However, the absence of p21 caused a distinct change in the positions of the reversion events within the retinal pigment epithelium. Those events that would normally arrest to produce single cell events continued to proliferate uncovering a cell cycle dysregulation phenotype. It is likely that p21 is involved in controlling the developmental pattern of the retinal pigment. We also found a C57BL/6J specific p21 dependent ocular defect in retinal folding, similar to those reported in the absence of p53. (C) 2005 Elsevier B.V. All rights reserved. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Pathol, Los Angeles, CA 90095 USA. RP Bishop, AJR (reprint author), Harvard Univ, Sch Med, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM abishop@genetics.med.harvard.edu; rschiestl@mednet.ucla.edu RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU NIEHS NIH HHS [R01 ES09519]; NIGMS NIH HHS [F32GM19147] NR 86 TC 2 Z9 3 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JAN 5 PY 2006 VL 5 IS 1 BP 111 EP 120 DI 10.1016/j.dnarep.2005.08.015 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 004VG UT WOS:000234780000012 PM 16202662 ER PT J AU Park, YY Jo, J Isaac, JTR Cho, K AF Park, YY Jo, J Isaac, JTR Cho, K TI Long-term depression of kainate receptor-mediated synaptic transmission SO NEURON LA English DT Article ID MOSSY FIBER SYNAPSES; PROTEIN-KINASE-C; METABOTROPIC GLUTAMATE RECEPTORS; DEPENDENT REGULATION; AMPA RECEPTORS; RAT-BRAIN; HIPPOCAMPUS; POTENTIATION; EXPRESSION; PLASTICITY AB Kainate receptors (KARs) have been shown to be involved in hippocampal mossy fiber long-term potentiation (LTP); however, it is not known if KARs are involved in the induction or expression of long-term depression (LTD), the other major form of long-term synaptic plasticity. Here we describe LTD of KAR-mediated synaptic transmission (EPSCKA LTD) in perirhinal cortex layer II/III neurons that is distinct from LTD of AMPAR-mediated transmission, which also coexists at the same synapses. Induction of EPSCKA LTD requires a rise in postsynaptic Ca2+ but is independent of NMDARs or T-type voltage-gated Ca2+ channels; however, it requires synaptic activation of inwardly rectifying KARs and release of Ca2+ from stores. The synaptic KARs are regulated by tonically activated mGluR5, and expression of EPSCKA LTD occurs via a mechanism involving mGluR5, PKC, and PICK1 PDZ domain interactions. Thus, we describe the induction and expression mechanism of a form of synaptic plasticity, EPSCKA LTD. C1 Univ Sheffield, Sch Med & Biomed Sci, Sheffield S10 2TN, S Yorkshire, England. Univ Bristol, Dept Anat, Sch Med Sci, MRC Ctr Synapt Plast, Bristol BS8 1TD, Avon, England. NINDS, NIH, Bethesda, MD 20892 USA. RP Cho, K (reprint author), Univ Sheffield, Sch Med & Biomed Sci, Western Bank, Sheffield S10 2TN, S Yorkshire, England. EM k.cho@sheffield.ac.uk FU Intramural NIH HHS; Wellcome Trust NR 39 TC 40 Z9 41 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 5 PY 2006 VL 49 IS 1 BP 95 EP 106 DI 10.1016/j.neuron.2005.11.035 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 031IZ UT WOS:000236699300012 PM 16387642 ER PT J AU Drayna, D AF Drayna, D TI Is our behavior written in our genes? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DROSOPHILA C1 NIDCD, Sect Syst Biol Commun Disorders, Rockville, MD USA. RP Drayna, D (reprint author), NIDCD, Sect Syst Biol Commun Disorders, Rockville, MD USA. NR 3 TC 4 Z9 4 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 5 PY 2006 VL 354 IS 1 BP 7 EP 9 DI 10.1056/NEJMp058215 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 998ZO UT WOS:000234358600003 PM 16394297 ER PT J AU Cai, LS Brouwer, C Sinclair, K Cuevas, J Pike, VW AF Cai, LS Brouwer, C Sinclair, K Cuevas, J Pike, VW TI Titanium(IV) chloride promoted syntheses of new imidazo[1,2-a]pyridine derivatives under microwave conditions SO SYNTHESIS-STUTTGART LA English DT Article DE titanium(IV) chloride; imidazo[1,2-a]pyridine; polycyclic; condensation; Schiff base formation; microwave ID BETA-AMYLOID PLAQUES; SUBSTITUTED IMIDAZO<1,2-A>PYRIDINES; ALZHEIMERS-DISEASE; ANTIULCER AGENTS; BRAIN; ANTHELMINTICS; LIGANDS; ANALOGS; IMPY AB A new method is described for the synthesis of imidazo[1,2-a]pyridine derivatives from the reaction of 2-aminopyridines with alpha-haloketones. The critical reagent is titanium(IV) chloride, which appears to serve as a strong dehydrating agent to promote formation of putative Schiff base intermediates, which cyclize subsequently to form the products. The reactions were performed rapidly under microwave conditions. Multiple reaction conditions were evaluated, including reaction temperature, solvent and other Lewis acids. Various combinations of substitution patterns in both the alpha-haloketone and 2-aminopyridine substrates were examined to evaluate the scope of the reaction. The reaction is quite sensitive to substituents in both substrates, especially those with basicity or coordination ability. C1 NIMH, Mol Imaging Branch, PET Radiopharmaceut Sci Sect, NIH, Bethesda, MD 20892 USA. RP Cai, LS (reprint author), NIMH, Mol Imaging Branch, PET Radiopharmaceut Sci Sect, NIH, Bldg 10,Room,B3C346,10 Ctr Dr, Bethesda, MD 20892 USA. EM cail@intra.nimh.nih.gov NR 55 TC 18 Z9 19 U1 1 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD JAN 5 PY 2006 IS 1 BP 133 EP 145 DI 10.1055/s-2005-918490 PG 13 WC Chemistry, Organic SC Chemistry GA 000NQ UT WOS:000234469300020 ER PT J AU Moss, B AF Moss, B TI Poxvirus entry and membrane fusion SO VIROLOGY LA English DT Article ID ACTIN-CONTAINING MICROVILLI; INTRACELLULAR MATURE VIRIONS; ENVELOPED VACCINIA VIRUS; CELL-CELL-FUSION; NEUTRALIZING MONOCLONAL-ANTIBODIES; SERINE PROTEASE INHIBITOR; SURFACE HEPARAN-SULFATE; OPEN READING FRAME; STRAIN L CELLS; PROTEOLYTIC ACTIVATION AB The study of poxvirus entry and membrane fusion has been invigorated by new biochemical and microscopic findings that lead to the following conclusions: (1) the surface of the mature virion (MV), whether isolated from an infected cell or by disruption of the membrane wrapper of an extracellular virion, is comprised of a single lipid membrane embedded with non-glycosylated viral proteins; (2) the MV membrane fuses with the cell membrane, allowing the core to enter the cytoplasm and initiate gene expression; (3) fusion is mediated by a newly recognized group of viral protein components of the MV membrane, which are conserved in all members of the poxvirus family; (4) the latter MV entry/fusion proteins are required for cell to cell spread necessitating the disruption of the membrane wrapper of extracellular virions prior to fusion; and furthermore (5) the same group of MV entry/fusion proteins are required for virus-induced cell-cell fusion. Future research priorities include delineation of the roles of individual entry/fusion proteins and identification of cell receptors. Published by Elsevier Inc. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS NR 71 TC 151 Z9 158 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 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2006 VL 344 IS 1 BP 48 EP 54 DI 10.1016/j.virol.2005.09.037 PG 7 WC Virology SC Virology GA 002KT UT WOS:000234611000007 PM 16364735 ER PT J AU Shalowitz, DI Miller, FG AF Shalowitz, DI Miller, FG TI Implications of disclosing individual results of clinical research - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TRIALS C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Shalowitz, DI (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM fmiller@nih.gov RI Shalowitz, David/A-7432-2009; OI Shalowitz, David/0000-0002-5189-4687 NR 3 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 4 PY 2006 VL 295 IS 1 BP 37 EP 38 DI 10.1001/jama.295.1.37-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 999HT UT WOS:000234381100016 ER PT J AU Martin, LJ Pan, Y Price, AC Sterling, W Copeland, NG Jenkins, NA Price, DL Lee, MK AF Martin, LJ Pan, Y Price, AC Sterling, W Copeland, NG Jenkins, NA Price, DL Lee, MK TI Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death SO JOURNAL OF NEUROSCIENCE LA English DT Article DE axonopathy; DNA damage; motor neuron disease; neuronal apoptosis; nitrative stress; peroxynitrite; synucleinopathy ID SINGLE-STRAND BREAKS; OXIDATIVE STRESS; SUBCELLULAR REDISTRIBUTION; HYALINE INCLUSIONS; HYPOXIA-ISCHEMIA; NERVOUS-SYSTEM; WILD-TYPE; IN-VITRO; APOPTOSIS; MUTATION AB alpha-Synuclein (alpha-Syn) is enriched in nerve terminals. Two mutations in the alpha-Syn gene (Ala53 -> Thr and Ala30 -> Pro) occur in autosomaldominant familial Parkinson's disease. Mice overexpressing the human A53T mutant alpha-Syn develop a severe movement disorder, paralysis, and synucleinopathy, but the mechanisms are not understood. We examined whether transgenic mice expressing human ild-type or familial Parkinson's disease-linked A53T or A30P mutant alpha-syn develop neuronal degeneration and cell death. Mutant mice were examined at early- to mid-stage disease and at near end- stage disease. Age-matched nontransgenic littermates were controls. In A53T mice, neurons in brainstem and spinal cord exhibited large axonal swellings, somal chromatolytic changes, and nuclear condensation. Spheroid eosinophilic Lewy body-like inclusions were present in the cytoplasm of cortical neurons and spinal motor neurons. These inclusions contained human alpha-syn and nitrated synuclein. Motor neurons were depleted (similar to 75%) in A53T mice but were affected less in A30P mice. Axonal degeneration was present in many regions. Electron microscopy confirmed the cell and axonal degeneration and revealed cytoplasmic inclusions in dendrites and axons. Some inclusions were degenerating mitochondria and were positive for human alpha-syn. Mitochondrial complex IV and V proteins were at control levels, but complex IV activity was reduced significantly in spinal cord. Subsets of neurons in neocortex, brainstem, and spinal cord ventral horn were positive for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, cleaved caspase-3, and p53. Mitochondria in neurons had terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive matrices and p53 at the outer membrane. Thus, A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Martin, LJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, 558 Ross Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM martinl@jhmi.edu RI Lee, Michael/D-9491-2013 OI Lee, Michael/0000-0001-5865-9682 FU NIA NIH HHS [AG16282]; NINDS NIH HHS [NS34100, NS38065, NS38377, NS52098, R01 NS038065] NR 56 TC 323 Z9 335 U1 3 U2 21 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 JAN 4 PY 2006 VL 26 IS 1 BP 41 EP 50 DI 10.1523/JNEUROSCI.4308-05.2006 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 999LM UT WOS:000234390800007 PM 16399671 ER PT J AU Travis, LB Rabkin, CS Brown, LM Allan, JM Alter, BP Ambrosone, CB Begg, CB Caporaso, N Chanock, S DeMichele, A Figg, WD Gospodarowicz, MK Hall, EJ Hisada, M Inskip, P Kleinerman, R Little, JB Malkin, D Ng, AK Offit, K Pui, CH Robison, LL Rothman, N Shields, PG Strong, L Taniguchi, T Tucker, MA Greene, MH AF Travis, LB Rabkin, CS Brown, LM Allan, JM Alter, BP Ambrosone, CB Begg, CB Caporaso, N Chanock, S DeMichele, A Figg, WD Gospodarowicz, MK Hall, EJ Hisada, M Inskip, P Kleinerman, R Little, JB Malkin, D Ng, AK Offit, K Pui, CH Robison, LL Rothman, N Shields, PG Strong, L Taniguchi, T Tucker, MA Greene, MH TI Cancer survivorship - Genetic susceptibility and second primary cancers: Research strategies and recommendations SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID LI-FRAUMENI-SYNDROME; ACUTE LYMPHOBLASTIC-LEUKEMIA; INDUCED GENOMIC INSTABILITY; TISSUE-SPECIFIC EXPRESSION; HEREDITARY BREAST-CANCER; CHECKPOINT CONTROL GENE; SECONDARY BRAIN-TUMORS; ACUTE MYELOID-LEUKEMIA; CELL LUNG-CANCER; HODGKINS-DISEASE AB Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene-environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)-sponsored workshop entitled '' Cancer Survivorship-Genetic Susceptibility and Second Primary Cancers.'' These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer. C1 NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ York, York YO10 5DD, N Yorkshire, England. Roswell Pk Canc Inst, Dept Epidemiol, Buffalo, NY 14263 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Columbia Univ, Ctr Radiol Res, New York, NY 10032 USA. Harvard Univ, Sch Publ Hlth, Radiobiol Lab, Boston, MA 02115 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Univ Minnesota, Minneapolis, MN USA. Vincent T Lombardi Canc Res Ctr, Washington, DC USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Travis, LB (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7086,MSC 7238, Bethesda, MD 20892 USA. EM travisl@mail.nih.gov RI Allan, James/B-4448-2009; Tucker, Margaret/B-4297-2015; Figg Sr, William/M-2411-2016; OI Kleinerman, Ruth/0000-0001-7415-2478 FU Intramural NIH HHS; NCI NIH HHS [CA-21765] NR 143 TC 138 Z9 141 U1 1 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 4 PY 2006 VL 98 IS 1 BP 15 EP 25 DI 10.1093/jnci/djj001 PG 11 WC Oncology SC Oncology GA 003XK UT WOS:000234715800007 PM 16391368 ER PT J AU Mayne, ST Risch, HA Dubrow, R Chow, WH Gammon, MD Vaughan, TL Borchardt, L Schoenberg, JB Stanford, JL West, AB Rotterdam, H Blot, WJ Fraumeni, JF AF Mayne, ST Risch, HA Dubrow, R Chow, WH Gammon, MD Vaughan, TL Borchardt, L Schoenberg, JB Stanford, JL West, AB Rotterdam, H Blot, WJ Fraumeni, JF TI Carbonated soft drink consumption and risk of esophageal adenocarcinoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GASTROESOPHAGEAL-REFLUX; GASTRIC CARDIA AB Carbonated soft drinks (CSDs) have been associated with gastroesophageal reflux, an established risk factor for esophageal adenocarcinoma. As both CSD consumption and esophageal adenocarcinoma incidence have sharply increased in recent decades, we examined CSD as a risk factor for esophageal and gastric cancers in a U.S. multicenter, population-based case-control study. Associations between CSD intake and risk were estimated by adjusted odds ratios (ORs), comparing the highest versus lowest quartiles of intake. All statistical tests were two-sided. Contrary to the proposed hypothesis, CSD consumption was inversely associated with esophageal adenocarcinoma risk (highest versus lowest quartiles, OR = 0.47, 95% confidence interval = 0.29 to 0.76; P-trend =.005), due primarily to intake of diet CSD. High CSD consumption did not increase risk of any esophageal or gastric cancer subtype in men or women or when analyses were restricted to nonproxy interviews. These findings indicate that CSD consumption (especially diet CSD) is inversely associated with risk of esophageal adenocarcinoma, and thus it is not likely to have contributed to the rising incidence rates. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. Yale Univ, Ctr Canc, Dept Epidemiol & Publ Hlth, New Haven, CT USA. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. New Jersey Dept Hlth & Senior Serv, Ctr Canc Initiat, Trenton, NJ USA. Columbia Univ, Dept Pathol, New York, NY USA. NYU, Med Ctr, Dept Pathol, New York, NY 10016 USA. Int Epidemiol Inst, Rockville, MD USA. RP Mayne, ST (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. EM Susan.Mayne@yale.edu FU Intramural NIH HHS; NCI NIH HHS [U01-CA57949, U01-CA57983, U01-CA57923] NR 9 TC 21 Z9 23 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 4 PY 2006 VL 98 IS 1 BP 72 EP 75 DI 10.1093/nci/djj007 PG 4 WC Oncology SC Oncology GA 003XK UT WOS:000234715800013 PM 16391374 ER PT J AU McDermott, MM Liu, K Ferrucci, L Criqui, MH Greenland, P Guralnik, JM Tian, L Schneider, JR Pearce, WH Tan, J Martin, GJ AF McDermott, MM Liu, K Ferrucci, L Criqui, MH Greenland, P Guralnik, JM Tian, L Schneider, JR Pearce, WH Tan, J Martin, GJ TI Physical performance in peripheral arterial disease: A slower rate of decline in patients who walk more SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ANKLE BRACHIAL INDEX; LEG SYMPTOMS; CLINICAL CHARACTERISTICS; EXERCISE REHABILITATION; CALTRAC ACCELEROMETER; OCCLUSIVE DISEASE; LONGITUDINAL DATA; 6-MINUTE WALK; RISK-FACTORS; PREVALENCE AB Background: Exercise rehabilitation programs increase treadmill walking performance in patients with peripheral arterial disease (PAD) and intermittent claudication. However, it is unknown whether patients with PAD who walk for exercise regularly have less functional decline than those with less walking activity. Objective: To determine whether patients with PAD who report that they walk for exercise 3 or more times per week have less annual functional decline than those who walk for exercise less frequently. Design: Prospective cohort study with a median follow-up of 36 months (interquartile range, 24 to 36 months). Setting: Academic medical center. Participants: 417 men and women with PAID. Measurements: Participants were classified at baseline and annually according to the number of times they reportedly walked for exercise each week. Functional assessments (6-minute walk distance, 4-meter walking speed, summary performance score) were measured at baseline and annually. Results were adjusted for age, sex, ethnicity, comorbid conditions, body mass index, ankle-brachial index, education, leg symptoms, cigarette use, geriatric depression score, previous year's level of functioning, and patterns of missing data. Results: Compared with those who exercised less frequently, patients who walked for exercise 3 or more times per week had a significantly smaller average annual decline in 6-minute walking distance (-48.0 feet per year compared with - 56.6 feet per year for those who walked 1 to 2 times per week and - 79.4 feet per year for nonexercisers; P for trend = 0.037). Patients who walked for exercise at least 3 times per week experienced a smaller average annual decline in the usual-paced 4-meter walking velocity (-0.014 m/s per year compared with - 0.022 m/s per year for those who walked 1 to 2 times per week and - 0.045 m/s per year for nonexercisers; P = 0.005). Similar findings were observed for the fast-paced 4-meter walk. The subset of asymptomatic patients who walked for exercise 3 or more times per week had annual declines in 6-minute walking performance (P = 0.107), normal-paced walking velocity (P = 0.065), and the summary performance score (P = 0.115); however, these declines were smaller than those observed in asymptomatic participants who walked fewer than 3 times per week. Limitations: Because this was an observational study, associations reported here cannot be construed as causal relationships. Sample sizes for subgroup analyses were small, which limited statistical power. Conclusion: Among patients with PAD, self-directed walking exercise performed at least 3 times weekly is associated with significantly less functional decline during the subsequent year. Similar trends were observed in the subset of asymptomatic patients with PAD. These findings may be particularly important for the numerous patients with PAD who do not have access to supervised walking exercise programs. C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Evanston NW Hosp, Evanston, IL USA. NIA, Baltimore, MD 21224 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU NCRR NIH HHS [RR-00048]; NHLBI NIH HHS [R01-HL58099, R01-HL64739] NR 40 TC 77 Z9 86 U1 1 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 3 PY 2006 VL 144 IS 1 BP 10 EP 20 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 000PL UT WOS:000234474200002 PM 16389250 ER PT J AU Miller, MF Humphrey, JH Iliff, PJ Malaba, LC Mbuya, NV Stoltzfus, RJ AF Miller, MF Humphrey, JH Iliff, PJ Malaba, LC Mbuya, NV Stoltzfus, RJ CA ZVITAMBO Study Grp TI Neonatal erythropoiesis and subsequent anemia in HIV-positive and HIV-negative Zimbabwean babies during the first year of life: a longitudinal study SO BMC INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; SERUM TRANSFERRIN RECEPTOR; IRON-DEFICIENCY; IMMUNOREACTIVE ERYTHROPOIETIN; FERRITIN CONCENTRATIONS; CHILDREN; INFANTS; PATHOGENESIS; HEMOGLOBIN; DIARRHEA AB Background: Anemia is common in HIV infection and independently associated with disease progression and mortality. The pathophysiology of HIV-related anemia is not well understood especially in infancy. Methods: We conducted a longitudinal cohort study nested within the Zimbabwe Vitamin A for Mothers and Babies Project. We measured hemoglobin, erythropoietin (EPO), serum transferrin receptor (TfR) and serum ferritin at 6 weeks, 3 and 6 months of age and hemoglobin at 9 and 12 months in 3 groups of randomly selected infants: 136 born to HIV-negative mothers, and 99 born to HIV-positive mothers and who were infected themselves by 6 weeks of age, and 324 born to HIV-positive mothers but who did not become infected in the 6 months following birth. Results: At one year of age, HIV-positive infants were 5.26 (adjusted odds ratio, P < 0.001) times more likely to be anemic compared to HIV- negative infants. Among, HIV- negative infants, EPO was or tended to be inversely associated with hemoglobin and was significantly positively associated with TfR throughout the first 6 months of life; TfR was significantly inversely associated with ferritin at 6 months; and EPO explained more of the variability in TfR than did ferritin. Among infected infants, the inverse association of EPO to hemoglobin was attenuated during early infancy, but significant at 6 months. Similar to HIV- negative infants, EPO was significantly positively associated with TfR throughout the first 6 months of life. However, the inverse association between TfR and ferritin observed among HIV- negative infants at 6 months was not observed among infected infants. Between birth and 6 months, mean serum ferritin concentration declined sharply (by similar to 90%) in all three groups of babies, but was significantly higher among HIV-positive compared to HIV- negative babies at all time points. Conclusion: HIV strongly increases anemia risk and confounds interpretation of hematologic indicators in infants. Among HIV- infected infants, the EPO response to anemia is attenuated near the time of infection in the first weeks of life, but normalizes by 6 months. C1 NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, Baltimore, MD USA. Univ Zimbabwe, Inst Food Nutr & Family Sci, Div Nutr, Harare, Zimbabwe. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. RP Miller, MF (reprint author), NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. EM millermeli@mail.nih.gov; jhumphrey@zvitambo.co.zw; piliff@zvitambo.co.zw; luciemalaba@yahoo.co.uk; Nkosi_Mbuya@cornell.edu; rjs62@cornell.edu NR 51 TC 25 Z9 25 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JAN 3 PY 2006 VL 6 AR 1 DI 10.1186/1471-2334-6-1 PG 11 WC Infectious Diseases SC Infectious Diseases GA 010PB UT WOS:000235205500001 PM 16390553 ER PT J AU Kathiresan, S Otvos, JD Sullivan, LM Keyes, MJ Schaefer, EJ Wilson, PWF D'Agostino, RB Vasan, RS Robins, SJ AF Kathiresan, S Otvos, JD Sullivan, LM Keyes, MJ Schaefer, EJ Wilson, PWF D'Agostino, RB Vasan, RS Robins, SJ TI Increased small low-density lipoprotein particle number - A prominent feature of the metabolic syndrome in the Framingham Heart Study SO CIRCULATION LA English DT Article DE cholesterol; lipids; lipoproteins; metabolic syndrome X; risk factors ID NUCLEAR-MAGNETIC-RESONANCE; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; APOLIPOPROTEIN-B; SUBFRACTION DISTRIBUTION; RISK-FACTORS; SIZE; SPECTROSCOPY; CHOLESTEROL; LDL AB Background-Levels of LDL cholesterol (LDL-C) are frequently not elevated in individuals with the metabolic syndrome (MetSyn). However, the atherogenic potential of LDL may depend on the number and size of LDL particles in addition to the cholesterol content of LDL. Methods and Results-We examined the sex-specific cross-sectional relations of small LDL particle number ( determined by nuclear magnetic resonance spectroscopy) to the presence of MetSyn and its components in 2993 Framingham Heart Study participants ( mean age, 51 years; 53% women) without cardiovascular disease (CVD) and the relations of small LDL particle number to CVD incidence in people with MetSyn. The MetSyn (>= 3 of 5 traits as defined by the National Cholesterol Education Adult Treatment Panel III) was present in 27% of men and 17% of women. In both sexes, small LDL particle number increased from 0 to 5 MetSyn traits, a pattern partly accounted for by strong correlations between small LDL particle number and serum triglycerides (r=0.61, P < 0.0001) and HDL-C (r=-0.55, P < 0.0001). Compared with participants without the MetSyn, those with the MetSyn had a higher CVD event rate. However, among participants with the MetSyn, CVD rates were similar for groups with an elevated versus a lower number of small LDL particles ( defined by the sex-specific median). Conclusions-Small LDL particle number is elevated in the MetSyn, increases with the number of MetSyn components, and most prominently is correlated with triglycerides and HDL-C. Whereas increased small LDL particle number identified the MetSyn with high sensitivity, a higher small LDL particle number was not associated with greater CVD event rates in people with the MetSyn. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. MIT, Cambridge, MA USA. LipoSci Inc, Raleigh, NC USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Stat & Consulting Unit, Boston, MA 02215 USA. Tufts Univ, Sch Med, Lipid Res Lab, Boston, MA 02111 USA. Med Univ S Carolina, Dept Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. RP Robins, SJ (reprint author), NHLBI, Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM sjrobins@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [2K24 HL04334, N01-HC-25195] NR 44 TC 158 Z9 164 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 3 PY 2006 VL 113 IS 1 BP 20 EP 29 DI 10.1161/CIRCULATINAHA.105.567107 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 998VC UT WOS:000234347000005 PM 16380547 ER PT J AU Stabile, E Kinnaird, T la Sala, A Hanson, SK Watkins, C Campia, U Shou, M Zbinden, S Fuchs, S Kornfeld, H Epstein, SE Burnett, MS AF Stabile, E Kinnaird, T la Sala, A Hanson, SK Watkins, C Campia, U Shou, M Zbinden, S Fuchs, S Kornfeld, H Epstein, SE Burnett, MS TI CD8(+) T lymphocytes regulate the arteriogenic response to ischemia by infiltrating the site of collateral vessel development and recruiting CD4(+) mononuclear cells through the expression of interleukin-16 SO CIRCULATION LA English DT Article; Proceedings Paper CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc DE angiogenesis; inflammation; interleukins; lymphocytes ID ARTERY GROWTH; ANGIOGENESIS; HINDLIMB; MICE; ACTIVATION; PERFUSION; MODEL; IL-16 AB Background-Previous studies have demonstrated that macrophages and CD4(+) T lymphocytes play pivotal roles in collateral development. Indirect evidence suggests that CD8(+) T cells also play a role. Thus, after acute cerebral ischemia, CD8(+) T cells infiltrate the perivascular space and secrete interleukin-16 (IL-16), a potent chemoattractant for monocytes and CD4(+) T cells. We tested whether CD8(+) T lymphocytes contribute to collateral vessel development and whether the lack of circulating CD8(+) T cells prevents IL-16 expression, impairs CD4(+) mononuclear cell recruitment, and reduces collateral vessel growth after femoral artery ligation in CD8(-/-) mice. Methods and Results-After surgical excision of the femoral artery, laser Doppler perfusion imaging demonstrated reduced blood flow recovery in CD8(-/-) mice compared with C57/BL6 mice (ischemic/nonischemic limb at day 28, 0.66 +/- 0.04 versus 0.87 +/- 0.04, respectively; P < 0.01). This resulted in greater calf muscle atrophy (mean fiber area, 785 +/- 68 versus 1067 +/- 69 mu m(2), respectively; P < 0.01) and increased fibrotic tissue content (10.8 +/- 1.2% versus 7 +/- 1%, respectively; P < 0.01). Moreover, CD8(-/-) mice displayed reduced IL-16 expression and decreased CD4(+) T-cell recruitment at the site of collateral vessel development. Exogenous CD8(+) T cells, infused into CD8(-/-) mice immediately after femoral artery ligation, selectively homed to the ischemic hind limb and expressed IL-16. The restoration of IL- 16 expression resulted in significant CD4(+) mononuclear cell infiltration of the ischemic limb, faster blood flow recovery, and reduced hindlimb muscle atrophy/fibrosis. When exogenous CD8(+) T cells deficient in IL-16 (IL-16(-/-)) were infused into CD8(-/-) mice immediately after femoral artery ligation, they selectively homed to the ischemic hind limb but were unable to recruit CD4(+) mononuclear cells and did not improve blood flow recovery. Conclusions-These results demonstrate that CD8(+) T cells importantly contribute to the early phase of collateral development. After femoral artery ligation, CD8(+) T cells infiltrate the site of collateral vessel growth and recruit CD4(+) mononuclear cells through the expression of IL-16. Our study provides further evidence of the significant role of the immune system in modulating collateral development in response to peripheral ischemia. C1 Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Lab Vasc Biol, Washington, DC 20010 USA. IRCCS, Mol & Cellular Biol Lab, Rome, Italy. NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02215 USA. RP Stabile, E (reprint author), Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Lab Vasc Biol, Suite 4B 1,110 Irving St NW, Washington, DC 20010 USA. EM geko50@tiscali.it RI la Sala, Andrea/A-3228-2009; OI la Sala, Andrea/0000-0003-1268-6516; stabile, eugenio/0000-0001-9763-6010; stabile, eugenio/0000-0002-4544-3142 FU NHLBI NIH HHS [HL72646] NR 23 TC 79 Z9 81 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 3 PY 2006 VL 113 IS 1 BP 118 EP 124 DI 10.1161/CIRCULATIONAHA.105.576702 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 998VC UT WOS:000234347000017 PM 16380545 ER PT J AU Baldwin, JT Borovetz, HS Duncan, BW Gartner, MJ Jarvik, RK Weiss, WJ Hoke, TR AF Baldwin, JT Borovetz, HS Duncan, BW Gartner, MJ Jarvik, RK Weiss, WJ Hoke, TR TI The national heart, lung, and blood institute pediatric circulatory support program SO CIRCULATION LA English DT Review DE heart-assist device; pediatrics; congenital heart defects; heart diseases; heart failure ID VENTRICULAR ASSIST DEVICE; EXTRACORPOREAL MEMBRANE-OXYGENATION; FULMINANT MYOCARDITIS; CLINICAL-EXPERIENCE; CARDIAC-DISEASE; UNITED-STATES; CHILDREN; TRANSPLANTATION; 1ST; VAD AB Options for the circulatory support of pediatric patients under the age of 5 years are currently limited to short-term extracorporeal devices, the use of which is often complicated by infection, bleeding, and thromboembolism. Recognizing this void, the National Heart, Lung, and Blood Institute solicited proposals for the development of novel circulatory support systems for infants and children from 2 to 25 kg with congenital or acquired cardiovascular disease. Five contracts were awarded to develop a family of devices that includes (1) an implantable mixed-flow ventricular assist device designed specifically for patients up to 2 years of age, (2) another mixed-flow ventricular assist device that can be implanted intravascularly or extravascularly depending on patient size, (3) compact integrated pediatric cardiopulmonary assist systems, (4) apically implanted axial-flow ventricular assist devices, and (5) pulsatile-flow ventricular assist devices. The common objective for these devices is to reliably provide circulatory support for infants and children while minimizing risks related to infection, bleeding, and thromboembolism. The devices are expected to be ready for clinical studies at the conclusion of the awards in 2009. C1 NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA USA. Cleveland Clin Fdn, Dept Pediat & Congenital Heart Surg, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Biomed Engn, Cleveland, OH 44195 USA. Ension Inc, Pittsburgh, PA USA. Jarvik Heart Inc, New York, NY USA. Penn State Univ, Coll Med, Dept Surg, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Dept Bioengn, Hershey, PA 17033 USA. RP Baldwin, JT (reprint author), NHLBI, Div Heart & Vasc Dis, 2 Rockledge Ctr,Room 9150,6701 Rockledge, Bethesda, MD 20892 USA. EM baldwint@nhlbi.nih.gov NR 37 TC 99 Z9 101 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 3 PY 2006 VL 113 IS 1 BP 147 EP 155 DI 10.1161/CIRCULATIONAHA.105.571422 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 998VC UT WOS:000234347000019 PM 16391168 ER PT J AU Yu, P Li, ZS Zhang, L Tagle, DA Cai, T AF Yu, P Li, ZS Zhang, L Tagle, DA Cai, T TI Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family SO GENE LA English DT Article; Proceedings Paper CT Symposium on Genome and RNA CY FEB 26-MAR 02, 2005 CL Puntarenas, COSTA RICA SP Int Soc Mol Evolut DE tryptophan metabolism; neurodegenerative disease; gene cloning; glutamine transaminase K; alpha-aminoadipate aminotransferase ID ALPHA-AMINOADIPATE AMINOTRANSFERASE; CONJUGATE BETA-LYASE; HUNTINGTONS-DISEASE; RAT-BRAIN; CAENORHABDITIS-ELEGANS; TRYPTOPHAN DEGRADATION; QUINOLINIC ACID; TRANSAMINASE-K; EXPRESSION; CYSTEINE AB Kynurenine aminotransferase (KAT) is an enzyme responsible for synthesis of kynurenic acid (KYNA), a well established neuroprotective and anticonvulsant agent, involved in synaptic transmission and implicated in the pathophysiology of schizophrenia, Huntington's disease and other neurological disorders. We have shown previously that kat2(-/-) mice had lower hippocampal KYNA levels and were more hyperactive than wild-type mice. However, these abnormalities occur early and are transitory coinciding with restoration of KYNA levels, suggesting that compensatory changes or ontogenetic expression of another unknown homolog may account for the normalization of KYNA levels in the adult kat2(-/-) mice brain. Here, we report the isolation of a novel KAT molecule, kat3, from mouse and human brain cDNA libraries. The encoded 454 amino acids of human KAT III share 64.8% similarity to that of KAT I and 30.1% to KAT II. Northern blot analysis demonstrated that kat3 mRNA is widely expressed but with higher expression levels in liver, kidney, heart, and neuroendocrine tissues. RT-PCR and Northern analysis showed that kat3 expression starts as early as postnatal day (PND) 7 and peaks in adult. The mRNA level of kat3 and kat1 when measured together is significantly higher at PND 60 in kat2(-/-) mice than those of wild-type mice indicating possible co-regulation of expression levels. RNA-interference (RNAi) directed towards transcripts for either R03A10.4 or F28H6.3 in Caenorhabditis elegans which are kat1 and kat3 orthologs, respectively, did not result in any gross abnormalities. Our results show that upregulation of kat3 and kat1 may be responsible for the phenotypic rescue on kat2(-/-) mice. Published by Elsevier B.V. C1 NIDCR, Expt Med Sect, NIH, Bethesda, MD 20892 USA. NCI, Prot Nucl Acid Interact Sect, Struct Biophys Lab, Frederick, MD 21702 USA. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NINDS, Ctr Neurosci, NIH, Bethesda, MD 20892 USA. RP Cai, T (reprint author), NIDCR, Expt Med Sect, NIH, B30 Rm 112,OIIB, Bethesda, MD 20892 USA. EM tcai@mail.nih.gov FU Intramural NIH HHS NR 35 TC 59 Z9 66 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 3 PY 2006 VL 365 BP 111 EP 118 DI 10.1016/J.gene.2005.09.034 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 026BQ UT WOS:000236312100016 PM 16376499 ER PT J AU Frontera, WR Fuhrer, MJ Jette, AM Chan, L Cooper, RA Duncan, PW Kemp, JD Ottenbacher, KJ Peckham, PH Roth, EJ Tate, DG AF Frontera, Walter R. Fuhrer, Marcus J. Jette, Alan M. Chan, Leighton Cooper, Rory A. Duncan, Pamela W. Kemp, John D. Ottenbacher, Kenneth J. Peckham, P. Hunter Roth, Elliot J. Tate, Denise G. TI Rehabilitation medicine summit: building research capacity Executive Summary SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Editorial Material AB The general objective of the "Rehabilitation Medicine Summit: Building Research Capacity" was to advance and promote research in medical rehabilitation by making recommendations to expand research capacity. The five elements of research capacity that guided the discussions were: 1) researchers; 2) research culture, environment, and infrastructure; 3) funding; 4) partnerships; and 5) metrics. The 100 participants included representatives of professional organizations, consumer groups, academic departments, researchers, governmental funding agencies, and the private sector. The small group discussions and plenary sessions generated an array of problems, possible solutions, and recommended actions. A post-Summit, multi-organizational initiative is called to pursue the agendas outlined in this report (see Additional File 1). C1 Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Boston, MA 02115 USA. Natl Inst Hlth, Bethesda, MD USA. Boston Univ, Boston, MA 02215 USA. Univ Washington, Seattle, WA 98195 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Florida, Gainesville, FL USA. Powers Pyles Sutter & Verville PC, Washington, DC USA. Univ Texas Galveston, Med Branch, Galveston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Rehabil Inst Chicago, Chicago, IL 60611 USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Frontera, WR (reprint author), Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Boston, MA 02115 USA. EM wfrontera@partners.org; fuhrerm@mail.nih.gov; ajette@bu.edu; leighton@u.washington.edu; rcooper@pitt.edu; pwduncan@phhp.ufl.edu; john.kemp@ppsv.com; kottenba@utmb.edu; pxp2@case.edu; ejr@northwestern.edu; dgtate@umich.edu OI Jette, Alan/0000-0002-2117-9973 NR 3 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD JAN 3 PY 2006 VL 3 AR 1 DI 10.1186/1743-0003-3-1 PG 6 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA 235FC UT WOS:000251217900001 PM 16390550 ER PT J AU Park, JH Aravind, L Wolff, EC Kaevel, J Kim, YS Park, MH AF Park, JH Aravind, L Wolff, EC Kaevel, J Kim, YS Park, MH TI Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: A HEAT-repeat-containing metalloenzyme SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE eukaryotic initiation factor 5A; hypusine; YJR070C ID INITIATION-FACTOR 5A; YEAST SACCHAROMYCES-CEREVISIAE; BIOCHEMICAL GENOMICS APPROACH; CELL VIABILITY; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; SWISS-MODEL; IN-VIVO; HYPUSINE; SYNTHASE AB The eukaryotic initiation factor 5A (eIF5A), a factor essential for eukaryotic cell proliferation, is the only cellular protein containing the polyamine-derived amino acid hypusine [N-epsilon-(4-amino-2-hydroxybutyl)lysine]. Hypusine is formed in a posttranslational modification that involves two sequential enzymatic steps catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase (DOHH). By screening a Saccharomyces cerevisiae GST-ORF library for expression of DOHH activity, we have cloned YJR070C as the gene encoding DOHH and identified the human homolog DOHH gene, HLRC1. Purified recombinant yeast and human DOHH enzymes effectively catalyzed hydroxylation of the deoxyhypusine residue in the eIF5A intermediate. Overexpression of human DOHH along with eIF5A precursor and deoxyhypusine synthase was require for overproduction of mature, hypusine-containing eIF5A in 293 and other mammalian cells. The Saccharomyces cerevisiae strain with deletion of YJR070C contained only deoxyhypusine but no hypusine, indicating that YJR070C was the single DOHH gene in this organism. One highly conserved DOHH homolog gene is found in a variety of eukaryotes from yeast to human. Sequence and structural analyses reveal that DOHH belongs to a family of HEAT-repeat-containing proteins, consisting of eight tandem repeats of an a-helical pair (HEAT motif) organized in a symmetrical dyad. The predicted structure is unrelated to the double-stranded beta-helix type structures of the Fe(II)- and 2-oxoacid-dependent dioxygenases, such as collagen prolyl or lysyl hydroxylases. However, metal coordination sites composed of four strictly conserved histidine-glutamate sequences were identified, suggesting that DOHH enzymes have convergently evolved an iron-dependent hydroxylation mechanism. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Park, MH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. EM mhpark@nih.gov FU Intramural NIH HHS [Z99 DE999999] NR 41 TC 84 Z9 90 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 JAN 3 PY 2006 VL 103 IS 1 BP 51 EP 56 DI 10.1073/pnas.0509348102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 003JL UT WOS:000234677800011 PM 16371467 ER PT J AU Woo, JH Liu, YY Neville, DM AF Woo, JH Liu, YY Neville, DM TI Minimization of aggregation of secreted bivalent anti-human T cell immunotoxin in Pichia pastoris bioreactor culture by optimizing culture conditions for protein secretion SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE Pichia pastoris; protein secretion; protein aggregation; recombinant bivalent immunotoxin; shearing force; foam formation ID YEAST ENDOPLASMIC-RETICULUM; SINGLE-CHAIN IMMUNOTOXIN; DIPHTHERIA-TOXIN; GROWTH-HORMONE; FRAGMENT; FORMULATIONS; STABILITY; EFFICACY; METHANOL; MUTANTS AB In a bioreactor culture of genetically engineered Pichia pastoris secreting a bivalent immunotoxin, 64% of the secreted immunotoxin was present in aggregate forms and this resulted in a loss of bioactivity. Biochemical analyses of the secreted immunotoxin and an in vitro aggregation study using purified monomeric immunotoxin suggested that aggregation was primarily an extracellular event. By employing limited methanol feeding at 0.75 ml min(-1) per 101 initial medium, oxygen consumption was reduced, permitting a lowering of the bioreactor agitation speed from 800 to 400 rpm. By increasing the anti-foam reagent to 0.6 ml(-1), the thickness of the air/liquid interfacial foam layer was reduced by 80%. These steps reduced the immunotoxin aggregates from 64% to 5%. Consequently immunotoxin purification yield was increased from 53.0% to 73.8%. Simultaneously this methodology enhanced immunotoxin secretion to 120 mg l(-1) at 163 h of methanol induction in a toxin resistant production strain. We conclude that minimizing shearing force and reducing the air/liquid interfacial foam area are crucial factors in reducing hydrophobic protein aggregation upon secretory expression in yeast bioreactor cultures. Published by Elsevier B.V. C1 NIMH, Sect Biophys Chem, Mol Biol Lab, Bethesda, MD 20892 USA. RP Woo, JH (reprint author), Texas A&M Univ, Syst Hlth Sci Ctr, Scott & White Mem Hosp, Canc Res Inst,Coll Med, 5701 S Airport Rd, Temple, TX 76502 USA. EM jwoo@swmail.sw.org NR 26 TC 18 Z9 19 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 J9 J BIOTECHNOL JI J. Biotechnol. PD JAN 2 PY 2006 VL 121 IS 1 BP 75 EP 85 DI 10.1016/j.jbiotec.2005.07.004 PG 11 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 998BD UT WOS:000234292000008 PM 16107287 ER PT J AU Hwang, K Scripture, CD Gutierrez, M Kummar, S Figg, WD Sparreboom, A AF Hwang, K Scripture, CD Gutierrez, M Kummar, S Figg, WD Sparreboom, A TI Determination of the heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin in plasma by liquid chromatography-electrospray mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE 17-DMAG; LC/MS; plasma; pharmacokinetics; cancer ID PHASE-I; 17-(DIMETHYLAMINOETHYLAMINO)-17-DEMETHOXYGELDANAMYCIN; PHARMACOKINETICS; GELDANAMYCIN; NSC-707545; MICE AB A rapid method was developed for the quantitative determination of the novel heat shock protein 90 inhibitor, 17-dimethylarminoethylamino-17-demethoxygeldanamycin (17-DMAG; NSC707545), in human plasma. Calibration curves were constructed, and were analyzed using a weight factor proportional to the nominal concentration. Sample pretreatment involved a one-step extraction with ethyl acetate of 0.5-ml samples. The analysis was performed in the range of 1-100 ng/ml on a column (75 mm x 2.1 mm internal diameter with 3.5 mu m C 18 particle size), using 55% methanol in water containing formic acid as the mobile phase. The column effluent was monitored by mass spectrometry with positive electrospray ionization. The values for precision and accuracy were always < 8% and < 10% relative error, respectively. The method was successfully applied to examine the pharmacokinetics of 17-DMAG in a cancer patient. Published by Elsevier B.V. C1 NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Ctr Canc Res, Med Oncol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 FU Intramural NIH HHS NR 13 TC 8 Z9 8 U1 0 U2 0 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 JAN 2 PY 2006 VL 830 IS 1 BP 35 EP 40 DI 10.1016/j.jchromb.2005.10.019 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 003GM UT WOS:000234669800006 PM 16260191 ER PT J AU Jiang, S Lai, CC Kelley, JA Roller, PP AF Jiang, S Lai, CC Kelley, JA Roller, PP TI A practical synthesis of fully protected L-gamma-carboxyglutamic acid SO TETRAHEDRON LETTERS LA English DT Article DE L-gamma-carboxyglutamic acid; aldol condensation; D-Garner's aldehyde; stereoselective synthesis ID CYCLIC PEPTIDE ANTAGONISTS; GRB2-SH2 DOMAIN; ANNONACEOUS ACETOGENINS; GLUTAMIC-ACID; AMINO-ACIDS; DERIVATIVES; MIMICRY; GLA AB We have developed a new synthetic route for the preparation of Fmoc protected L-gamma-carboxyglutamic acid in 60% overall yield (> 99% ee) via a six-step synthesis from D-Garner's aldehyde. An aldol condensation and the selective cleavage of the acetonide protective group are key steps. Published by Elsevier Ltd. C1 NCI, CCR, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Roller, PP (reprint author), NCI, CCR, Med Chem Lab, NIH, Frederick, MD 21702 USA. EM proll@helix.nih.gov NR 24 TC 2 Z9 2 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JAN 2 PY 2006 VL 47 IS 1 BP 23 EP 25 DI 10.1016/j.tetlet.2005.10.121 PG 3 WC Chemistry, Organic SC Chemistry GA 995IB UT WOS:000234092900004 ER PT S AU Mao, S Xu, Z Tjahjadi, T Thoma, GR AF Mao, Song Xu, Zheng Tjahjadi, Tardi Thoma, George R. BE Tang, YY Wang, SP Lorette, G Yeung, DS Yan, H TI Logical entity recognition in multi-style document page images SO 18TH INTERNATIONAL CONFERENCE ON PATTERN RECOGNITION, VOL 1, PROCEEDINGS SE International Conference on Pattern Recognition LA English DT Proceedings Paper CT 18th International Conference on Pattern Recognition (ICPR 2006) CY AUG 20-24, 2006 CL Hong Kong, PEOPLES R CHINA SP IAPR, CAA, Hong Kong Baptist Univ AB Logical entity recognition in document page images is the essential part of a document image analysis system. A heterogeneous collection of document pages usually has many layout styles. Features extracted from same logical entities in different styles may have very different values and vice versa. Therefore, logical entity classifiers learned from a training set of multi-style document pages may not be reliable due to possible feature overlap of different logical entities in different styles. In this paper, we propose a novel method in which style information is used in both logical entity classifier training and recognition phases. In the training phase, training data are first classified into distinct styles, and a dedicated Support Vector Machine (SVM) is then learned for each style. In the recognition phase, the style of a new document page image is first identified and its logical entities are then recognized using corresponding SVM. We show in our experiments that the use of the style information significantly improves the accuracy of logical entity recognition in multi-style document page images. C1 [Mao, Song; Thoma, George R.] US Natl Lib Med, Bethesda, MD 20894 USA. [Xu, Zheng; Tjahjadi, Tardi] Univ Warwick, Sch Engn, Coventry CV4 7AL, W Midlands, England. RP Mao, S (reprint author), US Natl Lib Med, Bethesda, MD 20894 USA. EM smao@mail.nih.gov; Zheng.Xu@warwick.ac.uk; T.Tjahjadi@warwick.ac.uk; gthoma@mail.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 1051-4651 BN 0-7695-2521-0 J9 INT C PATT RECOG PY 2006 BP 876 EP + PG 2 WC Computer Science, Artificial Intelligence SC Computer Science GA BFB27 UT WOS:000240678200211 ER PT S AU Franaszek, M Summers, RM AF Franaszek, Marek Summers, Ronald M. BE Lee, DJ Nutter, B Antani, S Mitra, S Archibald, J TI Asymmetric affinity in fuzzy connectedness segmentation for oral contrast-enhanced CT colonography SO 19TH IEEE INTERNATIONAL SYMPOSIUM ON COMPUTER-BASED MEDICAL SYSTEMS, PROCEEDINGS SE IEEE International Symposium on Computer-Based Medical Systems LA English DT Proceedings Paper CT 19th IEEE Symposium on Computer-Based Medical Systems CY JUN 22-23, 2006 CL Salt Lake City, UT SP IEEE Comp Soc, TCCM, Texas Tech Univ Coll Engn, Brigham Young Univ ID VIRTUAL COLONOSCOPY; POLYPS; COLON AB In oral contrast-enhanced CT colonography, patients are given barium- or iodine-containing solutions to drink to tag out remnants of stool and residual fluid in the colon. Frequently, residual fecal matter absorbs more tagging material and appears much brighter on CT images than surrounding opacified fluid. This may cause even advanced segmentation procedures, like fuzzy connectedness, to miss local regions of colonic lumen. This in turn leads to spurious deformations of the reconstructed colonic wall and impairs interpretation. We show that these problems may be avoided when the properly designed asymmetric affinities are used for segmenting air- and fluid-filled parts of the colon. After this improvement, the segmented volume does not contain holes of missed regions and resulting colonic surface is smooth and free from undesired distortion. C1 [Franaszek, Marek; Summers, Ronald M.] NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Franaszek, M (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. FU Intramural Research Program of the NIH; Warren Grant Magnuson Clinical Center FX This research was supported by the Intramural Research Program of the NIH, Warren Grant Magnuson Clinical Center. NR 15 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2372-9198 J9 COMP MED SY PY 2006 BP 419 EP + DI 10.1109/CBMS.2006.49 PG 3 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BFB38 UT WOS:000240724000070 ER PT S AU Yao, J Antani, S Long, R Thoma, G Zhang, Z AF Yao, Jian Antani, Sameer Long, Rodney Thoma, George Zhang, Zhongfei BE Lee, DJ Nutter, B Antani, S Mitra, S Archibald, J TI Automatic medical image annotation and retrieval using SECC SO 19TH IEEE INTERNATIONAL SYMPOSIUM ON COMPUTER-BASED MEDICAL SYSTEMS, PROCEEDINGS SE IEEE International Symposium on Computer-Based Medical Systems LA English DT Proceedings Paper CT 19th IEEE Symposium on Computer-Based Medical Systems CY JUN 22-23, 2006 CL Salt Lake City, UT SP IEEE Comp Soc, TCCM, Texas Tech Univ Coll Engn, Brigham Young Univ AB The demand for automatically annotating and retrieving medical images is growing faster than ever In this paper, we present a novel medical image annotation method based on the proposed Semantic Error-Correcting output Codes (SECC). With this annotation method, we present a new semantic image retrieval method, which exploits the high level semantic similarity. For example, a user may query the system using an image of arm while he/she expects images of hand This cannot be realized by traditional retrieval methods. The experimental results on the IMAGECLEF 2005 annotation data set clearly show the strength and the promise of the presented methods. C1 [Yao, Jian; Zhang, Zhongfei] SUNY Binghamton, Dept Comp Sci, Binghamton, NY 13902 USA. [Antani, Sameer; Long, Rodney; Thoma, George] Natl Lib Med, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Yao, J (reprint author), SUNY Binghamton, Dept Comp Sci, Binghamton, NY 13902 USA. EM jyao@binghamton.edu; santani@mail.nih.gov; rlong@mail.nih.gov; gthoma@mail.nih.gov; zzhang@binghamton.edu OI Antani, Sameer/0000-0002-0040-1387 FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). NR 7 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2372-9198 J9 COMP MED SY PY 2006 BP 820 EP + PG 3 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BFB38 UT WOS:000240724000136 ER PT S AU Long, LR Antani, S Jeronimo, J Schiffman, M Bopf, M Neve, L Cornwell, C Budihas, SR Thoma, GR AF Long, L. Rodney Antani, Sameer Jeronimo, Jose Schiffman, Mark Bopf, Mike Neve, Leif Cornwell, Carl Budihas, Scott R. Thoma, George R. BE Lee, DJ Nutter, B Antani, S Mitra, S Archibald, J TI Technology for medical education, research, and disease screening by exploitation of biomarkers in a large collection of uterine cervix images SO 19TH IEEE INTERNATIONAL SYMPOSIUM ON COMPUTER-BASED MEDICAL SYSTEMS, PROCEEDINGS SE IEEE International Symposium on Computer-Based Medical Systems LA English DT Proceedings Paper CT 19th IEEE Symposium on Computer-Based Medical Systems CY JUN 22-23, 2006 CL Salt Lake City, UT SP IEEE Comp Soc, TCCM, Texas Tech Univ Coll Engn, Brigham Young Univ AB The Communications Engineering Branch of the National Library of Medicine is collaborating with the National Cancer Institute (NCI) in developing applications for medical education, research, and disease screening for precancer detection in the uterine cervix. These applications include (1) expert marking/labeling of tissue regions, (2) Web viewing/interpretation of histology images, (3) image database/retrieval, and (4) training/testing in clinical image interpretation. Initial NCI studies have been conducted in expert cervicography marking and histology evaluation. We are working toward making cervix images searchable by content-based image retrieval (CBIR). Image pre-processing to remove specular reflection artifacts has achieved 90% success (120 images). Similar results have been obtained for automated location of cervix regions, using Gaussian Mixture Modeling (GMM) with Lab color and one geometric feature. We describe initial classification experiments to discriminate clinically significant tissue, using RGB, HSV Lab, and YCbCr color models, texture measures, and GMM, Fuzzy C-means, and deterministic annealing algorithms. C1 [Long, L. Rodney] NIH, Bethesda, MD 20894 USA. [Antani, Sameer] Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Long, LR (reprint author), NIH, Bethesda, MD 20894 USA. EM rlong@mail.nih.gov OI Antani, Sameer/0000-0002-0040-1387 FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). NR 11 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2372-9198 J9 COMP MED SY PY 2006 BP 826 EP + DI 10.1109/CBMS.2006.154 PG 3 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BFB38 UT WOS:000240724000137 ER PT S AU Kim, J Le, DX Thoma, GR AF Kim, Jongwoo Le, Daniel X. Thoma, George R. BE Lee, DJ Nutter, B Antani, S Mitra, S Archibald, J TI Automatic extraction of bibliographic information from biomedical online journal articles using a string matching algorithm SO 19TH IEEE INTERNATIONAL SYMPOSIUM ON COMPUTER-BASED MEDICAL SYSTEMS, PROCEEDINGS SE IEEE International Symposium on Computer-Based Medical Systems LA English DT Proceedings Paper CT 19th IEEE Symposium on Computer-Based Medical Systems CY JUN 22-23, 2006 CL Salt Lake City, UT SP IEEE Comp Soc, TCCM, Texas Tech Univ Coll Engn, Brigham Young Univ AB A system has been developed to extract bibliographic data (grant numbers and databank accession numbers) from online biomedical journal articles for the National Library of Medicine's MEDLINE (R) database. Rule-based algorithms and a string matching algorithm are proposed to extract the bibliographic data from HTML-formatted articles. Experiments conducted with 411 medical articles from 73 journal issues show an accuracy exceeding 96%. C1 [Kim, Jongwoo; Le, Daniel X.; Thoma, George R.] Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Kim, J (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM jongkim@mail.nih.gov; danle@mail.nih.gov; gthoma@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). NR 10 TC 0 Z9 0 U1 0 U2 1 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2372-9198 J9 COMP MED SY PY 2006 BP 905 EP + PG 3 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BFB38 UT WOS:000240724000149 ER PT B AU Van Uitert, R Bitter, I Summers, RM AF Van Uitert, R. Bitter, I. Summers, R. M. GP IEEE TI Detection of colon wall outer boundary and segmentation of the colon wall based on level set methods SO 2006 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Vols 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Sci ID CT COLONOGRAPHY; VIRTUAL COLONOSCOPY; POLYP DETECTION AB Virtual colonoscopy (VC) has become a more prevalent and accepted method to diagnosis colorectal cancer. An essential element to detecting cancerous poly s using VC in. p conjunction with computer-aided detection is the accurate segmentation of the colon wall. While the inner boundary of the colon wall, the lumen-mucosal boundary, has often been the focus of previous colon segmentation work, detection of the outer wall, the serosal tissue boundary, allows for the segmentation of the colon wall, which is useful in determining both potential polyps, muscular hypertrophy and diverticulitis of the colon. Unfortunately, automatic determination of the outer colon wall position often is difficult due to the low contrast between CT allenuation values of the colon wall and the surrounding fat tissue. We have developed a level set based method to determine from a CT colonography (CTC) scan the location of the colon serosal tissue boundary. After determining this location, the algorithm segments the entire colon wall at subvoxel accurate precision. The algorithm has been validated on several CTC datasets. C1 NCI, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Van Uitert, R (reprint author), NCI, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 506 EP 509 PG 4 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284700125 ER PT B AU Ozarslan, E Basser, PJ Shepherd, TM Thelwall, PE Vemuri, BC Blackband, SJ AF Ozarslan, Evren Basser, Peter J. Shepherd, Timothy M. Thelwall, Peter E. Vemuri, Baba C. Blackband, Stephen J. GP IEEE TI Characterization of anomalous diffusion from MR signal may be a new probe to tissue microstructure SO 2006 28TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Soc ID FIELD-GRADIENT SPECTROSCOPY; FRACTAL NETWORKS; SPIN ECHOES; NMR; ATTENUATION AB Observation of translational self-diffusion of water molecules using magnetic resonance (AIR) techniques has proven to be a powerful means to probe tissue microstructure. The collected MR signal depends on experimentally controllable parameters as well as the descriptors of tissue geometry. In order to obtain the latter, one needs to employ accurate models to characterize the dependence of the signal on the varied experimental parameters. In this work, a simple model describing diffusion in disordered media and fractal spaces is shown to describe the diffusion-time dependence of the diffusion attenuated MR signal obtained from biological specimens successfully. The model enables one to quantify the evolution of the average water displacement probabilities in terms of two exponents-d(w) and d(s). The experiments performed on excised human neural tissue samples and human red blood cell ghosts indicate that these two parameters are sensitive to tissue microstructure. Therefore, it may be possible to use the proposed scheme to generate novel contrast mechanism for classifying and segmenting tissue. C1 NIH, NICHD, LIMB, Sect Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. RP Ozarslan, E (reprint author), NIH, NICHD, LIMB, Sect Tissue Biophys & Biomimet, Bldg 10, Bethesda, MD 20892 USA. EM evren@helix.nih.gov RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 NR 15 TC 1 Z9 2 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 2256 EP 2259 PG 4 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284707098 ER PT B AU Amyot, F Small, A Gandjbakhche, AH AF Amyot, Franck Small, Alex Gandjbakhche, Amir H. GP IEEE TI Stochastic modeling of tumor induced angiogenesis in a heterogeneous medium, the extracellular matrix SO 2006 28TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Soc DE angiogenesis; cell migration; apoptosis; percolation; vascular network ID ENDOTHELIAL-CELLS; MIGRATION; ADHESION; NEOVASCULARIZATION AB Angiogenesis, the formation of blood vessels, is a process whereby capillary sprout are formed in response to external stimuli. We model the tumor induced angiogenesis on keys events such of migratory response of endothelial cells to tumor angiogenic factors and the local cell interaction with the extracellular matrix (ECM). We consider the ECM medium as a statistically inhomogeneous two-phase random medium. Numerical simulations of the model are presented. Using this model, we will compare the influence of ECM distribution on vascular network formation. By developing mathematical models of angiogenesis, we hope to provide a deeper insight into the mechanisms underlying angiogenesis. C1 [Amyot, Franck; Small, Alex; Gandjbakhche, Amir H.] NIH, NICHD, Lab Integrat & Med Biophys, Bldg 10, Bethesda, MD 20892 USA. RP Amyot, F (reprint author), NIH, NICHD, Lab Integrat & Med Biophys, Bldg 10, Bethesda, MD 20892 USA. EM amyotf@mail.nih.gov NR 22 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 2624 EP + PG 2 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284703025 ER PT B AU Gong, T Zhu, YT Xuan, JH Li, H Clarke, R Hoffman, EP Wang, Y AF Gong, Ting Zhu, Yitan Xuan, Jianhua Li, Huai Clarke, Robert Hoffman, Eric P. Wang, Yue GP IEEE TI Latent variable and nICA modeling of pathway gene module composite SO 2006 28TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Soc DE non-negative ICA; latent variable model; gene clustering; module discovery; microarray data analysis ID INDEPENDENT COMPONENT ANALYSIS; EXPRESSION; MICROARRAYS AB In this paper, we report a new gene clustering approach - non-negative independent component analysis (nICA) - for microarray data analysis. Due to positive nature of molecular expressions, nICA fits better to the reality of corresponding putative biological processes. In conjunction with nICA model, VIsual Statistical Data Analyzer (VISDA) is applied to group genes into modules in the latent variable space. The experimental results show that significant enrichment of gene annotations within clusters can be obtained. C1 [Gong, Ting; Zhu, Yitan; Xuan, Jianhua; Wang, Yue] Virginia Polytech Inst & State Univ, Dept ECE, Arlington, VA USA. [Xuan, Jianhua] Catholic Univ Amer, Dept EECS, Washington, DC 20064 USA. [Li, Huai] Natl Inst Hlth, RRB, Bioinformat Unit, Baltimore, MD 21201 USA. [Clarke, Robert] Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. [Hoffman, Eric P.] Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC USA. RP Gong, T (reprint author), Virginia Polytech Inst & State Univ, Dept ECE, Arlington, VA USA. FU National Institutes of Health [CA109872, NS29525, EB00830, CA096483]; Department of Defense [BC030280] FX This work was partially supported by the National Institutes of Health under Grants (CA109872, NS29525, EB00830, and CA096483) and the Department of Defense under Grant (BC030280). NR 9 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 2883 EP + PG 2 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284703090 ER PT B AU Lima, EG Bian, L Mauck, RL Byers, BA Tuan, RS Ateshian, GA Hung, CT AF Lima, Eric G. Bian, Liming Mauck, Robert L. Byers, Benjamin A. Tuan, Rocky S. Ateshian, Gerard A. Hung, Clark T. GP IEEE TI The effect of applied compressive loading on tissue-engineered cartilage constructs cultured with TGF-beta 3 SO 2006 28TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Soc ID TRANSFORMING GROWTH FACTOR-BETA-1; ARTICULAR-CARTILAGE; SULFATED GLYCOSAMINOGLYCANS; ORGAN-CULTURES; FACTOR-BETA; BIOSYNTHESIS; PROTEOGLYCAN; CHONDROCYTES; PROTEIN C1 [Lima, Eric G.; Bian, Liming; Ateshian, Gerard A.; Hung, Clark T.] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Mauck, Robert L.] Univ Penn, Philadelphia, PA 19104 USA. [Byers, Benjamin A.; Tuan, Rocky S.] Cartilage Biol & Orthopaed Branch, NIAMS, NIH, Bethesda, MD 20892 USA. RP Hung, CT (reprint author), Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. EM cth6@columbia.edu FU NIH [AR46568] FX This work was supported in part by the NIH grant AR46568. NR 27 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 6150 EP + PG 3 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284707035 ER PT B AU Kriegeskorte, N Bandettini, P AF Kriegeskorte, Nikolaus Bandettini, Peter GP IEEE TI The neuroscientific exploitation of high-resolution functional magnetic resonance imaging SO 2006 28TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Soc ID CORTICAL SURFACE; BRAIN ACTIVITY; VISUAL-CORTEX; FMRI DATA; PATTERNS; REPRESENTATIONS; OBJECTS; STATES; ACTIVATION; MACHINE AB High-resolution functional magnetic resonance imaging (hi-res fMRI) promises to bridge the gap between the macro- and the microview of brain function afforded by conventional neuroimaging and invasive cell recording, respectively. Hi-res fMRI (nominal voxel sizes <= (2 mm)(3)) is robustly achievable in human studies today using widely available clinical 3-Tesla scanners. However, the neuroscientific exploitation of the greater spatial detail poses three challenges: (1) Fine-scale neuronal activity patterns are inaccurately depicted in the hemodynamic images obtained. (2) Single small voxels yield very noisy measurements. (3) For groups of subjects, the interindividual correspondency mapping is unknown at the fine scale of millimeters. Here we argue that these challenges can be met by abstracting from the regional fitic-scale activity patterns themselves and instead asking how well they distinguish the experimental conditions. C1 [Kriegeskorte, Nikolaus; Bandettini, Peter] NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. RP Kriegeskorte, N (reprint author), NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 6228 EP + PG 3 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284707057 ER PT B AU Vogel, A Dasgeb, B Hassan, M Amyot, F Chemomordik, V Tao, Y Demos, SG Wyvile, K Aleman, K Little, R Yarchoan, R Gandjbakhche, AH AF Vogel, Abby Dasgeb, Bahar Hassan, Moinuddin Amyot, Franck Chemomordik, Victor Tao, Yang Demos, Stavros G. Wyvile, Kathleen Aleman, Karen Little, Richard Yarchoan, Robert Gandjbakhche, Amir H. GP IEEE TI Using quantitative imaging techniques to assess vascularity in AIDS-related Kaposi's sarcoma SO 2006 28TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Soc DE multi-modality imaging; laser Doppler imaging; thermography; near-infrared spectroscopy ID ENDOTHELIAL GROWTH-FACTOR; REFLECTANCE SPECTRA; SKIN AB Three quantitative and non-invasive techniques were used to monitor angiogenesis in Kaposi's sarcoma patients: thermography, laser Doppler imaging (LDI), and near-infrared spectroscopy. Before and after combination cytotoxic and antiangiogenesis therapy, blood volume, oxygenated hemoglobin, temperature, and blood flow were analyzed. These three techniques are objective, easy to perform, and appear to be very sensitive in assessing changes in the lesions upon administration of therapy. C1 [Vogel, Abby; Dasgeb, Bahar; Hassan, Moinuddin; Amyot, Franck; Chemomordik, Victor; Gandjbakhche, Amir H.] NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. [Vogel, Abby; Tao, Yang] Univ Maryland, Dept Biol Resources Engn, College Pk, MD 20742 USA. [Demos, Stavros G.] Lawrence Livermore Natl Lab, Livermore, CA 94550 USA. [Wyvile, Kathleen; Aleman, Karen; Little, Richard; Yarchoan, Robert] NCI, NIH, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Vogel, A (reprint author), NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM vogelab@mail.nih.gov NR 16 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 6242 EP + PG 2 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284707061 ER PT B AU de Zwart, JA van Gelderen, P Duyn, JH AF de Zwart, Jacco A. van Gelderen, Peter Duyn, Jeff H. GP IEEE TI Receive coil arrays and parallel imaging for functional magnetic resonance imaging of the human brain SO 2006 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Vols 1-15 LA English DT Proceedings Paper CT 28th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 30-SEP 03, 2006 CL New York, NY SP IEEE Engn Med & Biol Sci ID SPATIAL HARMONICS SMASH; HIGH-RESOLUTION; SIMULTANEOUS ACQUISITION; FIELD-STRENGTH; ACOUSTIC NOISE; PRESTO-SENSE; DATA SETS; 7 T; MRI; BOLD AB The use of multiple small receive coils has several advantages over a single larger (e.g. birdcage) coil. With an array of small receive coils, image signal-to-noise ratio (SNR) can be optimized throughout the field-of-view and the image acquisition process can be accelerated by use of parallel imaging (PI) techniques. In an accelerated PI experiment, data are undersampled during acquisition. Subsequently, artifact-free images are reconstructed based on the independently acquired signals from the elements of the receive coil array. PI techniques have recently been applied to functional MRI (fMRI) experiments of the human brain in order to improve the performance of commonly used single-shot techniques like echo-planar imaging (EPI). Potential benefits of PI-fMRI include the reduction of geometrical distortions due to oftresonance signals, the reduction of signal-loss in areas with substantial signal inhomogeneity, increases of the spatial and temporal resolution of the fMRI experiment and reduction of gradient acoustic noise. Although the loss in SNR, inherent to PI, can severely compromise MRI image quality, the effect on fMRi quality, which is governed by the temporal stability of the signal, is often not as severe. On the other hand, PlIs potential in mitigating the often severe image artifacts present in singleshot FMRI render it an important tool, in particular with the recent surge in high field MRI applications. C1 NIH, Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, Adv MRI Sect, Bethesda, MD 20892 USA. RP de Zwart, JA (reprint author), NIH, Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, Adv MRI Sect, Bldg 10, Bethesda, MD 20892 USA. NR 28 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0032-4 PY 2006 BP 6318 EP 6321 PG 4 WC Engineering, Biomedical SC Engineering GA BGI19 UT WOS:000247284707082 ER PT S AU Ozarslan, E Shepherd, TM Vemuri, BC Blackband, SJ Mareci, TH AF Ozarslan, Evren Shepherd, Timothy M. Vemuri, Baba C. Blackband, Stephen J. Mareci, Thomas H. GP IEEE TI A nonparametric reconstruction and its matrix implementation for the diffusion orientation transform (DOT) SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE ID TENSOR; MRI AB The diffusion orientation transform (DOT) enables the computation of orientational probability profiles from high angular resolution diffusion-weighted magnetic resonance imaging data, making it possible to map connectivity information even in regions with complex microstructure. The initial formulation of the DOT has yielded probabilities in terms of spherical harmonics. In this paper, an alternative reconstruction method is introduced that makes it possible to directly compute the probabilities. The proposed reconstruction effectively combines the reconstruction and surface estimation steps in the visualization of the probability profiles. A matrix formulation is proposed that simplifies the implementation of the DOT method. The simulation as well as experimental results demonstrate the accuracy and robustness of the approach. C1 [Ozarslan, Evren] NICHD, LIMB, STBB, NIH, Bethesda, MD USA. [Ozarslan, Evren; Vemuri, Baba C.] Dept Comp Sci & Informat Engn, Gainesville, FL USA. [Shepherd, Timothy M.; Blackband, Stephen J.] Dept Neurosci, Gainesville, FL USA. [Mareci, Thomas H.] Dept Biochem & Mol Biol, Gainesville, FL USA. RP Ozarslan, E (reprint author), NICHD, LIMB, STBB, NIH, Bethesda, MD USA. RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU National Institutes of Health [R01-NS42075, R01-NS36992, P41-RR16105]; National High Magnetic Field Laboratory (NHMFL), Tallahassee FX This research was supported by the National Institutes of Health Grants R01-NS42075, R01-NS36992 and P41-RR16105, and the National High Magnetic Field Laboratory (NHMFL), Tallahassee. NR 10 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 85 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000022 ER PT S AU Pickalov, V Basser, PJ AF Pickalov, Valery Basser, Peter J. GP IEEE TI 3-D tomographic reconstruction of the average propagator from MRI data SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE ID GENERALIZED DIFFUSION; TENSOR; SPACE; NMR; ANGLE AB The measurement of the 3-D "average propagator", P(r), from diffusion-weighted (DW) NMR or MRI data has been a "holy grail" in materials science and biomedicine, as P(r) provides detailed microstructural information, particularly about restriction, without assuming an underlying diffusion model. While Callaghan proposed a 3-D Fourier transform relationship between P(r) and the DW signal attenuation, E(q) [1], using it to measure P(r) from E(q) data is not currently feasible biologically or clinically, owing to the staggering amount of DW data required. To address this problem, we propose that computed tomography principles can be applied to reconstruct P(r) from DW signals. Moreover, this reconstruction can be performed efficiently using many fewer DW E(q) data as compared to conventional 3-D q-space MRI [1] or Diffusion Spectrum Imaging (DSI) [2] by employing a priori information about E(q) and P(r). C1 [Pickalov, Valery] Russian Acad Sci, Inst Theoret & Appl Mech, Novosibirsk 630090, Russia. [Basser, Peter J.] NIH, STBB LIMB NICHD, Bethesda, MD USA. RP Pickalov, V (reprint author), Russian Acad Sci, Inst Theoret & Appl Mech, Novosibirsk 630090, Russia. RI Pickalov, Valery/K-3848-2012; Pickalov, Valery/B-7262-2008 OI Pickalov, Valery/0000-0001-9362-6966; Pickalov, Valery/0000-0001-9362-6966 NR 19 TC 6 Z9 6 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 710 EP + PG 3 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000179 ER PT S AU Subramanian, S Johnson, CA Devasahayam, N Matsumoto, KI Hyodo, F Cook, J Krishna, MC AF Subramanian, Sankaran Johnson, Calvin A. Devasahayam, Nallathamby Matsumoto, Ken-ichiro Hyodo, Fuminori Cook, John Krishna, Murali C. GP IEEE TI In vivo spectral-spatial imaging for oxygen mapping using single-point, time-domain Electron Paramagnetic Resonance SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE AB Electron Paramagnetic Resonance (EPR) is a spectroscopic technique that detects and characterizes molecules with unpaired electrons (i.e., free radicals). Although it is closely related to nuclear magnetic resonance (NMR) spectroscopy, EPR is still under development as an imaging modality. Unlike other imaging modalities, EPR is able to take direct measurements of tissue oxygen concentration in a manner that is not dependent on complex biological processes such as ligand binding specificity or tracer metabolism. We describe the use of single-point imaging (SPI) in radiofrequency, Fourier-transform EPR. We present the techniques for performing oxygen imaging using EPR with phantoms and in vivo. We present results from a study in which the two mouse legs (one normal and the other with tumor) were imaged over time as the mouse breathed alternately air, carbogen (95% O-2, 5% CO2), and then air again. The reconstructed images demonstrate that the SPI EPR imaging technique readily distinguishes between the normal and tumor legs and can track the changes in tissue oxygen concentration in response to percentage of oxygen in breathing gas. C1 [Subramanian, Sankaran; Devasahayam, Nallathamby; Matsumoto, Ken-ichiro; Hyodo, Fuminori; Cook, John; Krishna, Murali C.] NCI, Radiat Biol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. [Johnson, Calvin A.] NIH, Ctr Informat Technol, Div Comp Biosci, Bethesda, MD 20892 USA. RP Subramanian, S (reprint author), NCI, Radiat Biol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. FU NIH; NCI; CIT FX This work was supported by the Intramural Research Program in NIH, NCI, and CIT. The authors appreciate the valuable contributions of Anthony Iano-Fletcher and Tin Phuc Doan . NR 3 TC 1 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1096 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000277 ER PT S AU Orlov, N Johnston, J Macura, T Wolkow, C Goldberg, I AF Orlov, N. Johnston, J. Macura, T. Wolkow, C. Goldberg, I. GP IEEE TI Pattern recognition approaches to compute image similarities: Application to age related morphological change SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE AB We are studying the genetic influence on rates of age related muscle degeneration in C. elegans. For this, we built pattern recognition tools to calculate a morphological score given an image of muscle tissue. We collected images of body wall muscle and the terminal bulb of the pharynx at four different ages. We extracted a large set of image descriptors (signatures) from both sets of images. Two different methods were used for pattern recognition within these two datasets. Both methods compute a single number that correlates with the known age of the sample. Because aging is a continuous process, the relative age computed from images of tissue can be viewed as a measure of image similarity. The techniques employed and validated in this work can be generalized to other areas such as image-based queries. C1 [Orlov, N.; Johnston, J.; Macura, T.; Wolkow, C.; Goldberg, I.] NIA, NIH, Genet Lab, Suite 3000,333 Cassell Dr, Baltimore, MD 21224 USA. RP Orlov, N (reprint author), NIA, NIH, Genet Lab, Suite 3000,333 Cassell Dr, Baltimore, MD 21224 USA. EM norlov@nih.gov; siah@nih.gov; tmacura@nih.gov; wolkowca@grc.nia.nih.gov; igg@nih.gov NR 9 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1152 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000291 ER PT S AU Badano, A Sempau, J AF Badano, Aldo Sempau, Josep GP IEEE TI Parallel Monte Carlo simulation of imaging systems SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE AB We describe the modification of MANTIS for parallel simulation of imaging systems that can simultaneously utilize x-ray, charged particle, or optical photon primary and secondary radiation. We report on the computational aspects of the parallelization, on the generation of independent random number sub-sequences, and on the parallel timing performance. C1 [Badano, Aldo] NIBIB, CDRH Lab Assessment Med Imaging Syst, Rockville, MD 20857 USA. [Sempau, Josep] Univ Politecn Cataluna, Inst Energy Technol, Barcelona 08028, Spain. RP Badano, A (reprint author), NIBIB, CDRH Lab Assessment Med Imaging Syst, Rockville, MD 20857 USA. EM aldo.badano@fda.hhs.gov; josep.sempau@upc.es RI Sempau, Josep/J-7834-2013; OI Sempau, Josep/0000-0002-2754-7685; badano, aldo/0000-0003-3712-6670 FU Fondo de Investigacion Sanitaria; Spanish Ministerio de Sanidad y Consumo [FIS 03/0980] FX The authors thank Frank Samuelson (CDRH, FDA) for providing Perl scripts for parallel execution, and Nick Petrick (CDRH, FDA) for management of the cluster. JS acknowledges partial financial support from the Fondo de Investigacion Sanitaria of the Spanish Ministerio de Sanidad y Consumo, project number FIS 03/0980. NR 10 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1216 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000307 ER PT S AU Kyprianou, IS Paquerault, S Gallas, BD Badano, A Park, S Myers, KJ AF Kyprianou, Iacovos S. Paquerault, Sophie Gallas, Brandon D. Badano, Aldo Park, Subok Myers, Kyle J. GP IEEE TI Framework for determimation of geometric parameters of a cone beam CT scanner for measuring the system response function and improved object reconstruction SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE AB We present a mathematical framework for image-based geometric calibration of flat-panel, cone-beam, circular-trajectory based Computed-Tomography (CT) scanners. The geometric parameters are used to determine the system response function corrected for misalignment. The system response function includes the shift-variant detector point response, and the location dependent response of the focal-spot. We propose a technique to automatically determine the relative geometric parameters of the scanner by including calibration marks on the object container. These parameters include the relative location and orientation of the detector and location of the focal-spot with respect to the object at each scanner rotation angle. The estimated parameters are used to determine the system response function and perform object reconstruction. Results of the system response function and object reconstruction with misalignment correction are provided, showing relevance of our mathematical framework and proposed technique. C1 [Kyprianou, Iacovos S.; Paquerault, Sophie; Gallas, Brandon D.; Badano, Aldo; Park, Subok; Myers, Kyle J.] US FDA, Lab Assessment Med Imaging Syst, CDRH, NIBIB, Rockville, MD 20857 USA. RP Kyprianou, IS (reprint author), US FDA, Lab Assessment Med Imaging Syst, CDRH, NIBIB, Rockville, MD 20857 USA. EM iacovos.kyprianou@fda.hhs.gov OI Gallas, Brandon/0000-0001-7332-1620; badano, aldo/0000-0003-3712-6670 NR 6 TC 4 Z9 4 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1248 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000315 ER PT S AU Hochheiser, H Goldberg, IG AF Hochheiser, Harry Goldberg, Ilya G. GP IEEE TI Quasi-hierarchical, interactive navigation of images and meta-data in the Open Microscopy Environment SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE AB Databases containing microscopy images and associated meta-data present users with the challenge of interpreting complex interrelationships between objects. Effective user tools must support users in the task of interactively navigating and filtering data to identify items of interest and understand relationships between these items. In the Open Microscopy Environment, these relationships often take the form of "quasi-hierarchies": tree-like structures where nodes can have multiple parents. A compact browser for selecting items in a quasi-hierarchy illustrates relationships between items and supports selection of items from any level in the quasi-hierarchy. Multiple interoperating browsers for orthogonal quasi-hierarchies can be coordinated to form a powerful filtering interface useful for simultaneously drilling down from multiple perspectives. These hierarchy browsers can be combined with information-specific displays, including summary views containing detailed information about image sets and image thumbnail displays. C1 [Hochheiser, Harry; Goldberg, Ilya G.] NIA, Image Informat & Comp Biol Unit, Genet Lab, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. RP Hochheiser, H (reprint author), NIA, Image Informat & Comp Biol Unit, Genet Lab, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM hsh@nih.gov; igg@nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1272 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000321 ER PT S AU Samuelson, FW Petrick, N AF Samuelson, Frank W. Petrick, Nicholas GP IEEE TI Comparing image detection algorithms using resampling SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE ID PERFORMANCE; OBSERVER; CURVES AB The ability to statistically compare the performance of two computer detection (CD) or computer-aided detection (CAD) algorithms is fundamental for the development and evaluation of medical image analysis tools. Automated detection tools for medical imaging are commonly characterized using free-response receiver operating characteristic (FROC) methods. However, few statistical tools are currently available to estimate statistical significance when comparing two FROC performance curves. In this study, we introduce a permutation and a bootstrap resampling method for the nonparametric estimation of statistical significance of performance metrics when comparing two FROC curves. We then provide an initial validation of the proposed methods using an area under the FROC performance metric and a simulation model for creating CD algorithm prompts. Validation is based on a comparison of the Type I error rate produced by two statistically identical CD algorithms. The results of 104 Monte Carlo trials show that both the permutation and bootstrap methods produced excellent estimates of the expected Type I error rate. C1 [Samuelson, Frank W.; Petrick, Nicholas] US FDA, Ctr Devives & Radiol Hlth, NIBIB CDRH Joint Lab Assessment Med Imaging Syst, HFZ 140,12720 Twinbrook Pkwy, Rockville, MD USA. RP Samuelson, FW (reprint author), US FDA, Ctr Devives & Radiol Hlth, NIBIB CDRH Joint Lab Assessment Med Imaging Syst, HFZ 140,12720 Twinbrook Pkwy, Rockville, MD USA. EM Frank.Samuelson@fda.hhs.gov NR 8 TC 33 Z9 33 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1312 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000331 ER PT S AU Yuan, XH Chi-Fishman, G AF Yuan, Xiaohui Chi-Fishman, Gloria GP IEEE TI Volumetric tongue reconstruction by fusing bidirectional MR images SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE ID INTERPOLATION METHODS AB In this paper we describe a 3D reconstruction method that fuses sagittal and coronal images. In our volumetric MRI study of the human tongue, multiple contiguous slices were acquired in the sagittal and the coronal planes. A bidirectional linear interpolation method was developed that estimated target voxel value using weighted neighbor pixels in the bounding slices. A wavelet fusion method was then employed to integrate prominent subband coefficients. Experiments have shown that fusion-based image reconstruction reduced artifacts, greatly improved reconstruction accuracy, and enhanced image details. Our method casts new light on MR imaging and image processing that demand high resolution in a short acquisition time. C1 [Yuan, Xiaohui; Chi-Fishman, Gloria] NIH, Phys Disabil Branch, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Yuan, XH (reprint author), NIH, Phys Disabil Branch, Dept Rehabil Med, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1352 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000341 ER PT S AU Johnston, J Nagaraja, A Hochheiser, H Goldberg, I AF Johnston, Josiah Nagaraja, Arpun Hochheiser, Harry Goldberg, Ilya GP IEEE TI A flexible framework for web interfaces to image databases: Supporting user-defined ontologies and links to external databases SO 2006 3RD IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE AB Vocabularies to describe research findings are needed to effectively use scientific databases. As understanding of data evolves, scientists need tools for extending the vocabularies. A web-based framework addresses these issues in the context of a microscopy image database. It allows definition of simple vocabularies and automatic generation of tools for annotating, displaying, and searching with this vocabulary. The resulting displays of annotated data can be linked to external data sources such as model organism databases. A case study involving publication of in-situ hybridization images cross-linked with the Mouse Gene Index is described, along with preliminary steps in extending the framework to handle fully structured ontologies. C1 [Johnston, Josiah; Nagaraja, Arpun; Hochheiser, Harry; Goldberg, Ilya] NIA, Image Informat & Computat Biol Unit, Genet Lab, IRP,NIH, Suite 3000,333 Cassell Dr, Baltimore, MD 21224 USA. RP Johnston, J (reprint author), NIA, Image Informat & Computat Biol Unit, Genet Lab, IRP,NIH, Suite 3000,333 Cassell Dr, Baltimore, MD 21224 USA. EM siah@nih.gov; arpun@mit.edu; hsh@nih.gov; igg@nih.gov NR 4 TC 4 Z9 4 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-0-7803-9576-3 J9 I S BIOMED IMAGING PY 2006 BP 1380 EP + PG 2 WC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BFS91 UT WOS:000244446000348 ER PT B AU Subramaniam, S AF Subramaniam, Sriram GP IEEE TI Bridging the imaging gap in nanobiology with three-dimensional electron microscopy SO 2006 Bio- Micro- and Nanosystems Conference LA English DT Proceedings Paper CT Bio- Micro- and Nanosystems Conference CY JAN 15-18, 2006 CL San Francisco, CA C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0056-0 PY 2006 BP 37 EP 37 DI 10.1109/BMN.2006.330920 PG 1 WC Nanoscience & Nanotechnology SC Science & Technology - Other Topics GA BGE52 UT WOS:000246328700025 ER PT B AU Yao, J Zhang, ZF Antani, S Long, R Thoma, G AF Yao, Jian Zhang, Zhongfei Antani, Sameer Long, Rodney Thoma, George GP IEEE TI Automatic medical image annotation and retrieval using SEMI-SECC SO 2006 IEEE INTERNATIONAL CONFERENCE ON MULTIMEDIA AND EXPO - ICME 2006, VOLS 1-5, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Conference on Multimedia and Expo (ICME 2006) CY JUL 09-12, 2006 CL Toronto, CANADA SP IEEE, IEEE Circuits & Syst Soc, IEEE Commun Soc, IEEE Comp Soc, IEEE Signal Proc Soc AB The demand for automatically annotating and retrieving medical images is growing faster than ever. In this paper, we present a novel medical image retrieval method based on SEMI-supervised Semantic Error-Correcting output Codes (SEMI-SECC). The experimental results on IMAGECLEF 2005 [1] annotation data set clearly show the strength and the promise of the presented methods. C1 [Yao, Jian; Zhang, Zhongfei] SUNY Binghamton, Dept Comp Sci, Binghamton, NY 13902 USA. [Antani, Sameer; Long, Rodney; Thoma, George] Natl Inst Hlth, Natl Lib Med, Bethesda, MD 20894 USA. RP Yao, J (reprint author), SUNY Binghamton, Dept Comp Sci, Binghamton, NY 13902 USA. OI Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health (NIH); NIntramural Research Program oational Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported in part by the f the National Institutes of Health (NIH), NIntramural Research Program oational Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). NR 6 TC 0 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0366-0 PY 2006 BP 2005 EP 2008 DI 10.1109/ICME.2006.262606 PG 4 WC Computer Science, Artificial Intelligence; Imaging Science & Photographic Technology; Telecommunications SC Computer Science; Imaging Science & Photographic Technology; Telecommunications GA BFY01 UT WOS:000245384804063 ER PT B AU Hua, JP Balagurunathan, Y Chen, YD Lowey, D Bittner, ML Xiong, ZX Suh, E Dougherty, ER AF Hua, Jianping Balagurunathan, Yoganand Chen, Yidong Lowey, Daines Bittner, Michael L. Xiong, Zixiang Suh, Edward Dougherty, Edward R. GP IEEE TI Effect of normalization on microarray-based classification SO 2006 IEEE INTERNATIONAL WORKSHOP ON GENOMIC SIGNAL PROCESSING AND STATISTICS LA English DT Proceedings Paper CT IEEE International Workshop on Genomic Signal Processing and Statistics CY MAY 28-30, 2006 CL College Stn, TX SP IEEE AB When using cDNA microarrays, normalization to correct biases is a common preliminary step before carrying out any data analysis, its objective being to reduce the systematic variations between the arrays. The biases are due to various systematic factors - scanner setting, amount of mRNA in the sample pool, and dye response characteristics between the channels. Since expression-based phenotype classification is a major use of microarrays, it is important to evaluate microarray normalization procedures relative to classification. Using a model-based approach, we model the systemic-error process to generate synthetic gene-expression values with known ground truth. Three normalization methods and three classification rules are then considered. Our simulation shows that normalization can have a significant benefit for classification under difficult experimental conditions. C1 [Hua, Jianping; Balagurunathan, Yoganand; Lowey, Daines; Bittner, Michael L.; Suh, Edward; Dougherty, Edward R.] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Chen, Yidong] NIH, NHGRI, Bethesda, MD USA. [Xiong, Zixiang; Dougherty, Edward R.] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA. RP Hua, JP (reprint author), Translat Genom Res Inst, Phoenix, AZ 85004 USA. EM jhua@tgen.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0384-4 PY 2006 BP 7 EP + DI 10.1109/GENSIPS.2006.353129 PG 2 WC Computer Science, Interdisciplinary Applications; Engineering, Electrical & Electronic; Statistics & Probability SC Computer Science; Engineering; Mathematics GA BGN05 UT WOS:000248551800004 ER PT B AU Singh, S Chen, HIH Hsu, FH Tsai, MH Chuang, EY Chen, YD AF Singh, Sher Chen, Hung-I Harry Hsu, Fang-Han Tsai, Mong-Hsun Chuang, Eric Y. Chen, Yidong GP IEEE TI Development of a normalization algorithm for array comparative genomic hybridization SO 2006 IEEE INTERNATIONAL WORKSHOP ON GENOMIC SIGNAL PROCESSING AND STATISTICS LA English DT Proceedings Paper CT IEEE International Workshop on Genomic Signal Processing and Statistics CY MAY 28-30, 2006 CL College Stn, TX SP IEEE ID CGH DATA AB Genomic instability is one of fundamental factors in tumorigenesis and tumor progression. Many studies have demonstrated that copy-number abnormailities at the DNA level are important in the pathogenesis of cancer. Array Comparative Genomic Hybridization (aCGH), developed based on expression microarray technology, can reveal the chromosomal aberrations it? segmental copy at a high-resolution. However, due to the nature of aCGH, many standard expression data processing tools, such as data normalization, often failed to yield satisfactory results. The proposed stud), demonstrated a novel aCGH normalization procedure, which provides all accurate aCGH data normalization by utilizing the dependency of neighboring probe measurements in aCGH experiments. To facilitate the study, we have developed a Hidden Markov Model (HMM) to simulate a series of aCGH experiment with random DNA copy number alteration. Furthermore, based on this new development, we will establish a user friendly web system in order to provide convenient aCGH analysis. C1 [Singh, Sher; Chen, Hung-I Harry; Hsu, Fang-Han; Tsai, Mong-Hsun; Chuang, Eric Y.] Natl Taiwan Univ, Ctr Genom Med, Dept Elect Engn Bioinformat & Biostat Core, Taipei 106, Taiwan. [Chen, Yidong] Natl Inst Hith, Canc Genet Branch, Bethesda, MD 20892 USA. [Chen, Yidong] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. RP Singh, S (reprint author), Natl Taiwan Univ, Ctr Genom Med, Dept Elect Engn Bioinformat & Biostat Core, Taipei 106, Taiwan. NR 7 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0384-4 PY 2006 BP 49 EP + DI 10.1109/GENSIPS.2006.353150 PG 2 WC Computer Science, Interdisciplinary Applications; Engineering, Electrical & Electronic; Statistics & Probability SC Computer Science; Engineering; Mathematics GA BGN05 UT WOS:000248551800025 ER PT S AU Wang, SM Ledden, PJ Duyn, JH AF Wang, Shumin Ledden, Patrick J. Duyn, Jeff H. GP IEEE TI SNR of multi-channel RF coil arrays for high-field brain functional magnetic resonance imaging SO 2006 IEEE MTT-S INTERNATIONAL MICROWAVE SYMPOSIUM DIGEST, VOLS 1-5 SE IEEE MTT-S International Microwave Symposium LA English DT Proceedings Paper CT IEEE MTT-S International Microwave Symposium CY JUN 11-16, 2006 CL San Francisco, CA SP IEEE MTTS DE magnetic resonance imaging; RF coils; signal-to-noise ratio ID ELECTROMAGNETIC SCATTERING AB We performed a comparative study of the signal-to-noise ratio (SNR) of 16-channel and 4-channel radio-frequency (RF) coil arrays for magnetic resonance imaging (MRI) at 7.0 Tesla (300 MHz). The Combined-Field Integral-Equation (CFIE) method was employed to resolve the fine geometric structures in coil arrays. The numerical approach is verified by MRI experiments of the 16-channel array at first and then applied to the 4-channel array. Results show that increasing the number of channels greatly benefits the average SNR and its coverage. C1 [Wang, Shumin; Duyn, Jeff H.] NINDS, LFMI, NIH, Bethesda, MD 20892 USA. [Ledden, Patrick J.] Nova Med Inc, Williamstown, MA USA. RP Wang, SM (reprint author), NINDS, LFMI, NIH, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 0149-645X BN 978-0-7803-9541-1 J9 IEEE MTT S INT MICR PY 2006 BP 1758 EP + DI 10.1109/MWSYM.2006.249385 PG 2 WC Engineering, Electrical & Electronic SC Engineering GA BFS69 UT WOS:000244379004024 ER PT S AU Green, MV Seidel, J Xi, WZ Choyke, PL AF Green, Michael V. Seidel, Jurgen Xi, Wenze Choyke, Peter L. GP IEEE TI Light Decay Time/Gain Shift in a LaBr(3):Ce/LYSO:Ce Phoswich Detector SO 2006 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD, VOL 1-6 SE IEEE Nuclear Science Symposium Conference Record LA English DT Proceedings Paper CT 15th International Workshop on Room-Temperature Semiconductor X- and Gamma-Ray Detectors/ 2006 IEEE Nuclear Science Symposium CY OCT 29-NOV 04, 2006 CL San Diego, CA SP IEEE AB We have found that scintillation light emitted by LaBr(3) is totally absorbed as it passes through an optically joined piece of LYSO on its way to the photocathode of a photomultiplier tube. However, scintillation events in the LaBr(3) reappear as events with a scintillation light decay time similar to the native light decay time of LYSO (40.8 ns) and much greater than the native light decay time of LaBr(3) (17.8 ns). The conversion of LaBr(3) events to scintillations with this new light decay time occurs, for this experimental arrangement, with about 41% gain efficiency, i.e. the photopeak energy is approximately 41% that of the LaBr(3) coupled directly to the phototube. The light decay time of LYSO events is unchanged in this phoswich configuration and the gain for LYSO scintillation events is moderately reduced to about 70% of the value measured with the LYSO crystal alone. Here, we describe experiments that confirm and characterize this effect. We conclude with an explanation consistent with these results. C1 [Green, Michael V.; Seidel, Jurgen; Xi, Wenze; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Green, MV (reprint author), NCI, Mol Imaging Program, Bethesda, MD 20892 USA. EM mg572k@nih.gov; js313j@nih.gov; xiwen@mail.nih.gov; pchoyke@mail.nih.gov NR 5 TC 1 Z9 1 U1 1 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3654 BN 978-1-4244-0561-9 J9 IEEE NUCL SCI CONF R PY 2006 BP 1915 EP 1918 DI 10.1109/NSSMIC.2006.354269 PG 4 WC Engineering, Electrical & Electronic; Physics, Applied SC Engineering; Physics GA BUC53 UT WOS:000288875601203 ER PT B AU Harry, GJ d'Hellencourt, CL Wine, R Aoyama, M AF Harry, G. J. d'Hellencourt, C. Lefebvre Wine, R. Aoyama, M. BE Tabira, T Yamamura, T Kira, J TI Tumor necrosis factor receptor in trimethyltin-induced dentate granule cell death SO 8TH INTERNATIONAL CONGRESS OF NEUROIMMUNOLOGY LA English DT Proceedings Paper CT 8th International Congress of Neuroimmunology CY OCT 15-19, 2006 CL Nagoya, JAPAN ID INJURY RESPONSE; MESSENGER-RNA; FACTOR-ALPHA; HIPPOCAMPAL; SUPERFAMILY; PATHWAYS; TARGET AB Using the trimethyltin (TMT) model of hippocampal damage, we demonstrate a progression of cell responses in the dentate region including an elevation in TNF alpha, neuronal expression of TNF receptors, and microglia activation that reflect dynamic cell-cell interactions contributing to the pattern of selective neuronal death within the hippocampus. These data suggest an extrinsic receptor mediated apoptotic pathway for the death of dentate granule cells. C1 [Harry, G. J.; d'Hellencourt, C. Lefebvre; Wine, R.; Aoyama, M.] Natl Inst Environm Hlth Sci, Neurobiol Lab, Neurotoxicol Grp, NIH,DHHS, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, Neurotoxicol Grp, NIH,DHHS, Res Triangle Pk, NC 27709 USA. NR 13 TC 0 Z9 0 U1 0 U2 1 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 978-88-7587-324-0 PY 2006 BP 303 EP 308 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA BGZ92 UT WOS:000251732700061 ER PT J AU Kreitman, RJ AF Kreitman, Robert J. TI Immunotoxins for targeted cancer therapy SO AAPS JOURNAL LA English DT Review DE monoclonal antibody; CD22; CD25; interleukin; Pseudomonas; diphtheria ID RICIN-A-CHAIN; PHASE-I TRIAL; B-CELL LYMPHOMA; PSEUDOMONAS EXOTOXIN-A; ACUTE MYELOID-LEUKEMIA; NON-HODGKINS-LYMPHOMA; PLASMINOGEN-ACTIVATOR RECEPTOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; EPIDERMAL-GROWTH-FACTOR; COLONY-STIMULATING FACTOR AB Immunotoxins are proteins that contain a toxin along with an antibody or growth factor that binds specifically to target cells. Nearly all protein toxins work by enzymatically inhibiting protein synthesis. For the immunotoxin to work, it must bind to and be internalized by the target cells, and the enzymatic fragment of the toxin must translocate to the cytosol. Once in the cytosol, 1 molecule is capable of killing a cell, making immunotoxins some of the most potent killing agents. Various plant and bacterial toxins have been genetically fused or chemically conjugated to ligands that bind to cancer cells. Among the most active clinically are those that bind to hematologic tumors. At present, only 1 agent, which contains human interleukin-2 and truncated diphtheria toxin, is approved for use in cutaneous T-cell lymphoma. Another, containing an anti-CD22 Fv and truncated Pseudomonas exotoxin, has induced complete remissions in a high proportion of cases of hairy-cell leukemia. Refinement of existing immunotoxins and development of new immunotoxins are underway to improve the treatment of cancer. C1 Canc Res Ctr, Clin Immunotherapy Sect, Mol Biol Lab, Natl Canc Inst,NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), Canc Res Ctr, Clin Immunotherapy Sect, Mol Biol Lab, Natl Canc Inst,NIH, 9000 Rockville Pike,Bldg 37,Room 5124B, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU Intramural NIH HHS NR 289 TC 150 Z9 160 U1 0 U2 10 PU AMER ASSOC PHARMACEUTICAL SCIENTISTS PI ARLINGTON PA 2107 WILSON BLVD, STE 700, ARLINGTON, VA 22201-3042 USA SN 1550-7416 J9 AAPS J PY 2006 VL 8 IS 3 BP E532 EP E551 DI 10.1208/aapsj080363 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 097HM UT WOS:000241437900013 PM 17025272 ER PT J AU Qasba, PK Ramakrishnan, B Boeggeman, E AF Qasba, PK Ramakrishnan, B Boeggeman, E TI Mutant glycosyltransferases assist in the development of a targeted drug delivery system and contrast agents for MRI SO AAPS JOURNAL LA English DT Review DE mutant glycosyltransferases; linkages via glycans; glycotargeting; drug delivery systems; cross-linking MRI agents via glycans ID RECEPTOR-MEDIATED ENDOCYTOSIS; FIBROBLAST-GROWTH-FACTOR; CELL-SURFACE; DONOR SPECIFICITY; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; GALACTOSYLTRANSFERASE; GLYCOSYLATION; BINDING; RECOGNITION AB The availability of structural information on glycosyltransferases is beginning to make structure-based reengineering of these enzymes possible. Mutant glycosyltransferases have been generated that can transfer a sugar residue with a chemically reactive unique functional group to a sugar moiety of glycoproteins, glycolipids, and proteoglycans (glycoconjugates). The presence of modified sugar moiety on a glycoprotein makes it possible to link bioactive molecules via modified glycan chains, thereby assisting in the assembly of bionanoparticles that are useful for developing the targeted drug delivery system and contrast agents for magnetic resonance imaging. The reengineered recombinant glycosyltransferases also make it possible to (1) remodel the oligosaccharide chains of glycoprotein drugs, and (2) synthesize oligosaccharides for vaccine development. C1 CCRNP, Struct Glycobiol Sect, NCI Frederick, Nanobiol Program, Frederick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. RP Qasba, PK (reprint author), CCRNP, Struct Glycobiol Sect, NCI Frederick, Nanobiol Program, Bldg 469,Room 221, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU Intramural NIH HHS; PHS HHS [N01-C0-12400] NR 64 TC 6 Z9 7 U1 1 U2 5 PU AMER ASSOC PHARMACEUTICAL SCIENTISTS PI ALEXANDRIA PA 1650 KING ST, STE 200, ALEXANDRIA, VA 22314-2747 USA SN 1550-7416 J9 AAPS J PY 2006 VL 8 IS 1 BP E190 EP E195 AR UNSP 23 DI 10.1208/aapsj080123 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 032VT UT WOS:000236804800023 PM 16584127 ER PT J AU Rice, O Saintvictor, S Michaelides, M Thanos, P Gatley, SJ AF Rice, Onarae Saintvictor, Sandra Michaelides, Michael Thanos, Panayotis Gatley, Samuel John TI MicroPET investigation of chronic long-term neurotoxicity from heavy ion irradiation SO AAPS JOURNAL LA English DT Review DE microPET; FDG; neurotoxicity; radiation; brain ID POSITRON-EMISSION-TOMOGRAPHY; CENTRAL-NERVOUS-SYSTEM; COGNITIVE DYSFUNCTION; GLUCOSE-UTILIZATION; SPACE RADIATION; HUMAN-BRAIN; RATS; EXPOSURE; PARTICLE; DEFICITS AB Positron emission tomography (PET) permits imaging of the regional biodistribution and pharmacokinetics of compounds labeled with short-lived positron-emitting isotopes. It has enabled evaluation of neurochemical systems in the living human brain, including effects of toxic substances. MicroPET devices allow studies of the rat brain with a spatial resolution of similar to 2 mm. This is much poorer resolution than obtained using ex vivo autoradiography. However, animals need not be euthanized before imaging, so repeat studies are possible. This in principle allows the effects of toxic insults to be followed over the lifetime of an individual animal. We used microPET to evaluate brain metabolic effects of irradiation with high-energy heavy ions (HZE radiation), a component of the space radiation environment, on regional glucose metabolism. A significant fraction of neurons would be traversed by these densely ionizing particles during a Mars mission, and there is a need to estimate human neurological risks of prolonged voyages beyond the geomagnetosphere. Rats were irradiated with 56 Fe (600 MeV/n) ions at doses up to 240 cGy. At 9 months post-irradiation we did not detect alterations in regional accumulation of the glucose analog [F-18]2-deoxy-2-fluoro-D-glucose. This may indicate that damage to the brain from HZE particles is less severe than feared. However, because radiation-induced alterations in some behaviors have been documented, it may reflect insensitivity of baseline cerebral glucose metabolism to HZE radiation. These studies will facilitate design of future studies of chronic, long-term exposure to both therapeutic and abused drugs using microPET. C1 Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA. Brookhaven Natl Lab, Ctr Translat Neuroimaging, Upton, NY 11973 USA. Brookhaven Natl Lab, NIAAA, Behav Neuropharmacol & Neuroimaging Lab Neuroimag, Intramural NIAAA Program, Upton, NY 11973 USA. RP Gatley, SJ (reprint author), Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. EM s.gatley@neu.edu RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 NR 47 TC 1 Z9 2 U1 0 U2 0 PU AMER ASSOC PHARMACEUTICAL SCIENTISTS PI ARLINGTON PA 2107 WILSON BLVD, STE 700, ARLINGTON, VA 22201-3042 USA SN 1550-7416 J9 AAPS J PY 2006 VL 8 IS 3 BP E508 EP E514 DI 10.1208/aapsj080360 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 097HM UT WOS:000241437900010 PM 17025269 ER PT J AU Rutter, JL AF Rutter, JL TI Symbiotic relationship of pharmacogenetics and drugs of abuse SO AAPS JOURNAL LA English DT Review DE pharmacogenomics; addiction; treatment; psychiatric disease; SNP ID MU-OPIOID-RECEPTOR; SINGLE-NUCLEOTIDE POLYMORPHISM; NICOTINE REPLACEMENT THERAPY; CORONARY HEART-DISEASE; SMOKING-CESSATION; CIGARETTE-SMOKING; METHAMPHETAMINE ABUSE; ASSOCIATION ANALYSIS; GENETIC ASSOCIATION; AFRICAN-AMERICANS AB Pharmacogenetics/pharmacogenomics is the study of how genetic variation affects pharmacology, the use of drugs to treat disease. When drug responses are predicted in advance, it is easier to tailor medications to different diseases and individuals. Pharmacogenetics provides the tools required to identify genetic predictors of probable drug response, drug efficacy, and drug-induced adverse events-identifications that would ideally precede treatment decisions. Drug abuse and addiction genetic data have advanced the field of pharmacogenetics in general. Although major findings have emerged, pharmacotherapy remains hindered by issues such as adverse events, time lag to drug efficacy, and heterogeneity of the disorders being treated. The sequencing of the human genome and high-throughput technologies are enabling pharmacogenetics to have greater influence on treatment approaches. This review highlights key studies and identifies important genes in drug abuse pharmacogenetics that provide a basis for better diagnosis and treatment of drug abuse disorders. C1 NIDA, NIH, DHHS, Bethesda, MD 20892 USA. RP Rutter, JL (reprint author), NIDA, NIH, DHHS, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM jrutter@mail.nih.gov NR 105 TC 22 Z9 22 U1 5 U2 8 PU AMER ASSOC PHARMACEUTICAL SCIENTISTS PI ALEXANDRIA PA 1650 KING ST, STE 200, ALEXANDRIA, VA 22314-2747 USA SN 1550-7416 J9 AAPS J PY 2006 VL 8 IS 1 BP E174 EP E184 AR UNSP 21 DI 10.1208/aapsj080121 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 032VT UT WOS:000236804800021 PM 16584126 ER PT J AU Woods, AS Jackson, SN AF Woods, Amina S. Jackson, Shelley N. TI Brain tissue lipidomics: Direct probing using matrix-assisted laser desorption/ionization mass spectrometry SO AAPS JOURNAL LA English DT Review DE lipids; MALDI; in situ analysis; tissue ID MALDI-TOF MS; PHOSPHOLIPID-COMPOSITION; RAT-BRAIN; DESORPTION; GANGLIOSIDES; GLYCOSYLPHOSPHATIDYLINOSITOL; PHOSPHATIDYLCHOLINES; LOCALIZATION; PROTEINS; DISEASE AB Lipidomics is the new frontier in biomolecular structural studies. Not only are lipids the main components in membranes that define the contours of the cell and its organelles, but they are also used for storage. Lipids form stable noncovalent complexes with proteins as well as with many drugs. Lipids are a storage depot for drugs and certain types of organic molecules. To study lipid composition and distribution, complex and time-consuming techniques are used. However, recent advances in mass spectrometry, mainly matrix-assisted laser desorption/ionization (MALDI) have made it possible to directly probe tissues to study structural components, as well as for the localization of drugs. Direct tissue imaging is a powerful tool as it gives a more complete and accurate structural picture and can trace and follow where drugs localize in tissue with minimal anatomical disruption and a minimum of manipulations. Hence, we believe that in addition to its accuracy and efficiency, this new approach will lead to a better understanding of physiological processes as well as the pathophysiology of disease. C1 Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov NR 33 TC 74 Z9 78 U1 3 U2 26 PU AMER ASSOC PHARMACEUTICAL SCIENTISTS PI ALEXANDRIA PA 1650 KING ST, STE 200, ALEXANDRIA, VA 22314-2747 USA SN 1550-7416 J9 AAPS J PY 2006 VL 8 IS 2 BP E391 EP E395 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 062WE UT WOS:000238975700019 PM 16796390 ER PT J AU Schreier, AA Wilson, K Resnik, D AF Schreier, AA Wilson, K Resnik, D TI Academic research record-keeping: Best practices for individuals, group leaders, and institutions SO ACADEMIC MEDICINE LA English DT Article AB During the last half of the 20th century, social and technological changes in academic research groups have challenged traditional research record-keeping practices, making them either insufficient or obsolete. New practices have developed but standards (best practices) are still evolving. Based on the authors' review and analysis of a number of sources, they present a set of systematically compiled best practices for research record-keeping for academic research groups. These best practices were developed as an adjunct to a research project on research ethics aimed at examining the actual research record-keeping practices of active academic scientists and their impact on research misconduct inquiries. The best practices differentiate and provide separate standards for three different levels within the university: the individual researcher, the research group leader, and the department/institution. They were developed using a combination of literature reviews, surveys of university integrity officials, focus groups of active researchers, and inspection of university policies on research record-keeping. The authors believe these best practices constitute a "snapshot" of the current normative standards for research records within the academic research community. They are offered as ethical and practical guidelines subject to continuing evolution and not as absolute rules. They may be especially useful in training the next generation of researchers. C1 E Carolina Univ, Div Res & Grad Studies, Greenville, NC 27858 USA. E Carolina Univ, Dept Sociol, Greenville, NC USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Schreier, AA (reprint author), E Carolina Univ, Div Res & Grad Studies, Greenville, NC 27858 USA. EM schreiera@mail.ecu.edu FU Intramural NIH HHS [ZIA ES102646-01] NR 25 TC 8 Z9 8 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JAN PY 2006 VL 81 IS 1 BP 42 EP 47 DI 10.1097/00001888-200601000-00010 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 998IY UT WOS:000234313200008 PM 16377817 ER PT J AU Schwab, JM Berg, JM AF Schwab, John M. Berg, Jeremy M. TI Chemical biology and the NIH SO ACS CHEMICAL BIOLOGY LA English DT Editorial Material C1 NIH, Div Pharmacol Physiol & Biol Chem, Bethesda, MD 20892 USA. NIH, Natl Inst Gen Med Sci, Bethesda, MD 20892 USA. RP Schwab, JM (reprint author), NIH, Div Pharmacol Physiol & Biol Chem, Bethesda, MD 20892 USA. EM schwabj@nigms.nih.gov OI Berg, Jeremy/0000-0003-3022-0963 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PY 2006 VL 1 IS 1 BP 9 EP 9 DI 10.1021/cb0600052 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 082XE UT WOS:000240419700009 ER PT J AU Ron, D Hinnebusch, AG AF Ron, David Hinnebusch, Alan G. TI Targeting transtation in hypoxic tumors SO ACS CHEMICAL BIOLOGY LA English DT Editorial Material ID MESSENGER-RNA TRANSLATION; PROTEIN-SYNTHESIS; STRESS-RESPONSE; ER STRESS; KINASE; EIF2-ALPHA; GROWTH; GCN2; PERK AB Recent insight into how mammalian cells adapt their translational machinery to hypoxic conditions raises the possibility of targeting components of the regulatory networks involved to selectively inhibit metabolically compromised tumor Celts and possibly manipulate a broad range of other physiological processes. C1 NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA. NYU, Sch Med, Dept Med, New York, NY 10016 USA. NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Ron, D (reprint author), NYU, Sch Med, Skirball Inst Biomol Med, 550 1St Ave, New York, NY 10016 USA. EM ron@saturn.med.nyu.edu; ahinnebusch@nih.gov NR 20 TC 3 Z9 3 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PY 2006 VL 1 IS 3 BP 145 EP 148 DI 10.1021/cb600125y PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 083OQ UT WOS:000240468500008 PM 17163661 ER PT J AU Chiosis, G Neckers, L AF Chiosis, Gabriela Neckers, Len TI Tumor selectivity of Hsp90 inhibitors: The explanation remains elusive SO ACS CHEMICAL BIOLOGY LA English DT Article ID MOLECULAR CHAPERONE HSP90; IN-VITRO; ONCOGENIC TRANSFORMATION; GELDANAMYCIN DERIVATIVES; BIOLOGICAL EVALUATION; HEAT-SHOCK-PROTEIN-90; CANCER; ANSAMYCINS; RADICICOL; PROTEINS AB Two recent papers attempt to solve both the tumor selectivity and the in vivo tumor accumulation profiles seen with some Hsp90 inhibitors. They spotlight the higher affinity of ansamycins' hydroquinone over the quinone form for Hsp90 and further discuss its possible contribution to ansamycins' tumor selectivity. C1 Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10021 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Chiosis, G (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM chiosisg@mskcc.org NR 49 TC 95 Z9 96 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PY 2006 VL 1 IS 5 BP 279 EP 284 DI 10.1021/cb600224w PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 083OS UT WOS:000240468700015 PM 17163756 ER PT J AU Rundle, NT Nelson, J Flory, MR Joseph, J Th'ng, J Aebersold, R Dasso, M Andersen, RJ Roberge, M AF Rundle, Natalie T. Nelson, Jim Flory, Mark R. Joseph, Jomon Th'ng, John Aebersold, Ruedi Dasso, Mary Andersen, Raymond J. Roberge, Michel TI An ent-kaurene that inhibits mitotic chromosome movement and binds the kinetochore protein Ran-binding protein 2 SO ACS CHEMICAL BIOLOGY LA English DT Article ID SMALL-MOLECULE INHIBITOR; CENP-E; NUCLEAR-PORE; AURORA-B; ANAPHASE; CHECKPOINT; ALIGNMENT; IDENTIFICATION; MITOSIS; CELLS AB Using a chemical genetics screen, we have identified ent-15-oxokaurenoic acid (EKA) as a chemical that causes prolonged mitotic arrest at a stage resembling prometaphase. EKA inhibits the association of the mitotic motor protein centromeric protein E with kinetochores and inhibits chromosome movement. Unlike most antimitotic agents, EKA does not inhibit the polymerization or depolymerization of tubulin. To identify EKA-interacting proteins, we used a cell-permeable biotinylated form that retains biological activity to isolate binding proteins from living cells. Mass spectrometric analysis identified six EKA-binding proteins, including Ran-binding protein 2, a kinetochore protein whose depletion by small interfering RNA causes a similar mitotic arrest phenotype. C1 Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada. Univ British Columbia, Dept Earth Ocean Sci, Vancouver, BC V6T 1Z1, Canada. Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. Inst Syst Biol, Seattle, WA 98103 USA. NICHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. NW Ontario Reg Canc Ctr, Canc Care Ontario, Thunder Bay, ON P7B 6V4, Canada. RP Roberge, M (reprint author), Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada. EM michelr@interchange.ubc.ca OI Dasso, Mary/0000-0002-5410-1371 FU Intramural NIH HHS [Z01 HD008740-06] NR 47 TC 11 Z9 11 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PY 2006 VL 1 IS 7 BP 443 EP 450 DI 10.1021/cb600196w PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131TX UT WOS:000243894000018 PM 17168522 ER PT J AU Berg, JM AF Berg, Jeremy M. TI Opportunities for chemical biologists: A view from the National Institutes of Health SO ACS CHEMICAL BIOLOGY LA English DT Editorial Material C1 Natl Inst Gen Med Sci, Bethesda, MD 20892 USA. RP Berg, JM (reprint author), Natl Inst Gen Med Sci, 45 Ctr Dr,2As-12, Bethesda, MD 20892 USA. EM bergj@mail.nih.gov OI Berg, Jeremy/0000-0003-3022-0963 NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PY 2006 VL 1 IS 9 BP 547 EP 548 DI 10.1021/cb6003993 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131UD UT WOS:000243894700003 PM 17168545 ER PT J AU Himmel, DM Sarafianos, SG Dharmasena, S Hossain, MM McCoy-Simandle, K Ilina, T Clark, AD Knight, JL Julias, JG Clark, PK Krogh-Jespersen, K Levy, RM Hughes, SH Parniak, MA Arnold, E AF Himmel, Daniel M. Sarafianos, Stefan G. Dharmasena, Sanjeewa Hossain, Mohammed M. McCoy-Simandle, Kessler Ilina, Tatiana Clark, Arthur D., Jr. Knight, Jennifer L. Julias, John G. Clark, Patrick K. Krogh-Jespersen, Karsten Levy, Ronald M. Hughes, Stephen H. Parniak, Michael A. Arnold, Eddy TI HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site SO ACS CHEMICAL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIBODY FAB FRAGMENT; DOUBLE-STRANDED DNA; NONNUCLEOSIDE INHIBITORS; ANGSTROM RESOLUTION; RIBONUCLEASE-H; CRYSTAL-STRUCTURE; PRIMER GRIP; POSITIONAL ADAPTABILITY; CONFORMATIONAL-CHANGES AB The rapid emergence of drug-resistant variants of human immunodeficiency virus, type 1 (HIV-1), has limited the efficacy of anti-acquired immune deficiency syndrome (AIDS) treatments, and new lead compounds that target novel binding sites are needed. We have determined the 3.15 angstrom resolution crystal structure of HIV-1 reverse transcriptase (RT) complexed with dihydroxy benzoyl naphthyl hydrazone (DHBNH), an HIV-1 RT RNase H (RNH) inhibitor (RNHI). DHBNH is effective against a variety of drug-resistant HIV-1 RT mutants. While DHBNH has little effect on most aspects of RT-catalyzed DNA synthesis, at relatively high concentrations it does inhibit the initiation of RNA-primed DNA synthesis. Although primarily an RNHI, DHBNH binds > 50 angstrom away from the RNH active site, at a novel site near both the polymerase active site and the non-nucleoside RT inhibitor (NNRTI) binding pocket. When DHBNH binds, both Tyr181 and Tyr188 remain in the conformations seen in unliganded HIV-1 RT. DHBNH interacts with conserved residues (Asp186, Trp229) and has substantial interactions with the backbones of several less well-conserved residues. On the basis of this structure, we designed substituted DHBNH derivatives that interact with the NNRTI-binding pocket. These compounds inhibit both the polymerase and RNH activities of RT. C1 Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. Rutgers State Univ, BIOMAPS Inst Quantitat Biol, Piscataway, NJ 08854 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu RI Krogh-Jespersen, Karsten/A-6493-2010; OI Sarafianos, Stefan G/0000-0002-5840-154X FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [F32 AI060300, AI 27690, F32 AI 060300, R37 AI027690, R37 AI027690-18]; NIGMS NIH HHS [GM64375, P01 GM 066671, P01 GM066671, P20 GM064375] NR 51 TC 88 Z9 92 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PY 2006 VL 1 IS 11 BP 702 EP 712 DI 10.1021/cb600303y PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131UI UT WOS:000243895300016 PM 17184135 ER PT J AU Whedon, GD Rambaut, PC AF Whedon, GD Rambaut, PC TI Effects of long-duration space flight on calcium metabolism: Review of human studies from Skylab to the present SO ACTA ASTRONAUTICA LA English DT Review ID ACUTE ANTERIOR POLIOMYELITIS; RENAL STONE FORMATION; PROLONGED BED REST; INDUCED BONE LOSS; POSTMENOPAUSAL WOMEN; BIOCHEMICAL MARKERS; ANTIORTHOSTATIC HYPOKINESIA; SODIUM FLUORIDE; MINERAL BALANCE; IN-VIVO AB One of the major effects of prolonged weightlessness seen in long-duration space flights has been an extended loss of bone from the skeleton. The principal characteristics of this loss were shown in the metabolic studies carried out on the Skylab flights of 1, 2 and 3 months in 1973 and 1974. These studies now provide the background for a comprehensive review of the considerable number of subsequent calcium studies in humans during space flights from that time until the present. Because of the close similarities in pattern and degree between space flight and bed rest in effects on calcium metabolism, relevant long-term human bed rest studies have been included. An analysis is presented of the bone calcium loss data with respect to degree, duration and significance, as well as relative failure of reversibility or recovery following flights. Possible mechanisms of bone loss are discussed: the physiological condition of disuse atrophy, increase in bone resorption, decrease (later and lesser) in bone formation, decrease in intestinal calcium absorption, increase in glucocorticoids, along with the threat of urinary tract stone formation and proposed countermeasures. Considerable future research is needed, particularly on mechanisms of bone loss and on countermeasures, to be carried out on the International Space Station and via bed rest studies, before a mission to and return from Mars is undertaken. (c) 2005 Elsevier Ltd. All rights reserved. C1 Natl Inst Arthrit Diabet Digest & Kidney Dis, NIH, Bethesda, MD USA. NASA, Biomed Res, Hilo, HI 96720 USA. RP Whedon, GD (reprint author), 1290 Gulf Blvd,Apt 1802, Clearwater Beach, FL 33767 USA. EM prambaut@compuserve.com NR 110 TC 10 Z9 12 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0094-5765 J9 ACTA ASTRONAUT JI Acta Astronaut. PD JAN PY 2006 VL 58 IS 2 BP 59 EP 81 DI 10.1016/j.actaastro.2005.03.074 PG 23 WC Engineering, Aerospace SC Engineering GA 993JI UT WOS:000233950000001 ER PT J AU Ziolkowska, NE Wlodawer, A AF Ziolkowska, Natasza E. Wlodawer, Alexander TI Structural studies of algal lectins with anti-HIV activity SO ACTA BIOCHIMICA POLONICA LA English DT Review DE lectin; HIV; AIDS; topical antivirals; protein structure ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN GP120; PROTEIN CYANOVIRIN-N; CYANOBACTERIUM SCYTONEMA-VARIUM; INACTIVATING PROTEIN; CULTURED CYANOBACTERIUM; CARBOHYDRATE INTERACTIONS; RECOMBINANT PRODUCTION; CRYSTAL-STRUCTURES; BINDING LECTIN AB A number of antiviral lectins, small proteins that bind carbohydrates found on viral envelopes, are currently in pre-clinical trials as potential drugs for prevention of transmission of human immunodeficiency virus (HIV) and other enveloped viruses, such as the Ebola virus and the coronavirus responsible for severe acute respiratory syndrome (SARS). Lectins of algal origin whose antiviral properties make them candidate agents for prevention of viral transmission through topical applications include cyanovirin-N, Microcystis viridis lectin, scytovirin, and griffithsin. Although all these proteins exhibit significant antiviral activity, their structures are unrelated and their mode of binding of carbohydrates differs significantly. This review summarizes the current state of knowledge of the structures of algal lectins, their mode of binding of carbohydrates, and their potential medical applications. C1 NCI, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21701 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21701 USA. EM wlodawer@ncifcrf.gov FU Intramural NIH HHS NR 60 TC 47 Z9 47 U1 1 U2 11 PU ACTA BIOCHIMICA POLONICA PI WARSAW PA PASTEURA 3, 02-093 WARSAW, POLAND SN 0001-527X J9 ACTA BIOCHIM POL JI Acta Biochim. Pol. PY 2006 VL 53 IS 4 BP 617 EP 626 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 122PR UT WOS:000243239400001 PM 17128290 ER PT J AU Dauter, Z AF Dauter, Z TI Current state and prospects of macromolecular crystallography SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Review ID X-RAY-DIFFRACTION; 3-DIMENSIONAL FOURIER SYNTHESIS; CRYSTAL-STRUCTURE DETERMINATION; ISOMORPHOUS REPLACEMENT METHOD; ELECTRON-DENSITY MAPS; RADIATION-DAMAGE; SYNCHROTRON-RADIATION; ANOMALOUS DIFFRACTION; PROTEIN CRYSTALS; STRUCTURAL GENOMICS AB The current situation and possible future development of macromolecular crystallography are reviewed. The rapid progress and maturation of this field in recent years have to a large extent been made possible by the inspiration and generous support of several active structural genomics initiatives. Two tendencies can be currently observed: one which treats protein crystallography as a highly automatic tool for investigating various biological problems without the need to engage in the intricacies of the technique and a second approach where this method is applied to crystals of difficult, large and complex biological systems, requiring a deeper knowledge of various aspects of crystallography. In the near future it is expected that these two trends will coexist, developing in a parallel fashion. C1 NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Bldg 202,9700 S Cass Ave, Argonne, IL 60439 USA. EM dauter@anl.gov NR 180 TC 32 Z9 34 U1 1 U2 11 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2006 VL 62 BP 1 EP 11 DI 10.1107/S0907444905034050 PN 1 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 993AT UT WOS:000233925800001 PM 16369088 ER PT J AU Sekar, K Yogavel, M Gayathri, D Velmurugan, D Krishna, R Poi, MJ Dauter, Z Dauter, M Tsai, MD AF Sekar, K Yogavel, M Gayathri, D Velmurugan, D Krishna, R Poi, MJ Dauter, Z Dauter, M Tsai, MD TI Atomic resolution structure of the double mutant (K53,56M) of bovine pancreatic phospholipase A(2) SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID TRIPLE MUTANT; CRYSTAL-STRUCTURES; REFINEMENT; INTERFACE; CALCIUM AB The structure of the double mutant K53,56M has previously been refined at 1.9 angstrom resolution using room-temperature data. The present paper reports the crystal structure of the same mutant K53,56M refined against 1.1 angstrom data collected using synchrotron radiation. A total of 116 main-chain atoms from 29 residues and 44 side chains are modelled in alternate conformations. Most of the interfacial binding residues are found to be disordered and alternate conformations could be recognized. The second calcium ion-binding site residue Glu92 adopts two alternate conformations. The minor and major conformations of Glu92 correspond to the second calcium ion bound and unbound states. C1 Indian Inst Sci, Bioinformat Ctr, Bangalore 560012, Karnataka, India. Indian Inst Sci, Supercomp Educ & Res Ctr, Bangalore 560012, Karnataka, India. Univ Madras, Dept Crystallog & Biophys, Madras 600025, Tamil Nadu, India. Ohio State Univ, Dept Chem, Columbus, OH 43210 USA. Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA. Natl Canc Inst, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. Acad Sinica, Taipei 115, Taiwan. RP Sekar, K (reprint author), Indian Inst Sci, Bioinformat Ctr, Bangalore 560012, Karnataka, India. EM sekar@physics.iisc.ernet.in OI Tsai, Ming-Daw/0000-0003-1374-0414 FU NIGMS NIH HHS [GM 41788] NR 29 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD JAN PY 2006 VL 62 BP 1 EP 5 DI 10.1107/S1744309105040984 PN 1 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 996JB UT WOS:000234169100001 PM 16511247 ER EF