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排序方式: 共有317条查询结果,搜索用时 31 毫秒
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Krystle A. Lang Kuhs Mark H. Kuniholm Ruth M. Pfeiffer Sabrina Chen Seema Desai Brian R. Edlin Marion G. Peters Michael Plankey Gerald B. Sharp Howard D. Strickler Maria C. Villacres Thomas C. Quinn Stephen J. Gange Ludmila Prokunina-Olsson Ruth M. Greenblatt Thomas R. O’Brien 《PloS one》2015,10(10)
IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women’s Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)–infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV–1 and HSV–2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV–2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV–1 and 79.0% were positive for HSV–2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV–1 or HSV–2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV–2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV–2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes. 相似文献
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Babu M Díaz-Mejía JJ Vlasblom J Gagarinova A Phanse S Graham C Yousif F Ding H Xiong X Nazarians-Armavil A Alamgir M Ali M Pogoutse O Pe'er A Arnold R Michaut M Parkinson J Golshani A Whitfield C Wodak SJ Moreno-Hagelsieb G Greenblatt JF Emili A 《PLoS genetics》2011,7(11):e1002377
As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among > 235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target. 相似文献
95.
Brumshtein B Greenblatt HM Butters TD Shaaltiel Y Aviezer D Silman I Futerman AH Sussman JL 《The Journal of biological chemistry》2007,282(39):29052-29058
Gaucher disease is caused by mutations in the gene encoding acid beta-glucosidase (GlcCerase), resulting in glucosylceramide (GlcCer) accumulation. The only currently available orally administered treatment for Gaucher disease is N-butyl-deoxynojirimycin (Zavesca, NB-DNJ), which partially inhibits GlcCer synthesis, thus reducing levels of GlcCer accumulation. NB-DNJ also acts as a chemical chaperone for GlcCerase, although at a different concentration than that required to completely inhibit GlcCer synthesis. We now report the crystal structures, at 2A resolution, of complexes of NB-DNJ and N-nonyl-deoxynojirimycin (NN-DNJ) with recombinant human GlcCerase, expressed in cultured plant cells. Both inhibitors bind at the active site of GlcCerase, with the imino sugar moiety making hydrogen bonds to side chains of active site residues. The alkyl chains of NB-DNJ and NN-DNJ are oriented toward the entrance of the active site where they undergo hydrophobic interactions. Based on these structures, we make a number of predictions concerning (i) involvement of loops adjacent to the active site in the catalytic process, (ii) the nature of nucleophilic attack by Glu-340, and (iii) the role of a conserved water molecule located in a solvent cavity adjacent to the active site. Together, these results have significance for understanding the mechanism of action of GlcCerase and the mode of GlcCerase chaperoning by imino sugars. 相似文献
96.
Matthew B. Greenblatt Jung-Min Kim Hwanhee Oh Kwang Hwan Park Min-Kyung Choo Yasuyo Sano Coralee E. Tye Ziedonis Skobe Roger J. Davis Jin Mo Park Marianna Bei Laurie H. Glimcher Jae-Hyuck Shim 《The Journal of biological chemistry》2015,290(1):284-295
An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997) J. Biol. Chem. 272, 27678–27685). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38α MAPK in ectodermal appendages using K14-cre mice (p38αK14 mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel because of defects in ameloblast differentiation and activity. In the absence of p38α, expression of amelogenin and β4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38α in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38α functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38α MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel. 相似文献
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Butland G Babu M Díaz-Mejía JJ Bohdana F Phanse S Gold B Yang W Li J Gagarinova AG Pogoutse O Mori H Wanner BL Lo H Wasniewski J Christopolous C Ali M Venn P Safavi-Naini A Sourour N Caron S Choi JY Laigle L Nazarians-Armavil A Deshpande A Joe S Datsenko KA Yamamoto N Andrews BJ Boone C Ding H Sheikh B Moreno-Hagelseib G Greenblatt JF Emili A 《Nature methods》2008,5(9):789-795
Physical and functional interactions define the molecular organization of the cell. Genetic interactions, or epistasis, tend to occur between gene products involved in parallel pathways or interlinked biological processes. High-throughput experimental systems to examine genetic interactions on a genome-wide scale have been devised for Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans and Drosophila melanogaster, but have not been reported previously for prokaryotes. Here we describe the development of a quantitative screening procedure for monitoring bacterial genetic interactions based on conjugation of Escherichia coli deletion or hypomorphic strains to create double mutants on a genome-wide scale. The patterns of synthetic sickness and synthetic lethality (aggravating genetic interactions) we observed for certain double mutant combinations provided information about functional relationships and redundancy between pathways and enabled us to group bacterial gene products into functional modules. 相似文献