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Wolgemuth D.J.,Institute of Human Nutrition | Wolgemuth D.J.,Columbia University | Wolgemuth D.J.,Columbia University Medical Center
Journal of Cellular Biochemistry | Year: 2016

The expression of BRDT, a member of the BET sub-family of double bromodomain-containing proteins, is restricted to the male germ line, specifically to pachytene-diplotene spermatocytes and early spermatids. We previously showed that loss of the first bromodomain of BRDT by targeted mutagenesis (BrdtΔBD1) resulted in sterility and abnormalities in spermiogenesis, but little is known about BRDT's function at the molecular level. As part of studies designed to identify BRDT-interacting proteins we stably introduced a FLAG-tagged BRDT cDNA into 293T cells, which do not normally express BRDT. Affinity-purification of FLAG-tagged BRDT complexes indicated that BRDT has novel interactions with the histone deacetylase HDAC1, the arginine-specific histone methyltransferase 5 PRMT5, and the Tripartite motif-containing 28 protein TRIM28. Immunofluorescent microscopy revealed that BRDT co-localized with each of these proteins in round spermatids and co-immunoprecipitation of testicular extracts showed that these proteins interact with BRDT. Furthermore, they bind the promoter of H1t, a putative target of BRDT-containing complexes. This binding of H1t was lost in mice expressing the BrdtΔBD1 mutant protein and concomitantly, H1t expression was elevated in round spermatids. Our study reveals a role for BRDT-containing complexes in the repression of gene expression in vivo that correlates with dramatic effects on chromatin remodeling and the progression of spermiogenesis. © 2015 Wiley Periodicals, Inc.

Wolgemuth D.J.,150 St Nicholas Avenue | Wolgemuth D.J.,Institute of Human Nutrition | Wolgemuth D.J.,Columbia University | Roberts S.S.,150 St Nicholas Avenue
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Key components of the cell cycle machinery are the regulatory subunits, the cyclins, and their catalytic partners the cyclin-dependent kinases. Regulating the cell cycle in the male germ line cells represents unique challenges for this machinery given the constant renewal of gametes throughout the reproductive lifespan and the induction of the unique process of meiosis, a highly specialized kind of cell division. With challenges come opportunities to the critical eye, recognizing that understanding these specialized modes of regulation will provide considerable insight into both normal differentiation as well as disease conditions, including infertility and oncogenesis. © 2010 The Royal Society.

Dong H.V.,Institute of Human Nutrition | Shiau S.,Gertrude rgievsky Center | Yin M.T.,Columbia University
AIDS | Year: 2014

Objective: There is growing evidence that fracture risk is increased in individuals with HIV and/or hepatitis C virus (HCV) infection. We systematically reviewed the literature to determine whether prevalence of osteoporosis and incidence of fracture is increased in HIV/HCV-coinfected individuals. Design: A systematic review and meta-analysis. Methods: A search was performed of Medline, Scopus and the Cochrane Library databases, as well as of abstracts from annual retroviral, liver and bone meetings (up to 2013) for studies with bone mineral density (BMD) or bone fracture data for HIV/ HCV-coinfected individuals. Osteoporosis odds ratios (ORs) and fracture incidence rate ratios (IRRs) were estimated from studies with data on HIV-monoinfected or HIV/HCVuninfected comparison groups. Results: Of 15 included studies, nine reported BMD data and six reported fracture data. For HIV/HCV-coinfected, the estimated osteoporosis prevalence was 22% [95% confidence interval (95% CI) 12-31] and the crude OR for osteoporosis compared with HIV-monoinfected was 1.63 (95% CI 1.27-2.11). The pooled IRR of overall fracture risk for HIV/HCV-coinfected individuals was 1.77 (95% CI 1.44-2.18) compared with HIV-monoinfected and 2.95 (95% CI 2.17-4.01) compared with uninfected individuals. In addition to HIV/HCV-coinfection, older age, lower BMI, smoking, alcohol and substance use were significant predictors of osteoporosis and fractures across studies. Conclusion: HIV/HCV coinfection is associated with a greater risk of osteoporosis and fracture than HIV monoinfection; fracture risk is even greater than uninfected controls. These data suggest that HIV/HCV-coinfected individuals should be targeted for fracture prevention through risk factor modification at all ages and DXA screening at age 50. © 2014 Wolters Kluwer Health.

Spurgeon D.J.,UK Center for Ecology and Hydrology | Jones O.A.H.,University of Cambridge | Jones O.A.H.,Durham University | Dorne J.-L.C.M.,Unit on Contaminants in the Food chain | And 4 more authors.
Science of the Total Environment | Year: 2010

Environmental mixtures of chemicals constitute a prevalent issue in ecotoxicology and the development of new methods to reduce the uncertainties associated with their ecological risk assessment is a critical research need. Historically, a number of models have been explored to predict the potential combined effects of chemicals on species. These models, especially concentration addition and the independent action, have been applied to a number of mixtures. While often providing a good prediction of joint effect, there are cases where these models can have limitations: notably in cases where there are interactions for which they fail to adequately predict joint effects. To support the better mechanistic understanding of interactions in mixture toxicology a framework to support experimental studies to investigate the basis of observed interactions is proposed. The conceptual framework is derived from the extension of a three stage scheme which has previously been applied to understand chemical bioavailability. The framework considers that interactions in mixtures result from processes related to 1) the speciation, binding and transport of chemicals in the exposure medium (external exposure); 2) the adsorption, distribution, metabolism and excretion of chemicals within the organisms (toxicokinetics); 3) associations governing the binding and toxicity of the chemical(s) at the target site (toxicodynamics). The current state of the art in (eco)toxicology in relation to investigation of the mechanisms of interactions between chemicals is discussed with particular emphasis towards the multi-disciplinary tools and techniques within environmental chemistry; toxicology; biochemistry and systems biology that can be used to address such effects. © 2010 Elsevier B.V.

Zarse K.,Friedrich - Schiller University of Jena | Terao T.,Oita University | Tian J.,Friedrich - Schiller University of Jena | Iwata N.,Hiroshima International University | And 3 more authors.
European Journal of Nutrition | Year: 2011

Purpose Lithium is a nutritionally essential trace element predominantly contained in vegetables, plant-derived foods, and drinking water. Environmental lithium exposure and concurrent nutritional intake vary considerably in different regions. We here have analyzed the possibility that low-dose lithium exposure may affect mortality in both metazoans and mammals. Methods Based on a large Japanese observational cohort, we have used weighted regression analysis to identify putative effects of tap water-derived lithium uptake on overall mortality. Independently, we have exposed Caenorhabditis elegans, a small roundworm commonly used for anti-aging studies, to comparable concentrations of lithium, and have quantified mortality during this intervention. Results In humans, we find here an inverse correlation between drinking water lithium concentrations and allcause mortality in 18 neighboring Japanese municipalities with a total of 1,206,174 individuals (β = -0.661, p = 0.003). Consistently, we find that exposure to a comparably low concentration of lithium chloride extends life span of C. elegans (p = 0.047). Conclusions Taken together, these findings indicate that long-term low-dose exposure to lithium may exert antiaging capabilities and unambiguously decreases mortality in evolutionary distinct species. © The Author(s) 2011. This article is published with open access at Springerlink.com.

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