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Author Gajer, P.; Brotman, R.M.; Bai, G.; Sakamoto, J.; Schutte, U.M.E.; Zhong, X.; Koenig, S.S.K.; Fu, L.; Ma, Z.S.; Zhou, X.; Abdo, Z.; Forney, L.J.; Ravel, J. file  url
Title Temporal dynamics of the human vaginal microbiota Type Journal Article
Year 2012 Publication Science Translational Medicine Abbreviated Journal Sci Transl Med  
Volume 4 Issue 132 Pages 132ra52  
Keywords Bacteria/classification/genetics; Female; Humans; Magnetic Resonance Spectroscopy; Metabolome; Metabolomics; Metagenome/genetics/*physiology; Models, Biological; Phylogeny; Time Factors; Vagina/*microbiology; Microbiome  
Abstract Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analysis revealed the dynamics of five major classes of bacterial communities and showed that some communities change markedly over short time periods, whereas others are relatively stable. Modeling community stability using new quantitative measures indicates that deviation from stability correlates with time in the menstrual cycle, bacterial community composition, and sexual activity. The women studied are healthy; thus, it appears that neither variation in community composition per se nor higher levels of observed diversity (co-dominance) are necessarily indicative of dysbiosis.  
Call Number Serial 2175  
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Author Burak, M.F.; Inouye, K.E.; White, A.; Lee, A.; Tuncman, G.; Calay, E.S.; Sekiya, M.; Tirosh, A.; Eguchi, K.; Birrane, G.; Lightwood, D.; Howells, L.; Odede, G.; Hailu, H.; West, S.; Garlish, R.; Neale, H.; Doyle, C.; Moore, A.; Hotamisligil, G.S. file  url
Title Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes Type Journal Article
Year 2015 Publication Science Translational Medicine Abbreviated Journal Sci Transl Med  
Volume 7 Issue 319 Pages 319ra205  
Keywords Adipose Tissue/drug effects; Amino Acid Sequence; Animals; Antibodies, Monoclonal/*therapeutic use; Body Composition/drug effects; Diabetes Mellitus, Type 2/complications/*drug therapy; Diet, High-Fat; Fatty Acid-Binding Proteins/chemistry/*immunology; Fatty Liver/complications/pathology; Glucose/metabolism; Humans; Insulin/pharmacology; Male; Metabolome/drug effects; Mice, Inbred C57BL; Mice, Obese  
Abstract The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb-mediated therapeutic constitutes a feasible approach for the treatment of diabetes.  
Call Number Serial 2042  
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Author Lawrance, A.K.; Racine, J.; Deng, L.; Wang, X.; Lachapelle, P.; Rozen, R. file  url
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Title Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes Type Journal Article
Year 2011 Publication Journal of Inherited Metabolic Disease Abbreviated Journal J Inherit Metab Dis  
Volume 34 Issue 1 Pages 147-157  
Keywords Animals; Female; Growth Disorders/blood/genetics/physiopathology; Homocystinuria/blood/complications/mortality/physiopathology; Individuality; Male; Metabolome/genetics; Methylenetetrahydrofolate Reductase (NADPH2)/blood/deficiency/genetics; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Muscle Spasticity/blood/complications/mortality/physiopathology; Pregnancy; Psychotic Disorders/blood/complications/mortality/physiopathology; Reproduction/genetics/*physiology; Retinal Diseases/*etiology/genetics; Survival Analysis  
Abstract Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with homocystinuria can result in early demise or later-onset neurological impairment, including developmental delay, motor dysfunction, and seizures. We previously characterized BALB/c Mthfr (-/-)mice as a model for this disorder and have recently backcrossed the disrupted allele onto the C57Bl/6 background to examine the variable phenotypes in MTHFR deficiency. Compared with BALB/c Mthfr (-/-)mice, C57Bl/6 Mthfr (-/-)mice have enhanced survival rates (81% vs 26.5%). Four-day-old BALB/c mutant pups had lower body, brain, and spleen weights relative to their wild-type counterparts compared with C57Bl/6 mutants. Pregnant BALB/c Mthfr (+/-)mice had increased resorptions and embryonic delays compared with wild-type littermates, whereas these outcomes in C57Bl/6 c Mthfr (+/-)mice were similar to those of wild-type C57Bl/6 mice. BALB/c-mutant pups had altered hematological profiles (higher hematocrit, hemoglobin, and white blood cell counts, with lower platelet counts) compared with C57Bl/6 mutants. Mutants of both strains had similar degrees of hepatic steatosis, hepatic activity of betaine:homocysteine methyltransferase, and altered cerebellar histology. Electroretinograms (ERG) in C57Bl/6 Mthfr (-/-)mice revealed decreased amplitude of scotopic and photopic waves in 6-week-old mice, with normalized ERGs at 13 weeks. Plasma homocysteine was modestly higher in C57Bl/6 compared with BALB/c mice. Our results emphasize the variable presentation of MTHFR deficiency in different genetic backgrounds and suggest that plasma homocysteine is not a predictor of severity. In addition, our novel findings of decreased spleen weights, thrombocytopenia, and impaired retinal function warrant investigation in patients with severe MTHFR deficiency or other forms of homocystinuria.  
Call Number Serial 307  
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