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Chapel Hill, NC, United States

Monda K.L.,Carolina Center for Genome science | North K.E.,Carolina Center for Genome science | Hunt S.C.,University of North Carolina at Chapel Hill | Rao D.C.,University of Utah | And 2 more authors.
Endocrine, Metabolic and Immune Disorders - Drug Targets | Year: 2010

In this review, we discuss the genetic architecture of obesity and the metabolic syndrome, highlighting recent advances in identifying genetic variants and loci responsible for a portion of the variation in components of the metabolic syndrome, namely, adiposity traits, serum HDL and triglycerides, blood pressure, and glycemic traits. We focus particularly on recent progress from large-scale genome-wide association studies (GWAS), by detailing their successes and how lessons learned can pave the way for future discovery. Results from recent GWAS coalesce with earlier work suggesting numerous interconnections between obesity and the metabolic syndrome, developed through several potentially pleiotropic effects. We detail recent work by way of a case study on the cadherin 13 gene and its relation with adiponectin in the HyperGEN and the Framingham Heart Studies, and its association with obesity and the metabolic syndrome. We provide also a gene network analysis of recent variants related to obesity and metabolic syndrome discovered through genome-wide association studies, and 4 gene networks based on searching the NCBI database. © 2010 Bentham Science Publishers Ltd.

Egelhofer T.A.,University of California at Santa Cruz | Minoda A.,University of California at Berkeley | Minoda A.,Lawrence Berkeley National Laboratory | Klugman S.,Ludwig Institute for Cancer Research | And 41 more authors.
Nature Structural and Molecular Biology | Year: 2011

We have tested the specificity and utility of more than 200 antibodies raised against 57 different histone modifications in Drosophila melanogaster, Caenorhabditis elegans and human cells. Although most antibodies performed well, more than 25% failed specificity tests by dot blot or western blot. Among specific antibodies, more than 20% failed in chromatin immunoprecipitation experiments. We advise rigorous testing of histone-modification antibodies before use, and we provide a website for posting new test results (http://compbio.med.harvard.edu/antibodies/). © 2011 Nature America, Inc. All rights reserved.

Jabara C.B.,Center for Research | Jabara C.B.,University of North Carolina at Chapel Hill | Jabara C.B.,Abbott Laboratories | Hu F.,Center for Research | And 15 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

HIV coinfection accelerates disease progression in chronic hepatitis C and reduces sustained antiviral responses (SVR) to interferon- based therapy. New direct-acting antivirals (DAAs) promise higher SVR rates, but the selection of preexisting resistanceassociated variants (RAVs) may lead to virologic breakthrough or relapse. Thus, pretreatment frequencies of RAVs are likely determinants of treatment outcome but typically are below levels at which the viral sequence can be accurately resolved. Moreover, it is not known how HIV coinfection influences RAV frequency. We adopted an accurate high-throughput sequencing strategy to compare nucleotide diversity in HCV NS3 protease-coding sequences in 20 monoinfected and 20 coinfected subjects with well-controlled HIV infection. Differences in mean pairwise nucleotide diversity (π), Tajima's D statistic, and Shannon entropy index suggested that the genetic diversity of HCV is reduced in coinfection. Among coinfected subjects, diversity correlated positively with increases in CD4± T cells on antiretroviral therapy, suggesting T cell responses are important determinants of diversity. At a median sequencing depth of 0.084%, preexisting RAVs were readily identified. Q80K, which negatively impacts clinical responses to simeprevir, was encoded by more than 99% of viral RNAs in 17 of the 40 subjects. RAVs other than Q80K were identified in 39 of 40 subjects, mostly at frequencies near 0.1%. RAV frequency did not differ significantly between monoinfected and coinfected subjects. We conclude that HCV genetic diversity is reduced in patients with well-controlled HIV infection, likely reflecting impaired T cell immunity. However, RAV frequency is not increased and should not adversely influence the outcome of DAA therapy. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Bartoli C.,University of Tuscia | Bartoli C.,French National Institute for Agricultural Research | Berge O.,French National Institute for Agricultural Research | Monteil C.L.,French National Institute for Agricultural Research | And 9 more authors.
Environmental Microbiology | Year: 2014

As a species complex, Pseudomonas syringae exists in both agriculture and natural aquatic habitats. P.viridiflava, a member of this complex, has been reported to be phenotypically largely homogenous. We characterized strains from different habitats, selected based on their genetic similarity to previously described P.viridiflava strains. We revealed two distinct phylogroups and two different kinds of variability in phenotypic traits and genomic content. The strains exhibited phase variation in phenotypes including pathogenicity and soft rot on potato. We showed that the presence of two configurations of the Type III Secretion System [single (S-PAI) and tripartite (T-PAI) pathogenicity islands] are not correlated with pathogenicity or with the capacity to induce soft rot in contrast to previous reports. The presence/absence of the avrE effector gene was the only trait we found to be correlated with pathogenicity of P.viridiflava. Other Type III secretion effector genes were not correlated with pathogenicity. A genomic region resembling an exchangeable effector locus (EEL) was found in S-PAI strains, and a probable recombination between the two PAIs is described. The ensemble of the variability observed in these phylogroups of P.syringae likely contributes to their adaptability to alternating opportunities for pathogenicity or saprophytic survival. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

Manning A.J.,University of Washington | Rogers S.L.,University of North Carolina at Chapel Hill | Rogers S.L.,Lineberger Comprehensive Cancer Center | Rogers S.L.,Carolina Center for Genome science
Developmental Biology | Year: 2014

Epithelia form the building blocks of many tissue and organ types. Epithelial cells often form a contiguous 2-dimensional sheet that is held together by strong adhesions. The mechanical properties conferred by these adhesions allow the cells to undergo dramatic three-dimensional morphogenetic movements while maintaining cell-cell contacts during embryogenesis and post-embryonic development. The Drosophila Folded gastrulation pathway triggers epithelial cell shape changes that drive gastrulation and tissue folding and is one of the most extensively studied examples of epithelial morphogenesis. This pathway has yielded key insights into the signaling mechanisms and cellular machinery involved in epithelial remodeling. In this review, we discuss principles of morphogenesis and signaling that have been discovered through genetic and cell biological examination of this pathway. We also consider various regulatory mechanisms and the system[U+05F3]s relevance to mammalian development. We propose future directions that will continue to broaden our knowledge of morphogenesis across taxa. © 2014 The Authors.

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