1,116 research outputs found

    MicroRNA-433 Dampens Glucocorticoid Receptor Signaling, Impacting Circadian Rhythm and Osteoblastic Gene Expression

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    FUNDING This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [AR44877]; the National Institutes for Dental and Craniofacial Research [5T90DE21989]; a Grant-in-Aid award from the American Society for Bone and Mineral Research; the UConn Health Center Research Advisory council; and the Center for Molecular Medicine at UConn Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Peer reviewedPublisher PD

    Risk factors for discordant immune response among HIV-infected patients initiating antiretroviral therapy: A retrospective cohort study

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    Background. The therapeutic goal of antiretroviral therapy (ART) is sustained immune recovery and viral suppression. However, some patients experience poor CD4 cell count responses despite achieving viral  suppression. Such discordant immune responses have been associated with poor clinical outcomes.Objective. We aimed to determine the prevalence of discordant immune response and explore associated factors in a retrospective cohort of patients attending 2 large public sector clinics, during the 6 months following ART initiation.Methods. Data were analysed from 810 HIV-infected adults initiated on first-line HAART at 2 clinics in Johannesburg, between 1 November 2008 and 31 December 2009. Multivariate logistic regression models were used to estimate adjusted odds ratios (AORs) to determine associations between discordant immune response and clinical and demographic factors.Results. At ART initiation, 65% (n=592) of participants were female, with a mean age of 38.5 years. Median baseline CD4 cell count was 155 cells/mm3, 70% (n=645) of patients had a haemoglobin level >11 g/dl and 88% (n=803) were initiated on stavudine-lamivudine-efavirenz/nevirapine (D4T-3TC-EFV/NVP). Six months after ART initiation, 24% (n=220) of patients had a discordant immune response and 7% (n=67) a discordant virological response. On multivariate analysis, baseline CD cell count .200 cells/mm3 (AOR 3.02; 95% confidence interval (CI) 2.08 - 4.38; p<0.001) and moderate anaemia (8.0 - 9.4 g/dl) atbaseline (AOR 2.30; 95% CI 1.25 - 4.59; p=0.007) were independently associated with the development of discordant immune response, after adjustment for education level, World Health Organization (WHO) clinical stage and ART regimen.Conclusions. Discordant immune response following ART initiation was common and associated with baseline anaemia and CD4 cell count in our cohort. Intensive monitoring of at-risk individuals may improve clinical outcomes

    Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

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    Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands

    Time to strengthen HIV treatment and prevention for youth

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    In The Lancet HIV, Mhairi Maskew and colleagues use data from a large national laboratory database in South Africa to examine trends in access to public sector HIV treatment programmes by children and adolescents aged 1–19 years between 2005 and 2016. The authors should be congratulated for highlighting important findings using national data in this often under-examined population, information that is needed to mount a national response. The authors report a ten times increase in the number of adolescents with viral load data, suggestive of antiretroviral therapy (ART) use, between 2005–08 and 2013–16. Prevention of mother-to-child transmission has worked remarkably well, with patients starting ART steadily decreasing since 2011 among patients aged 1–14 years. However, in line with global trends, the authors also identified large gaps in ART initiation among adolescents with presumed horizontal infection; less than half of patients seeking care aged 15–19 years started ART

    Multilayer Regulation of Neisseria meningitidis NHBA at Physiologically Relevant Temperatures

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    Neisseria meningitidis colonizes the nasopharynx of humans, and pathogenic strains can disseminate into the bloodstream, causing septicemia and meningitis. NHBA is a surface-exposed lipoprotein expressed by all N. meningitidis strains in different isoforms. Diverse roles have been reported for NHBA in heparin-mediated serum resistance, biofilm formation, and adherence to host tissues. We determined that temperature controls the expression of NHBA in all strains tested, with increased levels at 30–32◦C compared to 37◦C. Higher NHBA expression at lower temperatures was measurable both at mRNA and protein levels, resulting in higher surface exposure. Detailed molecular analysis indicated that multiple molecular mechanisms are responsible for the thermoregulated NHBA expression. The comparison of mRNA steady-state levels and half-lives at 30◦C and 37◦C demonstrated an increased mRNA stability/translatability at lower temperatures. Protein stability was also impacted, resulting in higher NHBA stability at lower temperatures. Ultimately, increased NHBA expression resulted in higher susceptibility to complement-mediated killing. We propose that NHBA regulation in response to temperature downshift might be physiologically relevant during transmission and the initial step(s) of interaction within the host nasopharynx. Together these data describe the importance of NHBA both as a virulence factor and as a vaccine antigen during neisserial colonization and invasion

    Genetic variation exists for telomeric array organization within and among the genomes of normal, immortalized, and transformed chicken systems

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    This study investigated telomeric array organization of diverse chicken genotypes utilizing in vivo and in vitro cells having phenotypes with different proliferation potencies. Our experimental objective was to characterize the extent and nature of array variation present to explore the hypothesis that mega-telomeres are a universal and fixed feature of chicken genotypes. Four different genotypes were studied including normal (UCD 001, USDA-ADOL Line 0), immortalized (DF-1), and transformed (DT40) cells. Both cytogenetic and molecular approaches were utilized to develop an integrated view of telomeric array organization. It was determined that significant variation exists within and among chicken genotypes for chromosome-specific telomeric array organization and total genomic-telomeric sequence content. Although there was variation for mega-telomere number and distribution, two mega-telomere loci were in common among chicken genetic lines (GGA 9 and GGA W). The DF-1 cell line was discovered to maintain a complex derivative karyotype involving chromosome fusions in the homozygous and heterozygous condition. Also, the DF-1 cell line was found to contain the greatest amount of telomeric sequence per genome (17%) as compared to UCD 001 (5%) and DT40 (1.2%). The chicken is an excellent model for studying unique and universal features of vertebrate telomere biology, and characterization of the telomere length variation among genotypes will be useful in the exploration of mechanisms controlling telomere length maintenance in different cell types having unique phenotypes

    A Single Nucleotide Change Affects Fur-Dependent Regulation of sodB in H. pylori

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    Helicobacter pylori is a significant human pathogen that has adapted to survive the many stresses found within the gastric environment. Superoxide Dismutase (SodB) is an important factor that helps H. pylori combat oxidative stress. sodB was previously shown to be repressed by the Ferric Uptake Regulator (Fur) in the absence of iron (apo-Fur regulation) [1]. Herein, we show that apo regulation is not fully conserved among all strains of H. pylori. apo-Fur dependent changes in sodB expression are not observed under iron deplete conditions in H. pylori strains G27, HPAG1, or J99. However, Fur regulation of pfr and amiE occurs as expected. Comparative analysis of the Fur coding sequence between G27 and 26695 revealed a single amino acid difference, which was not responsible for the altered sodB regulation. Comparison of the sodB promoters from G27 and 26695 also revealed a single nucleotide difference within the predicted Fur binding site. Alteration of this nucleotide in G27 to that of 26695 restored apo-Fur dependent sodB regulation, indicating that a single base difference is at least partially responsible for the difference in sodB regulation observed among these H. pylori strains. Fur binding studies revealed that alteration of this single nucleotide in G27 increased the affinity of Fur for the sodB promoter. Additionally, the single base change in G27 enabled the sodB promoter to bind to apo-Fur with affinities similar to the 26695 sodB promoter. Taken together these data indicate that this nucleotide residue is important for direct apo-Fur binding to the sodB promoter
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