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71.
Tammy M. Rickabaugh Ruth M. Baxter Mary Sehl Janet S. Sinsheimer Patricia M. Hultin Lance E. Hultin Austin Quach Otoniel Martínez-Maza Steve Horvath Eric Vilain Beth D. Jamieson 《PloS one》2015,10(3)
Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x10-200 and 0.47, p<1x10-200. Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: βage= 0.007088, p=2.08 x 10-9; βHIV= 0.099574, p=0.0011; Data set 2: βage= 0.008762, p=1.27x 10-5; βHIV= 0.128649, p= 0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10-6, odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age-associated patterns and suggest that general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging. 相似文献
72.
Craig Jamieson Robert A. Campbell Iain A. Cumming Kevin J. Gillen Jonathan Gillespie Bert Kazemier Michael Kiczun Yvonne Lamont Amanda J. Lyons John K.F. Maclean Frederic Martin Elizabeth M. Moir John A. Morrow John Pantling Zoran Rankovic Lynn Smith 《Bioorganic & medicinal chemistry letters》2010,20(20):6072-6075
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity. 相似文献
73.
Lisa C Willcocks Paul A Lyons Andrew J Rees Kenneth GC Smith 《Arthritis research & therapy》2010,12(1):202
The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here
we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we
discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute
to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals. 相似文献
74.
Most empirical evidence suggests that balancing selection does not counter the effects of genetic drift in shaping postbottleneck major histocompatibility complex (MHC) genetic diversity when population declines are severe or prolonged. However, few studies have been able to include data from historical specimens, or to compare populations/species with different bottleneck histories. In this study, we examined MHC class II B and microsatellite diversity in four New Zealand passerine (songbird) species that experienced moderate to very severe declines. We compared diversity from historical samples (collected c. 1884–1938) to present‐day populations. Using a Bayesian framework, we found that the change in genetic diversity from historical to contemporary samples was affected by three main factors: (i) whether the data were based on MHC or microsatellite markers, (ii) species (as a surrogate for bottleneck severity) and (iii) whether the comparison between historical and contemporary samples was made using historical samples originating from the mainland, or using historical samples originating from islands. The greatest losses in genetic diversity occurred for the most severely bottlenecked species, particularly between historical mainland and contemporary samples. Additionally, where loss of diversity occurred, the change was greater for MHC genes compared to microsatellite loci. 相似文献
75.
76.
Background
Current techniques used to obtain lung samples have significant limitations and do not provide reproducible biomarkers of inflammation. We have developed a novel technique that allows multiple sampling methods from the same area (or multiple areas) of the lung under direct bronchoscopic vision. It allows collection of mucosal lining fluid and bronchial brushing from the same site; biopsy samples may also be taken. The novel technique takes the same time as standard procedures and can be conducted safely.Methods
Eight healthy smokers aged 40–65 years were included in this study. An absorptive filter paper was applied to the bronchial mucosa under direct vision using standard bronchoscopic techniques. Further samples were obtained from the same site using bronchial brushings. Bronchoalveolar lavage (BAL) was obtained using standard techniques. Chemokine (C-C Motif) Ligand 20 (CCL20), CCL4, CCL5, Chemokine (C-X-C Motif) Ligand 1 (CXCL1), CXCL8, CXCL9, CXCL10, CXCL11, Interleukin 1 beta (IL-1β), IL-6, Vascular endothelial growth factor (VEGF), Matrix metalloproteinase 8 (MMP-8) and MMP-9 were measured in exudate and BAL. mRNA was collected from the bronchial brushings for gene expression analysis.Results
A greater than 10 fold concentration of all the biomarkers was detected in lung exudate in comparison to BAL. High yield of good quality RNA with RNA integrity numbers (RIN) between 7.6 and 9.3 were extracted from the bronchial brushings. The subset of genes measured were reproducible across the samples and corresponded to the inflammatory markers measured in exudate and BAL.Conclusions
The bronchoabsorption technique as described offers the ability to sample lung fluid direct from the site of interest without the dilution effects caused by BAL. Using this method we were able to successfully measure the concentrations of biomarkers present in the lungs as well as collect high yield mRNA samples for gene expression analysis from the same site. This technique demonstrates superior sensitivity to standard BAL for the measurement of biomarkers of inflammation. It could replace BAL as the method of choice for these measurements. This method provides a systems biology approach to studying the inflammatory markers of respiratory disease progression.Trial registration
NHS Health Research Authority (13/LO/0256). 相似文献77.
Jamieson C Maclean JK Brown CI Campbell RA Gillen KJ Gillespie J Kazemier B Kiczun M Lamont Y Lyons AJ Moir EM Morrow JA Pantling J Rankovic Z Smith L 《Bioorganic & medicinal chemistry letters》2011,21(2):805-811
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19. 相似文献
78.
In nonpedigreed wild populations, inbreeding depression is often quantified through the use of heterozygosity-fitness correlations (HFCs), based on molecular estimates of relatedness. Although such correlations are typically interpreted as evidence of inbreeding depression, by assuming that the marker heterozygosity is a proxy for genome-wide heterozygosity, theory predicts that these relationships should be difficult to detect. Until now, the vast majority of empirical research in this area has been performed on generally outbred, nonbottlenecked populations, but differences in population genetic processes may limit extrapolation of results to threatened populations. Here, we present an analysis of HFCs, and their implications for the interpretation of inbreeding, in a free-ranging pedigreed population of a bottlenecked species: the endangered takahe (Porphyrio hochstetteri). Pedigree-based inbreeding depression has already been detected in this species. Using 23 microsatellite loci, we observed only weak evidence of the expected relationship between multilocus heterozygosity and fitness at individual life-history stages (such as survival to hatching and fledging), and parameter estimates were imprecise (had high error). Furthermore, our molecular data set could not accurately predict the inbreeding status of individuals (as 'inbred' or 'outbred', determined from pedigrees), nor could we show that the observed HFCs were the result of genome-wide identity disequilibrium. These results may be attributed to high variance in heterozygosity within inbreeding classes. This study is an empirical example from a free-ranging endangered species, suggesting that even relatively large numbers (>20) of microsatellites may give poor precision for estimating individual genome-wide heterozygosity. We argue that pedigree methods remain the most effective method of quantifying inbreeding in wild populations, particularly those that have gone through severe bottlenecks. 相似文献
79.
Information theoretic approaches and model averaging are increasing in popularity, but this approach can be difficult to apply to the realistic, complex models that typify many ecological and evolutionary analyses. This is especially true for those researchers without a formal background in information theory. Here, we highlight a number of practical obstacles to model averaging complex models. Although not meant to be an exhaustive review, we identify several important issues with tentative solutions where they exist (e.g. dealing with collinearity amongst predictors; how to compute model-averaged parameters) and highlight areas for future research where solutions are not clear (e.g. when to use random intercepts or slopes; which information criteria to use when random factors are involved). We also provide a worked example of a mixed model analysis of inbreeding depression in a wild population. By providing an overview of these issues, we hope that this approach will become more accessible to those investigating any process where multiple variables impact an evolutionary or ecological response. 相似文献
80.
McFarlane SE Lane JE Taylor RW Gorrell JC Coltman DW Humphries MM Boutin S McAdam AG 《Biology letters》2011,7(3):368-371
The tendency of females to mate with multiple males is often explained by direct and indirect benefits that could outweigh the many potential costs of multiple mating. However, behaviour can only evolve in response to costs and benefits if there is sufficient genetic variation on which selection can act. We followed 108 mating chases of 85 North American red squirrels (Tamiasciurus hudsonicus) during 4 years, to measure each female's degree of multiple male mating (MMM), and used an animal model analysis of our multi-generational pedigree to provide what we believe is the first estimate of the heritability of MMM in the wild. Female red squirrels were highly polyandrous, mating with an average of 7.0 ± 0.2 males on their day of oestrus. Although we found evidence for moderate levels of additive genetic variation (CV(A) = 5.1), environmental variation was very high (CV(E) = 32.3), which resulted in a very low heritability estimate (h(2) < 0.01). So, while there is genetic variation in this trait, the large environmental variation suggests that any costs or benefits associated with differences among females in MMM are primarily owing to environmental and not genetic differences, which could constrain the evolutionary response to natural selection on this trait. 相似文献