Exceptional endocrine profiles characterise the meerkat: sex, status, and reproductive patterns.

In vertebrates, reproductive endocrine concentrations are strongly differentiated by sex, with androgen biases typifying males and estrogen biases typifying females. These sex differences can be reduced in female-dominant species; however, even the most masculinised of females have less testosterone (T) than do conspecific males. To test if aggressively dominant, female meerkats (Suricata suricatta) may be hormonally masculinised, we measured serum androstenedione (A4), T and estradiol (E2) in both sexes and social classes, during both 'baseline' and reproductive events. Relative to resident males, dominant females had greater A4, equivalent T and greater E2 concentrations. Males, whose endocrine values did not vary by social status, experienced increased T during reproductive forays, linking T to sexual behaviour, but not social status. Moreover, substantial E2 concentrations in male meerkats may facilitate their role as helpers. In females, dominance status and pregnancy magnified the unusual concentrations of measured sex steroids. Lastly, faecal androgen metabolites replicated the findings derived from serum, highlighting the female bias in total androgens. Female meerkats are thus strongly hormonally masculinised, possibly via A4's bioavailability for conversion to T. These raised androgen concentrations may explain female aggressiveness in this species and give dominant breeders a heritable mechanism for their daughters' competitive edge

The Secondary Bile acids, Ursodeoxycholic acid and Lithocholic Acid, Protect Against Intestinal Inflammation by Inhibition of Epithelial Apoptosis

Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non-metabolizable analog of UDCA, 6-methyl-UDCA (6-MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2.5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC-dextran uptake and caspase-3 cleavage, respectively. Cecal bile acids were measured by HPLC-MS/MS. UDCA and LCA, but not 6-MUDCA, were protective against DSS-induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase-3 cleavage both in DSS-treated mice and in an in vitro model of cytokine-induced epithelial injury. HPLC-MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted

An intergenerational androgenic mechanism of female intrasexual competition in the cooperatively breeding meerkat.

Female intrasexual competition can be intense in cooperatively breeding species, with some dominant breeders (matriarchs) limiting reproduction in subordinates via aggression, eviction or infanticide. In males, such tendencies bidirectionally link to testosterone, but in females, there has been little systematic investigation of androgen-mediated behaviour within and across generations. In 22 clans of wild meerkats (Suricata suricatta), we show that matriarchs 1) express peak androgen concentrations during late gestation, 2) when displaying peak feeding competition, dominance behaviour, and evictions, and 3) relative to subordinates, produce offspring that are more aggressive in early development. Late-gestation antiandrogen treatment of matriarchs 4) specifically reduces dominance behaviour, is associated with infrequent evictions, decreases social centrality within the clan, 5) increases aggression in cohabiting subordinate dams, and 6) reduces offspring aggression. These effects implicate androgen-mediated aggression in the operation of female sexual selection, and intergenerational transmission of masculinised phenotypes in the evolution of meerkat cooperative breeding

Reconstruction of cell population dynamics using CFSE

Background: Quantifying cell division and death is central to many studies in the biological sciences. The fluorescent dye CFSE allows the tracking of cell division in vitro and in vivo and provides a rich source of information with which to test models of cell kinetics. Cell division and death have a stochastic component at the single-cell level, and the probabilities of these occurring in any given time interval may also undergo systematic variation at a population level. This gives rise to heterogeneity in proliferating cell populations. Branching processes provide a natural means of describing this behaviour. Results: We present a likelihood-based method for estimating the parameters of branching process models of cell kinetics using CFSE-labeling experiments, and demonstrate its validity using synthetic and experimental datasets. Performing inference and model comparison with real CFSE data presents some statistical problems and we suggest methods of dealing with them. Conclusion: The approach we describe here can be used to recover the (potentially variable) division and death rates of any cell population for which division tracking information is available

Post-admission outcomes of participants in the PARAMEDIC trial : a cluster randomised trial of mechanical or manual chest compressions

Background: The PARAMEDIC cluster randomised trial evaluated the LUCAS mechanical chest compression device, and did not find evidence that use of mechanical chest compression led to an improvement in survival at 30 days. This paper reports patient outcomes from admission to hospital to 12 months after randomisation. Methods: Information about hospital length of stay and intensive care management was obtained through linkage with Hospital Episode Statistics and the Intensive Care National Audit and Research Centre. Patients surviving to hospital discharge were approached to complete questionnaires (SF-12v2, EQ-5D, MMSE, HADS and PTSD-CL) at 90 days and 12 months. The study is registered with Current Controlled Trials, number ISRCTN08233942. Results: 377 patients in the LUCAS arm and 658 patients in the manual chest compression were admitted to hospital. Hospital and intensive care length of stay were similar. Long term follow-up assessments were limited by poor response rates (53.7% at 3 months and 55.6% at 12 months). Follow-up rates were lower in those with worse neurological function. Among respondents, long term health related quality of life outcomes and emotional well-being was similar between groups. Cognitive function, measured by MMSE, was marginally lower in the LUCAS arm mean 26.9 (SD 3.7) compared to control mean 28.0 (SD 2.3), adjusted mean difference −1.5 (95% CI −2.6 to −0.4). Conclusion: There were no clinically important differences identified in outcomes at long term follow-up between those allocated to the mechanical chest compression compared to those receiving manual chest compression

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genetic variation across the HLA is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the HLA is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with post‐transplant eGFR at different time‐points, out to 5‐years post‐transplantation. We conducted GWAS meta‐analyses across 10,844 donors and recipients from five European ancestry cohorts. We also analysed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with non‐transplant eGFR, on post‐transplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year post‐transplant. 32% of the variability in eGFR at 1‐year post‐transplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR post‐transplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a post‐transplant context. Despite PRS being a significant predictor of eGFR post‐transplant, the effect size of common genetic factors is limited compared to clinical variables

Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalKR

Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen

Variations in Stress Sensitivity and Genomic Expression in Diverse S. cerevisiae Isolates

Interactions between an organism and its environment can significantly influence phenotypic evolution. A first step toward understanding this process is to characterize phenotypic diversity within and between populations. We explored the phenotypic variation in stress sensitivity and genomic expression in a large panel of Saccharomyces strains collected from diverse environments. We measured the sensitivity of 52 strains to 14 environmental conditions, compared genomic expression in 18 strains, and identified gene copy-number variations in six of these isolates. Our results demonstrate a large degree of phenotypic variation in stress sensitivity and gene expression. Analysis of these datasets reveals relationships between strains from similar niches, suggests common and unique features of yeast habitats, and implicates genes whose variable expression is linked to stress resistance. Using a simple metric to suggest cases of selection, we found that strains collected from oak exudates are phenotypically more similar than expected based on their genetic diversity, while sake and vineyard isolates display more diverse phenotypes than expected under a neutral model. We also show that the laboratory strain S288c is phenotypically distinct from all of the other strains studied here, in terms of stress sensitivity, gene expression, Ty copy number, mitochondrial content, and gene-dosage control. These results highlight the value of understanding the genetic basis of phenotypic variation and raise caution about using laboratory strains for comparative genomics

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF and supported by grant U01 DK062418 from the US National Institutes of Health. Further support was provided by grants from the NIDDK (DK046635 and DK085678) to P.C. and by a joint JDRF and Wellcome Trust grant (WT061858/09115) to the Diabetes and Inflammation Laboratory at Cambridge University, which also received support from the NIHR Cambridge Biomedical Research Centre. ImmunoBase receives support from Eli Lilly and Company. C.W. and H.G. are funded by the Wellcome Trust (089989). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council and the Wellcome Trust. We acknowledge use of DNA samples from the NIHR Cambridge BioResource. We thank volunteers for their support and participation in the Cambridge BioResource and members of the Cambridge BioResource Scientific Advisory Board (SAB) and Management Committee for their support of our study. We acknowledge the NIHR Cambridge Biomedical Research Centre for funding. Access to Cambridge BioResource volunteers and to their data and samples are governed by the Cambridge BioResource SAB. Documents describing access arrangements and contact details are available at http://www.cambridgebioresource.org.uk/. We thank the Avon Longitudinal Study of Parents and Children laboratory in Bristol, UK, and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton, for preparing and providing the control DNA samples. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113; a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/.This is the author accepted manuscript. The final version is available via NPG at http://www.nature.com/ng/journal/v47/n4/full/ng.3245.html