GABA_{C} Receptor Sensitivity Is Modulated by Interaction with MAP1B

GABA_{C} receptors contain ρ subunits and mediate feedback inhibition from retinal amacrine cells to bipolar cells. We previously identified the cytoskeletal protein MAP1B as a ρ1 subunit anchoring protein. Here, we analyze the structural basis and functional significance of the MAP1B-ρ1 interaction. Twelve amino acids at the C terminus of the large intracellular loop of ρ1 (and also ρ2) are sufficient for interaction with MAP1B. Disruption of the MAP1B-ρ interaction in bipolar cells in retinal slices decreased the EC₅₀ of their GABA_{C} receptors, doubling the receptors' current at low GABA concentrations without affecting their maximum current at high concentrations. Thus, anchoring to the cytoskeleton lowers the sensitivity of GABA_{C} receptors and provides a likely site for functional modulation of GABA_{C}receptor-mediated inhibition

Sex Differences in the Association between Serum Levels of Testosterone and Frailty in an Elderly Population: The Toledo Study for Healthy Aging

BACKGROUND: Age-associated decline in testosterone levels represent one of the potential mechanisms involved in the development of frailty. Although this association has been widely reported in older men, very few data are available in women. We studied the association between testosterone and frailty in women and assessed sex differences in this relationship. METHODS: We used cross-sectional data from the Toledo Study for Healthy Aging, a population-based cohort study of Spanish elderly. Frailty was defined according to Fried's approach. Multivariate odds-ratios (OR) and 95% confidence intervals (CI) associated with total (TT) and free testosterone (FT) levels were estimated using polytomous logistic regression. RESULTS: In women, there was a U-shaped relationship between FT levels and frailty (p for FT(2) = 0.03). In addition, very low levels of FT were observed in women with ≥ 4 frailty criteria (age-adjusted geometric means = 0.13 versus 0.37 in subjects with <4 components, p = 0.010). The association of FT with frailty appeared confined to obese women (p-value for interaction = 0.05).In men, the risk of frailty levels linearly decreased with testosterone (adjusted OR for frailty = 2.9 (95%CI, 1.6-5.1) and 1.6 (95%CI, 1.0-2.5), for 1 SD decrease in TT and FT, respectively). TT and FT showed association with most of frailty criteria. No interaction was found with BMI. CONCLUSION: There is a relationship between circulating levels of FT and frailty in older women. This relation seems to be modulated by BMI. The relevance and the nature of the association of FT levels and frailty are sex-specific, suggesting that different biological mechanisms may be involved

Rates of Viral Evolution Are Linked to Host Geography in Bat Rabies

Rates of evolution span orders of magnitude among RNA viruses with important implications for viral transmission and emergence. Although the tempo of viral evolution is often ascribed to viral features such as mutation rates and transmission mode, these factors alone cannot explain variation among closely related viruses, where host biology might operate more strongly on viral evolution. Here, we analyzed sequence data from hundreds of rabies viruses collected from bats throughout the Americas to describe dramatic variation in the speed of rabies virus evolution when circulating in ecologically distinct reservoir species. Integration of ecological and genetic data through a comparative Bayesian analysis revealed that viral evolutionary rates were labile following historical jumps between bat species and nearly four times faster in tropical and subtropical bats compared to temperate species. The association between geography and viral evolution could not be explained by host metabolism, phylogeny or variable selection pressures, and instead appeared to be a consequence of reduced seasonality in bat activity and virus transmission associated with climate. Our results demonstrate a key role for host ecology in shaping the tempo of evolution in multi-host viruses and highlight the power of comparative phylogenetic methods to identify the host and environmental features that influence transmission dynamics

How to increase earthquake and home fire preparedness: the fix-it intervention

Published, evaluated community intervention studies concerning natural hazard preparedness are rare. Most lack a rigorous methodology, thereby hampering the development of evidence-based interventions. This paper describes the rationale and methodology of a cross-cultural, longitudinal intervention study on earthquake and home fire preparedness, termed fix-it. The aim is to evaluate whether and how the intervention brings about behaviour change in the targeted communities in two coastal cities with high seismic risk: Seattle, USA and Izmir, Turkey. Participants are adult residents of these cities. The intervention group attends a 6-h workshop, which focuses on securing items in the household. The control group does not attend the workshop. All participants complete baseline and post-intervention, as well as 3- and 12-month follow-up assessments. The primary outcome measure is an observational measure of nine preparedness items for earthquake and fire in participants’ homes. This is evaluated alongside participants’ self-reports concerning their preparedness levels. Secondary outcomes are changes in levels of self-efficacy, perceived outcome, trust, corruption, empowerment, anxiety and social cohesion. Results from the first of the studies, conducted in Seattle in September 2015, indicate that while the fix-it intervention is effective, in the longer term, multi-hazard preparedness is increased by the mere act of going into people’s homes to observe their preparedness levels along with assessing self-reported preparedness and sociopsychological orientation towards natural hazards. This protocol and study aim to augment the empirical literature on natural hazard preparedness, informing national and international policy on delivery of evidence-based community interventions to promote multi-hazard preparedness in households

Unrequested Findings on Cardiac Computed Tomography: Looking Beyond the Heart

Objectives: To determine the prevalence of clinically relevant unrequested extra-cardiac imaging findings on cardiac Computed Tomography (CT) and explanatory factors thereof. Methods: A systematic review of studies drawn from online electronic databases followed by meta-analysis with metaregression was performed. The prevalence of clinically relevant unrequested findings and potentially explanatory variables were extracted (proportion of smokers, mean age of patients, use of full FOV, proportion of men, years since publication). Results: Nineteen radiological studies comprising 12922 patients met the inclusion criteria. The pooled prevalence of clinically relevant unrequested findings was 13 % (95 % confidence interval 9–18, range: 3–39%). The large differences in prevalence observed were not explained by the predefined (potentially explanatory) variables. Conclusions: Clinically relevant extra-cardiac findings are common in patients undergoing routine cardiac CT, and their prevalence differs substantially between studies. These differences may be due to unreported factors such as different definitions of clinical relevance and differences between populations. We present suggestions for basic reporting whic

Operationalizing frailty among older residents of assisted living facilities

<p>Abstract</p> <p>Background</p> <p>Frailty in later life is viewed as a state of heightened vulnerability to poor outcomes. The utility of frailty as a measure of vulnerability in the assisted living (AL) population remains unexplored. We examined the feasibility and predictive accuracy of two different interpretations of the Cardiovascular Health Study (CHS) frailty criteria in a population-based sample of AL residents.</p> <p>Methods</p> <p>CHS frailty criteria were operationalized using two different approaches in 928 AL residents from the Alberta Continuing Care Epidemiological Studies (ACCES). Risks of one-year mortality and hospitalization were estimated for those categorized as frail or pre-frail (compared with non-frail). The prognostic significance of individual criteria was explored, and the area under the ROC curve (AUC) was calculated for select models to assess the utility of frailty in predicting one-year outcomes.</p> <p>Results</p> <p>Regarding feasibility, complete CHS criteria could not be assessed for 40% of the initial 1,067 residents. Consideration of supplementary items for select criteria reduced this to 12%. Using absolute (CHS-specified) cut-points, 48% of residents were categorized as frail and were at greater risk for death (adjusted risk ratio [RR] 1.75, 95% CI 1.08-2.83) and hospitalization (adjusted RR 1.54, 95% CI 1.20-1.96). Pre-frail residents defined by absolute cut-points (48.6%) showed no increased risk for mortality or hospitalization compared with non-frail residents. Using relative cut-points (derived from AL sample), 19% were defined as frail and 55% as pre-frail and the associated risks for mortality and hospitalization varied by sex. Frail (but not pre-frail) women were more likely to die (RR 1.58 95% CI 1.02-2.44) and be hospitalized (RR 1.53 95% CI 1.25-1.87). Frail and pre-frail men showed an increased mortality risk (RR 3.21 95% CI 1.71-6.00 and RR 2.61 95% CI 1.40-4.85, respectively) while only pre-frail men had an increased risk of hospitalization (RR 1.58 95% CI 1.15-2.17). Although incorporating either frailty measure improved the performance of predictive models, the best AUCs were 0.702 for mortality and 0.633 for hospitalization.</p> <p>Conclusions</p> <p>Application of the CHS criteria for frailty was problematic and only marginally improved the prediction of select adverse outcomes in AL residents. Development and validation of alternative approaches for detecting frailty in this population, including consideration of female/male differences, is warranted.</p

Is a history of work-related low back injury associated with prevalent low back pain and depression in the general population?

<p>Abstract</p> <p>Background</p> <p>Little is known about the role of prior occupational low back injury in future episodes of low back pain and disability in the general population. We conducted a study to determine if a lifetime history of work-related low back injury is associated with prevalent severity-graded low back pain, depressive symptoms, or both, in the general population.</p> <p>Methods</p> <p>We used data from the Saskatchewan Health and Back Pain Survey – a population-based cross-sectional survey mailed to a random, stratified sample of 2,184 Saskatchewan adults 20 to 69 years of age in 1995. Information on the main independent variable was gathered by asking respondents whether they had ever injured their low back at work. Our outcomes, the 6-month period prevalence of severity-graded low back pain and depressive symptoms during the past week, were measured with valid and reliable questionnaires. The associations between prior work-related low back injury and our outcomes were estimated through multinomial and binary multivariable logistic regression with adjustment for age, gender, and other important covariates.</p> <p>Results</p> <p>Fifty-five percent of the eligible population participated. Of the 1,086 participants who responded to the question about the main independent variable, 38.0% reported a history of work-related low back injury. A history of work-related low back injury was positively associated with low intensity/low disability low back pain (OR, 3.66; 95%CI, 2.48–5.42), with high intensity/low disability low back pain (OR, 4.03; 95%CI, 2.41–6.76), and with high disability low back pain (OR, 6.76; 95%CI, 3.80–12.01). No association was found between a history of work-related low back injury and depression (OR, 0.85; 95%CI, 0.55–1.30).</p> <p>Conclusion</p> <p>Our analysis shows an association between past occupational low back injury and increasing severity of prevalent low back pain, but not depression. These results suggest that past work-related low back injury may be an important risk factor for future episodes of low back pain and disability in the general population.</p

A higher activation threshold of memory CD8+ T cells has a fitness cost that is modified by TCR affinity during Tuberculosis

All relevant data are within the paper and its Supporting Information files except for the primary TCR sequences. The data files for the primary TCR sequences are publicly deposited in the University of Massachusetts Medical School’s institutional repository, eScholarship@UMMS. The permanent link to the data is http://dx.doi.org/10.13028/M2CC70T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.This work was supported by NIH R01 AI106725 as well as fellowship funding to SC from NIH AI T32 007061 and the UMass GSBS Millennium Program. The Small Animal Biocontainment Suite was supported in part by Center for AIDS Research Grant P30 AI 060354. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Elevational Gradients in Bird Diversity in the Eastern Himalaya: An Evaluation of Distribution Patterns and Their Underlying Mechanisms

BACKGROUND: Understanding diversity patterns and the mechanisms underlying those patterns along elevational gradients is critically important for conservation efforts in montane ecosystems, especially those that are biodiversity hotspots. Despite recent advances, consensus on the underlying causes, or even the relative influence of a suite of factors on elevational diversity patterns has remained elusive. METHODS AND PRINCIPAL FINDINGS: We examined patterns of species richness, density and range size distribution of birds, and the suite of biotic and abiotic factors (primary productivity, habitat variables, climatic factors and geometric constraints) that governs diversity along a 4500-m elevational gradient in the Eastern Himalayan region, a biodiversity hotspot within the world's tallest mountains. We used point count methods for sampling birds and quadrats for estimating vegetation at 22 sites along the elevational gradient. We found that species richness increased to approximately 2000 m, then declined. We found no evidence that geometric constraints influenced this pattern, whereas actual evapotranspiration (a surrogate for primary productivity) and various habitat variables (plant species richness, shrub density and basal area of trees) accounted for most of the variation in bird species richness. We also observed that ranges of most bird species were narrow along the elevation gradient. We find little evidence to support Rapoport's rule for the birds of Sikkim region of the Himalaya. CONCLUSIONS AND SIGNIFICANCE: This study in the Eastern Himalaya indicates that species richness of birds is highest at intermediate elevations along one of the most extensive elevational gradients ever examined. Additionally, primary productivity and factors associated with habitat accounted for most of the variation in avian species richness. The diversity peak at intermediate elevations and the narrow elevational ranges of most species suggest important conservation implications: not only should mid-elevation areas be conserved, but the entire gradient requires equal conservation attention