P2X receptors: epithelial ion channels and regulators of salt and water transport.

When the results from electrophysiological studies of renal epithelial cells are combined with data from in vivo tubule microperfusion experiments and immunohistochemical surveys of the nephron, the accumulated evidence suggests that ATP-gated ion channels, P2X receptors, play a specialized role in the regulation of ion and water movement across the renal tubule and are integral to electrolyte and fluid homeostasis. In this short review, we discuss the concept of P2X receptors as regulators of salt and water salvage pathways, as well as acknowledging their accepted role as ATP-gated ion channels

Genomic differentiation during speciation-with-gene-flow: Comparing geographic and host-related variation in divergent life history adaptation in rhagoletis pomonella

A major goal of evolutionary biology is to understand how variation within populations gets partitioned into differences between reproductively isolated species. Here, we examine the degree to which diapause life history timing, a critical adaptation promoting population divergence, explains geographic and host-related genetic variation in ancestral hawthorn and recently derived apple-infesting races of Rhagoletis pomonella. Our strategy involved combining experiments on two different aspects of diapause (initial diapause intensity and adult eclosion time) with a geographic survey of genomic variation across four sites where apple and hawthorn flies co-occur from north to south in the Midwestern USA. The results demonstrated that the majority of the genome showing significant geographic and host-related variation can be accounted for by initial diapause intensity and eclosion time. Local genomic differences between sympatric apple and hawthorn flies were subsumed within broader geographic clines; allele frequency differences within the races across the Midwest were two to three-fold greater than those between the races in sympatry. As a result, sympatric apple and hawthorn populations displayed more limited genomic clustering compared to geographic populations within the races. The findings suggest that with reduced gene flow and increased selection on diapause equivalent to that seen between geographic sites, the host races may be recognized as different genotypic entities in sympatry, and perhaps species, a hypothesis requiring future genomic analysis of related sibling species to R. pomonella to test. Our findings concerning the way selection and geography interplay could be of broad significance for many cases of earlier stages of divergence-with-gene flow, including (1) where only modest increases in geographic isolation and the strength of selection may greatly impact genetic coupling and (2) the dynamics of how spatial and temporal standing variation is extracted by selection to generate differences between new and discrete units of biodiversity

Expectations and beliefs: How single young gay, bisexual and other men who have sex with men envision romantic relationships

We developed measures of relational beliefs and expectations among single young gay and bisexual men (YGBM). Data come from an online cross-sectional study YGBM, which ran from July 2012 until January 2013. There were 50 items on relational beliefs and 25 items on relational expectations. We used random split samples and a priori analysis to group items together and applied principal axis factoring with varimax orthogonal rotation. We had a total N = 1582 in our analytical sample and identified six constructs of relational expectations (restrictions, negative break up, masculine and gender norms, optimism, cheating, immediacy) and two constructs of relational beliefs (sex beliefs, equality). Our findings highlight specific relational cognitions among YGBM and offer insight into the beliefs and expectations that may inform their relationships. Findings may be useful for health professionals to help YGBM reflect and understand the health implications of their beliefs and expectations about same-sex relationships to promote healthy decision-making as they seek future partners

Multifactorial discrimination, discrimination salience, and prevalent experiences of internalized homophobia in middle-aged and older MSM

Objectives: We sought to test whether discrimination salience and multifactorial discrimination were associated with prevalent experiences of internalized homophobia among middle-aged and older men who have sex with men (MSM). Methods: We analyzed data from 498 middle-aged and older MSM from the Multicenter AIDS Cohort Study (MACS) who reported any lifetime discrimination experience. We estimated the prevalence ratio of current internalized homophobia using multivariable Poisson regressions, accounting for discrimination salience, multifactorial discrimination, and covariates. We then assessed whether multifactorial discrimination moderated the association between discrimination salience and internalized homophobia. Results: Over half (56.4%) of our sample reported any current experience of internalized homophobia. More than two-thirds reported multifactorial discrimination (68.2%) and more than one-third (36.7%) reported moderate-to-high discrimination salience. Increases in discrimination salience (PR = 1.11; 95% CI: 1.03-1.20) were associated with any current internalized homophobia among middle-aged and older MSM. Multifactorial discrimination was not statistically associated with internalized homophobia and did not moderate the association between discrimination salience and internalized homophobia. Conclusions: Our study underscores internalized homophobia as a persisting concern among MSM in midlife and older adulthood. Our findings suggest that salience, as a characteristic of discrimination experiences, may have a greater impact on internalized homophobia compared with exposure. Future research efforts should assess facets of discrimination salience, such as severity, frequency, and chronicity, to better understand how discrimination shapes psychosocial well-being across the life course. Mental health advocates at policy, organizational, and community levels should aim to reduce intersectional stigma and address individual experiences of internalized homophobia

Standing geographic variation in eclosion time and the genomics of host race formation in Rhagoletis pomonella fruit flies.

Taxa harboring high levels of standing variation may be more likely to adapt to rapid environmental shifts and experience ecological speciation. Here, we characterize geographic and host-related differentiation for 10,241 single nucleotide polymorphisms in Rhagoletis pomonella fruit flies to infer whether standing genetic variation in adult eclosion time in the ancestral hawthorn (Crataegus spp.)-infesting host race, as opposed to new mutations, contributed substantially to its recent shift to earlier fruiting apple (Malus domestica). Allele frequency differences associated with early vs. late eclosion time within each host race were significantly related to geographic genetic variation and host race differentiation across four sites, arrayed from north to south along a 430-km transect, where the host races co-occur in sympatry in the Midwest United States. Host fruiting phenology is clinal, with both apple and hawthorn trees fruiting earlier in the North and later in the South. Thus, we expected alleles associated with earlier eclosion to be at higher frequencies in northern populations. This pattern was observed in the hawthorn race across all four populations; however, allele frequency patterns in the apple race were more complex. Despite the generally earlier eclosion timing of apple flies and corresponding apple fruiting phenology, alleles on chromosomes 2 and 3 associated with earlier emergence were paradoxically at lower frequency in the apple than hawthorn host race across all four sympatric sites. However, loci on chromosome 1 did show higher frequencies of early eclosion-associated alleles in the apple than hawthorn host race at the two southern sites, potentially accounting for their earlier eclosion phenotype. Thus, although extensive clinal genetic variation in the ancestral hawthorn race exists and contributed to the host shift to apple, further study is needed to resolve details of how this standing variation was selected to generate earlier eclosing apple fly populations in the North

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Progress in understanding error-field physics in NSTX spherical torus plasmas

The low-aspect ratio, low magnetic field and wide range of plasma beta of NSTX plasmas provide new insight into the origins and effects of magnetic field errors. An extensive array of magnetic sensors has been used to analyse error fields, to measure error-field amplification and to detect resistive wall modes (RWMs) in real time. The measured normalized error-field threshold for the onset of locked modes shows a linear scaling with plasma density, a weak to inverse dependence on toroidal field and a positive scaling with magnetic shear. These results extrapolate to a favourable error-field threshold for ITER. For these low-beta locked-mode plasmas, perturbed equilibrium calculations find that the plasma response must be included to explain the empirically determined optimal correction of NSTX error fields. In high-beta NSTX plasmas exceeding the n = 1 no-wall stability limit where the RWM is stabilized by plasma rotation, active suppression of n = 1 amplified error fields and the correction of recently discovered intrinsic n = 3 error fields have led to sustained high rotation and record durations free of low-frequency core MHD activity. For sustained rotational stabilization of the n = 1 RWM, both the rotation threshold and the magnitude of the amplification are important. At fixed normalized dissipation, kinetic damping models predict rotation thresholds for RWM stabilization to scale nearly linearly with particle orbit frequency. Studies for NSTX find that orbit frequencies computed in general geometry can deviate significantly from those computed in the high-aspect ratio and circular plasma cross-section limit, and these differences can strongly influence the predicted RWM stability. The measured and predicted RWM stability is found to be very sensitive to the E 7 B rotation profile near the plasma edge, and the measured critical rotation for the RWM is approximately a factor of two higher than predicted by the MARS-F code using the semi-kinetic damping model