Enrichment of schizophrenia heritability in both neuronal and glia cell regulatory elements

Genome-wide association studies have identified over 100 robust risk loci for schizophrenia with thousands of variants mediating genetic heritability, the majority of which reside in non-coding regions. Analytical approaches have shown this heritability is strongly enriched at variants within regulatory elements identified from human post-mortem brain tissue. However, bulk post-mortem brain tissue has a heterogeneous cell composition, making biological interpretations difficult. We sought to refine the cell types mediating schizophrenia heritability by separating neuronal and glial signals using data from: (1) NeuN-sorted post-mortem brain and (2) cell culture systems. Schizophrenia heritability was partitioned using linkage disequilbrium (LD) score regression. Variants within genomic regions marked by H3K4me3 (marker of active promoters) from NeuN-positive (neuronal) and NeuN-negative (non-neuronal) cells explained a significant amount of schizophrenia heritability (P = 1.38 × 10−10 and P = 7.97 × 10−10). However, variants located in H3K4me3 sites specific to NeuN-positive (neuronal) cells were enriched (P = 3.13 × 10−4), while those specific to NeuN-negative (non-neuronal) cells were not (P = 0.470). Data from cell culture systems mimicked this pattern of association. We show the previously observed enrichment of heritability from variants at brain H3K4me3 sites is mediated by both neuronal and non-neuronal brain cell types. However, only neuronal cell populations showed a unique contribution driven by cell-type specific regulatory elements. Cell culture systems recapitulate disease relevant gene-regulatory landscapes, validating them as a tool for future investigation of genetic mechanisms underlying schizophrenia. Identifying the cell types in which risk variants operate will greatly increase our understanding of schizophrenia pathobiology and aid in the development of novel model systems and therapies

Optical spectroscopy of radio galaxies in the 7C Redshift Survey

We present optical spectroscopy of all 49 radio galaxies in the 7C-I and 7C-II regions of the 7C Redshift Survey (7CRS). The low-frequency (151 MHz) selected 7CRS sample contains all sources with flux-densities S_151 > 0.5 Jy in three regions of the sky; 7C-I and 7C-II were chosen to overlap with the 5C6 and 5C7 surveys respectively, and cover a total sky area of 0.013 sr. The sample has been completely identified and spectroscopy of the quasars and broad-lined radio galaxies has been presented in Willott et al. (1998). Only seven of the radio galaxies do not have redshift determinations from the spectroscopy, giving a redshift completeness for the sample of >90%. The median redshift of the 7CRS is 1.1. We present a composite 0.2<z<0.8 7CRS radio galaxy spectrum and investigate the strengths of the 4000 Angstrom breaks in these radio galaxies. We find an anti-correlation between the 4000 Angstrom break strength and emission line luminosity, indicating that departures from old elliptical galaxy continuum shapes are most likely due to non-stellar emission associated with the active nucleus.Comment: 14 pages, 6 figures, MNRAS in pres

Genetic risk for Alzheimer's disease is concentrated in specific macrophage and microglial transcriptional networks

Background: Genome-wide association studies of Alzheimer’s disease (AD) have identified a number of significant risk loci, the majority of which lie in non-coding regions of the genome. The lack of causal alleles and considerable polygenicity remains a significant barrier to translation into mechanistic understanding. This includes identifying causal variants and the cell/tissue types in which they operate. A fuller understanding of the cell types and transcriptional networks involved in AD genetic risk mechanisms will provide important insights into pathogenesis. Methods: We assessed the significance of the overlap between genome-wide significant AD risk variants and sites of open chromatin from data sets representing diverse tissue types. We then focussed on macrophages and microglia to investigate the role of open chromatin sites containing motifs for specific transcription factors. Partitioned heritability using LDscore regression was used to investigate the contribution of specific macrophage and microglia transcription factor motif-containing open chromatin sites to the heritability of AD. Results: AD risk single nucleotide polymorphisms (SNPs) are preferentially located at sites of open chromatin in immune cells, particularly monocytes (z score = 4.43; corrected P = 5.88 × 10− 3). Similar enrichments are observed for macrophages (z score = 4.10; corrected P < 2.40 × 10− 3) and microglia (z score = 4.34, corrected P = 0.011). In both macrophages and microglia, AD risk variants are enriched at a subset of open chromatin sites that contain DNA binding motifs for specific transcription factors, e.g. SPI1 and MEF2. Genetic variation at many of these motif-containing sites also mediate a substantial proportion of AD heritability, with SPI1-containing sites capturing the majority of the common variant SNP-chip heritability (microglia enrichment = 16.28, corrected enrichment P = 0.0044). Conclusions: AD risk alleles plausibly operate in immune cells, including microglia, and are concentrated in specific transcriptional networks. Combined with primary genetic association results, the SPI1 and MEF2 transcriptional networks appear central to AD risk mechanisms. Investigation of transcription factors targeting AD risk SNP associated regulatory elements could provide powerful insights into the molecular processes affected by AD polygenic risk. More broadly, our findings support a model of polygenic disease risk that arises from variants located in specific transcriptional networks

High Redshift Massive Quiescent Galaxies are as Flat as Star Forming Galaxies: The Flattening of Galaxies and the Correlation with Structural Properties in CANDELS/3D-HST

We investigate the median flattening of galaxies at $0.2<z<4.0$ in all five CANDELS/3D-HST fields via the apparent axis ratio $q$. We separate the sample into bins of redshift, stellar-mass, s\'ersic index, size, and UVJ determined star-forming state to discover the most important drivers of the median $q$ ($q_{med}$). Quiescent galaxies at $z10^{11}M_{\odot}$ are rounder than those at lower masses, consistent with the hypothesis that they have grown significantly through dry merging. The massive quiescent galaxies at higher redshift become flatter, and are as flat as star forming massive galaxies at $2.5<z<3.5$, consistent with formation through direct transformations or wet mergers. We find that in quiescent galaxies, correlations with $q_{med}$ and $M_{*}$, $z$ and $r_{e}$ are driven by the evolution in the s\'ersic index ($n$), consistent with the growing accumulation of minor mergers at lower redshift. Interestingly, $n$ does not drive these trends fully in star-forming galaxies. Instead, the strongest predictor of $q$ in star-forming galaxies is the effective radius, where larger galaxies are flatter. Our findings suggest that $q_{med}$ is tracing bulge-to-total ($B/T$) galaxy ratio which would explain why smaller/more massive star-forming galaxies are rounder than their extended/less massive analogues, although it is unclear why s\'ersic index correlates more weakly with flattening for star forming galaxies than for quiescent galaxies.Comment: 13 pages, 11 figures, accepted to Ap

Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells

Cancer associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here we show that CAFs exposed to chemotherapy play an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance

Public understandings of potential policy responses to health inequalities:Evidence from a UK national survey and citizens’ juries in three UK cities

A substantial body of research describes the distribution, causes and potential reduction of health inequalities, yet little scholarship examines public understandings of these inequalities. Existing work is dominated by small-scale, qualitative studies of the experiences of specific communities. As a result, we know very little about what broader publics think about health inequalities; and even less about public views of potential policy responses. This is an important gap since previous research shows many researchers and policymakers believe proposals for ‘upstream’ policies are unlikely to attract sufficient public support to be viable. This mixed methods study combined a nationally representative survey with three two-day citizens' juries exploring public views of health inequalities and potential policy responses in three UK cities (Glasgow, Manchester and Liverpool) in July 2016. Comparing public opinion elicited via a survey to public reasoning generated through deliberative processes offers insight into the formation of public views. The results challenge perceptions that there is a lack of public support for upstream, macro-level policy proposals and instead demonstrate support for proposals aiming to tackle health inequalities via improvements to living and working conditions, with more limited support for proposals targeting individual behavioural change. At the same time, some macro-economic proposals, notably those involving tax increases, proved controversial among study participants and results varied markedly by data source. Our analysis suggests that this results from three intersecting factors: a resistance to ideas viewed as disempowering (which include, fundamentally, the idea that health inequalities exist); the prevalence of individualising and fatalistic discourses, which inform resistance to diverse policy proposals (but especially those that are more ‘upstream’, macro-level proposals); and a lack of trust in (local and national) government. This suggests that efforts to enhance public support for evidence-informed policy responses to health inequalities may struggle unless these broader challenges are also addressed

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism

<p>Abstract</p> <p>Background</p> <p>Arginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (<it>AVPR1A</it>) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at <it>AVPR1A </it>has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of <it>AVPR1A </it>in variable gene expression and social behaviour.</p> <p>Methods</p> <p>We examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the <it>AVPR1A </it>gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human <it>AVPR1A</it>, RS3 and RS1, were also tested for their effect on relative promoter activity.</p> <p>Results</p> <p>The short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (<it>P </it>= 0.036 and <it>P </it>= 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y.</p> <p>Conclusions</p> <p>These aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased <it>AVPR1A </it>transcription, which may proffer increased susceptibility to the autism phenotype.</p

Creating a Culture of Voting in Direct and Generalist Practice: Training Field Instructors

Social workers have an ethical responsibility to be engaged in policy change, regardless of their practice area or specialization. Voter engagement and the importance of political power through voting is often overlooked in the literature as a valid and important component of social work practice. Creating a culture of nonpartisan voter engagement in practice settings can help empower individuals who have been historically and intentionally disenfranchised from our electoral system. Training for field instructors, faculty, and field staff is a key aspect of voter engagement in social work education. Unfortunately, social work education is unlikely to include substantive content on voter engagement or its connection to social work practice and impact. This article presents one component of a model for integrating voter engagement into social work education: the provision of training for field instructors on nonpartisan voter engagement at two universities over two years. Evaluation findings suggest that pre-existing levels of political efficacy affect the reaction of field instructors to nonpartisan voter engagement training. Furthermore, findings indicate that field instructors who receive voter engagement training are more likely to serve as resources for their students and to consider voter engagement as part of their own practice. We offer evidence on the important role field educators can play in the success of the larger national effort to integrate voter engagement in social work education. Increasing awareness of what social workers, nonprofit, and public agencies are allowed--or even required--to do is a critical first step

The mass, colour, and structural evolution of today's massive galaxies since z~5

In this paper, we use stacking analysis to trace the mass-growth, colour evolution, and structural evolution of present-day massive galaxies ($\log(M_{*}/M_{\odot})=11.5$) out to $z=5$. We utilize the exceptional depth and area of the latest UltraVISTA data release, combined with the depth and unparalleled seeing of CANDELS to gather a large, mass-selected sample of galaxies in the NIR (rest-frame optical to UV). Progenitors of present-day massive galaxies are identified via an evolving cumulative number density selection, which accounts for the effects of merging to correct for the systematic biases introduced using a fixed cumulative number density selection, and find progenitors grow in stellar mass by $\approx1.5~\mathrm{dex}$ since $z=5$. Using stacking, we analyze the structural parameters of the progenitors and find that most of the stellar mass content in the central regions was in place by $z\sim2$, and while galaxies continue to assemble mass at all radii, the outskirts experience the largest fractional increase in stellar mass. However, we find evidence of significant stellar mass build up at $r4$ probing an era of significant mass assembly in the interiors of present day massive galaxies. We also compare mass assembly from progenitors in this study to the EAGLE simulation and find qualitatively similar assembly with $z$ at $r<3~\mathrm{kpc}$. We identify $z\sim1.5$ as a distinct epoch in the evolution of massive galaxies where progenitors transitioned from growing in mass and size primarily through in-situ star formation in disks to a period of efficient growth in $r_{e}$ consistent with the minor merger scenario.Comment: 19 pages, 14 figures, accepted for publicatio

Behaviour and the safety of older people on stairs

Behaviour and the safety of older people on stair