Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis.

Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. The most common cause of death in people with SSc is lung disease, but the pathogenesis of lung disease in SSc is insufficiently understood to devise specific treatment strategies. Developing targeted treatments requires not only the identification of molecular processes involved in SSc-associated lung disease, but also understanding of how these processes interact to drive pathology. One potentially powerful approach is to identify alleles that interact genetically to influence lung outcomes in patients with SSc. Analysis of interactions, rather than individual allele effects, has the potential to delineate molecular interactions that are important in SSc-related lung pathology. However, detecting genetic interactions, or epistasis, in human cohorts is challenging. Large numbers of variants with low minor allele frequencies, paired with heterogeneous disease presentation, reduce power to detect epistasis. Here we present an analysis that increases power to detect epistasis in human genome-wide association studies (GWAS). We tested for genetic interactions influencing lung function and autoantibody status in a cohort of 416 SSc patients. Using Matrix Epistasis to filter SNPs followed by the Combined Analysis of Pleiotropy and Epistasis (CAPE), we identified a network of interacting alleles influencing lung function in patients with SSc. In particular, we identified a three-gene network comprising WNT5A, RBMS3, and MSI2, which in combination influenced multiple pulmonary pathology measures. The associations of these genes with lung outcomes in SSc are novel and high-confidence. Furthermore, gene coexpression analysis suggested that the interactions we identified are tissue-specific, thus differentiating SSc-related pathogenic processes in lung from those in skin

System-Level Analysis of Alzheimer\u27s Disease Prioritizes Candidate Genes for Neurodegeneration.

Alzheimer\u27s disease (AD) is a debilitating neurodegenerative disorder. Since the advent of the genome-wide association study (GWAS) we have come to understand much about the genes involved in AD heritability and pathophysiology. Large case-control meta-GWAS studies have increased our ability to prioritize weaker effect alleles, while the recent development of network-based functional prediction has provided a mechanism by which we can use machine learning to reprioritize GWAS hits in the functional context of relevant brain tissues like the hippocampus and amygdala. In parallel with these developments, groups like the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) have compiled rich compendia of AD patient data including genotype and biomarker information, including derived volume measures for relevant structures like the hippocampus and the amygdala. In this study we wanted to identify genes involved in AD-related atrophy of these two structures, which are often critically impaired over the course of the disease. To do this we developed a combined score prioritization method which uses the cumulative distribution function of a gene\u27s functional and positional score, to prioritize top genes that not only segregate with disease status, but also with hippocampal and amygdalar atrophy. Our method identified a mix of genes that had previously been identified in AD GWAS including APOE, TOMM40, and NECTIN2(PVRL2) and several others that have not been identified in AD genetic studies, but play integral roles in AD-effected functional pathways including IQSEC1, PFN1, and PAK2. Our findings support the viability of our novel combined score as a method for prioritizing region- and even cell-specific AD risk genes

A functional assay for serum detection of antibodies against SARS-CoV-2 nucleoprotein.

The humoral immune response to SARS-CoV-2 results in antibodies against spike (S) and nucleoprotein (N). However, whilst there are widely available neutralization assays for S antibodies, there is no assay for N-antibody activity. Here, we present a simple in vitro method called EDNA (electroporated-antibody-dependent neutralization assay) that provides a quantitative measure of N-antibody activity in unpurified serum from SARS-CoV-2 convalescents. We show that N antibodies neutralize SARS-CoV-2 intracellularly and cell-autonomously but require the cytosolic Fc receptor TRIM21. Using EDNA, we show that low N-antibody titres can be neutralizing, whilst some convalescents possess serum with high titres but weak activity. N-antibody and N-specific T-cell activity correlates within individuals, suggesting N antibodies may protect against SARS-CoV-2 by promoting antigen presentation. This work highlights the potential benefits of N-based vaccines and provides an in vitro assay to allow the antibodies they induce to be tested

State-Dependent Differences in Functional Connectivity in Young Children With Autism Spectrum Disorder

AbstractBackgroundWhile there is increasing evidence of altered brain connectivity in autism, the degree and direction of these alterations in connectivity and their uniqueness to autism has not been established. The aim of the present study was to compare connectivity in children with autism to that of typically developing controls and children with developmental delay without autism.MethodsWe assessed EEG spectral power, coherence, phase lag, Pearson and partial correlations, and epileptiform activity during the awake, slow wave sleep, and REM sleep states in 137 children aged 2 to 6years with autism (n=87), developmental delay without autism (n=21), or typical development (n=29).FindingsWe found that brain connectivity, as measured by coherence, phase lag, and Pearson and partial correlations distinguished children with autism from both neurotypical and developmentally delayed children. In general, children with autism had increased coherence which was most prominent during slow wave sleep.InterpretationFunctional connectivity is distinctly different in children with autism compared to samples with typical development and developmental delay without autism. Differences in connectivity in autism are state and region related. In this study, children with autism were characterized by a dynamically evolving pattern of altered connectivity

VA residential substance use disorder treatment program providers’ perceptions of facilitators and barriers to performance on pre-admission processes

Abstract Background In the U.S. Department of Veterans Affairs (VA), residential treatment programs are an important part of the continuum of care for patients with a substance use disorder (SUD). However, a limited number of program-specific measures to identify quality gaps in SUD residential programs exist. This study aimed to: (1) Develop metrics for two pre-admission processes: Wait Time and Engagement While Waiting, and (2) Interview program management and staff about program structures and processes that may contribute to performance on these metrics. The first aim sought to supplement the VA’s existing facility-level performance metrics with SUD program-level metrics in order to identify high-value targets for quality improvement. The second aim recognized that not all key processes are reflected in the administrative data, and even when they are, new insight may be gained from viewing these data in the context of day-to-day clinical practice. Methods VA administrative data from fiscal year 2012 were used to calculate pre-admission metrics for 97 programs (63 SUD Residential Rehabilitation Treatment Programs (SUD RRTPs); 34 Mental Health Residential Rehabilitation Treatment Programs (MH RRTPs) with a SUD track). Interviews were then conducted with management and front-line staff to learn what factors may have contributed to high or low performance, relative to the national average for their program type. We hypothesized that speaking directly to residential program staff may reveal innovative practices, areas for improvement, and factors that may explain system-wide variability in performance. Results Average wait time for admission was 16 days (SUD RRTPs: 17 days; MH RRTPs with a SUD track: 11 days), with 60% of Veterans waiting longer than 7 days. For these Veterans, engagement while waiting occurred in an average of 54% of the waiting weeks (range 3–100% across programs). Fifty-nine interviews representing 44 programs revealed factors perceived to potentially impact performance in these domains. Efficient screening processes, effective patient flow, and available beds were perceived to facilitate shorter wait times, while lack of beds, poor staffing levels, and lengths of stay of existing patients were thought to lengthen wait times. Accessible outpatient services, strong patient outreach, and strong encouragement of pre-admission outpatient treatment emerged as facilitators of engagement while waiting; poor staffing levels, socioeconomic barriers, and low patient motivation were viewed as barriers. Conclusions Metrics for pre-admission processes can be helpful for monitoring residential SUD treatment programs. Interviewing program management and staff about drivers of performance metrics can play a complementary role by identifying innovative and other strong practices, as well as high-value targets for quality improvement. Key facilitators of high-performing facilities may offer programs with lower performance useful strategies to improve specific pre-admission processes

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that the epigenetic landscape was highly variable across the DO founders and was associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice

A genetic locus complements resistance to Bordetella pertussis-induced histamine sensitization.

Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with

Effect of Dietary Fiber Intake on Lipoprotein Cholesterol Levels Independent of Estradiol in Healthy Premenopausal Women

High-fiber diets are associated with improved lipid profiles. However, pre- and postmenopausal women respond differently to fiber intake, suggesting that endogenous estradiol mediates the effect. The authors' objective was to determine the direct effect of fiber intake on lipoprotein cholesterol levels independent of estradiol among premenopausal women. The BioCycle Study, a prospective cohort study conducted at the State University of New York at Buffalo from 2005 to 2007, followed 259 healthy women for up to 2 complete menstrual cycles. Serum lipoprotein and hormone levels were measured at 16 visits timed using fertility monitors. Fiber intake was assessed by 8 24-hour recalls. Marginal structural models with inverse probability weights for both lipoprotein and estradiol levels were used to estimate controlled direct effects of the highest category of fiber intake (≥22 g/day vs. <22 g/day) while accounting for age, body mass index, total energy, vitamin E intake, physical activity, luteinizing hormone, follicle-stimulating hormone, and progesterone. Reductions were observed in total and low density lipoprotein cholesterol in women with higher fiber intakes. Direct effects were greater than total effects. These analyses suggested that estradiol mediates at least part of the association between fiber and cholesterol among premenopausal women. More research is needed to elucidate the biologic mechanisms driving these associations

A framework for evaluating the influence of climate, dispersal limitation, and biotic interactions using fossil pollen associations across the late Quaternary

Environmental conditions, dispersal lags, and interactions among species are major factors structuring communities through time and across space. Ecologists have emphasized the importance of biotic interactions in determining local patterns of species association. In contrast, abiotic limits, dispersal limitation, and historical factors have commonly been invoked to explain community structure patterns at larger spatiotemporal scales, such as the appearance of late Pleistocene no-analog communities or latitudinal gradients of species richness in both modern and fossil assemblages. Quantifying the relative influence of these processes on species co-occurrence patterns is not straightforward. We provide a framework for assessing causes of species associations by combining a null-model analysis of co-occurrence with additional analyses of climatic differences and spatial pattern for pairs of pollen taxa that are significantly associated across geographic space. We tested this framework with data on associations among 106 fossil pollen taxa and paleoclimate simulations from eastern North America across the late Quaternary. The number and proportion of significantly associated taxon pairs increased over time, but only 449 of 56 194 taxon pairs were significantly different from random. Within this significant subset of pollen taxa, biotic interactions were rarely the exclusive cause of associations. Instead, climatic or spatial differences among sites were most frequently associated with significant patterns of taxon association. Most taxon pairs that exhibited co-occurrence patterns indicative of biotic interactions at one time did not exhibit significant associations at other times. Evidence for environmental filtering and dispersal limitation was weakest for aggregated pairs between 16 and 11 kyr BP, suggesting enhanced importance of positive species interactions during this interval. The framework can thus be used to identify species associations that may reflect biotic interactions because these associations are not tied to environmental or spatial differences. Furthermore, temporally repeated analyses of spatial associations can reveal whether such associations persist through time

Sustaining The Saco Estuary: Final Report 2015

This study focuses on the Saco estuary, the tidal portion of the Saco River, which drains the largest watershed in southern Maine. With headwaters in the White Mountains of New Hampshire, the watershed encompasses more than 4,400 km2, and provides clean healthy drinking water to over 100,000 people living and working in communities in southern Maine. When the study began in 2009, very little was known about the ecology of the Saco estuary. Researchers at the University of New England and the Wells National Estuarine Research Reserve employed the process of collaborative learning to bring together people who care about the estuary in order to identify their concerns. A Stewardship Network composed of people employed by municipal, state and federal governments, water supply organizations and businesses, volunteers from municipal boards making land use decisions, land trusts, property owners and representatives from other organizations that are uniquely focused on the region was formed. The Stewardship Network helped to define the project goals and objectives, and provided input and guidance over the five-year project. This report explains what the researchers discovered about the ecology of the estuary, along with what they learned about its social and economic components. This baseline assessment contributes to the long-term goal of restoring and sustaining the structure and function of the estuary, and supports the efforts of government, businesses and local organizations that value the estuary and depend upon the natural services it provides