Endomembrane targeting of human OAS1 p46 augments antiviral activity

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity

Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4

Background: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. Objective: This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. Methods: We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP1-4 were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. Results: Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. Conclusions:Our data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition

Prima facie reasons to question enclosed intellectual property regimes and favor open-source regimes for germplasm

In principle, intellectual property protections (IPPs) promote and protect important but costly investment in research and development. However, the empirical reality of IPPs has often gone without critical evaluation, and the potential of alternative approaches to lend equal or greater support for useful innovation is rarely considered. In this paper, we review the mounting evidence that the global intellectual property regime (IPR) for germplasm has been neither necessary nor sufficient to generate socially beneficial improvements in crop plants and maintain agrobiodiversity. Instead, based on our analysis, the dominant global IPR appears to have contributed to consolidation in the seed industry while failing to genuinely engage with the potential of alternatives to support social goods such as food security, adaptability, and resilience. The dominant IPR also constrains collaborative and cumulative plant breeding processes that are built upon the work of countless farmers past and present. Given the likely limits of current IPR, we propose that social goods in agriculture may be better supported by alternative approaches, warranting a rapid move away from the dominant single-dimensional focus on encouraging innovation through ensuring monopoly profits to IPP holders

Genetic Landscape of the ACE2 Coronavirus Receptor

Background:SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood.Methods:We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics–based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.Results:We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis–protein quantitative trait loci–based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10–2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05–2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08–2.37]; P=0.02). Tissue- and cell type–specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells.Conclusions:Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Interlopers in Class: A Duoethnography of Working-Class Women Academics

This paper introduces the concept of the interloper for examining classed and gendered dislocation. Focusing on academia, which we view as a classed and gendered field, we draw on Bourdieu and feminist standpoint theory to account for how we, as women of working-class origin, have experienced ‘breaches’ through which we have come to understand ourselves in classed and gendered terms. Coming from different cultural backgrounds, we also reflect on how understandings of class are context-specific. We employ a duoethnographic method which emphasizes the value of subjective experiences for organizational and social analyses. The paper shows how the concept of the interloper may shed light on the dynamic, relational character of constructions of class and gender; the maintenance work that is performed; and how a sense of permanent inbetweenness characterizes our ongoing movement between the fields of the family and academia

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Family Resources in Two Generations and School Readiness Among Children of Teen Parents

Overall, children born to teen parents experience disadvantaged cognitive achievement at school entry compared with children born to older parents. However, within this population, there is variation, with a significant fraction of teen parents’ children acquiring adequate preparation for school entry during early childhood. We ask whether the family background of teen parents explains this variation. We use data on children born to teen mothers from three waves of the Early Childhood Longitudinal Study-Birth Cohort (N ~ 700) to study the association of family background with children’s standardized reading and mathematics achievement scores at kindergarten entry. When neither maternal grandparent has completed high school, children’s scores on standardized assessments of math and reading achievement are one-quarter to one-third of a standard deviation lower compared with families where at least one grandparent finished high school. This association is net of teen mothers’ own socioeconomic status in the year prior to children’s school entry

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease:a clinical study

Abstract Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been gaining importance in the treatment of advanced Parkinson's disease. This study was undertaken to evaluate the beneficial effects of bilateral STN stimulation on patient's clinical symptoms and quality of life related to the potential risks and side effects of the treatment. A consecutive series of 42 patients operated on for Parkinson's disease with STN DBS in Oulu University Hospital were included. A subgroup of these patients was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS), neuropsychological tests, and Health Related Quality of Life (HRQoL) instruments i.e. the Parkinson's Disease Questionnaire (PDQ-39) and the Finnish version of the Nottingham Health Profile (NHP). The costs of the treatment were calculated from the perspective of the health care provider. The possible effects of bilateral STN-operation on cardiovascular autonomic function were analyzed by measuring various time- and frequency domain indexes as well as non-linear indexes of heart rate variability (HRV) from 24-hour EKG recording before and 12 months after the operation. This study showed that STN DBS significantly improves the clinical symptoms and HRQoL of parkinsonian patients. The dyskinesia and clinical fluctuation scores were reduced very significantly in the UPDRS IV subscale. The clinical fluctuations were reduced by 53 %. After DBS best motor response (UPDRS III) scores also improved significantly. The HRQoL measured with both instruments improved significantly. Improvement was seen in the PDQ-39 summary index and the subscales of activities of daily living, emotional well-being, stigma and bodily discomfort. Only communication became worse during the follow-up. There was a statistically significant improvement in the score of the subscales of NHP measuring problems with energy, sleep, emotional reactions and social isolation. One patient died from pulmonary embolism and another contracted a late postoperative intracerebral hemorrhage leading to a permanent deterioration of her neurological condition to the bedridden stage. Other complications were much milder. Clinical improvement and improvement in HRQoL were positively correlated. STN DBS does not influence tonic autonomic cardiovascular regulation. The incremental costs of performing bilateral STN DBS in Finland compared to preoperative medical treatment amounted to an average of 25 591 EUR per patient during the first postoperative year. The majority of parkinsonian patients experienced significant and long lasting relief in their motor symptoms and an improvement in HRQoL following STN stimulation