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1.
European Respiratory Journal ; 58:2, 2021.
Article in English | Web of Science | ID: covidwho-1707071
3.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-328526

ABSTRACT

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

4.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326637

ABSTRACT

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

5.
Obesity ; 29(SUPPL 2):189-190, 2021.
Article in English | EMBASE | ID: covidwho-1616053

ABSTRACT

Background: Individuals living in rural areas have higher obesity and obesity related co-morbidities than their urban counterparts. Understanding rural-urban differences associated with weight management may inform the development of effective weight management interventions for adults living in rural areas. Methods: The International Weight Control Registry (IWCR) is an online registry designed to assess factors contributing to successes and challenges with weight loss and weight loss maintenance across the world. We examined demographics, weight history and weight management strategies in a sample of urban and rural residents in the Midwestern U.S. (IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, WI). Participants were classified as rural or urban by the Rural-Urban Commuting Area Code. Analyses included Chi-square tests for proportions and independent t-test and Wilcoxon rank sum test for continuous variables. Results: The sample was 45% rural (n = 78 of a total N = 174) with a mean age of 50.3 years. Rural residents were more likely to be white, non-college graduates, and have lower family income compared with urban areas (p < 0.05). Rural and urban residents reported similar weight histories and strategies for weight management. Work-related physical activity was higher and weekday sitting time was lower in rural compared to urban residents (p < 0.01). These data could potentially be impacted by the relative number of residents working from home during COVID-19 (Urban: 59% vs. Rural: 37%, p < 0.05). Rural residents were more likely to report a lack of neighborhood walkability (p < 0.01) and healthy food availability (p < 0.05) compared with urban residents. Conclusions: These data suggest rural-urban differences in demographic characteristics, opportunity for leisure time physical activity, and the availability of heathy foods should be considered in the development of weight management interventions. The consistency of the observed findings will be evaluated at the regional, national and international levels as the size of the available sample in the IWCR increases.

6.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-296972

ABSTRACT

The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

7.
Occupational and Environmental Medicine ; 78(SUPPL 1):A25-A26, 2021.
Article in English | EMBASE | ID: covidwho-1571265

ABSTRACT

Introduction 'Take-home exposures' occur when workers accidentally bring home contaminants from work. In construction, job responsibilities may expose workers to lead and other metals, which extend to their household members via the take-home pathway. It is crucial that construction workers are aware of the take-home pathway and learn about exposure prevention strategies. Objectives This work is part of the RECLEAN Pilot Study, which aims to reduce lead in the homes of construction workers through educational and environmental interventions. Methods We developed and evaluated a suite of educational materials to train construction workers and their families on strategies to prevent take-home lead exposure. Each of the two sessions targets a specific audience, with one tailored to construction workers and the other to workers' family or household members. The sessions were originally developed to take place in person but given the COVID-19 pandemic we adapted them for online delivery as well. Results Like traditional occupational health and safety trainings, the construction worker sessions present workers with best practices to prevent take-home lead and open discussion for how such practices may fit into their own routine after work. Alternatively, the family session is designed to engage household members in discussion through a process derived from motivational interviewing. The materials for both sessions include an introduction, behavior scoring sheet, behavior wheel, and action plan. Facilitators and participants discuss strategies to prevent take-home lead, identify barriers participants (and their coworkers or families) experience when trying to change their behaviors, and ultimately prioritize a prevention goal. Conclusion The materials for both educational sessions were developed based on current literature on take-home lead and behavioral theories and in partnership with lead and construction experts from multiple organizations. Using feedback from participants, project stakeholders, and session facilitators, we evaluate the feasibility and efficacy of these educational interventions.

8.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-8952

ABSTRACT

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

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