IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay

The IFNL3 (IL28B) gene has received immense attention in the hepatitis C virus (HCV) field as multiple independent genome-wide association studies identified a strong association between polymorphisms near the IFNL3 gene and HCV clearance. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) located in the 3′ untranslated region (3′ UTR) of the IFNL3 mRNA that dictates transcript stability. This polymorphism influences AU-rich element-mediated decay as well as the binding of HCV-induced microRNAs during infection. Together, these pathways mediate robust repression of the unfavorable IFNL3 genotype. These data reveal a novel mechanism by which HCV attenuates the antiviral response and uncover new potential therapeutic targets for HCV treatment

Bayesian Optimization of High‐Entropy Alloy Compositions for Electrocatalytic Oxygen Reduction**

Active, selective and stable catalysts are imperative for sustainable energy conversion, and engineering materials with such properties are highly desired. High-entropy alloys (HEAs) offer a vast compositional space for tuning such properties. Too vast, however, to traverse without the proper tools. Here, we report the use of Bayesian optimization on a model based on density functional theory (DFT) to predict the most active compositions for the electrochemical oxygen reduction reaction (ORR) with the least possible number of sampled compositions for the two HEAs Ag-Ir-Pd-Pt-Ru and Ir-Pd-Pt-Rh-Ru. The discovered optima are then scrutinized with DFT and subjected to experimental validation where optimal catalytic activities are verified for Ag-Pd, Ir-Pt, and Pd-Ru binary systems. This study offers insight into the number of experiments needed for exploring the vast compositional space of multimetallic alloys which has been determined to be on the order of 50 for ORR on these HEAs

IL-4, IL-13 and IFN-γ -induced genes in highly purified human neutrophils

Interleukin (IL)-4 and IL-13 are related cytokines with well-known specific roles in type 2 immune response. However, their effects on neutrophils are not completely understood. For this, we studied human primary neutrophil responses to IL-4 and IL-13. Neutrophils are dose-dependently responsive to both IL-4 and IL-13 as indicated by signal transducer and activator of transcription 6 (STAT6) phosphorylation upon stimulation, with IL-4 being more potent inducer of STAT6. IL-4-, IL-13- and Interferon (IFN)-γ-stimulated gene expression in highly purified human neutrophils induced both overlapping and unique gene expression in highly purified human neutrophils. IL-4 and IL-13 specifically regulate several immune-related genes, including IL-10, tumor necrosis factor (TNF) and leukemia inhibitory factor (LIF), while type1 immune response-related IFN-γ induced gene expression related for example, to intracellular infections. In analysis of neutrophil metabolic responses, oxygen independent glycolysis was specifically regulated by IL-4, but not by IL-13 or IFN-γ, suggesting specific role for type I IL-4 receptor in this process. Our results provide a comprehensive analysis of IL-4, IL-13 and IFN-γ -induced gene expression in neutrophils while also addressing cytokine-mediated metabolic changes in neutrophils.publishedVersionPeer reviewe

Assessing the impact of tailored biosecurity advice on farmer behaviour and pathogen presence in beef herds in England and Wales

The term ‘biosecurity’ encompasses many measures farmers can take to reduce the risk of pathogen incursion or spread. As the best strategy will vary between settings, veterinarians play an important role in assessing risk and providing advice, but effectiveness requires farmer acceptance and implementation. The aim of this study was to assess the effectiveness of specifically-tailored biosecurity advice packages in reducing endemic pathogen presence on UK beef suckler farms. One hundred and sixteen farms recruited by 10 veterinary practices were followed for three years. Farms were randomly allocated to intervention (receiving specifically-tailored advice, with veterinarians and farmers collaborating to develop an improved biosecurity strategy) or control (receiving general advice) groups. A spreadsheet-based tool was used annually to attribute a score to each farm reflecting risk of entry or spread of bovine viral diarrhoea virus (BVDV), bovine herpesvirus-1 (BHV1), Mycobacterium avium subsp. paratuberculosis (MAP), Leptospira interrogans serovar hardjo (L. hardjo) and Mycobacterium bovis (M. bovis). Objectives of these analyses were to identify evidence of reduction in risk behaviours during the study, as well as evidence of reductions in pathogen presence, as indications of effectiveness. Risk behaviours and pathogen prevalences were examined across study years, and on intervention compared with control farms, using descriptive statistics and multilevel regression. There were significant reductions in risk scores for all five pathogens, regardless of intervention status, in every study year compared with the outset. Animals on intervention farms were significantly less likely than those on control farms to be seropositive for BVDV in years 2 and 3 and for L. hardjo in year 3 of the study. Variations by study year in animal-level odds of seropositivity to BHV1 or MAP were not associated with farm intervention status. All farms had significantly reduced odds of BHV1 seropositivity in year 2 than at the outset. Variations in farm-level MAP seropositivity were not associated with intervention status. There were increased odds of M. bovis on intervention farms compared with control farms at the end of the study. Results suggest a structured annual risk assessment process, conducted as a collaboration between veterinarian and farmer, is valuable in encouraging improved biosecurity practices. There were some indications, but not conclusive evidence, that tailored biosecurity advice packages have potential to reduce pathogen presence. These findings will inform development of a collaborative approach to biosecurity between veterinarians and farmers, including adoption of cost-effective strategies effective across pathogens

Utilizing international networks for accelerating research and learning in transformational sustainability science

A promising approach for addressing sustainability problems is to recognize the unique conditions of a particular place, such as problem features and solution capabilities, and adopt and adapt solutions developed at other places around the world. Therefore, research and teaching in international networks becomes critical, as it allows for accelerating learning by sharing problem understandings, successful solutions, and important contextual considerations. This article identifies eight distinct types of research and teaching collaborations in international networks that can support such accelerated learning. The four research types are, with increasing intensity of collaboration: (1) solution adoption; (2) solution consultation; (3) joint research on different problems; and (4) joint research on similar problems. The four teaching types are, with increasing intensity of collaboration: (1) adopted course; (2) course with visiting faculty; (3) joint course with traveling faculty; and (4) joint course with traveling students. The typology is illustrated by extending existing research and teaching projects on urban sustainability in the International Network of Programs in Sustainability, with partner universities from Europe, North America, Asia, and Africa. The article concludes with challenges and strategies for extending individual projects into collaborations in international networks.Postprint (author's final draft

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