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

On the relational dynamics of caring: a psychotherapeutic approach to emotional and power dimensions of women’s care work

Care is double-edged and paradoxical, inspiring a vast range of strong feelings in both care-givers and care-recipients. This paper draws on ideas about psychotherapeutic relationships to offer a theorisation of the complex emotional and power dynamics and imaginative geographies of care. Examining the humanistic approach developed by Carl Rogers as well as the psychoanalytic tradition, I advance an interpretation of psychotherapeutic practices that foregrounds the fundamental importance of the emotional and power-inflected relationship between practitioners and those with whom they work. I show how different traditions offer conceptualisations of the shape of therapeutic relationships that are highly relevant to consideration of the emotional and power dynamics of giving and receiving care. Against this background I discuss current debates about care, emotions and power, drawing especially on feminist and disability perspectives and arguing that psychotherapeutic approaches offer a powerful lens through which to understand the emotional and power dynamics of caring relationships. I conclude by emphasising how this theorisation helps to illuminate ubiquitous features of women’s care work

Shear-wave splitting, lithospheric anisotropy, and mantle deformation beneath the Arabia–Eurasia collision zone in Iran

International audienceRecords of core-refracted phases from permanent and temporary seismological stations are analysed to provide a map of seismic anisotropy covering most tectonic provinces of Iran. Anisotropy is coherent at the scale of a single province, but it differs from one province to another. No significant shear-wave splitting is observed in the mountain ranges of Zagros, Alborz, and Kopeh-Dagh. Anisotropy with average time lags of 1.1 ± 0.3 s between fast and slow shear-waves with axes of the faster polarization oriented mostly NW–SE is observed in Central Iran, but the faster orientation is NE–SW in NE Iran. The orientations of fast axes do not coincide with the directions of absolute plate motion in the no-net rotation frame or in the hot-spot frame, suggesting that the observed anisotropy cannot be explained by a simple model of asthenospheric flow. The heterogeneous orientation of fast axes with differences in length scales of a few hundreds km suggests that the anisotropy originates in the lithospheric mantle. In the area where strike-slip shear dominates, the fast axes lie approximately parallel to the orientations of maximum shear estimated from GPS measurements, either with right-lateral shear associated with the NS-trending right-lateral faults in Central Iran, or left-lateral shear associated with EW-trending left-lateral faults in Northeast Iran. In the mountain belts, the null measurements may be related to horizontal shortening and thickening by pure shear, as proposed from synthetic models of olivine fabric which both imply a large amount of vertical strain, not seen by SKS splitting. Our data therefore do not agree with previous explanations of shear-wave splitting in the neighbouring regions of Eastern Anatolia and Saudi Arabia in terms of simple asthenospheric flow. They rather support the view that Iran deforms over a broad area, with vertically-coherent deformation at a lithospheric scale, that includes both shear between blocks in Central Iran and shortening at the mountain belts

A YAC Contig Encompassing the XRCC5 (Ku80) DNA Repair Gene and Complementation of Defective Cells by YAC Protoplast Fusion.

The Chinese hamster ovaryxrsmutants are sensitive to ionizing radiation, defective in DNA double-strand break rejoining, and unable to carry out V(D)J recombination effectively. Recently, the gene defective in these mutants, XRCC5, has been shown to encode Ku80, a component of the Ku protein and DNA-dependent protein kinase. We present here a YAC contig involving 25 YACs mapping to the region 2q33–q34, which encompasses the XRCC5 gene. Eight new markers for this region of chromosome 2 are identified. YACs encoding the Ku80 gene were transferred toxrscells by protoplast fusion, and complementation of all the defective phenotypes has been obtained with two YACs. We discuss the advantages and disadvantages of this approach as a strategy for cloning human genes complementing defective rodent cell lines