Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases

Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration–response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases

Mineral Resource Governance in the 21st Century: Gearing extractive industries towards sustainable development

The IRP Report on Mineral Resource Governance in the 21st Century was requested by\ua0the IRP Steering Committee at its 18th Meeting (Cape Town, 6–9 June 2016). The Report\ua0also responds to a Recommendation adopted at the 21st Meeting of the Convention on\ua0Biological Diversity Subsidiary Body on Scientific, Technical and Technological Advice\ua0(Montreal, 11–14 December 2017).1The structure and content of the Report was informed by a series of expert workshops\ua0convened in Davos (15–16 October 2015), Accra (26–27 September 2016), Helsinki\ua0(9-10 June 2017), and Lima (22–24 November 2017). It was also informed by a global\ua0stakeholder consultation process

Mechanical behavior of a bulk nanostructured iron alloy

Bulk, fully dense materials were prepared from Fe-10Cu with grain diameters between 45 run and 1.7 yum. The materials were prepared by ball milling of powders in a glove box, followed by hot isostatic pressing (hipping) or powder forging. Larger grain sizes were obtained by thermal treatment of the consolidated powders. The bulk materials were relatively clean, with oxygen levels below 1500 wpm and other contaminants less than 0.1 at. pet. The mechanical behavior of these materials was unique. At temperatures from 77 to 470 K, the first and only mechanism of plastic deformation was intense shear banding, which was accompanied by a perfectly plastic stress-strain response (absence of strain hardening). There was a large tension-compression asymmetry in the strength, and the shear bands did not occur on the plane of maximum shear stress or the plane of zero extension. This behavior, while unusual for metals, has been observed in amorphous polymers and metallic glasses. On the other hand, the fine-grained Fe-10Cu materials behaved like coarse-grained iron in some respects, particularly by obeying the Hall-Petch equation with constants reasonably close to those of pure iron and by exhibiting low-temperature mechanical behavior which was very similar to that of steels. Transmission electron microscopy (TEM) studies found highly elongated grains within shear bands, indicating that shear banding occurred by a dislocation-based mechanism, at least at grain sizes above 100 nm. Similarities and differences between the fine-grained Fe-10Cu and metals, polymers, metallic glasses, radiation-damaged metals, and quench-damaged metals are discussed