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

Measurement of the CKM angle γγ in B±→DK±B^\pm\to D K^\pm and B±→Dπ±B^\pm \to D π^\pm decays with D→KS0h+h−D \to K_\mathrm S^0 h^+ h^-

A measurement of $CP$-violating observables is performed using the decays $B^\pm\to D K^\pm$ and $B^\pm\to D \pi^\pm$, where the $D$ meson is reconstructed in one of the self-conjugate three-body final states $K_{\mathrm S}\pi^+\pi^-$ and $K_{\mathrm S}K^+K^-$ (commonly denoted $K_{\mathrm S} h^+h^-$). The decays are analysed in bins of the $D$-decay phase space, leading to a measurement that is independent of the modelling of the $D$-decay amplitude. The observables are interpreted in terms of the CKM angle $\gamma$. Using a data sample corresponding to an integrated luminosity of $9\,\text{fb}^{-1}$ collected in proton-proton collisions at centre-of-mass energies of $7$, $8$, and $13\,\text{TeV}$ with the LHCb experiment, $\gamma$ is measured to be $\left(68.7^{+5.2}_{-5.1}\right)^\circ$. The hadronic parameters $r_B^{DK}$, $r_B^{D\pi}$, $\delta_B^{DK}$, and $\delta_B^{D\pi}$, which are the ratios and strong-phase differences of the suppressed and favoured $B^\pm$ decays, are also reported

Study of the doubly charmed tetraquark T+cc

Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the D0D0π+ mass spectrum just below the D*+D0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar T+cc tetraquark with a quark content of ccu⎯⎯⎯d⎯⎯⎯ and spin-parity quantum numbers JP = 1+. Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*+ mesons is consistent with the observed D0π+ mass distribution. To analyse the mass of the resonance and its coupling to the D*D system, a dedicated model is developed under the assumption of an isoscalar axial-vector T+cc state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the T+cc state. In addition, an unexpected dependence of the production rate on track multiplicity is observed

A new stratigraphy for the glacial deposits around Lowestoft, Great Yarmouth, North Walsham and Cromer, East Anglia, UK

A new stratigraphical model for the glacial deposits around Lowestoft, Great Yarmouth, North Walsham and Cromer (east of Weybourne and Edgefield) is presented, based on a combined research programme by the British Geological Survey and the Department of Geography, Royal Holloway University of London. This stratigraphical model is founded upon evidence derived from sedimentological descriptions, geological mapping and analytical lithological techniques including clast lithological analysis, derived pre- Quaternary palynomorphs and heavy mineralogy. The previously accepted ‘North Sea Drift’ / ‘Lowestoft Formation’ scheme is abandoned in favour of four formations that relate to assemblages of till units and associated outwash lithofacies, the mapping of major discontinuities, and morpho- and tectono-stratigraphical associations. The new scheme consists of the Happisburgh, redefined Lowestoft, Sheringham Cliffs and Briton’s Lane formations

Revised Pre-Devensian glacial stratigraphy in Norfolk, England, based on mapping and till provenance

Mapping combined with till provenance studies have resulted in a re-appraisal of the pre-Devensian glacial stratigraphy of Norfolk, England. The traditional model invoked two formations, a North Sea Drift Formation (NSDF) overlain by a Lowestoft Formation, formed by co-existing icesheets originating in Scandinavia and Northern Britain respectively. The NSDF included three diamictons, the First, Second and Third Cromer tills. The Briton’s Lane Sands and Gravels were considered to overlie the Lowestoft Formation. However, our work has shown this stratigraphy to be untenable, and we propose a model of several glaciations instead of co-existing ice-sheets. In our revised stratigraphy, the oldest formation, the Happisburgh Formation (including the Happisburgh or First Cromer Till) includes massive, sandy tills derived from northern Britain. The overlying Lowestoft Formation, including the Second Cromer (Walcott) Till is confirmed as derived from the west, introducing much Jurassic material as well as Chalk. The Sheringham Cliffs Formation includes both brown sandy tills (the Third Cromer Till) and ‘marly drift’, in a variety of tectonic relationships, and derived from the north and NNW. Finally the Briton’s Lane Formation is the only formation to include Scandinavian erratics. Dating of the four formations is at varying levels of confidence, with the Lowestoft Formation most confidently confirmed as MIS 12. The Happisburgh Formation is believed to represent an earlier glaciation, and MIS 16 is proposed. The Sheringham Cliffs Formation is tentatively believed to date from MIS 10, and the Briton’s Lane Formation is assigned to MIS 6