Immunoediting role for major vault protein in apoptotic signaling induced by bacterial N-acyl homoserine lactones

The major vault protein (MVP) mediates diverse cellular responses, including cancer cell resistance to chemotherapy and protection against inflammatory responses to Pseudomonas aeruginosa. Here, we report the use of photoactive probes to identify MVP as a target of the N-(3-oxo-dodecanoyl) homoserine lactone (C12), a quorum sensing signal of certain proteobacteria including P. aeruginosa. A treatment of normal and cancer cells with C12 or other N-acyl homoserine lactones (AHLs) results in rapid translocation of MVP into lipid raft (LR) membrane fractions. Like AHLs, inflammatory stimuli also induce LR-localization of MVP, but the C12 stimulation reprograms (functionalizes) bioactivity of the plasma membrane by recruiting death receptors, their apoptotic adaptors, and caspase-8 into LR. These functionalized membranes control AHL-induced signaling processes, in that MVP adjusts the protein kinase p38 pathway to attenuate programmed cell death. Since MVP is the structural core of large particles termed vaults, our findings suggest a mechanism in which MVP vaults act as sentinels that fine-tune inflammation-activated processes such as apoptotic signaling mediated by immunosurveillance cytokines including tumor necrosis factor-related apoptosis inducing ligand (TRAIL).Bio-organic Synthesi

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

Timing, relations and cause of plutonic and volcanic activity of the Siluro-Devonian post-collision magmatic episode in the Grampian Terrane, Scotland

Calc-alkaline magmatism in the Grampian Terrane started at c. 430 Ma, after subduction of the edge of continental Avalonia beneath Laurentia, and it then persisted for at least 22 Ma. Isotope dilution thermal ionization mass spectrometry U–Pb zircon dating yields 425.0 ± 0.7 Ma for the Lorn Lava Pile, 422.5 ± 0.5 Ma for Rannoch Moor Pluton, 419.6 ± 5.4 Ma for a fault-intrusion at Glencoe volcano, 417.9 ± 0.9 Ma for Clach Leathad Pluton in Glencoe, and, in the Etive Pluton, 414.9 ± 0.7 Ma for the Cruachan Intrusion and 408.0 ± 0.5 Ma for the Inner Starav Intrusion. The Etive Dyke Swarm was mostly emplaced during 418–414 Ma, forming part of the plumbing of a large volcano (2000 km3) that became intruded by the Etive Pluton and was subsequently removed by erosion. During the magmatism large volumes (thousands of km3) of high Ba–Sr andesite and dacite were erupted repeatedly, but were mostly removed by contemporaneous uplift and erosion. This volcanic counterpart to the ’Newer Granite' plutons has not previously been fully recognized. The intermediate magmas forming both plutons and volcanoes originated mainly by partial melting of heterogeneous mafic to intermediate lowermost crust that had high Ba–Sr derived from previous melting of large ion lithophile element (LILE)-enriched mantle, possibly at c. 1.8 Ga. This crustal recycling was induced by heat and volatiles from underplated small-degree melts of LILE- and light REE-enriched lithospheric mantle (appinite–lamprophyre magmas). The post-collision magmatism and uplift resulted from breakoff of subducted oceanic lithosphere and consequent rise of asthenosphere