The geochemistry and petrogenesis of Carnley Volcano, Auckland Islands, SW Pacific

Intraplate volcanism across Zealandia, South Eastern Australia, the Ross Sea Embayment and Marie Byrd Land in Antarctica define a magmatic province characterised by basalts with elevated 206Pb/204Pb (18.9–22.5), 87Sr/86Sr = ∼0.7035, Light Rare Earth enrichment [(Ce/Yb)n > 10], and convex-up mantle normalised incompatible multi-element patterns, peaking at Nb-Ta, with negative K and Pb anomalies. Trace element abundances and ratios (e.g. Zr/Nb, Y/Zr) resemble Ocean Island Basalts (OIB), distinct from Mid-Ocean Ridge Basalt (MORB), suggesting derivation from OIB-like reservoirs. Our preferred scenario envisages partial melting across the garnet-spinel stability fields involving asthenospheric and lithospheric mantle components. Melts accumulate in a column where the deep (asthenospheric) source is PM and the shallower source a melange of PM and subcontinental lithospheric mantle (DMM+1) enriched by carbonatite. Evolution of primary and near-primary magmas is controlled by olivine + clinopyroxene fractionation. Trachybasalts, trachytes and rhyolites show isotopic evidence for interaction with continental crust

New petrological, geochemical, and geochronological perspectives on andesite-dacite magma genesis at Ruapehu volcano, New Zealand

Time–composition relationships in eruptive sequences at composite volcanoes can show how the ongoing intrusion of magmas progressively affects the lithosphere at continental convergent margins. Here, new whole-rock and microanalytical major and trace element data from andesite-dacite lava flows are integrated with previous studies and existing isotopic data, and placed within the framework of a high-resolution chronostratigraphy for Ruapehu volcano (southern Taupo Volcanic Zone, New Zealand). The geochemical evolution of lavas erupted over the ∼200 kyr lifetime of the exposed edifice reflects variable degrees of fractionation and systematic changes in the type of crustal assimilation in the Ruapehu magma system. Lavas erupted from ∼200–150 ka have previously been distinguished from those erupted <150 ka based on Sr-Nd isotopic characteristics, which indicate that the oldest lavas were sourced from magmas that assimilated oceanic crust. Such source rocks underlie the regionally widespread Mesozoic meta-sedimentary greywacke-argillite basement, which was conversely assimilated by <150 ka magmas. New results from this work reveal that since 150 ka, an upper limit of magma differentiation occurred from ∼50–35 ka. High K2O (∼6 wt%) and Rb contents (∼270 ppm) in melt inclusions, interstitial glass, and glass from in situ quenched melts of partially fused crustal xenoliths are reported for andesite-dacite lavas erupted during this period. In addition to crystal fractionation, selective partial melting and assimilation of K- and Rb-rich mineral phases (e.g., biotite, K-feldspar) that are significant components of the meta-sedimentary basement rocks is inferred to explain these geochemical characteristics. These processes coincided also with the effusion of high-MgO andesitedacite lavas that display petrological evidence for mixing between andesite-dacite and more mafic magmas. An influx of hotter mafic magma into the system explains why the extent of crustal assimilation recorded by Ruapehu lavas peaked during the ∼50–35 ka eruptive period. From 26 ka to the present, andesite lavas have reverted to more mafic compositions with less potassic melt inclusion and whole-rock compositions when compared to the ∼50–35 ka lavas. We suggest that the younger lavas assimilated less-enriched melts because fertile phases had been preferentially extracted from the crustal column during earlier magmatism. This scenario of bottom-up heating of the lithosphere and exhaustion of fertile phases due to the progressive intrusion of magma explains the geochemical evolution of Ruapehu lavas. This model may be applicable to other long-lived composite volcanoes of the circum-Pacific continental arcs

Development of the Reporting Infographics and Visual Abstracts of Comparative studies (RIVA-C) checklist and guide

People often use infographics (also called visual or graphical abstracts) as a substitute for reading the full text of an article. This is a concern because most infographics do not present sufficient information to interpret the research appropriately and guide wise health decisions. The Reporting Infographics and Visual Abstracts of Comparative studies (RIVA-C) checklist and guide aims to improve the completeness with which research findings of comparative studies are communicated and avoid research findings being misinterpreted if readers do not refer to the full text. The primary audience for the RIVA-C checklist and guide is developers of infographics that summarise comparative studies of health and medical interventions. The need for the RIVA-C checklist and guide was identified by a survey of how people use infographics. Possible checklist items were informed by a systematic review of how infographics report research. We then conducted a two-round, modified Delphi survey of 92 infographic developers/designers, researchers, health professionals and other key stakeholders. The final checklist includes 10 items. Accompanying explanation and both text and graphical examples linked to the items were developed and pilot tested over a 6-month period. The RIVA-C checklist and guide was designed to facilitate the creation of clear, transparent and sufficiently detailed infographics which summarise comparative studies of health and medical interventions. Accurate infographics can ensure research findings are communicated appropriately and not misinterpreted. By capturing the perspectives of a wide range of end users (eg, authors, informatics editors, journal editors, consumers), we are hopeful of rapid endorsement and implementation of RIVA-C.</p

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy

Mutational processes molding the genomes of 21 breast cancers

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The RESET project: constructing a European tephra lattice for refined synchronisation of environmental and archaeological events during the last c. 100 ka

This paper introduces the aims and scope of the RESET project (. RESponse of humans to abrupt Environmental Transitions), a programme of research funded by the Natural Environment Research Council (UK) between 2008 and 2013; it also provides the context and rationale for papers included in a special volume of Quaternary Science Reviews that report some of the project's findings. RESET examined the chronological and correlation methods employed to establish causal links between the timing of abrupt environmental transitions (AETs) on the one hand, and of human dispersal and development on the other, with a focus on the Middle and Upper Palaeolithic periods. The period of interest is the Last Glacial cycle and the early Holocene (c. 100-8 ka), during which time a number of pronounced AETs occurred. A long-running topic of debate is the degree to which human history in Europe and the Mediterranean region during the Palaeolithic was shaped by these AETs, but this has proved difficult to assess because of poor dating control. In an attempt to move the science forward, RESET examined the potential that tephra isochrons, and in particular non-visible ash layers (cryptotephras), might offer for synchronising palaeo-records with a greater degree of finesse. New tephrostratigraphical data generated by the project augment previously-established tephra frameworks for the region, and underpin a more evolved tephra 'lattice' that links palaeo-records between Greenland, the European mainland, sub-marine sequences in the Mediterranean and North Africa. The paper also outlines the significance of other contributions to this special volume: collectively, these illustrate how the lattice was constructed, how it links with cognate tephra research in Europe and elsewhere, and how the evidence of tephra isochrons is beginning to challenge long-held views about the impacts of environmental change on humans during the Palaeolithic. © 2015 Elsevier Ltd.RESET was funded through Consortium Grants awarded by the Natural Environment Research Council, UK, to a collaborating team drawn from four institutions: Royal Holloway University of London (grant reference NE/E015905/1), the Natural History Museum, London (NE/E015913/1), Oxford University (NE/E015670/1) and the University of Southampton, including the National Oceanography Centre (NE/01531X/1). The authors also wish to record their deep gratitude to four members of the scientific community who formed a consultative advisory panel during the lifetime of the RESET project: Professor Barbara Wohlfarth (Stockholm University), Professor Jørgen Peder Steffensen (Niels Bohr Institute, Copenhagen), Dr. Martin Street (Romisch-Germanisches Zentralmuseum, Neuwied) and Professor Clive Oppenheimer (Cambridge University). They provided excellent advice at key stages of the work, which we greatly valued. We also thank Jenny Kynaston (Geography Department, Royal Holloway) for construction of several of the figures in this paper, and Debbie Barrett (Elsevier) and Colin Murray Wallace (Editor-in-Chief, QSR) for their considerable assistance in the production of this special volume.Peer Reviewe

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