Ebola virus entry requires the cholesterol transporter Niemann-Pick C1

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.     

Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.     

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140?mm?Hg systolic blood pressure or ≥90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.     

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.     

Quantum gates and memory using microwave-dressed states

Trapped atomic ions have been used successfully to demonstrate basic elements of universal quantum information processing. Nevertheless, scaling up such methods to achieve large-scale, universal quantum information processing (or more specialized quantum simulations) remains challenging. The use of easily controllable and stable microwave sources, rather than complex laser systems, could remove obstacles to scalability. However, the microwave approach has drawbacks: it involves the use of magnetic-field-sensitive states, which shorten coherence times considerably, and requires large, stable magnetic field gradients. Here we show how to overcome both problems by using stationary atomic quantum states as qubits that are induced by microwave fields (that is, by dressing magnetic-field-sensitive states with microwave fields). This permits fast quantum logic, even in the presence of a small (effective) Lamb-Dicke parameter (and, therefore, moderate magnetic field gradients). We experimentally demonstrate the basic building blocks of this scheme, showing that the dressed states are long lived and that coherence times are increased by more than two orders of magnitude relative to those of bare magnetic-field-sensitive states. This improves the prospects of microwave-driven ion trap quantum information processing, and offers a route to extending coherence times in all systems that suffer from magnetic noise, such as neutral atoms, nitrogen-vacancy centres, quantum dots or circuit quantum electrodynamic systems.     

A hydrothermal origin for isotopically anomalous cap dolostone cements from south China

The release of methane into the atmosphere through destabilization of clathrates is a positive feedback mechanism capable of amplifying global warming trends that may have operated several times in the geological past. Such methane release is a hypothesized cause or amplifier for one of the most drastic global warming events in Earth history, the end of the Marinoan 'snowball Earth' ice age, ～635?Myr ago. A key piece of evidence supporting this hypothesis is the occurrence of exceptionally depleted carbon isotope signatures (δ(13)C(PDB) down to -48‰; ref. 8) in post-glacial cap dolostones (that is, dolostone overlying glacial deposits) from south China; these signatures have been interpreted as products of methane oxidation at the time of deposition. Here we show, on the basis of carbonate clumped isotope thermometry, (87)Sr/(86)Sr isotope ratios, trace element content and clay mineral evidence, that carbonates bearing the (13)C-depleted signatures crystallized more than 1.6?Myr after deposition of the cap dolostone. Our results indicate that highly (13)C-depleted carbonate cements grew from hydrothermal fluids and suggest that their carbon isotope signatures are a consequence of thermogenic methane oxidation at depth. This finding not only negates carbon isotope evidence for methane release during Marinoan deglaciation in south China, but also eliminates the only known occurrence of a Precambrian sedimentary carbonate with highly (13)C-depleted signatures related to methane oxidation in a seep environment. We propose that the capacity to form highly (13)C-depleted seep carbonates, through biogenic anaeorobic oxidation of methane using sulphate, was limited in the Precambrian period by low sulphate concentrations in sea water. As a consequence, although clathrate destabilization may or may not have had a role in the exit from the 'snowball' state, it would not have left extreme carbon isotope signals in cap dolostones.     

Carbon loss from an unprecedented Arctic tundra wildfire

Arctic tundra soils store large amounts of carbon (C) in organic soil layers hundreds to thousands of years old that insulate, and in some cases maintain, permafrost soils. Fire has been largely absent from most of this biome since the early Holocene epoch, but its frequency and extent are increasing, probably in response to climate warming. The effect of fires on the C balance of tundra landscapes, however, remains largely unknown. The Anaktuvuk River fire in 2007 burned 1,039 square kilometres of Alaska's Arctic slope, making it the largest fire on record for the tundra biome and doubling the cumulative area burned since 1950 (ref. 5). Here we report that tundra ecosystems lost 2,016?±?435?g?C?m(-2) in the fire, an amount two orders of magnitude larger than annual net C exchange in undisturbed tundra. Sixty per cent of this C loss was from soil organic matter, and radiocarbon dating of residual soil layers revealed that the maximum age of soil C lost was 50 years. Scaled to the entire burned area, the fire released approximately 2.1?teragrams of C to the atmosphere, an amount similar in magnitude to the annual net C sink for the entire Arctic tundra biome averaged over the last quarter of the twentieth century. The magnitude of ecosystem C lost by fire, relative to both ecosystem and biome-scale fluxes, demonstrates that a climate-driven increase in tundra fire disturbance may represent a positive feedback, potentially offsetting Arctic greening and influencing the net C balance of the tundra biome.