Search

The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic—termed post-acute sequelae of SARS-CoV-2 (PASC)—are rapidly evolving into a major public health concern1–3. While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses3–6and/or impaired organ recovery7–9after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune–epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8+T cell–macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8+T cells stimulated local macrophages to chronically release IL-1β, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1β markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention10, we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease.

Tiny cellular tubes between neurons and brain cells called microglia serve as conduits for the export of toxic protein aggregates from neurons and the import of healthy organelles, keeping neurodegeneration at bay.

As airborne methane surveys of oil and gas systems continue to discover large emissions that are missing from official estimates1–4, the true scope of methane emissions from energy production has yet to be quantified. We integrate approximately one million aerial site measurements into regional emissions inventories for six regions in the USA, comprising 52% of onshore oil and 29% of gas production over 15 aerial campaigns. We construct complete emissions distributions for each, employing empirically grounded simulations to estimate small emissions. Total estimated emissions range from 0.75% (95% confidence interval (CI) 0.65%, 0.84%) of covered natural gas production in a high-productivity, gas-rich region to 9.63% (95% CI 9.04%, 10.39%) in a rapidly expanding, oil-focused region. The six-region weighted average is 2.95% (95% CI 2.79%, 3.14%), or roughly three times the national government inventory estimate5. Only 0.05–1.66% of well sites contribute the majority (50–79%) of well site emissions in 11 out of 15 surveys. Ancillary midstream facilities, including pipelines, contribute 18–57% of estimated regional emissions, similarly concentrated in a small number of point sources. Together, the emissions quantified here represent an annual loss of roughly US$1 billion in commercial gas value and a US$9.3 billion annual social cost6. Repeated, comprehensive, regional remote-sensing surveys offer a path to detect these low-frequency, high-consequence emissions for rapid mitigation, incorporation into official emissions inventories and a clear-eyed assessment of the most effective emission-finding technologies for a given region.

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1–4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)—the largest public open-access human genome allele frequency reference dataset—and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1–5(ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6–8and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1Lassociates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P< 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS–STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.

Only a small proportion of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy and prevents ICB responsiveness by repressing immunogenic double-stranded RNAs (dsRNAs), such as those arising from the dysregulated expression of endogenous retroviral elements (EREs)1–4. These dsRNAs trigger an interferon-dependent antitumour response by activating A-form dsRNA (A-RNA)-sensing proteins such as MDA-5 and PKR5. Here we show that ADAR1 also prevents the accrual of endogenous Z-form dsRNA elements (Z-RNAs), which were enriched in the 3′ untranslated regions of interferon-stimulated mRNAs. Depletion or mutation of ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, which culminated in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumour immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily translatable avenue for rekindling the immune responsiveness of ICB-resistant human cancers.

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2Aand transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Overfishing is the primary cause of marine defaunation, yet declines in and increasing extinction risks of individual species are difficult to measure, particularly for the largest predators found in the high seas1–3. Here we calculate two well-established indicators to track progress towards Aichi Biodiversity Targets and Sustainable Development Goals4,5: the Living Planet Index (a measure of changes in abundance aggregated from 57 abundance time-series datasets for 18 oceanic shark and ray species) and the Red List Index (a measure of change in extinction risk calculated for all 31 oceanic species of sharks and rays). We find that, since 1970, the global abundance of oceanic sharks and rays has declined by 71% owing to an 18-fold increase in relative fishing pressure. This depletion has increased the global extinction risk to the point at which three-quarters of the species comprising this functionally important assemblage are threatened with extinction. Strict prohibitions and precautionary science-based catch limits are urgently needed to avert population collapse6,7, avoid the disruption of ecological functions and promote species recovery8,9.

Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes1–3. Recent data have indicated that thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat4,5. This model was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed. Here we provide direct evidence for the molecular basis of this futile creatine cycling activity in mice. Thermogenic fat cells have robust phosphocreatine phosphatase activity, which is attributed to tissue-nonspecific alkaline phosphatase (TNAP). TNAP hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. Unlike in other cells, TNAP in thermogenic fat cells is localized to the mitochondria, where futile creatine cycling occurs. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and leads to rapid-onset obesity in mice, with no change in movement or feeding behaviour. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle.

The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein—for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting chimaeras (PROTACs)1,2and others (for example, dTAGs3, Trim-Away4, chaperone-mediated autophagy targeting5and SNIPERs6) have been developed for proteins that are typically difficult to target; however, these methods involve the manipulation of intracellular protein degradation machinery and are therefore fundamentally limited to proteins that contain cytosolic domains to which ligands can bind and recruit the requisite cellular components. Extracellular and membrane-associated proteins—the products of 40% of all protein-encoding genes7—are key agents in cancer, ageing-related diseases and autoimmune disorders8, and so a general strategy to selectively degrade these proteins has the potential to improve human health. Here we establish the targeted degradation of extracellular and membrane-associated proteins using conjugates that bind both a cell-surface lysosome-shuttling receptor and the extracellular domain of a target protein. These initial lysosome-targeting chimaeras, which we term LYTACs, consist of a small molecule or antibody fused to chemically synthesized glycopeptide ligands that are agonists of the cation-independent mannose-6-phosphate receptor (CI-M6PR). We use LYTACs to develop a CRISPR interference screen that reveals the biochemical pathway for CI-M6PR-mediated cargo internalization in cell lines, and uncover the exocyst complex as a previously unidentified—but essential—component of this pathway. We demonstrate the scope of this platform through the degradation of therapeutically relevant proteins, including apolipoprotein E4, epidermal growth factor receptor, CD71 and programmed death-ligand 1. Our results establish a modular strategy for directing secreted and membrane proteins for lysosomal degradation, with broad implications for biochemical research and for therapeutics.

Following the detection of the new coronavirus1severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its spread outside of China, Europe has experienced large epidemics of coronavirus disease 2019 (COVID-19). In response, many European countries have implemented non-pharmaceutical interventions, such as the closure of schools and national lockdowns. Here we study the effect of major interventions across 11 European countries for the period from the start of the COVID-19 epidemics in February 2020 until 4 May 2020, when lockdowns started to be lifted. Our model calculates backwards from observed deaths to estimate transmission that occurred several weeks previously, allowing for the time lag between infection and death. We use partial pooling of information between countries, with both individual and shared effects on the time-varying reproduction number (Rt). Pooling allows for more information to be used, helps to overcome idiosyncrasies in the data and enables more-timely estimates. Our model relies on fixed estimates of some epidemiological parameters (such as the infection fatality rate), does not include importation or subnational variation and assumes that changes in Rtare an immediate response to interventions rather than gradual changes in behaviour. Amidst the ongoing pandemic, we rely on death data that are incomplete, show systematic biases in reporting and are subject to future consolidation. We estimate that—for all of the countries we consider here—current interventions have been sufficient to drive Rtbelow 1 (probability Rt< 1.0 is greater than 99%) and achieve control of the epidemic. We estimate that across all 11 countries combined, between 12 and 15 million individuals were infected with SARS-CoV-2 up to 4 May 2020, representing between 3.2% and 4.0% of the population. Our results show that major non-pharmaceutical interventions—and lockdowns in particular—have had a large effect on reducing transmission. Continued intervention should be considered to keep transmission of SARS-CoV-2 under control.

Methane is a powerful greenhouse gas and is targeted for emissions mitigation by the US state of California and other jurisdictions worldwide1,2. Unique opportunities for mitigation are presented by point-source emitters—surface features or infrastructure components that are typically less than 10 metres in diameter and emit plumes of highly concentrated methane3. However, data on point-source emissions are sparse and typically lack sufficient spatial and temporal resolution to guide their mitigation and to accurately assess their magnitude4. Here we survey more than 272,000 infrastructure elements in California using an airborne imaging spectrometer that can rapidly map methane plumes5–7. We conduct five campaigns over several months from 2016 to 2018, spanning the oil and gas, manure-management and waste-management sectors, resulting in the detection, geolocation and quantification of emissions from 564 strong methane point sources. Our remote sensing approach enables the rapid and repeated assessment of large areas at high spatial resolution for a poorly characterized population of methane emitters that often appear intermittently and stochastically. We estimate net methane point-source emissions in California to be 0.618 teragrams per year (95 per cent confidence interval 0.523–0.725), equivalent to 34–46 per cent of the state’s methane inventory8for 2016. Methane ‘super-emitter’ activity occurs in every sector surveyed, with 10 per cent of point sources contributing roughly 60 per cent of point-source emissions—consistent with a study of the US Four Corners region that had a different sectoral mix9. The largest methane emitters in California are a subset of landfills, which exhibit persistent anomalous activity. Methane point-source emissions in California are dominated by landfills (41 per cent), followed by dairies (26 per cent) and the oil and gas sector (26 per cent). Our data have enabled the identification of the 0.2 per cent of California’s infrastructure that is responsible for these emissions. Sharing these data with collaborating infrastructure operators has led to the mitigation of anomalous methane-emission activity10.

Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.

Engineering and enhancing the breaking of inversion symmetry in solids—that is, allowing electrons to differentiate between ‘up’ and ‘down’—is a key goal in condensed-matter physics and materials science because it can be used to stabilize states that are of fundamental interest and also have potential practical applications. Examples include improved ferroelectrics for memory devices and materials that host Majorana zero modes for quantum computing. Although inversion symmetry is naturally broken in several crystalline environments, such as at surfaces and interfaces, maximizing the influence of this effect on the electronic states of interest remains a challenge. Here we present a mechanism for realizing a much larger coupling of inversion-symmetry breaking to itinerant surface electrons than is typically achieved. The key element is a pronounced asymmetry of surface hopping energies—that is, a kinetic-energy-coupled inversion-symmetry breaking, the energy scale of which is a substantial fraction of the bandwidth. Using spin- and angle-resolved photoemission spectroscopy, we demonstrate that such a strong inversion-symmetry breaking, when combined with spin–orbit interactions, can mediate Rashba-like spin splittings that are much larger than would typically be expected. The energy scale of the inversion-symmetry breaking that we achieve is so large that the spin splitting in the CoO2- and RhO2-derived surface states of delafossite oxides becomes controlled by the full atomic spin–orbit coupling of the 3d and 4d transition metals, resulting in some of the largest known Rashba-like spin splittings. The core structural building blocks that facilitate the bandwidth-scaled inversion-symmetry breaking are common to numerous materials. Our findings therefore provide opportunities for creating spin-textured states and suggest routes to interfacial control of inversion-symmetry breaking in designer heterostructures of oxides and other material classes.

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4CRBNE3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN–DDB1–CC-885–GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a ‘hotspot’ on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon ‘neosubstrate’ selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

As scientists from myriad fields rush to perform algorithmic analyses, Google’s Patrick Riley calls for clear standards in research and reporting. As scientists from myriad fields rush to perform algorithmic analyses, Google’s Patrick Riley calls for clear standards in research and reporting.

Elongation of rod-shaped bacteria is mediated by a dynamic peptidoglycan-synthetizing machinery called the Rod complex. Here we report that, in Bacillus subtilis, this complex is functional in the absence of all known peptidoglycan polymerases. Cells lacking these enzymes survive by inducing an envelope stress response that increases the expression of RodA, a widely conserved core component of the Rod complex. RodA is a member of the SEDS (shape, elongation, division and sporulation) family of proteins, which have essential but ill-defined roles in cell wall biogenesis during growth, division and sporulation. Our genetic and biochemical analyses indicate that SEDS proteins constitute a family of peptidoglycan polymerases. Thus, B. subtilis and probably most bacteria use two distinct classes of polymerase to synthesize their exoskeleton. Our findings indicate that SEDS family proteins are core cell wall synthases of the cell elongation and division machinery, and represent attractive targets for antibiotic development.

Ebola emerged in West Africa around December 2013 and swept through Guinea, Sierra Leone and Liberia, giving rise to 27,748 confirmed, probable and suspected cases reported by 29 July 2015. Case diagnoses during the epidemic have relied on polymerase chain reaction-based tests. Owing to limited laboratory capacity and local transport infrastructure, the delays from sample collection to test results being available have often been 2 days or more. Point-of-care rapid diagnostic tests offer the potential to substantially reduce these delays. We review Ebola rapid diagnostic tests approved by the World Health Organization and those currently in development. Such rapid diagnostic tests could allow early triaging of patients, thereby reducing the potential for nosocomial transmission. In addition, despite the lower test accuracy, rapid diagnostic test-based diagnosis may be beneficial in some contexts because of the reduced time spent by uninfected individuals in health-care settings where they may be at increased risk of infection; this also frees up hospital beds. We use mathematical modelling to explore the potential benefits of diagnostic testing strategies involving rapid diagnostic tests alone and in combination with polymerase chain reaction testing. Our analysis indicates that the use of rapid diagnostic tests with sensitivity and specificity comparable with those currently under development always enhances control, whether evaluated at a health-care-unit or population level. If such tests had been available throughout the recent epidemic, we estimate, for Sierra Leone, that their use in combination with confirmatory polymerase chain-reaction testing might have reduced the scale of the epidemic by over a third.This article has not been written or reviewed by Nature editors. Nature accepts no responsibility for the accuracy of the information provided.

The amino acid sequence of the human fibrinogen α-chain reveals a structure that can be divided into three zones of unique amino acid composition. The middle of these contains the two primary α-chain cross-linking acceptor sites and consists of a remarkable series of internal duplications.

RNA transcription could take place without unwinding the DNA double helix if the RNA chain grows in the wide groove of the DNA by a specific stereochemical interaction between the ribonucleotides and the base pairs of the DNA.

A MAJOR episode of DNA synthesis occurs during the interphase preceding meiosis1–4. Additional periods of synthesis have been detected by autoradiography during leptotene, zygotene or pachytene in newt5, man6and mouse7. In Lilium and Trillium separate periods of synthesis have been demonstrated at zygotene and pachytene by 32P-phosphate labelling followed by DNA extraction8. Others have failed to detect prophase synthesis autoradiographically3,4, presumably because of the low level of label incorporation during synthesis of amounts of DNA estimated to represent 0.3–2.0% of the total nuclear DNA content5,9.

Rapidly labelled RNA and ribosomal RNA of HeLa and E. coli cells may be composed of smaller subunits.

Pre-B cells, the first cells in the B-lymphocyte differentiation pathway which express immunoglobulin1, have recently been shown to express cytoplasmic μ heavy chain (H) but not light chain (L)2,3. If, as is believed, pre-B cells are the precursors of immature B lymphocytes, which express surface IgM4–7, the differentiation of pre-B cells to immature B lymphocytes must be accompanied by the expression of light chains. In this case, it should be possible for the progeny of a single pre-B cell to express a variety of light chains in association with the same heavy chain. We have tested this hypothesis by hybridizing a pre-B cell line 18–81 expressing only cytoplasmic μ chains8with variant myeloma cells which do not express light chains. Hybridization of B-lymphoma cells with myeloma cells usually produces a hybrid with the phenotype of the more differentiated parent9–11. In this case, the fusion resulted in the induction of light chain expression from the 18–81 genes and we have been able to demonstrate that independent hybrids express different light chains, in accordance with the hypothesis that a pre-B cell committed to expression of a single μ heavy chain can generate progeny expressing different light chains2,12.

Haematopoietic progenitor cells proliferate and mature in semi-solid media when stimulated by exogenous haematopoietic cell growth factors (HCGFs) such as granulocyte-macrophage colony-stimulating factor (GM-CSF)1,2. They also proliferate in association with marrow-derived stromal cells3,4although biologically active amounts of HCGFs cannot be detected in stromal culture supernatants5. It is possible that HCGFs are synthesized in small amounts by stromal cells but remain bound to the stromal cells and/or their extracellular matrix (ECM). This interpretation accords with haematopoietic progenitor cell proliferation in close association with stromal layers in long-term cultures6. Glycosaminoglycans (GAGs) are found in the ECM produced by stromal cells27,8. They are prime candidates for selectively retaining HCGFs in the stromal layer9; they influence embryonic morphogenesis and cyto-differentiation10and they may regulate haematopoiesis11–13. We now report that granulocyte-macrophage colony-stimulating activity can be eluted from cultured stromal layers and that exogenous GM-CSF binds to GAGs from bone marrow stromal ECM. Selective Compartmentalization of HCGFs in this manner may be an important function of the marrow microenvironment and may be involved in haematopoietic cell regulation.

Skeletal motor neurones innervate the specialized ‘types’ of fibres comprising most mammalian muscles in a characteristic fashion: each motor neurone forms a ‘motor unit’ by innervating a set of fibres all of the same type1–4. Because the type expression of adult muscle fibres is plastic and apparently controlled by their innervation, each motor neurone is thought to impose a common type differentiation on all the fibres in its motor unit4–6. However, the situation in developing muscles cannot be this simple. Muscle fibres in neonates receive synaptic input from several motor neurones and achieve the adult, single innervation only after a period of ‘synapse elimination’7,8. Despite this polyneuronal innervation, differentiated fibre types are present in neonatal muscles9–14. This means either that the motor neurones polyne-uronally innervate fibres in a random fashion and type expression is not determined by innervation or that the polyneuronal innervation is ordered in such a way that each fibre could receive unambiguous instructions for type differentiation. We have investigated these possibilities here by determining the fibre type composition of motor units in neonatal rat soleus muscle. We find that even during the time of poly neuronal innervation each motor neurone confines its innervation to largely one of two fibre types present in the muscle. Therefore, some mechanism during early development segregates the synapses of two groups of soleus motor neurones onto two separate populations of soleus muscle fibres.

Cytochrome oxidase (cytochrome c oxidase; ferrocytochrome c: oxygen oxidoreductase, EC 1.9.2.1) has been introduced as an oxidative metabolic marker for neurones in the central nervous system1. Previous studies have shown that mature neurones remained sensitive to altered functional demands2–9, and that both developing and adult neurones responded to sensory deprivation or deafferentation by reducing their cytochrome oxidase (Cyt.Ox.) activity1,3,4,9–11. More recently, we showed that the blockage of retinal impulse transmission with tetrodotoxin led to a reversible reduction in Cyt.Ox. staining of affected lateral geniculate (LGN) and striate neurones in adult cats9. The present study sought to extend these findings to adult monkeys, where Cyt.Ox. ‘puffs’ or ‘blobs’ are uniquely present in the visual cortex10,12–14. We found that, while the retina remained histologically intact, with only moderate decreases in Cyt.Ox. staining of large ganglion cells and the two plexiform layers, subtle changes occurred in the LGN as early as 1 day post-tetrodotoxin injection, and clear reduction in enzyme levels was evident in both the LGN and the visual cortex by 3 days. Changes became progressively more severe up to 4 weeks post-injection. Within area 17, alternating bands of high and low Cyt.Ox. staining occurred in lamina IV, with alternating rows of dark and lightly reactive puffs superimposed in exact register. Thus, the mature visual neurones in the primate remain extremely sensitive to the cessation of retinal impulse transmission, and plastic metabolic changes occur through several synapses along the sensory pathway.

Normal haematopoietic cell regulation involves interaction between marrow stromal cells and haematopoietic progenitor cells1which may be facilitated by specific recognition and adhesion2–4. Some leukaemogenic events might produce a selective growth advantage by altering this regulatory network, possibly by diminishing the capacities of cells to adhere to stromal elements. Using an in vitro culture system which allows investigation of adhesion to stromal layers and subsequent colony formation by blast colony-forming cells (Bl–CFC) in normal marrow2–4and Ph+chronic myeloid leukaemic (CML) blood5, we compared the adhesive properties of normal and malignant progenitor cells. We present evidence that altered adhesive interactions between primitive progenitor cells and marrow stromal cells occur in CML.

Many researchers have attempted to duplicate under laboratory conditions the geochemicäl reactions that lead to economic deposits of liquid and gaseous hydrocarbons1–4. Experiments lasting from a few5,6to several hundred7days, usually at constant temperatures, have been devised. The differences in time scale and other parameters between geological processes and laboratory experiments are so great that the relevance of labora tory results is often questioned8,9. Consequently, we have heated potential source material from 100 to 400 °C over six years, increasing the temperature by 1 °C per week. This was done in an attempt to simulate the thermal history of a sample being buried in a continuously subsiding basin with a constant geothermal gradient. After four years, a product indistinguish able from a paraffinic crude oil was generated from a torbanite, while a brown coal gave a product distribution that could be related to a wet natural gas. Of great significance is the absence of olefins and carbon monoxide in all products. We believe the present experiments, which are possibly as slow as can be realistically planned within a human time scale, have for the first time successfully duplicated hydrocarbon generation in a continuously subsiding sedimentary basin.