Hand, foot and mouth disease (HFMD) caused by Human Enterovirus A71 (HEVA71) infection is typically a benign infection. However, in minority of cases, children can develop severe neuropathology that culminate in fatality. Approximately 36.9% of HEVA71-related hospitalizations develop neurological complications, of which 10.5% are fatal. Yet, the mechanism by which HEVA71 induces these neurological deficits remain unclear. Here, we show that HEVA71-infected astrocytes release CXCL1 which supports viral replication in neurons by activating the CXCR2 receptor-associated ERK1/2 signaling pathway. Elevated CXCL1 levels correlates with disease severity in a HEVA71-infected mice model. In humans infected with HEVA71, high CXCL1 levels are only present in patients presenting neurological complications. CXCL1 release is specifically triggered by VP4 synthesis in HEVA71-infected astrocytes, which then acts via its receptor CXCR2 to enhance viral replication in neurons. Perturbing CXCL1 signaling or VP4 myristylation strongly attenuates viral replication. Treatment with AZD5069, a CXCL1-specific competitor, improves survival and lessens disease severity in infected animals. Collectively, these results highlight the CXCL1-CXCR2 signaling pathway as a potential target against HFMD neuropathogenesis.
The past 40 years in Southeast Asia have seen about 50% of lowland rainforests converted to oil palm and other plantations, and much of the remaining forest heavily logged. Little is known about how fragmentation influences recovery and whether climate change will hamper restoration. Here, we use repeat airborne LiDAR surveys spanning the hot and dry 2015-16 El Niño Southern Oscillation event to measure canopy height growth across 3,300 ha of regenerating tropical forests spanning a logging intensity gradient in Malaysian Borneo. We show that the drought led to increased leaf shedding and branch fall. Short forest, regenerating after heavy logging, continued to grow despite higher evaporative demand, except when it was located close to oil palm plantations. Edge effects from the plantations extended over 300 metres into the forests. Forest growth on hilltops and slopes was particularly impacted by the combination of fragmentation and drought, but even riparian forests located within 40 m of oil palm plantations lost canopy height during the drought. Our results suggest that small patches of logged forest within plantation landscapes will be slow to recover, particularly as ENSO events are becoming more frequent.
Numerous studies have focused on the need to expand production of 'blue foods', defined as aquatic foods captured or cultivated in marine and freshwater systems, to meet rising population- and income-driven demand. Here we analyze the roles of economic, demographic, and geographic factors and preferences in shaping blue food demand, using secondary data from FAO and The World Bank, parameters from published models, and case studies at national to sub-national scales. Our results show a weak cross-sectional relationship between per capita income and consumption globally when using an aggregate fish metric. Disaggregation by fish species group reveals distinct geographic patterns; for example, high consumption of freshwater fish in China and pelagic fish in Ghana and Peru where these fish are widely available, affordable, and traditionally eaten. We project a near doubling of global fish demand by mid-century assuming continued growth in aquaculture production and constant real prices for fish. Our study concludes that nutritional and environmental consequences of rising demand will depend on substitution among fish groups and other animal source foods in national diets.
Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.
Small populations are often exposed to high inbreeding and mutational load that can increase the risk of extinction. The Sumatran rhinoceros was widespread in Southeast Asia, but is now restricted to small and isolated populations on Sumatra and Borneo, and most likely extinct on the Malay Peninsula. Here, we analyse 5 historical and 16 modern genomes from these populations to investigate the genomic consequences of the recent decline, such as increased inbreeding and mutational load. We find that the Malay Peninsula population experienced increased inbreeding shortly before extirpation, which possibly was accompanied by purging. The populations on Sumatra and Borneo instead show low inbreeding, but high mutational load. The currently small population sizes may thus in the near future lead to inbreeding depression. Moreover, we find little evidence for differences in local adaptation among populations, suggesting that future inbreeding depression could potentially be mitigated by assisted gene flow among populations.
Modern mangroves are among the most carbon-rich biomes on Earth, but their long-term (≥106 years) impact on the global carbon cycle is unknown. The extent, productivity and preservation of mangroves are controlled by the interplay of tectonics, global sea level and sedimentation, including tide, wave and fluvial processes. The impact of these processes on mangrove-bearing successions in the Oligo-Miocene of the South China Sea (SCS) is evaluated herein. Palaeogeographic reconstructions, palaeotidal modelling and facies analysis suggest that elevated tidal range and bed shear stress optimized mangrove development along tide-influenced tropical coastlines. Preservation of mangrove organic carbon (OC) was promoted by high tectonic subsidence and fluvial sediment supply. Lithospheric storage of OC in peripheral SCS basins potentially exceeded 4,000 Gt (equivalent to 2,000 p.p.m. of atmospheric CO2). These results highlight the crucial impact of tectonic and oceanographic processes on mangrove OC sequestration within the global carbon cycle on geological timescales.
Three-phase induction motors (TIMs) are widely used for machines in industrial operations. As an accurate and robust controller, fuzzy logic controller (FLC) is crucial in designing TIMs control systems. The performance of FLC highly depends on the membership function (MF) variables, which are evaluated by heuristic approaches, leading to a high processing time. To address these issues, optimisation algorithms for TIMs have received increasing interest among researchers and industrialists. Here, we present an advanced and efficient quantum-inspired lightning search algorithm (QLSA) to avoid exhaustive conventional heuristic procedures when obtaining MFs. The accuracy of the QLSA based FLC (QLSAF) speed control is superior to other controllers in terms of transient response, damping capability and minimisation of statistical errors under diverse speeds and loads. The performance of the proposed QLSAF speed controller is validated through experiments. Test results under different conditions show consistent speed responses and stator currents with the simulation results.
Reported incidence of the zoonotic malaria Plasmodium knowlesi has markedly increased across Southeast Asia and threatens malaria elimination. Nonzoonotic transmission of P. knowlesi has been experimentally demonstrated, but it remains unknown whether nonzoonotic transmission is contributing to increases in P. knowlesi cases. Here, we adapt model-based inference methods to estimate RC, individual case reproductive numbers, for P. knowlesi, P. falciparum and P. vivax human cases in Malaysia from 2012-2020 (n = 32,635). Best fitting models for P. knowlesi showed subcritical transmission (RC 1) was estimated historically for P. falciparum and P. vivax, with declines in RC estimates observed over time consistent with local elimination. Together, this suggests sustained nonzoonotic P. knowlesi transmission is highly unlikely and that new approaches are urgently needed to control spillover risks.
Protected Areas (PAs) are the cornerstone of biodiversity conservation. Here, we collated distributional data for >14,000 (~70% of) species of amphibians and reptiles (herpetofauna) to perform a global assessment of the conservation effectiveness of PAs using species distribution models. Our analyses reveal that >91% of herpetofauna species are currently distributed in PAs, and that this proportion will remain unaltered under future climate change. Indeed, loss of species' distributional ranges will be lower inside PAs than outside them. Therefore, the proportion of effectively protected species is predicted to increase. However, over 7.8% of species currently occur outside PAs, and large spatial conservation gaps remain, mainly across tropical and subtropical moist broadleaf forests, and across non-high-income countries. We also predict that more than 300 amphibian and 500 reptile species may go extinct under climate change over the course of the ongoing century. Our study highlights the importance of PAs in providing herpetofauna with refuge from climate change, and suggests ways to optimize PAs to better conserve biodiversity worldwide.
Policies aiming to preserve vegetated coastal ecosystems (VCE; tidal marshes, mangroves and seagrasses) to mitigate greenhouse gas emissions require national assessments of blue carbon resources. Here, we present organic carbon (C) storage in VCE across Australian climate regions and estimate potential annual CO2 emission benefits of VCE conservation and restoration. Australia contributes 5-11% of the C stored in VCE globally (70-185 Tg C in aboveground biomass, and 1,055-1,540 Tg C in the upper 1 m of soils). Potential CO2 emissions from current VCE losses are estimated at 2.1-3.1 Tg CO2-e yr-1, increasing annual CO2 emissions from land use change in Australia by 12-21%. This assessment, the most comprehensive for any nation to-date, demonstrates the potential of conservation and restoration of VCE to underpin national policy development for reducing greenhouse gas emissions.
Seagrass conservation is critical for mitigating climate change due to the large stocks of carbon they sequester in the seafloor. However, effective conservation and its potential to provide nature-based solutions to climate change is hindered by major uncertainties regarding seagrass extent and distribution. Here, we describe the characterization of the world's largest seagrass ecosystem, located in The Bahamas. We integrate existing spatial estimates with an updated empirical remote sensing product and perform extensive ground-truthing of seafloor with 2,542 diver surveys across remote sensing tiles. We also leverage seafloor assessments and movement data obtained from instrument-equipped tiger sharks, which have strong fidelity to seagrass ecosystems, to augment and further validate predictions. We report a consensus area of at least 66,000 km2 and up to 92,000 km2 of seagrass habitat across The Bahamas Banks. Sediment core analysis of stored organic carbon further confirmed the global relevance of the blue carbon stock in this ecosystem. Data from tiger sharks proved important in supporting mapping and ground-truthing remote sensing estimates. This work provides evidence of major knowledge gaps in the ocean ecosystem, the benefits in partnering with marine animals to address these gaps, and underscores support for rapid protection of oceanic carbon sinks.
Sharks and rays are key functional components of coral reef ecosystems, yet many populations of a few species exhibit signs of depletion and local extinctions. The question is whether these declines forewarn of a global extinction crisis. We use IUCN Red List to quantify the status, trajectory, and threats to all coral reef sharks and rays worldwide. Here, we show that nearly two-thirds (59%) of the 134 coral-reef associated shark and ray species are threatened with extinction. Alongside marine mammals, sharks and rays are among the most threatened groups found on coral reefs. Overfishing is the main cause of elevated extinction risk, compounded by climate change and habitat degradation. Risk is greatest for species that are larger-bodied (less resilient and higher trophic level), widely distributed across several national jurisdictions (subject to a patchwork of management), and in nations with greater fishing pressure and weaker governance. Population declines have occurred over more than half a century, with greatest declines prior to 2005. Immediate action through local protections, combined with broad-scale fisheries management and Marine Protected Areas, is required to avoid extinctions and the loss of critical ecosystem function condemning reefs to a loss of shark and ray biodiversity and ecosystem services, limiting livelihoods and food security.
The emergence of COVID-19 dramatically changed social behavior across societies and contexts. Here we study whether social norms also changed. Specifically, we study this question for cultural tightness (the degree to which societies generally have strong norms), specific social norms (e.g. stealing, hand washing), and norms about enforcement, using survey data from 30,431 respondents in 43 countries recorded before and in the early stages following the emergence of COVID-19. Using variation in disease intensity, we shed light on the mechanisms predicting changes in social norm measures. We find evidence that, after the emergence of the COVID-19 pandemic, hand washing norms increased while tightness and punishing frequency slightly decreased but observe no evidence for a robust change in most other norms. Thus, at least in the short term, our findings suggest that cultures are largely stable to pandemic threats except in those norms, hand washing in this case, that are perceived to be directly relevant to dealing with the collective threat.
While the printed circuit board (PCB) has been widely considered as the building block of integrated electronics, the world is switching to pursue new ways of merging integrated electronic circuits with textiles to create flexible and wearable devices. Herein, as an alternative for PCB, we described a non-printed integrated-circuit textile (NIT) for biomedical and theranostic application via a weaving method. All the devices are built as fibers or interlaced nodes and woven into a deformable textile integrated circuit. Built on an electrochemical gating principle, the fiber-woven-type transistors exhibit superior bending or stretching robustness, and were woven as a textile logical computing module to distinguish different emergencies. A fiber-type sweat sensor was woven with strain and light sensors fibers for simultaneously monitoring body health and the environment. With a photo-rechargeable energy textile based on a detailed power consumption analysis, the woven circuit textile is completely self-powered and capable of both wireless biomedical monitoring and early warning. The NIT could be used as a 24/7 private AI "nurse" for routine healthcare, diabetes monitoring, or emergencies such as hypoglycemia, metabolic alkalosis, and even COVID-19 patient care, a potential future on-body AI hardware and possibly a forerunner to fabric-like computers.
Coral reefs can provide significant coastal protection benefits to people and property. Here we show that the annual expected damages from flooding would double, and costs from frequent storms would triple without reefs. For 100-year storm events, flood damages would increase by 91% to $US 272 billion without reefs. The countries with the most to gain from reef management are Indonesia, Philippines, Malaysia, Mexico, and Cuba; annual expected flood savings exceed $400 M for each of these nations. Sea-level rise will increase flood risk, but substantial impacts could happen from reef loss alone without better near-term management. We provide a global, process-based valuation of an ecosystem service across an entire marine biome at (sub)national levels. These spatially explicit benefits inform critical risk and environmental management decisions, and the expected benefits can be directly considered by governments (e.g., national accounts, recovery plans) and businesses (e.g., insurance).
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Binary expression systems have revolutionised genetic research by enabling delivery of loss-of-function and gain-of-function transgenes with precise spatial-temporal resolution in vivo. However, at present, each existing platform relies on a defined exogenous transcription activator capable of binding a unique recognition sequence. Consequently, none of these technologies alone can be used to simultaneously target different tissues or cell types in the same organism. Here, we report a modular system based on programmable transcription activator-like effector (TALE) proteins, which enables parallel expression of multiple transgenes in spatially distinct tissues in vivo. Using endogenous enhancers coupled to TALE drivers, we demonstrate multiplexed orthogonal activation of several transgenes carrying cognate variable activating sequences (VAS) in distinct neighbouring cell types of the Drosophila central nervous system. Since the number of combinatorial TALE-VAS pairs is virtually unlimited, this platform provides an experimental framework for highly complex genetic manipulation studies in vivo.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Clostridial neurotoxins, including tetanus and botulinum neurotoxins, generally target vertebrates. We show here that this family of toxins has a much broader host spectrum, by identifying PMP1, a clostridial-like neurotoxin that selectively targets anopheline mosquitoes. Isolation of PMP1 from Paraclostridium bifermentans strains collected in anopheline endemic areas on two continents indicates it is widely distributed. The toxin likely evolved from an ancestral form that targets the nervous system of similar organisms, using a common mechanism that disrupts SNARE-mediated exocytosis. It cleaves the mosquito syntaxin and employs a unique receptor recognition strategy. Our research has an important impact on the study of the evolution of clostridial neurotoxins and provides the basis for the use of P. bifermentans strains and PMP1 as innovative, environmentally friendly approaches to reduce malaria through anopheline control.