The 100 most-cited articles in Proceedings of the National Academy of Sciences, 2021

In the field of artificial intelligence, a combination of scale in data and model capacity enabled by unsupervised learning has led to major advances in representation learning and statistical generation. In the life sciences, the anticipated growth of sequencing promises unprecedented data on natural sequence diversity. Protein language modeling at the scale of evolution is a logical step toward predictive and generative artificial intelligence for biology. To this end, we use unsupervised learning to train a deep contextual language model on 86 billion amino acids across 250 million protein sequences spanning evolutionary diversity. The resulting model contains information about biological properties in its representations. The representations are learned from sequence data alone. The learned representation space has a multiscale organization reflecting structure from the level of biochemical properties of amino acids to remote homology of proteins. Information about secondary and tertiary structure is encoded in the representations and can be identified by linear projections.…

Social media may limit the exposure to diverse perspectives and favor the formation of groups of like-minded users framing and reinforcing a shared narrative, that is, echo chambers. However, the interaction paradigms among users and feed algorithms greatly vary across social media platforms. This paper explores the key differences between the main social media platforms and how they are likely to influence information spreading and echo chambers' formation. We perform a comparative analysis of more than 100 million pieces of content concerning several controversial topics (e.g., gun control, vaccination, abortion) from Gab, Facebook, Reddit, and Twitter. We quantify echo chambers over social media by two main ingredients: 1) homophily in the interaction networks and 2) bias in the information diffusion toward like-minded peers. Our results show that the aggregation of users in homophilic clusters dominate online interactions on Facebook and Twitter. We conclude the paper by directly comparing news consumption on Facebook and Reddit, finding higher segregation on Facebook.

Nature is under siege. In the last 10,000 y the human population has grown from 1 million to 7.8 billion. Much of Earth’s arable lands are already in agriculture (1), millions of acres of tropical forest are cleared each year (2, 3), atmospheric CO2 levels are at their highest concentrations in more than 3 million y (4), and climates are erratically and steadily changing from pole to pole, triggering unprecedented droughts, fires, and floods across continents. Indeed, most biologists agree that the world has entered its sixth mass extinction event, the first since the end of the Cretaceous Period 66 million y ago, when more than 80% of all species, including the nonavian dinosaurs, perished. Ongoing losses have been clearly demonstrated for better-studied groups of organisms. Terrestrial vertebrate population sizes and ranges have contracted by one-third, and many mammals have experienced range declines of at least 80% over the last century (5). A 2019 assessment suggests that half of all amphibians are imperiled (2.5% of which have recently gone extinct) (6). Bird numbers across…

Significance School closures have been a common tool in the battle against COVID-19. Yet, their costs and benefits remain insufficiently known. We use a natural experiment that occurred as national examinations in The Netherlands took place before and after lockdown to evaluate the impact of school closures on students’ learning. The Netherlands is interesting as a “best-case” scenario, with a short lockdown, equitable school funding, and world-leading rates of broadband access. Despite favorable conditions, we find that students made little or no progress while learning from home. Learning loss was most pronounced among students from disadvantaged homes.

The science around the use of masks by the public to impede COVID-19 transmission is advancing rapidly. In this narrative review, we develop an analytical framework to examine mask usage, synthesizing the relevant literature to inform multiple areas: population impact, transmission characteristics, source control, wearer protection, sociological considerations, and implementation considerations. A primary route of transmission of COVID-19 is via respiratory particles, and it is known to be transmissible from presymptomatic, paucisymptomatic, and asymptomatic individuals. Reducing disease spread requires two things: limiting contacts of infected individuals via physical distancing and other measures and reducing the transmission probability per contact. The preponderance of evidence indicates that mask wearing reduces transmissibility per contact by reducing transmission of infected respiratory particles in both laboratory and clinical contexts. Public mask wearing is most effective at reducing spread of the virus when compliance is high. Given the current shortages of medical masks,…

Numerical simulation of fluids plays an essential role in modeling many physical phenomena, such as weather, climate, aerodynamics, and plasma physics. Fluids are well described by the Navier-Stokes equations, but solving these equations at scale remains daunting, limited by the computational cost of resolving the smallest spatiotemporal features. This leads to unfavorable trade-offs between accuracy and tractability. Here we use end-to-end deep learning to improve approximations inside computational fluid dynamics for modeling two-dimensional turbulent flows. For both direct numerical simulation of turbulence and large-eddy simulation, our results are as accurate as baseline solvers with 8 to 10× finer resolution in each spatial dimension, resulting in 40- to 80-fold computational speedups. Our method remains stable during long simulations and generalizes to forcing functions and Reynolds numbers outside of the flows where it is trained, in contrast to black-box machine-learning approaches. Our approach exemplifies how scientific computing can leverage machine learning and hardware…

, and serum protein interactions of SORT nanoparticles. Additionally, we provide evidence for an endogenous targeting mechanism whereby organ targeting occurs via 1) desorption of poly(ethylene glycol) lipids from the LNP surface, 2) binding of distinct proteins to the nanoparticle surface because of recognition of exposed SORT molecules, and 3) subsequent interactions between surface-bound proteins and cognate receptors highly expressed in specific tissues. These findings establish a crucial link between the molecular composition of SORT nanoparticles and their unique and precise organ-targeting properties and suggest that the recruitment of specific proteins to a nanoparticle's surface can enable drug delivery beyond the liver.

Archaeological and paleoecological evidence shows that by 10,000 BCE, all human societies employed varying degrees of ecologically transformative land use practices, including burning, hunting, species propagation, domestication, cultivation, and others that have left long-term legacies across the terrestrial biosphere. Yet, a lingering paradigm among natural scientists, conservationists, and policymakers is that human transformation of terrestrial nature is mostly recent and inherently destructive. Here, we use the most up-to-date, spatially explicit global reconstruction of historical human populations and land use to show that this paradigm is likely wrong. Even 12,000 y ago, nearly three quarters of Earth's land was inhabited and therefore shaped by human societies, including more than 95% of temperate and 90% of tropical woodlands. Lands now characterized as "natural," "intact," and "wild" generally exhibit long histories of use, as do protected areas and Indigenous lands, and current global patterns of vertebrate species richness and key biodiversity areas are more strongly…

Plant disease outbreaks are increasing and threaten food security for the vulnerable in many areas of the world. Now a global human pandemic is threatening the health of millions on our planet. A stable, nutritious food supply will be needed to lift people out of poverty and improve health outcomes. Plant diseases, both endemic and recently emerging, are spreading and exacerbated by climate change, transmission with global food trade networks, pathogen spillover, and evolution of new pathogen lineages. In order to tackle these grand challenges, a new set of tools that include disease surveillance and improved detection technologies including pathogen sensors and predictive modeling and data analytics are needed to prevent future outbreaks. Herein, we describe an integrated research agenda that could help mitigate future plant disease pandemics.

Major declines in insect biomass and diversity, reviewed here, have become obvious and well documented since the end of World War II. Here, we conclude that the spread and intensification of agriculture during the past half century is directly related to these losses. In addition, many areas, including tropical mountains, are suffering serious losses because of climate change as well. Crops currently occupy about 11% of the world's land surface, with active grazing taking place over an additional 30%. The industrialization of agriculture during the second half of the 20th century involved farming on greatly expanded scales, monoculturing, the application of increasing amounts of pesticides and fertilizers, and the elimination of interspersed hedgerows and other wildlife habitat fragments, all practices that are destructive to insect and other biodiversity in and near the fields. Some of the insects that we are destroying, including pollinators and predators of crop pests, are directly beneficial to the crops. In the tropics generally, natural vegetation is being destroyed rapidly…

) at the global, regional, national, and municipality levels, separating the contribution to exposure trajectories from urban population growth versus total urban warming. Using a daily maximum wet bulb globe temperature threshold of 30 °C, global exposure increased nearly 200% from 1983 to 2016. Total urban warming elevated the annual increase in exposure by 52% compared to urban population growth alone. Exposure trajectories increased for 46% of urban settlements, which together in 2016 comprised 23% of the planet's population (1.7 billion people). However, how total urban warming and population growth drove exposure trajectories is spatially heterogeneous. This study reinforces the importance of employing multiple extreme heat exposure metrics to identify local patterns and compare exposure trends across geographies. Our results suggest that previous research underestimates extreme heat exposure, highlighting the urgency for targeted adaptations and early warning systems to reduce harm from urban extreme heat exposure.

= 0.45 (95% CI [0.39, 0.52]). In addition, we find that the effectiveness of choice architecture interventions varies significantly as a function of technique and domain. Across behavioral domains, interventions that target the organization and structure of choice alternatives (decision structure) consistently outperform interventions that focus on the description of alternatives (decision information) or the reinforcement of behavioral intentions (decision assistance). Food choices are particularly responsive to choice architecture interventions, with effect sizes up to 2.5 times larger than those in other behavioral domains. Overall, choice architecture interventions affect behavior relatively independently of contextual study characteristics such as the geographical location or the target population of the intervention. Our analysis further reveals a moderate publication bias toward positive results in the literature. We end with a discussion of the implications of our findings for theory and behaviorally informed policy making.

Recent dramatic and deadly increases in global wildfire activity have increased attention on the causes of wildfires, their consequences, and how risk from wildfire might be mitigated. Here we bring together data on the changing risk and societal burden of wildfire in the United States. We estimate that nearly 50 million homes are currently in the wildland–urban interface in the United States, a number increasing by 1 million houses every 3 y. To illustrate how changes in wildfire activity might affect air pollution and related health outcomes, and how these linkages might guide future science and policy, we develop a statistical model that relates satellite-based fire and smoke data to information from pollution monitoring stations. Using the model, we estimate that wildfires have accounted for up to 25% of PM 2.5 (particulate matter with diameter <2.5 μm) in recent years across the United States, and up to half in some Western regions, with spatial patterns in ambient smoke exposure that do not follow traditional socioeconomic pollution exposure gradients. We combine the model…

The term "core microbiome" has become widely used in microbial ecology over the last decade. Broadly, the core microbiome refers to any set of microbial taxa, or the genomic and functional attributes associated with those taxa, that are characteristic of a host or environment of interest. Most commonly, core microbiomes are measured as the microbial taxa shared among two or more samples from a particular host or environment. Despite the popularity of this term and its growing use, there is little consensus about how a core microbiome should be quantified in practice. Here, we present a brief history of the core microbiome concept and use a representative sample of the literature to review the different metrics commonly used for quantifying the core. Empirical analyses have used a wide range of metrics for quantifying the core microbiome, including arbitrary occurrence and abundance cutoff values, with the focal taxonomic level of the core ranging from phyla to amplicon sequence variants. However, many of these metrics are susceptible to sampling and other biases. Developing a…

The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on conserving genome-wide genetic variation, and that the field should instead focus on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost…

Using a longitudinal dataset linking biometric and survey data from several cohorts of young adults before and during the COVID-19 pandemic ([Formula: see text]), we document large disruptions to physical activity, sleep, time use, and mental health. At the onset of the pandemic, average steps decline from 10,000 to 4,600 steps per day, sleep increases by 25 to 30 min per night, time spent socializing declines by over half to less than 30 min, and screen time more than doubles to over 5 h per day. Over the course of the pandemic from March to July 2020 the proportion of participants at risk for clinical depression ranges from 46% to 61%, up to a 90% increase in depression rates compared to the same population just prior to the pandemic. Our analyses suggest that disruption to physical activity is a leading risk factor for depression during the pandemic. However, restoration of those habits through a short-term intervention does not meaningfully improve mental well-being.

368, 1257-1260 (2020)]. Here, we use in situ observations of microplastic deposition combined with an atmospheric transport model and optimal estimation techniques to test hypotheses of the most likely sources of atmospheric plastic. Results suggest that atmospheric microplastics in the western United States are primarily derived from secondary re-emission sources including roads (84%), the ocean (11%), and agricultural soil dust (5%). Using our best estimate of plastic sources and modeled transport pathways, most continents were net importers of plastics from the marine environment, underscoring the cumulative role of legacy pollution in the atmospheric burden of plastic. This effort uses high-resolution spatial and temporal deposition data along with several hypothesized emission sources to constrain atmospheric plastic. Akin to global biogeochemical cycles, plastics now spiral around the globe with distinct atmospheric, oceanic, cryospheric, and terrestrial residence times. Though advancements have been made in the manufacture of biodegradable polymers, our data suggest that…

Observational knowledge of the epidemic intensity, defined as the number of deaths divided by global population and epidemic duration, and of the rate of emergence of infectious disease outbreaks is necessary to test theory and models and to inform public health risk assessment by quantifying the probability of extreme pandemics such as COVID-19. Despite its significance, assembling and analyzing a comprehensive global historical record spanning a variety of diseases remains an unexplored task. A global dataset of historical epidemics from 1600 to present is here compiled and examined using novel statistical methods to estimate the yearly probability of occurrence of extreme epidemics. Historical observations covering four orders of magnitude of epidemic intensity follow a common probability distribution with a slowly decaying power-law tail (generalized Pareto distribution, asymptotic exponent = −0.71). The yearly number of epidemics varies ninefold and shows systematic trends. Yearly occurrence probabilities of extreme epidemics, P y , vary widely: P y of an event with the…

The induction of type I interferons through the transcription factor interferon regulatory factor 3 (IRF3) is considered a major outcome of stimulator of interferon genes (STING) activation that drives immune responses against DNA viruses and tumors. However, STING activation can also trigger other downstream pathways such as nuclear factor κB (NF-κB) signaling and autophagy, and the roles of interferon (IFN)-independent functions of STING in infectious diseases or cancer are not well understood. Here, we generated a STING mouse strain with a mutation (S365A) that disrupts IRF3 binding and therefore type I interferon induction but not NF-κB activation or autophagy induction. We also generated STING mice with mutations that disrupt the recruitment of TANK-binding kinase 1 (TBK1), which is important for both IRF3 and NF-κB activation but not autophagy induction (L373A or ∆CTT, which lacks the C-terminal tail). The STING-S365A mutant mice, but not L373A or ∆CTT mice, were still resistant to herpes simplex virus 1 (HSV-1) infections and mounted an antitumor response after cyclic…

= 2,730,215), we found that posts about the political out-group were shared or retweeted about twice as often as posts about the in-group. Each individual term referring to the political out-group increased the odds of a social media post being shared by 67%. Out-group language consistently emerged as the strongest predictor of shares and retweets: the average effect size of out-group language was about 4.8 times as strong as that of negative affect language and about 6.7 times as strong as that of moral-emotional language-both established predictors of social media engagement. Language about the out-group was a very strong predictor of "angry" reactions (the most popular reactions across all datasets), and language about the in-group was a strong predictor of "love" reactions, reflecting in-group favoritism and out-group derogation. This out-group effect was not moderated by political orientation or social media platform, but stronger effects were found among political leaders than among news media accounts. In sum, out-group language is the strongest predictor of social media…

Significance Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of Alzheimer's disease (AD), but their interplay is not clear. AD mouse brains showed lower nicotinamide adenine dinucleotide (NAD + ) levels and alterations in inflammation. Treatment of AD mice with NR reduced neuroinflammation, attenuated DNA damage, and prevented cellular senescence. We present evidence that the beneficial effects of nicotinamide riboside (NR) are, in part, through a cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-dependent pathway. DNA damage was increased in AD and attenuated by NR. Both cGAS–STING and NAD + pathways are potential therapeutic targets for AD.

The COVID-19 pandemic has led to an increased demand for single-use plastics that intensifies pressure on an already out-of-control global plastic waste problem. While it is suspected to be large, the magnitude and fate of this pandemic-associated mismanaged plastic waste are unknown. Here, we use our MITgcm ocean plastic model to quantify the impact of the pandemic on plastic discharge. We show that 8.4 ± 1.4 million tons of pandemic-associated plastic waste have been generated from 193 countries as of August 23, 2021, with 25.9 ± 3.8 thousand tons released into the global ocean representing 1.5 ± 0.2% of the global total riverine plastic discharge. The model projects that the spatial distribution of the discharge changes rapidly in the global ocean within 3 y, with a significant portion of plastic debris landing on the beach and seabed later and a circumpolar plastic accumulation zone will be formed in the Arctic. We find hospital waste represents the bulk of the global discharge (73%), and most of the global discharge is from Asia (72%), which calls for better management of…

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2-infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a…

Abstract Insects have diversified through 400 million years of Earth’s changeable climate, yet recent and ongoing shifts in patterns of temperature and precipitation pose novel challenges as they combine with decades of other anthropogenic stressors including the conversion and degradation of land. Here we consider how insects are responding to recent climate change, while summarizing the literature on long-term monitoring of insect populations in the context of climatic fluctuations. Results to date suggest that climate change impacts on insects have the potential to be considerable, even when compared to changes in land use. The importance of climate is illustrated with a case study from the butterflies of Northern California, where we find that population declines have been severe in high-elevation areas removed from the most immediate effects of habitat loss. These results shed light on the complexity of montane-adapted insects responding to changing abiotic conditions and raise questions about the utility of temperate mountains as refugia during the Anthropocene. We consider…

The neuroscience of perception has recently been revolutionized with an integrative modeling approach in which computation, brain function, and behavior are linked across many datasets and many computational models. By revealing trends across models, this approach yields novel insights into cognitive and neural mechanisms in the target domain. We here present a systematic study taking this approach to higher-level cognition: human language processing, our species' signature cognitive skill. We find that the most powerful "transformer" models predict nearly 100% of explainable variance in neural responses to sentences and generalize across different datasets and imaging modalities (functional MRI and electrocorticography). Models' neural fits ("brain score") and fits to behavioral responses are both strongly correlated with model accuracy on the next-word prediction task (but not other language tasks). Model architecture appears to substantially contribute to neural fit. These results provide computationally explicit evidence that predictive processing fundamentally shapes the…

COVID-19 has resulted in a staggering death toll in the US: over 215,000 by mid-October 2020, according to the Centers for Disease Control and Prevention. Black and Latino Americans have experienced a disproportionate burden of COVID-19 morbidity and mortality, reflecting persistent structural inequalities that increase risk of exposure to COVID-19 and mortality risk for those infected. We estimate life expectancy at birth and at age 65 for 2020, for the total US population and by race and ethnicity, using four scenarios of deaths - one in which the COVID-19 pandemic had not occurred and three including COVID-19 mortality projections produced by the Institute for Health Metrics and Evaluation. Our medium estimate indicates a reduction in US life expectancy at birth of 1.13 years to 77.48 years, lower than any year since 2003. We also project a 0.87-year reduction in life expectancy at age 65. The Black and Latino populations are estimated to experience declines in life expectancy at birth of 2.10 and 3.05 years, respectively, both of which are several times the 0.68-year reduction…

Quantification of asymptomatic infections is fundamental for effective public health responses to the COVID-19 pandemic. Discrepancies regarding the extent of asymptomaticity have arisen from inconsistent terminology as well as conflation of index and secondary cases which biases toward lower asymptomaticity. We searched PubMed, Embase, Web of Science, and World Health Organization Global Research Database on COVID-19 between January 1, 2020 and April 2, 2021 to identify studies that reported silent infections at the time of testing, whether presymptomatic or asymptomatic. Index cases were removed to minimize representational bias that would result in overestimation of symptomaticity. By analyzing over 350 studies, we estimate that the percentage of infections that never developed clinical symptoms, and thus were truly asymptomatic, was 35.1% (95% CI: 30.7 to 39.9%). At the time of testing, 42.8% (95% prediction interval: 5.2 to 91.1%) of cases exhibited no symptoms, a group comprising both asymptomatic and presymptomatic infections. Asymptomaticity was significantly lower among the…

Significance Immunosuppressive Tregs constitutively express CTLA-4, an immune checkpoint receptor. Addressing the role of CTLA-4 in Treg-suppressive function, we show that Treg-expressed CTLA-4, even in the absence of its cytoplasmic portion, promoted the conjugation of Tregs and antigen-presenting cells (APCs), leading to CTLA-4–dependent trogocytosis of CD80/CD86 and concomitant transfer of membrane fragments from APCs to the Treg cell surface. The depletion or blockade of CD80 by trogocytosis or solubilized CTLA-4, respectively, increased free PD-L1 by disrupting cis-CD80/PD-L1 heterodimers on APCs. Thus, Tregs can exert dual suppressive effects through the limitation of CD80/CD86 and up-regulation of free PD-L1 on APCs. Cancer immunotherapy with anti–CTLA-4 and anti–PD-1/PD-L1 blocking antibodies may enhance tumor immunity by hindering this Treg-mediated immune suppression.

The current revival of the American economy is being predicated on social distancing, specifically the Six-Foot Rule, a guideline that offers little protection from pathogen-bearing aerosol droplets sufficiently small to be continuously mixed through an indoor space. The importance of airborne transmission of COVID-19 is now widely recognized. While tools for risk assessment have recently been developed, no safety guideline has been proposed to protect against it. We here build on models of airborne disease transmission in order to derive an indoor safety guideline that would impose an upper bound on the "cumulative exposure time," the product of the number of occupants and their time in an enclosed space. We demonstrate how this bound depends on the rates of ventilation and air filtration, dimensions of the room, breathing rate, respiratory activity and face mask use of its occupants, and infectiousness of the respiratory aerosols. By synthesizing available data from the best-characterized indoor spreading events with respiratory drop size distributions, we estimate an infectious…

The current rate of species extinction is rapidly approaching unprecedented highs, and life on Earth presently faces a sixth mass extinction event driven by anthropogenic activity, climate change, and ecological collapse. The field of conservation genetics aims at preserving species by using their levels of genetic diversity, usually measured as neutral genome-wide diversity, as a barometer for evaluating population health and extinction risk. A fundamental assumption is that higher levels of genetic diversity lead to an increase in fitness and long-term survival of a species. Here, we argue against the perceived importance of neutral genetic diversity for the conservation of wild populations and species. We demonstrate that no simple general relationship exists between neutral genetic diversity and the risk of species extinction. Instead, a better understanding of the properties of functional genetic diversity, demographic history, and ecological relationships is necessary for developing and implementing effective conservation genetic strategies.

ABSTRACT Most animal species on Earth are insects, and recent reports suggest that their abundance is in drastic decline. Although these reports come from a wide range of insect taxa and regions, the evidence to assess the extent of the phenomenon is still sparse. Insect populations are challenging to study and most monitoring methods are labour intensive and inefficient. Advances in computer vision and deep learning provide potential new solutions to this global challenge. Cameras and other sensors that can effectively, continuously, and non-invasively perform entomological observations throughout diurnal and seasonal cycles. The physical appearance of specimens can also be captured by automated imaging in the lab. When trained on these data, deep learning models can provide estimates of insect abundance, biomass, and diversity. Further, deep learning models can quantify variation in phenotypic traits, behaviour, and interactions. Here, we connect recent developments in deep learning and computer vision to the urgent demand for more cost-efficient monitoring of insects and other…

To investigate the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the immune population, we coincupi bated the authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for seven passages, but, after 45 d, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed, at day 80, by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom, South Africa, Brazil, and Japan of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.

Permafrost degradation may induce soil carbon (C) loss, critical for global C cycling, and be mediated by microbes. Despite larger C stored within the active layer of permafrost regions, which are more affected by warming, and the critical roles of Qinghai-Tibet Plateau in C cycling, most previous studies focused on the permafrost layer and in high-latitude areas. We demonstrate in situ that permafrost degradation alters the diversity and potentially decreases the stability of active layer microbial communities. These changes are associated with soil C loss and potentially a positive C feedback. This study provides insights into microbial-mediated mechanisms responsible for C loss within the active layer in degraded permafrost, aiding in the modeling of C emission under future scenarios.

We review changes in the status of butterflies in Europe, focusing on long-running population data available for the United Kingdom, the Netherlands, and Belgium, based on standardized monitoring transects. In the United Kingdom, 8% of resident species have become extinct, and since 1976 overall numbers declined by around 50%. In the Netherlands, 20% of species have become extinct, and since 1990 overall numbers in the country declined by 50%. Distribution trends showed that butterfly distributions began decreasing long ago, and between 1890 and 1940, distributions declined by 80%. In Flanders (Belgium), 20 butterflies have become extinct (29%), and between 1992 and 2007 overall numbers declined by around 30%. A European Grassland Butterfly Indicator from 16 European countries shows there has been a 39% decline of grassland butterflies since 1990. The 2010 Red List of European butterflies listed 38 of the 482 European species (8%) as threatened and 44 species (10%) as near threatened (note that 47 species were not assessed). A country level analysis indicates that the average Red…

Significance The North China Plain experiences severe summer ozone pollution, but ozone during winter haze (particulate) pollution events has been very low. Here, we show that the abrupt decrease in nitrogen oxide (NO x ) emissions following the COVID-19 lockdown in January 2020 drove fast ozone production during winter haze events to levels approaching the air quality standard. This fast ozone production was driven by formaldehyde originating from high emissions of volatile organic compounds (VOCs). The COVID-19 experience highlights a general 2013 to 2019 trend of rapidly increasing ozone pollution in winter–spring in China as NO x emissions have decreased. VOC emission controls would mitigate the spreading of ozone pollution into winter–spring with benefits for public health, crop production, and particulate pollution.

Inspired by the embodied intelligence observed in octopus arms, we introduce magnetically controlled origami robotic arms based on Kresling patterns for multimodal deformations, including stretching, folding, omnidirectional bending, and twisting. The highly integrated motion of the robotic arms is attributed to inherent features of the reconfigurable Kresling unit, whose controllable bistable deploying/folding and omnidirectional bending are achieved through precise magnetic actuation. We investigate single- and multiple-unit robotic systems, the latter exhibiting higher biomimetic resemblance to octopus' arms. We start from the single Kresling unit to delineate the working mechanism of the magnetic actuation for deploying/folding and bending. The two-unit Kresling assembly demonstrates the basic integrated motion that combines omnidirectional bending with deploying. The four-unit Kresling assembly constitutes a robotic arm with a larger omnidirectional bending angle and stretchability. With the foundation of the basic integrated motion, scalability of Kresling assemblies is…

Significance Genome editing technologies enable the permanent repair of disease-causing genetic mutations. However, the application of this technology has been limited by the technical challenge of achieving safe, effective, and specific in vivo delivery of the CRISPR-Cas9 genome editing components. Here, we report the development of a newly identified lipid nanoparticle (LNP) for specific delivery of CRISPR-Cas9 mRNA to the liver. While LNPs have been FDA approved for delivery of siRNA to the liver, here we examine their application for genome editing. When compared head-to-head, our delivery platform significantly outperforms the FDA-approved LNP in the efficient delivery of Cas9 mRNA for knockdown of the Angptl3 gene and subsequent regulation of hypercholesterolemia, while matching the safety and specificity of the approved platform.

Many intrinsically disordered proteins (IDPs) may undergo liquid-liquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalization of intracellular biochemical reactions. The phase behavior of IDPs is sequence dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intramolecular and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residue-level detail, based on an extensive set of experimental data on single-chain properties. Ensemble-averaged experimental observables are predicted from molecular simulations, and a data-driven parameter-learning procedure is used to identify the residue-specific model parameters that minimize the discrepancy between predictions and experiments. The model accurately reproduces the experimentally observed conformational propensities of a set of IDPs. Through two-body as well as large-scale molecular simulations,…

to heat stress prior to the onset of bleaching to identify processes involved in the breakdown of the coral-algal symbiosis. We show that altered nutrient cycling during heat stress is a primary driver of the functional breakdown of the symbiosis. Heat stress increased the metabolic energy demand of the coral host, which was compensated by the catabolic degradation of amino acids. The resulting shift from net uptake to release of ammonium by the coral holobiont subsequently promoted the growth of algal symbionts and retention of photosynthates. Together, these processes form a feedback loop that will gradually lead to the decoupling of carbon translocation from the symbiont to the host. Energy limitation and altered symbiotic nutrient cycling are thus key factors in the early heat stress response, directly contributing to the breakdown of the coral-algal symbiosis. Interpreting the stability of the coral holobiont in light of its metabolic interactions provides a missing link in our understanding of the environmental drivers of bleaching and may ultimately help uncover fundamental…

Federated learning (FL) enables edge devices, such as Internet of Things devices (e.g., sensors), servers, and institutions (e.g., hospitals), to collaboratively train a machine learning (ML) model without sharing their private data. FL requires devices to exchange their ML parameters iteratively, and thus the time it requires to jointly learn a reliable model depends not only on the number of training steps but also on the ML parameter transmission time per step. In practice, FL parameter transmissions are often carried out by a multitude of participating devices over resource-limited communication networks, for example, wireless networks with limited bandwidth and power. Therefore, the repeated FL parameter transmission from edge devices induces a notable delay, which can be larger than the ML model training time by orders of magnitude. Hence, communication delay constitutes a major bottleneck in FL. Here, a communication-efficient FL framework is proposed to jointly improve the FL convergence time and the training loss. In this framework, a probabilistic device selection scheme…

Humans learn about the world by collectively acquiring information, filtering it, and sharing what we know. Misinformation undermines this process. The repercussions are extensive. Without reliable and accurate sources of information, we cannot hope to halt climate change, make reasoned democratic decisions, or control a global pandemic. Most analyses of misinformation focus on popular and social media, but the scientific enterprise faces a parallel set of problems-from hype and hyperbole to publication bias and citation misdirection, predatory publishing, and filter bubbles. In this perspective, we highlight these parallels and discuss future research directions and interventions.

Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide…

Estimates of the global population of humans living at high altitude vary widely, and such data at the country level are unavailable. Herein, we use a geographic information system (GIS)-based approach to quantify human population at 500-m elevation intervals for each country. Based on georeferenced data for population (LandScan Global 2019) and elevation (Global Multiresolution Terrain Elevation Data), 500.3 million humans live at ≥1,500 m, 81.6 million at ≥2,500 m, and 14.4 million at ≥3,500 m. Ethiopia has the largest absolute population at ≥1,500 m and ≥2,500 m, while China has the greatest at ≥3,500 m. Lesotho has the greatest percentage of its population above 1,500 m, while Bolivia has the greatest at ≥2,500 m and ≥3,500 m. High altitude presents a myriad of environmental stresses that provoke physiological responses and adaptation, and consequently impact disease prevalence and severity. While the majority of high-altitude physiology research is based upon lowlanders from western, educated, industrialized, rich, and democratic countries ascending to high altitude, the global…

Significance Fires burn an area comparable to Europe each year, emitting greenhouse gases and aerosols. We compared burned area (BA) based on 20-m resolution images with a BA derived from 500-m data. It represents an 80% increase in BA in sub-Saharan Africa, responsible for about 70% of global BA. This difference is predominately (87%) attributed to small fires (<100 ha), which account for 41% of total BA but only for 5% in coarse-resolution products. We found that African fires were responsible for emissions of 1.44 PgC, 31–101% higher than previous estimates and representing 14% of global CO 2 emissions from fossil fuel burning. We conclude that small fires are critically important in characterizing the most important disturbance agent on a global scale.

The accessibility of global biodiversity information has surged in the past two decades, notably through widespread funding initiatives for museum specimen digitization and emergence of large-scale public participation in community science. Effective use of these data requires the integration of disconnected datasets, but the scientific impacts of consolidated biodiversity data networks have not yet been quantified. To determine whether data integration enables novel research, we carried out a quantitative text analysis and bibliographic synthesis of >4,000 studies published from 2003 to 2019 that use data mediated by the world's largest biodiversity data network, the Global Biodiversity Information Facility (GBIF). Data available through GBIF increased 12-fold since 2007, a trend matched by global data use with roughly two publications using GBIF-mediated data per day in 2019. Data-use patterns were diverse by authorship, geographic extent, taxonomic group, and dataset type. Despite facilitating global authorship, legacies of colonial science remain. Studies involving species…

Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants.…

Many Americans fail to get life-saving vaccines each year, and the availability of a vaccine for COVID-19 makes the challenge of encouraging vaccination more urgent than ever. We present a large field experiment (N=47,306) testing 19 nudges delivered to patients via text message and designed to boost adoption of the influenza vaccine. Our findings suggest that text messages sent prior to a primary care visit can boost vaccination rates by an average of 5%. Overall, interventions performed better when they were (a) framed as reminders to get flu shots that were already reserved for the patient and (b) congruent with the sort of communications patients expected to receive from their healthcare provider (i.e., not surprising, casual, or interactive). The best-performing intervention in our study reminded patients twice to get their flu shot at their upcoming doctor’s appointment and indicated it was reserved for them. This successful script could be used as a template for campaigns to encourage the adoption of life-saving vaccines, including against COVID-19.

Heavy monsoon rainfall ravaged a large swath of East Asia in summer 2020. Severe flooding of the Yangtze River displaced millions of residents in the midst of a historic public health crisis. This extreme rainy season was not anticipated from El Niño conditions. Using observations and model experiments, we show that the record strong Indian Ocean Dipole event in 2019 is an important contributor to the extreme Yangtze flooding of 2020. This Indian Ocean mode and a weak El Niño in the Pacific excite downwelling oceanic Rossby waves that propagate slowly westward south of the equator. At a mooring in the Southwest Indian Ocean, the thermocline deepens by a record 70 m in late 2019. The deepened thermocline helps sustain the Indian Ocean warming through the 2020 summer. The Indian Ocean warming forces an anomalous anticyclone in the lower troposphere over the Indo-Northwest Pacific region and intensifies the upper-level westerly jet over East Asia, leading to heavy summer rainfall in the Yangtze Basin. These coupled ocean-atmosphere processes beyond the equatorial Pacific provide…

Zoonotic diseases are infectious diseases of humans caused by pathogens that are shared between humans and other vertebrate animals. Previously, pristine natural areas with high biodiversity were seen as likely sources of new zoonotic pathogens, suggesting that biodiversity could have negative impacts on human health. At the same time, biodiversity has been recognized as potentially benefiting human health by reducing the transmission of some pathogens that have already established themselves in human populations. These apparently opposing effects of biodiversity in human health may now be reconcilable. Recent research demonstrates that some taxa are much more likely to be zoonotic hosts than others are, and that these animals often proliferate in human-dominated landscapes, increasing the likelihood of spillover. In less-disturbed areas, however, these zoonotic reservoir hosts are less abundant and nonreservoirs predominate. Thus, biodiversity loss appears to increase the risk of human exposure to both new and established zoonotic pathogens. This new synthesis of the effects of…

from fragranced VCPs and other anthropogenic sources, which is comparable to that of a summertime forest. Photochemical modeling of an extreme heat event, with ozone well in excess of US standards, illustrates the significant impact of VCPs on air quality. In the most populated regions of NYC, ozone was sensitive to anthropogenic VOCs (AVOCs), even in the presence of biogenic sources. Within this VOC-sensitive regime, AVOCs contributed upwards of ∼20 ppb to maximum 8-h average ozone. VCPs accounted for more than 50% of this total AVOC contribution. Emissions from fragranced VCPs, including personal care and cleaning products, account for at least 50% of the ozone attributed to VCPs. We show that model simulations of ozone depend foremost on the magnitude of VCP emissions and that the addition of oxygenated VCP chemistry impacts simulations of key atmospheric oxidation products. NYC is a case study for developed megacities, and the impacts of VCPs on local ozone are likely similar for other major urban regions across North America or Europe.

= 994) from the Person to Person Health Interview Study, fielded in 2019-2020 and again during Indiana's initial stay-at-home order, we provide a representative, probability-based assessment of adverse economic outcomes of the pandemic. Survey-weighted multivariate regressions, controlling for preexisting inequality, find Black adults over 3 times as likely as Whites to report food insecurity, being laid off, or being unemployed. Residents without a college degree are twice as likely to report food insecurity (compared to some college), while those not completing high school (compared to bachelor's degree) are 4 times as likely to do so. Younger adults and women were also more likely to report economic hardships. Together, the results support contentions of a Matthew Effect, where pandemic precarity disproportionately affects historically disadvantaged groups, widening inequality. Strategically deployed relief efforts and longer-term policy reforms are needed to challenge the perennial and unequal impact of disasters.

, and predict that with certain alloying, it becomes magnetic and metallic and features the aforementioned magnetic dualism. The calculated energy bands split antisymmetrically with respect to spin-degenerate nodal surfaces rather than nodal points, as in the case of spin-orbit splitting. The combination of a large (0.2-eV) spin splitting, compensated net magnetization with metallic ground state, and a specific magnetic easy axis generates a large anomalous Hall conductivity (∼150 S/cm) and a sizable magnetooptical Kerr effect, all deemed to be hallmarks of nonzero net magnetization. We identify a large contribution to the anomalous response originating from the spin-orbit interaction gapped anti-Kramers nodal surfaces, a mechanism distinct from the nodal lines and Weyl points in ferromagnets.

Near the 100th anniversary of the discovery of ferroelectricity, so-called sliding ferroelectricity has been proposed and confirmed recently in a series of experiments that have stimulated remarkable interest. Such ferroelectricity exists widely and exists only in two-dimensional (2D) van der Waals stacked layers, where the vertical electric polarization is switched by in-plane interlayer sliding. Reciprocally, interlayer sliding and the "ripplocation" domain wall can be driven by an external vertical electric field. The unique combination of intralayer stiffness and interlayer slipperiness of 2D van der Waals layers greatly facilitates such switching while still maintaining environmental and mechanical robustness at ambient conditions. In this perspective, we discuss the progress and future opportunities in this behavior. The origin of such ferroelectricity as well as a general rule for judging its existence are summarized, where the vertical stacking sequence is crucial for its formation. This discovery broadens 2D ferroelectrics from very few material candidates to most of the…

China has implemented an emission trading system (ETS) to reduce its ever-increasing greenhouse gas emissions while maintaining rapid economic growth. With low carbon prices and infrequent allowance trading, whether China's ETS is an effective approach for climate mitigation has entered the center of the policy and research debate. Utilizing China's regional ETS pilots as a quasi-natural experiment, we provide a comprehensive assessment of the effects of ETS on firm carbon emissions and economic outcomes by means of a matched difference-in-differences (DID) approach. The empirical analysis is based on a unique panel dataset of firm tax records in the manufacturing and public utility sectors during 2009 to 2015. We show unambiguous evidence that the regional ETS pilots are effective in reducing firm emissions, leading to a 16.7% reduction in total emissions and a 9.7% reduction in emission intensity. Regulated firms achieve emission abatement through conserving energy consumption and switching to low-carbon fuels. The economic consequences of the ETS are mixed. On one hand, the ETS…

It is well established that plasmids play an important role in the dissemination of antimicrobial resistance (AMR) genes; however, little is known about the role of the underlying interactions between different plasmid categories and other mobile genetic elements (MGEs) in shaping the promiscuous spread of AMR genes. Here, we developed a tool designed for plasmid classification, AMR gene annotation, and plasmid visualization and found that most plasmid-borne AMR genes, including those localized on class 1 integrons, are enriched in conjugative plasmids. Notably, we report the discovery and characterization of a massive insertion sequence (IS)-associated AMR gene transfer network (245 combinations covering 59 AMR gene subtypes and 53 ISs) linking conjugative plasmids and phylogenetically distant pathogens, suggesting a general evolutionary mechanism for the horizontal transfer of AMR genes mediated by the interaction between conjugative plasmids and ISs. Moreover, our experimental results confirmed the importance of the observed interactions in aiding the horizontal transfer and…

Since its outbreak, COVID-19 has impacted world regions differentially. Whereas some regions still record tens of thousands of new infections daily, other regions have contained the virus. What explains these striking regional differences? We advance a cultural psychological perspective on mask usage, a precautionary measure vital for curbing the pandemic. Four large-scale studies provide evidence that collectivism (versus individualism) positively predicts mask usage-both within the United States and across the world. Analyzing a dataset of all 3,141 counties of the 50 US states (based on 248,941 individuals), Study 1a revealed that mask usage was higher in more collectivistic US states. Study 1b replicated this finding in another dataset of 16,737 individuals in the 50 US states. Analyzing a dataset of 367,109 individuals in 29 countries, Study 2 revealed that mask usage was higher in more collectivistic countries. Study 3 replicated this finding in a dataset of 277,219 Facebook users in 67 countries. The link between collectivism and mask usage was robust to a host of control…

Significance The growth of coral reefs is threatened by the dual stressors of ocean warming and acidification. Despite a wealth of studies assessing the impacts of climate change on individual taxa, projections of their impacts on coral reef net carbonate production are limited. By projecting impacts across 233 different locations, we demonstrate that the majority of coral reefs will be unable to maintain positive net carbonate production globally by the year 2100 under representative concentration pathways RCP4.5 and 8.5, while even under RCP2.6, coral reefs will suffer reduced accretion rates. Our results provide quantitative projections of how different climate change stressors will influence whole ecosystem carbonate production across coral reefs in all major ocean basins.

Deep neural networks currently provide the best quantitative models of the response patterns of neurons throughout the primate ventral visual stream. However, such networks have remained implausible as a model of the development of the ventral stream, in part because they are trained with supervised methods requiring many more labels than are accessible to infants during development. Here, we report that recent rapid progress in unsupervised learning has largely closed this gap. We find that neural network models learned with deep unsupervised contrastive embedding methods achieve neural prediction accuracy in multiple ventral visual cortical areas that equals or exceeds that of models derived using today's best supervised methods and that the mapping of these neural network models' hidden layers is neuroanatomically consistent across the ventral stream. Strikingly, we find that these methods produce brain-like representations even when trained solely with real human child developmental data collected from head-mounted cameras, despite the fact that these datasets are noisy and…

ions and form a second solvation shell or a pseudo-LHCE which diminishes the benefits of LHCE. In addition, it is evident that the diluent has significant influence on the electrode/electrolyte interphases (EEIs) beyond retaining the high-concentration solvation structures. Diluent molecules surrounding the high-concentration clusters could accelerate or decelerate the anion decomposition through coparticipation of diluent decomposition in the EEI formation. The varied interphase features lead to significantly different battery performance. This study points out the importance of diluents and their synergetic effects with the conductive salt and the solvating solvent in designing LHCEs. These systematic comparisons and fundamental insights into LHCEs using different types of fluorinated solvents can guide further development of advanced electrolytes for high-voltage LMBs.

The environmental crises currently gripping the Earth have been codified in a new proposed geological epoch: the Anthropocene. This epoch, according to the Anthropocene Working Group, began in the mid-20th century and reflects the “great acceleration” that began with industrialization in Europe [J. Zalasiewicz et al., Anthropocene 19, 55–60 (2017)]. Ironically, European ideals of protecting a pristine “wilderness,” free from the damaging role of humans, is still often heralded as the antidote to this human-induced crisis [J. E. M. Watson et al., Nature , 563, 27–30 (2018)]. Despite decades of critical engagement by Indigenous and non-Indigenous observers, large international nongovernmental organizations, philanthropists, global institutions, and nation-states continue to uphold the notion of pristine landscapes as wilderness in conservation ideals and practices. In doing so, dominant global conservation policy and public perceptions still fail to recognize that Indigenous and local peoples have long valued, used, and shaped “high-value” biodiverse landscapes. Moreover, the…

In many academic fields, the number of papers published each year has increased significantly over time. Policy measures aim to increase the quantity of scientists, research funding, and scientific output, which is measured by the number of papers produced. These quantitative metrics determine the career trajectories of scholars and evaluations of academic departments, institutions, and nations. Whether and how these increases in the numbers of scientists and papers translate into advances in knowledge is unclear, however. Here, we first lay out a theoretical argument for why too many papers published each year in a field can lead to stagnation rather than advance. The deluge of new papers may deprive reviewers and readers the cognitive slack required to fully recognize and understand novel ideas. Competition among many new ideas may prevent the gradual accumulation of focused attention on a promising new idea. Then, we show data supporting the predictions of this theory. When the number of papers published per year in a scientific field grows large, citations flow…

Significance Forest soil carbon (C) storage plays a central role in sequestrating atmospheric CO 2 on timescales from centuries to millennia. However, our current understanding of soil C sequestration in response to N deposition mainly focuses on mid-to-high latitudes in the Northern Hemisphere, where N supply typically constrains forest growth. We lack data about changes in soil C stocks in tropical forests, where most ecosystems are N-rich or N-saturated. Using more than a decade of continuous N addition experiment and a meta-analysis, we found that excess N deposition can significantly increase soil C in N-rich tropical forests. However, enhanced C sequestration in tropical soils is not a good reason to justify excess N emissions to the atmosphere.

Airborne pollen has major respiratory health impacts and anthropogenic climate change may increase pollen concentrations and extend pollen seasons. While greenhouse and field studies indicate that pollen concentrations are correlated with temperature, a formal detection and attribution of the role of anthropogenic climate change in continental pollen seasons is urgently needed. Here, we use long-term pollen data from 60 North American stations from 1990 to 2018, spanning 821 site-years of data, and Earth system model simulations to quantify the role of human-caused climate change in continental patterns in pollen concentrations. We find widespread advances and lengthening of pollen seasons (+20 d) and increases in pollen concentrations (+21%) across North America, which are strongly coupled to observed warming. Human forcing of the climate system contributed ∼50% (interquartile range: 19-84%) of the trend in pollen seasons and ∼8% (4-14%) of the trend in pollen concentrations. Our results reveal that anthropogenic climate change has already exacerbated pollen seasons in the past…

= 172; both preregistered) experimentally demonstrate that 8- to 9-y-old girls are significantly less interested in an activity marked with a gender stereotype ("girls are less interested in this activity than boys") compared to an activity with no such stereotype ("girls and boys are equally interested in this activity"). Taken together, both ecologically valid real-world studies (Studies 1 and 2) and controlled preregistered laboratory experiments (Studies 3 and 4) reveal that stereotypes that girls are less interested than boys in computer science and engineering emerge early and may contribute to gender disparities.

Precipitation extremes have increased across many regions of the United States, with further increases anticipated in response to additional global warming. Quantifying the impact of these precipitation changes on flood damages is necessary to estimate the costs of climate change. However, there is little empirical evidence linking changes in precipitation to the historically observed increase in flood losses. We use >6,600 reports of state-level flood damage to quantify the historical relationship between precipitation and flood damages in the United States. Our results show a significant, positive effect of both monthly and 5-d state-level precipitation on state-level flood damages. In addition, we find that historical precipitation changes have contributed approximately one-third of cumulative flood damages over 1988 to 2017 (primary estimate 36%; 95% CI 20 to 46%), with the cumulative impact of precipitation change totaling $73 billion (95% CI 39 to $91 billion). Further, climate models show that anthropogenic climate forcing has increased the probability of exceeding…

The latitudinal gradient in species richness, with more species in the tropics and richness declining with latitude, is widely known and has been assumed to be stable over recent centuries. We analyzed data on 48,661 marine animal species since 1955, accounting for sampling variation, to assess whether the global latitudinal gradient in species richness is being impacted by climate change. We confirm recent studies that show a slight dip in species richness at the equator. Moreover, richness across latitudinal bands was sensitive to temperature, reaching a plateau or declining above a mean annual sea surface temperature of 20 °C for most taxa. In response, since the 1970s, species richness has declined at the equator relative to an increase at midlatitudes and has shifted north in the northern hemisphere, particularly among pelagic species. This pattern is consistent with the hypothesis that climate change is impacting the latitudinal gradient in marine biodiversity at a global scale. The intensification of the dip in species richness at the equator, especially for pelagic species,…

Significance Restoration of postinjury brain function is a signal neuroscience challenge. Animal models of stroke recovery demonstrate time-limited windows of heightened motor recovery, similar to developmental neuroplasticity. However, no equivalent windows have been demonstrated in humans. We report a randomized controlled trial applying essential elements of animal motor training paradigms to humans, to determine the existence of an analogous sensitive period in adults. We found a similar sensitive or optimal period 60 to 90 d after stroke, with lesser effects ≤30 d and no effect 6 mo or later after stroke. These findings prospectively demonstrated the existence of a sensitive period in adult humans. We urge the provision of more intensive motor rehabilitation within 60 to 90 d after stroke onset.

Alzheimer's disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α…

Significance Infrared neural stimulation (INS) is an emerging technology for neuromodulation and holds promise for clinical application. While most INS studies have been conducted at near-infrared wavelengths, whether midinfrared light with frequencies matching the chemical bond vibration of biomolecules can influence neuronal function remains unknown. We found that midinfrared light with low water absorption provides nonthermal and reversible modulation of neuronal spiking activity and sensorimotor behavior. Nonlinear resonance between light and chemical bond vibration at the selectivity sieve of the K + channel directly enhances ion conductivity and thus regulates AP waveform and spiking activity. Together, our results reveal nonthermal effects of MIRS on functional biomolecules, neuronal signaling, and behavior state. Therefore, MIRS could serve as a form of physical neuromodulation.

Significance Many effectors of the Coxiella burnetii Dot/Icm transporter are important for its virulence, but the lack of understanding of their biochemical activity prevents the use of them as potential therapeutic targets. Here, we found that the effector Cbu0513 (CinF) is a protein phosphatase that attacks IκBα, a key regulatory protein in NF-κB signaling. Unlike its homologs such as ST0318 from the archaeon Sulfolobus tokodaii , CinF has lost the enzymatic activity as a fructose-1,6-bisphosphate aldolase/phosphatase. Instead, it specifically targets IκBα to make it resistant to proteasome-mediated degradation in cells stimulated with NF-κB agonists. Our finding has expanded the strategy used by bacterial pathogens to inhibit host immunity, which may provide leads for the development of immune modulators for disease treatment.

Intensifying wildfire activity and climate change can drive rapid forest compositional shifts. In boreal North America, black spruce shapes forest flammability and depends on fire for regeneration. This relationship has helped black spruce maintain its dominance through much of the Holocene. However, with climate change and more frequent and severe fires, shifts away from black spruce dominance to broadleaf or pine species are emerging, with implications for ecosystem functions including carbon sequestration, water and energy fluxes, and wildlife habitat. Here, we predict that such reductions in black spruce after fire may already be widespread given current trends in climate and fire. To test this, we synthesize data from 1,538 field sites across boreal North America to evaluate compositional changes in tree species following 58 recent fires (1989 to 2014). While black spruce was resilient following most fires (62%), loss of resilience was common, and spruce regeneration failed completely in 18% of 1,140 black spruce sites. In contrast, postfire regeneration never failed in forests…

Collective behavior provides a framework for understanding how the actions and properties of groups emerge from the way individuals generate and share information. In humans, information flows were initially shaped by natural selection yet are increasingly structured by emerging communication technologies. Our larger, more complex social networks now transfer high-fidelity information over vast distances at low cost. The digital age and the rise of social media have accelerated changes to our social systems, with poorly understood functional consequences. This gap in our knowledge represents a principal challenge to scientific progress, democracy, and actions to address global crises. We argue that the study of collective behavior must rise to a "crisis discipline" just as medicine, conservation, and climate science have, with a focus on providing actionable insight to policymakers and regulators for the stewardship of social systems.

Significance cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling is critical for sensing cytosolic DNA to initiate host immune responses against invading pathogens and cancer. However, inappropriate activation of STING signaling causes severe and often fatal autoimmune or autoinflammatory diseases. Hence, STING is an attractive drug target for the treatment of STING-driven autoimmune and inflammatory disorders. Therefore, there is a need to identify lead compounds that effectively inhibit human STING for further drug development. Here, we identified and characterized a STING-specific inhibitor SN-011 with high efficiency, specificity, and safety, paving the way for therapeutically manipulating STING-mediated clinical diseases.

Abstract Maximal growth rate is a basic parameter of microbial lifestyle that varies over several orders of magnitude, with doubling times ranging from a matter of minutes to multiple days. Growth rates are typically measured using laboratory culture experiments. Yet, we lack sufficient understanding of the physiology of most microbes to design appropriate culture conditions for them, severely limiting our ability to assess the global diversity of microbial growth rates. Genomic estimators of maximal growth rate provide a practical solution to survey the distribution of microbial growth potential, regardless of cultivation status. We developed an improved maximal growth rate estimator, and implement this estimator in an easy-to-use R package (gRodon), which outperforms the state-of-the-art growth estimator in multiple settings, including in a community context where we implement a novel species abundance correction for metagenomes. Additionally, we estimate maximal growth rates from over 200,000 genomes, metagenome-assembled genomes, and single-cell amplified genomes to survey…

) air pollution worldwide. Observations during winter haze pollution episodes in urban China show that most of this SOA originates from fossil-fuel combustion but the chemical mechanisms involved are unclear. Here we report field observations in a Beijing winter haze event that reveal fast aqueous-phase conversion of fossil-fuel primary organic aerosol (POA) to SOA at high relative humidity. Analyses of aerosol mass spectra and elemental ratios indicate that ring-breaking oxidation of POA aromatic species, leading to functionalization as carbonyls and carboxylic acids, may serve as the dominant mechanism for this SOA formation. A POA origin for SOA could explain why SOA has been decreasing over the 2013-2018 period in response to POA emission controls even as emissions of volatile organic compounds (VOCs) have remained flat.

Abstract Widespread human SARS-CoV-2 infections combined with human-wildlife interactions create the potential for reverse zoonosis from humans to wildlife. We targeted white-tailed deer ( Odocoileus virginianus ) for serosurveillance based on evidence these deer have ACE2 receptors with high affinity for SARS-CoV-2, are permissive to infection, exhibit sustained viral shedding, can transmit to conspecifics, and can be abundant near urban centers. We evaluated 624 pre- and post-pandemic serum samples from wild deer from four U.S. states for SARS-CoV-2 exposure. Antibodies were detected in 152 samples (40%) from 2021 using a surrogate virus neutralization test. A subset of samples was tested using a SARS-CoV-2 virus neutralization test with high concordance between tests. These data suggest white-tailed deer in the populations assessed have been exposed to SARS-CoV-2. One-Sentence Summary Antibodies to SARS-CoV-2 were detected in 40% of wild white-tailed deer sampled from four U.S. states in 2021.

Diverse cognitive processes set different demands on locally segregated and globally integrated brain activity. However, it remains an open question how resting brains configure their functional organization to balance the demands on network segregation and integration to best serve cognition. Here we use an eigenmode-based approach to identify hierarchical modules in functional brain networks and quantify the functional balance between network segregation and integration. In a large sample of healthy young adults (n = 991), we combine the whole-brain resting state functional magnetic resonance imaging (fMRI) data with a mean-filed model on the structural network derived from diffusion tensor imaging and demonstrate that resting brain networks are on average close to a balanced state. This state allows for a balanced time dwelling at segregated and integrated configurations and highly flexible switching between them. Furthermore, we employ structural equation modeling to estimate general and domain-specific cognitive phenotypes from nine tasks and demonstrate that network…

Many natural systems exhibit tipping points where slowly changing environmental conditions spark a sudden shift to a new and sometimes very different state. As the tipping point is approached, the dynamics of complex and varied systems simplify down to a limited number of possible "normal forms" that determine qualitative aspects of the new state that lies beyond the tipping point, such as whether it will oscillate or be stable. In several of those forms, indicators like increasing lag-1 autocorrelation and variance provide generic early warning signals (EWS) of the tipping point by detecting how dynamics slow down near the transition. But they do not predict the nature of the new state. Here we develop a deep learning algorithm that provides EWS in systems it was not explicitly trained on, by exploiting information about normal forms and scaling behavior of dynamics near tipping points that are common to many dynamical systems. The algorithm provides EWS in 268 empirical and model time series from ecology, thermoacoustics, climatology, and epidemiology with much greater sensitivity…

About 50 y ago, Crow and Kimura [ An Introduction to Population Genetics Theory (1970)] and Ohta and Kimura [ Genet. Res. 22, 201–204 (1973)] laid the foundations of conservation genetics by predicting the relationship between population size and genetic marker diversity. This work sparked an enormous research effort investigating the importance of population dynamics, in particular small population size, for population mean performance, population viability, and evolutionary potential. In light of a recent perspective [J. C. Teixeira, C. D. Huber, Proc. Natl. Acad. Sci. U.S.A. 118, 10 (2021)] that challenges some fundamental assumptions in conservation genetics, it is timely to summarize what the field has achieved, what robust patterns have emerged, and worthwhile future research directions. We consider theory and methodological breakthroughs that have helped management, and we outline some fundamental and applied challenges for conservation genetics.

Previous research indicated that corrective information can sometimes provoke a so-called "backfire effect" in which respondents more strongly endorsed a misperception about a controversial political or scientific issue when their beliefs or predispositions were challenged. I show how subsequent research and media coverage seized on this finding, distorting its generality and exaggerating its role relative to other factors in explaining the durability of political misperceptions. To the contrary, an emerging research consensus finds that corrective information is typically at least somewhat effective at increasing belief accuracy when received by respondents. However, the research that I review suggests that the accuracy-increasing effects of corrective information like fact checks often do not last or accumulate; instead, they frequently seem to decay or be overwhelmed by cues from elites and the media promoting more congenial but less accurate claims. As a result, misperceptions typically persist in public opinion for years after they have been debunked. Given these realities, the…

= 1.63, 95% CI = 0.09, 3.16). Examples of beneficial outcomes include decreased pain, lower stress, improved mood, and enhanced cognitive performance. Given this evidence, and to facilitate incorporating public health in US national park soundscape management, we then examined the distribution of natural sounds in relation to anthropogenic sound at 221 sites across 68 parks. National park soundscapes with little anthropogenic sound and abundant natural sounds occurred at 11.3% of the sites. Parks with high visitation and urban park sites had more anthropogenic sound, yet natural sounds associated with health benefits also were frequent. These included animal sounds (audible for a mean of 59.3% of the time, SD: 23.8) and sounds from wind and water (mean: 19.2%, SD: 14.8). Urban and other parks that are extensively visited offer important opportunities to experience natural sounds and are significant targets for soundscape conservation to bolster health for visitors. Our results assert that natural sounds provide important ecosystem services, and parks can bolster public health by…

Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some of these patients do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the DNA of human cells in culture and that transcription of the integrated sequences might account for some of the positive PCR tests seen in patients. In support of this hypothesis, we found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected human cells. We found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites, consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition mechanism. We also found, in some patient-derived tissues, evidence suggesting that a large fraction of the viral sequences is transcribed from integrated DNA copies of viral sequences, generating…

The death toll and economic loss resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are stark reminders that we are vulnerable to zoonotic viral threats. Strategies are needed to identify and characterize animal viruses that pose the greatest risk of spillover and spread in humans and inform public health interventions. Using expert opinion and scientific evidence, we identified host, viral, and environmental risk factors contributing to zoonotic virus spillover and spread in humans. We then developed a risk ranking framework and interactive web tool, SpillOver, that estimates a risk score for wildlife-origin viruses, creating a comparative risk assessment of viruses with uncharacterized zoonotic spillover potential alongside those already known to be zoonotic. Using data from testing 509,721 samples from 74,635 animals as part of a virus discovery project and public records of virus detections around the world, we ranked the spillover potential of 887 wildlife viruses. Validating the risk assessment, the top 12 were known zoonotic viruses,…

Abstract Quantitatively describing the time course of the SARS-CoV-2 infection within an infected individual is important for understanding the current global pandemic and possible ways to combat it. Here we integrate the best current knowledge about the typical viral load of SARS-CoV-2 in bodily fluids and host tissues to estimate the total number and mass of SARS-CoV-2 virions in an infected person. We estimate that each infected person carries 10 9 -10 11 virions during peak infection, with a total mass in the range of 1-100 μg, which curiously implies that all SARS-CoV-2 virions currently circulating within human hosts have a collective mass of only 0.1-10 kg. We combine our estimates with the available literature on host immune response and viral mutation rates to demonstrate how antibodies markedly outnumber the spike proteins and the genetic diversity of virions in an infected host covers all possible single nucleotide substitutions. Significance Knowing the absolute numbers of virions in an infection promotes better understanding of the disease dynamics and the response of…

Abstract While there have been remarkable strides in microbiome research, the viral component of the microbiome has generally presented a more challenging target than the bacteriome. This is despite the fact that many thousands of shotgun sequencing runs from human metagenomic samples exist in public databases and all of them encompass large amounts of viral sequences. The lack of a comprehensive database for human-associated viruses, along with inadequate methods for high-throughput identification of highly divergent viruses in metagenomic data, has historically stymied efforts to characterize virus sequences in a comprehensive way. In this study, a new high-specificity and high-sensitivity bioinformatic tool, Cenote-Taker 2, was applied to thousands of human metagenome datasets, uncovering over 50,000 unique virus operational taxonomic units. Publicly available case-control studies were re-analyzed, and over 1,700 strong virus-disease associations were found.

What is the relationship between money and well-being? Research distinguishes between two forms of well-being: people's feelings during the moments of life (experienced well-being) and people's evaluation of their lives when they pause and reflect (evaluative well-being). Drawing on 1,725,994 experience-sampling reports from 33,391 employed US adults, the present results show that both experienced and evaluative well-being increased linearly with log(income), with an equally steep slope for higher earners as for lower earners. There was no evidence for an experienced well-being plateau above $75,000/y, contrary to some influential past research. There was also no evidence of an income threshold at which experienced and evaluative well-being diverged, suggesting that higher incomes are associated with both feeling better day-to-day and being more satisfied with life overall.

Personality traits predict important life outcomes such as success in love and work life, wellbeing, health, and longevity. Given these positive relations to important outcomes, economists, policy-makers, and scientists have proposed intervening to change personality traits to promote positive life outcomes. However, non-clinical interventions to change personality traits are lacking so far in large-scale naturalistic populations. This study (N = 1,523) examined the effects of a 3- month digital personality change intervention using a randomized controlled trial (RCT) and the smartphone application PEACH (PErsonality coACH). Participants who received the intervention showed greater self-reported changes compared to participants in the waitlist control group who had to wait one month before receiving the intervention. Self-reported changes aligned with intended goals for change and were significant for those desiring to increase on a trait (d = 0.52) and for those desiring to decrease on a trait (d = -0.58). Observers such as friends, family members or intimate partners also detected…

Significance Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. Although dysregulated hydrogen sulfide (H 2 S) metabolism has been reported in AD, and H 2 S donors are beneficial, molecular mechanisms underlying neuroprotective effects of H 2 S are largely unknown. We now show that H 2 S confers neuroprotection by sulfhydrating GSK3β to inhibit its activity, thereby preventing hyperphosphorylation of Tau, a key pathogenic event in AD. Administering H 2 S donors improves motor and cognitive functions in a mouse model of AD.

Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called "long COVID-19," reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly…

Rapid Arctic warming has intensified northern wildfires and is thawing carbon-rich permafrost. Carbon emissions from permafrost thaw and Arctic wildfires, which are not fully accounted for in global emissions budgets, will greatly reduce the amount of greenhouse gases that humans can emit to remain below 1.5 °C or 2 °C. The Paris Agreement provides ongoing opportunities to increase ambition to reduce society's greenhouse gas emissions, which will also reduce emissions from thawing permafrost. In December 2020, more than 70 countries announced more ambitious nationally determined contributions as part of their Paris Agreement commitments; however, the carbon budgets that informed these commitments were incomplete, as they do not fully account for Arctic feedbacks. There is an urgent need to incorporate the latest science on carbon emissions from permafrost thaw and northern wildfires into international consideration of how much more aggressively societal emissions must be reduced to address the global climate crisis.

Significance Osteoarthritis is a global health problem that affects load-bearing joints, causing loss of mobility and enormous healthcare costs. However, disease-modifying approaches are lacking. Here, we report a cellular mechanism of inflammatory signaling in chondrocytes, the cellular component of cartilage. We show how osteoarthritis-relevant levels of interleukin-1α reprogram articular chondrocytes so that they become more susceptible to mechanical trauma, which chondrocytes sense via Piezo1/2-mechanosensitive ion channels. We uncover that IL-1α enhances gene expression of P iezo 1 in primary articular chondrocytes underlying Piezo1 enhanced function. We elucidate signaling from membrane to nucleus, including transcription factors that enhance Piezo1 expression. We also define consequences of increased expression of Piezo1, for mechanotransduction and at rest, that implicate this reprogramming mechanism in osteoarthritis pathogenesis.

mutants display enhanced resistance against different classes of pathogens, such as bacteria, oomycete, and fungi. Notably, disease resistance correlates with increased salicylic acid (SA) levels and transcriptional activation of immune responses. Furthermore, we demonstrate that SlDMR6-1 and SlDMR6-2 display SA-5 hydroxylase activity, thus contributing to the elucidation of the enzymatic function of DMR6. We then propose that SlDMR6 duplication in tomato resulted in subsequent subfunctionalization, in which SlDMR6-2 specialized in balancing SA levels in flowers/fruits, while SlDMR6-1 conserved the ability to fine-tune SA levels during pathogen infection of the plant vegetative tissues. Overall, this work not only corroborates a mechanism underlying SA homeostasis in plants, but also presents a promising strategy for engineering broad-spectrum and durable disease resistance in crops.

The epithelial-to-mesenchymal transition (EMT) plays a critical role during normal development and in cancer progression. EMT is induced by various signaling pathways, including TGF-β, BMP, Wnt-β-catenin, NOTCH, Shh, and receptor tyrosine kinases. In this study, we performed single-cell RNA sequencing on MCF10A cells undergoing EMT by TGF-β1 stimulation. Our comprehensive analysis revealed that cells progress through EMT at different paces. Using pseudotime clustering reconstruction of gene-expression profiles during EMT, we found sequential and parallel activation of EMT signaling pathways. We also observed various transitional cellular states during EMT. We identified regulatory signaling nodes that drive EMT with the expression of important microRNAs and transcription factors. Using a random circuit perturbation methodology, we demonstrate that the NOTCH signaling pathway acts as a key driver of TGF-β-induced EMT. Furthermore, we demonstrate that the gene signatures of pseudotime clusters corresponding to the intermediate hybrid EMT state are associated with poor patient outcome.…

Abstract Understanding the trends in SARS-CoV-2 evolution is paramount to control the COVID- 19 pandemic. We analyzed more than 300,000 high quality genome sequences of SARS-CoV-2 variants available as of January 2021. The results show that the ongoing evolution of SARS-CoV-2 during the pandemic is characterized primarily by purifying selection, but a small set of sites appear to evolve under positive selection. The receptor-binding domain of the spike protein and the nuclear localization signal (NLS) associated region of the nucleocapsid protein are enriched with positively selected amino acid replacements. These replacements form a strongly connected network of apparent epistatic interactions and are signatures of major partitions in the SARS-CoV-2 phylogeny. Virus diversity within each geographic region has been steadily growing for the entirety of the pandemic, but analysis of the phylogenetic distances between pairs of regions reveals four distinct periods based on global partitioning of the tree and the emergence of key mutations. The initial period of rapid diversification…

of the Corn Belt. Our results indicate that 35 ± 11% of the cultivated area has lost A-horizon soil and that prior estimates of soil degradation from soil survey-based methods have significantly underestimated A-horizon soil loss. Convex hilltops throughout the region are often completely denuded of A-horizon soil. The association between soil loss and convex topography indicates that tillage-induced erosion is an important driver of soil loss, yet tillage erosion is not simulated in models used to assess nationwide soil loss trends in the United States. We estimate that A-horizon loss decreases crop yields by 6 ± 2%, causing $2.8 ± $0.9 billion in annual economic losses. Regionally, we estimate 1.4 ± 0.5 Pg of carbon have been removed from hillslopes by erosion of the A-horizon, much of which likely remains buried in depositional areas within the fields.

Here, we present a physiologically relevant model of the human pulmonary alveoli. This alveolar lung-on-a-chip platform is composed of a three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure, bonded to a compartmentalized polydimethylsiloxane chip. The inverse opal hydrogel structure features well-defined, interconnected pores with high similarity to human alveolar sacs. By populating the sacs with primary human alveolar epithelial cells, functional epithelial monolayers are readily formed. Cyclic strain is integrated into the device to allow biomimetic breathing events of the alveolar lung, which, in addition, makes it possible to investigate pathological effects such as those incurred by cigarette smoking and severe acute respiratory syndrome coronavirus 2 pseudoviral infection. Our study demonstrates a unique method for reconstitution of the functional human pulmonary alveoli in vitro, which is anticipated to pave the way for investigating relevant physiological and pathological events in the human distal lung.

Abstract The pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health threat. Epidemiological studies suggest that bats are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. It has been shown that human, palm civet, pig and bat ACE2 can support virus entry, while the murine ortholog cannot. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. We found that ACE2 is expressed in a wide range of species, with especially high conservation in mammals. By analyzing amino acid residues of ACE2 critical for virus entry, based on structure of SARS-CoV spike protein interaction with human, bat, palm…

Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA…

Nature underpins human well-being in critical ways, especially in health. Nature provides pollination of nutritious crops, purification of drinking water, protection from floods, and climate security, among other well-studied health benefits. A crucial, yet challenging, research frontier is clarifying how nature promotes physical activity for its many mental and physical health benefits, particularly in densely populated cities with scarce and dwindling access to nature. Here we frame this frontier by conceptually developing a spatial decision-support tool that shows where, how, and for whom urban nature promotes physical activity, to inform urban greening efforts and broader health assessments. We synthesize what is known, present a model framework, and detail the model steps and data needs that can yield generalizable spatial models and an effective tool for assessing the urban nature-physical activity relationship. Current knowledge supports an initial model that can distinguish broad trends and enrich urban planning, spatial policy, and public health decisions. New, iterative…

Inspired by crystallography, the periodic assembly of trusses into architected materials has enjoyed popularity for more than a decade and produced countless cellular structures with beneficial mechanical properties. Despite the successful and steady enrichment of the truss design space, the inverse design has remained a challenge: While predicting effective truss properties is now commonplace, efficiently identifying architectures that have homogeneous or spatially varying target properties has remained a roadblock to applications from lightweight structures to biomimetic implants. To overcome this gap, we propose a deep-learning framework, which combines neural networks with enforced physical constraints, to predict truss architectures with fully tailored anisotropic stiffness. Trained on millions of unit cells, it covers an enormous design space of topologically distinct truss lattices and accurately identifies architectures matching previously unseen stiffness responses. We demonstrate the application to patient-specific bone implants matching clinical stiffness data, and we…