The 100 most-cited articles in Proceedings of the National Academy of Sciences, 2017

The ability to learn tasks in a sequential fashion is crucial to the development of artificial intelligence. Until now neural networks have not been capable of this and it has been widely thought that catastrophic forgetting is an inevitable feature of connectionist models. We show that it is possible to overcome this limitation and train networks that can maintain expertise on tasks that they have not experienced for a long time. Our approach remembers old tasks by selectively slowing down learning on the weights important for those tasks. We demonstrate our approach is scalable and effective by solving a set of classification tasks based on a hand-written digit dataset and by learning several Atari 2600 games sequentially.

Significance Most nations recently agreed to hold global average temperature rise to well below 2 °C. We examine how much climate mitigation nature can contribute to this goal with a comprehensive analysis of “natural climate solutions” (NCS): 20 conservation, restoration, and/or improved land management actions that increase carbon storage and/or avoid greenhouse gas emissions across global forests, wetlands, grasslands, and agricultural lands. We show that NCS can provide over one-third of the cost-effective climate mitigation needed between now and 2030 to stabilize warming to below 2 °C. Alongside aggressive fossil fuel emissions reductions, NCS offer a powerful set of options for nations to deliver on the Paris Climate Agreement while improving soil productivity, cleaning our air and water, and maintaining biodiversity.

Significance Agricultural production is vulnerable to climate change. Understanding climate change, especially the temperature impacts, is critical if policymakers, agriculturalists, and crop breeders are to ensure global food security. Our study, by compiling extensive published results from four analytical methods, shows that independent methods consistently estimated negative temperature impacts on yields of four major crops at the global scale, generally underpinned by similar impacts at country and site scales. Multimethod analyses improved the confidence in assessments of future climate impacts on global major crops, with important implications for developing crop- and region-specific adaptation strategies to ensure future food supply of an increasing world population.

The population extinction pulse we describe here shows, from a quantitative viewpoint, that Earth's sixth mass extinction is more severe than perceived when looking exclusively at species extinctions. Therefore, humanity needs to address anthropogenic population extirpation and decimation immediately. That conclusion is based on analyses of the numbers and degrees of range contraction (indicative of population shrinkage and/or population extinctions according to the International Union for Conservation of Nature) using a sample of 27,600 vertebrate species, and on a more detailed analysis documenting the population extinctions between 1900 and 2015 in 177 mammal species. We find that the rate of population loss in terrestrial vertebrates is extremely high-even in "species of low concern." In our sample, comprising nearly half of known vertebrate species, 32% (8,851/27,600) are decreasing; that is, they have decreased in population size and range. In the 177 mammals for which we have detailed data, all have lost 30% or more of their geographic ranges and more than 40% of the species…

Human appropriation of land for agriculture has greatly altered the terrestrial carbon balance, creating a large but uncertain carbon debt in soils. Estimating the size and spatial distribution of soil organic carbon (SOC) loss due to land use and land cover change has been difficult but is a critical step in understanding whether SOC sequestration can be an effective climate mitigation strategy. In this study, a machine learning-based model was fitted using a global compilation of SOC data and the History Database of the Global Environment (HYDE) land use data in combination with climatic, landform and lithology covariates. Model results compared favorably with a global compilation of paired plot studies. Projection of this model onto a world without agriculture indicated a global carbon debt due to agriculture of 133 Pg C for the top 2 m of soil, with the rate of loss increasing dramatically in the past 200 years. The HYDE classes "grazing" and "cropland" contributed nearly equally to the loss of SOC. There were higher percent SOC losses on cropland but since more than twice as…

Many empirical studies throughout the social and biomedical sciences focus only on very narrow outcomes such as income, or a single specific disease state, or a measure of positive affect. Human well-being or flourishing, however, consists in a much broader range of states and outcomes, certainly including mental and physical health, but also encompassing happiness and life satisfaction, meaning and purpose, character and virtue, and close social relationships. The empirical literature from longitudinal, experimental, and quasiexperimental studies is reviewed in attempt to identify major determinants of human flourishing, broadly conceived. Measures of human flourishing are proposed. Discussion is given to the implications of a broader conception of human flourishing, and of the research reviewed, for policy, and for future research in the biomedical and social sciences.

Significance The most important single economic concept in the economics of climate change is the social cost of carbon (SCC). At present, regulations with more than $1 trillion of benefits have been written for the United States that use the SCC in their economic analysis. The DICE model (Dynamic Integrated model of Climate and the Economy) is one of three integrated assessment models used to estimate the SCC in the United States. The present study presents updated estimates based on a revised DICE model (DICE-2016R). The study estimates that the SCC is $31 per ton of CO 2 in 2010 US$ for the current period (2015). This study will be an important step in developing the next generation of estimates of the SCC in the United States and other countries.

= 563,312), we observed that the presence of moral-emotional words in messages increased their diffusion by a factor of 20% for each additional word. Furthermore, we found that moral contagion was bounded by group membership; moral-emotional language increased diffusion more strongly within liberal and conservative networks, and less between them. Our results highlight the importance of emotion in the social transmission of moral ideas and also demonstrate the utility of social network methods for studying morality. These findings offer insights into how people are exposed to moral and political ideas through social networks, thus expanding models of social influence and group polarization as people become increasingly immersed in social media networks.

Plant rooting depth affects ecosystem resilience to environmental stress such as drought. Deep roots connect deep soil/groundwater to the atmosphere, thus influencing the hydrologic cycle and climate. Deep roots enhance bedrock weathering, thus regulating the long-term carbon cycle. However, we know little about how deep roots go and why. Here, we present a global synthesis of 2,200 root observations of >1,000 species along biotic (life form, genus) and abiotic (precipitation, soil, drainage) gradients. Results reveal strong sensitivities of rooting depth to local soil water profiles determined by precipitation infiltration depth from the top (reflecting climate and soil), and groundwater table depth from below (reflecting topography-driven land drainage). In well-drained uplands, rooting depth follows infiltration depth; in waterlogged lowlands, roots stay shallow, avoiding oxygen stress below the water table; in between, high productivity and drought can send roots many meters down to the groundwater capillary fringe. This framework explains the contrasting rooting depths observed…

Significance A series of metal sulfides were systematically investigated as polar hosts to reveal the key parameters correlated to the energy barriers and polysulfide adsorption capability in Li−S batteries. The investigation demonstrates that the catalyzing oxidation capability of metal sulfides is critical in reducing the energy barrier and contributing to the remarkably improved battery performance. Density functional theory simulation allows us to identify the mechanism for how binding energy and polysulfides trapping dominate the Li 2 S decomposition process and overall battery performance. The understanding can serve as a general guiding principle for the rational design and screening of advanced materials for high-energy Li−S batteries.

Ride-sharing services are transforming urban mobility by providing timely and convenient transportation to anybody, anywhere, and anytime. These services present enormous potential for positive societal impacts with respect to pollution, energy consumption, congestion, etc. Current mathematical models, however, do not fully address the potential of ride-sharing. Recently, a large-scale study highlighted some of the benefits of car pooling but was limited to static routes with two riders per vehicle (optimally) or three (with heuristics). We present a more general mathematical model for real-time high-capacity ride-sharing that (i) scales to large numbers of passengers and trips and (ii) dynamically generates optimal routes with respect to online demand and vehicle locations. The algorithm starts from a greedy assignment and improves it through a constrained optimization, quickly returning solutions of good quality and converging to the optimal assignment over time. We quantify experimentally the tradeoff between fleet size, capacity, waiting time, travel delay, and operational costs…

= 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5-3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ∼36%. As in other coronaviruses, the spike (S) glycoprotein of MERS-CoV mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection. Here we use structure-based design to develop a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation and demonstrate that our engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV. We also determined high-resolution structures of the trimeric MERS-CoV S ectodomain in complex with G4, a stem-directed neutralizing antibody. The structures reveal that G4 recognizes a glycosylated loop that is variable among coronaviruses and they define four conformational states of the trimer wherein each receptor-binding domain is either tightly packed at the membrane-distal apex or rotated into a receptor-accessible…

Significance Theoretical predictions and subsequent experimental observations of high-temperature superconductivity in dense hydrogen-rich compounds have reinvigorated the field of superconductivity. A systematic computational study of the hydrides of lanthanum and yttrium over a wide composition range reveals hydrogen-rich structures with intriguing electronic properties under pressure. Electron–phonon coupling calculations predict the existence of new superconducting phases, some exhibiting superconductivity in the range of room temperature. Moreover, the calculated stabilities indicate the materials could be synthesized at pressures that are currently accessible in the laboratory. The results open the prospect for the design, synthesis, and recovery of new high-temperature superconductors with potential practical applications.

Significance We have experimentally investigated the immunoregulatory effects of human gut microbiota in multiple sclerosis (MS). We have identified specific bacteria that are associated with MS and demonstrated that these bacteria regulate T lymphocyte-mediated adaptive immune responses and contribute to the proinflammatory environment in vitro and in vivo. Thus, our results expand the knowledge of the microbial regulation of immunity and may provide a basis for the development of microbiome-based therapeutics in autoimmune diseases.

Significance Fighting wildfires in the United States costs billions of dollars annually. Public dialog and ongoing research have focused on increasing wildfire risk because of climate warming, overlooking the direct role that people play in igniting wildfires and increasing fire activity. Our analysis of two decades of government agency wildfire records highlights the fundamental role of human ignitions. Human-started wildfires accounted for 84% of all wildfires, tripled the length of the fire season, dominated an area seven times greater than that affected by lightning fires, and were responsible for nearly half of all area burned. National and regional policy efforts to mitigate wildfire-related hazards would benefit from focusing on reducing the human expansion of the fire niche.

Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression…

Exosomes are nanoscale extracellular vesicles that play an important role in many biological processes, including intercellular communications, antigen presentation, and the transport of proteins, RNA, and other molecules. Recently there has been significant interest in exosome-related fundamental research, seeking new exosome-based biomarkers for health monitoring and disease diagnoses. Here, we report a separation method based on acoustofluidics (i.e., the integration of acoustics and microfluidics) to isolate exosomes directly from whole blood in a label-free and contact-free manner. This acoustofluidic platform consists of two modules: a microscale cell-removal module that first removes larger blood components, followed by extracellular vesicle subgroup separation in the exosome-isolation module. In the cell-removal module, we demonstrate the isolation of 110-nm particles from a mixture of micro- and nanosized particles with a yield greater than 99%. In the exosome-isolation module, we isolate exosomes from an extracellular vesicle mixture with a purity of 98.4%. Integrating the…

, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

The multispecies coalescent model underlies many approaches used for species delimitation. In previous work assessing the performance of species delimitation under this model, speciation was treated as an instantaneous event rather than as an extended process involving distinct phases of speciation initiation (structuring) and completion. Here, we use data under simulations that explicitly model speciation as an extended process rather than an instantaneous event and carry out species delimitation inference on these data under the multispecies coalescent. We show that the multispecies coalescent diagnoses genetic structure, not species, and that it does not statistically distinguish structure associated with population isolation vs. species boundaries. Because of the misidentification of population structure as putative species, our work raises questions about the practice of genome-based species discovery, with cascading consequences in other fields. Specifically, all fields that rely on species as units of analysis, from conservation biology to studies of macroevolutionary…

Emotions are centered in subjective experiences that people represent, in part, with hundreds, if not thousands, of semantic terms. Claims about the distribution of reported emotional states and the boundaries between emotion categories-that is, the geometric organization of the semantic space of emotion-have sparked intense debate. Here we introduce a conceptual framework to analyze reported emotional states elicited by 2,185 short videos, examining the richest array of reported emotional experiences studied to date and the extent to which reported experiences of emotion are structured by discrete and dimensional geometries. Across self-report methods, we find that the videos reliably elicit 27 distinct varieties of reported emotional experience. Further analyses revealed that categorical labels such as amusement better capture reports of subjective experience than commonly measured affective dimensions (e.g., valence and arousal). Although reported emotional experiences are represented within a semantic space best captured by categorical labels, the boundaries between categories…

People are exposed to persuasive communication across many different contexts: Governments, companies, and political parties use persuasive appeals to encourage people to eat healthier, purchase a particular product, or vote for a specific candidate. Laboratory studies show that such persuasive appeals are more effective in influencing behavior when they are tailored to individuals' unique psychological characteristics. However, the investigation of large-scale psychological persuasion in the real world has been hindered by the questionnaire-based nature of psychological assessment. Recent research, however, shows that people's psychological characteristics can be accurately predicted from their digital footprints, such as their Facebook Likes or Tweets. Capitalizing on this form of psychological assessment from digital footprints, we test the effects of psychological persuasion on people's actual behavior in an ecologically valid setting. In three field experiments that reached over 3.5 million individuals with psychologically tailored advertising, we find that matching the content…

= 24 studies), when field experiments became more common and improved methodologically. Since 1989, whites receive on average 36% more callbacks than African Americans, and 24% more callbacks than Latinos. We observe no change in the level of hiring discrimination against African Americans over the past 25 years, although we find modest evidence of a decline in discrimination against Latinos. Accounting for applicant education, applicant gender, study method, occupational groups, and local labor market conditions does little to alter this result. Contrary to claims of declining discrimination in American society, our estimates suggest that levels of discrimination remain largely unchanged, at least at the point of hire.

The brain recruits neuronal populations in a temporally coordinated manner in task and at rest. However, the extent to which large-scale networks exhibit their own organized temporal dynamics is unclear. We use an approach designed to find repeating network patterns in whole-brain resting fMRI data, where networks are defined as graphs of interacting brain areas. We find that the transitions between networks are nonrandom, with certain networks more likely to occur after others. Further, this nonrandom sequencing is itself hierarchically organized, revealing two distinct sets of networks, or metastates, that the brain has a tendency to cycle within. One metastate is associated with sensory and motor regions, and the other involves areas related to higher order cognition. Moreover, we find that the proportion of time that a subject spends in each brain network and metastate is a consistent subject-specific measure, is heritable, and shows a significant relationship with cognitive traits.

Significance Therapies that harness the immune system have recently been approved for cancer treatment. Identification of biomarkers to monitor or predict patients’ responses to immunotherapies would help guide treatment decisions. Herein we analyzed changes in peripheral blood T cells from lung cancer patients receiving immunotherapy blocking the PD-1 inhibitory pathway. We detected CD8 T-cell responses following treatment in most patients. In addition, our data suggest that an increase in proliferation of PD-1+ CD8 T cells in the blood within 4 wk of treatment initiation may be associated with positive clinical outcome. Our analysis provides valuable insights into cancer patients’ responses to PD-1–targeted therapies and warrant further studies on peripheral blood biomarkers.

Significance The Li metal electrode is regarded as a “Holy Grail” anode for next-generation batteries due to its extremely high theoretical capacity and lowest reduction potential. Unfortunately, uncontrolled dendrite growth leads to serious safety issues. This work realizes a dendrite-free Li metal anode by introducing an anion-immobilized composite solid electrolyte, where anions are tethered to polymer chains and ceramic particles. Immobilized anions contribute to uniform distribution of Li ions and dendrite-free Li deposition. The flexible electrolyte can be applied in all–solid-state Li metal batteries with excellent specific capacities. This work demonstrates a concept to adjust ion distribution based on solid-state electrolytes for safe dendrite-free Li anodes, paving the way to practical Li metal batteries.

Perspiration-based wearable biosensors facilitate continuous monitoring of individuals' health states with real-time and molecular-level insight. The inherent inaccessibility of sweat in sedentary individuals in large volume (≥10 µL) for on-demand and in situ analysis has limited our ability to capitalize on this noninvasive and rich source of information. A wearable and miniaturized iontophoresis interface is an excellent solution to overcome this barrier. The iontophoresis process involves delivery of stimulating agonists to the sweat glands with the aid of an electrical current. The challenge remains in devising an iontophoresis interface that can extract sufficient amount of sweat for robust sensing, without electrode corrosion and burning/causing discomfort in subjects. Here, we overcame this challenge through realizing an electrochemically enhanced iontophoresis interface, integrated in a wearable sweat analysis platform. This interface can be programmed to induce sweat with various secretion profiles for real-time analysis, a capability which can be exploited to advance our…

Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In…

Agriculture has seen many revolutions, whether the domestication of animals and plants a few thousand years ago, the systematic use of crop rotations and other improvements in farming practice a few hundred years ago, or the “green revolution” with systematic breeding and the widespread use of man-made fertilizers and pesticides a few decades ago. We suggest that agriculture is undergoing a fourth revolution triggered by the exponentially increasing use of information and communication technology (ICT) in agriculture. New technologies, such as unmanned aerial vehicles with powerful, lightweight cameras, allow for improved farm management advice. Image courtesy of Shutterstock/Kleir. Autonomous, robotic vehicles have been developed for farming purposes, such as mechanical weeding, application of fertilizer, or harvesting of fruits. The development of unmanned aerial vehicles with autonomous flight control (1), together with the development of lightweight and powerful hyperspectral snapshot cameras that can be used to calculate biomass development and fertilization status of crops (2,…

Efforts to understand the influence of historical global warming on individual extreme climate events have increased over the past decade. However, despite substantial progress, events that are unprecedented in the local observational record remain a persistent challenge. Leveraging observations and a large climate model ensemble, we quantify uncertainty in the influence of global warming on the severity and probability of the historically hottest month, hottest day, driest year, and wettest 5-d period for different areas of the globe. We find that historical warming has increased the severity and probability of the hottest month and hottest day of the year at >80% of the available observational area. Our framework also suggests that the historical climate forcing has increased the probability of the driest year and wettest 5-d period at 57% and 41% of the observed area, respectively, although we note important caveats. For the most protracted hot and dry events, the strongest and most widespread contributions of anthropogenic climate forcing occur in the tropics, including…

Wildfires across western North America have increased in number and size over the past three decades, and this trend will continue in response to further warming. As a consequence, the wildland–urban interface is projected to experience substantially higher risk of climate-driven fires in the coming decades. Although many plants, animals, and ecosystem services benefit from fire, it is unknown how ecosystems will respond to increased burning and warming. Policy and management have focused primarily on specified resilience approaches aimed at resistance to wildfire and restoration of areas burned by wildfire through fire suppression and fuels management. These strategies are inadequate to address a new era of western wildfires. In contrast, policies that promote adaptive resilience to wildfire, by which people and ecosystems adjust and reorganize in response to changing fire regimes to reduce future vulnerability, are needed. Key aspects of an adaptive resilience approach are ( i ) recognizing that fuels reduction cannot alter regional wildfire trends; ( ii ) targeting fuels…

Recent expansion of the scale of human activities poses severe threats to Earth's life-support systems. Increasingly, protected areas (PAs) are expected to serve dual goals: protect biodiversity and secure ecosystem services. We report a nationwide assessment for China, quantifying the provision of threatened species habitat and four key regulating services-water retention, soil retention, sandstorm prevention, and carbon sequestration-in nature reserves (the primary category of PAs in China). We find that China's nature reserves serve moderately well for mammals and birds, but not for other major taxa, nor for these key regulating ecosystem services. China's nature reserves encompass 15.1% of the country's land surface. They capture 17.9% and 16.4% of the entire habitat area for threatened mammals and birds, but only 13.1% for plants, 10.0% for amphibians, and 8.5% for reptiles. Nature reserves encompass only 10.2-12.5% of the source areas for the four key regulating services. They are concentrated in western China, whereas much threatened species' habitat and regulating service…

Significance Many species of microbes colonize plants as members of complex communities. The high complexity of such plant microbial communities poses great difficulty for any experimental analyses aimed at understanding the principles underlying such microbe–plant interactions. In this work, we assembled a greatly simplified, yet representative, synthetic bacterial model community that allowed us to study the community assembly dynamics and function on axenic maize seedlings. This model community interfered with the growth of a plant pathogenic fungus, thus protecting the plant. This model system will prove to be a useful system for future research on plant–microbe interactions.

Artificial muscles hold promise for safe and powerful actuation for myriad common machines and robots. However, the design, fabrication, and implementation of artificial muscles are often limited by their material costs, operating principle, scalability, and single-degree-of-freedom contractile actuation motions. Here we propose an architecture for fluid-driven origami-inspired artificial muscles. This concept requires only a compressible skeleton, a flexible skin, and a fluid medium. A mechanical model is developed to explain the interaction of the three components. A fabrication method is introduced to rapidly manufacture low-cost artificial muscles using various materials and at multiple scales. The artificial muscles can be programed to achieve multiaxial motions including contraction, bending, and torsion. These motions can be aggregated into systems with multiple degrees of freedom, which are able to produce controllable motions at different rates. Our artificial muscles can be driven by fluids at negative pressures (relative to ambient). This feature makes actuation safer…

With rapid recent advances in quantum technology, we are close to the threshold of quantum devices whose computational powers can exceed those of classical supercomputers. Here, we show that a quantum computer can be used to elucidate reaction mechanisms in complex chemical systems, using the open problem of biological nitrogen fixation in nitrogenase as an example. We discuss how quantum computers can augment classical computer simulations used to probe these reaction mechanisms, to significantly increase their accuracy and enable hitherto intractable simulations. Our resource estimates show that, even when taking into account the substantial overhead of quantum error correction, and the need to compile into discrete gate sets, the necessary computations can be performed in reasonable time on small quantum computers. Our results demonstrate that quantum computers will be able to tackle important problems in chemistry without requiring exorbitant resources.

Significance An estimated 4.5 billion people are currently exposed to particulate matter (PM) levels at least twice the concentration that the WHO considers safe. Existing evidence linking health to air pollution is largely based on populations exposed to only modest levels of PM and almost entirely composed of observational studies, which are likely to confound air pollution with other unobserved determinants of health. This study uses quasiexperimental variation in particulate matter smaller than 10 μm (PM 10 ) generated by an arbitrary Chinese policy to find that a 10-μg/m 3 increase in PM 10 reduces life expectancy by 0.64 years. The estimates imply that bringing all of China into compliance with its Class I standards for PM 10 would save 3.7 billion life-years.

Significance Increasing evidence suggests that extracellular vesicles (EVs) can transfer genetic material to recipient cells. However, the mechanism and role of this phenomenon are largely unknown. Here we have made a remarkable discovery: EVs can harbor the full mitochondrial genome. These extracellular vesicles can in turn transfer their mtDNA to cells with impaired metabolism, leading to restoration of metabolic activity. We determined that hormonal therapy induces oxidative phosphorylation-deficient breast cancer cells, which can be rescued via the transfer of mtDNA-laden extracellular vesicles. Horizontal transfer of mtDNA occurred in cancer stem-like cells and was associated with increased self-renewal potential of these cells, leading to resistance to hormonal therapy. We propose that mtDNA transfer occurs in human cancer via EVs.

Glaciers cover ∼10% of the Earth's land surface, but they are shrinking rapidly across most parts of the world, leading to cascading impacts on downstream systems. Glaciers impart unique footprints on river flow at times when other water sources are low. Changes in river hydrology and morphology caused by climate-induced glacier loss are projected to be the greatest of any hydrological system, with major implications for riverine and near-shore marine environments. Here, we synthesize current evidence of how glacier shrinkage will alter hydrological regimes, sediment transport, and biogeochemical and contaminant fluxes from rivers to oceans. This will profoundly influence the natural environment, including many facets of biodiversity, and the ecosystem services that glacier-fed rivers provide to humans, particularly provision of water for agriculture, hydropower, and consumption. We conclude that human society must plan adaptation and mitigation measures for the full breadth of impacts in all affected regions caused by glacier shrinkage.

Significance A large part of all primary materials extracted globally accumulates in stocks of manufactured capital, including in buildings, infrastructure, machinery, and equipment. These in-use stocks of materials provide important services for society and the economy and drive long-term demand for materials and energy. Configuration and quantity of stocks determine future waste flows and recycling potential and are key to closing material loops and reducing waste and emissions in a circular economy. A better understanding of in-use material stocks and their dynamics is essential for sustainable development. We present a comprehensive estimate of global in-use material stocks and of related material flows, including a full assessment of uncertainties for the 20th century as we analyze changes in stock-flow relations.

Significance Iron-doped nickel oxide films are the most active nonnoble metal oxygen evolution reaction (OER) catalysts in alkaline electrolyte. Since Corrigan’s original discovery of enhanced activity with Fe doping in nickel oxides, the chemical basis for this synergy remains unclear. Recent studies suggest iron to assume a high valent oxidation state, thus promoting OER. We provide evidence for an alternative role of Fe 3+ as a Lewis acid in the host nickel oxide. We observe that Fe 3+ promotes the formation of Ni 4+ , which leads to enhanced catalytic activity. This result is consistent with Fe 3+ to be one of the strongest Lewis acidic metals by any measure of Lewis acidity, including hard–soft acid base theory, metal ion pK a s, and chemical inertness.

Emotional states of consciousness, or what are typically called emotional feelings, are traditionally viewed as being innately programmed in subcortical areas of the brain, and are often treated as different from cognitive states of consciousness, such as those related to the perception of external stimuli. We argue that conscious experiences, regardless of their content, arise from one system in the brain. In this view, what differs in emotional and nonemotional states are the kinds of inputs that are processed by a general cortical network of cognition, a network essential for conscious experiences. Although subcortical circuits are not directly responsible for conscious feelings, they provide nonconscious inputs that coalesce with other kinds of neural signals in the cognitive assembly of conscious emotional experiences. In building the case for this proposal, we defend a modified version of what is known as the higher-order theory of consciousness.

Significance Efficient thermal transport is critical for applications ranging from electronics and energy to advanced manufacturing and transportation; it is essential in emerging domains like wearable computing and soft robotics, which require thermally conductive materials that are also soft and stretchable. However, heat transport within soft materials is limited by the dynamics of phonon transport, which results in a trade-off between thermal conductivity and compliance. We overcome this by engineering an elastomer composite embedded with elongated inclusions of liquid metal (LM) that function as thermally conductive pathways. These composites exhibit an extraordinary combination of low stiffness (<100 kPa), high strain limit (>600%), and metal-like thermal conductivity (up to 9.8 W⋅m −1 ⋅K −1 ) that far exceeds any other soft materials.

Significance Converting CO 2 to fuels is of great interest nowadays. Copper (Cu) is the only metal that produces hydrocarbon products, making it of interest for learning the reaction mechanisms underlying the selectivity and activity of Cu catalysts. In this report, we examine the reaction mechanism of CO reduction on Cu(100) at pH 7 including explicitly the aqueous solvent with ab initio molecular metadynamics simulations (AIMμD) free-energy calculations, which we find to explain all experimental observations. We expect that this understanding will suggest how to modify the Cu catalyst or replace it with a new material to enhance production of just a single such product while reducing the energy requirements (overpotential).

Social bees harbor a simple and specialized microbiota that is spatially organized into different gut compartments. Recent results on the potential involvement of bee gut communities in pathogen protection and nutritional function have drawn attention to the impact of the microbiota on bee health. However, the contributions of gut microbiota to host physiology have yet to be investigated. Here we show that the gut microbiota promotes weight gain of both whole body and the gut in individual honey bees. This effect is likely mediated by changes in host vitellogenin, insulin signaling, and gustatory response. We found that microbial metabolism markedly reduces gut pH and redox potential through the production of short-chain fatty acids and that the bacteria adjacent to the gut wall form an oxygen gradient within the intestine. The short-chain fatty acid profile contributed by dominant gut species was confirmed in vitro. Furthermore, metabolomic analyses revealed that the gut community has striking impacts on the metabolic profiles of the gut compartments and the hemolymph, suggesting…

A common hypothesis for the rich biodiversity found in mountains is uplift-driven diversification-that orogeny creates conditions favoring rapid in situ speciation of resident lineages. We tested this hypothesis in the context of the Qinghai-Tibetan Plateau (QTP) and adjoining mountain ranges, using the phylogenetic and geographic histories of multiple groups of plants to infer the tempo (rate) and mode (colonization versus in situ diversification) of biotic assembly through time and across regions. We focused on the Hengduan Mountains region, which in comparison with the QTP and Himalayas was uplifted more recently (since the late Miocene) and is smaller in area and richer in species. Time-calibrated phylogenetic analyses show that about 8 million y ago the rate of in situ diversification increased in the Hengduan Mountains, significantly exceeding that in the geologically older QTP and Himalayas. By contrast, in the QTP and Himalayas during the same period the rate of in situ diversification remained relatively flat, with colonization dominating lineage accumulation. The Hengduan…

The age of Jupiter, the largest planet in our Solar System, is still unknown. Gas-giant planet formation likely involved the growth of large solid cores, followed by the accumulation of gas onto these cores. Thus, the gas-giant cores must have formed before dissipation of the solar nebula, which likely occurred within less than 10 My after Solar System formation. Although such rapid accretion of the gas-giant cores has successfully been modeled, until now it has not been possible to date their formation. Here, using molybdenum and tungsten isotope measurements on iron meteorites, we demonstrate that meteorites derive from two genetically distinct nebular reservoirs that coexisted and remained spatially separated between ∼1 My and ∼3-4 My after Solar System formation. The most plausible mechanism for this efficient separation is the formation of Jupiter, opening a gap in the disk and preventing the exchange of material between the two reservoirs. As such, our results indicate that Jupiter's core grew to ∼20 Earth masses within <1 My, followed by a more protracted growth to ∼50 Earth…

Significance Electrochemical conversion of CO 2 to carbon-based products, which can be used directly as fuels or indirectly as fuel precursors, is suggested as one of the promising solutions for sustainability. Not only does this process allow using renewables such as solar electricity as energy input, but CO 2 emitted from the consumption process can be recycled back into fuels. The success of this technology depends on the value added to the product that forms from CO 2 , and therefore it is important to facilitate multicarbon product generation. This work presents a copper-based catalyst, formed in situ from an ensemble of nanoparticles, that is able to selectively generate C 2 –C 3 products at low overpotentials with good stability, where their efficient formation has been difficult to achieve.

Strong decreases in greenhouse gas emissions are required to meet the reduction trajectory resolved within the 2015 Paris Agreement. However, even these decreases will not avert serious stress and damage to life on Earth, and additional steps are needed to boost the resilience of ecosystems, safeguard their wildlife, and protect their capacity to supply vital goods and services. We discuss how well-managed marine reserves may help marine ecosystems and people adapt to five prominent impacts of climate change: acidification, sea-level rise, intensification of storms, shifts in species distribution, and decreased productivity and oxygen availability, as well as their cumulative effects. We explore the role of managed ecosystems in mitigating climate change by promoting carbon sequestration and storage and by buffering against uncertainty in management, environmental fluctuations, directional change, and extreme events. We highlight both strengths and limitations and conclude that marine reserves are a viable low-tech, cost-effective adaptation strategy that would yield multiple…

Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability." Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for…

Significance A most promising approach to boosting both efficiency and selectivity for electrochemical reduction of CO 2 (CO 2 RR) is using Cu 2 O-based electrodes, and the surface Cu + is believed to play an essential role that is totally unclear from both experiment and theory. We find that the surface Cu + by itself actually deteriorates the performance of CO 2 RR. Instead we propose a Cu metal embedded in oxidized matrix (MEOM) model and show that it is synergy between surface Cu + and surface Cu 0 present in the MEOM model that improves significantly the kinetics and thermodynamics of both CO 2 activation and CO dimerization, thereby boosting the efficiency and selectivity of CO 2 RR. The MEOM model serves as a unique platform for design of better electrocatalysts for CO 2 RR.

The fundamental energy gap of a periodic solid distinguishes insulators from metals and characterizes low-energy single-electron excitations. However, the gap in the band structure of the exact multiplicative Kohn-Sham (KS) potential substantially underestimates the fundamental gap, a major limitation of KS density-functional theory. Here, we give a simple proof of a theorem: In generalized KS theory (GKS), the band gap of an extended system equals the fundamental gap for the approximate functional if the GKS potential operator is continuous and the density change is delocalized when an electron or hole is added. Our theorem explains how GKS band gaps from metageneralized gradient approximations (meta-GGAs) and hybrid functionals can be more realistic than those from GGAs or even from the exact KS potential. The theorem also follows from earlier work. The band edges in the GKS one-electron spectrum are also related to measurable energies. A linear chain of hydrogen molecules, solid aluminum arsenide, and solid argon provide numerical illustrations.

Although Americans generally hold science in high regard and respect its findings, for some contested issues, such as the existence of anthropogenic climate change, public opinion is polarized along religious and political lines. We ask whether individuals with more general education and greater science knowledge, measured in terms of science education and science literacy, display more (or less) polarized beliefs on several such issues. We report secondary analyses of a nationally representative dataset (the General Social Survey), examining the predictors of beliefs regarding six potentially controversial issues. We find that beliefs are correlated with both political and religious identity for stem cell research, the Big Bang, and human evolution, and with political identity alone on climate change. Individuals with greater education, science education, and science literacy display more polarized beliefs on these issues. We find little evidence of political or religious polarization regarding nanotechnology and genetically modified foods. On all six topics, people who trust the…

Peer review may be "single-blind," in which reviewers are aware of the names and affiliations of paper authors, or "double-blind," in which this information is hidden. Noting that computer science research often appears first or exclusively in peer-reviewed conferences rather than journals, we study these two reviewing models in the context of the 10th Association for Computing Machinery International Conference on Web Search and Data Mining, a highly selective venue (15.6% acceptance rate) in which expert committee members review full-length submissions for acceptance. We present a controlled experiment in which four committee members review each paper. Two of these four reviewers are drawn from a pool of committee members with access to author information; the other two are drawn from a disjoint pool without such access. This information asymmetry persists through the process of bidding for papers, reviewing papers, and entering scores. Reviewers in the single-blind condition typically bid for 22% fewer papers and preferentially bid for papers from top universities and companies.…

Significance Few patients with pancreatic cancer survive longer than 5 y, in part because most patients are identified only after their disease has progressed to an advanced stage. In this study, we show how combining mutations in circulating tumor DNA (ctDNA) with protein markers can result in a screening test with improved sensitivity while retaining specificity. The combination of the ctDNA and protein markers was superior to any single marker. Moreover, the combination detected nearly two-thirds of pancreatic cancers that had no evidence of distant metastasis at the time of surgical resection. The strategy may represent an approach to detect cancers of many types at an earlier stage.

In this work, we provide an overview of how well-established concepts in the fields of quantum chemistry and material sciences have to be adapted when the quantum nature of light becomes important in correlated matter-photon problems. We analyze model systems in optical cavities, where the matter-photon interaction is considered from the weak- to the strong-coupling limit and for individual photon modes as well as for the multimode case. We identify fundamental changes in Born-Oppenheimer surfaces, spectroscopic quantities, conical intersections, and efficiency for quantum control. We conclude by applying our recently developed quantum-electrodynamical density-functional theory to spontaneous emission and show how a straightforward approximation accurately describes the correlated electron-photon dynamics. This work paves the way to describe matter-photon interactions from first principles and addresses the emergence of new states of matter in chemistry and material science.

Significance The flow of water confined in nanopores is significantly different from that of bulk water. Moreover, understanding and controlling the flow of the confined water remains an open question, especially concerning whether the flow capacity of the confined water increases or not compared with that of bulk water. Here, combining a theoretical analysis and data from molecular dynamics simulations and experiments in the literature we develop a simple model for the flow of water confined in nanopores. We find that a contact angle and a nanopore dimension may substantially affect the confined water flow. We also quantitatively explain a controversy over an increase or decrease in flow capacity.

Significance Clinical evidence has indicated that the systemic spread of endotoxins from septic infection plays a crucial role in the pathogenesis of Gram-negative bacterial sepsis. However, currently there are no effective ways to manage the diverse endotoxins released by different bacterial genus, species, and strain. Herein, we demonstrate the therapeutic potential of a macrophage-like nanoparticle for sepsis control through a powerful two-step neutralization process: endotoxin neutralization in the first step followed by cytokine sequestration in the second step. The biomimetic nanoparticles possess an antigenic exterior identical to macrophage cells, thus inheriting their capability to bind to endotoxins and proinflammatory cytokines. This detoxification strategy may provide a first-in-class treatment option for sepsis and ultimately improve the clinical outcome of patients.

H3N2 viruses continuously acquire mutations in the hemagglutinin (HA) glycoprotein that abrogate binding of human antibodies. During the 2014-2015 influenza season, clade 3C.2a H3N2 viruses possessing a new predicted glycosylation site in antigenic site B of HA emerged, and these viruses remain prevalent today. The 2016-2017 seasonal influenza vaccine was updated to include a clade 3C.2a H3N2 strain; however, the egg-adapted version of this viral strain lacks the new putative glycosylation site. Here, we biochemically demonstrate that the HA antigenic site B of circulating clade 3C.2a viruses is glycosylated. We show that antibodies elicited in ferrets and humans exposed to the egg-adapted 2016-2017 H3N2 vaccine strain poorly neutralize a glycosylated clade 3C.2a H3N2 virus. Importantly, antibodies elicited in ferrets infected with the current circulating H3N2 viral strain (that possesses the glycosylation site) and humans vaccinated with baculovirus-expressed H3 antigens (that possess the glycosylation site motif) were able to efficiently recognize a glycosylated clade 3C.2a H3N2…

cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment. Consistently, intramuscular delivery of cGAMP inhibited melanoma growth and prolonged the survival of the tumor-bearing mice. The combination of cGAMP and PD-L1 antibody exerted stronger antitumor effects than did either treatment alone. cGAMP treatment activated dendritic cells and enhanced cross-presentation of tumor-associated antigens to CD8 T cells. These results indicate that activation of the cGAS pathway is important for intrinsic antitumor immunity and that cGAMP may be used directly for cancer immunotherapy.

According to electronic structure theory, bilayer graphene is expected to have anomalous electronic properties when it has long-period moiré patterns produced by small misalignments between its individual layer honeycomb lattices. We have realized bilayer graphene moiré crystals with accurately controlled twist angles smaller than 1° and studied their properties using scanning probe microscopy and electron transport. We observe conductivity minima at charge neutrality, satellite gaps that appear at anomalous carrier densities for twist angles smaller than 1°, and tunneling densities-of-states that are strongly dependent on carrier density. These features are robust up to large transverse electric fields. In perpendicular magnetic fields, we observe the emergence of a Hofstadter butterfly in the energy spectrum, with fourfold degenerate Landau levels, and broken symmetry quantum Hall states at filling factors ±1, 2, 3. These observations demonstrate that at small twist angles, the electronic properties of bilayer graphene moiré crystals are strongly altered by electron-electron…

Pick up any recent policy paper on women’s participation in science and you will find assurances that gender diversity enhances knowledge outcomes. Universities and science-policy stakeholders, including the European Commission and the US National Institutes of Health, readily subscribe to this argument (1⇓–3). But is there, in fact, a gender-diversity dividend in science? The data suggest that there is. Under the right conditions, teams may benefit from various types of diversity, including scientific discipline, work experience, gender, ethnicity, and nationality. In this paper, we highlight gender diversity (Fig. 1). Guided by key research findings, we propose the following “mechanisms for innovation” specifying why gender diversity matters for scientific discovery and what managers should do to maximize its benefits (Fig. 2). Encouraging greater diversity is not only the right thing to do: it allows scientific organizations to derive an “innovation dividend” that leads to smarter, more creative teams, hence opening the door to new discoveries. Fig. 1. When it comes to science…

Although habitat fragmentation is often assumed to be a primary driver of extinction, global patterns of fragmentation and its relationship to extinction risk have not been consistently quantified for any major animal taxon. We developed high-resolution habitat fragmentation models and used phylogenetic comparative methods to quantify the effects of habitat fragmentation on the world's terrestrial mammals, including 4,018 species across 26 taxonomic Orders. Results demonstrate that species with more fragmentation are at greater risk of extinction, even after accounting for the effects of key macroecological predictors, such as body size and geographic range size. Species with higher fragmentation had smaller ranges and a lower proportion of high-suitability habitat within their range, and most high-suitability habitat occurred outside of protected areas, further elevating extinction risk. Our models provide a quantitative evaluation of extinction risk assessments for species, allow for identification of emerging threats in species not classified as threatened, and provide maps of…

Significance The isolation of remote islands has, until recently, afforded protection from most human activities. However, society’s increasing desire for plastic products has resulted in plastic becoming ubiquitous in the marine environment, where it persists for decades. We provide a comprehensive analysis of the quantity and source of beach-washed plastic debris on one of the world’s remotest islands. The density of debris was the highest recorded anywhere in the world, suggesting that remote islands close to oceanic plastic accumulation zones act as important sinks for some of the waste accumulated in these areas. As global plastic production continues to increase exponentially, it will further impact the exceptional natural beauty and biodiversity for which remote islands have been recognized.

Sea level rise (SLR), a well-documented and urgent aspect of anthropogenic global warming, threatens population and assets located in low-lying coastal regions all around the world. Common flood hazard assessment practices typically account for one driver at a time (e.g., either fluvial flooding only or ocean flooding only), whereas coastal cities vulnerable to SLR are at risk for flooding from multiple drivers (e.g., extreme coastal high tide, storm surge, and river flow). Here, we propose a bivariate flood hazard assessment approach that accounts for compound flooding from river flow and coastal water level, and we show that a univariate approach may not appropriately characterize the flood hazard if there are compounding effects. Using copulas and bivariate dependence analysis, we also quantify the increases in failure probabilities for 2030 and 2050 caused by SLR under representative concentration pathways 4.5 and 8.5. Additionally, the increase in failure probability is shown to be strongly affected by compounding effects. The proposed failure probability method offers an…

Although the scale of impending urbanization is well-acknowledged, we have a limited understanding of how urban forms will change and what their impact will be on building energy use. Using both top-down and bottom-up approaches and scenarios, we examine building energy use for heating and cooling. Globally, the energy use for heating and cooling by the middle of the century will be between 45 and 59 exajoules per year (corresponding to an increase of 7-40% since 2010). Most of this variability is due to the uncertainty in future urban densities of rapidly growing cities in Asia and particularly China. Dense urban development leads to less urban energy use overall. Waiting to retrofit the existing built environment until markets are ready in about 5 years to widely deploy the most advanced renovation technologies leads to more savings in building energy use. Potential for savings in energy use is greatest in China when coupled with efficiency gains. Advanced efficiency makes the least difference compared with the business-as-usual scenario in South Asia and Sub-Saharan Africa but…

Comprehensive reverse genetic resources, which have been key to understanding gene function in diploid model organisms, are missing in many polyploid crops. Young polyploid species such as wheat, which was domesticated less than 10,000 y ago, have high levels of sequence identity among subgenomes that mask the effects of recessive alleles. Such redundancy reduces the probability of selection of favorable mutations during natural or human selection, but also allows wheat to tolerate high densities of induced mutations. Here we exploited this property to sequence and catalog more than 10 million mutations in the protein-coding regions of 2,735 mutant lines of tetraploid and hexaploid wheat. We detected, on average, 2,705 and 5,351 mutations per tetraploid and hexaploid line, respectively, which resulted in 35-40 mutations per kb in each population. With these mutation densities, we identified an average of 23-24 missense and truncation alleles per gene, with at least one truncation or deleterious missense mutation in more than 90% of the captured wheat genes per population. This…

Significance N6-methyladnosine (m6A) represents one of the most common RNA modifications. Biochemical analyses have identified ALKBH5 as an eraser of m6A. The present study represents the first molecular characterization of the Alkbh5 knockout mouse model. Our data associate m6A erasure with mRNA length control. Specifically, proper m6A demethylation is required for correct splicing and selective degradation of longer 3′-UTR transcripts, which are abundant in mitotic and meiotic male germ cells, but these longer 3′-UTR transcripts become rapidly degraded in the haploid male germ cells. Aberrant m6A levels in spermatogenic cells are incompatible with normal spermatogenesis and male fertility.

, to evaluate recent changes in these HABs. For both species, potential mean annual growth rates and duration of bloom seasons significantly increased within many coastal Atlantic regions between 40°N and 60°N, where incidents of these HABs have emerged and expanded in recent decades. Widespread trends were less evident across the North Pacific, although regions were identified across the Salish Sea and along the Alaskan coastline where blooms have recently emerged, and there have been significant increases in the potential growth rates and duration of these HAB events. We conclude that increasing ocean temperature is an important factor facilitating the intensification of these, and likely other, HABs and thus contributes to an expanding human health threat.

The tremendous pandemic potential of coronaviruses was demonstrated twice in the past few decades by two global outbreaks of deadly pneumonia. The coronavirus spike (S) glycoprotein initiates infection by promoting fusion of the viral and cellular membranes through conformational changes that remain largely uncharacterized. Here we report the cryoEM structure of a coronavirus S glycoprotein in the postfusion state, showing large-scale secondary, tertiary, and quaternary rearrangements compared with the prefusion trimer and rationalizing the free-energy landscape of this conformational machine. We also biochemically characterized the molecular events associated with refolding of the metastable prefusion S glycoprotein to the postfusion conformation using limited proteolysis, mass spectrometry, and single-particle EM. The observed similarity between postfusion coronavirus S and paramyxovirus F structures demonstrates that a conserved refolding trajectory mediates entry of these viruses and supports the evolutionary relatedness of their fusion subunits. Finally, our data provide a…

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having…

Significance Hydrogen peroxide is closely associated with many important physiological and pathological events. Herein, we develop a liposomal nanoprobe for in vivo H 2 O 2 -responsive chromogenic assay, which is highly specific and sensitive to H 2 O 2 . Using such a nanoprobe, photoacoustic imaging of H 2 O 2 -related inflammation processes in mice induced by either LPS or bacteria is realized. Meanwhile, such a nanoprobe, by reacting with endogenous H 2 O 2 produced by tumor cells, allows sensitive photoacoustic imaging of early-stage small tumors and orthotopic brain glioma and even enables accurate differentiation of metastatic sentinel lymph nodes from nonmetastatic ones. Furthermore, owing to its H 2 O 2 -responsive near-infrared absorbance, selective photothermal ablation of tumors is also achieved, illustrating the promise of using this nanoproble for tumor theranostics with great specificity.

Significance DNA methylation is generally considered an epigenetic mark for transcriptional gene silencing. In this work, we generated loss-of-function mutant alleles of SlDML2 . We characterized the mutant fruits that failed to ripen and discovered that SlDML2 is required for the demethylation and activation of genes important for fruit ripening, including genes involved in fruit pigment and flavor synthesis, ethylene synthesis and signaling, and cell wall hydrolysis. Unexpectedly, we found that SlDML2-mediated DNA demethylation is also necessary for fruit ripening-induced repression of hundreds of genes involved in photosynthesis and cell wall synthesis and organization. Our study has therefore revealed a broad and critical role of DNA methylation as an activation mark for the expression of many genes in a eukaryotic organism.

Membrane encapsulation is frequently used by the cell to sequester biomolecules and compartmentalize their function. Cells also concentrate molecules into phase-separated protein or protein/nucleic acid "membraneless organelles" that regulate a host of biochemical processes. Here, we use solution NMR spectroscopy to study phase-separated droplets formed from the intrinsically disordered N-terminal 236 residues of the germ-granule protein Ddx4. We show that the protein within the concentrated phase of phase-separated Ddx4, [Formula: see text], diffuses as a particle of 600-nm hydrodynamic radius dissolved in water. However, NMR spectra reveal sharp resonances with chemical shifts showing [Formula: see text] to be intrinsically disordered. Spin relaxation measurements indicate that the backbone amides of [Formula: see text] have significant mobility, explaining why high-resolution spectra are observed, but motion is reduced compared with an equivalently concentrated nonphase-separating control. Observation of a network of interchain interactions, as established by NOE spectroscopy,…

Cells alter their mechanical properties in response to their local microenvironment; this plays a role in determining cell function and can even influence stem cell fate. Here, we identify a robust and unified relationship between cell stiffness and cell volume. As a cell spreads on a substrate, its volume decreases, while its stiffness concomitantly increases. We find that both cortical and cytoplasmic cell stiffness scale with volume for numerous perturbations, including varying substrate stiffness, cell spread area, and external osmotic pressure. The reduction of cell volume is a result of water efflux, which leads to a corresponding increase in intracellular molecular crowding. Furthermore, we find that changes in cell volume, and hence stiffness, alter stem-cell differentiation, regardless of the method by which these are induced. These observations reveal a surprising, previously unidentified relationship between cell stiffness and cell volume that strongly influences cell biology.

F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT). Obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL) with a wide range (0.1-71%) in the ratio of activated BAT to inactive fat between individuals. Six anatomic regions had activated BAT-cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal-with 67 ± 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The amount and activity of BAT was significantly influenced by region of interest selection methods, PET threshold criteria, and PET resolutions. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated…

We estimate, for current and future climates, the annual probability of areally averaged hurricane rain of Hurricane Harvey's magnitude by downscaling large numbers of tropical cyclones from three climate reanalyses and six climate models. For the state of Texas, we estimate that the annual probability of 500 mm of area-integrated rainfall was about 1% in the period 1981-2000 and will increase to 18% over the period 2081-2100 under Intergovernmental Panel on Climate Change (IPCC) AR5 representative concentration pathway 8.5. If the frequency of such event is increasingly linearly between these two periods, then in 2017 the annual probability would be 6%, a sixfold increase since the late 20th century.

The first significant buildup in atmospheric oxygen, the Great Oxidation Event (GOE), began in the early Paleoproterozoic in association with global glaciations and continued until the end of the Lomagundi carbon isotope excursion ca. 2,060 Ma. The exact timing of and relationships among these events are debated because of poor age constraints and contradictory stratigraphic correlations. Here, we show that the first Paleoproterozoic global glaciation and the onset of the GOE occurred between ca. 2,460 and 2,426 Ma, ∼100 My earlier than previously estimated, based on an age of 2,426 ± 3 Ma for Ongeluk Formation magmatism from the Kaapvaal Craton of southern Africa. This age helps define a key paleomagnetic pole that positions the Kaapvaal Craton at equatorial latitudes of 11° ± 6° at this time. Furthermore, the rise of atmospheric oxygen was not monotonic, but was instead characterized by oscillations, which together with climatic instabilities may have continued over the next ∼200 My until ≤2,250-2,240 Ma. Ongeluk Formation volcanism at ca. 2,426 Ma was part of a large igneous…

Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.

Significance Combining ambient pressure X-ray photoelectron spectroscopy experiments and quantum mechanical density functional theory calculations, this work reveals the essential first step for activating CO 2 on a Cu surface, in particular, highlighting the importance of copper suboxide and the critical role of water. These findings provide the quintessential information needed to guide the future design of improved catalysts.

The United States spends more than $250 million each year on the American Community Survey (ACS), a labor-intensive door-to-door study that measures statistics relating to race, gender, education, occupation, unemployment, and other demographic factors. Although a comprehensive source of data, the lag between demographic changes and their appearance in the ACS can exceed several years. As digital imagery becomes ubiquitous and machine vision techniques improve, automated data analysis may become an increasingly practical supplement to the ACS. Here, we present a method that estimates socioeconomic characteristics of regions spanning 200 US cities by using 50 million images of street scenes gathered with Google Street View cars. Using deep learning-based computer vision techniques, we determined the make, model, and year of all motor vehicles encountered in particular neighborhoods. Data from this census of motor vehicles, which enumerated 22 million automobiles in total (8% of all automobiles in the United States), were used to accurately estimate income, race, education, and voting…

Significance Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.

We run a selection of algorithms on two state-of-the-art 5-qubit quantum computers that are based on different technology platforms. One is a publicly accessible superconducting transmon device (www. RESEARCH: ibm.com/ibm-q) with limited connectivity, and the other is a fully connected trapped-ion system. Even though the two systems have different native quantum interactions, both can be programed in a way that is blind to the underlying hardware, thus allowing a comparison of identical quantum algorithms between different physical systems. We show that quantum algorithms and circuits that use more connectivity clearly benefit from a better-connected system of qubits. Although the quantum systems here are not yet large enough to eclipse classical computers, this experiment exposes critical factors of scaling quantum computers, such as qubit connectivity and gate expressivity. In addition, the results suggest that codesigning particular quantum applications with the hardware itself will be paramount in successfully using quantum computers in the future.

In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes. Nutrients signal to mTORC1 through the lysosome-associated Rag GTPases and their many regulators and associated cytosolic and lysosomal nutrient sensors. mTOR signaling is deregulated in common diseases, like cancer and epilepsy, and mTORC1 is a well-validated modulator of aging in multiple model organisms. There is significant excitement around using mTORC1 inhibitors to treat cancer and neurological disease and, potentially,…

= 150) were randomly assigned to female or male peer mentors or no mentors for 1 y. Their experiences were assessed multiple times during the intervention year and 1-y postintervention. Female (but not male) mentors protected women's belonging in engineering, self-efficacy, motivation, retention in engineering majors, and postcollege engineering aspirations. Counter to common assumptions, better engineering grades were not associated with more retention or career aspirations in engineering in the first year of college. Notably, increased belonging and self-efficacy were significantly associated with more retention and career aspirations. The benefits of peer mentoring endured long after the intervention had ended, inoculating women for the first 2 y of college-the window of greatest attrition from science, technology, engineering, and mathematics (STEM) majors. Thus, same-gender peer mentoring for a short period during developmental transition points promotes women's success and retention in engineering, yielding dividends over time.

Significance Water is vital to our everyday life, but its structure at a molecular level is still not fully understood from either experiment or theory. The latter is hampered by our inability to construct a purely predictive, first principles model. The difficulty in modeling water lies in capturing the delicate interplay among the many strong and weak forces that govern its behavior and phase diagram. Herein, molecular simulations with a recently proposed nonempirical quantum mechanical approach (the SCAN density functional) yield an excellent description of the structural, electronic, and dynamic properties of liquid water. SCAN (strongly constrained and appropriately normed)-based approaches, which describe diverse types of bonds in materials on an equal, accurate footing, will likely enable efficient and reliable modeling of aqueous phase chemistry.

Significance Programmed cell death protein ligand 1 (PD-L1)–expressing cells mediate tumor evasion from immune system by suppressing activated T lymphocytes. A bioactive lipid prostaglandin E 2 (PGE 2 ) formed from arachidonic acid by COXs and PGE 2 synthases (PGESs) facilitates both cancer inflammation and immune suppression. Here, we show that tumor cells can induce PD-L1 expression in bone marrow–derived cells by affecting PGE 2 metabolism in hematopoietic cells. The tumor-induced PD-L1 expression was limited to the myeloid cell lineage and, specifically, to the macrophages and myeloid-derived suppressor cells. Collectively, the obtained results demonstrate that selective inhibition of PGE 2 -forming enzymes COX2, murine PGES1, or genetic overexpression of PGE 2 -degrading enzyme 15-hydroxyprostaglandin dehydrogenase could provide a novel approach to regulate both PGE 2 levels and PD-L1 expression in cancer, thus alleviating the immune suppression and stimulating antitumor immune response.

Humans challenge the phenotypic, genetic, and cultural makeup of species by affecting the fitness landscapes on which they evolve. Recent studies show that cities might play a major role in contemporary evolution by accelerating phenotypic changes in wildlife, including animals, plants, fungi, and other organisms. Many studies of ecoevolutionary change have focused on anthropogenic drivers, but none of these studies has specifically examined the role that urbanization plays in ecoevolution or explicitly examined its mechanisms. This paper presents evidence on the mechanisms linking urban development patterns to rapid evolutionary changes for species that play important functional roles in communities and ecosystems. Through a metaanalysis of experimental and observational studies reporting more than 1,600 phenotypic changes in species across multiple regions, we ask whether we can discriminate an urban signature of phenotypic change beyond the established natural baselines and other anthropogenic signals. We then assess the relative impact of five types of urban disturbances…

Significance Gadolinium (Gd)-based contrast agents (GBCAs) are currently the mainstream clinical MRI contrast agents. Some GBCAs have shown a long-term toxicity—nephrogenic systemic fibrosis (NSF)—and Gd depositions in the brain. The NSF has triggered a Food and Drug Administration (FDA) black-box warning and a contraindication of some GBCAs. The finding of Gd depositions led to an ongoing FDA investigation to monitor their possible long-term adverse effects. Here, we present T 1 -weighted contrast-enhanced MR imaging and angiography using zwitterion-coated exceedingly small superparamagnetic iron oxide nanoparticles (ZES-SPIONs) in mice and rats. Renal clearance and biodistribution results further demonstrate that ZES-SPIONs are qualitatively different from previously reported SPIONs. This work may open up opportunities to develop exceedingly small SPIONs that show effective T 1 contrast as Gd-free alternatives to GBCAs.

Entanglement and entropy are key concepts standing at the foundations of quantum and statistical mechanics. Recently, the study of quantum quenches revealed that these concepts are intricately intertwined. Although the unitary time evolution ensuing from a pure state maintains the system at zero entropy, local properties at long times are captured by a statistical ensemble with nonzero thermodynamic entropy, which is the entanglement accumulated during the dynamics. Therefore, understanding the entanglement evolution unveils how thermodynamics emerges in isolated systems. Alas, an exact computation of the entanglement dynamics was available so far only for noninteracting systems, whereas it was deemed unfeasible for interacting ones. Here, we show that the standard quasiparticle picture of the entanglement evolution, complemented with integrability-based knowledge of the steady state and its excitations, leads to a complete understanding of the entanglement dynamics in the space-time scaling limit. We thoroughly check our result for the paradigmatic Heisenberg chain.

Szent-Győrgi called water the "matrix of life" and claimed that there was no life without it. This statement is true, as far as we know, on our planet, but it is not clear whether it must hold throughout the cosmos. To evaluate that question requires a close consideration of the many varied and subtle roles that water plays in living cells-a consideration that must be free of both an assumed essentialism that gives water an almost mystical life-giving agency and a traditional tendency to see it as a merely passive solvent. Water is a participant in the "life of the cell," and here I describe some of the features of that active agency. Water's value for molecular biology comes from both the structural and dynamic characteristics of its status as a complex, structured liquid as well as its nature as a polar, protic, and amphoteric reagent. Any discussion of water as life's matrix must, however, begin with an acknowledgment that our understanding of it as both a liquid and a solvent is still incomplete.

Abstract Many animals are inhabited by microbial symbionts that influence their hosts’ development, physiology, ecological interactions, and evolutionary diversification. However, firm evidence for the existence and functional importance of resident microbiomes in larval Lepidoptera (caterpillars) is lacking, despite the fact that these insects are enormously diverse, major agricultural pests, and dominant herbivores in many ecosystems. Using 16S rRNA gene sequencing and quantitative PCR, we characterized the gut microbiomes of wild leaf-feeding caterpillars in the United States and Costa Rica, representing 124 species from 16 families. Compared with other insects and vertebrates assayed using the same methods, the microbes we detected in caterpillar guts were unusually low-density and highly variable among individuals. Furthermore, the abundance and composition of leaf-associated microbes were reflected in the feces of caterpillars consuming the same plants. Thus, microbes ingested with food are present (though possibly dead or dormant) in the caterpillar gut, but host-specific,…

Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1…

]. The empirical literature has shown significant increases in climate-driven impacts on overall consumption, yet has not focused on the cost implications of the increased intensity and frequency of extreme events driving peak demand, which is the highest load observed in a period. We use comprehensive, high-frequency data at the level of load balancing authorities to parameterize the relationship between average or peak electricity demand and temperature for a major economy. Using statistical models, we analyze multiyear data from 166 load balancing authorities in the United States. We couple the estimated temperature response functions for total daily consumption and daily peak load with 18 downscaled global climate models (GCMs) to simulate climate change-driven impacts on both outcomes. We show moderate and heterogeneous changes in consumption, with an average increase of 2.8% by end of century. The results of our peak load simulations, however, suggest significant increases in the intensity and frequency of peak events throughout the United States, assuming today's technology…

Human cultural traits-behaviors, ideas, and technologies that can be learned from other individuals-can exhibit complex patterns of transmission and evolution, and researchers have developed theoretical models, both verbal and mathematical, to facilitate our understanding of these patterns. Many of the first quantitative models of cultural evolution were modified from existing concepts in theoretical population genetics because cultural evolution has many parallels with, as well as clear differences from, genetic evolution. Furthermore, cultural and genetic evolution can interact with one another and influence both transmission and selection. This interaction requires theoretical treatments of gene-culture coevolution and dual inheritance, in addition to purely cultural evolution. In addition, cultural evolutionary theory is a natural component of studies in demography, human ecology, and many other disciplines. Here, we review the core concepts in cultural evolutionary theory as they pertain to the extension of biology through culture, focusing on cultural evolutionary applications…

dynamics, and control of organelle biogenesis and dynamics. Although these membrane contacts have previously been observed in neurons, their distribution and abundance have not been systematically analyzed. Here, we have used focused ion beam-scanning electron microscopy to generate 3D reconstructions of intracellular organelles and their membrane appositions involving the ER (distance ≤30 nm) in different neuronal compartments. ER-plasma membrane (PM) contacts were particularly abundant in cell bodies, with large, flat ER cisternae apposed to the PM, sometimes with a notably narrow lumen (thin ER). Smaller ER-PM contacts occurred throughout dendrites, axons, and in axon terminals. ER contacts with mitochondria were abundant in all compartments, with the ER often forming a network that embraced mitochondria. Small focal contacts were also observed with tubulovesicular structures, likely to be endosomes, and with sparse multivesicular bodies and lysosomes found in our reconstructions. Our study provides an anatomical reference for interpreting information about interorganelle…

The spatial presentation of mechanical information is a key parameter for cell behavior. We have developed a method of polymerization control in which the differential diffusion distance of unreacted cross-linker and monomer into a prepolymerized hydrogel sink results in a tunable stiffness gradient at the cell-matrix interface. This simple, low-cost, robust method was used to produce polyacrylamide hydrogels with stiffness gradients of 0.5, 1.7, 2.9, 4.5, 6.8, and 8.2 kPa/mm, spanning the in vivo physiological and pathological mechanical landscape. Importantly, three of these gradients were found to be nondurotactic for human adipose-derived stem cells (hASCs), allowing the presentation of a continuous range of stiffnesses in a single well without the confounding effect of differential cell migration. Using these nondurotactic gradient gels, stiffness-dependent hASC morphology, migration, and differentiation were studied. Finally, the mechanosensitive proteins YAP, Lamin A/C, Lamin B, MRTF-A, and MRTF-B were analyzed on these gradients, providing higher-resolution data on…

The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic substrate, and growth factor conditions, that enhance cardiac tissue viability, function, and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions, hPSC-CMs were refractory to mitogenic stimuli, and we found that key proliferation pathways including…

With more than a billion people lacking accessible drinking water, there is a critical need to convert nonpotable sources such as seawater to water suitable for human use. However, energy requirements of desalination plants account for half their operating costs, so alternative, lower energy approaches are equally critical. Membrane distillation (MD) has shown potential due to its low operating temperature and pressure requirements, but the requirement of heating the input water makes it energy intensive. Here, we demonstrate nanophotonics-enabled solar membrane distillation (NESMD), where highly localized photothermal heating induced by solar illumination alone drives the distillation process, entirely eliminating the requirement of heating the input water. Unlike MD, NESMD can be scaled to larger systems and shows increased efficiencies with decreased input flow velocities. Along with its increased efficiency at higher ambient temperatures, these properties all point to NESMD as a promising solution for household- or community-scale desalination.

The state of protein phosphorylation can be a key determinant of cellular physiology such as early-stage cancer, but the development of phosphoproteins in biofluids for disease diagnosis remains elusive. Here we demonstrate a strategy to isolate and identify phosphoproteins in extracellular vesicles (EVs) from human plasma as potential markers to differentiate disease from healthy states. We identified close to 10,000 unique phosphopeptides in EVs isolated from small volumes of plasma samples. Using label-free quantitative phosphoproteomics, we identified 144 phosphoproteins in plasma EVs that are significantly higher in patients diagnosed with breast cancer compared with healthy controls. Several biomarkers were validated in individual patients using paralleled reaction monitoring for targeted quantitation. This study demonstrates that the development of phosphoproteins in plasma EV as disease biomarkers is highly feasible and may transform cancer screening and monitoring.

Genome size in mammals and birds shows remarkably little interspecific variation compared with other taxa. However, genome sequencing has revealed that many mammal and bird lineages have experienced differential rates of transposable element (TE) accumulation, which would be predicted to cause substantial variation in genome size between species. Thus, we hypothesize that there has been covariation between the amount of DNA gained by transposition and lost by deletion during mammal and avian evolution, resulting in genome size equilibrium. To test this model, we develop computational methods to quantify the amount of DNA gained by TE expansion and lost by deletion over the last 100 My in the lineages of 10 species of eutherian mammals and 24 species of birds. The results reveal extensive variation in the amount of DNA gained via lineage-specific transposition, but that DNA loss counteracted this expansion to various extents across lineages. Our analysis of the rate and size spectrum of deletion events implies that DNA removal in both mammals and birds has proceeded mostly through…