The 100 most-cited articles in Proceedings of the National Academy of Sciences, 2019

From 2013 to 2017, with the implementation of the toughest-ever clean air policy in China, significant declines in fine particle (PM 2.5 ) concentrations occurred nationwide. Here we estimate the drivers of the improved PM 2.5 air quality and the associated health benefits in China from 2013 to 2017 based on a measure-specific integrated evaluation approach, which combines a bottom-up emission inventory, a chemical transport model, and epidemiological exposure-response functions. The estimated national population–weighted annual mean PM 2.5 concentrations decreased from 61.8 (95%CI: 53.3–70.0) to 42.0 µg/m 3 (95% CI: 35.7–48.6) in 5 y, with dominant contributions from anthropogenic emission abatements. Although interannual meteorological variations could significantly alter PM 2.5 concentrations, the corresponding effects on the 5-y trends were relatively small. The measure-by-measure evaluation indicated that strengthening industrial emission standards (power plants and emission-intensive industrial sectors), upgrades on industrial boilers, phasing out outdated industrial…

Machine-learning models have demonstrated great success in learning complex patterns that enable them to make predictions about unobserved data. In addition to using models for prediction, the ability to interpret what a model has learned is receiving an increasing amount of attention. However, this increased focus has led to considerable confusion about the notion of interpretability. In particular, it is unclear how the wide array of proposed interpretation methods are related and what common concepts can be used to evaluate them. We aim to address these concerns by defining interpretability in the context of machine learning and introducing the predictive, descriptive, relevant (PDR) framework for discussing interpretations. The PDR framework provides 3 overarching desiderata for evaluation: predictive accuracy, descriptive accuracy, and relevancy, with relevancy judged relative to a human audience. Moreover, to help manage the deluge of interpretation methods, we introduce a categorization of existing techniques into model-based and post hoc categories, with subgroups including…

-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated in mitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.

We use updated drainage inventory, ice thickness, and ice velocity data to calculate the grounding line ice discharge of 176 basins draining the Antarctic Ice Sheet from 1979 to 2017. We compare the results with a surface mass balance model to deduce the ice sheet mass balance. The total mass loss increased from 40 ± 9 Gt/y in 1979-1990 to 50 ± 14 Gt/y in 1989-2000, 166 ± 18 Gt/y in 1999-2009, and 252 ± 26 Gt/y in 2009-2017. In 2009-2017, the mass loss was dominated by the Amundsen/Bellingshausen Sea sectors, in West Antarctica (159 ± 8 Gt/y), Wilkes Land, in East Antarctica (51 ± 13 Gt/y), and West and Northeast Peninsula (42 ± 5 Gt/y). The contribution to sea-level rise from Antarctica averaged 3.6 ± 0.5 mm per decade with a cumulative 14.0 ± 2.0 mm since 1979, including 6.9 ± 0.6 mm from West Antarctica, 4.4 ± 0.9 mm from East Antarctica, and 2.5 ± 0.4 mm from the Peninsula (i.e., East Antarctica is a major participant in the mass loss). During the entire period, the mass loss concentrated in areas closest to warm, salty, subsurface, circumpolar deep water (CDW), that is,…

Breakthroughs in machine learning are rapidly changing science and society, yet our fundamental understanding of this technology has lagged far behind. Indeed, one of the central tenets of the field, the bias-variance trade-off, appears to be at odds with the observed behavior of methods used in modern machine-learning practice. The bias-variance trade-off implies that a model should balance underfitting and overfitting: Rich enough to express underlying structure in data and simple enough to avoid fitting spurious patterns. However, in modern practice, very rich models such as neural networks are trained to exactly fit (i.e., interpolate) the data. Classically, such models would be considered overfitted, and yet they often obtain high accuracy on test data. This apparent contradiction has raised questions about the mathematical foundations of machine learning and their relevance to practitioners. In this paper, we reconcile the classical understanding and the modern practice within a unified performance curve. This "double-descent" curve subsumes the textbook U-shaped bias-variance…

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor ( AR ) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1 , AR , and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and…

We compared students' self-reported perception of learning with their actual learning under controlled conditions in large-enrollment introductory college physics courses taught using 1) active instruction (following best practices in the discipline) and 2) passive instruction (lectures by experienced and highly rated instructors). Both groups received identical class content and handouts, students were randomly assigned, and the instructor made no effort to persuade students of the benefit of either method. Students in active classrooms learned more (as would be expected based on prior research), but their perception of learning, while positive, was lower than that of their peers in passive environments. This suggests that attempts to evaluate instruction based on students' perceptions of learning could inadvertently promote inferior (passive) pedagogical methods. For instance, a superstar lecturer could create such a positive feeling of learning that students would choose those lectures over active learning. Most importantly, these results suggest that when students experience the…

Significance An ecological community is a dynamic complex system with a myriad of interacting species, which are controlled by various scale-dependent deterministic and stochastic forces. With rapid advances in genomics technologies, categorizing biological diversity, particularly microbial diversity, becomes relatively easy, but the great challenge is to disentangle the mechanisms controlling biological diversity. The general null model-based framework developed in this study provides an effective and robust tool to ecologists for quantitatively assessing ecological stochasticity. By highlighting the caveats such as model selection, similarity metrics, and spatial scales, this study provides guidance for appropriate use of null model-based approaches for examining community assembly processes. Although this framework was tested with microbial data, it should also be applicable to plant and animal ecology.

There is growing interest in estimating and analyzing heterogeneous treatment effects in experimental and observational studies. We describe a number of metaalgorithms that can take advantage of any supervised learning or regression method in machine learning and statistics to estimate the conditional average treatment effect (CATE) function. Metaalgorithms build on base algorithms-such as random forests (RFs), Bayesian additive regression trees (BARTs), or neural networks-to estimate the CATE, a function that the base algorithms are not designed to estimate directly. We introduce a metaalgorithm, the X-learner, that is provably efficient when the number of units in one treatment group is much larger than in the other and can exploit structural properties of the CATE function. For example, if the CATE function is linear and the response functions in treatment and control are Lipschitz-continuous, the X-learner can still achieve the parametric rate under regularity conditions. We then introduce versions of the X-learner that use RF and BART as base learners. In extensive simulation…

) and occur with extensive temporal (on a daily, weekly, to monthly timescale) and spatial (over a million square kilometers) coverage. Although significant advances have been made in field measurements, model simulations, and laboratory experiments for fine PM over recent years, the causes for severe haze formation have not yet to be systematically/comprehensively evaluated. This review provides a synthetic synopsis of recent advances in understanding the fundamental mechanisms of severe haze formation in northern China, focusing on emission sources, chemical formation and transformation, and meteorological and climatic conditions. In particular, we highlight the synergetic effects from the interactions between anthropogenic emissions and atmospheric processes. Current challenges and future research directions to improve the understanding of severe haze pollution as well as plausible regulatory implications on a scientific basis are also discussed.

Significance Electrolysis of water to generate hydrogen fuel could be vital to the future renewable energy landscape. Electrodes that can sustain seawater splitting without chloride corrosion could address the issue of freshwater scarcity on Earth. Herein, a hierarchical anode consisting of a nickel–iron hydroxide electrocatalyst layer uniformly coated on a sulfide layer formed on Ni substrate was developed, affording superior catalytic activity and corrosion resistance in seawater electrolysis. In situ-generated polyanion-rich passivating layers formed in the anode are responsible for chloride repelling and high corrosion resistance, leading to new directions for designing and fabricating highly sustained seawater-splitting electrodes and providing an opportunity to use the vast seawater on Earth as an energy carrier.

Significance PD-1 blockade is a cancer immunotherapy effective in various types of cancer. However, we observed rapid cancer progression, called hyperprogressive disease (HPD), in ∼10% of advanced gastric cancer patients treated with anti–PD-1 monoclonal antibody. Tumors of HPD patients possessed highly proliferating FoxP3 + Treg cells after treatment, contrasting with their reduction in non-HPD tumors. In vitro PD-1 blockade augmented proliferation and suppressive activity of human Treg cells. Likewise, murine Treg cells that were deficient in PD-1 signaling were more proliferative and immunosuppressive. Thus, HPD may occur when PD-1 blockade activates and expands tumor-infiltrating PD-1 + Treg cells to overwhelm tumor-reactive PD-1 + effector T cells. Depletion of the former may therefore help treat and prevent HPD.

We reconstruct the mass balance of the Greenland Ice Sheet using a comprehensive survey of thickness, surface elevation, velocity, and surface mass balance (SMB) of 260 glaciers from 1972 to 2018. We calculate mass discharge, D, into the ocean directly for 107 glaciers (85% of D) and indirectly for 110 glaciers (15%) using velocity-scaled reference fluxes. The decadal mass balance switched from a mass gain of +47 ± 21 Gt/y in 1972-1980 to a loss of 51 ± 17 Gt/y in 1980-1990. The mass loss increased from 41 ± 17 Gt/y in 1990-2000, to 187 ± 17 Gt/y in 2000-2010, to 286 ± 20 Gt/y in 2010-2018, or sixfold since the 1980s, or 80 ± 6 Gt/y per decade, on average. The acceleration in mass loss switched from positive in 2000-2010 to negative in 2010-2018 due to a series of cold summers, which illustrates the difficulty of extrapolating short records into longer-term trends. Cumulated since 1972, the largest contributions to global sea level rise are from northwest (4.4 ± 0.2 mm), southeast (3.0 ± 0.3 mm), and central west (2.0 ± 0.2 mm) Greenland, with a total 13.7 ± 1.1 mm for the ice…

Significance Many people consume news via social media. It is therefore desirable to reduce social media users’ exposure to low-quality news content. One possible intervention is for social media ranking algorithms to show relatively less content from sources that users deem to be untrustworthy. But are laypeople’s judgments reliable indicators of quality, or are they corrupted by either partisan bias or lack of information? Perhaps surprisingly, we find that laypeople—on average—are quite good at distinguishing between lower- and higher-quality sources. These results indicate that incorporating the trust ratings of laypeople into social media ranking algorithms may prove an effective intervention against misinformation, fake news, and news content with heavy political bias.

Understanding the causes of economic inequality is critical for achieving equitable economic development. To investigate whether global warming has affected the recent evolution of inequality, we combine counterfactual historical temperature trajectories from a suite of global climate models with extensively replicated empirical evidence of the relationship between historical temperature fluctuations and economic growth. Together, these allow us to generate probabilistic country-level estimates of the influence of anthropogenic climate forcing on historical economic output. We find very high likelihood that anthropogenic climate forcing has increased economic inequality between countries. For example, per capita gross domestic product (GDP) has been reduced 17-31% at the poorest four deciles of the population-weighted country-level per capita GDP distribution, yielding a ratio between the top and bottom deciles that is 25% larger than in a world without global warming. As a result, although between-country inequality has decreased over the past half century, there is ∼90% likelihood…

We use data on police-involved deaths to estimate how the risk of being killed by police use of force in the United States varies across social groups. We estimate the lifetime and age-specific risks of being killed by police by race and sex. We also provide estimates of the proportion of all deaths accounted for by police use of force. We find that African American men and women, American Indian/Alaska Native men and women, and Latino men face higher lifetime risk of being killed by police than do their white peers. We find that Latina women and Asian/Pacific Islander men and women face lower risk of being killed by police than do their white peers. Risk is highest for black men, who (at current levels of risk) face about a 1 in 1,000 chance of being killed by police over the life course. The average lifetime odds of being killed by police are about 1 in 2,000 for men and about 1 in 33,000 for women. Risk peaks between the ages of 20 y and 35 y for all groups. For young men of color, police use of force is among the leading causes of death.

The discovery of governing equations from scientific data has the potential to transform data-rich fields that lack well-characterized quantitative descriptions. Advances in sparse regression are currently enabling the tractable identification of both the structure and parameters of a nonlinear dynamical system from data. The resulting models have the fewest terms necessary to describe the dynamics, balancing model complexity with descriptive ability, and thus promoting interpretability and generalizability. This provides an algorithmic approach to Occam's razor for model discovery. However, this approach fundamentally relies on an effective coordinate system in which the dynamics have a simple representation. In this work, we design a custom deep autoencoder network to discover a coordinate transformation into a reduced space where the dynamics may be sparsely represented. Thus, we simultaneously learn the governing equations and the associated coordinate system. We demonstrate this approach on several example high-dimensional systems with low-dimensional behavior. The resulting…

Anthropogenic greenhouse gases and aerosols are associated with climate change and human health risks. We used a global model to estimate the climate and public health outcomes attributable to fossil fuel use, indicating the potential benefits of a phaseout. We show that it can avoid an excess mortality rate of 3.61 (2.96-4.21) million per year from outdoor air pollution worldwide. This could be up to 5.55 (4.52-6.52) million per year by additionally controlling nonfossil anthropogenic sources. Globally, fossil-fuel-related emissions account for about 65% of the excess mortality, and 70% of the climate cooling by anthropogenic aerosols. The chemical influence of air pollution on aeolian dust contributes to the aerosol cooling. Because aerosols affect the hydrologic cycle, removing the anthropogenic emissions in the model increases rainfall by 10-70% over densely populated regions in India and 10-30% over northern China, and by 10-40% over Central America, West Africa, and the drought-prone Sahel, thus contributing to water and food security. Since aerosols mask the anthropogenic…

Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also…

Biocompatible gold nanoparticles designed to absorb light at wavelengths of high tissue transparency have been of particular interest for biomedical applications. The ability of such nanoparticles to convert absorbed near-infrared light to heat and induce highly localized hyperthermia has been shown to be highly effective for photothermal cancer therapy, resulting in cell death and tumor remission in a multitude of preclinical animal models. Here we report the initial results of a clinical trial in which laser-excited gold-silica nanoshells (GSNs) were used in combination with magnetic resonance-ultrasound fusion imaging to focally ablate low-intermediate-grade tumors within the prostate. The overall goal is to provide highly localized regional control of prostate cancer that also results in greatly reduced patient morbidity and improved functional outcomes. This pilot device study reports feasibility and safety data from 16 cases of patients diagnosed with low- or intermediate-risk localized prostate cancer. After GSN infusion and high-precision laser ablation, patients underwent…

As cities warm and the need for climate adaptation strategies increases, a more detailed understanding of the cooling effects of land cover across a continuum of spatial scales will be necessary to guide management decisions. We asked how tree canopy cover and impervious surface cover interact to influence daytime and nighttime summer air temperature, and how effects vary with the spatial scale at which land-cover data are analyzed (10-, 30-, 60-, and 90-m radii). A bicycle-mounted measurement system was used to sample air temperature every 5 m along 10 transects (∼7 km length, sampled 3-12 times each) spanning a range of impervious and tree canopy cover (0-100%, each) in a midsized city in the Upper Midwest United States. Variability in daytime air temperature within the urban landscape averaged 3.5 °C (range, 1.1-5.7 °C). Temperature decreased nonlinearly with increasing canopy cover, with the greatest cooling when canopy cover exceeded 40%. The magnitude of daytime cooling also increased with spatial scale and was greatest at the size of a typical city block (60-90 m). Daytime…

Concerns about public misinformation in the United States—ranging from politics to science—are growing. Here, we provide an overview of how and why citizens become (and sometimes remain) misinformed about science. Our discussion focuses specifically on misinformation among individual citizens. However, it is impossible to understand individual information processing and acceptance without taking into account social networks, information ecologies, and other macro-level variables that provide important social context. Specifically, we show how being misinformed is a function of a person’s ability and motivation to spot falsehoods, but also of other group-level and societal factors that increase the chances of citizens to be exposed to correct(ive) information. We conclude by discussing a number of research areas—some of which echo themes of the 2017 National Academies of Sciences, Engineering, and Medicine’s Communicating Science Effectively report—that will be particularly important for our future understanding of misinformation, specifically a systems approach to the problem of…

nanoparticles distributed inside multiwalled carbon nanotubes with inner diameter of ∼7 nm. Unlike the traditional Fenton-like processes, this delicately designed system was shown to selectively oxidize the organic dyes that could be adsorbed with oxidation rates linearly proportional to the adsorption affinity. It also exhibited remarkably higher degradation activity (22.5 times faster) toward a model pollutant methylene blue than its nonconfined analog. Strikingly, the unforeseen stability at pH value up to 9.0 greatly expands the use of Fenton-like catalysts in alkaline conditions. This work represents a fundamental breakthrough toward the design and understanding of the Fenton-like system under nanoconfinement, might cause implications in other fields, especially in biological systems.

Food choices are shifting globally in ways that are negatively affecting both human health and the environment. Here we consider how consuming an additional serving per day of each of 15 foods is associated with 5 health outcomes in adults and 5 aspects of agriculturally driven environmental degradation. We find that while there is substantial variation in the health outcomes of different foods, foods associated with a larger reduction in disease risk for one health outcome are often associated with larger reductions in disease risk for other health outcomes. Likewise, foods with lower impacts on one metric of environmental harm tend to have lower impacts on others. Additionally, of the foods associated with improved health (whole grain cereals, fruits, vegetables, legumes, nuts, olive oil, and fish), all except fish have among the lowest environmental impacts, and fish has markedly lower impacts than red meats and processed meats. Foods associated with the largest negative environmental impacts-unprocessed and processed red meat-are consistently associated with the largest…

synthesizes and secretes a complex glucorhamnan polysaccharide with a rhamnose backbone and glucose sidechains. Chemical and spectroscopic studies indicated that the glucorhamnan was largely a repeating unit of five sugars with a linear backbone formed from three rhamnose units and a short sidechain composed of two glucose units. The rhamnose backbone is made from 1,2- and 1,3-linked rhamnose units, and the sidechain has a terminal glucose linked to a 1,6-glucose. This glucorhamnan potently induces inflammatory cytokine (TNFα) secretion by dendritic cells, and TNFα secretion is dependent on toll-like receptor 4 (TLR4). We also identify a putative biosynthetic gene cluster for this molecule, which has the four biosynthetic genes needed to convert glucose to rhamnose and the five glycosyl transferases needed to build the repeating pentasaccharide unit of the inflammatory glucorhamnan.

T cells expressing chimeric antigen receptors (CAR T cells) have shown impressive therapeutic efficacy against leukemias and lymphomas. However, they have not been as effective against solid tumors because they become hyporesponsive (“exhausted” or “dysfunctional”) within the tumor microenvironment, with decreased cytokine production and increased expression of several inhibitory surface receptors. Here we define a transcriptional network that mediates CD8 + T cell exhaustion. We show that the high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using a previously established CAR T cell model, we show that TOX and TOX2 are highly induced in CD8 + CAR + PD-1 high TIM3 high (“exhausted”) tumor-infiltrating lymphocytes (CAR TILs), and CAR TILs deficient in both TOX and TOX2 ( Tox DKO) are more effective than wild-type (WT), TOX-deficient, or TOX2-deficient CAR TILs in suppressing tumor…

The expression profiles and spatial distributions of RNAs regulate many cellular functions. Image-based transcriptomic approaches provide powerful means to measure both expression and spatial information of RNAs in individual cells within their native environment. Among these approaches, multiplexed error-robust fluorescence in situ hybridization (MERFISH) has achieved spatially resolved RNA quantification at transcriptome scale by massively multiplexing single-molecule FISH measurements. Here, we increased the gene throughput of MERFISH and demonstrated simultaneous measurements of RNA transcripts from ∼10,000 genes in individual cells with ∼80% detection efficiency and ∼4% misidentification rate. We combined MERFISH with cellular structure imaging to determine subcellular compartmentalization of RNAs. We validated this approach by showing enrichment of secretome transcripts at the endoplasmic reticulum, and further revealed enrichment of long noncoding RNAs, RNAs with retained introns, and a subgroup of protein-coding mRNAs in the cell nucleus. Leveraging spatially resolved RNA…

One-sixth of the global terrestrial surface now falls within protected areas (PAs), making it essential to understand how far they mitigate the increasing pressures on nature which characterize the Anthropocene. In by far the largest analysis of this question to date and not restricted to forested PAs, we compiled data from 12,315 PAs across 152 countries to investigate their ability to reduce human pressure and how this varies with socioeconomic and management circumstances. While many PAs show positive outcomes, strikingly we find that compared with matched unprotected areas, PAs have on average not reduced a compound index of pressure change over the past 15 y. Moreover, in tropical regions average pressure change from cropland conversion has increased inside PAs even more than in matched unprotected areas. However, our results also confirm previous studies restricted to forest PAs, where pressures are increasing, but less than in counterfactual areas. Our results also show that countries with high national-level development scores have experienced lower rates of pressure…

Significance A newly completed 40-y record of satellite observations is used to quantify changes in Antarctic sea ice coverage since the late 1970s. Sea ice spreads over vast areas and has major impacts on the rest of the climate system, reflecting solar radiation and restricting ocean/atmosphere exchanges. The satellite record reveals that a gradual, decades-long overall increase in Antarctic sea ice extents reversed in 2014, with subsequent rates of decrease in 2014–2017 far exceeding the more widely publicized decay rates experienced in the Arctic. The rapid decreases reduced the Antarctic sea ice extents to their lowest values in the 40-y record, both on a yearly average basis (record low in 2017) and on a monthly basis (record low in February 2017).

Although the existence of a large carbon sink in terrestrial ecosystems is well-established, the drivers of this sink remain uncertain. It has been suggested that perturbations to forest demography caused by past land-use change, management, and natural disturbances may be causing a large component of current carbon uptake. Here we use a global compilation of forest age observations, combined with a terrestrial biosphere model with explicit modeling of forest regrowth, to partition the global forest carbon sink between old-growth and regrowth stands over the period 1981–2010. For 2001–2010 we find a carbon sink of 0.85 (0.66–0.96) Pg year −1 located in intact old-growth forest, primarily in the moist tropics and boreal Siberia, and 1.30 (1.03–1.96) Pg year −1 located in stands regrowing after past disturbance. Approaching half of the sink in regrowth stands would have occurred from demographic changes alone, in the absence of other environmental changes. These age-constrained results show consistency with those simulated using an ensemble of demographically-enabled terrestrial…

Significance Water is considered to be a stable and relatively inert molecule in bulk solution. We report an exceptional behavior of water: Water molecules are spontaneously oxidized to form hydrogen peroxide near the water−air interface of micron-sized water droplets. This process does not require any chemical reagent, catalyst, applied electric potential, or radiation. Only pure water in the form of microdroplets in air is necessary for the appearance of hydrogen peroxide. We suggest that this discovery opens various innovative opportunities including green and inexpensive production of hydrogen peroxide, green chemical synthesis, safe cleaning, and food processing.

Rapid advances in artificial intelligence (AI) and automation technologies have the potential to significantly disrupt labor markets. While AI and automation can augment the productivity of some workers, they can replace the work done by others and will likely transform almost all occupations at least to some degree. Rising automation is happening in a period of growing economic inequality, raising fears of mass technological unemployment and a renewed call for policy efforts to address the consequences of technological change. In this paper we discuss the barriers that inhibit scientists from measuring the effects of AI and automation on the future of work. These barriers include the lack of high-quality data about the nature of work (e.g., the dynamic requirements of occupations), lack of empirically informed models of key microlevel processes (e.g., skill substitution and human-machine complementarity), and insufficient understanding of how cognitive technologies interact with broader economic dynamics and institutional mechanisms (e.g., urban migration and international trade…

Compound extremes such as cooccurring soil drought (low soil moisture) and atmospheric aridity (high vapor pressure deficit) can be disastrous for natural and societal systems. Soil drought and atmospheric aridity are 2 main physiological stressors driving widespread vegetation mortality and reduced terrestrial carbon uptake. Here, we empirically demonstrate that strong negative coupling between soil moisture and vapor pressure deficit occurs globally, indicating high probability of cooccurring soil drought and atmospheric aridity. Using the Global Land Atmosphere Coupling Experiment (GLACE)-CMIP5 experiment, we further show that concurrent soil drought and atmospheric aridity are greatly exacerbated by land-atmosphere feedbacks. The feedback of soil drought on the atmosphere is largely responsible for enabling atmospheric aridity extremes. In addition, the soil moisture-precipitation feedback acts to amplify precipitation and soil moisture deficits in most regions. CMIP5 models further show that the frequency of concurrent soil drought and atmospheric aridity enhanced by…

Despite considerable advances in process understanding, numerical modeling, and the observational record of ice sheet contributions to global mean sea-level rise (SLR) since the Fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change, severe limitations remain in the predictive capability of ice sheet models. As a consequence, the potential contributions of ice sheets remain the largest source of uncertainty in projecting future SLR. Here, we report the findings of a structured expert judgement study, using unique techniques for modeling correlations between inter- and intra-ice sheet processes and their tail dependences. We find that since the AR5, expert uncertainty has grown, in particular because of uncertain ice dynamic effects. For a +2 °C temperature scenario consistent with the Paris Agreement, we obtain a median estimate of a 26 cm SLR contribution by 2100, with a 95th percentile value of 81 cm. For a +5 °C temperature scenario more consistent with unchecked emissions growth, the corresponding values are 51 and 178 cm, respectively. Inclusion of…

Urban residence is associated with a higher risk of some psychiatric disorders, but the underlying drivers remain unknown. There is increasing evidence that the level of exposure to natural environments impacts mental health, but few large-scale epidemiological studies have assessed the general existence and importance of such associations. Here, we investigate the prospective association between green space and mental health in the Danish population. Green space presence was assessed at the individual level using high-resolution satellite data to calculate the normalized difference vegetation index within a 210 × 210 m square around each person's place of residence (∼1 million people) from birth to the age of 10. We show that high levels of green space presence during childhood are associated with lower risk of a wide spectrum of psychiatric disorders later in life. Risk for subsequent mental illness for those who lived with the lowest level of green space during childhood was up to 55% higher across various disorders compared with those who lived with the highest level of green…

Significance Varroa destructor causes considerable damage to honey bees and subsequently the field of apiculture through just one process: feeding. For five decades, we have believed that these mites consume hemolymph like a tick consumes blood, and that Varroa cause harm primarily by vectoring viruses. Our work shows that they cause damage more directly. Varroa externally digest and consume fat body tissue rather than blood. These findings explain the failure of some previous attempts at developing effectively targeted treatment strategies for Varroa control. Furthermore, it provides some explanation for the diverse array of debilitating pathologies associated with Varroa that were unexplained by hemolymph removal alone. Our work provides a path forward for the development of novel treatment strategies for Varroa .

Plasticity theory aims at describing the yield loci and work hardening of a material under general deformation states. Most of its complexity arises from the nontrivial dependence of the yield loci on the complete strain history of a material and its microstructure. This motivated 3 ingenious simplifications that underpinned a century of developments in this field: 1) yield criteria describing yield loci location; 2) associative or nonassociative flow rules defining the direction of plastic flow; and 3) effective stress-strain laws consistent with the plastic work equivalence principle. However, 2 key complications arise from these simplifications. First, finding equations that describe these 3 assumptions for materials with complex microstructures is not trivial. Second, yield surface evolution needs to be traced iteratively, i.e., through a return mapping algorithm. Here, we show that these assumptions are not needed in the context of sequence learning when using recurrent neural networks, diverting the above-mentioned complications. This work offers an alternative to currently…

Significance Carbon dioxide (CO 2 ) drives climate change when released to the atmosphere. Alternatively, CO 2 could be captured and utilized as carbon source for chemicals. Here, we provide a global assessment of the technical climate change mitigation potential of carbon capture and utilization (CCU) in the chemical industry. We develop an engineering-level model of the global chemical industry representing 75% of current greenhouse gas (GHG) emissions. The model allows us to analyze the potential disruptive changes through large-scale CO 2 utilization and resulting emission reductions. Our study shows that CCU has the technical potential to lead to a carbon-neutral chemical industry and decouple chemical production from fossil resources. This transition, however, would cause largely increased mass flows and demand for low-carbon electricity.

), high strength (1 MPa), low Young's modulus (100 kPa), and high water content (70 to 80 wt %), which have not been achieved in synthetic hydrogels. The muscle-like properties are highly desirable for hydrogels' nascent applications in load-bearing artificial tissues and soft devices. Here, we propose a strategy of mechanical training to achieve the aligned nanofibrillar architectures of skeletal muscles in synthetic hydrogels, resulting in the combinational muscle-like properties. These properties are obtained through the training-induced alignment of nanofibrils, without additional chemical modifications or additives. In situ confocal microscopy of the hydrogels' fracturing processes reveals that the fatigue resistance results from the crack pinning by the aligned nanofibrils, which require much higher energy to fracture than the corresponding amorphous polymer chains. This strategy is particularly applicable for 3D-printed microstructures of hydrogels, in which we can achieve isotropically fatigue-resistant, strong yet compliant properties.

The order Coleoptera (beetles) is arguably the most speciose group of animals, but the evolutionary history of beetles, including the impacts of plant feeding (herbivory) on beetle diversification, remain poorly understood. We inferred the phylogeny of beetles using 4,818 genes for 146 species, estimated timing and rates of beetle diversification using 89 genes for 521 species representing all major lineages and traced the evolution of beetle genes enabling symbiont-independent digestion of lignocellulose using 154 genomes or transcriptomes. Phylogenomic analyses of these uniquely comprehensive datasets resolved previously controversial beetle relationships, dated the origin of Coleoptera to the Carboniferous, and supported the codiversification of beetles and angiosperms. Moreover, plant cell wall-degrading enzymes (PCWDEs) obtained from bacteria and fungi via horizontal gene transfers may have been key to the Mesozoic diversification of herbivorous beetles-remarkably, both major independent origins of specialized herbivory in beetles coincide with the first appearances of an…

While the physical dimensions of climate change are now routinely assessed through multimodel intercomparisons, projected impacts on the global ocean ecosystem generally rely on individual models with a specific set of assumptions. To address these single-model limitations, we present standardized ensemble projections from six global marine ecosystem models forced with two Earth system models and four emission scenarios with and without fishing. We derive average biomass trends and associated uncertainties across the marine food web. Without fishing, mean global animal biomass decreased by 5% (±4% SD) under low emissions and 17% (±11% SD) under high emissions by 2100, with an average 5% decline for every 1 °C of warming. Projected biomass declines were primarily driven by increasing temperature and decreasing primary production, and were more pronounced at higher trophic levels, a process known as trophic amplification. Fishing did not substantially alter the effects of climate change. Considerable regional variation featured strong biomass increases at high latitudes and decreases…

) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.

Fine particulate matter (PM 2.5 ) air pollution exposure is the largest environmental health risk factor in the United States. Here, we link PM 2.5 exposure to the human activities responsible for PM 2.5 pollution. We use these results to explore “pollution inequity”: the difference between the environmental health damage caused by a racial–ethnic group and the damage that group experiences. We show that, in the United States, PM 2.5 exposure is disproportionately caused by consumption of goods and services mainly by the non-Hispanic white majority, but disproportionately inhaled by black and Hispanic minorities. On average, non-Hispanic whites experience a “pollution advantage”: They experience ∼17% less air pollution exposure than is caused by their consumption. Blacks and Hispanics on average bear a “pollution burden” of 56% and 63% excess exposure, respectively, relative to the exposure caused by their consumption. The total disparity is caused as much by how much people consume as by how much pollution they breathe. Differences in the types of goods and services consumed by…

To reduce experimental effort associated with directed protein evolution and to explore the sequence space encoded by mutating multiple positions simultaneously, we incorporate machine learning into the directed evolution workflow. Combinatorial sequence space can be quite expensive to sample experimentally, but machine-learning models trained on tested variants provide a fast method for testing sequence space computationally. We validated this approach on a large published empirical fitness landscape for human GB1 binding protein, demonstrating that machine learning-guided directed evolution finds variants with higher fitness than those found by other directed evolution approaches. We then provide an example application in evolving an enzyme to produce each of the two possible product enantiomers (i.e., stereodivergence) of a new-to-nature carbene Si–H insertion reaction. The approach predicted libraries enriched in functional enzymes and fixed seven mutations in two rounds of evolution to identify variants for selective catalysis with 93% and 79% ee (enantiomeric excess). By…

Significance The discovery of numerous exoplanet systems containing diverse populations of planets orbiting very close to their host stars challenges the planet formation theories based on the solar system. Here, we focus on the planets with radii of 2–4 R ⊕ , whose compositions are debated. They are thought to be either gas dwarfs consisting of rocky cores embedded in H 2 -rich gas envelopes or water worlds containing significant amounts of H 2 O-dominated fluid/ice in addition to rock and gas. We argue that these planets are water worlds.

Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation…

Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype ("stemness") on the immunological properties of cancer has not been systematically explored. Using gene-expression-based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We found pervasive negative associations between cancer stemness and anticancer immunity. This occurred despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviruses and type I IFN signaling, and increased expression of multiple therapeutically accessible immunosuppressive pathways. Thus, stemness is not only a fundamental process in cancer progression but may provide a mechanistic link between antigenicity, intratumoral heterogeneity, and…

Agricultural landscape homogenization has detrimental effects on biodiversity and key ecosystem services. Increasing agricultural landscape heterogeneity by increasing seminatural cover can help to mitigate biodiversity loss. However, the amount of seminatural cover is generally low and difficult to increase in many intensively managed agricultural landscapes. We hypothesized that increasing the heterogeneity of the crop mosaic itself (hereafter "crop heterogeneity") can also have positive effects on biodiversity. In 8 contrasting regions of Europe and North America, we selected 435 landscapes along independent gradients of crop diversity and mean field size. Within each landscape, we selected 3 sampling sites in 1, 2, or 3 crop types. We sampled 7 taxa (plants, bees, butterflies, hoverflies, carabids, spiders, and birds) and calculated a synthetic index of multitrophic diversity at the landscape level. Increasing crop heterogeneity was more beneficial for multitrophic diversity than increasing seminatural cover. For instance, the effect of decreasing mean field size from 5 to 2.8…

Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous sequences. Here, we used 2 approaches, global inclusion of modified nucleotides and rational sequence design of exogenously delivered constructs, to understand the role of mRNA secondary structure independent from codon usage. Unexpectedly, highly expressed mRNAs contained a highly structured coding sequence (CDS). Modified nucleotides that stabilize mRNA secondary structure enabled high expression across a wide variety of primary sequences. Using a set of eGFP mRNAs with independently altered codon usage and CDS structure, we find that the structure of the CDS regulates protein expression through changes in functional mRNA half-life (i.e., mRNA being actively translated). This work highlights an underappreciated role of mRNA secondary structure in the regulation of mRNA stability.

Significance Atmospheric ammonia plays important roles in fine particle pollution, acid rain, and nitrogen deposition. China, known as the world’s top emitter of gaseous ammonia, plans to control ammonia emissions to mitigate the haze pollution that has recently emerged. However, the complex side effects are still unclear. By integrating a chemical transport model, nationwide measurements, and a sophisticated ammonia emission model, we find that ammonia emission control would significantly aggravate acid rain pollution, thereby offsetting the benefit from reduced fine particle pollution and nitrogen deposition. Our work suggests that region-specific ammonia-control strategies provide a more rational and effective way to achieve the dual benefits of protecting human and ecosystem health in China.

ABSTRACT The protracted development of structural and functional brain connectivity within distributed association networks coincides with improvements in higher-order cognitive processes such as working memory. However, it remains unclear how white matter architecture develops during youth to directly support coordinated neural activity. Here, we characterize the development of structure-function coupling using diffusion-weighted imaging and n -back fMRI data in a sample of 727 individuals (ages 8-23 years). We found that spatial variability in structure-function coupling aligned with cortical hierarchies of functional specialization and evolutionary expansion. Furthermore, hierarchy-dependent age effects on structure-function coupling localized to transmodal cortex in both cross-sectional data and a subset of participants with longitudinal data ( n =294). Moreover, structure-function coupling in rostrolateral prefrontal cortex was associated with executive performance, and partially mediated age-related improvements in executive function. Together, these findings delineate a…

Abstract Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single nucleus RNA sequencing (snRNAseq) on cryopreserved human diabetic kidney samples to generate 23,980 single nucleus transcriptomes from three control and three early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side by side comparison demonstrated cell-type-specific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic loop of Henle, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na-K + -ATPase, WNK1 , mineralocorticoid receptor and NEDD4L expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal…

The numerical solution of partial differential equations (PDEs) is challenging because of the need to resolve spatiotemporal features over wide length- and timescales. Often, it is computationally intractable to resolve the finest features in the solution. The only recourse is to use approximate coarse-grained representations, which aim to accurately represent long-wavelength dynamics while properly accounting for unresolved small-scale physics. Deriving such coarse-grained equations is notoriously difficult and often ad hoc. Here we introduce data-driven discretization, a method for learning optimized approximations to PDEs based on actual solutions to the known underlying equations. Our approach uses neural networks to estimate spatial derivatives, which are optimized end to end to best satisfy the equations on a low-resolution grid. The resulting numerical methods are remarkably accurate, allowing us to integrate in time a collection of nonlinear equations in 1 spatial dimension at resolutions 4× to 8× coarser than is possible with standard finite-difference methods.

This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. N-degrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as "N-degron pathways" and "C-degron pathways." The former notation replaces the earlier name "N-end rule pathways." The term "N-end rule" was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include…

The human respiratory tract hosts a diverse community of cocirculating viruses that are responsible for acute respiratory infections. This shared niche provides the opportunity for virus-virus interactions which have the potential to affect individual infection risks and in turn influence dynamics of infection at population scales. However, quantitative evidence for interactions has lacked suitable data and appropriate analytical tools. Here, we expose and quantify interactions among respiratory viruses using bespoke analyses of infection time series at the population scale and coinfections at the individual host scale. We analyzed diagnostic data from 44,230 cases of respiratory illness that were tested for 11 taxonomically broad groups of respiratory viruses over 9 y. Key to our analyses was accounting for alternative drivers of correlated infection frequency, such as age and seasonal dependencies in infection risk, allowing us to obtain strong support for the existence of negative interactions between influenza and noninfluenza viruses and positive interactions among noninfluenza…

Butterflies and moths (Lepidoptera) are one of the major superradiations of insects, comprising nearly 160,000 described extant species. As herbivores, pollinators, and prey, Lepidoptera play a fundamental role in almost every terrestrial ecosystem. Lepidoptera are also indicators of environmental change and serve as models for research on mimicry and genetics. They have been central to the development of coevolutionary hypotheses, such as butterflies with flowering plants and moths' evolutionary arms race with echolocating bats. However, these hypotheses have not been rigorously tested, because a robust lepidopteran phylogeny and timing of evolutionary novelties are lacking. To address these issues, we inferred a comprehensive phylogeny of Lepidoptera, using the largest dataset assembled for the order (2,098 orthologous protein-coding genes from transcriptomes of 186 species, representing nearly all superfamilies), and dated it with carefully evaluated synapomorphy-based fossils. The oldest members of the Lepidoptera crown group appeared in the Late Carboniferous (∼300 Ma) and fed…

Antimicrobial efficacy, which is central to many aspects of medicine, is being rapidly eroded by bacterial resistance. Since new resistance can be induced by antimicrobial action, highly lethal agents that rapidly reduce bacterial burden during infection should help restrict the emergence of resistance. To improve lethal activity, recent work has focused on toxic reactive oxygen species (ROS) as part of the bactericidal activity of diverse antimicrobials. We report that when Escherichia coli was subjected to antimicrobial stress and the stressor was subsequently removed, both ROS accumulation and cell death continued to occur. Blocking ROS accumulation by exogenous mitigating agents slowed or inhibited poststressor death. Similar results were obtained with a temperature-sensitive mutational inhibition of DNA replication. Thus, bacteria exposed to lethal stressors may not die during treatment, as has long been thought; instead, death can occur after plating on drug-free agar due to poststress ROS-mediated toxicity. Examples are described in which ( i ) primary stress-mediated damage…

Local adaptations can determine the potential of populations to respond to environmental changes, yet adaptive genetic variation is commonly ignored in models forecasting species vulnerability and biogeographical shifts under future climate change. Here we integrate genomic and ecological modeling approaches to identify genetic adaptations associated with climate in two cryptic forest bats. We then incorporate this information directly into forecasts of range changes under future climate change and assessment of population persistence through the spread of climate-adaptive genetic variation (evolutionary rescue potential). Considering climate-adaptive potential reduced range loss projections, suggesting that failure to account for intraspecific variability can result in overestimation of future losses. On the other hand, range overlap between species was projected to increase, indicating that interspecific competition is likely to play an important role in limiting species' future ranges. We show that although evolutionary rescue is possible, it depends on a population's adaptive…

Deployment of autonomous vehicles on public roads promises increased efficiency and safety. It requires understanding the intent of human drivers and adapting to their driving styles. Autonomous vehicles must also behave in safe and predictable ways without requiring explicit communication. We integrate tools from social psychology into autonomous-vehicle decision making to quantify and predict the social behavior of other drivers and to behave in a socially compliant way. A key component is Social Value Orientation (SVO), which quantifies the degree of an agent's selfishness or altruism, allowing us to better predict how the agent will interact and cooperate with others. We model interactions between agents as a best-response game wherein each agent negotiates to maximize their own utility. We solve the dynamic game by finding the Nash equilibrium, yielding an online method of predicting multiagent interactions given their SVOs. This approach allows autonomous vehicles to observe human drivers, estimate their SVOs, and generate an autonomous control policy in real time. We…

antigen marker combination, we isolated highly tumorigenic breast cancer cells residing stably-both in vitro and in vivo-in an intermediate phenotypic state and coexpressing both epithelial (E) and mesenchymal (M) markers. We demonstrate that tumorigenicity depends on individual cells residing in this E/M hybrid state and cannot be phenocopied by mixing two cell populations that reside stably at the two ends of the spectrum, i.e., in the E and in the M state. Hence, residence in a specific intermediate state along the E-M spectrum rather than phenotypic plasticity appears critical to the expression of tumor-initiating capacity. Acquisition of this E/M hybrid state is facilitated by the differential expression of EMT-inducing transcription factors (EMT-TFs) and is accompanied by the expression of adult stem cell programs, notably, active canonical Wnt signaling. Furthermore, transition from the highly tumorigenic E/M state to a fully mesenchymal phenotype, achieved by constitutive ectopic expression of Zeb1, is sufficient to drive cells out of the E/M hybrid state into a highly…

Climate change is increasing fire activity in the western United States, which has the potential to accelerate climate-induced shifts in vegetation communities. Wildfire can catalyze vegetation change by killing adult trees that could otherwise persist in climate conditions no longer suitable for seedling establishment and survival. Recently documented declines in postfire conifer recruitment in the western United States may be an example of this phenomenon. However, the role of annual climate variation and its interaction with long-term climate trends in driving these changes is poorly resolved. Here we examine the relationship between annual climate and postfire tree regeneration of two dominant, low-elevation conifers (ponderosa pine and Douglas-fir) using annually resolved establishment dates from 2,935 destructively sampled trees from 33 wildfires across four regions in the western United States. We show that regeneration had a nonlinear response to annual climate conditions, with distinct thresholds for recruitment based on vapor pressure deficit, soil moisture, and maximum…

Significance The root microbiome composition is largely determined by the soil inoculum, with a distinct contribution from the host. Yet, the molecular mechanisms with which the host influences its rhizobiome are only beginning to be discovered. Using a hydroponics-based synthetic community approach, we probe the impact of root-exuded specialized metabolites in shaping the root microbiome. We uncover a role for coumarins in structuring the rhizobiome, particularly by limiting the growth of a Pseudomonas strain, for which we propose a mechanism of action. Our findings support the exciting possibility that root-exuded coumarins form a part of the plant’s adaptive response to iron deficiency that goes beyond iron mobilization to modulate the rhizobiome, and highlights avenues towards engineering the rhizosphere for plant health. Abstract The factors that dictate the composition of the root microbiome and its role in plant fitness has been a long-standing question. Recent work has highlighted a major contribution of the soil inoculum in determining the composition of the root…

The white matter architecture of the brain imparts a distinct signature on neuronal coactivation patterns. Interregional projections promote synchrony among distant neuronal populations, giving rise to richly patterned functional networks. A variety of statistical, communication, and biophysical models have been proposed to study the relationship between brain structure and function, but the link is not yet known. In the present report we seek to relate the structural and functional connection profiles of individual brain areas. We apply a simple multilinear model that incorporates information about spatial proximity, routing, and diffusion between brain regions to predict their functional connectivity. We find that structure-function relationships vary markedly across the neocortex. Structure and function correspond closely in unimodal, primary sensory, and motor regions, but diverge in transmodal cortex, particularly the default mode and salience networks. The divergence between structure and function systematically follows functional and cytoarchitectonic hierarchies. Altogether,…

The ability to regulate behavior in service of long-term goals is a widely studied psychological construct known as self-regulation. This wide interest is in part due to the putative relations between self-regulation and a range of real-world behaviors. Self-regulation is generally viewed as a trait, and individual differences are quantified using a diverse set of measures, including self-report surveys and behavioral tasks. Accurate characterization of individual differences requires measurement reliability, a property frequently characterized in self-report surveys, but rarely assessed in behavioral tasks. We remedy this gap by ( i ) providing a comprehensive literature review on an extensive set of self-regulation measures and ( ii ) empirically evaluating test–retest reliability of this battery in a new sample. We find that dependent variables (DVs) from self-report surveys of self-regulation have high test–retest reliability, while DVs derived from behavioral tasks do not. This holds both in the literature and in our sample, although the test–retest reliability estimates in the…

In this study, we used large-scale representative panel data to disentangle the between-person and within-person relations linking adolescent social media use and well-being. We found that social media use is not, in and of itself, a strong predictor of life satisfaction across the adolescent population. Instead, social media effects are nuanced, small at best, reciprocal over time, gender specific, and contingent on analytic methods.

Collective phase transitions, including phase separation and gelation of multivalent protein and RNA molecules appears to underlie the biogenesis of biomolecular condensates such as membraneless organelles. In vivo, these condensates encompass hundreds of distinct types of molecules that are often organized into multi-layered structures supporting the differential partitioning of molecules into distinct regions with distinct material properties. The interplay between driven (active) versus spontaneous (passive) processes that are required for enabling the formation of condensates with coexisting layers of distinct material properties remains unclear. Here, we investigate the role of spontaneous driving forces as determinants of protein-RNA condensates with complex morphologies and distinct material properties. Through the use of systematic in vitro experiments and simulations based on coarse-grained models we find that that the collective interactions among the simplest, biologically relevant proteins and archetypal RNA molecules are sufficient for driving the spontaneous emergence…

Optical edge detection is a useful method for characterizing boundaries, which is also in the forefront of image processing for object detection. As the field of metamaterials and metasurface is growing fast in an effort to miniaturize optical devices at unprecedented scales, experimental realization of optical edge detection with metamaterials remains a challenge and lags behind theoretical proposals. Here, we propose a mechanism of edge detection based on a Pancharatnam-Berry-phase metasurface. We experimentally demonstrated broadband edge detection using designed dielectric metasurfaces with high optical efficiency. The metasurfaces were fabricated by scanning a focused laser beam inside glass substrate and can be easily integrated with traditional optical components. The proposed edge-detection mechanism may find important applications in image processing, high-contrast microscopy, and real-time object detection on compact optical platforms such as mobile phones and smart cameras.

We report the derivation of 30 patient-derived organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical of pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic, and underscores the importance of personalized approaches for effective cancer treatment. The PRMT5 inhibitor EZP015556, shown to target MTAP (a gene commonly lost in pancreatic cancer)-negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP-positive tumors. Taken together, the work presented here provides a platform to identify novel therapeutics to target pancreatic tumor cells using PDOs.

What accounts for the prevalence of negative news content? One answer may lie in the tendency for humans to react more strongly to negative than positive information. "Negativity biases" in human cognition and behavior are well documented, but existing research is based on small Anglo-American samples and stimuli that are only tangentially related to our political world. This work accordingly reports results from a 17-country, 6-continent experimental study examining psychophysiological reactions to real video news content. Results offer the most comprehensive cross-national demonstration of negativity biases to date, but they also serve to highlight considerable individual-level variation in responsiveness to news content. Insofar as our results make clear the pervasiveness of negativity biases on average, they help account for the tendency for audience-seeking news around the world to be predominantly negative. Insofar as our results highlight individual-level variation, however, they highlight the potential for more positive content, and suggest that there may be reason to…

Analysis of ‘big data’ frequently involves statistical comparison of millions of competing hypotheses to discover hidden processes underlying observed patterns of data, for example in the search for genetic determinants of disease in genome-wide association studies (GWAS). Controlling the family-wise error rate (FWER) is considered the strongest protection against false positives, but makes it difficult to reach the multiple testing-corrected significance threshold. Here I introduce the harmonic mean p -value (HMP) which controls the FWER while greatly improving statistical power by combining dependent tests using generalized central limit theorem. I show that the HMP easily combines information to detect statistically significant signals among groups of individually nonsignificant hypotheses in examples of a human GWAS for neuroticism and a joint human-pathogen GWAS for hepatitis C viral load. The HMP simultaneously tests all combinations of hypotheses, allowing the smallest groups of hypotheses that retain significance to be sought. The power of the HMP to detect significant…

The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRAS G12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These…

We present data from a nationally representative 2017 survey of American adults. For heterosexual couples in the United States, meeting online has become the most popular way couples meet, eclipsing meeting through friends for the first time around 2013. Moreover, among the couples who meet online, the proportion who have met through the mediation of third persons has declined over time. We find that Internet meeting is displacing the roles that family and friends once played in bringing couples together.

Northern hemisphere evergreen forests assimilate a significant fraction of global atmospheric CO 2 but monitoring large-scale changes in gross primary production (GPP) in these systems is challenging. Recent advances in remote sensing allow the detection of solar-induced chlorophyll fluorescence (SIF) emission from vegetation, which has been empirically linked to GPP at large spatial scales. This is particularly important in evergreen forests, where traditional remote-sensing techniques and terrestrial biosphere models fail to reproduce the seasonality of GPP. Here, we examined the mechanistic relationship between SIF retrieved from a canopy spectrometer system and GPP at a winter-dormant conifer forest, which has little seasonal variation in canopy structure, needle chlorophyll content, and absorbed light. Both SIF and GPP track each other in a consistent, dynamic fashion in response to environmental conditions. SIF and GPP are well correlated ( R 2 = 0.62–0.92) with an invariant slope over hourly to weekly timescales. Large seasonal variations in SIF yield capture changes in…

Soft robotics represents a new set of technologies aimed at operating in natural environments and near the human body. To interact with their environment, soft robots require artificial muscles to actuate movement. These artificial muscles need to be as strong, fast, and robust as their natural counterparts. Dielectric elastomer actuators (DEAs) are promising soft transducers, but typically exhibit low output forces and low energy densities when used without rigid supports. Here, we report a soft composite DEA made of strain-stiffening elastomers and carbon nanotube electrodes, which demonstrates a peak energy density of 19.8 J/kg. The result is close to the upper limit for natural muscle (0.4-40 J/kg), making these DEAs the highest-performance electrically driven soft artificial muscles demonstrated to date. To obtain high forces and displacements, we used low-density, ultrathin carbon nanotube electrodes which can sustain applied electric fields upward of 100 V/μm without suffering from dielectric breakdown. Potential applications include prosthetics, surgical robots, and wearable…

= 27) were engaged in music listening. We orally administrated to each participant a dopamine precursor (levodopa), a dopamine antagonist (risperidone), and a placebo (lactose) in three different sessions. We demonstrate that levodopa and risperidone led to opposite effects in measures of musical pleasure and motivation: while the dopamine precursor levodopa, compared with placebo, increased the hedonic experience and music-related motivational responses, risperidone led to a reduction of both. This study shows a causal role of dopamine in musical pleasure and indicates that dopaminergic transmission might play different or additive roles than the ones postulated in affective processing so far, particularly in abstract cognitive activities.

Learning and using an additional language is shown to have an impact on the structure and function of the brain, including in regions involved in cognitive control and the connections between them. However, the available evidence remains variable in terms of the localization, extent, and trajectory of these effects. Variability likely stems from the fact that bilingualism has been routinely operationalized as a categorical variable (bilingual/monolingual), whereas it is a complex and dynamic experience with a number of potentially deterministic factors affecting neural plasticity. Here we present a study investigating the combined effects of experience-based factors (EBFs) in bilingual language use on brain structure and functional connectivity. EBFs include an array of measures of everyday usage of a second language in different types of immersive settings (e.g., amount of use in social settings). Analyses reveal specific adaptations in the brain, both structural and functional, correlated to individual EBFs and their combined effects. Taken together, the data show that the brain…

Significance Many applications in engineering require stretchable materials that dissipate little energy during normal operation of cyclic loads (low hysteresis), but dissipate much energy to resist rupture (high toughness), and survive prolonged cyclic loads (fatigue resistant). However, existing stretchable materials cannot meet these requirements simultaneously. Here we present a principle to achieve this goal, and demonstrate the principle by a composite of two stretchable materials of low hysteresis, with large modulus contrast and strong adhesion. The composite retains the low hysteresis, but is much tougher and more fatigue resistant than the constituents. The same principle applies to elastomers, gels, and elastomer–gel hybrids. This class of materials provides opportunities to create high-cycle and low-dissipation soft robots and soft human–machine interfaces.

The alpha rhythm is the longest-studied brain oscillation and has been theorized to play a key role in cognition. Still, its physiology is poorly understood. In this study, we used microelectrodes and macroelectrodes in surgical epilepsy patients to measure the intracortical and thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in both visual and somatosensory cortex propagates from higher-order to lower-order areas. In posterior cortex, alpha propagates from higher-order anterosuperior areas toward the occipital pole, whereas alpha in somatosensory cortex propagates from associative regions toward primary cortex. Several analyses suggest that this cortical alpha leads pulvinar alpha, complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortical layers. Together, these results suggest that the alpha rhythm likely reflects short-range supragranular feedback, which propagates from higher- to lower-order cortex and cortex to thalamus. These physiological insights suggest…

Significance Electric lighting has fundamentally altered how the human circadian clock synchronizes to the day/night cycle. Exposure to light after dusk is pervasive in the modern world. We examined group-level sensitivity of the circadian system to evening light and the degree to which sensitivity varies between individuals. We found that, on average, humans are highly sensitive to evening light. Specifically, 50% suppression of melatonin occurred at <30 lux, which is comparable to or lower than typical indoor lighting used at night, as well as light produced by electronic devices. Significantly, there was a >50-fold difference in sensitivity to evening light across individuals. Interindividual differences in light sensitivity may explain differential vulnerability to circadian disruption and subsequent impact on human health.

Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass,…

Atmospheric methane plays a major role in controlling climate, yet contemporary methane trends (1982–2017) have defied explanation with numerous, often conflicting, hypotheses proposed in the literature. Specifically, atmospheric observations of methane from 1982 to 2017 have exhibited periods of both increasing concentrations (from 1982 to 2000 and from 2007 to 2017) and stabilization (from 2000 to 2007). Explanations for the increases and stabilization have invoked changes in tropical wetlands, livestock, fossil fuels, biomass burning, and the methane sink. Contradictions in these hypotheses arise because our current observational network cannot unambiguously link recent methane variations to specific sources. This raises some fundamental questions: ( i ) What do we know about sources, sinks, and underlying processes driving observed trends in atmospheric methane? ( ii ) How will global methane respond to changes in anthropogenic emissions? And ( iii ), What future observations could help resolve changes in the methane budget? To address these questions, we discuss potential…

Shape-morphing structured materials have the ability to transform a range of applications. However, their design and fabrication remain challenging due to the difficulty of controlling the underlying metric tensor in space and time. Here, we exploit a combination of multiple materials, geometry, and 4-dimensional (4D) printing to create structured heterogeneous lattices that overcome this problem. Our printable inks are composed of elastomeric matrices with tunable cross-link density and anisotropic filler that enable precise control of their elastic modulus ( E ) and coefficient of thermal expansion ( α ) . The inks are printed in the form of lattices with curved bilayer ribs whose geometry is individually programmed to achieve local control over the metric tensor. For independent control of extrinsic curvature, we created multiplexed bilayer ribs composed of 4 materials, which enables us to encode a wide range of 3-dimensional (3D) shape changes in response to temperature. As exemplars, we designed and printed planar lattices that morph into frequency-shifting antennae and a human…

Global power production increasingly relies on wind farms to supply low-carbon energy. The recent Intergovernmental Panel on Climate Change (IPCC) Special Report predicted that renewable energy production must leap from [Formula: see text] of the global energy mix in 2018 to [Formula: see text] by 2050 to keep global temperatures from rising 1.5°C above preindustrial levels. This increase requires reliable, low-cost energy production. However, wind turbines are often placed in close proximity within wind farms due to land and transmission line constraints, which results in wind farm efficiency degradation of up to [Formula: see text] for wind directions aligned with columns of turbines. To increase wind farm power production, we developed a wake steering control scheme. This approach maximizes the power of a wind farm through yaw misalignment that deflects wakes away from downstream turbines. Optimization was performed with site-specific analytic gradient ascent relying on historical operational data. The protocol was tested in an operational wind farm in Alberta, Canada, resulting…

RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. Furthermore, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of ALS as well as other inflammatory and neurodegenerative diseases. Importantly, unique allosteric small-molecule inhibitors of RIPK1 that offer high selectivity have been developed. These molecules can penetrate the blood-brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer's disease, ALS, and multiple sclerosis as well as acute neurological diseases such as stroke and traumatic brain injuries. We discuss the current understanding of RIPK1 regulatory mechanisms and emerging evidence for the pathological roles of RIPK1 in human diseases, especially in the context of the central…

Significance More intense extreme events are projected under future climate change. However, the impacts of climate extremes on future air quality and associated health implications are not well recognized and are rarely quantified in China, with an enormous health burden from air pollution. Here, we estimate the climate-driven air pollution mortality in China and find that future climate change is likely to exacerbate air pollution mortality, largely influenced by the more intense extreme events such as stagnation events and heat waves. Our analysis provides quantitative assessments and insights regarding the links between climate extremes, future air quality, and public health, suggesting that extreme weather events may be an important mechanism by which climate change will affect air quality, and especially fine particulate matter.

The human visual system is an intricate network of brain regions that enables us to recognize the world around us. Despite its abundant lateral and feedback connections, object processing is commonly viewed and studied as a feedforward process. Here, we measure and model the rapid representational dynamics across multiple stages of the human ventral stream using time-resolved brain imaging and deep learning. We observe substantial representational transformations during the first 300 ms of processing within and across ventral-stream regions. Categorical divisions emerge in sequence, cascading forward and in reverse across regions, and Granger causality analysis suggests bidirectional information flow between regions. Finally, recurrent deep neural network models clearly outperform parameter-matched feedforward models in terms of their ability to capture the multiregion cortical dynamics. Targeted virtual cooling experiments on the recurrent deep network models further substantiate the importance of their lateral and top-down connections. These results establish that recurrent models…

Significance Although immune checkpoint blockade (ICB) along with nab-paclitaxel has increased progression-free survival in triple-negative breast cancer patients, a large fraction of metastatic breast cancer (mBC) patients do not benefit from ICBs. The presence of a fibrotic tumor microenvironment can suppress the immune response to cancer. Here we found fibrosis and immunosuppression in both primary and metastatic breast cancer lesions. We show that targeting CXCR4/CXCL12 signaling, using plerixafor, an Food and Drug Administration-approved drug, reduces fibrosis, alleviates immunosuppression, and significantly enhances the efficacy of immune checkpoint blockers in preclinical models of mBC. Our findings provide a deeper understanding of mechanisms by which desmoplasia promotes immunosuppression in mBC and suggest a clinically translatable approach that can be combined with immunotherapy in patients to enhance therapeutic response.

Abstract Direct coupling analysis (DCA) for protein folding has made very good progress, but it is not effective for proteins that lack many sequence homologs, even coupled with time-consuming folding simulation. We show that we can accurately predict the distance matrix of a protein by deep learning, even for proteins with ∼60 sequence homologs. Using only the geometric constraints given by the resulting distance matrix we may construct 3D models without involving any folding simulation. Our method successfully folded 21 of the 37 CASP12 hard targets with a median family size of 58 effective sequence homologs within 4 hours on a Linux computer of 20 CPUs. In contrast, DCA cannot fold any of these hard targets in the absence of folding simulation, and the best CASP12 group folded only 11 of them by integrating DCA-predicted contacts into complex, fragment-based folding simulation. Rigorous experimental validation in CASP13 shows that our distance-based folding server successfully folded 17 of 32 hard targets (with a median family size of 36 sequence homologs) and obtained 70%…

The sunflower family, Asteraceae, comprises 10% of all flowering plant species and displays an incredible diversity of form. Asteraceae are clearly monophyletic, yet resolving phylogenetic relationships within the family has proven difficult, hindering our ability to understand its origin and diversification. Recent molecular clock dating has suggested a Cretaceous origin, but the lack of deep sampling of many genes and representative taxa from across the family has impeded the resolution of migration routes and diversifications that led to its global distribution and tremendous diversity. Here we use genomic data from 256 terminals to estimate evolutionary relationships, timing of diversification(s), and biogeographic patterns. Our study places the origin of Asteraceae at ∼83 MYA in the late Cretaceous and reveals that the family underwent a series of explosive radiations during the Eocene which were accompanied by accelerations in diversification rates. The lineages that gave rise to nearly 95% of extant species originated and began diversifying during the middle Eocene,…

Avian diversification has been influenced by global climate change, plate tectonic movements, and mass extinction events. However, the impact of these factors on the diversification of the hyperdiverse perching birds (passerines) is unclear because family level relationships are unresolved and the timing of splitting events among lineages is uncertain. We analyzed DNA data from 4,060 nuclear loci and 137 passerine families using concatenation and coalescent approaches to infer a comprehensive phylogenetic hypothesis that clarifies relationships among all passerine families. Then, we calibrated this phylogeny using 13 fossils to examine the effects of different events in Earth history on the timing and rate of passerine diversification. Our analyses reconcile passerine diversification with the fossil and geological records; suggest that passerines originated on the Australian landmass ∼47 Ma; and show that subsequent dispersal and diversification of passerines was affected by a number of climatological and geological events, such as Oligocene glaciation and inundation of the New…

Increasing plant diversity can increase ecosystem functioning, stability, and services in both natural and managed grasslands, but the effects of herbivore diversity, and especially of livestock diversity, remain underexplored. Given that managed grazing is the most extensive land use worldwide, and that land managers can readily change livestock diversity, we experimentally tested how livestock diversification (sheep, cattle, or both) influenced multidiversity (the diversity of plants, insects, soil microbes, and nematodes) and ecosystem multifunctionality (including plant biomass production, plant leaf N and P, above-ground insect abundance, nutrient cycling, soil C stocks, water regulation, and plant-microbe symbiosis) in the world's largest remaining grassland. We also considered the potential dependence of ecosystem multifunctionality on multidiversity. We found that livestock diversification substantially increased ecosystem multifunctionality by increasing multidiversity. The link between multidiversity and ecosystem multifunctionality was always stronger than the link…

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case–control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case–control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case–control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three…

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median…

Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS G12C –SOS1, SOS1, and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the…

Biodiversity encompasses multiple attributes such as the richness and abundance of species (taxonomic diversity), the presence of different evolutionary lineages (phylogenetic diversity), and the variety of growth forms and resource use strategies (functional diversity). These biodiversity attributes do not necessarily relate to each other and may have contrasting effects on ecosystem functioning. However, how they simultaneously influence the provision of multiple ecosystem functions related to carbon, nitrogen, and phosphorus cycling (multifunctionality) remains unknown. We evaluated the effects of the taxonomic, phylogenetic, and functional attributes of dominant (mass ratio effects) and subordinate (richness effect) plant species on the multifunctionality of 123 drylands from six continents. Our results highlight the importance of the phylogenetic and functional attributes of subordinate species as key drivers of multifunctionality. In addition to a higher taxonomic richness, we found that simultaneously increasing the richness of early diverging lineages and the functional…

The gender imbalance in science, technology, engineering, and math (STEM) fields has remained constant for decades and increases the farther up the STEM career pipeline one looks. Why does the underrepresentation of women endure? This study investigated the role of parenthood as a mechanism of gender-differentiated attrition from STEM employment. Using a nationally representative 8-year longitudinal sample of US STEM professionals, we examined the career trajectories of new parents after the birth or adoption of their first child. We found substantial attrition of new mothers: 43% of women leave full-time STEM employment after their first child. New mothers are more likely than new fathers to leave STEM, to switch to part-time work, and to exit the labor force. These gender differences hold irrespective of variation by discipline, race, and other demographic factors. However, parenthood is not just a "mother's problem"; 23% of new fathers also leave STEM after their first child. Suggesting the difficulty of combining STEM work with caregiving responsibilities generally, new parents…

Much of life's complexity depends upon contacts between proteins with precise affinity and specificity. The successful application of engineered proteins often depends on high-stability binding to their target. In recent years, various approaches have enabled proteins to form irreversible covalent interactions with protein targets. However, the rate of such reactions is a major limitation to their use. Infinite affinity refers to the ideal where such covalent interaction occurs at the diffusion limit. Prototypes of infinite affinity pairs have been achieved using nonnatural reactive groups. After library-based evolution and rational design, here we establish a peptide-protein pair composed of the regular 20 amino acids that link together through an amide bond at a rate approaching the diffusion limit. Reaction occurs in a few minutes with both partners at low nanomolar concentration. Stopped flow fluorimetry illuminated the conformational dynamics involved in docking and reaction. Hydrogen-deuterium exchange mass spectrometry gave insight into the conformational flexibility of this…

Human betacoronaviruses OC43 and HKU1 are endemic respiratory pathogens and, while related, originated from independent zoonotic introductions. OC43 is in fact a host-range variant of the species Betacoronavirus-1 , and more closely related to bovine coronavirus (BCoV)—its presumptive ancestor—and porcine hemagglutinating encephalomyelitis virus (PHEV). The β1-coronaviruses (β1CoVs) and HKU1 employ glycan-based receptors carrying 9- O -acetylated sialic acid (9- O -Ac-Sia). Receptor binding is mediated by spike protein S, the main determinant of coronavirus host specificity. For BCoV, a crystal structure for the receptor-binding domain S1 A is available and for HKU1 a cryoelectron microscopy structure of the complete S ectodomain. However, the location of the receptor-binding site (RBS), arguably the single-most important piece of information, is unknown. Here we solved the 3.0-Å crystal structure of PHEV S1 A . We then took a comparative structural analysis approach to map the β1CoV S RBS, using the general design of 9- O -Ac-Sia-binding sites as blueprint, backed-up by automated…

Lithium is the most attractive anode material for high-energy density rechargeable batteries, but its cycling is plagued by morphological irreversibility and dendrite growth that arise in part from its heterogeneous "native" solid electrolyte interphase (SEI). Enriching the SEI with lithium fluoride (LiF) has recently gained popularity to improve Li cyclability. However, the intrinsic function of LiF-whether chemical, mechanical, or kinetic in nature-remains unknown. Herein, we investigated the stability of LiF in model LiF-enriched SEIs that are either artificially preformed or derived from fluorinated electrolytes, and thus, the effect of the LiF source on Li electrode behavior. We discovered that the mechanical integrity of LiF is easily compromised during plating, making it intrinsically unable to protect Li. The ensuing in situ repair of the interface by electrolyte, either regenerating LiF or forming an extra elastomeric "outer layer," is identified as the more critical determinant of Li electrode performance. Our findings present an updated and dynamic picture of the…

The human retinal pigment epithelium (RPE) and choroid are complex tissues that provide crucial support to the retina. Disease affecting either of these supportive tissues can lead to irreversible blindness in the setting of age-related macular degeneration. In this study, single-cell RNA sequencing was performed on macular and peripheral regions of RPE-choroid from 7 human donor eyes in 2 independent experiments. In the first experiment, total RPE/choroid preparations were evaluated and expression profiles specific to RPE and major choroidal cell populations were identified. As choroidal endothelial cells represent a minority of the total RPE/choroidal cell population but are strongly implicated in age-related macular degeneration (AMD) pathogenesis, a second single-cell RNA-sequencing experiment was performed using endothelial cells enriched by magnetic separation. In this second study, we identified gene expression signatures along the choroidal vascular tree, classifying the transcriptome of human choriocapillaris, arterial, and venous endothelial cells. We found that the…