The 100 most-cited articles in Science, 2019

Health systems rely on commercial prediction algorithms to identify and help patients with complex health needs. We show that a widely used algorithm, typical of this industry-wide approach and affecting millions of patients, exhibits significant racial bias: At a given risk score, Black patients are considerably sicker than White patients, as evidenced by signs of uncontrolled illnesses. Remedying this disparity would increase the percentage of Black patients receiving additional help from 17.7 to 46.5%. The bias arises because the algorithm predicts health care costs rather than illness, but unequal access to care means that we spend less money caring for Black patients than for White patients. Thus, despite health care cost appearing to be an effective proxy for health by some measures of predictive accuracy, large racial biases arise. We suggest that the choice of convenient, seemingly effective proxies for ground truth can be an important source of algorithmic bias in many contexts.

BACKGROUND As the world continues to transition toward carbon emissions–free energy technologies, there remains a need to also reduce the carbon emissions of the chemical production industry. Today many of the world’s chemicals are produced from fossil fuel–derived feedstocks. Electrochemical conversion of carbon dioxide (CO 2 ) into chemical feedstocks offers a way to turn waste emissions into valuable products, closing the carbon loop. When coupled to renewable sources of electricity, these products can be made with a net negative carbon emissions footprint, helping to sequester CO 2 into usable goods. Research and development into electrocatalytic materials for CO 2 reduction has intensified in recent years, with advances in selectivity, efficiency, and reaction rate progressing toward practical implementation. A variety of chemical products can be made from CO 2 , such as alcohols, oxygenates, synthesis gas (syngas), and olefins—staples in the global chemical industry. Because these products are produced at substantial scale, a switch to renewably powered production could result…

The human impact on life on Earth has increased sharply since the 1970s, driven by the demands of a growing population with rising average per capita income. Nature is currently supplying more materials than ever before, but this has come at the high cost of unprecedented global declines in the extent and integrity of ecosystems, distinctness of local ecological communities, abundance and number of wild species, and the number of local domesticated varieties. Such changes reduce vital benefits that people receive from nature and threaten the quality of life of future generations. Both the benefits of an expanding economy and the costs of reducing nature's benefits are unequally distributed. The fabric of life on which we all depend-nature and its contributions to people-is unravelling rapidly. Despite the severity of the threats and lack of enough progress in tackling them to date, opportunities exist to change future trajectories through transformative action. Such action must begin immediately, however, and address the root economic, social, and technological causes of nature's…

Abstract The spatial organization of cells in tissue has a profound influence on their function, yet a high-throughput, genome-wide readout of gene expression with cellular resolution is lacking. Here, we introduce Slide-seq, a highly scalable method that enables facile generation of large volumes of unbiased spatial transcriptomes with 10 µm spatial resolution, comparable to the size of individual cells. In Slide-seq, RNA is transferred from freshly frozen tissue sections onto a surface covered in DNA-barcoded beads with known positions, allowing the spatial locations of the RNA to be inferred by sequencing. To demonstrate Slide-seq’s utility, we localized cell types identified by large-scale scRNA-seq datasets within the cerebellum and hippocampus. We next systematically characterized spatial gene expression patterns in the Purkinje layer of mouse cerebellum, identifying new axes of variation across Purkinje cell compartments. Finally, we used Slide-seq to define the temporal evolution of cell-type-specific responses in a mouse model of traumatic brain injury. Slide-seq will…

Materials with flat electronic bands often exhibit exotic quantum phenomena owing to strong correlations. An isolated low-energy flat band can be induced in bilayer graphene by simply rotating the layers by 1.1°, resulting in the appearance of gate-tunable superconducting and correlated insulating phases. In this study, we demonstrate that in addition to the twist angle, the interlayer coupling can be varied to precisely tune these phases. We induce superconductivity at a twist angle larger than 1.1°-in which correlated phases are otherwise absent-by varying the interlayer spacing with hydrostatic pressure. Our low-disorder devices reveal details about the superconducting phase diagram and its relationship to the nearby insulator. Our results demonstrate twisted bilayer graphene to be a distinctively tunable platform for exploring correlated states.

Exceptional points are branch point singularities in the parameter space of a system at which two or more eigenvalues, and their corresponding eigenvectors, coalesce and become degenerate. Such peculiar degeneracies are distinct features of non-Hermitian systems, which do not obey conservation laws because they exchange energy with the surrounding environment. Non-Hermiticity has been of great interest in recent years, particularly in connection with the quantum mechanical notion of parity-time symmetry, after the realization that Hamiltonians satisfying this special symmetry can exhibit entirely real spectra. These concepts have become of particular interest in photonics because optical gain and loss can be integrated and controlled with high resolution in nanoscale structures, realizing an ideal playground for non-Hermitian physics, parity-time symmetry, and exceptional points. As we control dissipation and amplification in a nanophotonic system, the emergence of exceptional point singularities dramatically alters their overall response, leading to a range of exotic optical…

The restoration of trees remains among the most effective strategies for climate change mitigation. We mapped the global potential tree coverage to show that 4.4 billion hectares of canopy cover could exist under the current climate. Excluding existing trees and agricultural and urban areas, we found that there is room for an extra 0.9 billion hectares of canopy cover, which could store 205 gigatonnes of carbon in areas that would naturally support woodlands and forests. This highlights global tree restoration as our most effective climate change solution to date. However, climate change will alter this potential tree coverage. We estimate that if we cannot deviate from the current trajectory, the global potential canopy cover may shrink by ~223 million hectares by 2050, with the vast majority of losses occurring in the tropics. Our results highlight the opportunity of climate change mitigation through global tree restoration but also the urgent need for action.

Species extinctions have defined the global biodiversity crisis, but extinction begins with loss in abundance of individuals that can result in compositional and functional changes of ecosystems. Using multiple and independent monitoring networks, we report population losses across much of the North American avifauna over 48 years, including once-common species and from most biomes. Integration of range-wide population trajectories and size estimates indicates a net loss approaching 3 billion birds, or 29% of 1970 abundance. A continent-wide weather radar network also reveals a similarly steep decline in biomass passage of migrating birds over a recent 10-year period. This loss of bird abundance signals an urgent need to address threats to avert future avifaunal collapse and associated loss of ecosystem integrity, function, and services.

Lithium-ion batteries, which power portable electronics, electric vehicles, and stationary storage, have been recognized with the 2019 Nobel Prize in chemistry. The development of nanomaterials and their related processing into electrodes and devices can improve the performance and/or development of the existing energy storage systems. We provide a perspective on recent progress in the application of nanomaterials in energy storage devices, such as supercapacitors and batteries. The versatility of nanomaterials can lead to power sources for portable, flexible, foldable, and distributable electronics; electric transportation; and grid-scale storage, as well as integration in living environments and biomedical systems. To overcome limitations of nanomaterials related to high reactivity and chemical instability caused by their high surface area, nanoparticles with different functionalities should be combined in smart architectures on nano- and microscales. The integration of nanomaterials into functional architectures and devices requires the development of advanced manufacturing…

The propensity of metals to form irregular and nonplanar electrodeposits at liquid-solid interfaces has emerged as a fundamental barrier to high-energy, rechargeable batteries that use metal anodes. We report an epitaxial mechanism to regulate nucleation, growth, and reversibility of metal anodes. The crystallographic, surface texturing, and electrochemical criteria for reversible epitaxial electrodeposition of metals are defined and their effectiveness demonstrated by using zinc (Zn), a safe, low-cost, and energy-dense battery anode material. Graphene, with a low lattice mismatch for Zn, is shown to be effective in driving deposition of Zn with a locked crystallographic orientation relation. The resultant epitaxial Zn anodes achieve exceptional reversibility over thousands of cycles at moderate and high rates. Reversible electrochemical epitaxy of metals provides a general pathway toward energy-dense batteries with high reversibility.

The spread of fake news on social media became a public concern in the United States after the 2016 presidential election. We examined exposure to and sharing of fake news by registered voters on Twitter and found that engagement with fake news sources was extremely concentrated. Only 1% of individuals accounted for 80% of fake news source exposures, and 0.1% accounted for nearly 80% of fake news sources shared. Individuals most likely to engage with fake news sources were conservative leaning, older, and highly engaged with political news. A cluster of fake news sources shared overlapping audiences on the extreme right, but for people across the political spectrum, most political news exposure still came from mainstream media outlets.

Collagen is the primary component of the extracellular matrix in the human body. It has proved challenging to fabricate collagen scaffolds capable of replicating the structure and function of tissues and organs. We present a method to 3D-bioprint collagen using freeform reversible embedding of suspended hydrogels (FRESH) to engineer components of the human heart at various scales, from capillaries to the full organ. Control of pH-driven gelation provides 20-micrometer filament resolution, a porous microstructure that enables rapid cellular infiltration and microvascularization, and mechanical strength for fabrication and perfusion of multiscale vasculature and tri-leaflet valves. We found that FRESH 3D-bioprinted hearts accurately reproduce patient-specific anatomical structure as determined by micro-computed tomography. Cardiac ventricles printed with human cardiomyocytes showed synchronized contractions, directional action potential propagation, and wall thickening up to 14% during peak systole.

When two sheets of graphene are stacked at a small twist angle, the resulting flat superlattice minibands are expected to strongly enhance electron-electron interactions. Here, we present evidence that near three-quarters ([Formula: see text]) filling of the conduction miniband, these enhanced interactions drive the twisted bilayer graphene into a ferromagnetic state. In a narrow density range around an apparent insulating state at [Formula: see text], we observe emergent ferromagnetic hysteresis, with a giant anomalous Hall (AH) effect as large as 10.4 kilohms and indications of chiral edge states. Notably, the magnetization of the sample can be reversed by applying a small direct current. Although the AH resistance is not quantized, and dissipation is present, our measurements suggest that the system may be an incipient Chern insulator.

Magnetism, originating from the moving charges and spin of elementary particles, has revolutionized important technologies such as data storage and biomedical imaging, and continues to bring forth new phenomena in emergent materials and reduced dimensions. The recently discovered two-dimensional (2D) magnetic van der Waals crystals provide ideal platforms for understanding 2D magnetism, the control of which has been fueling opportunities for atomically thin, flexible magneto-optic and magnetoelectric devices (such as magnetoresistive memories and spin field-effect transistors). The seamless integration of 2D magnets with dissimilar electronic and photonic materials opens up exciting possibilities for unprecedented properties and functionalities. We review the progress in this area and identify the possible directions for device applications, which may lead to advances in spintronics, sensors, and computing.

Reducing human reliance on energy-inefficient cooling methods such as air conditioning would have a large impact on the global energy landscape. By a process of complete delignification and densification of wood, we developed a structural material with a mechanical strength of 404.3 megapascals, more than eight times that of natural wood. The cellulose nanofibers in our engineered material backscatter solar radiation and emit strongly in mid-infrared wavelengths, resulting in continuous subambient cooling during both day and night. We model the potential impact of our cooling wood and find energy savings between 20 and 60%, which is most pronounced in hot and dry climates.

Three's a charm for iron and CO 2 Large-scale electrochemical reduction of CO 2 to CO could be a promising first step in sustainable conversion of the greenhouse gas to commodity chemicals. Currently, gold and silver are the most active catalysts for this process, whereas more abundant, less expensive metals tend to require impractically high potentials. Jun Gu et al. now report an iron catalyst with activity equaling or exceeding that of the precious metals. The key proved to be stabilization of the dispersed single iron ions in the +3 oxidation state. Science , this issue p. 1091

MicroRNAs (miRNAs) act within Argonaute proteins to guide repression of messenger RNA targets. Although various approaches have provided insight into target recognition, the sparsity of miRNA-target affinity measurements has limited understanding and prediction of targeting efficacy. Here, we adapted RNA bind-n-seq to enable measurement of relative binding affinities between Argonaute-miRNA complexes and all sequences ≤12 nucleotides in length. This approach revealed noncanonical target sites specific to each miRNA, miRNA-specific differences in canonical target-site affinities, and a 100-fold impact of dinucleotides flanking each site. These data enabled construction of a biochemical model of miRNA-mediated repression, which was extended to all miRNA sequences using a convolutional neural network. This model substantially improved prediction of cellular repression, thereby providing a biochemical basis for quantitatively integrating miRNAs into gene-regulatory networks.

Development of efficient and robust electrocatalysts is critical for practical fuel cells. We report one-dimensional bunched platinum-nickel (Pt-Ni) alloy nanocages with a Pt-skin structure for the oxygen reduction reaction that display high mass activity (3.52 amperes per milligram platinum) and specific activity (5.16 milliamperes per square centimeter platinum), or nearly 17 and 14 times higher as compared with a commercial platinum on carbon (Pt/C) catalyst. The catalyst exhibits high stability with negligible activity decay after 50,000 cycles. Both the experimental results and theoretical calculations reveal the existence of fewer strongly bonded platinum-oxygen (Pt-O) sites induced by the strain and ligand effects. Moreover, the fuel cell assembled by this catalyst delivers a current density of 1.5 amperes per square centimeter at 0.6 volts and can operate steadily for at least 180 hours.

Neuron activity across the brain How is it that groups of neurons dispersed through the brain interact to generate complex behaviors? Three papers in this issue present brain-scale studies of neuronal activity and dynamics (see the Perspective by Huk and Hart). Allen et al. found that in thirsty mice, there is widespread neural activity related to stimuli that elicit licking and drinking. Individual neurons encoded task-specific responses, but every brain area contained neurons with different types of response. Optogenetic stimulation of thirst-sensing neurons in one area of the brain reinstated drinking and neuronal activity across the brain that previously signaled thirst. Gründemann et al. investigated the activity of mouse basal amygdala neurons in relation to behavior during different tasks. Two ensembles of neurons showed orthogonal activity during exploratory and nonexploratory behaviors, possibly reflecting different levels of anxiety experienced in these areas. Stringer et al. analyzed spontaneous neuronal firing, finding that neurons in the primary visual cortex encoded…

Quantum anomalous Hall goes intrinsic Quantum anomalous Hall effect—the appearance of quantized Hall conductance at zero magnetic field—has been observed in thin films of the topological insulator Bi 2 Se 3 doped with magnetic atoms. The doping, however, introduces inhomogeneity, reducing the temperature at which the effect occurs. Two groups have now observed quantum anomalous Hall effect in intrinsically magnetic materials (see the Perspective by Wakefield and Checkelsky). Serlin et al. did so in twisted bilayer graphene aligned to hexagonal boron nitride, where the effect enabled the switching of magnetization with tiny currents. In a complementary work, Deng et al. observed quantum anomalous Hall effect in the antiferromagnetic layered topological insulator MnBi 2 Te 4 . Science , this issue p. 900 , p. 895 ; see also p. 848

Abstract: We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system. One Sentence Summary: We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of…

Solid organs transport fluids through distinct vascular networks that are biophysically and biochemically entangled, creating complex three-dimensional (3D) transport regimes that have remained difficult to produce and study. We establish intravascular and multivascular design freedoms with photopolymerizable hydrogels by using food dye additives as biocompatible yet potent photoabsorbers for projection stereolithography. We demonstrate monolithic transparent hydrogels, produced in minutes, comprising efficient intravascular 3D fluid mixers and functional bicuspid valves. We further elaborate entangled vascular networks from space-filling mathematical topologies and explore the oxygenation and flow of human red blood cells during tidal ventilation and distension of a proximate airway. In addition, we deploy structured biodegradable hydrogel carriers in a rodent model of chronic liver injury to highlight the potential translational utility of this materials innovation.

Anthropogenic trade and development have broken down dispersal barriers, facilitating the spread of diseases that threaten Earth's biodiversity. We present a global, quantitative assessment of the amphibian chytridiomycosis panzootic, one of the most impactful examples of disease spread, and demonstrate its role in the decline of at least 501 amphibian species over the past half-century, including 90 presumed extinctions. The effects of chytridiomycosis have been greatest in large-bodied, range-restricted anurans in wet climates in the Americas and Australia. Declines peaked in the 1980s, and only 12% of declined species show signs of recovery, whereas 39% are experiencing ongoing decline. There is risk of further chytridiomycosis outbreaks in new areas. The chytridiomycosis panzootic represents the greatest recorded loss of biodiversity attributable to a disease.

Surface trap-mediated nonradiative charge recombination is a major limit to achieving high-efficiency metal-halide perovskite photovoltaics. The ionic character of perovskite lattice has enabled molecular defect passivation approaches through interaction between functional groups and defects. However, a lack of in-depth understanding of how the molecular configuration influences the passivation effectiveness is a challenge to rational molecule design. Here, the chemical environment of a functional group that is activated for defect passivation was systematically investigated with theophylline, caffeine, and theobromine. When N-H and C=O were in an optimal configuration in the molecule, hydrogen-bond formation between N-H and I (iodine) assisted the primary C=O binding with the antisite Pb (lead) defect to maximize surface-defect binding. A stabilized power conversion efficiency of 22.6% of photovoltaic device was demonstrated with theophylline treatment.

Soil organisms represent the most biologically diverse community on land and govern the turnover of the largest organic matter pool in the terrestrial biosphere. The highly complex nature of these communities at local scales has traditionally obscured efforts to identify unifying patterns in global soil biodiversity and biogeochemistry. As a result, environmental covariates have generally been used as a proxy to represent the variation in soil community activity in global biogeochemical models. Yet over the past decade, broad-scale studies have begun to see past this local heterogeneity to identify unifying patterns in the biomass, diversity, and composition of certain soil groups across the globe. These unifying patterns provide new insights into the fundamental distribution and dynamics of organic matter on land.

Maintaining the bandgap The bandgap of the black α-phase of formamidinium-based lead triiodide (FAPbI 3 ) is near optimal for creating high-efficiency perovskite solar cells. However, this phase is unstable, and the additives normally used to stabilize this phase at ambient temperature—such as methylammonium, caesium, and bromine—widen its bandgap. Min et al. show that doping of the α-FAPbI 3 phase with methylenediammonium dichloride enabled power conversion efficiencies of 23.7%, which were maintained after 600 hours of operation. Unencapsulated devices had high thermal stability and retained >90% efficiency even after annealing for 20 hours at 150°C in air. Science , this issue p. 749

Understanding the behavior of Earth through the diverse fields of the solid Earth geosciences is an increasingly important task. It is made challenging by the complex, interacting, and multiscale processes needed to understand Earth's behavior and by the inaccessibility of nearly all of Earth's subsurface to direct observation. Substantial increases in data availability and in the increasingly realistic character of computer simulations hold promise for accelerating progress, but developing a deeper understanding based on these capabilities is itself challenging. Machine learning will play a key role in this effort. We review the state of the field and make recommendations for how progress might be broadened and accelerated.

Tetragonal phases for perovskite solar cells The power conversion efficiencies (PCEs) of all-inorganic perovskites are lower than those of materials with organic cations. This is in part because these materials have larger bandgaps. The cubic crystal phases of these materials also exhibit poor stability. Wang et al. synthesized the tetragonal β-phase of CsPbI 3 from HPbI 3 and CsI. The material exhibited higher stability and a more favorable bandgap, which allowed for PCEs of 15%. Passivation of the surface trap state with choline iodide boosted PCEs to 18%. Science , this issue p. 591

Harvested by advanced technical systems honed over decades of research and development, wind energy has become a mainstream energy resource. However, continued innovation is needed to realize the potential of wind to serve the global demand for clean energy. Here, we outline three interdependent, cross-disciplinary grand challenges underpinning this research endeavor. The first is the need for a deeper understanding of the physics of atmospheric flow in the critical zone of plant operation. The second involves science and engineering of the largest dynamic, rotating machines in the world. The third encompasses optimization and control of fleets of wind plants working synergistically within the electricity grid. Addressing these challenges could enable wind power to provide as much as half of our global electricity needs and perhaps beyond.

To achieve homeostasis, cells evolved dynamic and self-regulating quality control processes to adapt to new environmental conditions and to prevent prolonged damage. We discuss the importance of two major quality control systems responsible for degradation of proteins and organelles in eukaryotic cells: the ubiquitin-proteasome system (UPS) and autophagy. The UPS and autophagy form an interconnected quality control network where decision-making is self-organized on the basis of biophysical parameters (binding affinities, local concentrations, and avidity) and compartmentalization (through membranes, liquid-liquid phase separation, or the formation of aggregates). We highlight cellular quality control factors that delineate their differential deployment toward macromolecular complexes, liquid-liquid phase-separated subcellular structures, or membrane-bound organelles. Finally, we emphasize the need for continuous promotion of quantitative and mechanistic research into the roles of the UPS and autophagy in human pathophysiology.

A direct route to pure peroxide Despite the widespread use of hydrogen peroxide as an oxidant and disinfectant, its commercial synthesis still requires inefficient concentration and purification steps. Xia et al. now report an electrochemical approach to synthesizing pure peroxide solutions straight from hydrogen and oxygen. Using a solid-state electrolyte, they avoid contamination of the product solution by extraneous ions. Varying the flow rate of water through the electrochemical cell tunes the final concentration over a range from 0.3% to 20% by weight. Science , this issue p. 226

Sleep is essential for both cognition and maintenance of healthy brain function. Slow waves in neural activity contribute to memory consolidation, whereas cerebrospinal fluid (CSF) clears metabolic waste products from the brain. Whether these two processes are related is not known. We used accelerated neuroimaging to measure physiological and neural dynamics in the human brain. We discovered a coherent pattern of oscillating electrophysiological, hemodynamic, and CSF dynamics that appears during non-rapid eye movement sleep. Neural slow waves are followed by hemodynamic oscillations, which in turn are coupled to CSF flow. These results demonstrate that the sleeping brain exhibits waves of CSF flow on a macroscopic scale, and these CSF dynamics are interlinked with neural and hemodynamic rhythms.

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.

The global scale-up in demand for animal protein is the most notable dietary trend of our time. Antimicrobial consumption in animals is threefold that of humans and has enabled large-scale animal protein production. The consequences for the development of antimicrobial resistance in animals have received comparatively less attention than in humans. We analyzed 901 point prevalence surveys of pathogens in developing countries to map resistance in animals. China and India represented the largest hotspots of resistance, with new hotspots emerging in Brazil and Kenya. From 2000 to 2018, the proportion of antimicrobials showing resistance above 50% increased from 0.15 to 0.41 in chickens and from 0.13 to 0.34 in pigs. Escalating resistance in animals is anticipated to have important consequences for animal health and, eventually, for human health.

As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called "clonal hematopoiesis," is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

Ultrahigh energy density dielectric film Dielectrics help hold charge as capacitors and are fundamental energy storage components. Improving energy density and other properties may help these materials be more competitive with batteries for energy storage applications. Pan et al. introduced a specific type of nanodomain structure in a BiFeO 3 -BaTiO 3 -SrTiO 3 solid solution that dramatically increased the energy density. The nanodomains were organized so as to minimize energy loss during polarization switching. The enhancement in the dielectric properties suggests that the strategy may be useful for designing high-performance dielectrics. Science , this issue p. 578

Protecting plants from the inside out Some soils show a remarkable ability to suppress disease caused by plant pathogens, an ability that is attributed to plant-associated microbiota. Carrión et al. investigated the role of endophytes, the intimate microbial community found within roots, in fungal disease suppression (see the Perspective by Tringe). The wilt fungus Rhizoctonia solani infects sugar beets, whereupon transcriptional analysis shows that several bacterial endophyte species activate biosynthetic gene clusters to cause disease suppression. These organisms produce antifungal effectors, including enzymes that can digest fungal cell walls, and secondary metabolites, including phenazines, polyketides, and siderophores, which may contribute to the antifungal phenotype. Science , this issue p. 606 ; see also p. 568

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.

Tissue macrophages have a split personality Resident tissue macrophages (RTMs) reside in various tissue-specific niches during development. They evince microenvironment-directed phenotypes that support host defense and tissue homeostasis. Chakarov et al. used single-cell RNA sequencing and fate-mapping of murine lung RTMs to interrogate RTM-subset heterogeneity, interrelationships, and ontogeny (see the Perspective by Mildner and Yona). In addition to alveolar macrophages, they identified two different interstitial macrophage populations. One population mostly abutted nerve fibers; the other population preferentially localized near blood vessels and appeared to support vessel integrity and inhibit inflammatory cell infiltration into tissues. Science , this issue p. eaau0964 ; see also p. 1154

A redox road to recovery Device longevity is a key issue for organic-inorganic perovskite solar cells. Encapsulation can limit degradation arising from reactions with oxygen and water, but light, electric-field, and thermal stresses can lead to metastable elemental lead and halide atom defects. Wang et al. show that for the lead-iodine system, the introduction of the rare earth europium ion pair Eu 3+ -Eu 2+ can shuttle electrons and recover lead and iodine ions (Pb 2+ and I − ). Devices incorporating this redox shuttle maintained more than 90% of their initial power conversion efficiencies under various aging conditions. Science , this issue p. 265

Emerging vulnerabilities demand new conversations

DNA is highly immunogenic. It represents a key pathogen-associated molecular pattern (PAMP) during infection. Host DNA can, however, also act as a danger-associated molecular pattern (DAMP) and elicit strong inflammatory responses. The cGAS-STING pathway has emerged as a major pathway that detects intracellular DNA. Here, we highlight recent advances on how cGAS and STING mediate inflammatory responses and how these are regulated, allowing cells to readily respond to infections and noxious agents while avoiding the inappropriate sensing of self-DNA. A particular focus is placed on the role of cGAS in the context of sterile inflammatory conditions. Manipulating cGAS or STING may open the door for new therapeutic strategies for the treatment of acute and chronic inflammation relevant to many human diseases.

Increased concentrations of atmospheric greenhouse gases have led to a global mean surface temperature 1.0°C higher than during the pre-industrial period. We expand on the recent IPCC Special Report on global warming of 1.5°C and review the additional risks associated with higher levels of warming, each having major implications for multiple geographies, climates, and ecosystems. Limiting warming to 1.5°C rather than 2.0°C would be required to maintain substantial proportions of ecosystems and would have clear benefits for human health and economies. These conclusions are relevant for people everywhere, particularly in low- and middle-income countries, where the escalation of climate-related risks may prevent the achievement of the United Nations Sustainable Development Goals.

We used ultrahigh-speed synchrotron x-ray imaging to quantify the phenomenon of vapor depressions (also known as keyholes) during laser melting of metals as practiced in additive manufacturing. Although expected from welding and inferred from postmortem cross sections of fusion zones, the direct visualization of the keyhole morphology and dynamics with high-energy x-rays shows that (i) keyholes are present across the range of power and scanning velocity used in laser powder bed fusion; (ii) there is a well-defined threshold from conduction mode to keyhole based on laser power density; and (iii) the transition follows the sequence of vaporization, depression of the liquid surface, instability, and then deep keyhole formation. These and other aspects provide a physical basis for three-dimensional printing in laser powder bed machines.

The synthesis of complex organic molecules requires several stages, from ideation to execution, that require time and effort investment from expert chemists. Here, we report a step toward a paradigm of chemical synthesis that relieves chemists from routine tasks, combining artificial intelligence-driven synthesis planning and a robotically controlled experimental platform. Synthetic routes are proposed through generalization of millions of published chemical reactions and validated in silico to maximize their likelihood of success. Additional implementation details are determined by expert chemists and recorded in reusable recipe files, which are executed by a modular continuous-flow platform that is automatically reconfigured by a robotic arm to set up the required unit operations and carry out the reaction. This strategy for computer-augmented chemical synthesis is demonstrated for 15 drug or drug-like substances.

All-perovskite-based polycrystalline thin-film tandem solar cells have the potential to deliver efficiencies of >30%. However, the performance of all-perovskite-based tandem devices has been limited by the lack of high-efficiency, low-band gap tin-lead (Sn-Pb) mixed-perovskite solar cells (PSCs). We found that the addition of guanidinium thiocyanate (GuaSCN) resulted in marked improvements in the structural and optoelectronic properties of Sn-Pb mixed, low-band gap (~1.25 electron volt) perovskite films. The films have defect densities that are lower by a factor of 10, leading to carrier lifetimes of greater than 1 microsecond and diffusion lengths of 2.5 micrometers. These improved properties enable our demonstration of >20% efficient low-band gap PSCs. When combined with wider-band gap PSCs, we achieve 25% efficient four-terminal and 23.1% efficient two-terminal all-perovskite-based polycrystalline thin-film tandem solar cells.

Additive manufacturing promises enormous geometrical freedom and the potential to combine materials for complex functions. The speed, geometry, and surface quality limitations of additive processes are linked to their reliance on material layering. We demonstrated concurrent printing of all points within a three-dimensional object by illuminating a rotating volume of photosensitive material with a dynamically evolving light pattern. We printed features as small as 0.3 millimeters in engineering acrylate polymers and printed soft structures with exceptionally smooth surfaces into a gelatin methacrylate hydrogel. Our process enables us to construct components that encase other preexisting solid objects, allowing for multimaterial fabrication. We developed models to describe speed and spatial resolution capabilities and demonstrated printing times of 30 to 120 seconds for diverse centimeter-scale objects.

We show that converting the surfaces of lead halide perovskite to water-insoluble lead (II) oxysalt through reaction with sulfate or phosphate ions can effectively stabilize the perovskite surface and bulk material. These capping lead oxysalt thin layers enhance the water resistance of the perovskite films by forming strong chemical bonds. The wide-bandgap lead oxysalt layers also reduce the defect density on the perovskite surfaces by passivating undercoordinated surface lead centers, which are defect-nucleating sites. Formation of the lead oxysalt layer increases the carrier recombination lifetime and boosts the efficiency of the solar cells to 21.1%. Encapsulated devices stabilized by the lead oxysalt layers maintain 96.8% of their initial efficiency after operation at maximum power point under simulated air mass (AM) 1.5 G irradiation for 1200 hours at 65°C.

Optical metasurfaces have provided us with extraordinary ways to control light by spatially structuring materials. The space-time duality in Maxwell's equations suggests that additional structuring of metasurfaces in the time domain can even further expand their impact on the field of optics. Advances toward this goal critically rely on the development of new materials and nanostructures that exhibit very large and fast changes in their optical properties in response to external stimuli. New physics is also emerging as ultrafast tuning of metasurfaces is becoming possible, including wavelength shifts that emulate the Doppler effect, Lorentz nonreciprocity, time-reversed optical behavior, and negative refraction. The large-scale manufacturing of dynamic flat optics has the potential to revolutionize many emerging technologies that require active wavefront shaping with lightweight, compact, and power-efficient components.

Mountains contribute disproportionately to the terrestrial biodiversity of Earth, especially in the tropics, where they host hotspots of extraordinary and puzzling richness. With about 25% of all land area, mountain regions are home to more than 85% of the world's species of amphibians, birds, and mammals, many entirely restricted to mountains. Biodiversity varies markedly among these regions. Together with the extreme species richness of some tropical mountains, this variation has proven challenging to explain under traditional climatic hypotheses. However, the complex climatic characteristics of rugged mountain regions differ fundamentally from those of lowland regions, likely playing a key role in generating and maintaining diversity. With ongoing global changes in climate and land use, the role of mountains as refugia for biodiversity may well come under threat.

Recent developments have enabled the practical realization of optical elements in which the polarization of light may vary spatially. We present an extension of Fourier optics-matrix Fourier optics-for understanding these devices and apply it to the design and realization of metasurface gratings implementing arbitrary, parallel polarization analysis. We show how these gratings enable a compact, full-Stokes polarization camera without standard polarization optics. Our single-shot polarization camera requires no moving parts, specially patterned pixels, or conventional polarization optics and may enable the widespread adoption of polarization imaging in machine vision, remote sensing, and other areas.

Dexterous manipulation is one of the primary goals in robotics. Robots with this capability could sort and package objects, chop vegetables, and fold clothes. As robots come to work side by side with humans, they must also become human-aware. Over the past decade, research has made strides toward these goals. Progress has come from advances in visual and haptic perception and in mechanics in the form of soft actuators that offer a natural compliance. Most notably, immense progress in machine learning has been leveraged to encapsulate models of uncertainty and to support improvements in adaptive and robust control. Open questions remain in terms of how to enable robots to deal with the most unpredictable agent of all, the human.

The state of ocean CO 2 uptake The ocean is an important sink for anthropogenic CO 2 and has absorbed roughly 30% of our emissions between the beginning of the industrial revolution and the mid-1990s. This effect is an important moderator of climate change, but can we count on it to remain as strong in the future? Gruber et al. calculated the ocean uptake of anthropogenic CO 2 for the interval from 1994 to 2007, which continued as expected. They also observed clear regional deviations from this pattern, suggesting that there is no guarantee that uptake will remain as robust with time. Science , this issue p. 1193

Flowing CO 2 boosts a molecular catalyst Molecular electrocatalysts for CO 2 reduction have often appeared to lack sufficient activity or stability for practical application. Ren et al. now show that design of the surrounding electrochemical cell can substantially boost both features. They directly exposed a known molecular catalyst, cobalt phthalocyanine, to gaseous CO 2 in a flow cell architecture, rather than an aqueous electrolyte. The configuration accommodated current densities exceeding 150 milliamperes per square centimeter, with longevity limited by local proton concentration rather than catalyst stability. Science , this issue p. 367

Organoids are microscopic self-organizing, three-dimensional structures that are grown from stem cells in vitro. They recapitulate many structural and functional aspects of their in vivo counterpart organs. This versatile technology has led to the development of many novel human cancer models. It is now possible to create indefinitely expanding organoids starting from tumor tissue of individuals suffering from a range of carcinomas. Alternatively, CRISPR-based gene modification allows the engineering of organoid models of cancer through the introduction of any combination of cancer gene alterations to normal organoids. When combined with immune cells and fibroblasts, tumor organoids become models for the cancer microenvironment enabling immune-oncology applications. Emerging evidence indicates that organoids can be used to accurately predict drug responses in a personalized treatment setting. Here, we review the current state and future prospects of the rapidly evolving tumor organoid field.

Samarium supersensors Piezoelectric materials produce electric charge in response to changes in stress and are thus good sensor materials. One challenge has been growing single-crystal piezoelectrics with uniform properties. As of now, much of the crystal is discarded because of compositional variations. Li et al. synthesized single crystals of samarium-doped Pb(Mg 1/3 Nb 2/3 )O 3 -PbTiO 3 that have uniform and extremely high piezoelectric properties (see the Perspective by Hlinka). These crystals are ideal for a variety of sensing applications and could reduce cost by eliminating waste. Science , this issue p. 264 ; see also p. 228

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

Many factors influence global change Global environmental change is driven by multiple natural and anthropogenic factors. With a focus on global change as it affects soils, Rillig et al. point out that nearly all published studies consider just one or two factors at a time (see the Perspective by Manning). In a laboratory experiment, they tested 10 drivers of global change both individually and in combination, at levels ranging from 2 to 10 factors. They found that soil properties, processes, and microbial communities could not be predicted from single-effect responses and that multiple factors in combination produced unsuspected responses. They concluded that single-factor studies remain important for uncovering mechanisms but that global change biology needs to embrace more fully the multitude of drivers impinging on ecosystems. Science , this issue p. 886 ; see also p. 801

Living tissues, such as muscle, autonomously grow and remodel themselves to adapt to their surrounding mechanical environment through metabolic processes. By contrast, typical synthetic materials cannot grow and reconstruct their structures once formed. We propose a strategy for developing "self-growing" polymeric materials that respond to repetitive mechanical stress through an effective mechanochemical transduction. Robust double-network hydrogels provided with a sustained monomer supply undergo self-growth, and the materials are substantially strengthened under repetitive loading through a structural destruction-reconstruction process. This strategy also endows the hydrogels with tailored functions at desired positions by mechanical stamping. This work may pave the way for the development of self-growing gel materials for applications such as soft robots and intelligent devices.

Eukaryotic genomes are folded into loops and topologically associating domains, which contribute to chromatin structure, gene regulation, and gene recombination. These structures depend on cohesin, a ring-shaped DNA-entrapping adenosine triphosphatase (ATPase) complex that has been proposed to form loops by extrusion. Such an activity has been observed for condensin, which forms loops in mitosis, but not for cohesin. Using biochemical reconstitution, we found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilo-base pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL-MAU2, but not on topological entrapment of DNA by cohesin. During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Our results show that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudo-topologically or non-topologically to extrude genomic interphase DNA into loops.

coiled-coil NLR ZAR1, the pseudokinase RKS1, uridylated protein kinase PBL2, and 2'-deoxyadenosine 5'-triphosphate (dATP), demonstrating the oligomerization of the complex during immune activation. The cryo-electron microscopy structure reveals a wheel-like pentameric ZAR1 resistosome. Besides the nucleotide-binding domain, the coiled-coil domain of ZAR1 also contributes to resistosome pentamerization by forming an α-helical barrel that interacts with the leucine-rich repeat and winged-helix domains. Structural remodeling and fold switching during activation release the very N-terminal amphipathic α helix of ZAR1 to form a funnel-shaped structure that is required for the plasma membrane association, cell death triggering, and disease resistance, offering clues to the biochemical function of a plant resistosome.

Many chemical methods have been developed to favor a particular product in transformations of compounds that have two or more reactive sites. We explored a different approach to site selectivity using vibrational strong coupling (VSC) between a reactant and the vacuum field of a microfluidic optical cavity. Specifically, we studied the reactivity of a compound bearing two possible silyl bond cleavage sites-Si-C and Si-O, respectively-as a function of VSC of three distinct vibrational modes in the dark. The results show that VSC can indeed tilt the reactivity landscape to favor one product over the other. Thermodynamic parameters reveal the presence of a large activation barrier and substantial changes to the activation entropy, confirming the modified chemical landscape under strong coupling.

A major challenge for implantable medical systems is the inclusion or reliable delivery of electrical power. We use ultrasound to deliver mechanical energy through skin and liquids and demonstrate a thin implantable vibrating triboelectric generator able to effectively harvest it. The ultrasound can induce micrometer-scale displacement of a polymer thin membrane to generate electrical energy through contact electrification. We recharge a lithium-ion battery at a rate of 166 microcoulombs per second in water. The voltage and current generated ex vivo by ultrasound energy transfer reached 2.4 volts and 156 microamps under porcine tissue. These findings show that a capacitive triboelectric electret is the first technology able to compete with piezoelectricity to harvest ultrasound in vivo and to power medical implants.

Magnetic Weyl semimetals Weyl semimetals (WSMs)—materials that host exotic quasiparticles called Weyl fermions—must break either spatial inversion or time-reversal symmetry. A number of WSMs that break inversion symmetry have been identified, but showing unambiguously that a material is a time-reversal-breaking WSM is tricky. Three groups now provide spectroscopic evidence for this latter state in magnetic materials (see the Perspective by da Silva Neto). Belopolski et al. probed the material Co 2 MnGa using angle-resolved photoemission spectroscopy, revealing exotic drumhead surface states. Using the same technique, Liu et al. studied the material Co 3 Sn 2 S 2 , which was complemented by the scanning tunneling spectroscopy measurements of Morali et al. These magnetic WSM states provide an ideal setting for exotic transport effects. Science , this issue p. 1278 , p. 1282 , p. 1286 ; see also p. 1248

Recent studies have demonstrated an array of stem cell-derived, self-organizing miniature organs, termed organoids, that replicate the key structural and functional characteristics of their in vivo counterparts. As organoid technology opens up new frontiers of research in biomedicine, there is an emerging need for innovative engineering approaches for the production, control, and analysis of organoids and their microenvironment. In this Review, we explore organ-on-a-chip technology as a platform to fulfill this need and examine how this technology may be leveraged to address major technical challenges in organoid research. We also discuss emerging opportunities and future obstacles for the development and application of organoid-on-a-chip technology.

The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease-specific myeloid subsets exist and what their transcriptional profiles and dynamics during CNS pathology are. Combining deep single-cell transcriptome analysis, fate mapping, in vivo imaging, clonal analysis, and transgenic mouse lines, we comprehensively characterized unappreciated myeloid subsets in several CNS compartments during neuroinflammation. During inflammation, CNS macrophage subsets undergo self-renewal, and random proliferation shifts toward clonal expansion. Last, functional studies demonstrated that endogenous CNS tissue macrophages are redundant for antigen presentation. Our results highlight myeloid cell diversity and provide insights into the brain's innate immune system.

Nanomaterials are critical components in the Earth system's past, present, and future characteristics and behavior. They have been present since Earth's origin in great abundance. Life, from the earliest cells to modern humans, has evolved in intimate association with naturally occurring nanomaterials. This synergy began to shift considerably with human industrialization. Particularly since the Industrial Revolution some two-and-a-half centuries ago, incidental nanomaterials (produced unintentionally by human activity) have been continuously produced and distributed worldwide. In some areas, they now rival the amount of naturally occurring nanomaterials. In the past half-century, engineered nanomaterials have been produced in very small amounts relative to the other two types of nanomaterials, but still in large enough quantities to make them a consequential component of the planet. All nanomaterials, regardless of their origin, have distinct chemical and physical properties throughout their size range, clearly setting them apart from their macroscopic equivalents and necessitating…

The El Niño-Southern Oscillation (ENSO), which originates in the Pacific, is the strongest and most well-known mode of tropical climate variability. Its reach is global, and it can force climate variations of the tropical Atlantic and Indian Oceans by perturbing the global atmospheric circulation. Less appreciated is how the tropical Atlantic and Indian Oceans affect the Pacific. Especially noteworthy is the multidecadal Atlantic warming that began in the late 1990s, because recent research suggests that it has influenced Indo-Pacific climate, the character of the ENSO cycle, and the hiatus in global surface warming. Discovery of these pantropical interactions provides a pathway forward for improving predictions of climate variability in the current climate and for refining projections of future climate under different anthropogenic forcing scenarios.

Mountain regions are unusually biodiverse, with rich aggregations of small-ranged species that form centers of endemism. Mountains play an array of roles for Earth's biodiversity and affect neighboring lowlands through biotic interchange, changes in regional climate, and nutrient runoff. The high biodiversity of certain mountains reflects the interplay of multiple evolutionary mechanisms: enhanced speciation rates with distinct opportunities for coexistence and persistence of lineages, shaped by long-term climatic changes interacting with topographically dynamic landscapes. High diversity in most tropical mountains is tightly linked to bedrock geology-notably, areas comprising mafic and ultramafic lithologies, rock types rich in magnesium and poor in phosphate that present special requirements for plant physiology. Mountain biodiversity bears the signature of deep-time evolutionary and ecological processes, a history well worth preserving.

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

Most photoredox catalysts in current use are precious metal complexes or synthetically elaborate organic dyes, the cost of which can impede their application for large-scale industrial processes. We found that a combination of triphenylphosphine and sodium iodide under 456-nanometer irradiation by blue light-emitting diodes can catalyze the alkylation of silyl enol ethers by decarboxylative coupling with redox-active esters in the absence of transition metals. Deaminative alkylation using Katritzky's N-alkylpyridinium salts and trifluoromethylation using Togni's reagent are also demonstrated. Moreover, the phosphine/iodide-based photoredox system catalyzes Minisci-type alkylation of N-heterocycles and can operate in tandem with chiral phosphoric acids to achieve high enantioselectivity in this reaction.

Thrifty thermoelectric cooling Currently available thermoelectric devices for cooling rely on expensive bismuth telluride. Mao et al. systematically developed a far less expensive n-type magnesium-bismuth–based material with good thermoelectric properties. They built a device that could generate a temperature difference of up to 90 kelvin when coupled with a commercially available p-type material. Such materials should provide an excellent basis for cost-effective thermoelectric cooling technology. Science , this issue p. 495

Existing vital sign monitoring systems in the neonatal intensive care unit (NICU) require multiple wires connected to rigid sensors with strongly adherent interfaces to the skin. We introduce a pair of ultrathin, soft, skin-like electronic devices whose coordinated, wireless operation reproduces the functionality of these traditional technologies but bypasses their intrinsic limitations. The enabling advances in engineering science include designs that support wireless, battery-free operation; real-time, in-sensor data analytics; time-synchronized, continuous data streaming; soft mechanics and gentle adhesive interfaces to the skin; and compatibility with visual inspection and with medical imaging techniques used in the NICU. Preliminary studies on neonates admitted to operating NICUs demonstrate performance comparable to the most advanced clinical-standard monitoring systems.

Elastic ceramics Aerogels hold promise as lightweight replacements for thermal insulation. However, poor mechanical stability has hampered progress in moving toward commercialization. Xu et al. designed a mechanical metamaterial that pinches in a small amount when you compress it (see the Perspective by Chhowalla and Jariwala). This is characteristic of materials with a negative Poisson's ratio and dramatically improves mechanical stability. The trick was using three-dimensional graphene structures to template the ceramic aerogels, thus producing a superinsulating material endowed with excellent mechanical properties. Science , this issue p. 723 ; see also p. 694

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type Ι interferon (IFN) response. Mitochondrial outer membrane permeabilization, which is required for mtDNA release, has been extensively studied in apoptotic cells, but little is known about its role in live cells. We found that oxidatively stressed mitochondria release short mtDNA fragments via pores formed by the voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane. Furthermore, the positively charged residues in the N-terminal domain of VDAC1 interact with mtDNA, promoting VDAC1 oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. Thus, inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release.

River ecosystems are highly biodiverse, influence global biogeochemical cycles, and provide valued services. However, humans are increasingly degrading fluvial ecosystems by altering their streamflows. Effective river restoration requires advancing our mechanistic understanding of how flow regimes affect biota and ecosystem processes. Here, we review emerging advances in hydroecology relevant to this goal. Spatiotemporal variation in flow exerts direct and indirect control on the composition, structure, and dynamics of communities at local to regional scales. Streamflows also influence ecosystem processes, such as nutrient uptake and transformation, organic matter processing, and ecosystem metabolism. We are deepening our understanding of how biological processes, not just static patterns, affect and are affected by stream ecosystem processes. However, research on this nexus of flow-biota-ecosystem processes is at an early stage. We illustrate this frontier with evidence from highly altered regulated rivers and urban streams. We also identify research challenges that should be…

Spotting off-targets from gene editing Unintended genomic modifications limit the potential therapeutic use of gene-editing tools. Available methods to find off-targets generally do not work in vivo or detect single-nucleotide changes. Three papers in this issue report new methods for monitoring gene-editing tools in vivo (see the Perspective by Kempton and Qi). Wienert et al. followed the recruitment of a DNA repair protein to DNA breaks induced by CRISPR-Cas9, enabling unbiased detection of off-target editing in cellular and animal models. Zuo et al. identified off-targets without the interference of natural genetic heterogeneity by injecting base editors into one blastomere of a two-cell mouse embryo and leaving the other genetically identical blastomere unedited. Jin et al. performed whole-genome sequencing on individual, genome-edited rice plants to identify unintended mutations. Cytosine, but not adenine, base editors induced numerous single-nucleotide variants in both mouse and rice. Science , this issue p. 286 , p. 289 , p. 292 ; see also p. 234

By sequencing 523 ancient humans, we show that the primary source of ancestry in modern South Asians is a prehistoric genetic gradient between people related to early hunter-gatherers of Iran and Southeast Asia. After the Indus Valley Civilization's decline, its people mixed with individuals in the southeast to form one of the two main ancestral populations of South Asia, whose direct descendants live in southern India. Simultaneously, they mixed with descendants of Steppe pastoralists who, starting around 4000 years ago, spread via Central Asia to form the other main ancestral population. The Steppe ancestry in South Asia has the same profile as that in Bronze Age Eastern Europe, tracking a movement of people that affected both regions and that likely spread the distinctive features shared between Indo-Iranian and Balto-Slavic languages.

Neuromorphic computers could overcome efficiency bottlenecks inherent to conventional computing through parallel programming and readout of artificial neural network weights in a crossbar memory array. However, selective and linear weight updates and <10-nanoampere read currents are required for learning that surpasses conventional computing efficiency. We introduce an ionic floating-gate memory array based on a polymer redox transistor connected to a conductive-bridge memory (CBM). Selective and linear programming of a redox transistor array is executed in parallel by overcoming the bridging threshold voltage of the CBMs. Synaptic weight readout with currents <10 nanoamperes is achieved by diluting the conductive polymer with an insulator to decrease the conductance. The redox transistors endure >1 billion write-read operations and support >1-megahertz write-read frequencies.

The dope on l -dopa metabolism The efficacy of l -dopa treatment for Parkinson's disease is hugely variable between individuals, depending on the composition of their microbiota. l -Dopa is decarboxylated into active dopamine, but if the gut microbiota metabolize l -dopa before it crosses the blood-brain barrier, medication is ineffective. Maini Rekdal et al. found that different species of bacterium are involved in l -dopa metabolism (see the Perspective by O'Neill). Tyrosine decarboxylase (TDC) from Enterococcus faecalis and dopamine dehydroxylase (Dadh) from Eggerthella lenta A2 sequentially metabolized l -dopa into m -tyramine. The microbial l -dopa decarboxylase can be inactivated by ( S )-α-fluoromethyltyrosine (AFMT), which indicates possibilities for developing combinations of Parkinson's drugs to circumvent microbial inactivation. Science , this issue p. eaau6323 ; see also p. 1030

Skyrmions in a frustrated magnet Skyrmions—tiny, topologically protected whirlpools of spin—have been investigated as potential information carriers in spintronic devices. Usually, skyrmions appear in noncentrosymmetric materials or at interfaces between materials. In contrast to this rule of thumb, Kurumaji et al. observed a skyrmion lattice phase in the centrosymmetric material Gd 2 PdSi 3 . The magnetic frustration present in this material helped stabilize the skyrmion phase, which was detected through transport measurements in magnetic field. Science , this issue p. 914

Computing equilibrium states in condensed-matter many-body systems, such as solvated proteins, is a long-standing challenge. Lacking methods for generating statistically independent equilibrium samples in "one shot," vast computational effort is invested for simulating these systems in small steps, e.g., using molecular dynamics. Combining deep learning and statistical mechanics, we developed Boltzmann generators, which are shown to generate unbiased one-shot equilibrium samples of representative condensed-matter systems and proteins. Boltzmann generators use neural networks to learn a coordinate transformation of the complex configurational equilibrium distribution to a distribution that can be easily sampled. Accurate computation of free-energy differences and discovery of new configurations are demonstrated, providing a statistical mechanics tool that can avoid rare events during sampling without prior knowledge of reaction coordinates.

Mix of metabolites tunes root microbiota Uncharacterized biosynthetic genes in plant genomes suggest that plants make a plethora of specialized metabolites. Huang et al. reconstructed three biosynthetic networks from the small mustard plant Arabidopsis thaliana . Promiscuous acyltransferases and dehydrogenases contributed to metabolite diversification. The plant may use these specialized metabolites to modulate the microbiota surrounding its roots. Disruption of the pathways and intervention with purified compounds caused changes in the root microbiota. Science , this issue p. eaau6389

Visible-light photoredox catalysis offers a distinct activation mode complementary to thermal transition metal catalyzed reactions. The vast majority of photoredox processes capitalizes on precious metal ruthenium(II) or iridium(III) complexes that serve as single-electron reductants or oxidants in their photoexcited states. As a low-cost alternative, organic dyes are also frequently used but in general suffer from lower photostability. Copper-based photocatalysts are rapidly emerging, offering not only economic and ecological advantages but also otherwise inaccessible inner-sphere mechanisms, which have been successfully applied to challenging transformations. Moreover, the combination of conventional photocatalysts with copper(I) or copper(II) salts has emerged as an efficient dual catalytic system for cross-coupling reactions.

Linking enhancers to disease Enhancers are genomic regions that regulate gene expression, sometimes in a cell-dependent manner. However, most of our knowledge of human brain cell–type enhancers derives from studies of bulk human brain tissue. Nott et al. examined chromatin and promoter activity in cell nuclei isolated from human brains. Genetic variants associated with brain traits and disease showed cell-specific patterns of enhancer enrichment. These data indicate that Alzheimer's disease is regulated by genetic variants within microglial cells, whereas psychiatric diseases tend to affect neurons. Science , this issue p. 1134

Beyond adaptive immunity Prokaryotic CRISPR-Cas systems defend bacterial cells from phage and plasmid infection. Strecker et al. characterized a CRISPR-Cas system that functions beyond adaptive immunity (see the Perspective by Hou and Zhang). Type V-K CRISPR-Cas from cyanobacteria was associated with a Tn7-like transposon and a natural nuclease–deficient effector Cas12k. Cas12k directed the insertion of Tn7-like transposons into target sites via RNA-guided Tn7 transposition. This system was reprogrammed to efficiently and specifically insert DNA both in vitro and into the Escherichia coli genome. Science , this issue p. 48 ; see also p. 25

Luminescent complexes of heavy metals such as iridium, platinum, and ruthenium play an important role in photocatalysis and energy conversion applications as well as organic light-emitting diodes (OLEDs). Achieving comparable performance from more-earth-abundant copper requires overcoming the weak spin-orbit coupling of the light metal as well as limiting the high reorganization energies typical in copper(I) [Cu(I)] complexes. Here we report that two-coordinate Cu(I) complexes with redox active ligands in coplanar conformation manifest suppressed nonradiative decay, reduced structural reorganization, and sufficient orbital overlap for efficient charge transfer. We achieve photoluminescence efficiencies >99% and microsecond lifetimes, which lead to an efficient blue-emitting OLED. Photophysical analysis and simulations reveal a temperature-dependent interplay between emissive singlet and triplet charge-transfer states and amide-localized triplet states.

Cohesin is a chromosome-bound, multisubunit adenosine triphosphatase complex. After loading onto chromosomes, it generates loops to regulate chromosome functions. It has been suggested that cohesin organizes the genome through loop extrusion, but direct evidence is lacking. Here, we used single-molecule imaging to show that the recombinant human cohesin-NIPBL complex compacts both naked and nucleosome-bound DNA by extruding DNA loops. DNA compaction by cohesin requires adenosine triphosphate (ATP) hydrolysis and is force sensitive. This compaction is processive over tens of kilobases at an average rate of 0.5 kilobases per second. Compaction of double-tethered DNA suggests that a cohesin dimer extrudes DNA loops bidirectionally. Our results establish cohesin-NIPBL as an ATP-driven molecular machine capable of loop extrusion.

Abstract Microglia are the main immune cells in the brain with emerging roles in brain homeostasis and neurological diseases, while mechanisms underlying microglia-neuron communication remain elusive. Here, we identify a novel site of interaction between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia-neuron junctions possess specialized nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria is linked with microglial junction formation, which is rapidly induced in response to neuronal activation and blocked by inhibition of P2Y12-receptors (P2Y12R). Brain injury-induced changes at somatic junctions trigger P2Y12R-dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Collectively, our results suggest that microglial processes at these junctions are in ideal position to monitor and protect neuronal functions in both the healthy and injured brain. One-sentence summary Neuronal cell bodies possess specialized, pre-formed sites, through which microglia monitor their…

The biggest bloom Floating mats of Sargassum seaweed in the center of the North Atlantic were first reported by Christopher Columbus in the 15th century. These mats, although abundant, have until recently been limited and discontinuous. However, Wang et al. report that, since 2011, the mats have increased in density and aerial extent to generate a 8850-kilometer-long belt that extends from West Africa to the Caribbean Sea and Gulf of Mexico (see the Perspective by Gower and King). This represents the world's largest macroalgal bloom. Such recurrent blooms may become the new normal. Science , this issue p. 83 ; see also p. 27

Predicting catalyst selectivity Asymmetric catalysis is widely used in chemical research and manufacturing to access just one of two possible mirror-image products. Nonetheless, the process of tuning catalyst structure to optimize selectivity is still largely empirical. Zahrt et al. present a framework for more efficient, predictive optimization. As a proof of principle, they focused on a known coupling reaction of imines and thiols catalyzed by chiral phosphoric acid compounds. By modeling multiple conformations of more than 800 prospective catalysts, and then training machine-learning algorithms on a subset of experimental results, they achieved highly accurate predictions of enantioselectivities. Science , this issue p. eaau5631

Pericytes put the squeeze on cognition Like a computer, the brain needs a reliable source of power, which is provided as oxygen and glucose in the blood. However, in many neurological disorders this energy supply is disrupted. Brain blood flow is controlled by adjustment of the diameters of the vessels supplying the blood. Nortley et al. found that, both in humans developing Alzheimer's disease (AD) and in a mouse model of AD, brain capillaries become squeezed by pericytes (see the Perspective by Liesz). By defining the underlying mechanism, they suggest potential targets for therapy in early AD. Science , this issue p. eaav9518 ; see also p. 223

Fixing photosynthetic inefficiencies In some of our most useful crops (such as rice and wheat), photosynthesis produces toxic by-products that reduce its efficiency. Photorespiration deals with these by-products, converting them into metabolically useful components, but at the cost of energy lost. South et al. constructed a metabolic pathway in transgenic tobacco plants that more efficiently recaptures the unproductive by-products of photosynthesis with less energy lost (see the Perspective by Eisenhut and Weber). In field trials, these transgenic tobacco plants were ∼40% more productive than wild-type tobacco plants. Science , this issue p. eaat9077 ; see also p. 32

Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.

The practice of rewilding has been both promoted and criticized in recent years. Benefits include flexibility to react to environmental change and the promotion of opportunities for society to reconnect with nature. Criticisms include the lack of a clear conceptualization of rewilding, insufficient knowledge about possible outcomes, and the perception that rewilding excludes people from landscapes. Here, we present a framework for rewilding that addresses these concerns. We suggest that rewilding efforts should target trophic complexity, natural disturbances, and dispersal as interacting processes that can improve ecosystem resilience and maintain biodiversity. We propose a structured approach to rewilding projects that includes assessment of the contributions of nature to people and the social-ecological constraints on restoration.

Carbon allotropes built from rings of two-coordinate atoms, known as cyclo[ n ]carbons, have fascinated chemists for many years, but until now they could not be isolated or structurally characterized because of their high reactivity. We generated cyclo[18]carbon (C 18 ) using atom manipulation on bilayer NaCl on Cu(111) at 5 kelvin by eliminating carbon monoxide from a cyclocarbon oxide molecule, C 24 O 6 . Characterization of cyclo[18]carbon by high-resolution atomic force microscopy revealed a polyynic structure with defined positions of alternating triple and single bonds. The high reactivity of cyclocarbon and cyclocarbon oxides allows covalent coupling between molecules to be induced by atom manipulation, opening an avenue for the synthesis of other carbon allotropes and carbon-rich materials from the coalescence of cyclocarbon molecules.

Cross-cultural analysis of song It is unclear whether there are universal patterns to music across cultures. Mehr et al. examined ethnographic data and observed music in every society sampled (see the Perspective by Fitch and Popescu). For songs specifically, three dimensions characterize more than 25% of the performances studied: formality of the performance, arousal level, and religiosity. There is more variation in musical behavior within societies than between societies, and societies show similar levels of within-society variation in musical behavior. At the same time, one-third of societies significantly differ from average for any given dimension, and half of all societies differ from average on at least one dimension, indicating variability across cultures. Science , this issue p. eaax0868 ; see also p. 944

Magnetic Weyl semimetals Weyl semimetals (WSMs)—materials that host exotic quasiparticles called Weyl fermions—must break either spatial inversion or time-reversal symmetry. A number of WSMs that break inversion symmetry have been identified, but showing unambiguously that a material is a time-reversal-breaking WSM is tricky. Three groups now provide spectroscopic evidence for this latter state in magnetic materials (see the Perspective by da Silva Neto). Belopolski et al. probed the material Co 2 MnGa using angle-resolved photoemission spectroscopy, revealing exotic drumhead surface states. Using the same technique, Liu et al. studied the material Co 3 Sn 2 S 2 , which was complemented by the scanning tunneling spectroscopy measurements of Morali et al. These magnetic WSM states provide an ideal setting for exotic transport effects. Science , this issue p. 1278 , p. 1282 , p. 1286 ; see also p. 1248

Spotting off-targets from gene editing Unintended genomic modifications limit the potential therapeutic use of gene-editing tools. Available methods to find off-targets generally do not work in vivo or detect single-nucleotide changes. Three papers in this issue report new methods for monitoring gene-editing tools in vivo (see the Perspective by Kempton and Qi). Wienert et al. followed the recruitment of a DNA repair protein to DNA breaks induced by CRISPR-Cas9, enabling unbiased detection of off-target editing in cellular and animal models. Zuo et al. identified off-targets without the interference of natural genetic heterogeneity by injecting base editors into one blastomere of a two-cell mouse embryo and leaving the other genetically identical blastomere unedited. Jin et al. performed whole-genome sequencing on individual, genome-edited rice plants to identify unintended mutations. Cytosine, but not adenine, base editors induced numerous single-nucleotide variants in both mouse and rice. Science , this issue p. 286 , p. 289 , p. 292 ; see also p. 234

A singular focus on fat Fatty tissue can expand in two ways: through increases in the size of individual adipocytes or through increases in the number of adipocytes. The former process promotes metabolic disease, and the latter protects against it. Merrick et al. used single-cell RNA sequencing to define the hierarchy of mesenchymal progenitor cells that give rise to adipose tissue in mice and humans (see the Perspective by Chau and Cawthorn). They found that progenitor cells expressing a protein called DPP4 give rise to two distinct types of preadipocytes in response to different signals. The DPP4 progenitors reside in a fluid-filled network of collagen and elastin fibers surrounding adipose tissue. In principle, therapeutic interventions that increase progenitor cell differentiation into adipocytes could ameliorate metabolic disease. Science , this issue p. eaav2501 ; see also p. 328