Intervention strategies are urgently needed to control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The trimeric viral spike (S) protein catalyzes fusion between viral and target cell membranes to initiate infection. Here, we report two cryo–electron microscopy structures derived from a preparation of the full-length S protein, representing its prefusion (2.9-angstrom resolution) and postfusion (3.0-angstrom resolution) conformations, respectively. The spontaneous transition to the postfusion state is independent of target cells. The prefusion trimer has three receptor-binding domains clamped down by a segment adjacent to the fusion peptide. The postfusion structure is strategically decorated by N-linked glycans, suggesting possible protective roles against host immune responses and harsh external conditions. These findings advance our understanding of SARS-CoV-2 entry and may guide the development of vaccines and therapeutics.

Since its discovery 16 years ago, roaming has become a ubiquitous mechanism in molecular photochemistry. Its general features are now understood, but little detail is known about how the potential energy surface (PES) determines reaction outcomes. We performed detailed experiments on formaldehyde (H₂CO) photodissociation and determined fully correlated quantum state distributions of the molecular hydrogen and carbon monoxide products. These experiments reveal previously undetected bimodal carbon monoxide rotational distributions. Insights from classical trajectory calculations demonstrate that these features arise from resonances as the PES directs the reaction into cis and trans O–C–H···H critical geometries, which produce rebound and stripping mechanisms, respectively. These subtle and pervasive effects demonstrate additional complexity in this prototypical roaming reaction, which we expect to be general. They also provide detailed benchmarks for predictive theories of roaming.

The design and fabrication of robust metallic states in graphene nanoribbons (GNRs) are challenging because lateral quantum confinement and many-electron interactions induce electronic band gaps when graphene is patterned at nanometer length scales. Recent developments in bottom-up synthesis have enabled the design and characterization of atomically precise GNRs, but strategies for realizing GNR metallicity have been elusive. Here we demonstrate a general technique for inducing metallicity in GNRs by inserting a symmetric superlattice of zero-energy modes into otherwise semiconducting GNRs. We verify the resulting metallicity using scanning tunneling spectroscopy as well as first-principles density-functional theory and tight-binding calculations. Our results reveal that the metallic bandwidth in GNRs can be tuned over a wide range by controlling the overlap of zero-mode wave functions through intentional sublattice symmetry breaking.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.

Sexual parasitism has evolved as a distinctive mode of reproduction among deep-sea anglerfishes. The permanent attachment of males to host females observed in these species represents a form of anatomical joining, which is otherwise unknown in nature. Pronounced modifications to immune facilities are associated with this reproductive trait. The genomes of species with temporarily attaching males lack functional aicda genes that underpin affinity maturation of antibodies. Permanent attachment is associated with additional alterations, culminating in the loss of functional rag genes in some species, abolishing somatic diversification of antigen receptor genes, the hallmark of canonical adaptive immunity. In anglerfishes, coevolution of innate and adaptive immunity has been disentangled, implying that an alternative form of immunity supported the emergence of this evolutionarily successful group of vertebrates.

Further improvement and stabilization of perovskite solar cell (PSC) performance are essential to achieve the commercial viability of next-generation photovoltaics. Considering the benefits of fluorination to conjugated materials for energy levels, hydrophobicity, and noncovalent interactions, two fluorinated isomeric analogs of the well-known hole-transporting material (HTM) Spiro-OMeTAD are developed and used as HTMs in PSCs. The structure–property relationship induced by constitutional isomerism is investigated through experimental, atomistic, and theoretical analyses, and the fabricated PSCs feature high efficiency up to 24.82% (certified at 24.64% with 0.3-volt voltage loss), along with long-term stability in wet conditions without encapsulation (87% efficiency retention after 500 hours). We also achieve an efficiency of 22.31% in the large-area cell.

Marine heatwaves (MHWs)—periods of extremely high ocean temperatures in specific regions—have occurred in all of Earth’s ocean basins over the past two decades, with severe negative impacts on marine organisms and ecosystems. However, for most individual MHWs, it is unclear to what extent they have been altered by human-induced climate change. We show that the occurrence probabilities of the duration, intensity, and cumulative intensity of most documented, large, and impactful MHWs have increased more than 20-fold as a result of anthropogenic climate change. MHWs that occurred only once every hundreds to thousands of years in the preindustrial climate are projected to become decadal to centennial events under 1.5°C warming conditions and annual to decadal events under 3°C warming conditions. Thus, ambitious climate targets are indispensable to reduce the risks of substantial MHW impacts.

Subjective experiences that can be consciously accessed and reported are associated with the cerebral cortex. Whether sensory consciousness can also arise from differently organized brains that lack a layered cerebral cortex, such as the bird brain, remains unknown. We show that single-neuron responses in the pallial endbrain of crows performing a visual detection task correlate with the birds’ perception about stimulus presence or absence and argue that this is an empirical marker of avian consciousness. Neuronal activity follows a temporal two-stage process in which the first activity component mainly reflects physical stimulus intensity, whereas the later component predicts the crows’ perceptual reports. These results suggest that the neural foundations that allow sensory consciousness arose either before the emergence of mammals or independently in at least the avian lineage and do not necessarily require a cerebral cortex.

Addressing the ultrafast coherent evolution of electronic wave functions has long been a goal of nonlinear x-ray physics. A first step toward this goal is the investigation of stimulated x-ray Raman scattering (SXRS) using intense pulses from an x-ray free-electron laser. Earlier SXRS experiments relied on signal amplification during pulse propagation through dense resonant media. By contrast, our method reveals the fundamental process in which photons from the primary radiation source directly interact with a single atom. We introduce an experimental protocol in which scattered neutral atoms rather than scattered photons are detected. We present SXRS measurements at the neon K edge and a quantitative theoretical analysis. The method should become a powerful tool in the exploration of nonlinear x-ray physics.

Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs’ cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.

Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells using specific combinations of proteins present on their surfaces. In this study, we design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations. We implement AND gates to redirect T cell specificity against tumor cells expressing two surface antigens while avoiding off-target recognition of single-antigen cells, and three-input switches that add NOT or OR logic to avoid or include cells expressing a third antigen. Thus, de novo designed proteins can perform computations on the surface of cells, integrating multiple distinct binding interactions into a single output.

Schistosomiasis is a neglected tropical disease that infects 240 million people. With no vaccines and only one drug available, new therapeutic targets are needed. The causative agents, schistosomes, are intravascular flatworm parasites that feed on blood and lay eggs, resulting in pathology. The function of the parasite’s various tissues in successful parasitism are poorly understood, hindering identification of therapeutic targets. Using single-cell RNA sequencing (RNA-seq), we characterize 43,642 cells from the adult schistosome and identify 68 distinct cell populations, including specialized stem cells that maintain the parasite’s blood-digesting gut. These stem cells express the gene hnf4, which is required for gut maintenance, blood feeding, and pathology in vivo. Together, these data provide molecular insights into the organ systems of this important pathogen and identify potential therapeutic targets.

Schistosome parasites kill 250,000 people every year. Treatment of schistosomiasis relies on the drug praziquantel. Unfortunately, a scarcity of molecular tools has hindered the discovery of new drug targets. Here, we describe a large-scale RNA interference (RNAi) screen in adult Schistosoma mansoni that examined the function of 2216 genes. We identified 261 genes with phenotypes affecting neuromuscular function, tissue integrity, stem cell maintenance, and parasite survival. Leveraging these data, we prioritized compounds with activity against the parasites and uncovered a pair of protein kinases (TAO and STK25) that cooperate to maintain muscle-specific messenger RNA transcription. Loss of either of these kinases results in paralysis and worm death in a mammalian host. These studies may help expedite therapeutic development and invigorate studies of these neglected parasites.

Ancient DNA has provided new insights into many aspects of human history. However, we lack comprehensive studies of the Y chromosomes of Denisovans and Neanderthals because the majority of specimens that have been sequenced to sufficient coverage are female. Sequencing Y chromosomes from two Denisovans and three Neanderthals shows that the Y chromosomes of Denisovans split around 700 thousand years ago from a lineage shared by Neanderthals and modern human Y chromosomes, which diverged from each other around 370 thousand years ago. The phylogenetic relationships of archaic and modern human Y chromosomes differ from the population relationships inferred from the autosomal genomes and mirror mitochondrial DNA phylogenies, indicating replacement of both the mitochondrial and Y chromosomal gene pools in late Neanderthals. This replacement is plausible if the low effective population size of Neanderthals resulted in an increased genetic load in Neanderthals relative to modern humans.

The challenge of prebiotic chemistry is to trace the syntheses of life’s key building blocks from a handful of primordial substrates. Here we report a forward-synthesis algorithm that generates a full network of prebiotic chemical reactions accessible from these substrates under generally accepted conditions. This network contains both reported and previously unidentified routes to biotic targets, as well as plausible syntheses of abiotic molecules. It also exhibits three forms of nontrivial chemical emergence, as the molecules within the network can act as catalysts of downstream reaction types; form functional chemical systems, including self-regenerating cycles; and produce surfactants relevant to primitive forms of biological compartmentalization. To support these claims, computer-predicted, prebiotic syntheses of several biotic molecules as well as a multistep, self-regenerative cycle of iminodiacetic acid were validated by experiment.

Although the development of effective vaccines has saved countless lives from infectious diseases, the basic workings of the human immune system are complex and have required the development of animal models, such as inbred mice, to define mechanisms of immunity. More recently, new strategies and technologies have been developed to directly explore the human immune system with unprecedented precision. We discuss how these approaches are advancing our mechanistic understanding of human immunology and are facilitating the development of vaccines and therapeutics for infection, autoimmune diseases, and cancer.

Although the avian pallium seems to lack an organization akin to that of the cerebral cortex, birds exhibit extraordinary cognitive skills that are comparable to those of mammals. We analyzed the fiber architecture of the avian pallium with three-dimensional polarized light imaging and subsequently reconstructed local and associative pallial circuits with tracing techniques. We discovered an iteratively repeated, column-like neuronal circuitry across the layer-like nuclear boundaries of the hyperpallium and the sensory dorsal ventricular ridge. These circuits are connected to neighboring columns and, via tangential layer-like connections, to higher associative and motor areas. Our findings indicate that this avian canonical circuitry is similar to its mammalian counterpart and might constitute the structural basis of neuronal computation.

Organelle identity depends on protein composition. How mistargeted proteins are selectively recognized and removed from organelles is incompletely understood. Here, we found that the orphan P5A–adenosine triphosphatase (ATPase) transporter ATP13A1 (Spf1 in yeast) directly interacted with the transmembrane segment (TM) of mitochondrial tail–anchored proteins. P5A-ATPase activity mediated the extraction of mistargeted proteins from the endoplasmic reticulum (ER). Cryo–electron microscopy structures of Saccharomyces cerevisiae Spf1 revealed a large, membrane-accessible substrate-binding pocket that alternately faced the ER lumen and cytosol and an endogenous substrate resembling an α-helical TM. Our results indicate that the P5A-ATPase could dislocate misinserted hydrophobic helices flanked by short basic segments from the ER. TM dislocation by the P5A-ATPase establishes an additional class of P-type ATPase substrates and may correct mistakes in protein targeting or topogenesis.