Protein structures can provide invaluable information, both for reasoning about biological processes and for enabling interventions such as structure-based drug development or targeted mutagenesis. After decades of effort, 17% of the total residues in human protein sequences are covered by an experimentally-determined structure1. Here we dramatically expand structural coverage by applying the state-of-the-art

The classic mode of STING activation is through binding the cyclic dinucleotide 2′3′-cyclic GMP–AMP (cGAMP), produced by the DNA sensor cyclic GMP–AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity

Hepatocellular carcinoma (HCC)—the most common form of liver cancer—is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR–Cas9 genetic screen, we show that inhibition

Infection-induced aversion against enteropathogens is a conserved sickness behaviour that can promote host survival1,2. The aetiology of this behaviour remains poorly understood, but studies in Drosophila have linked olfactory and gustatory perception to avoidance behaviours against toxic microorganisms3,4,5. Whether and how enteric infections directly influence sensory perception to induce or modulate

The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels1. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational

Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1,2,3; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity

In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex1. Separation of chromosomes during anaphase is triggered by separase—a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD212,3,4). Separase is activated by degradation of its inhibitors, securin5 and cyclin B6, but the molecular mechanisms of separase regulation are not

Nearly 50 years ago, Intel created the world’s first commercially produced microprocessor—the 4004 (ref. 1), a modest 4-bit CPU (central processing unit) with 2,300 transistors fabricated using 10 μm process technology in silicon and capable only of simple arithmetic calculations. Since this ground-breaking achievement, there has been continuous technological development with increasing sophistication

X-ray free-electron lasers can generate intense and coherent radiation at wavelengths down to the sub-ångström region1,2,3,4,5, and have become indispensable tools for applications in structural biology and chemistry, among other disciplines6. Several X-ray free-electron laser facilities are in operation2,3,4,5; however, their requirement for large, high-cost, state-of-the-art radio-frequency accelerators

Moiré quantum matter has emerged as a materials platform in which correlated and topological phases can be explored with unprecedented control. Among them, magic-angle systems constructed from two or three layers of graphene have shown robust superconducting phases with unconventional characteristics1,2,3,4,5. However, direct evidence of unconventional pairing remains to be experimentally demonstrated

Although Venus is a terrestrial planet similar to Earth, its atmospheric circulation is much different and poorly characterized1. Winds at the cloud top have been measured predominantly on the dayside. Prominent poleward drifts have been observed with dayside cloud tracking and interpreted to be caused by thermal tides and a Hadley circulation2,3,4; however, the lack of nightside measurements over

Whereas ferromagnets have been known and used for millennia, antiferromagnets were only discovered in the 1930s1. At large scale, because of the absence of global magnetization, antiferromagnets may seem to behave like any non-magnetic material. At the microscopic level, however, the opposite alignment of spins forms a rich internal structure. In topological antiferromagnets, this internal structure

Since its discovery1,2, the deep-sea glass sponge Euplectella aspergillum has attracted interest in its mechanical properties and beauty. Its skeletal system is composed of amorphous hydrated silica and is arranged in a highly regular and hierarchical cylindrical lattice that begets exceptional flexibility and resilience to damage3,4,5,6. Structural analyses dominate the literature, but hydrodynamic

The unconventional T cell compartment encompasses a variety of cell subsets that straddle the line between innate and adaptive immunity, often reside at mucosal surfaces and can recognize a wide range of non-polymorphic ligands. Recent advances have highlighted the role of unconventional T cells in tissue homeostasis and disease. In this Review, we recast unconventional T cell subsets according to

Rigid molecular sieving materials work well for small molecules with the complete exclusion of large ones1,2,3, and molecules with matching physiochemical properties may be separated using dynamic molecular sieving materials4,5,6. Metal–organic frameworks (MOFs)7,8,9 are known for their precise control of structures and functions on a molecular level10,11,12,13,14,15. However, the rational design of

Synthetic chemistry is built around the formation of carbon−carbon bonds. Conversely, selective methods for C−C bond cleavage is a largely unmet challenge1–6, the solution of which will provide promising applications in synthesis, coal liquefaction, petroleum cracking, polymer degradation and biomass conversion. For example, aromatic rings are ubiquitous skeletal features in inert chemical feed stocks

The recent emergence of SARS-CoV-2 variants of concern (VOC)1–10 and the recurrent spillovers of coronaviruses11,12 in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved

Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort1–4, the structures of around 100,000 unique proteins have been determined5, but this represents a small fraction of the billions of known protein sequences6,7. Structural coverage is bottlenecked by the months to years of painstaking

Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger 2′3′-cGAMP and controls activation of innate immunity in mammalian cells1–5. Animal genomes typically encode multiple proteins with predicted homology to cGAS6–10, but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors capable of

In mammals, cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide (CDN) 2'3'-cGAMP in response to cytosolic DNA and this triggers an antiviral immune response. cGAS belongs to a large family of cGAS/DncV-like nucleotidyltransferases, present in both prokaryotes1 and eukaryotes2–5. In bacteria, these enzymes synthesize a range of cyclic oligonucleotide and have recently emerged as

An ideal anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse SARS-related coronaviruses (sarbecoviruses)4–7, and be highly protective through viral neutralization8–11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively

The evolution of the global carbon and silicon cycles is thought to have contributed to the long-term stability of Earth’s climate1,2,3. Many questions remain, however, regarding the feedback mechanisms at play, and there are limited quantitative constraints on the sources and sinks of these elements in Earth’s surface environments4,5,6,7,8,9,10,11,12. Here we argue that the lithium-isotope record

Isotope abundance ratios have an important role in astronomy and planetary sciences, providing insights into the origin and evolution of the Solar System, interstellar chemistry and stellar nucleosynthesis1,2. In contrast to deuterium/hydrogen ratios, carbon isotope ratios are found to be roughly constant (around 89) in the Solar System1,3, but do vary on galactic scales with a 12C/13C isotopologue

Realizing the potential of quantum computing requires sufficiently low logical error rates1. Many applications call for error rates as low as 10−15 (refs. 2,3,4,5,6,7,8,9), but state-of-the-art quantum platforms typically have physical error rates near 10−3 (refs. 10,11,12,13,14). Quantum error correction15,16,17 promises to bridge this divide by distributing quantum logical information across many

Pathogenic fungi reside in the intestinal microbiota but rarely cause disease. Little is known about the interactions between fungi and the immune system that promote commensalism. Here we investigate the role of adaptive immunity in promoting mutual interactions between fungi and host. We find that potentially pathogenic Candida species induce and are targeted by intestinal immunoglobulin A (IgA)

The balance between bacterial colonization and its containment in the intestine is indispensable for the symbiotic relationship between humans and their bacteria. One component to maintain homeostasis at the mucosal surfaces is immunoglobulin A (IgA), the most abundant immunoglobulin in mammals1,2. Several studies have revealed important characteristics of poly-reactive IgA3,4, which is produced naturally

The ability to accurately control the dynamics of physical systems by measurement and feedback is a pillar of modern engineering1. Today, the increasing demand for applied quantum technologies requires adaptation of this level of control to individual quantum systems2,3. Achieving this in an optimal way is a challenging task that relies on both quantum-limited measurements and specifically tailored

Communication within the glial cell ecosystem is essential for neuronal and brain health1,2,3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that

With the rapid growth and development of proton-exchange membrane fuel cell (PEMFC) technology, there has been increasing demand for clean and sustainable global energy applications. Of the many device-level and infrastructure challenges that need to be overcome before wide commercialization can be realized, one of the most critical ones is increasing the PEMFC power density, and ambitious goals have

Tests of quantum mechanics on a macroscopic scale require extreme control over mechanical motion and its decoherence1,2,3. Quantum control of mechanical motion has been achieved by engineering the radiation–pressure coupling between a micromechanical oscillator and the electromagnetic field in a resonator4,5,6,7. Furthermore, measurement-based feedback control relying on cavity-enhanced detection schemes

Amazonia hosts the Earth’s largest tropical forests and has been shown to be an important carbon sink over recent decades1,2,3. This carbon sink seems to be in decline, however, as a result of factors such as deforestation and climate change1,2,3. Here we investigate Amazonia’s carbon budget and the main drivers responsible for its change into a carbon source. We performed 590 aircraft vertical profiling

G-protein-coupled receptor (GPCR) kinases (GRKs) selectively phosphorylate activated GPCRs, thereby priming them for desensitization1. Although it is unclear how GRKs recognize these receptors2,3,4, a conserved region at the GRK N terminus is essential for this process5,6,7,8. Here we report a series of cryo-electron microscopy single-particle reconstructions of light-activated rhodopsin (Rho*) bound

The emergency use authorization of two mRNA vaccines in less than a year since the emergence of SARS-CoV-2 represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers vaccinated with

The remaining carbon budget for limiting global warming to 1.5°C will likely be exhausted within this decade1,2. Carbon debt3 generated thereafter will need to be compensated by net negative emissions4. However, economic policy instruments to guarantee potentially very costly net carbon-dioxide removal (CDR) have not yet been devised. Here, we propose intertemporal instruments to provide the basis

There is a realistic expectation that the global effort in vaccination will bring the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic under control. Nonetheless, uncertainties remain about the type of long-term association the virus will establish with the human population, particularly whether the coronavirus disease 2019 (COVID-19) will become an endemic disease. Although the

The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity1,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1–5. It has since then become dominant in some indian regions and UK and further spread to many countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), harbouring diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines1–3. VITT resembles heparin-induced thrombocytopenia (HIT) as it is associated with platelet-activating antibodies against platelet factor 4 (PF4)4; however, patients with VITT develop thrombocytopenia and thrombosis without heparin exposure. The objective of this study was to determine

Biomolecular condensates have emerged as an important subcellular organizing principle1. Replication of many viruses, including human respiratory syncytial virus (RSV), occurs in virus-induced compartments called inclusion bodies (IBs) or viroplasm2,3. IBs of negative-strand RNA viruses were recently shown to be biomolecular condensates that form through phase separation4,5. Here we report that the

The neuronal-type (N-type) voltage-gated calcium (Cav) channels, which are designated Cav2.2, have an important role in the release of neurotransmitters1,2,3. Ziconotide is a Cav2.2-specific peptide pore blocker that has been clinically used for treating intractable pain4,5,6. Here we present cryo-electron microscopy structures of human Cav2.2 (comprising the core α1 and the ancillary α2δ-1 and β3

Food supply shocks are increasing worldwide1,2, particularly the type of shock wherein food production or distribution loss in one location propagates through the food supply chain to other locations3,4. Analogous to biodiversity buffering ecosystems against external shocks5,6, ecological theory suggests that food supply chain diversity is crucial for managing the risk of food shock to human populations7

Single-phase high- and medium-entropy alloys with face-centred cubic (fcc) structure can exhibit high tensile ductility1,2 and excellent toughness2,3, but their room-temperature strengths are low1,2,3. Dislocation obstacles such as grain boundaries4, twin boundaries5, solute atoms6 and precipitates7,8,9 can increase strength. However, with few exceptions8,9,10,11, such obstacles tend to decrease ductility

Peptide-chain elongation during protein synthesis entails sequential aminoacyl-tRNA selection and translocation reactions that proceed rapidly (2–20 per second) and with a low error rate (around 10−3 to 10−5 at each step) over thousands of cycles1. The cadence and fidelity of ribosome transit through mRNA templates in discrete codon increments is a paradigm for movement in biological systems that must

The role of subducting topography on the mode of fault slip—particularly whether it hinders or facilitates large megathrust earthquakes—remains a controversial topic in subduction dynamics1,2,3,4,5. Models have illustrated the potential for subducting topography to severely alter the structure, stress state and mechanics of subduction zones4,6; however, direct geophysical imaging of the complex fracture

T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFH cells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFH cell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with

Exotic phenomena can be achieved in quantum materials by confining electronic states into two dimensions. For example, relativistic fermions are realized in a single layer of carbon atoms1, the quantized Hall effect can result from two-dimensional (2D) systems2,3, and the superconducting transition temperature can be considerably increased in a one-atomic-layer material4,5. Ordinarily, a 2D electronic

Long-lasting internal arousal states motivate and pattern ongoing behaviour, enabling the temporary emergence of innate behavioural programs that serve the needs of an animal, such as fighting, feeding, and mating. However, how internal states shape sensory processing or behaviour remains unclear. In Drosophila, male flies perform a lengthy and elaborate courtship ritual that is triggered by the activation

The cation channel of sperm (CatSper) is essential for sperm motility and fertility1,2. CatSper comprises the pore-forming CatSper1-4 and multiple auxiliary subunits, including CatSperβ, γ, δ, ε, ζ, and EFCAB91,3–9. Here, we report the cryo-EM structure of the CatSper complex isolated from mouse sperms. In the extracellular view, CatSper1-4 conform to the conventional domain-swapped voltage-gated ion

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, data are scarce on vaccine efficacy against variants of concern (VOC) in individuals above 80 years of age1. Here we analysed immune responses following vaccination with mRNA vaccine BNT162b22 in elderly participants and younger health care workers. Serum neutralisation and binding IgG/IgA after the first vaccine dose

Following the first wave of SARS-CoV-2 infections in spring 2020, Europe experienced a resurgence of the virus starting in late summer 2020 that was deadlier and more difficult to contain1. Relaxed intervention measures and summer travel have been implicated as drivers of the second wave2. Here, we build a phylogeographic model to evaluate how newly introduced lineages, as opposed to the rekindling

Computational social science is more than just large repositories of digital data and the computational methods needed to construct and analyse them. It also represents a convergence of different fields with different ways of thinking about and doing science. The goal of this Perspective is to provide some clarity around how these approaches differ from one another and to propose how they might be

Atomic clocks, which lock the frequency of an oscillator to the extremely stable quantized energy levels of atoms, are essential for navigation applications such as deep space exploration1 and global navigation satellite systems2, and are useful tools with which to address questions in fundamental physics3,4,5,6. Such satellite systems use precise measurement of signal propagation times determined

When the Coulomb repulsion between electrons dominates over their kinetic energy, electrons in two-dimensional systems are predicted to spontaneously break continuous-translation symmetry and form a quantum crystal1. Efforts to observe2,3,4,5,6,7,8,9,10,11,12 this elusive state of matter, termed a Wigner crystal, in two-dimensional extended systems have primarily focused on conductivity measurements

It has been the historic responsibility of the social sciences to investigate human societies. Fulfilling this responsibility requires social theories, measurement models and social data. Most existing theories and measurement models in the social sciences were not developed with the deep societal reach of algorithms in mind. The emergence of ‘algorithmically infused societies’—societies whose very

Social and cultural forces shape almost every aspect of infectious disease transmission in human populations, as well as our ability to measure, understand, and respond to epidemics. For directly transmitted infections, pathogen transmission relies on human-to-human contact, with kinship, household, and societal structures shaping contact patterns that in turn determine epidemic dynamics. Social, economic

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism1. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric

One of the first theoretically predicted manifestations of strong interactions in many-electron systems was the Wigner crystal1,2,3, in which electrons crystallize into a regular lattice. The crystal can melt via either thermal or quantum fluctuations4. Quantum melting of the Wigner crystal is predicted to produce exotic intermediate phases5,6 and quantum magnetism7,8 because of the intricate interplay

Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut–brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical

The size of the transcriptional program of long non-coding RNAs in the mammalian genome has engendered discussions about their biological roles1, particularly the promoter antisense (PAS) transcripts2,3. Here we report the development of an assay—referred to as chromatin isolation by RNA–Cas13a complex—to quantitatively detect the distribution of RNA in the genome. The assay revealed that PAS RNAs

The natural world provides many examples of multiphase transport and reaction processes that have been optimized by evolution. These phenomena take place at multiple length and time scales and typically include gas–liquid–solid interfaces and capillary phenomena in porous media1,2. Many biological and living systems have evolved to optimize fluidic transport. However, living things are exceptionally