A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the global coronavirus infectious disease (COVID-19) public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved the expression and immunogenicity of betacoronavirus spike proteins1. Using this established immunogen design, the release of SARS-CoV-2

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or

The tuatara (Sphenodon punctatus)—the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana1,2—is an iconic species that is endemic to New Zealand2,3. A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes2,4. Here we analyse the

Lightning flashes have been observed by a number of missions that visited or flew by Jupiter over the past several decades. Imagery led to a flash rate estimate of about 4 × 10−3 flashes per square kilometre per year (refs. 1,2). The spatial extent of Voyager flashes was estimated to be about 30 kilometres (half-width at half-maximum intensity, HWHM), but the camera was unlikely to have detected the

As the temperature of a cooling object decreases as it relaxes to thermal equilibrium, it is intuitively assumed that a hot object should take longer to cool than a warm one. Yet, some 2,300 years ago, Aristotle observed that “to cool hot water quickly, begin by putting it in the sun”1,2. In the 1960s, this counterintuitive phenomenon was rediscovered as the statement that “hot water can freeze faster

The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity1,2,3. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which

Colonization by the microbiota causes a marked stimulation of B cells and induction of immunoglobulin, but mammals colonized with many taxa have highly complex and individualized immunoglobulin repertoires1,2. Here we use a simplified model of defined transient exposures to different microbial taxa in germ-free mice3 to deconstruct how the microbiota shapes the B cell pool and its functional responsiveness

In pathophysiology, reactive oxygen species oxidize biomolecules that contribute to disease phenotypes1. One such modification, 8-oxoguanine2 (o8G), is abundant in RNA3 but its epitranscriptional role has not been investigated for microRNAs (miRNAs). Here we specifically sequence oxidized miRNAs in a rat model of the redox-associated condition cardiac hypertrophy4. We find that position-specific o8G

White dwarfs represent the final state of evolution for most stars1,2,3. Certain classes of white dwarfs pulsate4,5, leading to observable brightness variations, and analysis of these variations with theoretical stellar models probes their internal structure. Modelling of these pulsating stars provides stringent tests of white dwarf models and a detailed picture of the outcome of the late stages of

Land use change—for example, the conversion of natural habitats to agricultural or urban ecosystems—is widely recognized to influence the risk and emergence of zoonotic disease in humans1,2. However, whether such changes in risk are underpinned by predictable ecological changes remains unclear. It has been suggested that habitat disturbance might cause predictable changes in the local diversity and

Semiclassical quantization of electronic states under a magnetic field, as proposed by Onsager, describes not only the Landau level spectrum but also the geometric responses of metals under a magnetic field1,2,3,4,5. Even in graphene with relativistic energy dispersion, Onsager’s rule correctly describes the π Berry phase, as well as the unusual Landau level spectrum of Dirac particles6,7. However

New Guinea is the world’s largest tropical island and has fascinated naturalists for centuries1,2. Home to some of the best-preserved ecosystems on the planet3 and to intact ecological gradients—from mangroves to tropical alpine grasslands—that are unmatched in the Asia-Pacific region4,5, it is a globally recognized centre of biological and cultural diversity6,7. So far, however, there has been no

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases1,2,3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational

Marine heatwaves (MHWs)—discrete but prolonged periods of anomalously warm ocean temperatures—can drastically alter ocean ecosystems, with profound ecological and socioeconomic impacts1,2,3,4,5,6,7,8. Considerable effort has been directed at understanding the patterns, drivers and trends of MHWs globally9,10,11. Typically, MHWs are characterized on the basis of their intensity and persistence at a

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response

The coevolution of mammalian hosts and their beneficial commensal microbes has led to development of a symbiotic host-microbiota relationship1. Epigenetic machinery permits mammalian cells to integrate environmental signals2, however, how these pathways are finely tuned by diverse cues from commensal bacteria is not well understood. Here, we reveal a highly selective pathway through which microbiota-derived

Members of the conserved Argonaute protein family use small RNA guides to find their mRNA targets to regulate gene expression and suppress mobile genetic elements in eukaryotes1,2. Argonautes are also present in many bacterial and archaeal species3–5. Unlike eukaryotic proteins, several studied prokaryotic Argonautes use small DNA guides to cleave DNA, a process dubbed DNA interference6–10. However

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1–8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms determining such variable outcomes remain unresolved. Here, we investigated SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral

Seeing—the angular size of stellar images blurred by atmospheric turbulence—is a critical parameter used to assess the quality of astronomical sites at optical/infrared wavelengths. Median values at the best mid-latitude sites are generally in the range of 0.6–0.8 arcseconds1,2,3. Sites on the Antarctic plateau are characterized by comparatively weak turbulence in the free atmosphere above a strong

Coronavirus disease 2019 (COVID-19) is a new pandemic disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. The C5a anaphylatoxin and its receptor C5aR1 (CD88) play a key role in the initiation and maintenance of several inflammatory responses, by recruiting and activating neutrophils and monocytes in the lungs1. We provide a longitudinal analysis of immune

The novel Coronavirus SARS-CoV-2 causes a respiratory illness called COVID-19 leading to a pandemic. An effective preventive vaccine against this virus is urgently needed. As the most critical step during infection, SARS-CoV-2 uses its Spike protein receptor-binding domain (S-RBD) to engage with the host cell receptor angiotensin-converting enzyme 2 (ACE2)1,2. Here we showed that a recombinant vaccine

The papain-like protease PLpro is an essential coronavirus enzyme required for processing viral polyproteins to generate a functional replicase complex and enable viral spread1,2. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host anti-viral immune responses3–5. Here, we provide biochemical, structural and functional

The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein—for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting

Cytosine DNA methylation is essential for mammalian development but understanding of its spatiotemporal distribution in the developing embryo remains limited1,2. Here, as part of the mouse Encyclopedia of DNA Elements (ENCODE) project, we profiled 168 methylomes from 12 mouse tissues or organs at 9 developmental stages from embryogenesis to adulthood. We identified 1,808,810 genomic regions that showed

All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1,2,3,4, a phenomenon that occurs in hypoxia4,5,6,7,8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed

Models of light–matter interactions in quantum electrodynamics typically invoke the dipole approximation1,2, in which atoms are treated as point-like objects when compared to the wavelength of the electromagnetic modes with which they interact. However, when the ratio between the size of the atom and the mode wavelength is increased, the dipole approximation no longer holds and the atom is referred

Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory

The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery1. Although the response of epidermal cells to stretching has been studied in vitro2,3, it remains unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a

Organic–inorganic hybrid perovskites have electronic and optoelectronic properties that make them appealing in many device applications1,2,3,4. Although many approaches focus on polycrystalline materials5,6,7, single-crystal hybrid perovskites show improved carrier transport and enhanced stability over their polycrystalline counterparts, due to their orientation-dependent transport behaviour8,9,10

Transcription factors are DNA-binding proteins that have key roles in gene regulation1,2. Genome-wide occupancy maps of transcriptional regulators are important for understanding gene regulation and its effects on diverse biological processes3,4,5,6. However, only a minority of the more than 1,600 transcription factors encoded in the human genome has been assayed. Here we present, as part of the ENCODE

During ontogeny, proliferating cells become restricted in their fate through the combined action of cell-type-specific transcription factors and ubiquitous epigenetic machinery, which recognizes universally available histone residues or nucleotides in a context-dependent manner1,2. The molecular functions of these regulators are generally well understood, but assigning direct developmental roles to

Although habitat loss is the predominant factor leading to biodiversity loss in the Anthropocene1,2, exactly how this loss manifests—and at which scales—remains a central debate3,4,5,6. The ‘passive sampling’ hypothesis suggests that species are lost in proportion to their abundance and distribution in the natural habitat7,8, whereas the ‘ecosystem decay’ hypothesis suggests that ecological processes

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)—an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent

In the regime of deep strong light–matter coupling, the coupling strength exceeds the transition energies of the material1,2,3, fundamentally changing its properties4,5; for example, the ground state of the system contains virtual photons and the internal electromagnetic field gets redistributed by photon self-interaction1,6. So far, no electronic excitation of a material has shown such strong coupling

During mammalian embryogenesis, differential gene expression gradually builds the identity and complexity of each tissue and organ system1. Here we systematically quantified mouse polyA-RNA from day 10.5 of embryonic development to birth, sampling 17 tissues and organs. The resulting developmental transcriptome is globally structured by dynamic cytodifferentiation, body-axis and cell-proliferation

The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we

Globular clusters are some of the oldest bound stellar structures observed in the Universe1. They are ubiquitous in large galaxies and are believed to trace intense star-formation events and the hierarchical build-up of structure2,3. Observations of globular clusters in the Milky Way, and a wide variety of other galaxies, have found evidence for a ‘metallicity floor’, whereby no globular clusters are

Many proteins regulate the expression of genes by binding to specific regions encoded in the genome1. Here we introduce a new data set of RNA elements in the human genome that are recognized by RNA-binding proteins (RBPs), generated as part of the Encyclopedia of DNA Elements (ENCODE) project phase III. This class of regulatory elements functions only when transcribed into RNA, as they serve as the

DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA1,2,3,4,5 and contain genetic variations associated with diseases and phenotypic traits6,7,8. We created high-resolution maps of DHSs from 733 human biosamples encompassing 438 cell and tissue types and states, and integrated these to delineate and numerically index approximately 3.6 million DHSs within the human genome sequence

Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer1,2. Here we studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal cancer caused by Csnk1a1 deletion3,4 or ApcMin mutation5. Cancer in these models is

RAG endonuclease initiates V(D)J recombination in progenitor (pro)-B cells1. Upon binding a recombination center (RC)-based JH, RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin, to locate Ds and assemble a DJH-based RC2. CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG-scanning3–5; but their inactivation allows scanning to proximal VHs

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1–4. Yet, longitudinal immunological correlates of disease outcome remain unclear. Here, we serially analysed immune responses in 113 COVID-19 patients with moderate (non-ICU) and severe (ICU) disease. Immune profiling revealed an overall increase in innate cell lineages with a concomitant reduction in

Tandem DNA repeats vary by the size and sequence of each unit (motif). When expanded, they have been associated with more than 40 monogenic disorders1. Their involvement in complex disorders is largely unknown, as is the extent of their heterogeneity. Here, we interrogated genome-wide characteristics of tandem repeats with 2–20-bp motifs in 17,231 genomes of families with autism2,3 and population controls4

The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly

MeCP2 (methyl CpG binding protein 2) is a key component of constitutive heterochromatin, which plays important roles in chromosome maintenance and transcriptional silencing1–3. Mutations in MeCP2 cause Rett syndrome (RTT)3–5, a postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like symptoms that manifests in girls during early childhood. Heterochromatin

The COVID-19 pandemic, which is caused by the novel coronavirus SARS-CoV-2, has been associated with more than 470,000 fatal cases worldwide. In order to develop antiviral interventions quickly, drugs used for treatment of unrelated diseases are currently being repurposed to combat COVID-19. Chloroquine is a anti-malaria drug that is frequently employed for COVID-19 treatment since it inhibits SARS-CoV-2

Persistently depolarizing sodium (Na+) leak currents that enhance electrical excitability have been described for decades1,2. The entity responsible for the major background Na+ conductance in neurons had remained a mystery until characterization of NALCN (Na+ leak channel, non-selective)3,4. NALCN-mediated currents regulate neuronal excitability linked to respiration, locomotion and circadian rhythm4–10

The G protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signaling of a vast variety of bile acids and is a signaling hub in the liver–bile-acid–microbiota–metabolism axis1–3. Here, we report the cryo-EM structures of GPBAR–Gs complexes stabilized by either the high-affinity P3954 or the semisynthesized bile acid derivative INT-7771,3 at 3-Å resolution. These structures revealed

The SARS-CoV-2 pandemic rages on with devasting consequences on human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this novel coronavirus. Here we report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among

COVID-19 has rapidly become a pandemic for which no antiviral drug or vaccine is yet available2–4. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro. Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals worldwide but definitive evidence for HCQ efficacy in treatment of COVID-19

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations

A relatively small number of proteins have been suggested to act as morphogens—signalling molecules that spread within tissues to organize tissue repair and the specification of cell fate during development. Among them are Wnt proteins, which carry a palmitoleate moiety that is essential for signalling activity1,2,3. How a hydrophobic lipoprotein can spread in the aqueous extracellular space is unknown

The initial colonization of the Americas remains a highly debated topic1, and the exact timing of the first arrivals is unknown. The earliest archaeological record of Mexico—which holds a key geographical position in the Americas—is poorly known and understudied. Historically, the region has remained on the periphery of research focused on the first American populations2. However, recent investigations

Efforts to improve sea level forecasting on a warming planet have focused on determining the temperature, sea level and extent of polar ice sheets during Earth’s past interglacial warm periods1,2,3. About 400,000 years ago, during the interglacial period known as Marine Isotopic Stage 11 (MIS11), the global temperature was 1 to 2 degrees Celsius greater2 and sea level was 6 to 13 metres higher1,3.

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition1,2,3,4,5. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders6,7,8,9. However, little is known about the organizational principles

The peopling of the Americas marks a major expansion of humans across the planet. However, questions regarding the timing and mechanisms of this dispersal remain, and the previously accepted model (termed ‘Clovis-first’)—suggesting that the first inhabitants of the Americas were linked with the Clovis tradition, a complex marked by distinctive fluted lithic points1—has been effectively refuted. Here

The electron–hole plasma in charge-neutral graphene is predicted to realize a quantum critical system in which electrical transport features a universal hydrodynamic description, even at room temperature1,2. This quantum critical ‘Dirac fluid’ is expected to have a shear viscosity close to a minimum bound3,4, with an interparticle scattering rate saturating1 at the Planckian time, the shortest possible

Complex organisms can rapidly induce select genes in response to diverse environmental cues. This regulation occurs in the context of large genomes condensed by histone proteins into chromatin. The sensing of pathogens by macrophages engages conserved signalling pathways and transcription factors to coordinate the induction of inflammatory genes1,2,3. Enriched integration of histone H3.3, the ancestral