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Stone tools stratified in alluvium and loess at Korolevo, western Ukraine, have been studied by several research groups1–3since the discovery of the site in the 1970s. Although Korolevo’s importance to the European Palaeolithic is widely acknowledged, age constraints on the lowermost lithic artefacts have yet to be determined conclusively. Here, using two methods of burial dating with cosmogenic nuclides4,5, we report ages of 1.42 ± 0.10 million years and 1.42 ± 0.28 million years for the sedimentary unit that contains Mode-1-type lithic artefacts. Korolevo represents, to our knowledge, the earliest securely dated hominin presence in Europe, and bridges the spatial and temporal gap between the Caucasus (around 1.85–1.78 million years ago)6and southwestern Europe (around 1.2–1.1 million years ago)7,8. Our findings advance the hypothesis that Europe was colonized from the east, and our analysis of habitat suitability9suggests that early hominins exploited warm interglacial periods to disperse into higher latitudes and relatively continental sites—such as Korolevo—well before the Middle Pleistocene Transition.

Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations1–6in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories7, we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees.

Oncoproteins of the MYC family drive the development of numerous human tumours1. In unperturbed cells, MYC proteins bind to nearly all active promoters and control transcription by RNA polymerase II2,3. MYC proteins can also coordinate transcription with DNA replication4,5and promote the repair of transcription-associated DNA damage6, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks7,8. MYC multimerization is triggered in a HUWE16and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double strand break formation during S-phase, suggesting that the multimerization of MYC enables tumour cells to proliferate under stressful conditions.

Colorectal malignancies are a leading cause of cancer-related death1and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4–7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.

Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather ‘plastic’. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.

Long-term analyses of biodiversity data highlight a ‘biodiversity conservation paradox’: biological communities show substantial species turnover over the past century1,2, but changes in species richness are marginal1,3–5. Most studies, however, have focused only on the incidence of species, and have not considered changes in local abundance. Here we asked whether analysing changes in the cover of plant species could reveal previously unrecognized patterns of biodiversity change and provide insights into the underlying mechanisms. We compiled and analysed a dataset of 7,738 permanent and semi-permanent vegetation plots from Germany that were surveyed between 2 and 54 times from 1927 to 2020, in total comprising 1,794 species of vascular plants. We found that decrements in cover, averaged across all species and plots, occurred more often than increments; that the number of species that decreased in cover was higher than the number of species that increased; and that decrements were more equally distributed among losers than were gains among winners. Null model simulations confirmed that these trends do not emerge by chance, but are the consequence of species-specific negative effects of environmental changes. In the long run, these trends might result in substantial losses of species at both local and regional scales. Summarizing the changes by decade shows that the inequality in the mean change in species cover of losers and winners diverged as early as the 1960s. We conclude that changes in species cover in communities represent an important but understudied dimension of biodiversity change that should more routinely be considered in time-series analyses.

Moiré superlattices in atomically thin van der Waals heterostructures hold great promise for extended control of electronic and valleytronic lifetimes1–7, the confinement of excitons in artificial moiré lattices8–13and the formation of exotic quantum phases14–18. Such moiré-induced emergent phenomena are particularly strong for interlayer excitons, where the hole and the electron are localized in different layers of the heterostructure19,20. To exploit the full potential of correlated moiré and exciton physics, a thorough understanding of the ultrafast interlayer exciton formation process and the real-space wavefunction confinement is indispensable. Here we show that femtosecond photoemission momentum microscopy provides quantitative access to these key properties of the moiré interlayer excitons. First, we elucidate that interlayer excitons are dominantly formed through femtosecond exciton–phonon scattering and subsequent charge transfer at the interlayer-hybridized Σ valleys. Second, we show that interlayer excitons exhibit a momentum fingerprint that is a direct hallmark of the superlattice moiré modification. Third, we reconstruct the wavefunction distribution of the electronic part of the exciton and compare the size with the real-space moiré superlattice. Our work provides direct access to interlayer exciton formation dynamics in space and time and reveals opportunities to study correlated moiré and exciton physics for the future realization of exotic quantum phases of matter.

The gut microbiome is associated with diverse diseases1–3, but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.

Self-organizing neural organoids grown from pluripotent stem cells1–3combined with single-cell genomic technologies provide opportunities to examine gene regulatory networks underlying human brain development. Here we acquire single-cell transcriptome and accessible chromatin data over a dense time course in human organoids covering neuroepithelial formation, patterning, brain regionalization and neurogenesis, and identify temporally dynamic and brain-region-specific regulatory regions. We developed Pando—a flexible framework that incorporates multi-omic data and predictions of transcription-factor-binding sites to infer a global gene regulatory network describing organoid development. We use pooled genetic perturbation with single-cell transcriptome readout to assess transcription factor requirement for cell fate and state regulation in organoids. We find that certain factors regulate the abundance of cell fates, whereas other factors affect neuronal cell states after differentiation. We show that the transcription factor GLI3 is required for cortical fate establishment in humans, recapitulating previous research performed in mammalian model systems. We measure transcriptome and chromatin accessibility in normal or GLI3-perturbed cells and identify two distinct GLI3 regulomes that are central to telencephalic fate decisions: one regulating dorsoventral patterning with HES4/5 as direct GLI3 targets, and one controlling ganglionic eminence diversification later in development. Together, we provide a framework for how human model systems and single-cell technologies can be leveraged to reconstruct human developmental biology.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response1. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and—concomitantly—protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model2and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD–foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD–foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD ‘down’, one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+and IFNγ+CD8+T cell responses. Prime–boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2–18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1–3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).

Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1–3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC–seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2as a myofibroblast-specific target in human kidney fibrosis.

BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in preventing COVID-191. Here we extend a previous phase-I/II trial report2by presenting data on the immune response induced by BNT162b2 prime–boost vaccination from an additional phase-I/II trial in healthy adults (18–55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNγ+or IL-2+CD8+and CD4+T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide–MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8+T cells of the early-differentiated effector-memory phenotype comprised 0.02–2.92% of total circulating CD8+T cells and were detectable (0.01–0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.

An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18–55 years of age. Two doses of 1–50 µg of BNT162b1 elicited robust CD4+and CD8+T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-µg dose) to 3.5-fold (50-µg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+and CD4+T cell expansion. Interferon-? was produced by a large fraction of RBD-specific CD8+and CD4+T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.

In March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1, a pandemic. With rapidly accumulating numbers of cases and deaths reported globally2, a vaccine is urgently needed. Here we report the available safety, tolerability and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose-escalation study (ClinicalTrials.gov identifier NCT04368728) among 45 healthy adults (18–55 years of age), who were randomized to receive 2 doses—separated by 21 days—of 10 µg, 30 µg or 100 µg of BNT162b1. BNT162b1 is a lipid-nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes the trimerized receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 µg was not administered because of the increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared with the 30-µg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second dose. Geometric mean neutralizing titres reached 1.9–4.6-fold that of a panel of COVID-19 convalescent human sera, which were obtained at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate.

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 processes3–6. 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 (Encyclopedia of DNA Elements) project, data and analyses from chromatin immunoprecipitation followed by high-throughput sequencing (ChIP–seq) experiments using the human HepG2 cell line for 208 chromatin-associated proteins (CAPs). These comprise 171 transcription factors and 37 transcriptional cofactors and chromatin regulator proteins, and represent nearly one-quarter of CAPs expressed in HepG2 cells. The binding profiles of these CAPs form major groups associated predominantly with promoters or enhancers, or with both. We confirm and expand the current catalogue of DNA sequence motifs for transcription factors, and describe motifs that correspond to other transcription factors that are co-enriched with the primary ChIP target. For example, FOX family motifs are enriched in ChIP–seq peaks of 37 other CAPs. We show that motif content and occupancy patterns can distinguish between promoters and enhancers. This catalogue reveals high-occupancy target regions at which many CAPs associate, although each contains motifs for only a minority of the numerous associated transcription factors. These analyses provide a more complete overview of the gene regulatory networks that define this cell type, and demonstrate the usefulness of the large-scale production efforts of the ENCODE Consortium.

Screening mammography aims to identify breast cancer at earlier stages of the disease, when treatment can be more successful1. Despite the existence of screening programmes worldwide, the interpretation of mammograms is affected by high rates of false positives and false negatives2. Here we present an artificial intelligence (AI) system that is capable of surpassing human experts in breast cancer prediction. To assess its performance in the clinical setting, we curated a large representative dataset from the UK and a large enriched dataset from the USA. We show an absolute reduction of 5.7% and 1.2% (USA and UK) in false positives and 9.4% and 2.7% in false negatives. We provide evidence of the ability of the system to generalize from the UK to the USA. In an independent study of six radiologists, the AI system outperformed all of the human readers: the area under the receiver operating characteristic curve (AUC-ROC) for the AI system was greater than the AUC-ROC for the average radiologist by an absolute margin of 11.5%. We ran a simulation in which the AI system participated in the double-reading process that is used in the UK, and found that the AI system maintained non-inferior performance and reduced the workload of the second reader by 88%. This robust assessment of the AI system paves the way for clinical trials to improve the accuracy and efficiency of breast cancer screening.

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1–8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.

The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)1,2. However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage3–5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)+fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+population: FAPα+THY1+immune effector fibroblasts located in the synovial sub-lining, and FAPα+THY1−destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+THY1−fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+THY1+fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve around the world, generating new variants that are of concern on the basis of their potential for altered transmissibility, pathogenicity, and coverage by vaccines and therapeutic agents1–5. Here we show that serum samples taken from twenty human volunteers, two or four weeks after their second dose of the BNT162b2 vaccine, neutralize engineered SARS-CoV-2 with a USA-WA1/2020 genetic background (a virus strain isolated in January 2020) and spike glycoproteins from the recently identified B.1.617.1, B.1.617.2, B.1.618 (all of which were first identified in India) or B.1.525 (first identified in Nigeria) lineages. Geometric mean plaque reduction neutralization titres against the variant viruses—particularly the B.1.617.1 variant—seemed to be lower than the titre against the USA-WA1/2020 virus, but all sera tested neutralized the variant viruses at titres of at least 1:40. The susceptibility of the variant strains to neutralization elicited by the BNT162b2 vaccine supports mass immunization as a central strategy to end the coronavirus disease 2019 (COVID-19) pandemic globally.

A key regulated step of transcription is promoter melting by RNA polymerase (RNAP) to form the open promoter complex1–3. To generate the open complex, the conserved catalytic core of the RNAP combines with initiation factors to locate promoter DNA, unwind 12–14 base pairs of the DNA duplex and load the template-strand DNA into the RNAP active site. Formation of the open complex is a multi-step process during which transient intermediates of unknown structure are formed4–6. Here we present cryo-electron microscopy structures of bacterial RNAP–promoter DNA complexes, including structures of partially melted intermediates. The structures show that late steps of promoter melting occur within the RNAP cleft, delineate key roles for fork-loop 2 and switch 2—universal structural features of RNAP—in restricting access of DNA to the RNAP active site, and explain why clamp opening is required to allow entry of single-stranded template DNA into the active site. The key roles of fork-loop 2 and switch 2 suggest a common mechanism for late steps in promoter DNA opening to enable gene expression across all domains of life.

The GABAA-receptor family has a crucial role in neural inhibition in the human brain. New structures of a GABAAreceptor highlight the mechanisms of crosstalk between its binding sites.

The X-ray flux of the bright galactic bulge source GX5-1 shows intensity-dependent quasi-periodic oscillations between ∼20 and ∼40 Hz, appearing as a broad peak in the power spectrum whose centroid frequency, width and integrated excess power strongly depend on the source intensity. The strength and steepness of low-frequency noise present in the power spectra below 15 Hz also depend on the source intensity. No evidence is found for coherent X-ray pulsations between 0.5 and 2,000 Hz. We discuss possible mechanisms to explain these new phenomena.

Cygnus X-3, a bright X-ray source at a distance1of more than ∼12 kpc beyond the edge of the galactic plane, has peculiar properties including very strong radio outbursts2, possibly showing jet-like features3, and emission in various γ-ray bands4–6(but see ref. 7). The discovery of its 4.8-h X-ray period8showed that the source is probably a compact (∼1011cm) binary system, but its nature and that of its companion, the mode of energy generation (accretion or Crab-like pulsar) and also the cause of the X-ray modulation are still uncertain. We describe here X-ray data on Cyg X-3, obtained with EXOSAT, showing transient quasi-periodic oscillations with amplitudes between 5 and 20% of the 1–10-keV flux and periods in the range 50–1,500 s. The oscillations persisted typically for 5–40 (quasi-oscillation) cycles, occurred exclusively in the phase interval 0.0–0.75 (rising branch and top of the X-ray light curve), were seen during the high state and probably also during the low state of the source, and, at least once, were observed with two different periods simultaneously. We suggest that the quasi-periodic flux variations are caused by quasi-periodic phenomena in an accretion disk which partially occults the X-ray source. This tentative interpretation is in accordance with the idea9that the 4.8-h modulation of the X-ray flux in Cyg X-3 arises by partial occultations of the X-ray source by an accretion disk, like in low-mass X-ray binaries such as 4U1822–37.

Eukaryotic cells contain genes termed proto-oncogenes (c-onc) which have the potential to transform cells in culture and induce tumours in vivo. Most of these genes have been identified by their occasional incorporation into retroviral genomes which can act as natural transducing vectors for these and perhaps other cellular genes1,2. Cell-derived oncogenes of retroviruses (v-onc) are associated mostly with the induction of mesenchymal tumours whereas carcinoma induction is rare3. One of these rare carcinoma-inducing viruses is the acutely transforming avian retrovirus MH2 (refs 3–5). Recently we6,7and others8have shown that this virus carries a novel putative oncogene, v-mil, in addition to the known oncogene v-myc. While the transforming ability of v-mil has not been directly established, we have recently discovered by hybridization analysis that v-mil is homologous to v-raf (ref. 9), the transforming gene of the murine retrovirus 3611 MSV (ref. 10). Both viruses express the mil/raf oncogene product as a gag-fusion polyprotein6,11, while the myc oncogene of MH2 is expressed via a subgenomic mRNA12. Here we report the complete nucleotide sequence of v-mil and compare it with that of v-raf34. The 80% homology between the nucleotide sequences and the 94% homology between the predicted amino acid sequences of the two viral genes clearly indicate that these are the avian and murine forms of the same gene. Comparison of the two sequences with that of the human cellular homologue13(T. I. Bonner et al., manuscript in preparation) indicates that v-raf has more 3′ untranslated sequences while v-mil has additional sequences from two 5′ exons of the cellular homologue. Although the mil/raf amino acid sequences reveal partial homology to that of the v-src product, no tyrosine-specific protein kinase activity is detected for the gag–mil and the gag–raf hybrid proteins.

Retroviral oncogenes (v-onc) are derived from cellular genes (c-onc) which are highly conserved among different species1–3. Retrovirus-transduced oncogenes are most commonly associated with the induction of haematopoietic tumours and sarcomas4. The avian retrovirus Mill Hill no. 2 (MH2) was isolated from a spontaneous ovarian tumour of a chicken and is distinguished by the predominant induction of liver and kidney carcinomas in fowl4–6. MH2 also induces transformation of fibroblasts, macrophages and epithelial cells in culture2,6,7. The genome of MH2 contains two unrelated and independently expressed cell-derived oncogenes, v-mil and v-myc8,9. Three other viral isolates among avian acute transforming retroviruses contain the v-myc oncogene2,10, but only MH2 contains both v-myc and v-mil. Hence, some of the pathogenic specificities of MH2 may be due to the simultaneous expression of two oncogenes. The murine sarcoma virus 3611 (3611-MSV) isolated from a mouse carrying lung carcinoma and peritoneal tumours11, induces fibrosarcomas in newborn mice and the transformation of fibro blasts and epithelial cells in culture11,12. The oncogenic properties of 3611-MSV are due to the presence in its genome of a cell-derived oncogene termed v-raf13. We report here that the two independently transduced oncogenes v-mil and v-raf are closely related and that they were apparently derived from homologous cellular genes of avian and mammalian species.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03102-w

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03098-3.

It is generally accepted that saturated polycyclic hydrocarbons such as steranes and triterpanes, present in crude oils and sediments, originate from naturally occurring steroids and triter-penoids. The occurrence of individual steranes and triterpanes can be used to relate the oil or sediment sample to the biological material from which it is derived. All previously known saturated C30pentacyclic hydrocarbons could be related to a naturally occurring triterpenoid. Here we report that the structure of a novel C30H52pentacyclic isoprenoid hydrocarbon present in some Far Eastern crude oils has been established as 2,6a,12-trimethyl-4,9-diisopropyl-perhydrobenzo[de]naphthacene by joint application of Chromatographie methods, mass spectrometry (MS), nuclear magnetic resonance (NMR), molecular mechanics and X-ray diffraction. As far as we know, this is the first report of the occurrence in nature of a pentacyclic C30isoprenoid compound with a perhy-drobenzo[de]naphthacene skeleton. It can be considered as a dimer of the sesquiterpane cadinane. A biosynthesis of the skeleton by direct cyclization of squalene seems impossible in this case.

CYTOPLASM of animal cells contains mRNA associated with ribosomes (in polysomes) and mRNA free of ribosome attachment. Both classes of mRNA occur as ribonucleoprotein (mRNP) complexes1–3. The role of the untranslated pool of free mRNA (referred to as informosomes3) is uncertain. They represent the form in which mRNA exists in transit from the nucleus to the cytoplasm awaiting association with ribosomes3, and in addition the pool of free cytoplasmic mRNA contains inactive (or inactivated) and storage forms of mRNA4. It has been established that most of the polysomal mRNP complexes contain predominantly two proteins with approximate molecular weights (MW) of 49,000–52,000 and 73,000–78,000 respectively5–9. It is generally accepted that the larger of these proteins is attached to the 3′ poly A tail of mRNA10–12. We present evidence here that the poly A segments of non-polysomal mRNA of Ehrlich ascites tumour cells and of rabbit reticulocytes—in contrast to the polysomal poly A segments10–13—do not contain the 76,000 MW protein.

During the past few years, several methods have been developed for the detection of specific nucleic acid sequences by in situ hybridization using non-radioactive labels such as fluorochromes, cytochemically detectable enzymes and electron-dense markers1–4. These methods are preferable to autoradiography in terms of speed of performance and topological resolution. Their limited sensitivity, however, has so far restricted their use to the detection of repeated sequences. Here we report single gene detection with a procedure using 2-acetylaminofluorene (AFF)-modified probes, immunoperoxidase cytochemistry and reflection-contrast microscopy. We confirmed the autoradiographic data on the localization of the human thyroglobulin (Tg) gene to the distal end of the long arm of chromosome 8 (ref. 5). A mixture of cosmid cHT2-derived subclones of the 3′ part of the Tg gene, 22.3 kilobase pairs (kbp) in total, was used as a hybridization probe. This procedure can be used to map other unique sequences, if genomic clones are available from which clones with an appropriate amount of inserts can be isolated.

Somatomedins (SM) or insulin-like growth factors (IGF) constitute a heterogeneous group of peptides1with important growth-promoting effects in vitro2,3as well as in vivo4,5. Amino acid sequences have been determined for only two of them, IGF-I and IGF-II, which are highly homologous6,7. IGF-I, which is identical with SM-C8, is composed of 70 amino acid residues and IGF-II contains 73 amino acids and may be identical with SM-A9. Other peptides with different charge properties but with similar SM-like or insulin-like behaviour in biological and receptor assays, have been described but have not yet been fully characterized1. The liver is known to be a major site of production of these peptides10, but many other tissues—especially in the fetus11—may synthesize them as well. We report here the nucleotide sequence of a human liver cDNA encoding the complete amino acid sequence of IGF-I. The IGF-I coding region is flanked by sequences encoding an amino-terminal peptide of at least 25 amino acid residues and a carboxyl-terminal peptide of 35 amino acids. This provides evidence that IGF-I is synthesized as a precursor protein and that formation of IGF-I from this precursor requires proteolytic processing at both ends.

IN the photolysis of the visual pigment rhodopsin the intermediate first observed is bathorhodopsin1,2(formerly called prelumirhodopsin). It is generally held that isomerisation of 11-cis to all-trans retinal occurs during this initial step. On theoretical grounds, however, an hexaene–amine structure (Fig. 1) has been proposed as an alternative for the chromophore of bathorodopsin (ref. 3 and unpublished results of K. Van der Meer, J. J. C. Mulder and J.L.). This chromophore has an exomethylene double bond between the atoms C5 and C18 and the nitrogen of its ene–amine moiety derives from the ɛ-amino group of a lysine residue of opsin. It is a retrotautomer of the chromophoric group in native rhodopsin which is a protonated Schiff base of 11-cis retinal. We now present two lines of evidence which support the structure depicted in Fig. 1: first, the interpretation of a recently published laser resonance Raman spectrum of bathorhodopsin4, and second, experiments which establish hydrogen (deuterium) exchange during photolysis of rhodopsin.

Several attempts to attack tumours in experimental systems have been made using conjugates of chemotherapeutic agents or potent toxins with antibodies (immunotoxins)1–8. In vitro studies have been highly successful, showing target specificity of a high order in some cases6–8. However, so far, such conjugates have been inadequate in vivo, probably for two main reasons. First, conventional heteroclonal antibodies are perhaps inappropriate, because purification by biochemical methods leaves a large amount of non-antibody γ-globulins. The use of monoclonal antibodies may overcome this problem. Second, when whole toxins have been conjugated to antibodies there has been a strong residual nonspecific cytotoxicity due to the binding capacity of a subunit, the B-piece of the toxin. (Diphtheria toxin or ricin consist of two polypeptide subunits. The A-piece is responsible for inhibition of protein synthesis on ribosomes, and the B-piece binds to galactose residues on the cell membrane and facilitates the transmembrane passage of the A-piece.) In the present work the problem of nonspecific binding by the B-piece has been circumvented by using the A-piece only as the toxin component of immunotoxins; these immunotoxins are active both in vitro and in vivo.

WE recently reported that in (C57BL6/Rij × A/HeJ) F1(=B6AF1) mice, in which cellular immunity was temporarily suppressed by anti-lymphocyte serum, established B10.D2 skin allografts were hyperacutely rejected after the administration of specific alloantibody and rabbit complement1. From this it was concluded that mouse skin allografts are sensitive to the cytotoxic action of alloantibody in vivo provided an effective species of complement is present at the same time.

CUBANE-TYPE clusters containing the unit M4A4have been the subject of many investigations. Several of these systems have been characterised by X-ray structure determination. Such clusters are important from a bioinorganic point of view, for example, Fe4S4clusters in iron–sulphur proteins1. From a catalytic point of view, clustered compounds are becoming increasingly important as models for heterogeneous catalysts, and even as catalysts by themselves2. Monoatomic ligands (for example, A = S, Cl, P, Br, Se) have been reported as bridging ligands in cubane-type clusters, but larger groups are known in which C, N, and O act in a similar way3. No cubane-type clusters have been previously reported with the highly electronegative F−ion as a bridging ligand. We describe here the synthesis and structure of the first fluoro-bridged cubane-type cluster, having the formula [M4F4(L)12.] (BF4)4, in which M = Mn, Cd, Co and L = N-ethylimidazole or N-propylimidazole. On reaction of M(H2O)6(BF4)2in ethanol–triethyl orthoformate with an ethanolic solution of the ligand, finely-divided white powders (Mn, Cd) or purple crystals (Co) separate, analysing as M(ligand)3BF5. In these circumstances the F−ions are spontaneously generated by a slow decomposition of the BF4−ion. Such a decomposition of tetrafluoroborates, yielding fluoro complexes, has been reported in a few other cases, yielding polymeric fluoro-bridged systems4, dimers (M2F2)5and also monomers MF2(ligand)4(ref. 6).

IT is generally believed that synaptic transmission is effected by a quantal release of transmitter substances, such as has been demonstrated for the neuromuscular junction1. The quantal nature of synaptic transmission in the central nervous system is more difficult to investigate, one reason being that many presynaptic fibres usually contribute to the EPSP (excitatory postsynaptic potential), whereas at the neuromuscular junction the entire effect is evoked from a single presynaptic fibre. Thus at central synapses the total synaptic action should be described both in terms of the number of unitary EPSPs (the EPSP contributed by a single presynaptic fibre) and the quantal composition of each unitary EPSP. In motoneurones, impulses in Ia afferents (large muscle spindle afferents) usually evoke small unitary EPSPs with a low quantal content2, but larger unitary Ia EPSPs with quantal content “possibly as high as ten or fifteen” have also been found3.