Early or sorting endosomes are dynamic organelles that play key roles in proteome control by triaging plasma membrane proteins for either recycling or degradation in the lysosome1,2. These events are coordinated by numerous transiently associated regulatory complexes and integral membrane components that contribute to organelle identity during endosome maturation3. Although a subset of the several hundred protein components and cargoes known to associate with endosomes have been studied at the biochemical and/or structural level, interaction partners and higher-order molecular assemblies for many endosomal components remain unknown. Here, we combine crosslinking and native gel mass spectrometry4-7 of purified early endosomes with AlphaFold8,9 and computational analysis to create a systematic human endosomal structural interactome. We present 229 structural models for endosomal protein pairs and additional higher-order assemblies supported by experimental crosslinks from their native subcellular context, suggesting structural mechanisms for previously reported regulatory processes. Using induced neurons, we validate two candidate complexes whose interactions are supported by crosslinks and structural predictions: TMEM230 as a subunit of ATP8 and ATP11 lipid flippases10 and TMEM9 and TMEM9B as subunits of the chloride-proton antiporters CLCN3, CLCN4 and CLCN5 (ref. 11). This resource and its accompanying structural network viewer provide an experimental framework for understanding organellar structural interactomes and large-scale validation of structural predictions.

The emergence of infectious diseases, particularly those caused by fungal pathogens, poses serious threats to public health, wildlife and ecosystem stability1. Host-fungus interactions and environmental factors have been extensively examined2-4. However, the role of genetic variability in pathogens is often less well-studied, even for diseases such as white-nose in bats, which has caused one of the highest disease-driven death tolls documented in nonhuman mammals5. Previous research on white-nose disease has primarily focused on variations in disease outcomes attributed to host traits or environmental conditions6-8, but has neglected pathogen variability. Here we leverage an extensive reference collection of 5,479 fungal isolates from 27 countries to reveal that the widespread causative agent is not a single species but two sympatric cryptic species, each exhibiting host specialization. Our findings provide evidence of recombination in each species, but significant genetic differentiation across their genomes, including differences in genome organization. Both species contain geographically differentiated populations, which enabled us to identify the species introduced to North America and trace its source population to a region in Ukraine. In light of our discovery of the existence of two cryptic species of the causative agent of white-nose disease, our research underscores the need to integrate the study of pathogen variability into comprehensive disease surveillance, management and prevention strategies. This holistic approach is crucial for enhancing our understanding of diseases and implementing effective measures to prevent their spread.

The multicellular coordination that underlies tissue homeostasis and disease progression is of fundamental interest1-5. However, how diverse cell types are organized within tissue niches for cohesive functioning remains largely unknown. Here we systematically characterized cross-tissue coordinated cellular modules in healthy tissues, uncovering their spatiotemporal dynamics and phenotypic associations, and examined their rewiring in cancer. We first compiled a comprehensive single-cell transcriptomic atlas from 35 human tissues, revealing substantial inter-tissue variability in cellular composition. By leveraging covariance in cellular abundance, we identified 12 cellular modules with distinct cellular compositions, tissue prevalences and spatial organizations, and demonstrated coordinated intercellular communication within cellular modules using in situ spatial and in vivo perturbation data. Among them, two immune cellular modules in the spleen showed contrasting chronological dynamics with ageing. Analysis of multicellular changes in the breast revealed a menopausal trajectory associated with fibroblast dynamics. Furthermore, interrogation across cancer types uncovered simultaneous rewiring of two types of multicellular ecosystem during tumour progression, including the loss of tissue-specific healthy organization and the emergence of a convergent cancerous ecosystem. These findings reveal fundamental organizing principles of multicellular ecosystems in health and cancer, laying a foundation for further investigations into tissue-level functional coordination across diverse contexts.

Scientists and inventors set the direction of their work amid evolving questions, opportunities and challenges, yet the understanding of pivots between research areas and their outcomes remains limited1-5. Theories of creative search highlight the potential benefits of exploration but also emphasize difficulties in moving beyond one's expertise6-14. Here we introduce a measurement framework to quantify how far researchers move from their existing work, and apply it to millions of papers and patents. We find a pervasive 'pivot penalty', in which the impact of new research steeply declines the further a researcher moves from their previous work. The pivot penalty applies nearly universally across science and patenting, and has been growing in magnitude over the past five decades. Larger pivots further exhibit weak engagement with established mixtures of prior knowledge, lower publication success rates and less market impact. Unexpected shocks to the research landscape, which may push researchers away from existing areas or pull them into new ones, further demonstrate substantial pivot penalties, including in the context of the COVID-19 pandemic. The pivot penalty generalizes across fields, career stage, productivity, collaboration and funding contexts, highlighting both the breadth and depth of the adaptive challenge. Overall, the findings point to large and increasing challenges in effectively adapting to new opportunities and threats, with implications for individual researchers, research organizations, science policy and the capacity of science and society as a whole to confront emergent demands.

Anyons1,2 are low-dimensional quasiparticles that obey fractional statistics, hence interpolating between bosons and fermions. In two dimensions, they exist as elementary excitations of fractional quantum Hall states3-5 and are believed to enable topological quantum computing6,7. One-dimensional anyons have been theoretically proposed, but their experimental realization has proven to be difficult. Here we observed emergent anyonic correlations in a one-dimensional strongly interacting quantum gas, resulting from the phenomenon of spin-charge separation8-10. A mobile impurity provides the necessary spin degree of freedom to engineer anyonic correlations in the charge sector and simultaneously acts as a probe to reveal these correlations. Starting with bosons, we tune the statistical phase to transmute bosons through anyons to fermions and observe an asymmetric momentum distribution11-14, a hallmark of anyonic correlations. Going beyond equilibrium conditions, we observed dynamical fermionization of the anyons15. This study opens the door to the exploration of non-equilibrium anyonic phenomena in a highly controllable setting15-17.

Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body1. Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss2,3, but genetic aetiologies of euploid pregnancy loss remain largely unexplained4. Here we characterize sequence diversity in early pregnancy loss through whole-genome sequencing of 1,007 fetal samples and 934 parental samples from 467 trios affected by pregnancy loss (fetus, mother and father). Sequenced parental genomes enabled us to determine both the parental and meiotic origins of chromosomal abnormalities, detected in half of our set. It further enabled us to assess de novo mutations on both homologous chromosomes from parents transmitting extra chromosomes, and date them, revealing that 6.6% of maternal mutations occurred before sister chromatid formation in fetal oocytes. We find a similar number of de novo mutations in the trios affected by pregnancy loss as in 9,651 adult trios, but three times the number of pathogenic small (<50 bp) sequence variant genotypes in the loss cases compared with adults. Overall, our findings indicate that around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus. Our results highlight the vast sequence diversity that is lost in early pregnancy.

Reliable forecasting of the Earth system is essential for mitigating natural disasters and supporting human progress. Traditional numerical models, although powerful, are extremely computationally expensive1. Recent advances in artificial intelligence (AI) have shown promise in improving both predictive performance and efficiency2,3, yet their potential remains underexplored in many Earth system domains. Here we introduce Aurora, a large-scale foundation model trained on more than one million hours of diverse geophysical data. Aurora outperforms operational forecasts in predicting air quality, ocean waves, tropical cyclone tracks and high-resolution weather, all at orders of magnitude lower computational cost. With the ability to be fine-tuned for diverse applications at modest expense, Aurora represents a notable step towards democratizing accurate and efficient Earth system predictions. These results highlight the transformative potential of AI in environmental forecasting and pave the way for broader accessibility to high-quality climate and weather information.

Cell heterogeneity is a universal feature of life. Although biological processes affected by cell-to-cell variation are manifold, from developmental plasticity to tumour heterogeneity and differential drug responses, the sources of cell heterogeneity remain largely unclear1,2. Mutational and epigenetic signatures from cancer (epi)genomics are powerful for deducing processes that shaped cancer genome evolution3-5. However, retrospective analyses face difficulties in resolving how cellular heterogeneity emerges and is propagated to subsequent cell generations. Here, we used multigenerational single-cell tracking based on endogenously labelled proteins and custom-designed computational tools to elucidate how oncogenic perturbations induce sister cell asymmetry and phenotypic heterogeneity. Dual CRISPR-based genome editing enabled simultaneous tracking of DNA replication patterns and heritable endogenous DNA lesions. Cell lineage trees of up to four generations were tracked in asynchronously growing cells, and time-resolved lineage analyses were combined with end-point measurements of cell cycle and DNA damage markers through iterative staining. Besides revealing replication and repair dynamics, damage inheritance and emergence of sister cell heterogeneity across multiple cell generations, through combination with single-cell transcriptomics, we delineate how common oncogenic events trigger multiple routes towards polyploidization with distinct outcomes for genome integrity. Our study provides a framework to dissect phenotypic plasticity at the single-cell level and sheds light onto cellular processes that may resemble early events during cancer development.

The earliest record of tooth antecedents and the tissue dentine1,2, an early-vertebrate novelty, has been controversially represented by fragmentary Cambrian fossils identified as Anatolepis heintzi3-5. Anatolepis exoskeletons have the characteristic tubules of dentine that prompted their interpretation as the first precursors of teeth3, known as odontodes. Debates over whether Anatolepis is a legitimate vertebrate6-8 have arisen because of limitations in imaging and the lack of comparative exoskeletal tissues. Here, to resolve this controversy and understand the origin of dental tissues, we synchrotron-scanned diverse extinct and extant vertebrate and invertebrate exoskeletons. We find that the tubules of Anatolepis have been misidentified as dentine tubules and instead represent aglaspidid arthropod sensory sensilla structures9,10. Synchrotron scanning reveals that deep ultrastructural similarities between odontodes and sensory structures also extend to definitive vertebrate tissues. External odontodes of the Ordovician vertebrate Eriptychius11-13 feature large dentine tubules1 that are morphologically convergent with invertebrate sensilla. Immunofluorescence analysis shows that the external odontodes of extant chondrichthyans and teleosts retain extensive innervation suggestive of a sensory function akin to teeth14-16. These patterns of convergence and innervation reveal that dentine evolved as a sensory tissue in the exoskeleton of early vertebrates, a function retained in modern vertebrate teeth16. Middle-Ordovician fossils now represent the oldest known evidence for vertebrate dental tissues.

The amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signalling centres that together fuel regeneration1. Anterior and posterior identities are established during development and are thought to persist for the whole life in the form of positional memory2. However, the molecular basis of positional memory and whether positional memory can be altered remain unknown. Here, we identify a positive-feedback loop that is responsible for posterior identity in the limb of an axolotl (Ambystoma mexicanum). Posterior cells express residual Hand2 transcription factor from development, and this primes them to form a Shh signalling centre after limb amputation. During regeneration, Shh signalling is also upstream of Hand2 expression. After regeneration, Shh is shut down but Hand2 is sustained, safeguarding posterior memory. We used this regeneration circuitry to convert anterior cells to a posterior-cell memory state. Transient exposure of anterior cells to Shh during regeneration kick-started an ectopic Hand2-Shh loop, leading to stable Hand2 expression and lasting competence to express Shh. Our results implicate positive-feedback in the stability of positional memory and reveal that positional memory is reprogrammed more easily in one direction (anterior to posterior) than in the other. Modifying positional memory in regenerative cells changes their signalling outputs, which has implications for tissue engineering.

Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound's backbone structure1,2. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Instead of constructing a heteroarene classically from basic building blocks, structural variants are readily accessible directly starting from a lead compound or approved pharmacophore. Here we present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Reactions proceed through ring-opened oximes as intermediates. These ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzoxazoles. The compound classes obtained through these methods-indazoles3,4, benzisoxazoles5, benzimidazoles6,7 and benzoxazoles8-are biologically relevant moieties found as substructures in natural products and pharmaceuticals. The procedures introduced substantially enlarge the methods portfolio in the emerging field of skeletal editing.

Carbon has a central role in biology and organic chemistry, and its solid allotropes provide the basis of much of our modern technology1. However, the liquid form of carbon remains nearly uncharted2, and the structure of liquid carbon and most of its physical properties are essentially unknown3. But liquid carbon is relevant for modelling planetary interiors4,5 and the atmospheres of white dwarfs6, as an intermediate state for the synthesis of advanced carbon materials7,8, inertial confinement fusion implosions9, hypervelocity impact events on carbon materials10 and our general understanding of structured fluids at extreme conditions11. Here we present a precise structure measurement of liquid carbon at pressures of around 1 million atmospheres obtained by in situ X-ray diffraction at an X-ray free-electron laser. Our results show a complex fluid with transient bonding and approximately four nearest neighbours on average, in agreement with quantum molecular dynamics simulations. The obtained data substantiate the understanding of the liquid state of one of the most abundant elements in the universe and can test models of the melting line. The demonstrated experimental abilities open the path to performing similar studies of the structure of liquids composed of light elements at extreme conditions.

Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.

The isotopic composition of lavas associated with mantle plumes has previously been interpreted in the light of core-mantle interaction, suggesting that mantle plumes may transport core material to Earth's surface1-5. However, a definitive fingerprint of Earth's core in the mantle remains unconfirmed. Precious metals, such as ruthenium (Ru), are highly concentrated in the metallic core but extremely depleted in the silicate mantle. Recently discovered mass-independent Ru isotope variations (ε100Ru) in ancient rocks show that the Ru isotope composition of accreted material changed during later stages of Earth's growth6, indicating that the core and mantle must have different Ru isotope compositions. This illustrates the potential of Ru isotopes as a new tracer for core-mantle interaction. Here we report Ru isotope anomalies for ocean island basalts. Basalts from Hawaii have higher ε100Ru than the ambient mantle. Combined with unradiogenic tungsten (W) isotope ratios, this is diagnostic of a core contribution to their mantle sources. The combined Ru and W isotope systematics of Hawaiian basalts are best explained by simple core entrainment but addition of core-derived oxide minerals at the core-mantle boundary is a possibility.

One-carbon homologues are structurally related and functionally identical organic molecules whose chain lengths differ by a single methylene (-CH2-) unit1. Across many classes of molecule-including pharmaceutical agents, natural products, agrochemicals, fragrances and petroleum products-the physicochemical characteristics exhibited by members of a homologous series subtly differ from one compound to another, which can impart remarkable differences to their function2. The efficient generation of homologues is, therefore, an important strategy in molecular discovery programmes3,4. Despite the availability of homologation strategies for several functional groups5,6, direct and general methods for one-carbon chain extension in alkenes remain an unmet synthetic need7,8. Here we report a catalytic one-carbon homologation process that is effective for many classes of alkene in simple and complex molecules. By leveraging the intrinsic reactivity of a new multifaceted allylsulfone reagent, a streamlined one-pot process, involving cross-metathesis and a fragmentation-retro-ene cascade, formally inserts a single methylene unit into the alkene chain. Among the applications of this process to several structurally and functionally complex molecules, we demonstrate how this practical transformation generates previously unexplored homologues of cyclosporine A9. These homologues exhibit modulated pharmacological and biological properties and could provide promising leads as cyclophilin inhibitors, a target that has great potential in many disease areas10.