Latest Articles

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Nature · Dec 04, 2025

Persuading voters using human–artificial intelligence dialogues

There is great public concern about the potential use of generative artificial intelligence (AI) for political persuasion and the resulting impacts on elections and democracy1,2,3,4,5,6. We inform these concerns using pre-registered experiments to assess the ability of large language models to influence voter attitudes. In the context of the 2024 US presidential election, the 2025 Canadian federal election and the 2025 Polish presidential election, we assigned participants randomly to have a conversation with an AI model that advocated for one of the top two candidates. We observed significant treatment effects on candidate preference that are larger than typically observed from traditional video advertisements7,8,9. We also document large persuasion effects on Massachusetts residents’ support for a ballot measure legalizing psychedelics. Examining the persuasion strategies9used by the models indicates that they persuade with relevant facts and evidence, rather than using sophisticated psychological persuasion techniques. Not all facts and evidence presented, however, were accurate; across all three countries, the AI models advocating for candidates on the political right made more inaccurate claims. Together, these findings highlight the potential for AI to influence voters and the important role it might play in future elections.

Politics Psychology Social sciences Machine Learning Human Political Science Elections

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Nature · Dec 03, 2025

Video-call glitches trigger uncanniness and harm consequential life outcomes

People are increasingly using video calls for high-stakes interactions that once required face-to-face contact: from medical consultations1,2, to job interviews3, to court proceedings4. But video calling introduces a new communication issue: minor glitches, or intermittent errors in the transmission of audiovisual information during a virtual interaction5. Here, through five experiments and three supplementary studies using both live and recorded interactions, we show that minor audiovisual glitches during video calls harm interpersonal judgements in consequential life domains (for example, hiring decisions after a virtual interview, or trust in a medical provider after a telehealth visit). In addition, two archival datasets from real-world video calls reveal that glitches are associated with both reduced social connection and a lower likelihood of being granted criminal parole. We find that audiovisual glitches damage interpersonal judgements because they break the illusion of face-to-face contact (for example, by distorting faces, misaligning audio and visual cues or making movements appear ‘choppy’), evoking ‘uncanniness’—a strange, creepy or eerie feeling6,7. As the uncanniness of a glitch increases, so does its negative effect on interpersonal judgements. Furthermore, audiovisual glitches undermine interpersonal judgements only in video calls that simulate face-to-face interaction, showing that the negative effect produced by glitches goes beyond mere disruptiveness, comprehension difficulties and negative attributions. These findings have important implications for digital equity. Despite being considered a boon to access, virtual communication might unintentionally perpetuate inequality. Because disadvantaged groups often have poorer internet connections8,9,10,11,12, they are likely to encounter more glitches, and, in turn, to experience worse outcomes in consequential contexts such as health, careers, justice and social connection.

Human behaviour Human Clinical Machine Learning Neuroscience

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Nature · Dec 03, 2025

Homo sapiens-specific evolution unveiled by ancient southern African genomes

Homo sapiensevolved hundreds of thousands of years ago in Africa, later spreading across the globe1, but the early evolutionary process is debated2,3,4,5,6. Here we present whole-genome sequencing data for 28 ancient southern African individuals, including six individuals with 25× to 7.2× genome coverage, dated to between 10,200 and 150 calibrated years before present (cal.bp). All ancient southern Africans dated to more than 1,400 cal.bpshow a genetic make-up that is outside the range of genetic variation in modern-day humans (including southern African Khoe-San people, although some retain up to 80% ancient southern African ancestry), manifesting in a large fraction ofHomo sapiens-specific variants that are unique to ancient southern Africans.Homo sapiens-specific variants at amino acid-altering sites fixed for all humans—which are likely to have evolved rapidly on theHomo sapiensbranch—were enriched for genes associated with kidney function. SomeHomo sapiens-specific variants fixed in ancient southern Africans—which are likely to have adapted rapidly on the southern African branch—were enriched for genes associated with protection against ultraviolet light. The ancient southern Africans show little spatiotemporal stratification for 9,000 years, consistent with a large, stable Holocene population transcending archaeological phases. While southern Africa served as a long-standing geographical refugium, there is outward gene flow over 8,000 years ago; however, inward gene flow manifests only after around 1,400 years ago. The ancient genomes reported here are therefore key to the evolution ofHomo sapiens, and are important for advancing our understanding of human genomic variation.

Biological anthropology Evolutionary biology Evolutionary genetics Genetic variation biology

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Nature · Dec 03, 2025

Search for light sterile neutrinos with two neutrino beams at MicroBooNE

The existence of three distinct neutrino flavours,νe,νμandντ, is a central tenet of the Standard Model of particle physics1,2. Quantum-mechanical interference can allow a neutrino of one initial flavour to be detected sometime later as a different flavour, a process called neutrino oscillation. Several anomalous observations inconsistent with this three-flavour picture have motivated the hypothesis that an additional neutrino state exists, which does not interact directly with matter, termed as ‘sterile’ neutrino,νs(refs.3,4,5,6,7,8,9). This includes anomalous observations from the Liquid Scintillator Neutrino Detector (LSND)3experiment and Mini-Booster Neutrino Experiment (MiniBooNE)4,5, consistent withνμ→νetransitions at a distance inconsistent with the three-neutrino picture. Here we use data obtained from the MicroBooNE liquid-argon time projection chamber10in two accelerator neutrino beams to exclude the single light sterile neutrino interpretation of the LSND and MiniBooNE anomalies at the 95% confidence level (CL). Moreover, we rule out a notable portion of the parameter space that could explain the gallium anomaly6,7,8. This is one of the first measurements to use two accelerator neutrino beams to break a degeneracy betweenνeappearance and disappearance, which would otherwise weaken the sensitivity to the sterile neutrino hypothesis. We find no evidence for eitherνμ→νeflavour transitions orνedisappearance that would indicate non-standard flavour oscillations. Our results indicate that previous anomalous observations consistent withνμ→νetransitions cannot be explained by introducing a single sterile neutrino state.

Experimental particle physics Theoretical particle physics other

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Nature · Dec 03, 2025

Built environment disparities are amplified during extreme weather recovery

Extreme weather events such as hurricanes and floods cause increasing damage to communities, leading to substantial economic losses and displacement of populations1,2,3,4,5,6. Previous research suggests that there are disparities in the resilience capacity of neighbourhoods, predicting a recovery mechanism of either segmented withdrawal or reinforcement across different neighbourhood groups7,8,9,10,11,12. Assessing these hypotheses and investigating if—and to what extent—neighbourhood built environments recover at scale has been difficult because previous measures have relied on aggregated survey data1,7,9,10,11,12,13,14. Here we construct a building-level disaster recovery dataset covering 2,195 census tracts spanning 16 states and across 12 extreme weather events in the USA from 2007 to 2023 using historical street view imagery and multimodal machine learning. Our analysis shows that in the aftermath of extreme weather events, lower-income neighbourhoods are less likely to rebuild and do not return to their pre-disaster state, whereas higher-income areas rebuild and tend to improve compared with their pre-disaster state, highlighting increasing disparities in their built environments. We further investigate those disparities by examining the deployment of disaster recovery assistance and insurance policies, and identify a resource gap for lower-income neighbourhoods that may explain unequal community responses to extreme weather events. Our findings demonstrate the value of analysing neighbourhood recovery trajectories at a higher resolution and larger scale to inform responsive policy designs, and suggest the importance of restructuring the recovery financial assistance framework to promote more climate resilient communities.

Climate-change adaptation Climate-change policy Governance Natural hazards other

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Nature · Dec 03, 2025

Dated gene duplications elucidate the evolutionary assembly of eukaryotes

The origin of eukaryotes was a formative but poorly understood event in the history of life. Current hypotheses of eukaryogenesis differ principally in the timing of mitochondrial endosymbiosis relative to the acquisition of other eukaryote novelties1. Discriminating among these hypotheses has been challenging, because there are no living lineages representative of intermediate steps within eukaryogenesis. However, many eukaryotic cell functions are contingent on genes that emerged from duplication events during eukaryogenesis2,3. Consequently, the timescale of these duplications can provide insights into the sequence of steps in the evolutionary assembly of the eukaryotic cell. Here we show, using a relaxed molecular clock4, that the process of eukaryogenesis spanned the Mesoarchaean to late Palaeoproterozoic eras. Within these constraints, we dated the timing of these gene duplications, revealing that the eukaryotic host cell already had complex cellular features before mitochondrial endosymbiosis, including an elaborated cytoskeleton, membrane trafficking, endomembrane, phagocytotic machinery and a nucleus, all between 3.0 and 2.25 billion years ago, after which mitochondrial endosymbiosis occurred. Our results enable us to reject mitochondrion-early scenarios of eukaryogenesis5, instead supporting a complexified-archaean, late-mitochondrion sequence for the assembly of eukaryote characteristics. Our inference of a complex archaeal host cell is compatible with hypotheses on the adaptive benefits of syntrophy6,7in oceans that would have remained largely anoxic for more than a billion years8,9.

Palaeontology Phylogenetics biology

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Nature · Dec 03, 2025

Determination of the spin and parity of all-charm tetraquarks

The traditional quark model1,2accounts for the existence of baryons, such as protons and neutrons, which consist of three quarks, as well as mesons, composed of a quark–antiquark pair. Only recently has substantial evidence started to accumulate for exotic states composed of four or five quarks and antiquarks3. The exact nature of their internal structure remains uncertain4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29. Here we report the first measurement of quantum numbers of the recently discovered family of three all-charm tetraquarks30,31,32, using data collected by the CMS experiment at the Large Hadron Collider from 2016 to 2018 (refs.33,34). The angular analysis techniques developed for the discovery and characterization of the Higgs boson35,36,37have been applied to the new exotic states. Here we show that the quantum numbers for parityPand charge conjugationCsymmetries are found to be +1. The spinJof these exotic states is determined to be consistent with 2ħ, while 0ħand 1ħare excluded at 95% and 99% confidence levels, respectively. TheJPC= 2++assignment implies particular configurations of constituent spins and orbital angular momenta, which constrain the possible internal structure of these tetraquarks.

Particle physics Physics Particle Physics Quantum Numbers Large Hadron Collider Tetraquarks

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Nature · Dec 03, 2025

Satellite megaconstellations will threaten space-based astronomy

Rapidly growing satellite constellations have raised strong concerns among the scientific community1,2,3,4. Reflections from satellites can be visible to the unaided eye and extremely bright for professional telescopes. These trails already affect astronomical images across the complete electromagnetic spectrum, with a noticeable cost for operations and mitigation efforts. Contrary to popular perception, satellite trails affect not only ground-based observatories but also space observatories such as the Hubble Space Telescope5. However, the current number of satellites is only a fraction (less than 3%) of those to be launched in the next decade. Here we show a forecast of the satellite trail contamination levels for a series of international low-Earth-orbit telescopes on the basis of the proposed telecommunication industry constellations. Our results show that if these constellations are completed, one-third of the images of the Hubble Space Telescope will be contaminated, while the SPHEREx (Spectro-Photometer for the History of the Universe, Epoch of Reionization and Ices Explorer), ARRAKIHS (Analysis of Resolved Remnants of Accreted galaxies as a Key Instrument for Halo Surveys) and Xuntian space telescopes will have more than 96% of their exposures affected, with\({5.6}_{-0.3}^{+0.3}\),\({69}_{-22}^{+21}\)and\({92}_{-10}^{+11}\)trails per exposure, respectively, with an average surface brightness ofμ= 19 ± 2 mag arcsec−2. Our results demonstrate that light contamination is a growing threat for space telescope operations. We propose a series of actions to minimize the impact of satellite constellations, allowing researchers to predict, model and correct unwanted satellite light pollution from science observations.

Astronomical instrumentation other

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Nature · Dec 03, 2025

Sterile-neutrino search based on 259 days of KATRIN data

Neutrinos are the most abundant fundamental matter particles in the Universe and play a crucial part in particle physics and cosmology. Neutrino oscillation, discovered about 25 years ago, shows that the three known species mix with each other. Anomalous results from reactor and radioactive-source experiments1suggest a possible fourth neutrino state, the sterile neutrino, which does not interact through the weak force. The Karlsruhe Tritium Neutrino (KATRIN) experiment2, primarily designed to measure the neutrino mass using tritium β-decay, also searches for sterile neutrinos suggested by these anomalies. A sterile-neutrino signal would appear as a distortion in the β-decay energy spectrum, characterized by a discontinuity in curvature (kink) related to the sterile-neutrino mass. This signature, which depends only on the shape of the spectrum rather than its absolute normalization, offers a robust, complementary approach to reactor experiments. Here we report the analysis of the energy spectrum of 36 million tritium β-decay electrons recorded in 259 measurement days within the last 40 eV below the endpoint. The results exclude a substantial part of the parameter space suggested by the gallium anomaly and challenge the Neutrino-4 claim. Together with other neutrino-disappearance experiments, KATRIN probes sterile-to-active mass splittings from a fraction of an eV2to several hundred eV2, excluding light sterile neutrinos with mixing angles above a few per cent.

Experimental nuclear physics Experimental particle physics other

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Nature · Dec 03, 2025

A place-based assessment of biodiversity intactness in sub-Saharan Africa

Maintaining biodiversity is central to the sustainable development agenda1. However, a lack of context-specific biodiversity information at policy-relevant scales has posed major limitations to decision-makers2,3. To address this challenge, we undertook a comprehensive assessment of the biodiversity intactness of sub-Saharan Africa4using place-based knowledge of 200 African biodiversity experts5. We estimate that the region has on average lost 24% of its pre-colonial and pre-industrial faunal and floral population abundances, ranging from losses of <20% for disturbance-adapted herbaceous plants to 80% for some large mammals. Rwanda and Nigeria are the least intact (<55%), whereas Namibia and Botswana are the most intact (>85%). Notably, most remaining organisms occur in unprotected, relatively untransformed rangelands and natural forests. Losses in biodiversity intactness in the worst-affected biomes are driven by land transformation into cropland in grasslands and fynbos (Mediterranean-type ecosystems), by non-agricultural degradation in forests and by a combination of the two drivers in savannas. This assessment provides decision-makers with multifaceted, contextually appropriate and policy-relevant information on the state of biodiversity in an understudied region of the world. Our approach could be used in other regions, including better-studied localities, to integrate contextual, place-based knowledge into multiscale assessments of biodiversity status and impacts.

Biodiversity Conservation biology Developing world Ecosystem ecology biology

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Nature · Dec 03, 2025

Decay of driver mutations shapes the landscape of intestinal transformation

Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of theAPCtumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins1,2,3,4. Here, by mediating transformation on different mouse backgrounds containing mutations inKrasor other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations inApcandCtnnb1that are otherwise lost due to negative selection. These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development.

Cancer genomics Cancer models Colorectal cancer biology mouse experiments

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Nature · Dec 03, 2025

Architecture of the neutrophil compartment

Neutrophils exhibit remarkable phenotypic and functional diversity across tissues and diseases1,2, yet the lack of understanding of how this immune compartment is globally organized challenges translation to the clinic. Here we performed single-cell transcriptional profiling of neutrophils spanning 47 anatomical, physiological and pathological scenarios to generate an integrated map of the global neutrophil compartment in mice, which we refer to as NeuMap. NeuMap integrates and expands existing models3,4to generate fundamental new insights; it reveals that neutrophils organize in a finite number of functional hubs that distribute sequentially during maturation to then branch out into interferon-responsive and immunosuppressive states, as well as a functionally silent state that dominates in the healthy circulation. Computational modelling and timestamp analyses identify prototypical trajectories that connect these hubs, and reveal that the dynamics and preferred paths vary during health, inflammation and cancer. We show that TGFβ, IFNβ and GM-CSF push neutrophils along the different trajectories, and projection of chromatin accessibility sites onto NeuMap reveals that the transcription factor JUNB controls angiogenic and immunosuppressive states and promotes tissue revascularization. The architecture of NeuMap appears to be conserved across sex, environmental and genetic backgrounds, as well as in humans. Finally, we show that NeuMap enables inference of the pathophysiological state of the host by profiling blood neutrophils. Our study delineates the global architecture of the neutrophil compartment and establishes a framework for exploration and exploitation of neutrophil biology.

Computational biology and bioinformatics Neutrophils biology mouse experiments

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Nature · Dec 03, 2025

Viral RNA blocks circularization to evade host codon usage control

Codon usage bias—the preferential use of certain synonymous codons—is a fundamental feature of all genomes. Codon usage has a key role in determining gene-expression levels in all organisms that have so far been studied1,2,3. Nearly all human-infecting viruses show patterns of codon usage that are distinct from those of human genes—yet they express their proteins efficiently in host cells to cause diseases and pandemics. The mechanism behind this evasion of codon usage control by viral RNA translation is unknown. Here we show that viral proteins are subject to strong codon usage control when they are translated like human genes, but that they can evade this control when translated from viral replicons. This evasion is mediated by viral 5′ untranslated regions (UTRs) in diverse human viruses, which support codon-usage-insensitive translation. Canonical mRNA translation depends on codon usage, requiring the 5′ cap, 3′ polyA tail and their associated proteins, which suggests that mRNA looping has a role in the effect of codon usage on translation. Notably, RNA circularization for mRNAs with viral 5′ UTRs restores codon-usage-dependent translation, owing mainly to non-optimal codon-usage-mediated repression. These results suggest that mRNA circularization is crucial for initiating codon-usage-dependent translation, and that viral RNAs bypass this mechanism by blocking circularization, allowing efficient translation despite their poor codon usage profiles.

Gene regulation Ribosome biology

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Nature · Dec 03, 2025

Computational enzyme design by catalytic motif scaffolding

Enzymes find broad use as biocatalysts in industry and medicine owing to their exquisite selectivity, efficiency and mild reaction conditions. Custom-designed enzymes can produce tailor-made biocatalysts with potential applications that extend beyond natural reactions. However, current design methods require testing a large number of designs and mostly produce de novo enzymes with low catalytic activities1,2,3. As a result, they require costly experimental optimization and high-throughput screening to be industrially viable4,5. Here we present rotamer inverted fragment finder–diffusion (Riff-Diff), a hybrid machine learning and atomistic modelling strategy for scaffolding catalytic arrays in de novo proteins. We highlight the general applicability of Riff-Diff by designing enzymes for two mechanistically distinct chemical transformations, the retro-aldol reaction and the Morita–Baylis–Hillman reaction. We show that in both cases, it is possible to generate catalysts that exhibit activities rivalling those optimized by in vitro evolution, along with exquisite stereoselectivity. High-resolution structures of six of the designs revealed near-atomic active site design precision. The design strategy can, in principle, be applied to any catalytically competent amino acid array. These findings lay the basis for practical applicability of de novo protein catalysts in synthesis and describe fundamental principles of protein design and enzyme catalysis.

Biocatalysis Enzymes Protein design biology

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Nature · Dec 03, 2025

The Microflora Danica atlas of Danish environmental microbiomes

Over the past 20 years, there have been considerable advances in revealing the microbiomes that underpin processes in natural and human-associated environments. Recent large-scale metagenome surveys have recorded the variety of microbial life in the oceans1, in the human gut2and on Earth3, with compilations encompassing thousands of public datasets4,5. However, despite their broad scope, these studies often lack functional information, and their sample locations are frequently sparsely distributed, limited in resolution or lacking metadata. Here we present Microflora Danica—an atlas of Danish environmental microbiomes encompassing 10,683 shotgun metagenomes and 450 nearly full-length 16S and 18S rRNA datasets, linked to a five-level habitat classification scheme. We show that although human-disturbed habitats have high alpha diversity, species reoccur, revealing hidden homogeneity. This underlines the role of natural systems in maintaining total species (gamma) diversity and emphasizes the need for national baselines for tracking microbial responses to land-use and climate change. Consequently, we focused our dataset exploration on nitrifiers, a functional group closely linked to climate change and of major importance for Denmark’s primary land use: agriculture. We identify several lineages encoding nitrifier key genes and reveal the effects of land disturbance on the abundance of well-studied, as well as uncharacterized, nitrifier groups, with potential implications for N2O emissions. Microflora Danica offers an unparalleled resource for addressing fundamental questions in microbial ecology about what drives microbial diversity, distribution and function.

Genetic databases Metagenomics Microbial ecology Soil microbiology biology

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Nature · Dec 03, 2025

Modelling late gastrulation in stem cell-derived monkey embryo models

Stem cell-derived embryo models could greatly facilitate our understanding of embryonic development. Although human and monkey embryo models have reached early gastrulation stage1,2,3,4,5,6,7, the development of robust models beyond this time remains to be accomplished8. Here, using an optimized 3D suspension culture system, we have successfully advanced the in vitro culture of a stem cell-derived monkey blastoid to day 25. Morphological and histological analyses showed that these monkey embryoids underwent gastrulation and largely recapitulated key developmental events of the late gastrulation stage observed in vivo, with the appearance of a neural plate, haematopoietic system, allantois, primitive gut, primordial germ cells, yolk sac structures and progenitors of other organs, excluding trophoblast derivatives. Single-cell transcriptomic analyses revealed that the lineage composition and differentiation trajectories of cells in these monkey embryoids were similar to those found in natural embryos during gastrulation. Thus, this primate stem cell-derived embryo model provides a valuable platform for dissecting the mechanisms of primate embryonic development from blastocyst to late gastrulation stage.

Embryonic stem cells Gastrulation biology

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Nature · Dec 03, 2025

TSC tunes progenitor balance and upper-layer neuron generation in neocortex

The appropriate generation of upper-layer neurons is necessary to create the circuits that underlie complex brain functions. Radial progenitors divide asymmetrically to generate neurogenic intermediate progenitors (IPs; also known as intermediate precursors), and the symmetric proliferation of IPs rapidly expands the cortical neuronal population. The dynamic maintenance of balanced diversity of cortical progenitors and the resultant generation, placement and connectivity of appropriate numbers of different classes of neurons serve to guide the formation of a properly wired cerebral cortex1,2,3,4,5,6,7,8,9,10,11,12. However, the molecular logic that instructs progenitor balance remains unclear. Here we show that members of the tuberous sclerosis complex (TSC)—proteins that are major regulators of cellular metabolism—function to sculpt radial progenitor–intermediate progenitor balance, radial unit organization and the resultant generation of upper-layer neurons. Developmental deletion of TSC proteins alters the radial progenitor and IP balance and changes radial unit composition, leading to increased upper-layer neuron generation and aberrant cortical connectivity. Human-specific modulation of TSC protein expression through human-gained enhancers affects progenitor balance and generation of upper-layer neurons. Evolutionary downregulation of TSC protein expression may therefore provide an effective route to radial unit sculpting and the expanded generation of upper-layer neurons necessary for higher-order brain functions in humans.

Developmental disorders Developmental neurogenesis Lamination Neural circuits Neural progenitors biology

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Nature · Dec 03, 2025

Whole-genome landscapes of 1,364 breast cancers

Breast cancer remains a major global health challenge1. Here, to comprehensively characterize its genomic landscape and the clinical significance of genomic characteristics, we analysed whole-genome sequences from 1,364 clinically annotated breast cancers, with transcriptome data available for most cases. Our study expands the repertoire of oncogenic alterations and identifies novel driver genes, recurrent gene fusions, structural variants and copy number alterations. Timing analyses on copy number alterations suggest that genomic instability emerges decades before tumour diagnosis, and offer insights into early initiation of tumorigenesis. Pattern-driven genomic features, including mutational signatures2, homologous recombination deficiency3, tumour mutational burden and tumour heterogeneity scores4, were associated with clinical outcomes, highlighting their potential utility as predictive biomarkers for clinical evaluation of treatments such as CDK4/6 and HER2 inhibitors, as well as adjuvant and neoadjuvant chemotherapy. These findings highlight the power of large-scale, clinically annotated whole-genome sequencing in advancing our understanding of how genomic alterations shape patient outcomes.

Breast cancer Cancer genetics Genetics research biology

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Nature · Dec 03, 2025

Computational design of metallohydrolases

De novo enzyme design seeks to build proteins containing ideal active sites with catalytic residues surrounding and stabilizing the transition state(s) of the target chemical reaction1,2,3,4,5,6,7. The generative artificial intelligence method RFdiffusion8,9solves this problem, but requires specifying both the sequence position and backbone coordinates for each catalytic residue, limiting sampling. Here we introduce RFdiffusion2, which eliminates these requirements, and use it to design zinc metallohydrolases starting from quantum chemistry-derived active site geometries. From an initial set of 96 designs tested experimentally, the most active has a catalytic efficiency (kcat/KM) of 16,000 M−1s−1, orders of magnitude higher than previously designed metallohydrolases6,7,10,11. A second round of 96 designs yielded 3 additional highly active enzymes, withkcat/KMvalues of up to 53,000 M−1s−1and a catalytic rate constant (kcat) of up to 1.5 s−1. The design models of the four most active designs differ from known structures and from each other, and the crystal structure of the most active design is very close to the design model, demonstrating the accuracy of the design method. The most active enzymes are predicted by PLACER12and Chai-1 (ref.13) to have preorganized active sites that effectively position the substrate for nucleophilic attack by a water molecule activated by the bound metal. The ability to generate highly active enzymes directly from the computer, without experimental optimization, should enable a new generation of potent designer catalysts14,15.

Hydrolases Protein design biology

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Nature · Dec 02, 2025

Bulk superconductivity up to 96 K in pressurized nickelate single crystals

Recently, the Ruddlesden-Popper bilayer nickelate La3Ni2O7has emerged as a superconductor with a transition temperature (Tc) of ~80 K above 14 GPa1-3. Achieving higherTcin nickelate superconductors, along with the synthesis of reproducible high-quality single crystals without relying on high oxygen-pressure growth conditions, remains a significant challenge4-7. Here we report superconductivity up to 96 K under high pressure in bilayer nickelate single crystals synthesized at ambient pressure. Energy dispersive spectroscopy, single-crystal X-ray diffraction, nuclear quadrupole resonance, and scanning transmission electron microscopy evidenced high homogeneity and crystal quality of the flux-grown La2SmNi2O7-δsingle crystals. La2SmNi2O7exhibits clear bulk superconductivity, including zero resistivity (Tc,maxonset= 92 K andTc,maxzero= 73 K at 21 GPa) and Meissner effect (Tc= 60 K at 20.6 GPa). Low-temperature high-pressure structural study indicates that both monoclinic and tetragonal structures can support superconductivity in this bilayer nickelate. Furthermore, we established a correlation between higherTcunder high pressures and larger in-plane lattice distortion at ambient conditions, corroborated by observing even higherTconsetof 96 K in La1.57Sm1.43Ni2O7-δ. This study overcomes key limitations in nickelate superconductor crystal growth, resolves the crystal structure in the superconducting state, and demonstrates an effective pathway towards achieving higherTc.

Structure of solids and liquids Superconducting properties and materials other

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Nature · Dec 01, 2025

Correlates of HIV-1 control after combination immunotherapy

The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority.1Combination immunotherapy including HIV vaccination, immune stimulation/latency reversal, and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models,2–6but few studies have translated such approaches into people. We performed a single-arm, proof-of-concept study in ten people with HIV on ART combining the following three approaches: (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074, VRC07-523LS) and a toll-like receptor 9 agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption (NCT04357821). Seven of the ten participants exhibited post-intervention control after stopping ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower median viral load following peak viremia off ART. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized.

DNA vaccines HIV infections Immunological memory Translational immunology biology

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Nature · Dec 01, 2025

Sustained HIV-1 remission after heterozygous CCR5Δ32 stem cell transplantation

HIV cure is exceptionally rare, documented in only six cases among the estimated 88 million individuals who have acquired HIV since the epidemic's onset1–6. Successful cures, including the pioneering Berlin patient, are limited to individuals receiving allogeneic stem cell transplants (allo-SCT) for hematological cancers. HIV resistance from stem cell donors with the rare homozygous CCR5 Δ32 mutation was long considered the main mechanism for HIV remission without antiretroviral therapy (ART), but recent reports highlight CCR5-independent mechanisms as important contributors to HIV cure6–8. Here, we provide new evidence for this conceptual shift, reporting exceptionally long, treatment-free HIV remission following allo-SCT with functionally active CCR5. A heterozygous CCR5 wild-type/Δ32 male living with HIV received allo-SCT from an HLA-matched unrelated heterozygous CCR5 wild-type/Δ32 donor as treatment for acute myeloid leukemia. Three years after allo-SCT, the patient discontinued ART. To date, HIV remission has been sustained for over six years with undetectable plasma HIV RNA. Reservoir analysis revealed intact proviral HIV before transplantation, but no replication-competent virus in blood or intestinal tissues after allo-SCT. Declining or absent HIV-specific antibody and T cell responses support the absence of viral activity. High antibody-dependent cellular cytotoxicity (ADCC) activity at the time of transplantation may have contributed to HIV reservoir clearance. These results demonstrate that CCR5Δ32-mediated HIV resistance is not essential for durable remission, underscoring the importance of effective viral reservoir reductions in HIV cure strategies.

Stem-cell research Viral infection biology other

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Nature · Dec 01, 2025

CD8+T cell stemness precedes post-intervention control of HIV viremia

Interventions to induce lasting HIV remission are needed to obviate the requirement for lifelong antiretroviral therapy (ART). Durable post-intervention control (PIC) of viremia has been achieved in a subset of individuals following broadly neutralizing anti-HIV-1 antibody (bNAb) administration and analytical treatment interruption (ATI)1-4. Prior studies support a role for CD8+T cells5-9but the precise features of CD8+T cells involved in PIC remain unclear. Here we mapped and functionally profiled CD8+T cell responses to autologous HIV epitopes using longitudinal samples from four ATI trials in bNAb recipients. PIC was associated with superior pre-intervention HIV-specific CD8+T cell proliferative capacity, stem cell-like memory phenotype, and recall cytotoxicity against autologous HIV peptide-pulsed CD4+T cells. CD8+T cell stemness was further increased following bNAb administration without emergence of new clonotypes targeting defined HLA-optimal epitopes. Multimodal single-cell analyses revealed molecular features associated with PIC and HIV-specific CD8+T cell stemness, including signatures of metabolic fitness and reduced T cell exhaustion. These results identify immune features that precede subsequent PIC to inform the development of combination immunotherapies that will elicit durable HIV remission.

Cellular immunity HIV infections Immunotherapy biology

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Nature · Nov 26, 2025

Progressive coevolution of the yeast centromere and kinetochore

During mitosis, stable but dynamic interactions between centromere DNA and the kinetochore complex enable accurate and efficient chromosome segregation. Even though many proteins of the kinetochore are highly conserved1,2, centromeres are among the fastest evolving regions in a genome3,4, showing extensive variation even on short evolutionary timescales. Here we sought to understand how organisms evolve completely new sets of centromeres that still effectively engage with the kinetochore machinery by identifying and tracking thousands of centromeres across two major fungal clades, including more than 2,500 natural strain isolates and representing over 1,000 million years of evolution. We show that new centromeres spread progressively via drift and subsequent selection and that the kinetochore, which is evolving slowly in relative terms, appears to act as a filter to determine which new centromere variants are tolerated. Together, our findings provide insight into the evolutionary constraints and trajectories shaping centromere evolution.

Centromeres Evolutionary biology Evolutionary genetics Genome evolution Kinetochores biology

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Nature · Nov 26, 2025

Inhibitors supercharge kinase turnover through native proteolytic circuits

Targeted protein degradation is a pharmacological strategy that relies on small molecules such as proteolysis-targeting chimeras (PROTACs) or molecular glues, which induce proximity between a target protein and an E3 ubiquitin ligase to prompt target ubiquitination and proteasomal degradation1. Sporadic reports indicated that ligands designed to inhibit a target can also induce its destabilization2,3,4. Among others, this has repeatedly been observed for kinase inhibitors5,6,7. However, we lack an understanding of the frequency, generalizability and mechanistic underpinnings of these phenomena. Here, to address this knowledge gap, we generated dynamic abundance profiles of 98 kinases after cellular perturbations with 1,570 kinase inhibitors, revealing 160 selective instances of inhibitor-induced kinase destabilization. Kinases prone to degradation are frequently annotated as HSP90 clients, therefore affirming chaperone deprivation as an important route of destabilization. However, detailed investigation of inhibitor-induced degradation of LYN, BLK and RIPK2 revealed a differentiated, common mechanistic logic whereby inhibitors function by inducing a kinase state that is more efficiently cleared by endogenous degradation mechanisms. Mechanistically, effects can manifest by ligand-induced changes in cellular activity, localization or higher-order assemblies, which may be triggered by direct target engagement or network effects. Collectively, our data suggest that inhibitor-induced kinase degradation is a common event and positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.

Kinases Mechanism of action Proteolysis biology

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Nature · Nov 26, 2025

Evolution of taste processing shifts dietary preference

Food choice is an important driver of speciation and invasion of novel ecological niches. However, we know little about the mechanisms leading to changes in dietary preference. Here we use three closely related species,Drosophila sechellia(Dsec),Drosophila simulansandDrosophila melanogaster, to study taste circuit1and food choice evolution.Dsec, a host specialist, feeds exclusively on a single fruit (Morinda citrifolia; noni), whereas the other two are generalists living on diverse diets2. Using quantitative feeding assays, we recapitulate the preference for noni inDsecand detect conserved sweet but altered bitter sensitivity by means of calcium imaging in peripheral taste neurons. Noni activates bitter-sensing neurons more strongly inDsecthan in the other two species owing to a small deletion in a single gustatory receptor. Using volumetric calcium imaging in the ventral brain3, we show that instead of peripheral physiology, species-specific processing of noni and sucrose signals in sensorimotor circuits recapitulates differences in dietary preference. Our data indicate that altered food choice may not be explained by peripheral receptor changes alone but rather by modifications in how sensory information is transformed into feeding motor commands.

Feeding behaviour Gustatory system Neural circuits biology

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Nature · Nov 26, 2025

Inhibitory PD-1 axis maintains high-avidity stem-like CD8+T cells

Stem-like progenitors are self-renewing cytotoxic T cells that expand as effector cells during successful checkpoint immunotherapy1,2. Emerging evidence suggests that tumour-draining lymph nodes support the continuous generation of these stem-like cells that replenish tumour sites and are a key source of expanded effector populations3,4,5,6, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Here, using advanced three-dimensional multiplex immunofluorescence imaging, we identify antigen-presentation niches in tumour-draining lymph nodes that support the expansion, maintenance and affinity evolution of TCF-1+PD-1+SLAMF6highstem-like CD8+T cells. Contrary to the prevailing view that persistent T cell receptor (TCR) signalling drives terminal effector differentiation, prolonged antigen engagement days beyond initial priming sustains the proliferation and self-renewal of these stem-like T cells in vivo. The inhibitory PD-1 pathway has a central role in this process through fine-tuning the TCR signal input that enables the selective expansion of high-affinity TCR stem-like clones as a renewable source of effector cells. PD-1 blockade disrupts this tuning, leading to terminal differentiation or death of the most avid anti-tumour stem-like cells. Our results therefore reveal a relationship between TCR ligand affinity recognition, a key negative-feedback regulatory loop and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 blockade during cancer immunotherapy provides a short-term anti-tumour effect at the cost of diminishing efficacy due to progressive loss of these critical high-affinity precursors.

Cellular immunity Imaging the immune system Immunotherapy Tumour immunology biology mouse experiments

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Nature · Nov 26, 2025

iHALT unlocks liver functionality as a surrogate secondary lymphoid organ

Upon viral infection, the current paradigm of humoral immunity posits that germinal centre reactions occurring within secondary lymphoid organs (SLOs) yield effector plasma cells that subsequently traffic to infected organs or the bone marrow1,2,3. However, it is not well understood how viral tissue tropism may govern the spatiotemporal dynamics of such responses. Here we demonstrate that infection with a prototypical systemic virus indeed induces liver-trafficking plasma cells generated in SLOs, whereas strictly hepatotropic hepaciviral infection elicits locally primed, virus-specific plasma cells in the liver independently of SLO contribution. Such locally derived progenies emerged from inducible hepatic-associated lymphoid tissue (iHALT) structures containing generative foci of T follicular helper cells, myeloid cells and germinal centre-like B cells, often arising from single founder clones unique to individual periportal structures and locally supporting somatic hypermutation. Critically, the cellular composition, cell–cell contact partners and microarchitecture of such iHALT structures in mice were closely mirrored upon hepaciviral infection in humans. Functionally dependent upon CD40L signalling and cognate B cell receptor specificity, emerging CXCR4+VLA-4+LFA-1+CD44+CD138+plasma cells were immediately retained along CXCL12+fibronectin+ICAM2+osteopontin+type I collagen+periportal fibroblast tracts, acting as cognate anchoring pairs that were critical to their maintenance therein. In summary, we characterize humoral immunity exclusively generated and maintained within its extralymphoid site of viral infection in the liver amidst SLO dormancy, in which functional iHALT successfully compensates for strictly hepatotropic virus-induced SLO-evasion strategies to prevent persistent infection.

Adaptive immunity Humoral immunity biology mouse experiments

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Nature · Nov 26, 2025

Ethylene modulates cell wall mechanics for root responses to compaction

Soil stresses affect crop yields and present global agricultural challenges1. Soil compaction triggers reduction in root length and radial expansion driven by the plant hormone ethylene2. Here we report how ethylene controls cell wall biosynthesis to promote root radial expansion. We demonstrate how soil compaction stress, via ethylene, upregulatesAuxin Response Factor1in the root cortex, which represses cellulose synthase (CESA) genes. CESA repression drives radial expansion of root cortical cells by modifying the thickness of their cell walls, which results in a thicker epidermis and thinner cortex. Our research links ethylene signalling with root cell wall remodelling, and reveals how dynamic regulation of cellulose synthesis controls root growth in compacted soil.

Cell biology Plant sciences biology

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Nature · Nov 26, 2025

Slipknot-gauged mechanical transmission and robotic operation

Mechanical transmission is essential in force-related activities ranging from the daily tying of shoe laces1to sophisticated surgical2and robotic operations3,4. Modern machines and robots typically use complex electronic devices designed to sense and limit force5, some of which still face challenges when operating space is limited (for example, in minimally invasive surgeries)6or when resources are scarce (for example, operations in remote areas without electricity). Here we describe an alternative slipknot-based mechanical transmission mechanism to control the intelligent operation of both human and robotic systems. Through topological design, slipknot tying and release can encode and deliver force with a consistency of 95.4% in repeating operations, which circumvents the need for additional sensors and controllers. When applied to surgical repair, this mechanism helped inexperienced surgeons to improve their knotting-force precision by 121%, enabling them to perform surgical knots as good as those of experienced surgeons. Moreover, blood supply and tissue healing after surgery were improved. The mechano-intelligence exhibited in slipknots may inspire investigations of knotted structures across multiple length scales. This slipknot-gauged mechanical transmission strategy can be widely deployed, opening up opportunities for resource-limited healthcare, science education and field exploration.

Biomedical engineering other

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Nature · Nov 26, 2025

Building compositional tasks with shared neural subspaces

Cognition is highly flexible—we perform many different tasks1and continually adapt our behaviour to changing demands2,3. Artificial neural networks trained to perform multiple tasks will reuse representations4and computational components5across tasks. By composing tasks from these subcomponents, an agent can flexibly switch between tasks and rapidly learn new tasks6,7. Yet, whether such compositionality is found in the brain is unclear. Here we show the same subspaces of neural activity represent task-relevant information across multiple tasks, with each task flexibly engaging these subspaces in a task-specific manner. We trained monkeys to switch between three compositionally related tasks. In neural recordings, we found that task-relevant information about stimulus features and motor actions were represented in subspaces of neural activity that were shared across tasks. When monkeys performed a task, neural representations in the relevant shared sensory subspace were transformed to the relevant shared motor subspace. Monkeys adapted to changes in the task by iteratively updating their internal belief about the current task and then, based on this belief, flexibly engaging the shared sensory and motor subspaces relevant to the task. In summary, our findings suggest that the brain can flexibly perform multiple tasks by compositionally combining task-relevant neural representations.

Cognitive control Decision Dynamical systems biology

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Nature · Nov 26, 2025

NSD2 targeting reverses plasticity and drug resistance in prostate cancer

Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance1,2. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)3,4,5. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase6. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice7that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting ofNSD2reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment.

Epigenetics Prostate cancer biology mouse experiments

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Nature · Nov 26, 2025

Thalamocortical transcriptional gates coordinate memory stabilization

The molecular mechanisms that enable memories to persist over long timescales from days to weeks and months are still poorly understood1. Here, to develop insights into this process, we created a behavioural task in which mice formed multiple memories but only consolidated some, while forgetting others, over the span of weeks. We then monitored circuit-specific molecular programs that diverged between consolidated and forgotten memories. We identified multiple distinct waves of transcription, that is, cellular macrostates, in the thalamocortical circuit that defined memory persistence. Of note, a small set of transcriptional regulators orchestrated broad molecular programs that enabled entry into these macrostates. Targeted CRISPR-knockout studies revealed that although these transcriptional regulators had no effects on memory formation, they had prominent, causal and strikingly time-dependent roles in memory stabilization. In particular, the calmodulin-dependent transcription factor CAMTA1 was required for initial memory maintenance over days, whereas the transcription factor TCF4 and the histone methyltransferase ASH1L were required later to maintain memory over weeks. These results identify a critical CAMTA1–TCF4–ASH1L thalamocortical transcriptional cascade that is required for memory stabilization and put forth a model in which the sequential recruitment of circuit-specific transcriptional programs enables memory maintenance over progressively longer timescales.

Learning and memory Molecular neuroscience biology mouse experiments

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Nature · Nov 25, 2025

Polyclonal origins of human premalignant colorectal lesions

Cancer is generally thought to be caused by expansion of a single mutant cell1. However, analyses of early colorectal cancer lesions suggest that tumors may instead originate from multiple, genetically distinct cell populations2,3. Detecting polyclonal tumor initiation is challenging in patients, as it requires profiling early-stage lesions before clonal sweeps obscure diversity. To investigate this, we analyzed normal colorectal mucosa, benign and dysplastic premalignant polyps, and malignant adenocarcinomas (123 samples) from six individuals with familial adenomatous polyposis (FAP). Individuals with FAP have a germline heterozygousAPCmutation, predisposing them to colorectal cancer and numerous premalignant polyps by early adulthood4. Whole-genome and/or whole-exome sequencing revealed that many premalignant polyps—40% with benign histology and 28% with dysplasia—were composed of multiple genetic lineages that diverged early, consistent with polyclonal origins. This conclusion was reinforced by whole-genome sequencing of single crypts from multiple polyps in additional patients which showed limited sharing of mutations among crypts within the same lesion. In some cases, multiple distinctAPCmutations co-existed in different lineages of a single polyp, consistent with polyclonality. These findings reshape our understanding of early neoplastic events, demonstrating that tumor initiation can arise from the convergence of diverse mutant clones. They also suggest that cell-intrinsic growth advantages alone may not fully explain tumor initiation, highlighting the importance of microenvironmental and tissue-level factors in early cancer evolution.

Colorectal cancer Computational models Tumour heterogeneity biology

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Nature · Nov 24, 2025

MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance

The colorectal epithelium is rapidly renewing, with remarkable capacity to regenerate following injury. In colorectal cancer (CRC), this regenerative capacity can be co-opted to drive epithelial plasticity. While oncogenic MAPK signalling in CRC is common, with frequent mutations of bothKRAS(40-50%) andBRAF(10%)1, inhibition of this pathway typically drives resistance clinically. Given the development of KRAS inhibitors, and licensing of BRAF inhibitor combinations2-4, we have interrogated key mechanisms of resistance to these agents in advanced preclinical CRC models. We show that oncogenic MAPK signalling induces epithelial state changesin vivo, driving adoption of a regenerative/revival stem like population, while inhibition leads to rapid transcriptional remodeling of bothKras-andBraf-mutant tumours, favoring a Wnt-associated, canonical stem phenotype. This drives acute therapeutic resistance inKras-and delayed resistance inBraf-driven models. Importantly, where plasticity is restrained, such as in early metastatic disease, or through targeting ligand-dependent Wnt-pathwayRnf43mutations, marked therapeutic responses are observed. This explains the super response to BRAF+EGFR targeted therapies previously observed in a BRAF/RNF43 co-mutant patient population, highlighting the criticality of cellular plasticity in therapeutic response. Together, our data provides clear insight into the mechanisms underpinning resistance to MAPK targeted therapies in CRC. Moreover, strategies that aim to corral stem cell fate, restrict epithelial plasticity or intervene when tumours lack heterogeneity may improve therapeutic efficacy of these agents.

Cancer models Cancer stem cells Cancer therapeutic resistance Targeted therapies biology mouse experiments

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Nature · Nov 19, 2025

Genetic elements promote retention of extrachromosomal DNA in cancer cells

Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer1,2. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division3,4,5,6and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear3,7. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter–enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome.

Cancer genetics Cell division Oncogenes biology

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Nature · Nov 19, 2025

Rare microbial relict sheds light on an ancient eukaryotic supergroup

During the past decade, our understanding of eukaryotic evolution has increased immensely. Newly recognized eukaryotic supergroups have been established1,2,3, and most enigmatic orphan lineages have had their relationships resolved4,5,6. Studies on unicellular protist eukaryotes have also been key to understanding the evolution of mitochondria, the fundamental organelles of the eukaryotic cell, which originated from an alphaproteobacterial ancestor. The retention of ancestral alphaproteobacterial pathways in some protist lineages reveals that the mitochondrion of the last eukaryotic common ancestor was more metabolically versatile than are the highly derived mitochondria that are found in most modern eukaryotes7,8. Here we report the discovery of such a unicellular eukaryote,Solarion arienaegen. et sp. nov., an inconspicuous, free-living heterotrophic protist with two morphologically distinct cell types and a novel type of predatory extrusome. We assignSolarionto the new phylum Caelestes. Together with Provora, hemimastigophoreans andMeteora, they form a new eukaryotic supergroup, Disparia. Moreover,S. arienaehas some noteworthy traits associated with the mitochondrial genome; in particular, the mitochondrially encodedsecAgene, a remnant of an ancestral alphaproteobacterial protein secretion pathway, which has been lost almost entirely in extant mitochondria9,10. The discovery ofS. arienaebroadens our understanding of early eukaryotic evolution and facilitates the study of proto-mitochondrial metabolic remnants, shedding light on the complexity of ancestral eukaryotic life.

Classification and taxonomy Microbiology Mitochondrial genome Phylogenetics Taxonomy biology

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Nature · Nov 19, 2025

A skin-permeable polymer for non-invasive transdermal insulin delivery

Non-invasive skin permeation is widely used for convenient transdermal delivery of small-molecule therapeutics (less than 500 Da) with appropriate hydrophobicities1. However, it has long been deemed infeasible for large molecules—particularly polymers, proteins and peptides2,3—due to the formidable barrier posed by the skin structure. Here we show that the fast skin-permeable polyzwitterion poly[2-(N-oxide-N,N-dimethylamino)ethyl methacrylate] (OP) can efficiently penetrate the stratum corneum, viable epidermis and dermis into circulation. OP is protonated to be cationic and is therefore enriched in the acidic sebum and paracellular stratum corneum lipids containing fatty acids, and subsequently diffuses through the intercorneocyte lipid lamella. Beneath the stratum corneum, at the normal physiological pH, OP becomes a neutral polyzwitterion, ‘hopping’ on cell membranes, enabling its efficient migration through the epidermis and dermis and ultimately entering dermal lymphatic vessels and systemic circulation. As a result, OP-conjugated insulin efficiently permeates through the skin into the blood circulation; transdermal administration of OP-conjugated insulin at a dose of 116 U kg−1into mice with type 1 diabetes quickly lowers their blood glucose levels to the normal range, and a transdermal dose of 29 U kg−1normalizes the blood glucose levels of diabetic minipigs. Thus, the skin-permeable polymer may enable non-invasive transdermal delivery of insulin, relieving patients with diabetes from subcutaneous injections and potentially facilitating patient-friendly use of other protein- and peptide-based therapeutics through transdermal delivery.

Biomedical engineering Drug delivery Peptide delivery Protein delivery biology mouse experiments

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Nature · Nov 19, 2025

Triplets electrically turn on insulating lanthanide-doped nanoparticles

Insulating nanomaterials have large energy gaps and are only electrically accessible under extreme conditions, such as high-intensity radiation and high temperature, pressure or voltage1,2. Lanthanide-doped insulating nanoparticles (LnNPs) are widely studied owing to their exceptional luminescence properties, including bright, narrow-linewidth, non-blinking and non-bleaching emission in the second near-infrared (NIR-II) range3,4. However, it has not been possible to electrically generate excited states in these insulating nanomaterials under low biases and, therefore, not possible to fabricate optoelectronic devices from these systems. Here we report an electrical excitation pathway to obtain emission from LnNPs. By forming LnNP@organic molecule nanohybrids, in which the recombination of electrically injected charges on the organic molecule is followed by efficient triplet energy transfer (TET) to the LnNP, it is possible to turn on LnNPs under a low operating bias. We demonstrate this excitation pathway in light-emitting diodes (LEDs), with low turn-on voltages of about 5 V, very narrow electroluminescence (EL) spectra and a peak external quantum efficiency (EQE) greater than 0.6% in the NIR-II window5. Our LnNP-based LEDs (LnLEDs) also allow for widely tunable EL properties, by changing the type and concentration of lanthanide dopants. These results open up a new field of hybrid optoelectronic devices and provide new opportunities for the electrically driven excitation sources based on lanthanide nanomaterials for biomedical and optoelectronic applications.

Electronic devices Electronics photonics and device physics Lasers LEDs and light sources Optical spectroscopy Optoelectronics Nanomaterials Lanthanide LEDs

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Nature · Nov 19, 2025

Rewiring an olfactory circuit by altering cell-surface combinatorial code

Proper brain function requires the precise assembly of neural circuits during development. Despite the identification of many cell-surface proteins (CSPs) that help guide axons to their targets1,2, it remains mostly unknown how multiple CSPs work together to assemble a functional circuit. Here we used synaptic partner matching in theDrosophilaolfactory circuit3,4to address this question. By systematically altering the combination of differentially expressed CSPs in a single type of olfactory receptor neuron (ORN), which senses a male pheromone that inhibits male–male courtship, we switched its connection nearly completely from its endogenous postsynaptic projection neuron (PN) type to a new PN type that promotes courtship. From this switch, we deduced a combinatorial code including CSPs that mediate both attraction between synaptic partners and repulsion between non-partners5,6. The anatomical switch changed the odour response of the new PN partner and markedly increased male–male courtship. We generalized three manipulation strategies from this rewiring—increasing repulsion with the old partner, decreasing repulsion with the new partner and matching attraction with the new partner—to successfully rewire a second ORN type to multiple distinct PN types. This work shows that manipulating a small set of CSPs is sufficient to respecify synaptic connections, paving the way to investigations of how neural systems evolve through changes of circuit connectivity.

Axon and dendritic guidance Neural circuits biology

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Nature · Nov 19, 2025

Electro-generated excitons for tunable lanthanide electroluminescence

Lanthanide nanocrystals offer unique advantages for electroluminescence (EL) applications, including narrow-band emission, high colour purity and compositionally tunable output1,2,3,4. However, their insulating nature poses a challenge for carrier transport and injection, impeding their application in electrically driven optoelectronic devices5. Here we demonstrate efficient EL from insulating lanthanide fluoride nanocrystals (4 nm; NaGdF4:X; X = Tb3+, Eu3+or Nd3+) coated with a series of functionalized 2-(diphenylphosphoryl)benzoic acids (ArPPOA). These ligands, featuring donor–phosphine oxide acceptor hybrids with carboxyl and P=O coordination sites, effectively sensitize the luminescence of lanthanide nanocrystals by modulating the intraligand charge transfer characteristics. Ultrafast spectroscopic investigations reveal that strong coupling between ArPPOA and lanthanide nanocrystals facilitates intersystem crossing (ISC; <1 ns) and highly efficient triplet energy transfer to nanocrystals (up to 96.7%). Through careful control of dopant composition and concentration in nanocrystals, we also achieve wide-ranging multicolour EL without altering the device architecture, reaching an external quantum efficiency exceeding 5.9% for Tb3+. This ligand-functionalized nanocrystal platform provides a modular strategy for exciton control in insulating nanocrystal systems, offering a pathway for spectrally precise electroluminescent materials.

Electronic devices Inorganic LEDs other

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Nature · Nov 19, 2025

Hepatic zonation determines tumorigenic potential of mutant β-catenin

Oncogenic mutations in phenotypically normal tissue are common across adult organs1,2. This suggests that multiple events need to converge to drive tumorigenesis and that many processes such as tissue differentiation may protect against carcinogenesis. WNT–β-catenin signalling maintains zonal differentiation during liver homeostasis3,4. However, theCTNNB1oncogene—encoding β-catenin—is also frequently mutated in hepatocellular carcinoma, resulting in aberrant WNT signalling that promotes cell growth5,6. Here we investigated the antagonistic interplay between WNT-driven growth and differentiation in zonal hepatocyte populations during liver tumorigenesis. We found that β-catenin mutations co-operate with exogenous MYC expression to drive a proliferative translatome. Differentiation of hepatocytes to an extreme zone 3 fate suppressed this proliferative translatome. Furthermore, a GLUL andLgr5-positive perivenous subpopulation of zone 3 hepatocytes were refractory to WNT-induced and MYC-induced tumorigenesis. However, when mutantCTNNB1andMYCalleles were activated sporadically across the liver lobule, a subset of mutant hepatocytes became proliferative and tumorigenic. These early lesions were characterized by reduced WNT pathway activation and elevated MAPK signalling, which suppresses zone 3 differentiation. The proliferative lesions were also dependent on IGFBP2–mTOR–cyclin D1 pathway signalling, in which inhibition of either IGFBP2 or mTOR suppressed proliferation and tumorigenesis. Therefore, we propose that zonal identity dictates hepatocyte susceptibility to WNT-driven tumorigenesis and that escaping WNT-induced differentiation is essential for liver cancer.

Cancer genetics Cancer models Liver cancer Mutation biology mouse experiments

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Nature · Nov 19, 2025

Integrator dynamics in the cortico-basal ganglia loop for flexible motor timing

Flexible control of motor timing is crucial for behaviour1,2,3,4. Before volitional movement begins, the frontal cortex and striatum exhibit ramping spiking activity, with variable ramp slopes anticipating movement onsets5,6,7,8,9,10,11,12. This activity in the cortico-basal ganglia loop may function as an adjustable ‘timer,’ triggering actions at the desired timing. However, because the frontal cortex and striatum share similar ramping dynamics and are both necessary for timing behaviours, distinguishing their individual roles in this timer function remains challenging. Here, to address this, we conducted perturbation experiments combined with multi-regional electrophysiology in mice performing a flexible lick-timing task. Following transient silencing of the frontal cortex, cortical and striatal activity swiftly returned to pre-silencing levels and resumed ramping, leading to a shift in lick timing close to the silencing duration. Conversely, briefly inhibiting the striatum caused a gradual decrease in ramping activity in both regions, with ramping resuming from post-inhibition levels, shifting lick timing beyond the inhibition duration. Thus, inhibiting the frontal cortex and striatum effectively paused and rewound the timer, respectively. These findings are consistent with a model in which the striatum is part of a network that temporally integrates input from the frontal cortex and generates ramping activity that regulates motor timing.

Basal ganglia Dynamical systems Neural circuits Premotor cortex biology mouse experiments

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Nature · Nov 19, 2025

Tumour-reactive heterotypic CD8 T cell clusters from clinical samples

Emerging evidence suggests a correlation between CD8+T cell–tumour cell proximity and anti-tumour immune response1,2. However, it remains unclear whether these cells exist as functional clusters that can be isolated from clinical samples. Here, using conventional and imaging flow cytometry, we show that from 21 out of 21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+T cells interacting with one or more tumour cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing analysis revealed that T cells from clusters were enriched for gene signatures associated with tumour reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, whereas TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than when conjugated to tumour cells. T cells that were expanded from clusters ex vivo exerted on average ninefold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. After adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumour-reactive CD8+T cells are enriched in functional clusters with tumour cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single-cell gating in flow cytometry, these distinct heterotypic T cell clusters are a valuable source to decipher functional tumour–immune cell interactions and may also be therapeutically explored.

Cancer microenvironment Tumour immunology biology mouse experiments

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Nature · Nov 19, 2025

Structural basis of regulated N-glycosylation at the secretory translocon

Most human secretory pathway proteins are N-glycosylated by oligosaccharyltransferase (OST) complexes as they enter the endoplasmic reticulum (ER)1,2,3. Recent work revealed a substrate-assisted mechanism by which N-glycosylation of the chaperone glucose-regulated protein 94 (GRP94) is regulated to control cell surface receptor signalling4. Here we report the structure of a natively isolated GRP94 folding intermediate tethered to a specialized CCDC134-bound translocon. Together with functional analysis, the data reveal how a conserved N-terminal extension in GRP94 inhibits OST-A and how structural rearrangements within the translocon shield the tethered nascent chain from inappropriate OST-B glycosylation. These interactions depend on a hydrophobic CCDC134 groove, which recognizes a non-native conformation of nascent GRP94. Our results define a mechanism of regulated N-glycosylation and illustrate how the nascent chain remodels the translocon to facilitate its own biogenesis.

Cryoelectron microscopy Endoplasmic reticulum Glycosylation Protein translocation biology

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Nature · Nov 19, 2025

Repulsions instruct synaptic partner matching in an olfactory circuit

Neurons exhibit extraordinary precision in selecting synaptic partners. Although cell-surface proteins (CSPs) that mediate attractive interactions between developing axons and dendrites have been shown to instruct synaptic partner matching1,2, the degree to which repulsive interactions have a role is less clear. Here, using a genetic screen guided by single-cell transcriptomes3,4, we identified three CSP pairs, Toll2–Ptp10D, Fili–Kek1 and Hbs/Sns–Kirre, that mediate repulsive interactions between non-partner olfactory receptor neuron (ORN) axons and projection neuron (PN) dendrites in the developingDrosophilaolfactory circuit. Each CSP pair exhibits inverse expression patterns in the select ORN–PN partners. Loss of each CSP in ORNs led to similar synaptic partner matching deficits as the loss of its partner CSP in PNs, and mistargeting phenotypes caused by overexpressing one CSP could be suppressed by loss of its partner CSP. All CSP pairs are also differentially expressed in other brain regions. Together, our data reveal that multiple repulsive CSP pairs work together to ensure precise synaptic partner matching during development by preventing neurons from forming connections with non-cognate partners.

Axon and dendritic guidance Olfactory system biology

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Nature · Nov 19, 2025

Semantic design of functional de novo genes from a genomic language model

Generative genomic models can design increasingly complex biological systems1. However, controlling these models to generate novel sequences with desired functions remains challenging. Here, we show that Evo, a genomic language model, can leverage genomic context to perform function-guided design that accesses novel regions of sequence space. By learning semantic relationships across prokaryotic genes2, Evo enables a genomic ‘autocomplete’ in which a DNA prompt encoding genomic context for a function of interest guides the generation of novel sequences enriched for related functions, which we refer to as ‘semantic design’. We validate this approach by experimentally testing the activity of generated anti-CRISPR proteins and type II and III toxin–antitoxin systems, including de novo genes with no significant sequence similarity to natural proteins. In-context design of proteins and non-coding RNAs with Evo achieves robust activity and high experimental success rates even in the absence of structural priors, known evolutionary conservation or task-specific fine-tuning. We then use Evo to complete millions of prompts to produce SynGenome, a database containing over 120 billion base pairs of artificial intelligence-generated genomic sequences that enables semantic design across many functions. More broadly, these results demonstrate that generative genomics with biological language models can extend beyond natural sequences.

Computational models Genetic databases Machine learning Protein design biology

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Nature · Nov 19, 2025

ZAK activation at the collided ribosome

Ribosome collisions activate the ribotoxic stress response mediated by the MAP3K ZAK, which in turn regulates cell-fate consequences through downstream phosphorylation of the MAPKs p38 and JNK1. Despite the critical role of ZAK during cellular stress, a mechanistic and structural understanding of ZAK–ribosome interactions and how these lead to activation remain elusive. Here we combine biochemistry and cryo-electron microscopy to discover distinct ZAK–ribosome interactions required for constitutive recruitment and for activation. We find that upon induction of ribosome collisions, interactions between ZAK and the ribosomal protein RACK1 enable its activation by dimerization of its SAM domains at the collision interface. Furthermore, we discover how this process is negatively regulated by the ribosome-binding protein SERBP1 to prevent constitutive ZAK activation. Characterization of novel SAM variants as well as a known pathogenic variant of the SAM domain of ZAK supports a key role of the SAM domain in regulating kinase activity on and off the ribosome, with some mutants bypassing the ribosome requirement for ZAK activation. Collectively, our data provide a mechanistic blueprint of the kinase activity of ZAK at the collided ribosome interface.

Cryoelectron microscopy Ribosome biology

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Nature · Nov 19, 2025

Prime editing-installed suppressor tRNAs for disease-agnostic genome editing

Precise genome-editing technologies such as base editing1,2and prime editing3can correct most pathogenic gene variants, but their widespread clinical application is impeded by the need to develop new therapeutic agents for each mutation. For diseases that are caused by premature stop codons, suppressor tRNAs (sup-tRNAs) offer a more general strategy. Existing approaches to use sup-tRNAs therapeutically, however, require lifelong administration4,5or show modest potency, necessitating potentially toxic overexpression. Here we present prime editing-mediated readthrough of premature termination codons (PERT), a strategy to rescue nonsense mutations in a disease-agnostic manner by using prime editing to permanently convert a dispensable endogenous tRNA into an optimized sup-tRNA. Iterative screening of thousands of variants of all 418 human tRNAs identified tRNAs with the strongest sup-tRNA potential. We optimized prime editing agents to install an engineered sup-tRNA at a single genomic locus without overexpression and observed efficient readthrough of premature termination codons and protein rescue in human cell models of Batten disease, Tay–Sachs disease and cystic fibrosis. In vivo delivery of a single prime editor that converts an endogenous mouse tRNA into a sup-tRNA extensively rescued disease pathology in a model of Hurler syndrome. PERT did not induce detected readthrough of natural stop codons or cause significant transcriptomic or proteomic changes. Our findings suggest the potential of disease-agnostic therapeutic genome-editing approaches that require only a single composition of matter to treat diverse genetic diseases.

CRISPR-Cas9 genome editing Gene therapy biology mouse experiments

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Nature · Nov 19, 2025

The Asymmetric Synthesis of an AcyclicN-Stereogenic Amine

Most molecules of chemistry and biology are chiral, leading to mirror image variants, so called enantiomers. However, while the selective chemical synthesis of molecules where the stereogenicity arises from a carbon atom is well-established, enantioselective approaches tonitrogen-stereogenic molecules are much less common,1-3and in case of acyclic,N-stereogenic amines, even elusive, due to their rapid pyramidal inversion. We describe here the catalytic asymmetric synthesis of stable, acyclicN-stereogenic amines by the addition of enol silanes to nitronium ions that ion pair to a confined chiral anion. In the produced so-called anomeric amines, the commonly observed isomerization is slowed down by twoN-oxy-substituents, which hamper nitrogen inversion. The critical stereogenicity creating step challenges previously established stereochemical descriptors of enantiodifferentiation. Computational studies provide additional insight into the origin of the observed stereocontrol. Our work opens up a new avenue to investigate the fascinating and previously underexplored chemistry of enantiopure anomeric amines.

Asymmetric catalysis Synthetic chemistry methodology Chemistry Catalysis Amines Stereochemistry

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Nature · Nov 19, 2025

Connectivity underlying motor cortex activity during goal-directed behaviour

Neural representations of information are shaped by long-range input and local network interactions. Previous studies linking neural coding and cortical connectivity have focused on input-driven activity in the sensory cortex1,2,3. Here we studied neural activity in the motor cortex while mice gathered rewards with multidirectional tongue reaching. This behaviour does not require training, allowing us to probe neural coding and connectivity before activity is shaped by extended learning. Motor cortex neurons were tuned to target location and reward outcome, and typically responded during and after movements. We studied the underlying network interactions in vivo by estimating causal neural connections using an all-optical method3,4,5,6. Mapping connectivity between more than 20,000,000 excitatory neuron pairs showed a multi-scale columnar architecture in layer 2/3 of the motor cortex. Neurons displayed local (less than 100 µm) like-to-like excitatory connectivity according to target-location tuning, and inhibition over longer spatial scales. Connectivity patterns comprised a continuum, with abundant sparsely connected neurons and rare densely connected neurons that function as network hubs. Hub neurons were weakly tuned to target location and reward outcome but influenced more neighbouring neurons. This network of neurons, encoding location and outcome of movements to different motor goals, may be a general substrate for rapid learning of complex, goal-directed behaviours.

Motor cortex Neural circuits Reward biology mouse experiments

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Nature · Nov 19, 2025

Topological nodali-wave superconductivity in PtBi2

Most superconducting materials are well understood and conventional—that is, the pairs of electrons that cause the superconductivity by their condensation have the highest possible symmetry. Famous exceptions are the enigmatic high-temperature (high-Tc) cuprate superconductors1. Nodes in their superconducting gap are the fingerprint of their unconventional character and imply superconducting pairing ofd-wave symmetry. Here, by using angle-resolved photoemission spectroscopy, we observe that the Weyl semimetal PtBi2harbours nodes in its superconducting gap, implying unconventionali-wave pairing symmetry. At temperatures below 10 K, the superconductivity in PtBi2gaps out its topological surface states, the Fermi arcs, whereas its bulk states remain normal2. The nodes in the superconducting gap that we observe are located exactly at the centre of the Fermi arcs and imply the presence of topologically protected Majorana cones around this locus in momentum space. From this, we infer theoretically that robust zero-energy Majorana flat bands emerge at surface step edges. This establishes PtBi2surfaces not only as unconventional, topologicali-wave superconductors but also as a promising material platform in the ongoing effort to generate and manipulate Majorana bound states.

Superconducting properties and materials Topological matter other

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Nature · Nov 19, 2025

Shared and language-specific phonological processing in the human temporal lobe

All spoken languages are produced by the human vocal tract, which defines the limited set of possible speech sounds. Despite this constraint, however, there exists incredible diversity in the world’s 7,000 spoken languages, each of which is learned through extensive experience hearing speech in language-specific contexts1. It remains unknown which elements of speech processing in the brain depend on daily language experience and which do not. In this study, we recorded high-density cortical activity from adult participants with diverse language backgrounds as they listened to speech in their native language and an unfamiliar foreign language. We found that, regardless of language experience, both native and foreign languages elicited similar cortical responses in the superior temporal gyrus (STG), associated with shared acoustic–phonetic processing of foundational speech sound features2,3, such as vowels and consonants. However, only during native language listening did we observe enhanced neural encoding in the STG for word boundaries, word frequency and language-specific sound sequence statistics. In a separate cohort of bilingual participants, this encoding of word- and sequence-level information appeared for both familiar languages in the same individual and in the same STG neural populations. These results indicate that experience-dependent language processing involves dynamic integration of both shared acoustic–phonetic and language-specific sequence- and word-level information in the STG.

Language Neural encoding Perception Neuroscience Human Language Processing Cortical Recording

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Nature · Nov 13, 2025

Multi-omics analysis of a pig-to-human decedent kidney xenotransplant

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution1–3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure4. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host’s blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft wasCXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked byS100A65,SPP16(Osteopontin), andCOLEC117, at POD21–POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

Predictive medicine Proteomics Transcriptomics Translational immunology Transplant immunology biology mouse experiments

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Nature · Nov 13, 2025

Physiology and immunology of pig-to-human decedent kidney xenotransplant

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.1We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

Preclinical research Translational research Transplant immunology biology mouse experiments

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Nature · Nov 12, 2025

Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy

Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded byACLY), mitochondrial citrate/malate antiporter (encoded bySLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded byACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA–NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.

Cancer metabolism Mitophagy biology

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Nature · Nov 12, 2025

A molecularly impermeable polymer from two-dimensional polyaramids

All polymers exhibit gas permeability through the free volume of entangled polymer chains1,2,3. By contrast, two-dimensional (2D) materials including graphene stack densely and can exhibit molecular impermeability4,5,6. Solution-synthesized 2D polymers that exhibit the latter by poly-condensation have been a longstanding goal. Herein, we demonstrate self-supporting, spin-coated 2D polyaramid nanofilms that exhibit nitrogen permeability below 3.1 × 10−9Barrer, nearly four orders of magnitude lower than every class of existing polymer, and similar for other gases tested (helium, argon, oxygen, methane and sulfur hexafluoride). Optical interference during the pressurization of nanofilm-coated microwells allows measurement of mechanosensitive rim opening and sealing, creating gas-filled bulges that are stable exceeding three years. This discovery enables 2D polymer resonators with high resonance frequencies (about 8 MHz) and quality factors up to 537, similar to graphene. A 60-nm coating of air-sensitive perovskites reduces the lattice degradation rate 14-fold with an oxygen permeability of 3.3 × 10−8Barrer. Molecularly impermeable polymers promise the next generation of barriers that are synthetically processable, chemically amenable and maximize molecular rejection with minimal material, ultimately advancing sustainability goals.

Polymers Two-dimensional materials other

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Nature · Nov 12, 2025

An ancient recombination desert is a speciation supergene in placental mammals

Gene flow between biological species is a common and often adaptive evolutionary phenomenon throughout the tree of life1,2,3,4. Given the pervasive nature of genetic exchange, a daunting challenge is how best to infer the correct relationships between species from the complex collection of histories arrayed across genomes5. The local rate of meiotic recombination influences the distribution of signatures of, and barriers to, gene flow during the early stages of speciation6. Still, a broader understanding of this relationship and its application to accurately discerning phylogeny is lacking due to a scarcity of recombination maps. Here we applied deep learning methods to genome alignments from 22 divergent placental mammal species to infer the evolution of the recombination landscape. We identified a large and evolutionarily conserved X-linked recombination desert constituting 30% of the chromosome. Recombination-aware phylogenomic analyses from 94 species revealed that the X-linked recombination desert is an ancient and recurrent barrier to gene flow and retains the species history when introgression dominates genome-wide ancestry. The functional basis for this supergene is manifold, enriched with genes that influence sex chromosome silencing and reproduction traits. Because the locus underpins reproductive isolation across ordinal lineages, it may represent a reliable marker for resolving challenging relationships across the mammalian phylogeny.

Comparative genomics Evolutionary genetics Phylogenetics Speciation biology mouse experiments

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Nature · Nov 12, 2025

Synthesis of enantioenriched atropisomers by biocatalytic deracemization

The synthesis of enantiopure materials is vital for pharmaceutical and agrochemical industries owing to the inherently chiral nature of biological systems and the fact that two enantiomers can have markedly different biochemical properties1. In particular, enantioselective preparation of atropisomers is of great interest owing to their privileged status as chiral ligands and pharmacophores2,3,4. Although chromatographic- or crystallization-based methods are commonly used to separate atropisomers, we urgently need more efficient and economical approaches to access enantioenriched atropisomers5,6. The use of stereoconvergent methods to access molecules with point chirality is well established but we have not tapped the potential of stereoconvergent catalytic methods to arrive at enantioenriched atropisomers. Here we report deracemization activity of a P450 enzyme and explore its ability to deliver a stereoconvergent route towards enantioenriched atropisomers. Using a curated set of P450 variants, we found that a wide variety of symmetric and non-symmetrically substituted 2,2′-binaphthol (BINOL) building blocks can be deracemized to high enantiomeric purity. This deracemization activity is mechanistically distinct from the activity of previously reported P450 enzymes, which operate through enantioselective bond formation to afford enantioenriched atropisomers. By contrast, the deracemization process reported here is proposed to proceed through bond rotation. As engineered variants have complementary selectivity profiles and substrate scope, this biocatalytic platform should be readily tunable for any desired substitution pattern. We anticipate that these results will inspire new stereoconvergent approaches to synthesizing conformationally stable atropisomers.

Biocatalysis biology

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Nature · Nov 12, 2025

Rare genetic variants confer a high risk of ADHD and implicate neuronal biology

Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a large genetic component1. It affects around 5% of children and 2.5% of adults2, and is associated with several severe outcomes3,4,5,6,7,8,9,10,11. Common genetic variants associated with the disorder have been identified12,13, but the role of rare variants in ADHD is mostly unknown. Here, by analysing rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals, we identify three genes (MAP1A,ANO8andANK2;P< 3.07 × 10−6; odds ratios 5.55–15.13) that are implicated in ADHD. The protein–protein interaction networks of these three genes were enriched for rare-variant risk genes of other neurodevelopmental disorders, and for genes involved in cytoskeleton organization, synapse function and RNA processing. Top associated rare-variant risk genes showed increased expression across pre- and postnatal brain developmental stages and in several neuronal cell types, including GABAergic (γ-aminobutyric-acid-producing) and dopaminergic neurons. Deleterious variants were associated with lower socioeconomic status and lower levels of education in individuals with ADHD, and a decrease of 2.25 intelligence quotient (IQ) points per rare deleterious variant in a sample of adults with ADHD (n= 962). Individuals with ADHD and intellectual disability showed an increased load of rare variants overall, whereas other psychiatric comorbidities had an increased load only for specific gene sets associated with those comorbidities. This suggests that psychiatric comorbidity in ADHD is driven mainly by rare variants in specific genes, rather than by a general increased load across constrained genes.

ADHD Next-generation sequencing biology

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Nature · Nov 12, 2025

Silicon solar cells with hybrid back contacts

Silicon solar cells are essential for sustainable energy but remain limited by efficiency losses, particularly in the fill factor1,2,3. Here we develop a hybrid interdigitated back-contact solar cell that combines advanced all-surface passivation with laser-treated tunnelling contacts. This approach achieves a power conversion efficiency of 27.81%, approaching 95% of the theoretical limit4. By integrating high- and low-temperature processes, we suppress recombination and enhance contact performance, achieving a fill factor of 87.55%—nearly 98% of the theoretical limit. A model links the ideality factor to carrier loss mechanisms, elucidating carrier recombination in both the bulk and the surface and clarifies key fill factor losses owing to recombination. These innovations provide both experimental and theoretical advances towards scalable, high-efficiency silicon photovoltaics.

Devices for energy harvesting Solar cells

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Nature · Nov 12, 2025

Photoinduced twist and untwist of moiré superlattices

Two-dimensional moiré materials are formed by artificially stacking atomically thin monolayers. Correlated and topological quantum phases can be engineered by precise choice of stacking geometry1,2,3. These designer electronic properties depend crucially on interlayer coupling and atomic registry4,5. An open question is how the atomic registry responds on ultrafast timescales to optical excitation and whether the moiré geometry can be dynamically reconfigured to tune emergent phenomena in real time. Here we show that femtosecond photoexcitation drives a coherent twist–untwist motion of the moiré superlattice in 2° and 57° twisted WSe2/MoSe2heterobilayers, resolved directly by ultrafast electron diffraction. On above-band-gap photoexcitation, the moiré superlattice diffraction features are enhanced within 1 ps and subsequently suppressed several picoseconds after, deviating markedly from typical photoinduced lattice heating. Kinetic diffraction analysis, supported by simulations of the sample dynamics, indicates a peak-to-trough local twist angle modulation of 0.6°, correlated with a sub-THz frequency moiré phonon. This motion is driven by ultrafast charge transfer that transiently increases interlayer attraction. Our results could lead to ultrafast control of moiré periodic lattice distortions and, by extension, the local moiré potential that shapes excitons, polarons and correlation-driven behaviours.

Condensed-matter physics Two-dimensional materials other

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Nature · Nov 12, 2025

Aligning machine and human visual representations across abstraction levels

Deep neural networks have achieved success across a wide range of applications, including as models of human behaviour and neural representations in vision tasks1,2. However, neural network training and human learning differ in fundamental ways, and neural networks often fail to generalize as robustly as humans do3,4, raising questions regarding the similarity of their underlying representations. We need to determine what is missing for modern learning systems to exhibit more human-aligned behaviour. Here we highlight a key misalignment between vision models and humans: whereas human conceptual knowledge is hierarchically organized from fine- to coarse-scale distinctions (for example, ref.5), model representations do not accurately capture all these levels of abstraction. To address this misalignment, we first train a teacher model to imitate human judgements, then transfer human-aligned structure from its representations to refine the representations of pretrained state-of-the-art vision foundation models via fine-tuning. These human-aligned models more accurately approximate human behaviour and uncertainty across a wide range of similarity tasks, including a dataset of human judgements spanning multiple levels of semantic abstractions. They also perform better on a diverse set of machine learning tasks, increasing generalization and out-of-distribution robustness. Thus, infusing neural networks with additional human knowledge yields a best-of-both-worlds representation that is both more consistent with human cognitive judgements and more practically useful, paving the way towards more robust, interpretable and human-aligned artificial intelligence systems.

Computational science Human behaviour other

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Nature · Nov 12, 2025

Florigen activation complex forms via multifaceted assembly inArabidopsis

Florigen, encoded byFTgenes, is synthesized in leaves and transported to the shoot apical meristem (SAM) to induce flower development1,2,3. At the SAM, 14-3-3 proteins are proposed to act as receptors for FT protein and to mediate the indirect interaction between FT and the basic leucine zipper (bZIP) transcription factor FD to form the florigen activation complex (FAC) that activates transcription of flowering genes4,5,6. Here we demonstrate a different mechanism of FAC assembly, diverse functions for the 14-3-3 proteins within the complex, and an unexpected spatiotemporal distribution of the FAC. We show that FT is not recruited by 14-3-3 alone, but that it interacts with the DNA–FD–14-3-3 complex through two interfaces, one of which binds DNA via the unstructured C terminus of FT. We also find that interaction of 14-3-3 proteins with the C terminus of phosphorylated FD reduces liquid phase condensation of the intrinsically disordered FD protein, allowing it to bind DNA, and that the 14-3-3 proteins strengthen DNA binding of FD by promoting dimerization, which ultimately results in the recruitment of FT. Unexpectedly, we also find that after FT movement to the shoot apex,FTandFDare co-transcribed in young floral primordia, forming a boundary with the suppressed bract and allowing formation of the FAC during the first stages of floral development. Our studies propose a new mechanism by which the florigen FT transcriptional complex is formed, and indicate distinct functions for the complex during SAM and floral primordium development.

Plant molecular biology Protein trafficking in plants Shoot apical meristem biology

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Nature · Nov 12, 2025

Estimation and mapping of the missing heritability of human phenotypes

Rare coding variants shape inter-individual differences in human phenotypes1. However, the contribution of rare non-coding variants to those differences remains poorly characterized. Here we analyse whole-genome sequence (WGS) data from 347,630 individuals with European ancestry in the UK Biobank2,3to quantify the relative contribution of 40 million single-nucleotide and short indel variants (with a minor allele frequency (MAF) larger than 0.01%) to the heritability of 34 complex traits and diseases. On average across phenotypes, we find that WGS captures approximately 88% of the pedigree-based narrow sense heritability: that is, 20% from rare variants (MAF < 1%) and 68% from common variants (MAF ≥ 1%). We show that coding and non-coding genetic variants account for 21% and 79% of the rare-variant WGS-based heritability, respectively. We identified 15 traits with no significant difference between WGS-based and pedigree-based heritability estimates, suggesting their heritability is fully accounted for by WGS data. Finally, we performed genome-wide association analyses of all 34 phenotypes and, overall, identified 11,243 common-variant associations and 886 rare-variant associations. Altogether, our study provides high-precision estimates of rare-variant heritability, explains the heritability of many phenotypes and demonstrates for lipid traits that more than 25% of rare-variant heritability can be mapped to specific loci using fewer than 500,000 fully sequenced genomes.

Genome-wide association studies Population genetics Quantitative trait loci Rare variants biology

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Nature · Nov 12, 2025

Spatial fibroblast niches define Crohn’s fistulae

Crohn’s disease often presents with fistulae, abnormal tunnels that connect the intestine to the skin or other organs. Despite their profound effect on morbidity, the molecular basis of fistula formation remains unclear, largely owing to the challenge of capturing intact fistula tracts and their inherent heterogeneity1,2,3. Here we construct a subcellular-resolution spatial atlas of 68 intestinal fistulae spanning diverse anatomical locations. We describe fistula-associated epithelial, immune and stromal cell states, revealing abnormal zonation of growth factors and morphogens linked to establishment of tunnelling anatomy. We identify fistula-associated stromal (FAS) fibroblasts, which are assembled in concentric layers: a proliferative, lumen-adjacent zone beneath neutrophil and macrophage-rich granulation tissue, an active lesion core of FAS cells and a quiescent, pro-fibrotic outer zone. We examine the architecture of the extracellular matrix in the fistula tract and demonstrate that FAS populations associate with distinct collagen structures, exhibiting properties ranging from proliferation, migration and extracellular matrix remodelling to dense collagen deposition and fibrosis. We define niches supporting epithelialization of fistula tunnels and a FAS-like population that is detected at the base of ulcers in non-penetrating Crohn’s disease. Our study demonstrates that common molecular pathways and cellular niches underpin fistulae across intestinal locations, revealing the cellular protagonists of fistula establishment and persistence. This resource will inform the development of model systems and interventions to mitigate aberrant fibroblast activity while preserving their regenerative properties in Crohn’s disease.

Crohn's disease Experimental models of disease Immunopathogenesis Mucosal immunology biology

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Nature · Nov 12, 2025

Ecology and spread of the North American H5N1 epizootic

Since late 2021, a panzootic of highly pathogenic H5N1 has devastated wild birds, agriculture and mammals. Here an analysis of 1,818 haemagglutinin sequences from wild birds, domestic birds and mammals reveals that the North American panzootic was driven by around nine introductions into the Atlantic and Pacific flyways, followed by rapid dissemination through wild, migratory birds. Transmission was primarily driven by Anseriformes, while non-canonical species acted as dead-end hosts. In contrast to the epizootic of 2015 (refs.1,2), outbreaks in domestic birds were driven by around 46–113 independent introductions from wild birds that persisted for up to 6 months. Backyard birds were infected around 9 days earlier on average than commercial poultry, suggesting potential as early-warning signals for transmission upticks. We pinpoint wild birds as critical drivers of the epizootic, implying that enhanced surveillance in wild birds and strategies that reduce transmission at the wild–agriculture interface will be key for future tracking and outbreak prevention.

Influenza virus Viral epidemiology Viral reservoirs Viral transmission biology mouse experiments

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Nature · Nov 12, 2025

In situ structural mechanism of epothilone-B-induced CNS axon regeneration

Axons in the adult central nervous system (CNS) do not regenerate following injury, in contrast to neurons in the peripheral nervous system and neuronal growth during embryonic development. The molecular mechanisms that prevent regeneration of neurons in the CNS remain largely unknown1,2. Here, to address the intracellular response to injury, we developed an in situ cryo-electron tomography and cryo-electron microscopy platform to mimic axonal damage and present the structural mechanism underlying thalamic axon regeneration induced by the drug epothilone B. We observed that stabilized microtubules extend beyond the injury site, generating membrane tension and driving membrane expansion. Cryo-electron microscopy reveals the in situ structure of microtubules at 3.19 Å resolution, which engage epothilone B within the microtubule lattice at the regenerating front. During repair, tubulin clusters are delivered and incorporated into polymerizing microtubules at the regenerating site. These microtubule shoots serve as scaffolds for various types of vesicles and endoplasmic reticulum, facilitating the supply of materials necessary for axon repair until membrane tension normalizes. We demonstrate the unexpected ability of neuronal cells to adjust to strain induced by epothilone B, which creates homeostatic imbalances and activates axons to regeneration mode.

Cryoelectron tomography Microtubules biology

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Nature · Nov 12, 2025

Controlling pyramidal nitrogen chirality by asymmetric organocatalysis

Chirality is central to life, and controlling the formation of one of a pair of mirror-image molecules (enantiomers) is a central tenet of synthetic chemistry. Although controlling stereogenic carbon1,2,3, silicon4,5, phosphorus6,7and sulfur8,9centres is commonplace, nitrogen centres in amines are not typically stable. Limited achievements in the enantioselective construction of nitrogen chirality have primarily been established in quaternary ammonium salts10,11,12and bridged bicyclic amines13,14,15,16,17, which have a restricted pyramidal configuration. The asymmetric synthesis of non-bridged pyramidal nitrogen-chirogenic compounds suffers from a super-stoichiometric chiral source and exhibits poor stereoselectivity18,19,20,21,22,23,24. Here we present a catalytic enantioselective strategy for construction of acyclic nitrogen stereocentres via a chiral Brønsted acid-catalysed chlorination reaction. We designed a stereospecific intramolecular reaction to overcome the structural and configurational instabilities of nitrogen-chlorinated hydroxylamines. The resulting 2-alkoxy-1,2-oxazolidines showed good enantiopurities, and density functional theory calculations confirmed successful enantiocontrol of nitrogen chirality during the chlorination process. Furthermore, this strategy has been applied successfully to synthesize the enantioselectiveN-chloroaziridines with a configurationally stable nitrogen stereogenic centre. Control experiments provide evidence for an SN2 pathway for the intramolecular nucleophilic substitution event.

Synthetic chemistry methodology Stereochemistry biology

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Nature · Nov 12, 2025

Olympiad-level formal mathematical reasoning with reinforcement learning

A long-standing goal of artificial intelligence is to build systems capable of complex reasoning in vast domains, a task epitomized by mathematics with its boundless concepts and demand for rigorous proof. Recent AI systems, often reliant on human data, typically lack the formal verification necessary to guarantee correctness. By contrast, formal languages such as Lean1offer an interactive environment that grounds reasoning, and reinforcement learning (RL) provides a mechanism for learning in such environments. We present AlphaProof, an AlphaZero-inspired2agent that learns to find formal proofs through RL by training on millions of auto-formalized problems. For the most difficult problems, it uses Test-Time RL, a method of generating and learning from millions of related problem variants at inference time to enable deep, problem-specific adaptation. AlphaProof substantially improves state-of-the-art results on historical mathematics competition problems. At the 2024 IMO competition, our AI system, with AlphaProof as its core reasoning engine, solved three out of the five non-geometry problems, including the competition’s most difficult problem. Combined with AlphaGeometry 23, this performance, achieved with multi-day computation, resulted in reaching a score equivalent to that of a silver medallist, marking the first time an AI system achieved any medal-level performance. Our work demonstrates that learning at scale from grounded experience produces agents with complex mathematical reasoning strategies, paving the way for a reliable AI tool in complex mathematical problem-solving.

Computational science Computer science

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Nature · Nov 12, 2025

Potent neutralization of Marburg virus by a vaccine-elicited antibody

Marburg virus (MARV) is a filovirus that causes a severe and often lethal hemorrhagic fever1,2. Despite the increasing frequency of MARV outbreaks, no vaccines or therapeutics are licensed for use in humans. Here, we designed mutations that improve the expression, thermostability, and immunogenicity of the prefusion MARV glycoprotein (GP) ectodomain trimer, which is the sole target of neutralizing antibodies and vaccines in development3–8. We discovered a fully human, pan-marburgvirus monoclonal antibody, MARV16, that broadly neutralizes all MARV isolates as well as Ravn virus and Dehong virus with 40 to 100-fold increased potency relative to previously described antibodies9. Moreover, MARV16 provides therapeutic protection in guinea pigs challenged with MARV. We determined a cryo-electron microscopy structure of MARV16-bound MARV GP showing that MARV16 recognizes a prefusion-specific epitope spanning GP1 and GP2, blocking receptor binding and preventing conformational changes required for viral entry. We further reveal the architecture of the MARV GP glycan cap, which shields the receptor binding site (RBS), underscoring architectural similarities with distantly related filovirus GPs. MARV16 and previously identified RBS-directed antibodies9–11can bind MARV GP simultaneously. These antibody cocktails require multiple mutations to escape neutralization by both antibodies, paving the way for MARV therapeutics resilient to viral evolution. MARV GP stabilization along with the discovery of MARV16 advance prevention and treatment options for MARV.

Cryoelectron microscopy Marburg virus Protein vaccines biology

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Nature · Nov 11, 2025

High performance tandem perovskite LEDs through interlayer photon recycling

Tandem light-emitting diodes (LEDs), achieved by vertically stacking multiple units in series to combine the luminance of individual light-emitting elements, are effective for improving efficiency and lifespan compared to single-unit devices1–3. In particular, tandem perovskite LEDs benefit from the small Stokes shifts of perovskites4, which in principle can enable significant photon recycling between individual perovskite layers and enhance light extraction from trapped modes. However, a tandem structure that effectively merges the luminance of each perovskite units still remains a significant challenge. Here, we demonstrate efficient and stable tandem LEDs by combining two solution-processed perovskite light-emitting units. This tandem structure effectively combines the original luminance of each light-emitting units; we argue that the emissions are also significantly enhanced through photon recycling between the individual light-emitting units. Consequently, we achieve tandem perovskite LEDs with a low turn-on voltage of 3.2 V, a high peak external quantum efficiency (EQE) of 45.5% (even 20% higher than the sum of peak EQEs of single-unit devices), an average peak EQE of 40.9%, and a half-lifetime of 64 h at an initial radiance of 70 W Sr−1m−2. These findings represent a significant advancement in achieving high-performance and multicolor LEDs through the stacking of perovskite LEDs.

Lasers LEDs and light sources Materials for devices

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Nature · Nov 11, 2025

Comprehensive echocardiogram evaluation with view primed vision language AI

Echocardiography is the most widely used cardiac imaging modality, capturing ultrasound video data to assess cardiac structure and function1. Artificial intelligence (AI) in echocardiography has the potential to streamline manual tasks and improve reproducibility and precision2. However, most echocardiography AI models are single-view, single-task systems that do not synthesize complementary information from multiple views captured during a full exam3,4, and thus lead to limited performance and scope of applications. To address this problem, we introduce EchoPrime, a multi-view, view-informed, video-based vision-language foundation model trained on over 12 million video-report pairs. EchoPrime uses contrastive learning to train a unified embedding model for all standard views in a comprehensive echocardiogram study with representation of both rare and common diseases and diagnoses. EchoPrime then utilizes view-classification and a view-informed anatomic attention module to weight video-specific embeddings that accurately map the relationship between echocardiographic views and anatomical structures. With retrieval-augmented interpretation, EchoPrime integrates information from all echocardiogram videos in a comprehensive study and performs holistic clinical interpretation. In datasets from five international independent healthcare systems, EchoPrime achieves state-of-the art performance on 23 diverse benchmarks of cardiac form and function, surpassing the performance of both task-specific approaches and prior foundation models. Following rigorous clinical evaluation, EchoPrime can assist physicians in the automated preliminary assessment of comprehensive echocardiography.

Cardiomyopathies Computer science

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Nature · Nov 10, 2025

Flexible perovskite/silicon tandem solar cell with a dual buffer layer

Perovskite/silicon tandem solar cells have emerged as promising candidates for next-generation photovoltaic technology due to their ultra-high power conversion efficiency (PCE)1-3. However, the mechanical stress generated during repeated environmental stress cycles remains a critical challenge for flexible perovskite/silicon tandem solar cells, leading to interfacial delamination and device degradation. In this work, we propose a dual-buffer-layer strategy with a stress-release mechanism to synergistically mitigate ion bombardment during subsequent sputtering deposition and enhance interfacial adhesion while preserving efficient charge extraction. The loose SnOxbuffer layer, engineered by adjusting the purging time of atomic layer deposition, can dissipate strain energy, whereas the compact SnOxlayer can ensure robust electrical contact. Based on this dual-buffer-layer, the flexible tandem solar cell, constructed on a 60-micron thick ultra-thin silicon bottom cell, achieves a certified PCE of 33.4% on 1-cm2area, and an certified PCE of 29.8% on wafer-sized area of 260-cm2with a power-per-weight of up to 1.77 W/g. The modified tandem solar cells demonstrate good durability, retaining over 97% of their initial power conversion efficiencies after 43000 bending cycles under a maximum curvature radius of around 40 mm in air, and around 97% after thermal cycling testing (−40 °C to 85 °C) for 250 cycles.

Devices for energy harvesting Solar cells other

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Nature · Nov 10, 2025

Flexible perovskite/silicon tandem solar cells with 33.6% efficiency

Flexible solar cells have a transformative potential for niche applications, yet face fundamental challenges in simultaneously achieving high power conversion efficiency (PCE), extreme mechanical resilience and operational stability1–4. Herein, we demonstrate a certified 33.6%-efficient flexible perovskite/crystalline silicon (c-Si) tandem solar cell with a record open-circuit voltage (Voc) of 2.015 V, rivaling its rigid counterpart. The flexible tandem retains 91% of its initial PCE after 5,000 cycles under a bending radius (Rb) of 17.6 mm, and demonstrates exceptional operational and damp-heat (DH) stability, featuring aT80lifetime exceeding 2,000 hours under continuous illumination and retaining 90% of its initial PCE after 1,000 hours DH test. This advancement is enabled by implementation of the reactive-plasma-deposited (RPD) cerium and hydrogen co-doped indium oxide (ICO:H) recombination layer (RL) that promotes self-assembled monolayers (SAMs) coverage and interfacial charge transfer, andin-situannealed zinc-doped indium oxide (IZO) front transparent electrode with significantly enhanced optoelectronic and mechanical properties.

Materials science Solar cells other

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Nature · Nov 06, 2025

An ATP-gated molecular switch orchestrates human messenger RNA export

The nuclear export of messenger RNA (mRNA) is an important step in eukaryotic gene expression1. Despite recent molecular insights into how newly transcribed mRNAs are packaged into ribonucleoprotein complexes (mRNPs)2,3, the subsequent events that govern mRNA export are poorly understood. Here, we uncover the molecular basis underlying key events of human mRNA export, including the remodeling of mRNP-bound transcription-export complexes (TREX), the formation of export-competent mRNPs, the docking of mRNPs at the nuclear pore complex (NPC), and the release of mRNPs at the NPC to initiate their export. Our biochemical and structural data show that the ATPase DDX39/UAP56 acts as a central molecular switch that directs nucleoplasmic mRNPs from TREX to NPC-anchored TREX-2 complexes through its ATP-gated mRNA-binding cycle. Collectively, these findings establish a mechanistic framework for a general and evolutionarily conserved mRNA export pathway.

Biochemistry Electron microscopy Kinetics Protein structure predictions RNA transport biology

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