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

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

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

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

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

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

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

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

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

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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