Latest Articles

A chemical agonist and the Golgi-resident lipid PI4P activate STING by inducing transmembrane helix rearrangement

While the phospholipid PI4P is implicated in STING activation, its molecular mechanism has remained elusive. Han et al. reveal that PI4P cooperates with the transmembrane agonist GNE-6468 to activate the STING immune response, highlighting its therapeutic potential for immunotherapy.

Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks

Psilocybin reshapes brain networks through activity-dependent plasticity, including a weakening of recurrent cortical loops that could underlie its therapeutic effects.

The striatal indirect pathway mediates hesitation

Hesitation—that is, pausing an action in the face of uncertainty—is ubiquitous in daily life, yet little is known about its underlying neural circuitry. We present a new experimental paradigm that reliably evokes hesitation in mice and find that hesitation is mediated by indirect, but not direct, pathway neurons in the dorsomedial striatum. These data establish a new role for the indirect pathway in suppressing action under uncertainty.

Bioengineered photosynthetic nanothylakoids reshape the inflammatory microenvironment for rheumatoid arthritis therapy

Reducing individual inflammatory factors does not always translate into clinical efficacy in rheumatoid arthritis (RA), an autoimmune disease characterized by joint inflammation. Proinflammatory M1 macrophages are a key driver of the hyperinflammatory joint microenvironment, which also promotes the progression of RA. Here we show that folate-receptor-targeted photosynthetic nanothylakoid (FA-PEG-NTK)-based phototherapy reprogrammes macrophages from M1 to anti-inflammatory M2, and successfully remodels the inflammatory RA microenvironment. The nanothylakoids were sourced from plant-derived thylakoids and developed by surface modification with distearoyl phosphoethanolamine–polyethylene glycol (PEG) via hydrophobic interactions to preserve their photocatalytic enzymes. We show that upon light irradiation in a mouse macrophage model of inflammation, the FA-PEG-NTK system generates oxygen and nicotinamide adenine dinucleotide phosphate, alleviating hypoxia and reducing reactive oxygen species. This rebalances the oxidative stress in M1 macrophages, thereby remodelling the inflammatory microenvironment in RA. We also show that in a collagen-induced arthritis rat model, FA-PEG-NTK-mediated phototherapy notably alleviated synovial hyperplasia and enhanced bone and cartilage regeneration, outperforming the clinical treatment methotrexate, with no apparent side effects.

Interkingdom sensing of fungal tyrosol promotes bacterial antifungal T6SS activity in the murine gut

Type VI secretion systems (T6SSs) are molecular machines used by bacteria to release effectors that target either host cells, competing bacteria or fungi. Regulatory mechanisms underlying antifungal T6SS activity remain unexplored. Here we show, using mouse infection with wild-type and T6SS mutant bacteria, that T6SS activity of the enteropathogen,Yersinia pseudotuberculosis(Yptb), reduces fungal prevalence in the gut microbiota and has direct activity onCandida albicans. Screening of bacterial effector mutant strains, and structural and biochemical analyses identify TfeC as an antifungal chitinase T6SS effector that can killC. albicans. In vivo experiments confirm that TfeC expression promotesYptbcolonization and reducesC. albicansabundance. We also show thatYptbsenses the fungal quorum-sensing molecule, tyrosol, through the two-component system, EnvZ–OmpR, and responds by activating T6SS4. Our findings suggest thatYptbmodulates its antifungal activities by detecting changes in fungal population density cues, revealing a mechanism of fungal–bacterial interkingdom communication mediated by fungal quorum-sensing molecules.

Interpretation of the binding energy shifts in the Mo 3dcore-level XPS spectra of molybdenene

arising fromT. K. Satu et al.Nature Nanotechnologyhttps://doi.org/10.1038/s41565-023-01484-2(2023)

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene–gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.

Revealing the impact of microenvironment on gold-catalysed CO2electroreduction via Marcus–Hush–Chidsey kinetics

The microenvironment at electrochemical interfaces plays a crucial role in governing electrode-mediated electron transfer processes. However, elucidating the complex effects of the microenvironment remains challenging. The Butler–Volmer equation has been used in deducing reaction mechanisms and identifying rate-determining steps, but its empirical nature makes it challenging to deduce the molecular-level picture of interfacial electron transfer processes. By contrast, the application of the Marcus–Hush–Chidsey (MHC) electron transfer theory has been constrained by its tenuous connection to experimentally measurable parameters beyond reaction rates. Here we develop a mechanistic framework based on the MHC theory to systematically analyse the cation effect on the Au-catalysed CO2reduction reaction using experimentally accessible variables. Our analysis reveals consistent trends for both inorganic and organic cations through thermodynamic and kinetic parameters derived from the MHC theory, with potential applications for probing ionomer–electrode interface microenvironments. This study establishes a universal strategy for investigating interfacial microenvironments in electron transfer processes by bridging theoretical parameters with experimental descriptors.

Influenza A(H5N8) vaccine induces humoral and cell-mediated immunity against highly pathogenic avian influenza clade 2.3.4.4b A(H5N1) viruses in at-risk individuals

Finland faced an outbreak of highly pathogenic clade 2.3.4.4b A(H5N1) avian influenza in 2023, which spread from wild birds to fur farms. Vaccinations of at-risk individuals began in June 2024 using the MF59-adjuvanted inactivated A(H5N8) vaccine (Seqirus; A/Astrakhan/3212/2020, clade 2.3.4.4b). Here, in an observational study, we assessed vaccine-induced immune responses in occupational at-risk individuals participating in the phase IV trial, including virus-specific antibody (n= 39 individuals) and T-cell (n= 18 individuals) responses. Vaccination elicited functional antibodies against the vaccine virus and two heterologous clade 2.3.4.4b strains associated with outbreaks on Finnish fur farms and dairy cattle in the United States. Among previously unvaccinated individuals, seroprotection rates against the vaccine virus were 83% (95% CI 70–97%) by microneutralization assay (titre ≥20) and 97% (90–100%) by haemagglutination inhibition assay (titre ≥40). In those previously vaccinated against avian influenza, a single dose induced seroprotection. A(H5N8)-specific memory CD4+T-cell responses were detectable, with ~5-fold increase in IFNγ secretion after two doses. These results demonstrate that the vaccine probably provides cross-protection against circulating H5 clade 2.3.4.4b viruses. EU Clinical Trial Number 2023-509178-44-00.

Accurate single-domain scaffolding of three nonoverlapping protein epitopes using deep learning

De novo protein design has seen major success in scaffolding single functional motifs; however, in nature, most proteins present multiple functional sites. Here, we describe an approach to simultaneously scaffold multiple functional sites in a single-domain protein using deep learning. We designed small single-domain immunogens, under 130 residues, that present three distinct and irregular motifs from respiratory syncytial virus. These motifs together comprise nearly half of the designed proteins; hence, the overall folds are quite unusual with little global similarity to proteins in the Protein Data Bank. Despite this, X-ray crystal structures confirmed the accuracy of presentation of each of the motifs and the multiepitope design yields improved cross-reactive titers and neutralizing response compared to a single-epitope immunogen. The successful presentation of three distinct binding surfaces in a small single-domain protein highlights the power of generative deep learning methods to solve complex protein design problems.

In vivo gene editing of human hematopoietic stem and progenitor cells using envelope-engineered virus-like particles

Engineered virus-like particles (VLPs) are a promising technology for in vivo gene editing of human hematopoietic stem and progenitor cells (HSPCs). Here we design and test two different VLP envelopes for human HSPC editing in vitro and in vivo. The first is an optimized version of the baboon envelope BaEVTR, which efficiently transduces human HSPCs in vitro. We show that the optimized BaEVTR VLP enables in vivo editing of β2 microglobulin in long-term human HSPCs (31% at 8 weeks after dosing) and editing of two hemoglobinopathy-relevant loci,BCL11AandHBG1/2(26% and 7.5%, respectively, at 5 days after dosing), inducing fetal hemoglobin. Our second VLP design uses a CD133-targeted envelope designed to reduce the transduction of mature blood cells and achieves higher in vivo specificity for HSPCs compared to the optimized BaEVTR VLP. As avoiding delivery in filter organs such as the liver would enhance efficiency and safety, we also demonstrate that both VLPs avoid human hepatocytes in a humanized liver model.

Renal PIEZO2 is an essential regulator of renin

The force-sensing ion channel PIEZO2 is an essential regulator of the renin-angiotensin-aldosterone system (RAAS), a pathway that controls blood volume. Loss of PIEZO2 in the kidney cells that produce renin disrupts cellular calcium dynamics and levels of the enzyme in mice, linking mechanotransduction in the kidney to the RAAS.

Autoantibody-triggered podocyte membrane budding drives autoimmune kidney disease

Kidney podocytes of the blood-urine filter form autoimmunoglobulin-triggered extracellular vesicles (AIT-EVs) for intra- and extracellular waste removal into the urine, a cellular reaction that links basal immune complex clearance to podocyte injury and allows non-invasive diagnosis and monitoring of kidney autoimmune activity.

A stoichiometrically conserved homologous series with infinite structural diversity

We describe a compositionally guided structural evolution within a stoichiometrically conserved framework, BaSbQ3 (Q = Te1−xSx), where each value of x gives rise to a distinct phase. The fundamental building blocks, A1 (BaSbSTe2) and Bn (BanSbnSn−1Te2n+1)...

A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis

A fin-like structural loop in GPX4 is critical for anchoring the enzyme to cellular membranes, thereby preventing ferroptosis. A patient-associated R152H mutation destabilizes this loop, leading to ferroptotic neurodegeneration in human cells and mouse models and revealing Alzheimer’s-like molecular signatures. These findings position ferroptosis as a critical driver (and potential therapeutic target) of neurodegenerative disease.

Improved solvent systems for commercially viable perovskite photovoltaic modules

Commercializing perovskite photovoltaics requires overcoming three critical barriers: the use of toxic solvents in manufacturing, variations in perovskite film quality across large areas, and limited operational reliability. Here, we address these ...

The levers of political persuasion with conversational artificial intelligence

There are widespread fears that conversational artificial intelligence (AI) could soon exert unprecedented influence over human beliefs. In this work, in three large-scale experiments (N = 76,977 participants), we deployed 19 large language models (LLMs)—...

Cell wall patterning regulates plant stem cell dynamics

The plant cell wall regulates development through spatiotemporal modulation of its chemical and mechanical properties. Pectin methylesterification is recognized as a rheological switch controlling wall stiffness. Here, we reveal a bimodal ...

Multispecies grasslands produce more yield from lower nitrogen inputs across a climatic gradient

High-yielding forage grasslands frequently comprise low species diversity and receive high inputs of nitrogen fertilizer. To investigate multispecies mixtures as an alternative strategy, the 26-site international ‘LegacyNet’ experiment systematically ...

The specificity and structure of DNA cross-linking by the gut bacterial genotoxin colibactin

Accumulating evidence has connected the chemically unstable, DNA-damaging gut bacterial natural product colibactin to colorectal cancer, including the identification of mutational signatures that are thought to arise from colibactin-DNA interstrand cross-...

A diminutive tyrannosaur lived alongsideTyrannosaurus rex

Whether Nanotyrannus lancensis represents a distinct taxon or an immature Tyrannosaurus rex is a decades-long controversy. The N. lancesis holotype is an isolated skull and ceratobranchials, but limb osteohistology of Nanotyrannus-like individuals ...

Cohesin drives chromatin scanning during the RAD51-mediated homology search

Cohesin folds genomes into chromatin loops, the roles of which are under debate. We found that double-strand breaks (DSBs) induce de novo formation of chromatin loops in human cells, with the loop base positioned at the DSB site. These loops form in the ...

Cohesin guides homology search during DNA repair using loops and sister chromatid linkages

Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability, and defective repair underlies diseases such as cancer. Homologous recombination uses an intact homologous sequence to faithfully restore damaged DNA, yet how broken ...

High-fidelity human chromosome transfer and elimination

The synthesis of human genomes and other gigabase-scale genomes will require new strategies. Here, we realized key steps in our pipeline for building synthetic human chromosomes. We established: (i) the facile transfer of human chromosomes from human ...

Hexatic phase in covalent two-dimensional silver iodide

According to the Kosterlitz-Thouless-Halperin-Nelson-Young (KTHNY) theory, the transition from a solid to liquid in two dimensions proceeds through an orientationally ordered liquid-like hexatic phase. However, alternative mixed melting scenarios, in ...

Macrophage MR1 antigen presentation promotes MAIT cell immunity and lung microbiota modulation

Mucosal associated invariant T (MAIT) cells mediate tissue homeostasis and antimicrobial immunity. However, the cells that express MHC class I-related protein 1 (MR1) and present microbial vitamin B-derived antigens (VitBAg) to MAIT cells remain unknown. ...

Multiscale structure of chromatin condensates explains phase separation and material properties

The structure and interaction networks of molecules within biomolecular condensates are poorly understood. Using cryo–electron tomography and molecular dynamics simulations, we elucidated the structure of phase-separated chromatin condensates across ...

Semiseparated biphasic bicontinuous dielectric elastomer for high-performance artificial muscle

Electrically driven dielectric elastomer artificial muscles represent a transformative advancement in the field of soft robotics. However, their output performance has encountered a bottleneck owing to the insufficient electromechanical sensitivity of ...

Pre- and postantibiotic epoch: The historical spread of antimicrobial resistance

Plasmids are now the primary vectors of antimicrobial resistance, but our understanding of how human industrialization of antibiotics influenced their evolution is limited by a paucity of data predating the antibiotic era (PAE). By investigating plasmids ...

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.

In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation

Here we established an in vivo CRISPR screening pipeline using genetically editable progenitor cells to dissect macrophage regulation in mouse models of multiple sclerosis (MS). Screening over 100 cytokine receptors and signaling molecules identified interferon-γ, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and transforming growth factor-β as essential regulators of macrophage polarization in vivo. Single-cell transcriptomics confirmed that transferred progenitor cells generate all blood-derived CNS myeloid cell populations, enabling Perturb-seq analysis of cytokine actions in neuroinflammation. Combined with biosensor expression, our approach allows monitoring cytokine effects on myeloid cell migration, debris phagocytosis and oxidative activity in vivo. Comparative transcriptomic analyses revealed conserved neuroinflammatory cytokine signatures across myeloid populations, CNS compartments and species, elucidating cytokine cues shaping myeloid function in the cerebrospinal fluid and parenchyma of individuals with MS. This versatile pipeline thus provides a scalable framework for high-resolution analysis of macrophage states and uncovers the cytokine signals that underlie their regulation in MS and MS models.

A human gut metagenome-assembled genome catalogue spanning 41 countries supports genome-scale metabolic models

Understanding the human gut microbiome requires comprehensive genomic catalogues, yet many lack geographic diversity and contain medium-quality metagenome-assembled genomes (MAGs) missing up to 50% of genomic regions, potentially distorting functional insights. Here we describe an enhanced Human Reference Gut Microbiome (HRGM2) resource, a catalogue of near-complete MAGs (≥90% completeness, ≤5% contamination) and isolate genomes. HRGM2 comprises 155,211 non-redundant near-complete genomes from 4,824 prokaryotic species across 41 countries, representing a 66% increase in genome count and a 50% boost in species diversity compared to the Unified Human Gastrointestinal Genome catalogue. It enabled improved DNA-based species profiling, resolution of strain heterogeneity and survey of the human gut resistome. The exclusive use of these genomes improved metabolic capacity assessment, enabling high-confidence, automated genome-scale metabolic models of the entire microbiota and revealing disease-associated microbial metabolic interactions. This resource will facilitate reliable functional insights into gut microbiomes.

Phage resistance mutations in a marine bacterium impact biogeochemically relevant cellular processes

Phage–bacteria interactions shape ecology and biogeochemistry across biomes. Resistance, arising from their evolutionary arms race, is well documented for receptor mutations, but other resistance mechanisms and their ecological implications remain unexplored. Here we isolated, sequenced and characterized 13 phage-resistant mutants of marineCellulophaga baltica(Flavobacteriia). Mechanistically, mutations in surface proteins provided broad and complete extracellular resistance against multiple phages through decreased adsorption. Intracellular mutations affecting serine, glycine and threonine metabolism produced narrower resistance against a single phage, permitting viral DNA replication, and, in one mutant, were shown to be lipid mediated. Putative ecosystem impacts inferred from in vitro experiments include: (1) altered carbon utilization for all mutants, but especially by surface ones, (2) increased metabolite secretion for one modelled intracellular mutant (including experimentally verified acetate) and (3) increased ‘stickiness’ for all mutants, with surface mutants also sedimenting faster. Our findings highlight new resistance mechanisms and suggest that the phage–host arms race could result in ecosystem-level biogeochemical impacts in marine microorganisms.

C-COMPASS: a user-friendly neural network tool profiles cell compartments at protein and lipid levels

Systematic proteomic organelle profiling methods including protein correlation profiling and LOPIT have advanced our understanding of cellular compartmentalization. To manage the complexity of organelle profiling data, we introduce C-COMPASS, a user-friendly open-source software that employs a neural network-based regression model to predict the spatial cellular distribution of proteins. C-COMPASS handles complex multilocalization patterns and integrates protein abundance to model organelle composition changes across conditions. We apply C-COMPASS to mice with humanized livers to elucidate organelle remodeling during metabolic perturbations. Additionally, by training neural networks with co-generated marker protein profiles, C-COMPASS extends spatial profiling to lipids, overcoming the lack of organelle-specific lipid markers, allowing for determination of localization and tracking of lipid species across different compartments. This provides integrated snapshots of organelle lipid and protein compositions. Overall, C-COMPASS offers an accessible tool for multiomic studies of organelle dynamics without needing advanced computational skills, empowering researchers to explore new questions in lipidomics, proteomics and organelle biology.

Latent space-based network analysis for brain–behavior linking in neuroimaging

We propose a latent space-based statistical network analysis (LatentSNA) method that implements network science in a generative Bayesian framework, preserves neurologically meaningful brain topology and improves statistical power for imaging biomarker detection. LatentSNA (1) addresses the lack of power and inflated type II errors in current analytic approaches when detecting imaging biomarkers, (2) allows unbiased estimation of the influence of biomarkers on behavioral variants, (3) quantifies uncertainty and evaluates the likelihood of estimated biomarker effects against chance and (4) improves brain–behavior prediction in new samples as well as the clinical utility of neuroimaging findings. LatentSNA is broadly applicable across multiple imaging modalities and outcome measures in developing, aging and transdiagnostic cohorts, totaling 8,003 to 11,861 participants. LatentSNA achieves substantial accuracy gains (averaging 110–150%) and replicability improvements (averaging 153%) over existing approaches in moderate to large datasets. As a result, LatentSNA elucidates how network topology is implicated in brain–behavior relationships.

Deep Imputation for Skeleton data (DISK) for behavioral science

Pose estimation methods and motion capture systems have opened doors to quantitative measurements of animal kinematics. While animal behavior experiments are expensive and complex, tracking errors sometimes make large portions of the experimental data unusable. Here our deep learning method, Deep Imputation for Skeleton data (DISK), uncovers dependencies between keypoints and their dynamics to impute missing tracking data without the help of any manual annotations. We demonstrate the utility and performance of DISK on seven animal skeletons including multi-animal setups. The imputed recordings allow us to detect more episodes of motion, such as steps, and obtain more statistically robust results when comparing these episodes between experimental conditions. In addition, by learning to impute the missing content, DISK learns meaningful representations of the data capturing, for example, underlying actions. This stand-alone imputation package, available athttps://github.com/bozeklab/DISK.git/, is applicable to outputs of tracking methods (marker-based or markerless) and allows for varied types of downstream analysis.

Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy

Glioblastoma (GBM) is an aggressive, immunotherapy-resistant brain tumor. Here, we engineered an oncolytic virus platform based on herpes simplex virus 1 for GBM viroimmunotherapy. We mutated the highly cytopathic MacIntyre strain to increase spread and oncolytic activity, limit genetic drift, prevent neuron infection and enable PET tracing. We incorporated microRNA target cassettes to attenuate replication in healthy brain cells. Moreover, we engineered the gD envelope protein to specifically target GBM using EGFR-specific or integrin-specific binders. Lastly, we incorporated five immunomodulators to remodel the tumor microenvironment (TME) by locally expressing IL-12, anti-PD1, a bispecific T cell engager, 15-hydroxyprostaglandin dehydrogenase and anti-TREM2 to target T cells and myeloid cells in the GBM TME. A single intratumoral injection increased survival in GBM preclinical models, while promoting tumor-specific T cell, natural killer cell and myeloid cell responses in the TME. In summary, we engineered a retargeted, safe and traceable oncolytic virus with strong cytotoxic and immunostimulatory activities for GBM immunotherapy.

Rapid motor skill adjustment is associated with population-level modulation of cerebellar error signals

A core principle of cerebellar learning theories is that climbing fibers from the inferior olive convey error signals about movement execution to Purkinje cells in the cerebellar cortex. These inputs trigger synaptic changes, which are purported to drive progressive adjustment of future movements. Individually, binary complex spike signals lack information about the sign and magnitude of errors which presents a problem for cerebellar learning paradigms exhibiting fast adaptation. Here, using a newly developed behavioral paradigm in mice, we introduced sensorimotor perturbations into a simple joystick-pulling behavior and found parasagittal bands of Purkinje cells with reciprocal modulation of complex spike activity, along with rapid adaptation of the behavior. Whereas complex spiking showed little modulation in the unperturbed condition, alternating bands were activated or inhibited when the perturbation was introduced and this modulation encoded the sign and magnitude of the resulting sensorimotor mismatch. These findings provide important insight about how the cerebellum uses supervised learning to quickly adapt motor behavior in response to perturbations.

Geometry-induced spin chirality in a non-chiral ferromagnet at zero field

Spin chirality is a fundamental property that manifests non-reciprocal transport—magnetochiral anisotropy (MChA). However, the application of MChA in technology is constrained by the necessity for an external magnetic field, complex non-centrosymmetric crystal synthesis and cryogenic environments. Here we overcome these challenges by imprinting geometric chirality onto a nickel tube via three-dimensional nanoengineering. We use two-photon lithography to create a structurally twisted polymeric template with micrometre-sized pitch and diameters and cover it with a uniform 30-nm-thick nickel shell. The nickel tube exhibits spontaneous MChA—non-reciprocal transport at zero magnetic field and room temperature. X-ray magnetic circular dichroism microscopy confirms helical spin textures stabilized by the torsion- and curvature-engineered shape anisotropy, while inelastic light scattering spectroscopy demonstrates robust non-reciprocal magnon transport at remanence, reconfigurable via magnetic field history. The chiral parameter in our device surpasses that of natural chiral magnets such as Cu2OSeO3. Analytical theory and micromagnetic simulations demonstrate that the non-reciprocity is further enhanced by downscaling the feature sizes. Our results establish a scalable, geometry-driven nanotechnology that imprints spin chirality on non-chiral ferromagnets and may enable nanoscale integration of chirality-enhanced magnonics and spintronics for real-world use cases.

Fertilization triggers early proteomic symmetry breaking in mammalian embryos

Single-cell proteomics finds asymmetries between sister blastomeres from the 2-cell stage in human and mouse embryos, defining two states: alpha and beta. Alpha-beta asymmetry can be traced back to the zygote, is triggered by fertilization, and is linked to differential developmental potential, with beta blastomeres having a higher potential.

Retraction notice to: Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells

(Cell187, 7637–7654.e1–e29; December 26, 2024)

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.

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.

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.

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.

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.

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.

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.

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.

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.

Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation

One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.

Transcription co-inhibition alters drug resistance evolution and enhancesMycobacterium tuberculosisclearance from granulomas

Mycobacterium tuberculosis(Mtb), the causative agent of tuberculosis, remains the deadliest human pathogen. Treatment is hampered by drug resistance and the persistence of slow-growing or non-replicating populations. Rifampicin, a cornerstone of first-line therapy, inhibits transcription during promoter escape, but resistance mutations undermine efficacy and drive resistance spread. We revisited the transcription cycle as an antibacterial target by characterizing AAP-SO2, an RNA polymerase inhibitor with whole-cell activity against Mtb. AAP-SO2slows the nucleotide addition cycle, disrupting elongation and termination. Rifampicin-resistant mutations impose fitness costs by perturbing the balance of these steps, creating exploitable weaknesses. Inhibition of transcription with AAP-SO2reduced the evolution of rifampicin resistance and was especially effective against the most common resistant mutant. Combination treatment with rifampicin and AAP-SO2synergistically killed non-replicating Mtb in an ex vivo rabbit granuloma model. These findings show that exploiting functional vulnerabilities of the transcription cycle can counter rifampicin resistance and improve clearance of recalcitrant Mtb populations.

Gut microbiome-mediated transformation of dietary phytonutrients is associated with health outcomes

Food, especially plant-based diet, has complex chemical diversity. However, large-scale phytonutrient-metabolizing activities of gut bacteria are largely unknown. Here we integrated and systematically analysed multiple databases containing information on enzymatic reactions and food health benefits, and 3,068 global public human microbiomes. Transformation of 775 phytonutrients from edible plants was associated with enzymes encoded by diverse gut microbes. In vitro assays validated the biotransformation activity of gut species, for example,Eubacterium ramulus. The biotransformation of phytonutrients demonstrated high interpersonal and geographical variability. Machine learning models based on 2,486 public case–control microbiomes, using the abundances of enzymes associated with modification of phytonutrients present in health-associated foods, discriminated the health status of individuals in multiple disease contexts, suggesting altered biotransformation potential in disease. We validated the association of microbiome-encoded enzymes with the anti-inflammatory activity of common edible plants by combining metagenomics and metatranscriptomics analysis in specific-pathogen-free and germ-free mice. These findings have implications for designing precise, personalized diets to guide an individual towards a healthy state.

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic–endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.

Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.

Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis

The anatomical source of infection is a major determinant of sepsis outcomes; however, how distinct sites shape immunity remains unclear. Here we applied multi-omic profiling, integrating single-cell transcriptomics, single-cell T cell receptor and B cell receptor sequencing, CITE-seq, bulk RNA sequencing and plasma proteomics, to analyze peripheral blood mononuclear cells and plasma from 281 adult and pediatric individuals with sepsis and controls. We identified an NR4A2+central memory CD4+T cell subset enriched in abdominal, pulmonary and skin sepsis, with features of exhaustion; genetic perturbations showedNr4a2loss improved survival, while overexpression worsened it. Proinflammatory CD8+T, natural killer and natural killer T subsets expressingCCL4,CCL3and tumor necrosis factor expanded in adult abdominal and pulmonary sepsis, while pediatric pulmonary sepsis featured proliferative CD14+monocytes, findings validated in external single-cell cohorts and confirmed in 164 independent individuals. Plasma proteomics revealed shared mediators including interleukin-6 and EN-RAGE across anatomical sites and ages. Together, our findings delineate anatomical-specific and age-specific immune programs in sepsis, highlighting candidate targets for precision immunotherapy.

ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity

Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5—termed as immunogenic dsRNAs—remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized.

Selective partitioning and uphill transport enable effective Li/Mg ion separation by negatively charged membranes

Efficient separation of lithium (Li+) and magnesium (Mg2+) is critical for enhancing sustainable lithium extraction from natural brines, which is vital for battery production and renewable energy technologies. Here we present a method for highly selective Li+/Mg2+separation driven by concentration gradients across negatively charged membranes with high charge densities. In contrast to typical electric field-driven transport in negatively charged membranes, where divalent cations generally permeate faster than monovalent cations, Li+ions in our system permeate the membrane at substantially higher rates than Mg2+ions. This unexpected selectivity stems from the selective ion partitioning properties of the membrane and the uphill transport of Mg2+ions against their external concentration gradient. We demonstrate the efficacy of this separation approach through bench-scale dialysis experiments using a model Atacama brine solution, achieving efficient separation of monovalent and divalent cations. The high separation efficiency observed in this study suggests a promising approach for monovalent/divalent ion separations, offering higher selectivity compared to current technologies.

A human epiblast model reveals dynamic TGFβ-mediated control of epithelial identity during mammalian epiblast development

Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN—a distinct TGFβ family ligand—induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity.

Mapping single-cell diploid chromatin fiber architectures using DAF-seq

Gene regulation is orchestrated by the co-binding of proteins along chromosome-length chromatin fibers within single cells, yet the heterogeneity of this occupancy between haplotypes and cells remains poorly resolved in diploid organisms. Here we present Deaminase-Assisted single-molecule chromatin Fiber sequencing (DAF-seq), which enables single-molecule footprinting at near-nucleotide resolution while synchronously profiling single-molecule chromatin states and DNA sequence. DAF-seq illuminates cooperative protein occupancy at individual regulatory elements and resolves the functional impact of somatic variants and rare chromatin epialleles. Single-cell DAF-seq (scDAF-seq) generates chromosome-length protein co-occupancy maps across 99% of each individual cell’s mappable genome. scDAF-seq uncovers extensive chromatin plasticity both within and between single diploid cells, with chromatin actuation diverging by 61% between haplotypes within a cell, and 63% between cells. Moreover, we find that regulatory elements are preferentially co-actuated along the same fiber in a distance-dependent manner that mirrors cohesin-mediated loops. Overall, DAF-seq enables the characterization of protein occupancy across entire chromosomes with single-nucleotide, single-molecule, single-haplotype and single-cell precision.

Standardized metrics for assessment and reproducibility of imaging-based spatial transcriptomics datasets

Spatial transcriptomics lacks standardized metrics for evaluating imaging-based in situ hybridization technologies across sites. In this study, we generated the Spatial Touchstone (ST) dataset from six tissue types across several global sites with centralized sectioning, analyzed on both Xenium and CosMx platforms. These platforms were selected for their widespread use and distinct chemistries. We assessed reproducibility, sensitivity, dynamic ranges, signal-to-noise ratio, false discovery rates, cell type annotation and congruence with single-cell profiling. This study offers ST standardized operating procedures (STSOPs) and an open-source software, SpatialQM, enabling evaluation of samples across all technical metrics and direct imputation of cell annotations. The generated imaging-based spatial transcriptomics data repository comprises 254 spatial profiles, incorporating both public and newly generated ST datasets in a web-based application, which enables analysis and comparison of user data against an extensive collection of imaging-based datasets. Finally, we establish best practices and metrics to evaluate and integrate imaging-based multi-omics data from single cells into spatial transcriptomics to spatial proteomics.

Atom-level enzyme active site scaffolding using RFdiffusion2

Designing new enzymes typically begins with idealized arrangements of catalytic functional groups around a reaction transition state, then attempts to generate protein structures that precisely position these groups. Current AI-based methods can create active enzymes but require predefined residue positions and rely on reverse-building residue backbones from side-chain placements, which limits design flexibility. Here we show that a new deep generative model, RoseTTAFold diffusion 2 (RFdiffusion2), overcomes these constraints by designing enzymes directly from functional group geometries without specifying residue order or performing inverse rotamer generation. RFdiffusion2 successfully generates scaffolds for all 41 active sites in a diverse benchmark, compared to 16 using previous methods. We further design enzymes for three distinct catalytic mechanisms and identify active candidates after experimentally testing fewer than 96 sequences in each case. These results highlight the potential of atomic-level generative modeling to create de novo enzymes directly from reaction mechanisms.

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.

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.

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.

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.

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.

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.

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.

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.

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.

In This Issue

A host-centric view of the microbiota metabolome

Our current understanding of microbial-host communication is largely based on context-dependent examples and anecdotes. Yamada and Palm present a teleological framework that organizes microbial metabolites based on their impacts on the host. These fundamental principles of host-microbe interplay enhance our perspectives of how microbial metabolites influence host immunity and beyond.

A stepwise decoding mechanism for heat sensing in plants connects lipid remodeling to a nuclear signaling cascade

A complete hierarchical thermo-decoding mechanism in plants connects cell membrane lipid remodeling during heat stress to the downstream signaling cascade in the nucleus. Field trials demonstrate the potential application of this mechanism in customized heat-tolerant crop design in rice.

The unique architecture of umbrella toxins permits a two-tiered molecular bet-hedging strategy for interbacterial antagonism

Umbrella toxin particles produced by Actinobacteria contain five spokes tipped with variable lectin domains. Here, Zhao et al. show that these lectins mediate species-specific binding to a previously unrecognized cell surface carbohydrate polymer and propose that the modular nature of umbrella particles enables bet hedging against unpredictable competitor encounters.

pTα enhances mRNA translation and potentiates CAR T cells for solid tumor eradication

Addition of a pre-TCR domain to chimeric antigen receptors boosts mRNA translation and enables durable tumor control by T cells in both blood and solid cancers.

Membrane potential mediates the cellular response to mechanical pressure

Cells in tissues need to know when to start growing and when to stop growing to quickly heal wounds but prevent tumorous overgrowth. Membrane potential allows cells to sense physical forces, including those from neighboring cells, and thereby regulates growth.

The effect of shingles vaccination at different stages of the dementia disease course

A natural experiment found that herpes zoster vaccination reduced the occurrence of mild cognitive impairment and deaths due to dementia, indicating that the vaccine may slow the progression of dementia throughout its clinical disease course.

The regulatory code of injury-responsive enhancers enables precision cell-state targeting in the CNS

Enhancer elements direct cell-type-specific gene expression programs. After injury, cells change their transcriptional state to adapt to stress and initiate repair. Here we investigate how injury-induced transcriptional programs are encoded within enhancers in the mammalian CNS. Leveraging single-nucleus transcriptomics and chromatin accessibility profiling, we identify thousands of injury-induced, cell-type-specific enhancers in the mouse spinal cord after a contusion injury. These are abundant in glial cells and retain cell-type specificity, even when regulating shared wound response genes. By modeling glial injury-responsive enhancers using deep learning, we reveal that their architecture encodes cell-type specificity by integrating generic stimulus response elements with cell identity programs. Finally, through in vivo enhancer screening, we demonstrate that injury-responsive enhancers can selectively target reactive astrocytes across the CNS using therapeutically relevant gene delivery vectors. Our decoding of the principles of injury-responsive enhancers enables the design of sequences that can be programmed to target disease-associated cell states.

High-frequency bursts facilitate fast communication for human spatial attention

Brain-wide communication supporting flexible behavior requires coordination between sensory and associative regions but how brain networks route sensory information at fast timescales to guide action remains unclear. Using human intracranial electrophysiology and spiking neural networks during spatial attention tasks, where participants detected targets at cued locations, we show that high-frequency activity bursts (HFAbs) mark temporal windows of elevated population firing that enable fast, long-range communications. HFAbs were evoked by sensory cues and targets, dynamically coupled to low-frequency rhythms. Notably, both the strength of cue-evoked HFAbs and their decoupling from slow rhythms predicted behavioral accuracy. HFAbs synchronized across the brain, revealing distinct cue- and target-activated subnetworks. These subnetworks exhibited lead–lag dynamics following target onset, with cue-activated subnetworks preceding target-activated subnetworks when cues were informative. Computational modeling suggested that HFAbs reflect transitions to population spiking, denoting temporal windows for network communications supporting attentional performance. These findings establish HFAbs as signatures of population state transitions, supporting information routing across distributed brain networks.

Molecular-scale isotropic 3D super-resolution microscopy via interference localization

Three-dimensional (3D) nanoscale imaging reveals the detailed morphology of subcellular structures; however, conventional single-molecule localization microscopy is constrained by limited axial resolution. Here we introduce ROSE-3D, an interferometric localization approach that enables isotropic 3D super-resolution imaging with uniform performance across the entire depth of field. Compared with conventional astigmatism-based methods, ROSE-3D improves lateral localization precision by 2–6 times and axial precision by 3.5–8 times over a depth of field of approximately 1.2 μm. Leveraging its multicolor and whole-cell imaging capabilities, ROSE-3D resolves, in situ, the nanoscale organization of nuclear lamins and the assemblies of mitochondrial fission-related protein DRP1. These results establish ROSE-3D as a powerful tool for interrogating nanoscale cellular architecture.

CaBLAM: a high-contrast bioluminescent Ca2+indicator derived from an engineeredOplophorus gracilirostrisluciferase

Monitoring intracellular calcium is central to understanding cell signaling across nearly all cell types and organisms. Fluorescent genetically encoded calcium indicators (GECIs) remain the standard tools for in vivo calcium imaging, but require intense excitation light, leading to photobleaching, background autofluorescence and phototoxicity. Bioluminescent GECIs, which generate light enzymatically, eliminate these artifacts but have been constrained by low dynamic range and suboptimal calcium affinities. Here we show that CaBLAM (‘calcium bioluminescence activity monitor’), an engineered bioluminescent calcium indicator, achieves an order-of-magnitude improvement in signal contrast and a tunable affinity matched to physiological cytosolic calcium. CaBLAM enables single-cell and subcellular activity imaging at video frame rates in cultured neurons and sustained imaging over hours in awake, behaving animals. These capabilities establish CaBLAM as a robust and general alternative to fluorescent GECIs, extending calcium imaging to regimes where excitation light is undesirable or infeasible.

Parallel stopped-flow interrogation of diverse biological systems at the single-molecule scale

Single-molecule imaging techniques have provided unprecedented insights into functional changes in composition and conformation across diverse biological systems. As with other biophysical methods, single-molecule fluorescence and Förster resonance energy transfer investigations are typically limited to examination of one sample at a time. Consequently, experimental throughput is restricted, and experimental variances are introduced that can obscure functional distinctions in closely related systems. Here, to address these limitations, we introduce parallel rapid exchange single-molecule fluorescence and single-molecule Förster resonance energy transfer to enable simultaneous steady-state and pre-steady-state interrogations of diverse systems. Using this approach, we elucidate the timing of distinct conformational events underpinning β-arrestin1 activation, unmask antibiotic-induced impacts on messenger RNA decoding fidelity and demonstrate that endogenously encoded ribosomal RNA sequence variation modulates antibiotic sensitivity. This generalizable and scalable method promises to broaden the scope and reproducibility of quantitative single-molecule interrogations of biomolecular function.

Iridium(III)-catalysed ionic hydrogenation of pyridines to multisubstituted piperidines

Piperidine and pyridine are nitrogen heterocyclic motifs prominently used in pharmaceuticals and consequently of great importance. The direct reduction of planar pyridines into piperidines with highsp3-carbon content is highly attractive as this offers a route to producing high-value products and broadening the structural space. However, direct hydrogenation of pyridines with homogeneous catalysts is challenging due to their aromatic stability and catalyst-poisoning abilities. Here we describe a robust and selective iridium(III)-catalysed ionic hydrogenation of pyridines to corresponding functionalized piperidines. Important highly reduction-sensitive groups, including nitro, azido, bromo, alkenyl and alkynyl, are inert, enabling access to a broad range of multisubstituted piperidines in high yields, substantially expanding the available chemical space for this relevant scaffold. The method requires low catalyst loadings, is scalable to decagrams and delivers the most synthetically valuable free secondary amines as easily isolable and stable piperidinium salts. Applied in a complex late-stage setting, the pyridine motif in several FDA-approved drugs was successfully and selectively hydrogenated.

Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation

Multiple enhancers, often separated by vast genomic distances, regulate key genes. However, how the folding of individual chromatin fibres enables cell-type-restricted multi-enhancer regulation remains unclear. Here, using acute protein degradation and time-resolved chromatin conformation capture in mantle cell lymphoma, we found that the B cell-lineage-determining factor EBF1 organizes multiple enhancers around sparsely distributed genes essential for B cell identity and oncogenesis. Time-resolved sub-diffraction optical tracing of more than 100,000 chromatin fibres further revealed diverse topological conformations that facilitate multi-enhancer interactions. Mechanistically, we discovered that enhancer positioning at local topological centres is required for promoter engagement, with EBF1 acting as a permeable barrier to loop-extruding cohesin at enhancers. Extending these findings to T cell leukaemia, we show that lineage-determining transcription factors such as EBF1 and TCF1 radially position enhancers within gene loci to enable multi-enhancer regulation of key oncogenes at the single-allele level.

Karyopherins remodel the dynamic organization of the nuclear pore complex transport barrier

Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organization that contrasts with many of the bulk properties of in vitro FG-domain assemblies.

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.

Lantibiotic-producing bacteria impact microbiome resilience and colonization resistance

Lantibiotic-producing gut commensals are prevalent in human gut microbiomes. Cole et al. demonstrate that gut colonization with lantibiotic-producingBlautia pseudococcoidesSCSK (BpSCSK) prevents recovery of antibiotic-induced dysbiosis and increases susceptibility toKlebsiella pneumoniaeandClostridioides difficileinfection.

A commensal bacterium secretes effector proteins to establish population heterogeneity in the gut

Zagieboylo and colleagues demonstrate that the human commensalBacteroides thetaiotaomicronsecretes two self-targeting proteins that induce heterogeneity within its own population. Differential expression of these effectors and a cognate protective factor provide a mechanism by which a single commensal strain diversifies into sub-populations within the gut environment.

Cryptococcusexploits delayed microglial activation, and microglial osteopontin/Spp1impairs peripheral host control

Cryptococcal meningoencephalitis (CM) is a leading cause of death in HIV/AIDS. Reyes et al. found that microglial activation is markedly delayed afterCryptococcusinvasion compared withCandida. Microglia require Th1-derived IFN-γ for activation, and their osteopontin expression worsens disease—revealing a deficient microglial response that permits brain infection.

Diet modulatesVibrio choleraecolonization and competitive outcomes with the gut microbiota

Liu et al. show that dietary protein sources differentially restrict colonization of the pathogenVibrio cholerae. Specific diets downregulateV. choleraetype VI secretion system (T6SS) expression, leading to the loss of pathogen competitiveness against commensal bacteria, as well as alterations in the abundance and composition of the gut microbiota.

Clonal persistence dominates homeostatic intestinal IgA responses

Gut plasma cells secrete IgA, which prevents infections, neutralizes toxins, and regulates the gut microbiota. Simons et al. demonstrate that stable IgA production results not from the persistence of individual plasma cells but rather a continuous dynamic renewal of the gut plasma cell population through diversification of large B cell clones.

An archaeal transcription factor bridges prokaryotic and eukaryotic regulatory paradigms

Methanogenic archaea use the one-component system AmzR to sense methylamines and regulate the expression of methylamine-metabolizing genes. Unlike other prokaryotic one-component systems, the DNA-binding motif of AmzR resembles a structural fold typically found in eukaryotic transcription factors. This discovery narrows the gap between prokaryotic and eukaryotic regulatory proteins.

Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling

Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology inCasp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS.

Liraglutide in mild to moderate Alzheimer’s disease: a phase 2b clinical trial

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer’s disease syndrome. ‘Evaluating liraglutide in Alzheimer’s disease’ (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer’s disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = −0.17; 95% confidence interval: −0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome—score on the Alzheimer’s Disease Assessment Scale-Executive domain (ADAS-Exec)—performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03−0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (−0.58; 95% confidence interval: −3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (−0.06; 95% confidence interval: −0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer’s disease. ClinicalTrials.gov identifier: NCT01843075 . Results from the phase ELAD 2 trial reveal that liraglutide is safe and well tolerated in people with mild to moderate Alzheimer’s disease but does not significantly slow brain metabolism decline.

RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer

Therapeutic targeting of mutant KRAS pathways driving cancers is being actively investigated to identify feedback mechanisms responsible for the development of adaptive resistance to mutant KRAS inhibitors undergoing clinical trials. Here we report RASH3D19 as a mediator of RAS pathway activation through a positive feedback loop involving the KRAS–microRNA signalling axis. KRAS-induced miR-222 represses ETS1 expression and downstream transactivation of miR-301a leading to elevation of its target RASH3D19. RASH3D19 facilitates activation of RAS pathways by promoting dimerization and interaction of EGFR with the SOS2, GRB2, SHP2 and GAB1 complex. Genetic deletion of RASH3D19 in mutant KRAS-expressing cancer cells exhibits growth retardation in vitro, in vivo and sensitized pancreatic ductal adenocarcinoma and colorectal cancer cells, organoids and xenografts to mutant KRAS inhibitors, suppressing feedback reactivation of RAS pathways. Therapeutic targeting of RASH3D19 is expected to lead to tumour debulking and alleviating resistance to KRAS inhibitors in mutant KRAS-expressing cancers.

Fat sensory cues in early life program central response to food and obesity

Maternal obesity predisposes offspring to metabolic diseases. Here, we show that non-nutritive sensory components of a high-fat diet (HFD), beyond its hypercaloric, obesogenic effects, are sufficient to alter metabolic health in the offspring. To dissociate the caloric and sensory components of HFD, we fed dams a bacon-flavoured diet, isonutritional to a normal chow diet but enriched with fat-related odours. Offspring exposed to these fat-related odours during development display metabolic inflexibility and increased adiposity when fed HFD in adulthood independently of maternal metabolic health. Developmental exposure to fat-related odours shifts mesolimbic dopaminergic circuits and Agouti-related peptide (AgRP) hunger neurons’ responses to phenocopy those of obese mice, including a desensitization of AgRP neurons to dietary fat. While neither neonatal optogenetic activation of sensory circuits nor passive exposure to fat-related odours is sufficient to alter metabolic responses to HFD, coupling optogenetic stimulation of sensory circuits with caloric intake exacerbates obesity. Collectively, we report that fat-related sensory cues during development act as signals that can prime central responses to food cues and whole-body metabolism regulation.

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.

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.

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.