Reliable future climate projections and water deficiency assessments require precipitation observations that are both spatially comprehensive and temporally complete, yet many global regions still suffer from observation sparsity1,2. Here we evaluate the distribution of 221,483 internationally exchanged precipitation gauges worldwide, with records across 1900-2022, and further explore where new gauges are most needed under different scenarios. We find that at present only 13.4% of the global land surface meets the World Meteorological Organization requirements for annual precipitation monitoring, indicating widespread scarcity that has serious socioeconomic implications. Europe has the highest continental gauge density (2.4 gauges per 1,000 km2), with Germany leading among countries over 50,000 km2 (22.4 gauges per 1,000 km2). Globally, 25% of land surface already requires urgent expansion of gauge networks because of climate variability, including northern South America, northern North America, Central Africa and southern Asia. Considering projected precipitation changes and socioeconomic conditions under a high-emission scenario further identifies high-need regions in India, Greenland, Bolivia and China because of climate sensitivity and socioeconomic vulnerabilities, increasing this share to 32.1% of global land. Our findings highlight important gaps in global precipitation monitoring that require strategic investments in new gauges and underscore the need for open data access.

The idea that atmospheric oxygen has dictated the maximum body size of insects across their evolutionary history is ingrained in popular and scientific literature1-3. In Nature 30 years ago, the hypothesis was put forward that a limitation on oxygen diffusion at the level of the tracheoles constrains the maximum body size of insects and that increased atmospheric oxygen concentration in the late Palaeozoic permitted insect gigantism4. Here we contest this hypothesis by showing that the relative space occupied by tracheoles in the flight muscle of insects (1) increases by only 1.8-fold over a 10,000-fold body mass range (1,320 micrographs, 44 species, 10 orders), (2) is typically 1% or less in most species, and (3) that this observation holds when we extend our relationship to the long-extinct gigantic dragonfly-like Meganeuropsis permiana (approximately 100 g). The small space requirement and the lack of a strong increase in tracheolar investment with body size, despite clear evolutionary potential to do so, provide convincing evidence that diffusive oxygen transport through the tracheolar-muscle system does not constrain the maximum body size of extant or gigantic prehistoric insects.

CRISPR-Cas9 is a powerful genome-editing tool1, but genome-wide off-target activity can hinder therapeutic applications. Negative supercoiling ((-)SC) has been implicated in off-target activity, but a molecular-level understanding is lacking. Here, using (-)SC DNA minicircles, we observe supercoiling-driven structural defects in the DNA that are resolved by Cas9 binding. Cryo-electron microscopy structures of Cas9 bound in both the on-target and off-target configurations highlight that the Cas9 HNH domain is poised in a more catalytically competent conformation. New DNA-RNA mismatch geometries are accommodated across the protospacer and structural plasticity in the protospacer adjacent motif distal region of the protospacer is topology dependent. Together, our study reveals the molecular basis for (-)SC-induced Cas9 targeting and provides a framework for the design of next-generation high-fidelity CRISPR effectors with topological context.

The conditions under which magma accumulates and is stored are fundamental to unravelling the processes of crust formation, planetary differentiation, geothermal heat recharge and volcanic eruptions. Storage pressure, temperature and volatile saturation are typically inferred from erupted volcanic products. However, changes during kilometres of magma ascent induce disequilibrium crystallization and vesiculation, and inverting back to storage conditions comes with unresolvable uncertainties. Here we explore opportunities arising from magma drilling at Krafla volcano, Iceland, to reconstruct real, in situ magmatic conditions. The findings show that, over the approximately 5 min in which the magma is quenched, vapour bubbles consisting of H2O and CO2 exsolve, grow and resorb, but the changes can be accounted for by multiparametric inversion (for chemistry, vesicularity and vitrification), and that the magma was stored under volatile-saturated lithostatic conditions, unlike previous assertions of lower vapour pressures based on classic methods1. These new disequilibrium simulations reconcile the glass chemistry with conceptual models of magma storage and provide us with the unique pairing of precisely measured depth and volatile pressure on a single magma body and thus a robust method to improve our understanding of magma storage conditions and evolution.

Posterior fossa type A (PFA) ependymoma is an unusual infantile brain tumour with few known somatic mutations, thought to be driven by epigenetic mechanisms1. PFA ependymoma has a markedly higher incidence and worse prognosis in male children than in female children2. The mechanisms that underlie these sex differences are at present unknown. Here we show that the cellular hierarchy of PFA ependymoma is less differentiated in male individuals than it is in female individuals. In the normal developing mouse hindbrain, male gliogenic progenitors are less differentiated than matched female sibling controls. To further parse the effects of chromosomal versus gonadal contributions in the male hindbrain, we used the four-core genotype mouse model3, which showed that androgen signalling, rather than sex chromosomes, prolongs hindbrain differentiation in male mice. Androgen supplementation promotes the growth of PFA ependymoma, but not that of other brain tumours. Conversely, androgen blockade diminishes both the stem-like potential and the proliferation of PFA ependymoma. We conclude that androgen signalling in both the normal developing hindbrain and PFA ependymoma is sufficient to promote growth and delay differentiation. Anti-androgen therapies represent a potential clinical avenue to target this currently untreatable childhood cancer.

Parasitic infections modulate both immune and sensory responses, but how these systems collaborate to elicit protective behaviours remains incompletely understood. The gut epithelium contains specialized sensory cells that detect pathogens and irritants. These include cholinergic tuft cells, which sense parasites and initiate type 2 immune responses1-3, as well as serotonergic enterochromaffin (EC) cells, which detect irritants and communicate with afferent nerve fibres to transmit nociceptive signals4-6. Here we show that paracrine signalling between these cells constitutes a mechanism for neuro-immune interaction and gut-brain communication. We find that tuft cells use two distinct mechanisms of acetylcholine (ACh) release despite lacking synaptic vesicles and excitable membranes. These include acute release in response to parasite-derived metabolites, followed by constitutive 'leak-like' release, which occurs with type 2 inflammation. Although both mechanisms can activate muscarinic receptors on crypt-residing EC cells, only the sustained mode of ACh release elicits levels of serotonin sufficient to stimulate vagal afferent neurons that suppress food intake. This two-phase paracrine signalling mechanism explains how parasitic infection progresses from an initial asymptomatic phase to symptomatic established disease, in which type 2 immune and sensory signalling pathways within the gut-brain axis collaborate to evoke protective behaviours.

Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear1,2. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days. Here we find that memory of colitis is characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. This approach reveals that memory of colitis is propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others. Finally, we show that colitis primes stem cells for increased expression of an AP-1-regulated gene program following oncogenic mutation that accelerates tumour growth, a phenotype dependent on AP-1 activity. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential diagnostic and therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.

Many viruses have adapted to persist in infected humans for life1,2. Variable host control of their ongoing abundance (viral load) can lead to clearance or disease3-5. Here we analysed the viral DNA load of 31 common viruses in human blood and saliva using whole-genome sequencing data from UK Biobank (n = 490,401), All of Us (n = 414,817) and Simons Foundation Powering Autism Research for Knowledge (SPARK; n = 12,519). Viral DNA load varied markedly with age, time of day and season; most viruses were also present at greater abundance in men than in women. Human genetic variation at dozens of loci associated with DNA load of seven viruses: Epstein-Barr virus (EBV, 45 loci), human herpesvirus (HHV)-7 (37 loci), HHV-6B, Merkel cell polyomavirus and three anelloviruses. Variation at the major histocompatibility complex (MHC) locus generated the strongest associations (P = 5.8 × 10-9 to 2.5 × 10-1459), which were specific to each virus. The HLA-B*08:01 allele also exhibited a host-virus genetic interaction with EBV subtype (P = 7.4 × 10-70). Other human genetic effects implicated genes encoding proteins that process peptides for antigen presentation, such as ERAP1 (HHV-7, P = 2.7 × 10-78) and ERAP2 (EBV, P = 4.6 × 10-111). Mendelian randomization analyses supported a strong causal effect of EBV DNA load on increased risk of Hodgkin's lymphoma (P = 1.8 × 10-3), but not multiple sclerosis (P = 0.52). This suggests that higher chronic EBV load increases lymphoma risk, whereas associations of EBV infection with autoimmune conditions reflect host immune responses to particular viral epitopes.

In cancer and chronic infection, CD8 T cell exhaustion is hallmarked by expression of inhibitory receptors such as PD1, TIM3, LAG3 and others1-3. Thus, inhibitory molecule focus has been limited to cell-surface proteins. Here we evaluate the surface lipid metabolite phosphatidylserine (PS) as a regulator of exhaustion. PS primarily localizes to the inner plasma membrane of live cells but is well known to be externalized to the outer membrane during cell death. The role of exposed PS on live immune cells is less clear. We show that viable, antigen-specific CD8 T cells externalize PS during lymphocytic choriomeningitis virus (LCMV) infection. T cell activation induced initial PS exposure, and chronic antigen stimulation sustained externalization. Transcriptomic and lipidomic analyses also identified PS accumulation in exhausted CD8 T cells. To evaluate a role for exposed PS in exhaustion, we treated LCMV chronically infected mice with a PS-targeting antibody (mch1N11)4 and found that it expanded LCMV-specific CD8 responses. PD1+TCF1+ stem-like CD8 T cells downregulated quiescence-associated gene modules and increased proliferation after antibody treatment, highlighting an inhibitory role for PS. Mechanistically, exposed PS on T cells functioned extrinsically to suppress dendritic cell immunostimulatory phenotypes, in turn limiting CD8 T cell responses. PS-targeting antibody with anti-PDL1 synergized to increase CD8 responses and improve viral control. Finally, we show that PD1+ CD8 T cells from human tumours can also expose PS. In summary, we detail CD8 T cell PS biology and provide insight into a mechanism by which exposed PS functions as a 'non-classical' extrinsic inhibitory molecule in exhaustion.

Autoimmunity and anti-cancer immunity lie on the same biological continuum1,2, but their link remains obscure. The paraneoplastic neurological syndrome ANRE (anti-NMDA receptor (NMDAR) encephalitis) is a paradigm for their connectivity3, given that intratumoural NMDAR expression is correlated with the generation of anti-NMDAR antibodies4,5. Here we verify ectopic expression of GluN1 and GluN2B NMDAR subunits in triple-negative breast cancer (TNBC)6 and model this using orthotopic TNBC tumours with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce the recruitment of B cells and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoural B cell phylogenies and cryogenic electron microscopy structural analyses demonstrate that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE4,5. We further identify a correlation between intratumoural NMDAR expression and anti-NMDAR antibody titres in patients with TNBC. Taken together, our data establish a direct connection between intratumoural NMDAR expression, antibody maturation and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease after maturation, revealing a mechanistic trade-off between cancer immunity and neurotoxicity.

Large-scale gradients of functional connectivity between brain areas organize the human neocortex, linking brain topography to the texture of cognition1,2. In adults, three dominant axes-sensory-association, visual-somatosensory and modulation-representation-run, respectively, from primary sensory to transmodal association areas, from visual to body-centred systems and from control and attention networks to default mode and sensory areas1-4. These gradients provide a compact description of large-scale cortical hierarchies that underlie distinct modes of information processing. However, how these gradients and their multiscale biological and cognitive correlates evolve across the lifespan is unknown. Here we establish a continuous normative reference of functional organization from birth to 100 years of age, revealing complex, nonlinear developmental trajectories. Gradient architecture is anchored by primary sensory systems in infancy, differentiates along association and control axes during childhood and adolescence and gradually dedifferentiates during ageing. The importance of this functional architecture is corroborated by biology and behaviour: gradient metrics predict cognitive performance across development; structure-function coupling varies by axis and age; and distinct transcriptomic signatures are strongest early in life and weaken with age, consistent with a transient genetic scaffold for gradient architecture. Our lifespan gradients unify diverse research into developmental brain connectivity and provide a shared multimodal reference for future studies.

Thermosensitive transient receptor potential (TRP) ion channels enable somatosensory nerve fibres to detect changes in our thermal environment over a wide physiologic range1-3. In mammals, the menthol receptor, TRPM8, is activated by temperatures below approximately 26 °C and is essential for the perception of cold or chemical cooling agents4-6. A fascinating, yet still unachieved goal is to elucidate mechanisms, both structural and thermodynamic, whereby TRPM8 or other thermosensitive channels are gated by changes in ambient temperature. Recent studies using cryogenic electron microscopy have attempted to address this challenging question but are limited by difficulties in visualizing temperature-evoked conformational sub-states or assessing the energetic landscape governing gating transitions7,8. Here we close this gap by combining cryogenic electron microscopy with hydrogen-deuterium exchange mass spectrometry to elucidate a mechanism for cold-evoked activation of TRPM8. First, we visualize TRPM8 channels in cellular membranes, where bona fide menthol- and cold-evoked open states are captured. We also identify a new 'semi-swapped' architecture in which interdigitation of channel sub-units is rearranged substantially following repositioning of the S6 transmembrane helix and elements of the pore region. We then use hydrogen-deuterium exchange mass spectrometry to pinpoint the pore and TRP helices as the regions exhibiting the greatest stimulus-evoked energetic changes that drive channel gating. Specifically, cold-evoked stabilization of the outer pore region repositions the pore lining S6 transmembrane helix while enabling binding of a regulatory lipid to stabilize the open channel. Structural mechanisms associated with activation are validated by comparison of human TRPM8 with the menthol-sensitive but relatively cold-insensitive avian orthologue. We propose a free energy landscape and conformational pathway whereby cold or cooling agents activate this thermosensory receptor.

Rice is a staple crop for more than half of the world's population, and its sustainable production is vital to ensure global food security. However, rice is susceptible to several devastating fungal diseases1, including blast disease caused by Magnaporthe oryzae, sheath blight by Rhizoctonia solani, false smut by Ustilaginoidea virens, brown spot by Bipolaris oryzae, bakanae by Fusarium fujikuroi and head blight by Fusarium graminearum. The mechanisms underlying the susceptibility to these fungal diseases remain unclear. Here we report that the β subunit of SnRK1, SnRK1β1A, confers broad-spectrum susceptibility to these fungal diseases. Our findings show that diverse rice fungal pathogens have convergently evolved an effector-like protein, Gas2, which interacts with SnRK1β1A to prevent its ubiquitination-mediated degradation and promotes its nuclear translocation. SnRK1β1A is markedly induced on fungal infection, promoting susceptibility by inhibiting SnRK1α1, an α subunit of SnRK1 known to positively regulate broad-spectrum resistance in rice2. Notably, rice lines with disrupted SnRK1β1A are resistant to several fungal diseases without compromising growth and yield in the field under normal farming conditions. This study demonstrates that broad-spectrum disease resistance in crops can be achieved by disrupting inducible susceptibility genes whose encoded proteins are targeted by effectors conserved across several pathogens.