前沿速递 | NCS 集萃： 2025-03-20 期 [Up]

『Abstract』Abstract Marine mammals rely on maintaining sufficient blood oxygen levels while diving to prevent drowning. Generally, oxygen is cognitively imperceptible to mammals that instead sense rising carbon dioxide as a proxy for low oxygen. Not perceiving oxygen, however, is risky for diving mammals. We argue that any ability to alter dives based upon direct perception of oxygen should have been strongly selected for. We exposed diving seals to inhaled gas mixes that were experimentally altered to affect circulating levels of oxygen and carbon dioxide. Dive duration was positively correlated with circulating oxygen levels but unaffected by carbon dioxide levels and pH. These results suggest that seals do cognitively perceive circulating oxygen and use this to alter dive behavior.

『Abstract』Abstract Terrestrial sequestration of carbon has mitigated ≈30% of anthropogenic carbon emissions. However, its distribution across different pools, live or dead biomass and soil and sedimentary organic carbon, remains uncertain. Analyzing global observational datasets of changes in terrestrial carbon pools, we found that ≈35 ± 14 gigatons of carbon (GtC) have been sequestered on land between 1992 and 2019, whereas live biomass changed by ≈1 ± 7 GtC. Global vegetation models instead imply that sequestration has been mostly in live biomass. We identify key processes not included in most models that can explain this discrepancy. Most terrestrial carbon gains are sequestered as nonliving matter and thus are more persistent than previously appreciated, with a substantial fraction linked to human activities such as river damming, wood harvest, and garbage disposal in landfills.

『Abstract』Abstract On 3 October 2023, a multihazard cascade in the Sikkim Himalaya, India, was triggered by 14.7 million cubic meters of frozen lateral moraine collapsing into South Lhonak Lake. The impact generated an ~20-meter tsunami-like impact wave, which breached the moraine and drained ~50 million cubic meters of the lake’s water. The ensuing glacial lake outburst flood (GLOF) eroded ~270 million cubic meters of sediment, which overwhelmed infrastructure, including hydropower installations along the Teesta River. The physical scale and human and economic impacts of this event prompt urgent reflection on the role of climate change and human activities in exacerbating such disasters. Insights into multihazard evolution are pivotal for informing policy development, enhancing early warning systems (EWS), and spurring paradigm shifts in GLOF risk management strategies in the Himalaya and other mountain environments.

『Abstract』Abstract Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these complexes in native cells is debated. We used in situ cryo–electron tomography to visualize the native structures and organization of several major mitochondrial complexes in Chlamydomonas reinhardtii cells. ATP synthases and respiratory complexes segregate into curved and flat crista membrane domains, respectively. Respiratory complexes I, III, and IV assemble into a respirasome supercomplex, from which we determined a native 5-angstrom (Å) resolution structure showing binding of electron carrier cytochrome c . Combined with single-particle cryo–electron microscopy at 2.4-Å resolution, we model how the respiratory complexes organize inside native mitochondria.

『Abstract』Abstract During infections, CD4 Foxp3 regulatory T (T reg ) cells must control autoreactive CD4 conventional T (T conv ) cell responses against self-peptide antigens while permitting those against pathogen-derived “nonself” peptides. We defined the basis of this selectivity using mice in which T reg cells reactive to a single prostate-specific self-peptide were selectively depleted. We found that self-peptide–specific T reg cells were dispensable for the control of T conv cells of matched specificity at homeostasis. However, they were required to control such T conv cells and prevent autoimmunity toward the prostate after exposure to elevated self-peptide during infection. Notably, the T reg cell response to self-peptide did not affect protective T conv cell responses to a pathogen-derived peptide. Thus, self-peptide–specific T reg cells promoted self-nonself discrimination during infection by selectively controlling T conv cells of shared self-specificity.

『Abstract』Abstract Establishment of the apoplastic root barrier known as the Casparian strip occurs early in root development. In legumes, this area overlaps with nitrogen-fixing nodule formation, which raises the possibility that nodulation and barrier formation are connected. Nodules also contain Casparian strips, yet, in this case, their role is unknown. We established mutants with defective barriers in Lotus japonicus . This revealed that effective apoplastic blockage in the endodermis is important for root-to-shoot signals underlying nodulation. Our findings further revealed that in nodules, the genetic machinery for Casparian strip formation is shared with roots. Apoplastic blockage controls the metabolic source-sink status required for nitrogen fixation. This identifies Casparian strips as a model system to study spatially constrained symbiotic plant-microbe relationships.

『Abstract』Abstract Neutral-atom quantum processors are a promising platform for large-scale quantum computing. Integrating them with optical cavities enables fast nondestructive qubit readout and access to fast remote entanglement generation for quantum networking. In this work, we introduce a platform for coupling single atoms in optical tweezers to a Fabry-Perot fiber cavity. Leveraging the strong atom-cavity coupling, we demonstrated fast qubit-state readout with 99.960 − 24 + 14 % fidelity and two methods for cavity-mediated entanglement generation with integrated error detection. First, we used cavity-carving to generate a Bell state with 91(4)% fidelity and a 32(1)% success rate (the number in parentheses is the standard deviation). Second, we performed a cavity-mediated gate with a deterministic entanglement fidelity of 52.5(18)%, increased to 76(2)% with error detection. Our approach provides a route toward modular quantum computing and networking.

『Abstract』Abstract Despite advances in theory and experiments, how biodiversity influences the structure and functioning of natural ecosystems remains debated. By applying new theory to data on 84,695 plant, animal, and protist assemblages, we show that the general positive effect of species richness on stocks of biomass, as well as much of the variation in the strength and sign of this effect, is predicted by a fundamental macroecological quantity: the scaling of species abundance with body mass. Standing biomass increases with richness when large-bodied species are numerically rare but is independent of richness when species size and abundance are uncoupled. These results suggest a new fundamental law in the structure of ecological communities and show that the impacts of changes in species richness on biomass are predictable.

『Abstract』Abstract Memory engrams are formed through experience-dependent plasticity of neural circuits, but their detailed architectures remain unresolved. Using three-dimensional electron microscopy, we performed nanoscale reconstructions of the hippocampal CA3-CA1 pathway after chemogenetic labeling of cellular ensembles recruited during associative learning. Neurons with a remote history of activity coinciding with memory acquisition showed no strong preference for wiring with each other. Instead, their connectomes expanded through multisynaptic boutons independently of the coactivation state of postsynaptic partners. The rewiring of ensembles representing an initial engram was accompanied by input-specific, spatially restricted upscaling of individual synapses, as well as remodeling of mitochondria, smooth endoplasmic reticulum, and interactions with astrocytes. Our findings elucidate the physical hallmarks of long-term memory and offer a structural basis for the cellular flexibility of information coding.

『Abstract』Abstract For applications of single-walled carbon nanotubes (SWNTs) in integrated circuits, it is crucial to have high–tube density arrays of SWNTs that are well aligned and purely semiconducting. In this work, we report on the direct growth of close-packed SWNT arrays on hexagonal boron nitride (hBN) substrates, demonstrating high alignment and uniform chirality within each array. Molecular dynamics simulations suggest that a self-assembly growth mechanism resulted from the intertube van der Waals attraction and the ultralow sliding friction of SWNTs on the atomically flat hBN substrate. Field-effect transistors constructed from the grown SWNT array exhibit high performance at room temperature, with mobilities of up to 2000 square centimeters per volt per second, on/off ratios of ~10 , and a maximum current density of ~6 milliamperes per micrometer.

『Abstract』Abstract Humans lack memories for specific events from the first few years of life. We investigated the mechanistic basis of this infantile amnesia by scanning the brains of awake infants with functional magnetic resonance imaging while they performed a subsequent memory task. Greater activity in the hippocampus during the viewing of previously unseen photographs was related to later memory-based looking behavior beginning around 1 year of age, suggesting that the capacity to encode individual memories comes online during infancy. The availability of encoding mechanisms for episodic memory during a period of human life that is later lost from our autobiographical record implies that postencoding mechanisms, whereby memories from infancy become inaccessible for retrieval, may be more responsible for infantile amnesia.

『Abstract』Abstract Biodiversity hotspots in Earth’s mountain ranges suggest a strong connection between topographic development and biological processes. However, it remains unclear whether high biodiversity in mountain ranges is an evolutionary response to the rate of relief generation during mountain building. Focusing on small mammals, such as rodents, we used coupled landscape-biological simulations to show that biodiversity increases with the magnitude and rate of tectonic uplift. This relationship, visible in depositional lowlands over millions of years, underscores the considerable role of mountain building in shaping past and present terrestrial biodiversity. Our results provide insights into the influence of topographic changes on evolutionary processes, offering a potential link between mountain formation and paleodiversity records.

『Abstract』Abstract While both species richness and ecosystem stability increase with area, how these scaling patterns are linked remains unclear. Our theoretical and empirical analyses of plant and fish communities show that the spatial scaling of ecosystem stability is determined primarily by the scaling of species asynchrony, which is in turn driven by the scaling of species richness. In wetter regions, plant species richness and ecosystem stability both exhibit faster accumulation with area, implying potentially greater declines in biodiversity and stability following habitat loss. The decline in ecosystem stability after habitat loss can be delayed, creating a stability debt mirroring the extinction debt of species. By unifying two foundational scaling laws in ecology, our work underscores that ongoing biodiversity loss may destabilize ecosystems across spatial scales.

『Abstract』Abstract Volcanism on the Moon has produced surface basalt deposits, which record lunar interior processes. The Chang’e-6 mission retrieved samples from the South Pole–Aitken basin (SPA) on the Moon’s far side. We analyzed basalt fragments collected by Chang’e-6 and found that their composition resembles that of low-titanium basalts previously sampled by the Apollo missions. Uranium-lead (U-Pb) dating indicated a basalt age of 2823.0 ± 5.9 million years and a source U/ Pb ratio (μ-value) of 480 ± 56. This high μ-value indicates that the source contained materials that formed during the late stages of lunar magma ocean (LMO) crystallization. The results are consistent with the LMO model, but the Chang’e-6 basalt deviates from the trend in Apollo mission samples of younger basalts having higher μ-values. We suggest that this indicates post-LMO modification of the mantle by the SPA impact.

『Abstract』Abstract For cells to polarize collectively along a tissue plane, asymmetrically localized planar cell polarity (PCP) complexes must form intercellular contacts between neighboring cells. Yet, it is unknown whether asymmetric segregation of PCP complexes requires cell-cell contact, or if cell autonomous, antagonistic interactions are sufficient for polarization. To test this, we generated mouse chimeras consisting of dual PCP-reporter cells mixed with unlabeled cells that cannot form PCP bridges. In the absence of intercellular interactions, PCP proteins failed to polarize cell autonomously. Rather, PCP-mediated contacts along single cell-cell interfaces were sufficient to sort PCP components to opposite sides of the junction, independent of junction orientation. Thus, intercellular binding of PCP complexes is the critical step that initiates sorting of opposing PCP complexes to generate asymmetry.

『Abstract』The electroluminescence performance of heavy-metal-free blue quantum dot (QD) light-emitting diodes (QLEDs) is much lower than that of state-of-the-art cadmium-based counterparts. Ecofriendly ZnSeTe QDs are an ideal alternative to cadmium-based blue QDs , but face issues with colour impurity and inferior stability caused by the aggregated tellurium (Te n ≥2 ) that dominates compositional inhomogeneity . Here we developed an isoelectronic control strategy using congeneric sulfur coordinated with triphenyl phosphite (TPP-S) to construct homogeneous ZnSeTeS QDs with pure-blue emissions and near-unity photoluminescence quantum yield. TPP with low electron-donating capability promotes the reactivity balance among anionic precursors, favouring the growth of QDs with uniform composition. The acceptor-like S with high electronegativity weakens the hole localization of the Te atoms by interfering with their surrounding carriers, thereby suppressing the formation of Te n ≥2 isoelectronic centres. Furthermore, the congeneric S increases the configurational entropy of the QDs and eliminates the stacking faults and oxygen defects, leading to improved structural stability and reduced non-radiative carrier density. Consequently, the resulting pure-blue QLEDs based on core–shell ZnSeTeS/ZnSe/ZnS QDs emitting at 460 nm show a high external quantum efficiency of 24.7%, a narrow linewidth of 17 nm, and long operational half-lifetime ( T 50 ) close to 30,000 hours at 100 cd cm , rivalling state-of-the-art cadmium-based blue QLEDs.

『Abstract』Artificial intelligence (AI) edge devices demand high-precision energy-efficient computations, large on-chip model storage, rapid wakeup-to-response time and cost-effective foundry-ready solutions. Floating point (FP) computation provides precision exceeding that of integer (INT) formats at the cost of higher power and storage overhead. Multi-level-cell (MLC) memristor compute-in-memory (CIM) provides compact non-volatile storage and energy-efficient computation but is prone to accuracy loss owing to process variation. Digital static random-access memory (SRAM)-CIM enables lossless computation; however, storage is low as a result of large bit-cell area and model loading is required during inference. Thus, conventional approaches using homogeneous CIM architectures and computation formats impose a trade-off between efficiency, storage, wakeup latency and inference accuracy. Here we present a mixed-precision heterogeneous CIM AI edge processor, which supports the layer-granular/kernel-granular partitioning of network layers among on-chip CIM architectures (that is, memristor-CIM, SRAM-CIM and tiny-digital units) and computation number formats (INT and FP) based on sensitivity to error. This layer-granular/kernel-granular flexibility allows simultaneous optimization within the two-dimensional design space at the hardware level. The proposed hardware achieved high energy efficiency (40.91 TFLOPS W for ResNet-20 with CIFAR-100 and 28.63 TFLOPS W for MobileNet-v2 with ImageNet), low accuracy degradation (<0.45% for ResNet-20 with CIFAR-100 and for MobilNet-v2 with ImageNet) and rapid wakeup-to-response time (373.52 μs).

『Abstract』The design of functional materials with desired properties is essential in driving technological advances in areas such as energy storage, catalysis and carbon capture . Generative models accelerate materials design by directly generating new materials given desired property constraints, but current methods have a low success rate in proposing stable crystals or can satisfy only a limited set of property constraints . Here we present MatterGen, a model that generates stable, diverse inorganic materials across the periodic table and can further be fine-tuned to steer the generation towards a broad range of property constraints. Compared with previous generative models , structures produced by MatterGen are more than twice as likely to be new and stable, and more than ten times closer to the local energy minimum. After fine-tuning, MatterGen successfully generates stable, new materials with desired chemistry, symmetry and mechanical, electronic and magnetic properties. As a proof of concept, we synthesize one of the generated structures and measure its property value to be within 20% of our target. We believe that the quality of generated materials and the breadth of abilities of MatterGen represent an important advancement towards creating a foundational generative model for materials design.

『Abstract』The Antarctic ozone ‘hole’ was discovered in 1985 (ref. ) and man-made ozone-depleting substances (ODSs) are its primary cause . Following reductions of ODSs under the Montreal Protocol , signs of ozone recovery have been reported, based largely on observations and broad yet compelling model–data comparisons . Although such approaches are highly valuable, they do not provide rigorous statistical detection of the temporal and spatial structure of Antarctic ozone recovery in the presence of internal climate variability. Here we apply pattern-based detection and attribution methods as used in climate-change studies to separate anthropogenically forced ozone responses from internal variability, relying on trend pattern information as a function of month and height. The analysis uses satellite observations together with single-model and multi-model ensemble simulations to identify and quantify the month–height Antarctic ozone recovery ‘fingerprint’ . We demonstrate that the data and simulations show compelling agreement in the fingerprint pattern of the ozone response to decreasing ODSs since 2005. We also show that ODS forcing has enhanced ozone internal variability during the austral spring, influencing detection of forced responses and their time of emergence. Our results provide robust statistical and physical evidence that actions taken under the Montreal Protocol to reduce ODSs are indeed resulting in the beginning of Antarctic ozone recovery, defined as increases in ozone consistent with expected month–height patterns.

『Abstract』Rates of relative sea-level rise during the final stage of the last deglaciation, the early Holocene, are key to understanding future ice melt and sea-level change under a warming climate . Data about these rates are scarce , and this limits insight into the relative contributions of the North American and Antarctic ice sheets to global sea-level rise during the early Holocene. Here we present an early Holocene sea-level curve based on 88 sea-level data points (13.7–6.2 thousand years ago (ka)) from the North Sea (Doggerland ). After removing the pattern of regional glacial isostatic adjustment caused by the melting of the Eurasian Ice Sheet, the residual sea-level signal highlights two phases of accelerated sea-level rise. Meltwater sourced from the North American and Antarctic ice sheets drove these two phases, peaking around 10.3 ka and 8.3 ka with rates between 8 mm yr and 9 mm yr . Our results also show that global mean sea-level rise between 11 ka and 3 ka amounted to 37.7 m (2 σ range, 29.3–42.2 m), reconciling the mismatch that existed between estimates of global mean sea-level rise based on ice-sheet reconstructions and previously limited early Holocene sea-level data. With its broad spatiotemporal coverage, the North Sea dataset provides critical constraints on the patterns and rates of the late-stage deglaciation of the North American and Antarctic ice sheets, improving our understanding of the Earth-system response to climate change.

『Abstract』Recent breakthroughs in artificial intelligence (AI) are increasingly driven by systems orchestrating multiple large language models (LLMs) and other specialized tools, such as search engines and simulators. So far, these systems are primarily handcrafted by domain experts and tweaked through heuristics rather than being automatically optimized, presenting a substantial challenge to accelerating progress. The development of artificial neural networks faced a similar challenge until backpropagation and automatic differentiation transformed the field by making optimization turnkey. Analogously, here we introduce TextGrad, a versatile framework that performs optimization by backpropagating LLM-generated feedback to improve AI systems. By leveraging natural language feedback to critique and suggest improvements to any part of a system—from prompts to outputs such as molecules or treatment plans—TextGrad enables the automatic optimization of generative AI systems across diverse tasks. We demonstrate TextGrad’s generality and effectiveness through studies in solving PhD-level science problems, optimizing plans for radiotherapy treatments, designing molecules with specific properties, coding, and optimizing agentic systems. TextGrad empowers scientists and engineers to easily develop impactful generative AI systems.

『Abstract』Mechanical metamaterials with high recoverable elastic energy density, which we refer to as high-enthalpy elastic metamaterials, can offer many enhanced properties, including efficient mechanical energy storage , load-bearing capability, impact resistance and motion agility. These qualities make them ideal for lightweight, miniaturized and multi-functional structures . However, achieving high enthalpy is challenging, as it requires combining conflicting properties: high stiffness, high strength and large recoverable strain . Here, to address this challenge, we construct high-enthalpy elastic metamaterials from freely rotatable chiral metacells. Compared with existing non-chiral lattices, the non-optimized chiral metamaterials simultaneously maintain high stiffness, sustain larger recoverable strain, offer a wider buckling plateau, improve the buckling strength by 5–10 times, enhance enthalpy by 2–160 times and increase energy per mass by 2–32 times. These improvements arise from torsional buckling deformation that is triggered by chirality and is absent in conventional metamaterials. This deformation mode stores considerable additional energy while having a minimal impact on peak stresses that define material failure. Our findings identify a mechanism and provide insight into the design of metamaterials and structures with high mechanical energy storage capacity, a fundamental and general problem of broad engineering interest.

『Abstract』Many children from low-income backgrounds worldwide fail to master school mathematics ; however, some children extensively use mental arithmetic outside school . Here we surveyed children in Kolkata and Delhi, India, who work in markets ( n = 1,436), to investigate whether maths skills acquired in real-world settings transfer to the classroom and vice versa. Nearly all these children used complex arithmetic calculations effectively at work. They were also proficient in solving hypothetical market maths problems and verbal maths problems that were anchored to concrete contexts. However, they were unable to solve arithmetic problems of equal or lesser complexity when presented in the abstract format typically used in school. The children’s performance in market maths problems was not explained by memorization, access to help, reduced stress with more familiar formats or high incentives for correct performance. By contrast, children with no market-selling experience ( n = 471), enrolled in nearby schools, showed the opposite pattern. These children performed more accurately on simple abstract problems, but only 1% could correctly answer an applied market maths problem that more than one third of working children solved ( β = 0.35, s.e.m. = 0.03; 95% confidence interval = 0.30–0.40, P < 0.001). School children used highly inefficient written calculations, could not combine different operations and arrived at answers too slowly to be useful in real-life or in higher maths. These findings highlight the importance of educational curricula that bridge the gap between intuitive and formal maths.

『Abstract』How new structures emerge during evolution has long fascinated biologists. An example is how the diminutive bones of the mammalian middle ear arose from ancestral fish jawbones . By contrast, the evolutionary origin of the outer ear, another mammalian innovation, remains a mystery, partly because it is supported by non-mineralized elastic cartilage, which is rarely recovered in fossils. Whether the outer ear arose de novo or through the reuse of ancestral developmental programs has remained unknown. Here we show that the outer ear shares gene regulatory programs with the gills of fishes and amphibians for both its initial outgrowth and the later development of the elastic cartilage. Comparative single-nucleus multiomics of the human outer ear and zebrafish gills reveals conserved gene expression and putative enhancers enriched for common transcription factor binding motifs. This is reflected by the transgenic activity of human outer-ear enhancers in gills, and of fish gill enhancers in the outer ear. Furthermore, single-cell multiomics of the cartilaginous book gills of horseshoe crabs reveals a developmental program shared with the distal-less homeobox ( DLX )-mediated gill program of vertebrates, with a book-gill distal-less enhancer driving expression in zebrafish gills. We propose that elements of an invertebrate gill program were reutilized in vertebrates to generate first gills and then the outer ear.

『Abstract』Human recombination maps are a valuable resource for association and linkage studies and crucial for many inferences of population history and natural selection. Existing maps are based solely on cross-over (CO) recombination, omitting non-cross-overs (NCOs)—the more common form of recombination —owing to the difficulty in detecting them. Using whole-genome sequence data in families, we estimate the number of NCOs transmitted from parent to offspring and derive complete, sex-specific recombination maps including both NCOs and COs. Mothers have fewer but longer NCOs than fathers, and oocytes accumulate NCOs in a non-regulated fashion with maternal age. Recombination, primarily NCO, is responsible for 1.8% (95% confidence interval: 1.3–2.3) and 11.3% (95% confidence interval: 9.0–13.6) of paternal and maternal de novo mutations, respectively, and may drive the increase in de novo mutations with maternal age. NCOs are substantially more prominent than COs in centromeres, possibly to avoid large-scale genomic changes that may cause aneuploidy. Our results demonstrate that NCOs highlight to a much greater extent than COs the differences in the meiotic process between the sexes, in which maternal NCOs may reflect the safeguarding of oocytes from infancy until ovulation.

『Abstract』Climate change is expected to increase heavy rainfall with concomitant increases in flooding . Causes of increased heavy rainfall include the higher water-holding capacity of a warmer atmosphere and changes in atmospheric circulation patterns , which may translate into future heavy rainfall increases in most of Europe . However, gathering evidence on the time evolution of past changes has been hampered by data limitations and measurement uncertainties, in particular for short rainfall durations, such as 1 h. Here we show an 8% increase in daily and 15% increase in hourly heavy rainfall over the last four decades by analysing a new dataset comprising 883 stations in Austria from 1900 to 2023. These increases are fully consistent between two independent networks and occurred after a retarding phase between 1960 and 1980. Hourly heavy rainfall changes are aligned with temperature increases with the sensitivity of a 7% increase per 1 °C of warming, in line with Clausius–Clapeyron scaling. Daily heavy rainfall changes, however, are aligned with atmospheric circulation indices with little correlation to air temperature, which suggests a bigger role of atmospheric circulation modes than previously thought. The daily heavy rainfall changes are remarkably consistent with observed flood increases of about 8% in large catchments. The hourly heavy rainfall changes are similarly consistent with flood changes in small catchments, although the flood increase is stronger (25% over the last four decades). Climate adaptation measures in flood management may therefore be more pressing for rivers draining smaller catchment areas than for large rivers.

『Abstract』Machine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards—an approach known as distributional reinforcement learning (RL) . The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum , but little is known about whether, where and how neurons in this circuit encode information about higher-order moments of reward distributions . Here, to fill this gap, we used high-density probes (Neuropixels) to record striatal activity from mice performing a classical conditioning task in which reward mean, reward variance and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons—D1 and D2—contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 medium spiny neurons to reap the computational benefits of distributional RL.

『Abstract』Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution . However, given the instability of newly formed polyploid genomes , understanding how WGDs arise in a population, persist, and underpin adaptations remains a challenge. Here, using our ongoing Multicellularity Long Term Evolution Experiment (MuLTEE) , we show that diploid snowflake yeast ( Saccharomyces cerevisiae ) under selection for larger multicellular size rapidly evolve to be tetraploid. From their origin within the first 50 days of the experiment, tetraploids persisted for the next 950 days (nearly 5,000 generations, the current leading edge of our experiment) in 10 replicate populations, despite being genomically unstable. Using synthetic reconstruction, biophysical modelling and counter-selection, we found that tetraploidy evolved because it confers immediate fitness benefits under this selection, by producing larger, longer cells that yield larger clusters. The same selective benefit also maintained tetraploidy over long evolutionary timescales, inhibiting the reversion to diploidy that is typically seen in laboratory evolution experiments. Once established, tetraploidy facilitated novel genetic routes for adaptation, having a key role in the evolution of macroscopic multicellular size via the origin of evolutionarily conserved aneuploidy. These results provide unique empirical insights into the evolutionary dynamics and impacts of WGD, showing how it can initially arise due to its immediate adaptive benefits, be maintained by selection and fuel long-term innovations by creating additional dimensions of heritable genetic variation.

『Abstract』State-of-the-art climate models project a substantial decline in precipitation for the Mediterranean region in the future . Supporting this notion, several studies based on observed precipitation data spanning recent decades have suggested a decrease in Mediterranean precipitation , with some attributing a large fraction of this change to anthropogenic influences . Conversely, certain researchers have underlined that Mediterranean precipitation exhibits considerable spatiotemporal variability driven by atmospheric circulation patterns maintaining stationarity over the long term . These conflicting perspectives underscore the need for a comprehensive assessment of precipitation changes in this region, given the profound social, economic and environmental implications. Here we show that Mediterranean precipitation has largely remained stationary from 1871 to 2020, albeit with significant multi-decadal and interannual variability. This conclusion is based on the most comprehensive dataset available for the region, encompassing over 23,000 stations across 27 countries. While trends can be identified for some periods and subregions, our findings attribute these trends primarily to atmospheric dynamics, which would be mostly linked to internal variability. Furthermore, our assessment reconciles the observed precipitation trends with Coupled Model Intercomparison Project Phase 6 model simulations, neither of which indicate a prevailing past precipitation trend in the region. The implications of our results extend to environmental, agricultural and water resources planning in one of the world’s prominent climate change hotspots .

『Abstract』The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions . However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies . Here we combine single-nucleus sequencing of 433,369 human hypothalamic cells with spatial transcriptomics, generating a comprehensive spatio-cellular transcriptional map of the hypothalamus, the ‘HYPOMAP’. Although conservation of neuronal cell types between humans and mice, as based on transcriptomic identity, is generally high, there are notable exceptions. Specifically, there are significant disparities in the identity of pro-opiomelanocortin neurons and in the expression levels of G-protein-coupled receptors between the two species that carry direct implications for currently approved obesity treatments. Out of the 452 hypothalamic cell types, we find that 291 neuronal clusters are significantly enriched for expression of body mass index (BMI) genome-wide association study genes. This enrichment is driven by 426 ‘effector’ genes. Rare deleterious variants in six of these ( MC4R , PCSK1 , POMC , CALCR , BSN and CORO1A ) associate with BMI at population level, and CORO1A has not been linked previously to BMI. Thus, HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context and serves as an important resource to identify new druggable targets for treating a wide range of conditions, including reproductive, circadian and metabolic disorders.

『Abstract』Topological defects and disorder counteract each other . Intuitively, disorder is considered detrimental, requiring efforts to mitigate its effects in conventional topological photonics . We propose a counter-intuitive approach that exploits a real–momentum topological photonic crystal that harnesses real-space disorder to generate a Pancharatnam–Berry phase , without disrupting the momentum-space singularity originating from bound states in the continuum . This methodology allows flat optical devices to encode spatial information or even extra topological charge in real space while preserving the topology of bound states in the continuum in momentum space with inherent alignment. Here, as a proof of concept, we demonstrate the simultaneous and independent generation of a real-space broadband vortex or a holographic image alongside resonant momentum-space vortex beams with a narrow bandwidth, which cannot be achieved with conventional methods. Such engineered disorder contributes to vast intrinsic freedoms without adding extra dimensions or compromising the optical flatness . Our findings of real–momentum duality not only lay the foundation for disorder engineering in topological photonics but also open new avenues for optical wavefront shaping, encryption and communications.

『Abstract』Intranasal administration through the olfactory epithelium (OE) presents a direct pathway for brain-targeted therapeutic delivery, although its feasibility is hampered by the anatomical and absorptive limitations of the OE. In this study, we identified Lactobacillus plantarum WCFS1 (Lp), a commensal strain with a natural affinity for the OE and engineered it to function as a vector for cerebral drug delivery. Upon intranasal administration, Lp released specific payload molecules within the OE, with subsequent transport and accumulation in the brain. The therapeutic efficacy of Lp was further validated by the recombinant production and secretion of appetite-regulating hormones. When administered intranasally in a murine model of obesity prevention, the engineered Lp significantly alleviated obesity-related symptoms. This was evidenced by decreased appetite, reduced body weight gain, and improved glucose metabolism and fat mass deposition. Our study demonstrates the capability of Lp as an intranasal delivery vehicle, emphasizing its potential for brain-targeted therapeutic applications.

『Abstract』Breastfeeding is an obligatory requirement of mammalian survival. This fundamental process is associated with the adaptation of maternal physiology, including the transformation of the mammary gland into a milk-secreting organ. How maternal immunity contributes to mammary gland remodeling and function remains largely unknown. Here, we show that maternal adaptive immunity plays a critical role in shaping lactogenesis. Specifically, physiological adaptation during pregnancy is associated with thymic involution and a paradoxical enrichment in intraepithelial lymphocyte (IEL) precursors that no longer migrate to the gut but instead preferentially accumulate within the mammary gland. IEL precursors differentiate into T-bet-expressing unconventional CD8αα lymphocytes in an IL-15-dependent manner. Mammary IELs control milk production by favoring the differentiation and maturation of contractile and milk-secreting cells, thereby promoting offspring fitness. Altogether, this work uncovers a contribution of the maternal adaptive immune system in organismal remodeling during pregnancy that is associated with mammary gland development and function.

『Abstract』DPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity of ACE2 utilization among merbecoviruses and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing Pipistrellus abramus ( P.abr ) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. We defined the molecular determinants of receptor species tropism and identified a single amino acid mutation enabling HKU5 to utilize human ACE2, providing proof of principle for machine-learning-assisted outbreak preparedness. We show that MERS-CoV and HKU5 have markedly distinct antigenicity and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution, as several merbecovirus clades independently evolved ACE2 utilization, and pave the way for developing countermeasures against viruses poised for human emergence.

『Abstract』Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.

『Abstract』Merbecoviruses comprise four viral species with remarkable genetic diversity: MERS-related coronavirus , Tylonycteris bat coronavirus HKU4 , Pipistrellus bat coronavirus HKU5 , and Hedgehog coronavirus 1 . However, the potential human spillover risk of animal merbecoviruses remains to be investigated. Here, we reported the discovery of HKU5-CoV lineage 2 (HKU5-CoV-2) in bats that efficiently utilize human angiotensin-converting enzyme 2 (ACE2) as a functional receptor and exhibits a broad host tropism. Cryo-EM analysis of HKU5-CoV-2 receptor-binding domain (RBD) and human ACE2 complex revealed an entirely distinct binding mode compared with other ACE2-utilizing merbecoviruses with RBD footprint largely shared with ACE2-using sarbecoviruses and NL63. Structural and functional analyses indicate that HKU5-CoV-2 has a better adaptation to human ACE2 than lineage 1 HKU5-CoV. Authentic HKU5-CoV-2 infected human ACE2-expressing cell lines and human respiratory and enteric organoids. This study reveals a distinct lineage of HKU5-CoVs in bats that efficiently use human ACE2 and underscores their potential zoonotic risk.

『Abstract』Huntington’s disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to neuronal pathogenesis remain unclear. Here, we genetically tested 9 HD genome-wide association study (GWAS)/MMR genes in mutant Huntingtin (mHtt) mice with 140 inherited CAG repeats (Q140). Knockout (KO) of genes encoding a distinct MMR complex either strongly ( Msh3 and Pms1 ) or moderately ( Msh2 and Mlh1 ) rescues phenotypes with early onset in striatal medium-spiny neurons (MSNs) and late onset in the cortical neurons: somatic CAG-repeat expansion, transcriptionopathy, and mHtt aggregation. Msh3 deficiency ameliorates open-chromatin dysregulation in Q140 neurons. Mechanistically, the fast linear rate of mHtt modal-CAG-repeat expansion in MSNs (8.8 repeats/month) is drastically reduced or stopped by MMR mutants. Msh3 or Pms1 deficiency prevents mHtt aggregation by keeping somatic MSN CAG length below 150. Importantly, Msh3 deficiency corrects synaptic, astrocytic, and locomotor defects in HD mice. Thus, Msh3 and Pms1 drive fast somatic mHtt CAG-expansion rates in HD-vulnerable neurons to elicit repeat-length/threshold-dependent, selective, and progressive pathogenesis in vivo .

『Abstract』Androgens, such as 5α-dihydrotestosterone (5α-DHT), regulate numerous functions by binding to nuclear androgen receptors (ARs) and potential unknown membrane receptors. Here, we report that the androgen 5α-DHT activates membrane receptor GPR133 in muscle cells, thereby increasing intracellular cyclic AMP (cAMP) levels and enhancing muscle strength. Further cryoelectron microscopy (cryo-EM) structural analysis of GPR133-Gs in complex with 5α-DHT or its derivative methenolone (MET) reveals the structural basis for androgen recognition. Notably, the presence of the “Φ(F/L) -F -W ” and the “F ××N/D ” motifs, which recognize the hydrophobic steroid core and polar groups, respectively, are common in adhesion GPCRs (aGPCRs), suggesting that many aGPCRs may recognize different steroid hormones. Finally, we exploited in silico screening methods to identify a small molecule, AP503, which activates GPR133 and separates the beneficial muscle-strengthening effects from side effects mediated by AR. Thus, GPR133 represents an androgen membrane receptor that contributes to normal androgen physiology and has important therapeutic potentials.

『Abstract』Human accelerated regions (HARs) have been implicated in human brain evolution. However, insight into the genes and pathways they control is lacking, hindering the understanding of their function. Here, we identify 2,963 conserved gene targets for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs). Conserved gene targets are enriched for neurodevelopmental functions and are overrepresented among differentially expressed genes (DEGs) identified in human NSCs (hNSCs) and chimpanzee NSCs (cNSCs) as well as in human versus non-human primate brains. Species-specific gene targets do not converge on any function and are not enriched among DEGs. HAR targets also show cell-type-specific expression in the human fetal brain, including in outer radial glia, which are linked to cortical expansion. Our findings support that HARs influence brain evolution by altering the expression of ancestral gene targets shared between human and chimpanzee rather than by gaining new targets in human and facilitate hypothesis-directed studies of HAR biology.

『Abstract』We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O 2 ) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.

『Abstract』Hunger is evolutionarily hardwired to ensure that an animal has sufficient energy to survive and reproduce. Just as important as knowing when to start eating is knowing when to stop eating. Here, using spatially resolved single-cell phenotyping, we characterize a population of neuropeptidergic neurons in the brainstem’s dorsal raphe nucleus (DRN) and describe how they regulate satiation. These neurons track food from sensory presentation through ingestion, integrate these signals with slower-acting humoral cues, and express cholecystokinin (CCK). These CCK neurons bidirectionally regulate meal size, driving a sustained meal termination signal with a built-in delay. They are also well positioned to sense and respond to ingestion: they express a host of metabolic signaling factors and are integrated into an extended network known to regulate feeding. Together, this work demonstrates how DRN CCK neurons regulate satiation and identifies a likely conserved cellular mechanism that transforms diverse neurohumoral signals into a key behavioral output.

『Abstract』Viruses encode proteins that inhibit host defenses, but sifting through the millions of available viral sequences for immune-modulatory proteins has been so far impractical. Here, we develop a process to systematically screen virus-encoded proteins for inhibitors that physically bind host immune proteins. Focusing on Thoeris and CBASS, bacterial defense systems that are the ancestors of eukaryotic Toll/interleukin-1 receptor (TIR) and cyclic GMP-AMP synthase (cGAS) immunity, we discover seven families of Thoeris and CBASS inhibitors, encompassing thousands of genes widespread in phages. Verified inhibitors exhibit extensive physical interactions with the respective immune protein counterpart, with all inhibitors blocking the active site of the immune protein. Remarkably, a phage-encoded inhibitor of bacterial TIR proteins can bind and inhibit distantly related human and plant immune TIRs, and a phage-derived inhibitor of bacterial cGAS-like enzymes can inhibit the human cGAS. Our results demonstrate that phages are a reservoir for immune-modulatory proteins capable of inhibiting bacterial, animal, and plant immunity.

『Abstract』Although subsets with immunosuppressive properties exist, neutrophils are typically known for their pro-inflammatory role and pathogen clearance capabilities. Here, we reveal that neutrophils can paradoxically aid in resolving inflammation by actively producing anti-inflammatory extracellular vesicles. These large aging-neutrophil-derived vesicles (LAND-Vs) do not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They are protected from efferocytotic clearance by phagocytes due to surface “do not eat me” signals and accumulate in the resolution phase of inflammation. CD55 on LAND-Vs exerts a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase, thereby reducing neutrophil recruitment and tissue damage. CD55 LAND-Vs originate in ordered lipid raft domains, where CD55 accumulates asymmetrically during neutrophil aging, and are subsequently formed through RhoA-dependent budding. Collectively, LAND-V emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a therapeutic target for inflammatory and infectious diseases.

『Abstract』Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β 2 that dimerizes with integrin α X and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β 2 decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β 2 levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β 2 as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.

『Abstract』Males of many species have evolved behavioral traits to both attract females and repel rivals. Here, we explore mate selection in Drosophila from both the male and female perspective to shed light on how these key components of sexual selection—female choice and male-male competition—work in concert to guide reproductive strategies. We find that male flies fend off competing suitors by interleaving their courtship of a female with aggressive wing flicks, which both repel competitors and generate a “song” that obscures the female’s auditory perception of other potential mates. Two higher-order circuit nodes—P1a and pC1x neurons—are coordinately recruited to allow males to flexibly interleave these agonistic actions with courtship displays, assuring they persistently pursue females until their rival falters. Together, our results suggest that female mating decisions are shaped by male-male interactions, underscoring how a male’s ability to subvert his rivals is central to his reproductive success.

『Abstract』The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two bat MERS-related coronaviruses (MERSr-CoVs) infecting Pipistrellus nathusii ( P.nat )—MOW15-22 and PnNL2018B—use ACE2 as their receptor, with narrow ortholog specificity. Cryoelectron microscopy structures of the MOW15-22/PnNL2018B RBD-ACE2 complexes unveil an unexpected and entirely distinct binding mode, mapping >45 Å away from that of any other known ACE2-using coronaviruses. Functional profiling of ACE2 orthologs from 105 mammalian species led to the identification of host tropism determinants, including an ACE2 N432-glycosylation restricting viral recognition, and the design of a soluble P.nat ACE2 mutant with potent viral neutralizing activity. Our findings reveal convergent acquisition of ACE2 usage for merbecoviruses found in European bats, underscoring the extraordinary diversity of ACE2 recognition modes among coronaviruses and the promiscuity of this receptor.