经典100 | NCS： 2025-04-10 期

『Abstract』Human pelvic evolution following the human-chimpanzee divergence is thought to result in an obstetrical dilemma, a mismatch between large infant brains and narrowed female birth canals, but empirical evidence has been equivocal. By using deep learning on 31,115 dual-energy x-ray absorptiometry scans from UK Biobank, we identified 180 loci associated with seven highly heritable pelvic phenotypes. Birth canal phenotypes showed sex-specific genetic architecture, aligning with reproductive function. Larger birth canals were linked to slower walking pace and reduced back pain but increased hip osteoarthritis risk, whereas narrower birth canals were associated with reduced pelvic floor disorder risk but increased obstructed labor risk. Lastly, genetic correlation between birth canal and head widths provides evidence of coevolution between the human pelvis and brain, partially mitigating the dilemma.

『Abstract』Electrostatic dielectric capacitors with ultrahigh power densities are sought after for advanced electronic and electrical systems owing to their ultrafast charge-discharge capability. However, low energy density resulting from low breakdown strength and suppressed polarization still remains a daunting challenge for practical applications. We propose a microstructural strategy with dendritic nanopolar (DNP) regions self-assembled into an insulator, which simultaneously enhances breakdown strength and high-field polarizability and minimizes energy loss and thus markedly improves energy storage performance and stability. For illustration, in this study, we achieved a high energy density of 215.8 joules per cubic centimeter with an efficiency of 80.7% at a high electric field of 7.4 megavolts per centimeter in a DNP structure–designed PbZr 0.53 Ti 0.47 O 3 -MgO film. The proposed strategy is generally applicable for development of high-performance dielectric microcapacitors.

『Abstract』Despite the growing threat of pharmaceutical pollution, we lack an understanding of whether and how such pollutants influence animal behavior in the wild. Using laboratory- and field-based experiments across multiple years in Atlantic salmon ( Salmo salar ; n = 730), we show that the globally detected anxiolytic pollutant clobazam accumulates in the brain of exposed fish and influences river-to-sea migration success. Clobazam exposure increased the speed with which fish passed through two hydropower dams along their migration route, resulting in more clobazam-exposed fish reaching the sea compared with controls. We argue that such effects may arise from altered shoaling behavior in fish exposed to clobazam. Drug-induced behavioral changes are expected to have wide-ranging consequences for the ecology and evolution of wild populations.

『Abstract』T cell priming is characterized by an initial activation phase that involves stable interactions with dendritic cells (DCs). How activated T cells receive the paracrine signals required for their differentiation once they have disengaged from DCs and resumed their migration has been unclear. We identified a distinct priming phase that favors CD8 T cells expressing receptors with high affinity for antigen. CXCR3 expression by CD8 T cells was required for their hours-long reengagement with DCs in specific subfollicular niches in lymph nodes. CD4 T cells paused briefly at the sites of CD8 T cell and DC interactions and provided Interleukin-2 (IL-2) before moving to another DC. Our results highlight a previously unappreciated phase of cell-cell interactions during T cell priming and have direct implications for vaccinations and cellular immunotherapies.

『Abstract』Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. In this work, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Pharmacologic blockade of the integrated stress response in vivo restored β cell identity after the loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.

『Abstract』Quantum computers hold the promise of solving certain problems that lie beyond the reach of conventional computers. However, establishing this capability, especially for impactful and meaningful problems, remains a central challenge. Here, we show that superconducting quantum annealing processors can rapidly generate samples in close agreement with solutions of the Schrodinger equation. We demonstrate area-law scaling of entanglement in the model quench dynamics of two-, three-, and infinite-dimensional spin glasses, supporting the observed stretched-exponential scaling of effort for matrix-product-state approaches. We show that several leading approximate methods based on tensor networks and neural networks cannot achieve the same accuracy as the quantum annealer within a reasonable time frame. Thus, quantum annealers can answer questions of practical importance that may remain out of reach for classical computation.

『Abstract』Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depression, yet the biological mechanisms underlying these behavioral symptoms and their relationship to the disease remain unclear. In a mouse cancer model, cachexia specifically induced increased effort-sensitivity, apathy-like symptoms through a cytokine-sensing brainstem-to-basal ganglia circuit. This neural circuit detects elevated interleukin-6 (IL-6) at cachexia onset and translates inflammatory signals into decreased mesolimbic dopamine, thereby increasing effort sensitivity. We alleviated these apathy-like symptoms by targeting key circuit nodes: administering an anti–IL-6 antibody treatment, ablating cytokine sensing in the brainstem, and optogenetically or pharmacologically boosting mesolimbic dopamine. Our findings uncovered a central neural circuit that senses systemic inflammation and orchestrates behavioral changes, providing mechanistic insights into the connection between chronic inflammation and depressive symptoms.

『Abstract』Huanglongbing (HLB) is a devastating citrus disease. In this work, we report an HLB resistance regulatory circuit in Citrus composed of an E3 ubiquitin ligase, PUB21, and its substrate, the MYC2 transcription factor, which regulates jasmonate-mediated defense responses. A helitron insertion in the PUB21 promoter introduced multiple MYC2-binding cis-elements to create a regulatory circuit linking the PUB21 activity with MYC2 degradation. Ectopic expression of a natural dominant-negative PUB21 paralog discovered in distant Citrus relatives stabilized MYC2 and conferred resistance to HLB. Antiproteolysis peptides (APPs), identified by artificial intelligence, stabilized MYC2 by binding and inhibiting PUB21 activity. A 14–amino acid peptide, APP3-14, molecularly controlled HLB in greenhouse and field trials. This approach represents a strategy to combat uncultivable pathogens through targeted disease resistance protein stabilization.

『Abstract』The arrangement of genes along bacterial chromosomes influences their expression through growth rate–dependent gene copy number changes during DNA replication. Although translation- and transcription-related genes often cluster near the origin of replication, the extent of positional biases across gene families remains unclear. We hypothesized that natural selection broadly favors specific chromosomal positions to optimize growth rate–dependent expression. Analyzing 910 bacterial species and proteomics data from Escherichia coli and Bacillus subtilis , we found that about two-thirds of bacterial gene families are positionally biased. Natural selection drives genes mainly toward the origin or terminus of replication, with the strongest selection in fast-growing species. Our findings reveal chromosomal positioning as a fundamental mechanism for coordinating gene expression with growth rate, highlighting evolutionary constraints on bacterial genome architecture.

『Abstract』One approach for closed-loop plastics recycling relies on reverting polymers back into monomers because one can then make new plastics without loss of properties. This depolymerization requirement restricts the molecular design to making polymers with high mechanical performance. We report a three-dimensional (3D) printing chemistry through stepwise photopolymerization by forming dithioacetal bonds. The polymerized network can be transformed back into a photoreactive oligomer by dissociation of the dithioacetal bonds. This network-oligomer transformation is reversible, therefore allowing circular 3D printing using the same material. Our approach offers the flexibility of making modular adjustments in the design of the network backbone of a polymer. This allows access to fully recyclable elastomers, crystalline polymers, and rigid glassy polymers with high mechanical toughness, making them potentially suitable for diverse applications.

『Abstract』That neutrinos carry a nonvanishing rest mass is evidence of physics beyond the Standard Model of elementary particles. Their absolute mass holds relevance in fields from particle physics to cosmology. We report on the search for the effective electron antineutrino mass with the KATRIN experiment. KATRIN performs precision spectroscopy of the tritium β-decay close to the kinematic endpoint. On the basis of the first five measurement campaigns, we derived a best-fit value of m ν 2 = − 0.14 − 0.15 + 0.13 eV , resulting in an upper limit of m ν < 0.45 eV at 90% confidence level. Stemming from 36 million electrons collected in 259 measurement days, a substantial reduction of the background level, and improved systematic uncertainties, this result tightens KATRIN’s previous bound by a factor of almost two.

『Abstract』The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively. We elucidated a structural pathway of enzyme activation through cryo–electron microscopy analysis of PI3KC3-C1. The inactive conformation of the VPS15 pseudokinase stabilizes the inactive conformation, sequestering its N -myristate in the N-lobe of the pseudokinase. Upon activation, the myristate is liberated such that the VPS34 lipid kinase catalyzes phosphatidylinositol-3 phosphate production on membranes. The VPS15 pseudokinase domain binds tightly to guanosine triphosphate and stabilizes a web of interactions to autoinhibit the cytosolic complex and promote activation upon membrane binding. These findings show in atomistic detail how the VPS34 lipid kinase is activated in the context of a complete PI3K complex.

『Abstract』Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain–containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain–containing protein 22 (CCDC22)/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity. Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk. Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.

『Abstract』Denisovans are an extinct hominin group defined by ancient genomes of Middle to Late Pleistocene fossils from southern Siberia. Although genomic evidence suggests their widespread distribution throughout eastern Asia and possibly Oceania, so far only a few fossils from the Altai and Tibet are confidently identified molecularly as Denisovan. We identified a hominin mandible (Penghu 1) from Taiwan (10,000 to 70,000 years ago or 130,000 to 190,000 years ago) as belonging to a male Denisovan by applying ancient protein analysis. We retrieved 4241 amino acid residues and identified two Denisovan-specific variants. The increased fossil sample of Denisovans demonstrates their wider distribution, including warm and humid regions, as well as their shared distinct robust dentognathic traits that markedly contrast with their sister group, Neanderthals.

『Abstract』We used Hi-C, imaging, proteomics, and polymer modeling to define rules of engagement for SMC (structural maintenance of chromosomes) complexes as cells refold interphase chromatin into rod-shaped mitotic chromosomes. First, condensin disassembles interphase chromatin loop organization by evicting or displacing extrusive cohesin. Second, condensin bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion as sisters separate. Studies of mitotic chromosomes formed by cohesin, condensin II, and condensin I alone or in combination lead to refined models of mitotic chromosome conformation. In these models, loops are consecutive and not overlapping, implying that condensins stall upon encountering each other. The dynamics of Hi-C interactions and chromosome morphology reveal that during prophase, loops are extruded in vivo at ∼1 to 3 kilobases per second by condensins as they form a disordered discontinuous helical scaffold within individual chromatids.

『Abstract』Mammalian genomes are folded through the distinct actions of structural maintenance of chromosome (SMC) complexes, which include the chromatin loop-extruding cohesin (extrusive cohesin), the sister chromatid cohesive cohesin and the mitotic chromosome-associated condensins . Although these complexes function at different stages of the cell cycle, they exist together on chromatin during the G2-to-M phase transition, when the genome structure undergoes substantial reorganization . Yet, how the different SMC complexes affect each other and how their interactions orchestrate the dynamic folding of the three-dimensional genome remain unclear. Here we engineered all possible cohesin and condensin configurations on mitotic chromosomes to delineate the concerted, mutually influential action of SMC complexes. We show that condensin disrupts the binding of extrusive cohesin at CCCTC-binding factor (CTCF) sites, thereby promoting the disassembly of interphase topologically associating domains (TADs) and loops during mitotic progression. Conversely, extrusive cohesin impedes condensin-mediated mitotic chromosome spiralization. Condensin reduces peaks of cohesive cohesin, whereas cohesive cohesin antagonizes condensin-mediated longitudinal shortening of mitotic chromosomes. The presence of both extrusive and cohesive cohesin synergizes these effects and inhibits mitotic chromosome condensation. Extrusive cohesin positions cohesive cohesin at CTCF-binding sites. However, cohesive cohesin by itself cannot be arrested by CTCF molecules and is insufficient to establish TADs or loops. Moreover, it lacks loop-extrusion capacity, which indicates that cohesive cohesin has nonoverlapping functions with extrusive cohesin. Finally, cohesive cohesin restricts chromatin loop expansion mediated by extrusive cohesin. Collectively, our data describe a three-way interaction among major SMC complexes that dynamically modulates chromatin architecture during cell cycle progression.

『Abstract』Trees are an important carbon sink as they accumulate biomass through photosynthesis . Identifying tree species that grow fast is therefore commonly considered to be essential for effective climate change mitigation through forest planting. Although species characteristics are key information for plantation design and forest management, field studies often fail to detect clear relationships between species functional traits and tree growth . Here, by consolidating four independent datasets and classifying the acquisitive and conservative species based on their functional trait values, we show that acquisitive tree species, which are supposedly fast-growing species, generally grow slowly in field conditions. This discrepancy between the current paradigm and field observations is explained by the interactions with environmental conditions that influence growth. Acquisitive species require moist mild climates and fertile soils, conditions that are generally not met in the field. By contrast, conservative species, which are supposedly slow-growing species, show generally higher realized growth due to their ability to tolerate unfavourable environmental conditions. In general, conservative tree species grow more steadily than acquisitive tree species in non-tropical forests. We recommend planting acquisitive tree species in areas where they can realize their fast-growing potential. In other regions, where environmental stress is higher, conservative tree species have a larger potential to fix carbon in their biomass.

『Abstract』The complexity of neural circuits makes it challenging to decipher the brain’s algorithms of intelligence. Recent breakthroughs in deep learning have produced models that accurately simulate brain activity, enhancing our understanding of the brain’s computational objectives and neural coding. However, it is difficult for such models to generalize beyond their training distribution, limiting their utility. The emergence of foundation models trained on vast datasets has introduced a new artificial intelligence paradigm with remarkable generalization capabilities. Here we collected large amounts of neural activity from visual cortices of multiple mice and trained a foundation model to accurately predict neuronal responses to arbitrary natural videos. This model generalized to new mice with minimal training and successfully predicted responses across various new stimulus domains, such as coherent motion and noise patterns. Beyond neural response prediction, the model also accurately predicted anatomical cell types, dendritic features and neuronal connectivity within the MICrONS functional connectomics dataset . Our work is a crucial step towards building foundation models of the brain. As neuroscience accumulates larger, multimodal datasets, foundation models will reveal statistical regularities, enable rapid adaptation to new tasks and accelerate research.

『Abstract』Although quantum computers can perform a wide range of practically important tasks beyond the abilities of classical computers , realizing this potential remains a challenge. An example is to use an untrusted remote device to generate random bits that can be certified to contain a certain amount of entropy . Certified randomness has many applications but is impossible to achieve solely by classical computation. Here we demonstrate the generation of certifiably random bits using the 56-qubit Quantinuum H2-1 trapped-ion quantum computer accessed over the Internet. Our protocol leverages the classical hardness of recent random circuit sampling demonstrations : a client generates quantum ‘challenge’ circuits using a small randomness seed, sends them to an untrusted quantum server to execute and verifies the results of the server. We analyse the security of our protocol against a restricted class of realistic near-term adversaries. Using classical verification with measured combined sustained performance of 1.1 × 10 floating-point operations per second across multiple supercomputers, we certify 71,313 bits of entropy under this restricted adversary and additional assumptions. Our results demonstrate a step towards the practical applicability of present-day quantum computers.

『Abstract』Mammalian neocortex contains a highly diverse set of cell types. These cell types have been mapped systematically using a variety of molecular, electrophysiological and morphological approaches . Each modality offers new perspectives on the variation of biological processes underlying cell-type specialization. Cellular-scale electron microscopy provides dense ultrastructural examination and an unbiased perspective on the subcellular organization of brain cells, including their synaptic connectivity and nanometre-scale morphology. In data that contain tens of thousands of neurons, most of which have incomplete reconstructions, identifying cell types becomes a clear challenge for analysis . Here, to address this challenge, we present a systematic survey of the somatic region of all cells in a cubic millimetre of cortex using quantitative features obtained from electron microscopy. This analysis demonstrates that the perisomatic region is sufficient to identify cell types, including types defined primarily on the basis of their connectivity patterns. We then describe how this classification facilitates cell-type-specific connectivity characterization and locating cells with rare connectivity patterns in the dataset.

『Abstract』The landscapes of somatic mutation in normal cells inform us about the processes of mutation and selection operative throughout life, providing insight into normal ageing and the earliest stages of cancer development . Here, by whole-genome sequencing of 238 microdissections from 30 individuals, including 18 with gastric cancer, we elucidate the developmental trajectories of normal and malignant gastric epithelium. We find that gastric glands are units of monoclonal cell populations that accrue roughly 28 somatic single-nucleotide variants per year, predominantly attributable to endogenous mutational processes. In individuals with gastric cancer, metaplastic glands often show elevated mutation burdens due to acceleration of mutational processes linked to proliferation and oxidative damage. Unusually for normal cells, gastric epithelial cells often carry recurrent trisomies of specific chromosomes, which are highly enriched in a subset of individuals. Surveying 829 polyclonal gastric microbiopsies by targeted sequencing, we find somatic ‘driver’ mutations in a distinctive repertoire of known cancer genes, including ARID1A , ARID1B , ARID2 , CTNNB1 and KDM6A . The prevalence of mutant clones increases with age to occupy roughly 8% of the gastric epithelial lining by age 60 years and is significantly increased by the presence of severe chronic inflammation. Our findings provide insights into intrinsic and extrinsic influences on somatic evolution in the gastric epithelium in healthy, precancerous and malignant states.

『Abstract』Magnetism typically arises from the effect of exchange interactions on highly localized fermionic wavefunctions in f- and d-atomic orbitals. By contrast, in rhombohedral multilayer graphene (RMG), magnetism—manifesting as spontaneous polarization into one or more spin and valley flavours —originates from itinerant electrons near a Van Hove singularity. Here we show experimentally that the electronic entropy in this system indicates signatures typically associated with disordered local magnetic moments, unexpected for electrons in a fully itinerant metal. Specifically, we find a contribution Δ S ≈ 1 k B per charge carrier that begins at the Curie temperature and survives more than one order of magnitude in temperature. First-order phase transitions show an isospin ‘Pomeranchuk effect’ in which the fluctuating moment phase is entropically favoured over the nearby symmetric Fermi liquid . Our results imply that, despite the itinerant nature of the electron wavefunctions, the spin and valley polarization of individual electrons is decoupled, a phenomenon typically associated with localized moments, as happens, for example, in solid He (ref. ). Transport measurements, surprisingly, show a finite-temperature resistance minimum in the fluctuating moment regime, which we attribute to the interplay of fluctuating magnetic moments and electron–phonon scattering. Our results highlight the universality of soft isospin modes to two-dimensional flat-band systems.

『Abstract』Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between them . Neural cell types have previously been defined by morphology , electrophysiology , transcriptomic expression , connectivity or a combination of such modalities . The Patch-seq technique enables the characterization of morphology, electrophysiology and transcriptomic properties from individual cells . These properties were integrated to define 28 inhibitory, morpho-electric-transcriptomic (MET) cell types in mouse visual cortex , which do not include synaptic connectivity. Conversely, large-scale electron microscopy (EM) enables morphological reconstruction and a near-complete description of a neuron’s local synaptic connectivity, but does not include transcriptomic or electrophysiological information. Here, we leveraged morphological information from Patch-seq to predict the transcriptomically defined cell subclass and/or MET-type of inhibitory neurons within a large-scale EM dataset. We further analysed Martinotti cells—a somatostatin ( Sst )-positive morphological cell type —which were classified successfully into Sst MET-types with distinct axon myelination and synaptic output connectivity patterns. We demonstrate that morphological features can be used to link cell types across experimental modalities, enabling further comparison of connectivity to gene expression and electrophysiology. We observe unique connectivity rules for predicted Sst cell types.

『Abstract』Understanding the relationship between circuit connectivity and function is crucial for uncovering how the brain computes. In mouse primary visual cortex, excitatory neurons with similar response properties are more likely to be synaptically connected ; however, broader connectivity rules remain unknown. Here we leverage the millimetre-scale MICrONS dataset to analyse synaptic connectivity and functional properties of neurons across cortical layers and areas. Our results reveal that neurons with similar response properties are preferentially connected within and across layers and areas—including feedback connections—supporting the universality of ‘like-to-like’ connectivity across the visual hierarchy. Using a validated digital twin model, we separated neuronal tuning into feature (what neurons respond to) and spatial (receptive field location) components. We found that only the feature component predicts fine-scale synaptic connections beyond what could be explained by the proximity of axons and dendrites. We also discovered a higher-order rule whereby postsynaptic neuron cohorts downstream of presynaptic cells show greater functional similarity than predicted by a pairwise like-to-like rule. Recurrent neural networks trained on a simple classification task develop connectivity patterns that mirror both pairwise and higher-order rules, with magnitudes similar to those in MICrONS data. Ablation studies in these recurrent neural networks reveal that disrupting like-to-like connections impairs performance more than disrupting random connections. These findings suggest that these connectivity principles may have a functional role in sensory processing and learning, highlighting shared principles between biological and artificial systems.

『Abstract』Integrated photonics, particularly silicon photonics, have emerged as cutting-edge technology driven by promising applications such as short-reach communications, autonomous driving, biosensing and photonic computing . As advances in AI lead to growing computing demands, photonic computing has gained considerable attention as an appealing candidate. Nonetheless, there are substantial technical challenges in the scaling up of integrated photonics systems to realize these advantages, such as ensuring consistent performance gains in upscaled integrated device clusters, establishing standard designs and verification processes for complex circuits, as well as packaging large-scale systems. These obstacles arise primarily because of the relative immaturity of integrated photonics manufacturing and the scarcity of advanced packaging solutions involving photonics. Here we report a large-scale integrated photonic accelerator comprising more than 16,000 photonic components. The accelerator is designed to deliver standard linear matrix multiply–accumulate (MAC) functions, enabling computing with high speed up to 1 GHz frequency and low latency as small as 3 ns per cycle. Logic, memory and control functions that support photonic matrix MAC operations were designed into a cointegrated electronics chip. To seamlessly integrate the electronics and photonics chips at the commercial scale, we have made use of an innovative 2.5D hybrid advanced packaging approach. Through the development of this accelerator system, we demonstrate an ultralow computation latency for heuristic solvers of computationally hard Ising problems whose performance greatly relies on the computing latency.

『Abstract』We are in the era of millimetre-scale electron microscopy volumes collected at nanometre resolution . Dense reconstruction of cellular compartments in these electron microscopy volumes has been enabled by recent advances in machine learning . Automated segmentation methods produce exceptionally accurate reconstructions of cells, but post hoc proofreading is still required to generate large connectomes that are free of merge and split errors. The elaborate 3D meshes of neurons in these volumes contain detailed morphological information at multiple scales, from the diameter, shape and branching patterns of axons and dendrites, down to the fine-scale structure of dendritic spines. However, extracting these features can require substantial effort to piece together existing tools into custom workflows. Here, building on existing open source software for mesh manipulation, we present Neural Decomposition (NEURD), a software package that decomposes meshed neurons into compact and extensively annotated graph representations. With these feature-rich graphs, we automate a variety of tasks such as state-of-the-art automated proofreading of merge errors, cell classification, spine detection, axonal-dendritic proximities and other annotations. These features enable many downstream analyses of neural morphology and connectivity, making these massive and complex datasets more accessible to neuroscience researchers.

『Abstract』Magnonic systems provide a fertile playground for bosonic topology , for example, Dirac and Weyl magnons, leading to a variety of exotic phenomena such as charge-free topologically protected boundary modes , the magnon thermal Hall effect and the magnon spin Nernst effect . However, their understanding has been hindered by the absence of fundamental symmetry descriptions of magnetic geometries and spin Hamiltonians primarily governed by isotropic Heisenberg interactions. The ensuing magnon dispersions enable gapless magnon band nodes that go beyond the scenario of representation theory of the magnetic space groups , thus referred to as unconventional magnons. Here we developed spin space group theory to elucidate collinear magnetic configurations, classifying the 1,421 collinear spin space groups into 4 types, constructing their band representations and providing a comprehensive tabulation of unconventional magnons, such as duodecuple points, octuple nodal lines and charge-4 octuple points. On the basis of the MAGNDATA database , we identified 498 collinear magnets with unconventional magnons, among which more than 200 magnon band structures were obtained by using first-principles calculations and linear spin wave theory. In addition, we evaluated the influence of the spin–orbit-coupling-induced exchange interaction in these magnets and found that more than 80 per cent are predominantly governed by the Heisenberg interactions, indicating that the spin space group serves as an ideal framework for describing magnon band nodes in most 3 d , 4 d and half-filled 4 f collinear magnets.

『Abstract』The coronavirus membrane protein (M) is the main organizer of coronavirus assembly . Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation. CIM-834 inhibits the replication of SARS-CoV-2 (including a broad panel of variants) and SARS-CoV. In SCID mice and Syrian hamsters intranasally infected with SARS-CoV-2, oral treatment reduced lung viral titres to nearly undetectable levels, even (as shown in mice) when treatment was delayed until 24 h before the end point. Treatment of infected hamsters prevented transmission to untreated sentinels. Transmission electron microscopy studies show that virion assembly is completely absent in cells treated with CIM-834. Single-particle cryo-electron microscopy reveals that CIM-834 binds and stabilizes the M protein in its short form, thereby preventing the conformational switch to the long form, which is required for successful particle assembly. In conclusion, we have discovered a new druggable target in the replication cycle of coronaviruses and a small molecule that potently inhibits it.

『Abstract』Understanding the brain requires understanding neurons’ functional responses to the circuit architecture shaping them. Here we introduce the MICrONS functional connectomics dataset with dense calcium imaging of around 75,000 neurons in primary visual cortex (VISp) and higher visual areas (VISrl, VISal and VISlm) in an awake mouse that is viewing natural and synthetic stimuli. These data are co-registered with an electron microscopy reconstruction containing more than 200,000 cells and 0.5 billion synapses. Proofreading of a subset of neurons yielded reconstructions that include complete dendritic trees as well the local and inter-areal axonal projections that map up to thousands of cell-to-cell connections per neuron. Released as an open-access resource, this dataset includes the tools for data retrieval and analysis . Accompanying studies describe its use for comprehensive characterization of cell types , a synaptic level connectivity diagram of a cortical column , and uncovering cell-type-specific inhibitory connectivity that can be linked to gene expression data . Functionally, we identify new computational principles of how information is integrated across visual space , characterize novel types of neuronal invariances and bring structure and function together to uncover a general principle for connectivity between excitatory neurons within and across areas .

『Abstract』Macrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation . Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1β secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies.

『Abstract』Mammalian cortex features a vast diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties . Synaptic connectivity shapes how each cell type participates in the cortical circuit, but mapping connectivity rules at the resolution of distinct cell types remains difficult. Here we used millimetre-scale volumetric electron microscopy to investigate the connectivity of all inhibitory neurons across a densely segmented neuronal population of 1,352 cells spanning all layers of mouse visual cortex, producing a wiring diagram of inhibition with more than 70,000 synapses. Inspired by classical neuroanatomy, we classified inhibitory neurons based on targeting of dendritic compartments and developed an excitatory neuron classification based on dendritic reconstructions with whole-cell maps of synaptic input. Single-cell connectivity showed a class of disinhibitory specialist that targets basket cells. Analysis of inhibitory connectivity onto excitatory neurons found widespread specificity, with many interneurons exhibiting differential targeting of spatially intermingled subpopulations. Inhibitory targeting was organized into ‘motif groups’, diverse sets of cells that collectively target both perisomatic and dendritic compartments of the same excitatory targets. Collectively, our analysis identified new organizing principles for cortical inhibition and will serve as a foundation for linking contemporary multimodal neuronal atlases with the cortical wiring diagram.

『Abstract』Although Earth, together with other terrestrial planets, must have had an early-formed protocrust, the chemical composition of this crust has received little attention. The protocrust was extracted from an extensive magma ocean formed by accretion and melting of asteroidal bodies . Both experimental and chronological data suggest that the silicate melt ascending from this magma ocean formed in equilibrium with, or after, metal was extracted to form Earth’s core. Here we show that a protocrust formed under these conditions would have had incompatible (with respect to silicate minerals) trace-element characteristics remarkably similar to those of the current average continental crust. This has major implications for subsequent planetary evolution. Many geochemical arguments for when and how plate tectonics began implicitly assume that subduction is required to produce the continental trace-element signature. These arguments are severely compromised if this signature was already a feature of the Hadean protocrust.

『Abstract』Acoustic oscillations in stars are sensitive to stellar interiors . Frequency differences between overtone modes—large separations—probe stellar density , whereas differences between low-degree modes—small separations—probe the sound-speed gradient in the energy-generating core of main-sequence Sun-like stars , and hence their ages. At later phases of stellar evolution, characterized by inert cores, small separations are believed to lose much of their power to probe deep interiors and become proportional to large separations . Here we present evidence of a rapidly evolving convective zone as stars evolve from the subgiant phase into red giants. By measuring acoustic oscillations in 27 stars from the open cluster M67, we observe deviations of proportionality between small and large separations, which are caused by the influence of the bottom of the convective envelope. These deviations become apparent as the convective envelope penetrates deep into the star during subgiant and red giant evolutions, eventually entering an ultradeep regime that leads to the red-giant-branch luminosity bump. The tight sequence of cluster stars, free of large spreads in ages and fundamental properties, is essential for revealing the connection between the observed small separations and the chemical discontinuities occurring at the bottom of the convective envelope. We use this sequence to show that combining large and small separations can improve estimations of the masses and ages of field stars well after the main sequence.

『Abstract』The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly . Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log 10 -transformed RNA copies and 50% tissue culture infective dose (TCID 50 ) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after infection, when peak viral loads were observed. The M protein is an attractive antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.

『Abstract』Limited strategies exist for chemical recycling of commodity diene polymers, like those found in tyres . Here we apply C–H amination and backbone rearrangement of polymers to deconstruct these materials into precursors for epoxy resins. Specifically, we develop a sulfur diimide reagent that enables up to about 35% allylic amination of diene polymers and rubber. Then, we apply the cationic 2-aza-Cope rearrangement to deconstruct aminated diene polymers. In a model system, we see molecular weight reduction from 58,100 to approximately 400 g mol , and aminated post-consumer rubber is deconstructed over 6 hours into soluble amine-functionalized polymers, which can be utilized to prepare epoxy thermosets with similar stiffnesses to commercial bisphenol A-derived resins . Altogether, this work demonstrates the power of C–H amination and backbone rearrangement to enable chemical recycling of post-consumer materials.

『Abstract』Cortical networks for the production of spoken language in humans are organized by phonetic features , such as articulatory parameters and vocal pitch . Previous research has failed to find an equivalent forebrain representation in other species . To investigate whether this functional organization is unique to humans, here we performed population recordings in the vocal production circuitry of the budgerigar ( Melopsittacus undulatus ), a small parrot that can generate flexible vocal output , including mimicked speech sounds . Using high-density silicon probes , we measured the song-related activity of a forebrain region, the central nucleus of the anterior arcopallium (AAC), which directly projects to brainstem phonatory motor neurons . We found that AAC neurons form a functional vocal motor map that reflects the spectral properties of ongoing vocalizations. We did not observe this organizing principle in the corresponding forebrain circuitry of the zebra finch, a songbird capable of more limited vocal learning . We further demonstrated that the AAC represents the production of distinct vocal features (for example, harmonic structure and broadband energy). Furthermore, we discovered an orderly representation of vocal pitch at the population level, with single neurons systematically selective for different frequency values. Taken together, we have uncovered a functional representation in a vertebrate brain that displays unprecedented commonalities with speech-related motor cortices in humans. This work therefore establishes the parrot as an important animal model for investigating speech motor control and for developing therapeutic solutions for addressing a range of communication disorders .

『Abstract』Humans emerged across Africa shortly before 300 thousand years ago (ka) . Although this pan-African evolutionary process implicates diverse environments in the human story, the role of tropical forests remains poorly understood. Here we report a clear association between late Middle Pleistocene material culture and a wet tropical forest in southern Cote d’Ivoire, a region of present-day rainforest. Twinned optically stimulated luminescence and electron spin resonance dating methods constrain the onset of human occupations at Bete I to around 150 ka, linking them with Homo sapiens . Plant wax biomarker, stable isotope, phytolith and pollen analyses of associated sediments all point to a wet forest environment. The results represent the oldest yet known clear association between humans and this habitat type. The secure attribution of stone tool assemblages with the wet forest environment demonstrates that Africa’s forests were not a major ecological barrier for H. sapiens as early as around 150 ka.

『Abstract』The tetraploid genome and clonal propagation of the cultivated potato ( Solanum tuberosum L.) dictate a slow, non-accumulative breeding mode of the most important tuber crop. Transitioning potato breeding to a seed-propagated hybrid system based on diploid inbred lines has the potential to greatly accelerate its improvement . Crucially, the development of inbred lines is impeded by manifold deleterious variants; explaining their nature and finding ways to eliminate them is the current focus of hybrid potato research . However, most published diploid potato genomes are unphased, concealing crucial information on haplotype diversity and heterozygosity . Here we develop a phased potato pangenome graph of 60 haplotypes from cultivated diploids and the ancestral wild species, and find evidence for the prevalence of transposable elements in generating structural variants. Compared with the linear reference, the graph pangenome represents a broader diversity (3,076 Mb versus 742 Mb). Notably, we observe enhanced heterozygosity in cultivated diploids compared with wild ones (14.0% versus 9.5%), indicating extensive hybridization during potato domestication. Using conservative criteria, we identify 19,625 putatively deleterious structural variants (dSVs) and reveal a biased accumulation of deleterious single nucleotide polymorphisms (dSNPs) around dSVs in coupling phase. Based on the graph pangenome, we computationally design ideal potato haplotypes with minimal dSNPs and dSVs. These advances provide critical insights into the genomic basis of clonal propagation and will guide breeders to develop a suite of promising inbred lines.

『Abstract』Over the past decade, photonics research has explored accelerated tensor operations, foundational to artificial intelligence (AI) and deep learning , as a path towards enhanced energy efficiency and performance . The field is centrally motivated by finding alternative technologies to extend computational progress in a post-Moore’s law and Dennard scaling era . Despite these advances, no photonic chip has achieved the precision necessary for practical AI applications, and demonstrations have been limited to simplified benchmark tasks. Here we introduce a photonic AI processor that executes advanced AI models, including ResNet and BERT , along with the Atari deep reinforcement learning algorithm originally demonstrated by DeepMind . This processor achieves near-electronic precision for many workloads, marking a notable entry for photonic computing into competition with established electronic AI accelerators and an essential step towards developing post-transistor computing technologies.

『Abstract』Existing wearable technologies rely on physical coupling to the body to establish optical , fluidic , thermal and/or mechanical measurement interfaces. Here we present a class of wearable device platforms that instead relies on physical decoupling to define an enclosed chamber immediately adjacent to the skin surface. Streams of vapourized molecular substances that pass out of or into the skin alter the properties of the microclimate defined in this chamber in ways that can be precisely quantified using an integrated collection of wireless sensors. A programmable, bistable valve dynamically controls access to the surrounding environment, thereby creating a transient response that can be quantitatively related to the inward and outward fluxes of the targeted species by analysing the time-dependent readings from the sensors. The systems reported here offer unique capabilities in measuring the flux of water vapour, volatile organic compounds and carbon dioxide from various locations on the body, each with distinct relevance to clinical care and/or exposure to hazardous vapours. Studies of healing processes associated with dermal wounds in models of healthy and diabetic mice and of responses in models using infected wounds reveal characteristic flux variations that provide important insights, particularly in scenarios in which the non-contact operation of the devices avoids potential damage to fragile tissues.

『Abstract』The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources . Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood . Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point . Here we examined whether cooperation among tumour cells may be a potential therapeutic target. We identified a cooperative mechanism that enables tumour cells to proliferate under the amino acid-deprived conditions found in the tumour microenvironment. Disruption of this mechanism drove cultured tumour populations to the critical extinction point and resulted in a marked reduction in tumour growth in vivo. Mechanistically, we show that tumour cells collectively digest extracellular oligopeptides through the secretion of aminopeptidases. The resulting free amino acids benefit both aminopeptidase-secreting cells and neighbouring cells. We identified CNDP2 as the key enzyme that hydrolyses these peptides extracellularly, and loss of this aminopeptidase prevents tumour growth in vitro and in vivo. These data show that cooperative scavenging of nutrients is key to survival in the tumour microenvironment and reveal a targetable cancer vulnerability.