经典100 | NCS： 2025-03-27 期

『Abstract』 Rising atmospheric and ocean temperatures have caused substantial changes in terrestrial water circulation and land surface water fluxes, such as precipitation and evapotranspiration, potentially leading to abrupt shifts in terrestrial water storage. The European Centre for Medium-Range Weather Forecasts (ECMWF) Reanalysis v5 (ERA5) soil moisture (SM) product reveals a sharp depletion during the early 21st century. During the period 2000 to 2002, soil moisture declined by approximately 1614 gigatonnes, much larger than Greenland’s ice loss of about 900 gigatonnes (2002–2006). From 2003 to 2016, SM depletion continued, with an additional 1009-gigatonne loss. This depletion is supported by two independent observations of global mean sea level rise (~4.4 millimeters) and Earth’s pole shift (~45 centimeters). Precipitation deficits and stable evapotranspiration likely caused this decline, and SM has not recovered as of 2021, with future recovery unlikely under present climate conditions.

『Abstract』 Prior research on racial profiling has found that in encounters with law enforcement, minorities are punished more severely than white civilians. Less is known about the causes of these encounters and their implications for our understanding of racial profiling. Using high-frequency location data of rideshare drivers in Florida ( N = 222,838 individuals), we estimate the effect of driver race on citations and fines for speeding using 19.3 million location pings. Compared with a white driver traveling the same speed, we find that racial or ethnic minority drivers are 24 to 33% more likely to be cited for speeding and pay 23 to 34% more money in fines. We find no evidence that accident and reoffense rates explain these estimates, which suggests that an animus against minorities underlies our results.

『Abstract』 We present a bulk nanocrystalline copper alloy that can operate at near-melting temperatures with minimal coarsening and creep deformation. The thermal stability of the Cu-3Ta-0.5Li atomic % (at %) alloy is attributed to coherent, ordered L1 2 Cu 3 Li precipitates surrounded by a tantalum-rich atomic bilayer phase boundary complexion. Adding 0.5 at % lithium to the immiscible Cu-Ta system changes the morphology of the nanoscale precipitates from spherical to cuboidal while simultaneously tailoring the phase boundary. The resultant complexion-stabilized nanoscale precipitates provide excellent thermal stability, strength, and creep resistance. The underlying alloy design principles may guide the development of next-generation copper alloys for high-temperature applications such as heat exchangers.

『Abstract』 Horses are among nature’s greatest athletes, yet the ancestral molecular adaptations fueling their energy demands are poorly understood. Within a clinically important pathway regulating redox and metabolic homeostasis (NRF2/KEAP1), we discovered an ancient mutation—conserved in all extant equids—that increases mitochondrial respiration while decreasing tissue-damaging oxidative stress. This mutation is a de novo premature opal stop codon in KEAP1 that is translationally recoded into a cysteine through previously unknown mechanisms, producing an R15C mutation in KEAP1 that is more sensitive to electrophiles and reactive oxygen species. This recoding enables increased NRF2 activity, which enhances mitochondrial adenosine 5′-triphosphate production and cellular resistance to oxidative damage. Our study illustrates how recoding of a de novo stop codon, a strategy thought restricted to viruses, can facilitate adaptation in vertebrates.

『Abstract』 Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain–containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.

『Abstract』 Tandem kinase proteins underlie the innate immune systems of cereal plants, but how they initiate plant immune responses remains unclear. This report identifies wheat protein wheat tandem NBD 1 (WTN1), a noncanonical nucleotide-binding leucine-rich repeat (NLR) receptor featuring tandem nucleotide binding adaptor shared by APAF-1, plant R proteins, and CED-4 (NB-ARC) domains, required for WTK3-mediated disease resistance. Both WTK3 and its allelic variant Rwt4—known for conferring resistance to wheat powdery mildew and blast, respectively—are capable of recognizing the blast effector PWT4. They activate WTN1 to form calcium-permeable channels, akin to ZAR1 and Sr35. Thus, tandem kinase proteins and their associated NLRs operate as “sensor-executor” pairs against fungal pathogens. Additionally, evolutionary analyses reveal a coevolutionary trajectory of the tandem kinase-NLR module, highlighting their cooperative role in triggering plant immunity.

『Abstract』 Hedonic eating is defined as food consumption driven by palatability without physiological need. However, neural control of palatable food intake is poorly understood. We discovered that hedonic eating is controlled by a neural pathway from the peri–locus ceruleus to the ventral tegmental area (VTA). Using photometry-calibrated optogenetics, we found that VTA dopamine (VTA ) neurons encode palatability to bidirectionally regulate hedonic food consumption. VTA neuron responsiveness was suppressed during food consumption by semaglutide, a glucagon-like peptide receptor 1 (GLP-1R) agonist used as an antiobesity drug. Mice recovered palatable food appetite and VTA neuron activity during repeated semaglutide treatment, which was reversed by consumption-triggered VTA neuron inhibition. Thus, hedonic food intake activates VTA neurons, which sustain further consumption, a mechanism that opposes appetite reduction by semaglutide.

『Abstract』 Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways, including transiently from hydrazones, to achieve a net reductive arylation of carbonyl compounds. We show their utility as versatile radical precursors, as exemplified with seven C–C bond–forming, redox-neutral cross-couplings with activated olefins, alkyl halides, redox-active esters, aryl halides, alkenyl halides, alkynyl halides, and a trifluoromethylating reagent, to forge C(sp )-C(sp ), C(sp )-C(sp ), and C(sp )-C(sp) bonds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary because these functional groups serve the dual role of radical precursor and electron donor. The homogeneous, water-compatible reaction conditions are operationally simple and contribute to streamlining synthesis and mild late-stage functionalization.

『Abstract』 Eukaryotes have linear DNA, and their telomeres are hotspots for transposons, which in some cases took over telomere maintenance. We identified several families of independently evolved telomeric transposons in linear chromosomes and plasmids of cyanobacteria and Streptomyces . Although these elements have one specific transposon end sequence, with the second boundary being the telomere, we can show that they move using two transposon ends, likely when transiently bridged by the telomere maintenance systems. Mobilization of the element and the associated telomere allows replacement of native telomeres, making the host cell dependent on the new transposon telomere system for genome maintenance. This work indicates how telomeric transposons can promote gene transfer both between and within genomes, substantially influencing the evolutionary dynamics of linear genomes.

『Abstract』 Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score—a measure of obesity—in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B ( DENND1B ). Each copy of the alternate allele was associated with ~7% greater body fat. We demonstrate a role for this gene in regulating signaling and trafficking of melanocortin 4 receptor, a critical controller of energy homeostasis. Thus, canine genetics identified obesity genes and mechanisms relevant to both dogs and humans.

『Abstract』 The role of nucleotide-binding leucine-rich repeat (NLR) receptors in plant immunity is well studied, but the function of a class of tandem kinases (TKs) that confer disease resistance in wheat and barley remains unclear. In this study, we show that the SR62 locus is a digenic module encoding the Sr62 TK and an NLR (Sr62 ), and we identify the corresponding AvrSr62 effector. AvrSr62 binds to the N-terminal kinase 1 of Sr62 , triggering displacement of kinase 2, which activates Sr62 . Modeling and mutation analysis indicated that this is mediated by overlapping binding sites (i) on kinase 1 for binding AvrSr62 and kinase 2 and (ii) on kinase 2 for binding kinase 1 and Sr62 . Understanding this two-component resistance complex may help engineering and breeding plants for durable resistance.

『Abstract』 In mammals, fertilized eggs undergo genome-wide epigenetic reprogramming to generate the organism. However, our understanding of epigenetic dynamics during preimplantation development at single-cell resolution remains incomplete. Here, we developed scNanoATAC-seq2, a single-cell assay for transposase-accessible chromatin using long-read sequencing for scarce samples. We present a detailed chromatin accessibility landscape of mouse preimplantation development, revealing distinct chromatin signatures in the epiblast, primitive endoderm, and trophectoderm during lineage segregation. Differences between zygotes and two-cell embryos highlight reprogramming in chromatin accessibility during the maternal-to-zygotic transition. Single-cell long-read sequencing enables in-depth analysis of chromatin accessibility in noncanonical imprinting, imprinted X chromosome inactivation, and low-mappability genomic regions, such as repetitive elements and paralogs. Our data provide insights into chromatin dynamics during mammalian preimplantation development and lineage differentiation.

『Abstract』 Describing the distribution of genetic variation across individuals is a fundamental goal of population genetics. We present a method that capitalizes on the rich genealogical information encoded in genomic tree sequences to infer the geographic locations of the shared ancestors of a sample of sequenced individuals. We used this method to infer the geographic history of genetic ancestry of a set of human genomes sampled from Europe, Asia, and Africa, accurately recovering major population movements on those continents. Our findings demonstrate the importance of defining the spatiotemporal context of genetic ancestry when describing human genetic variation and caution against the oversimplified interpretations of genetic data prevalent in contemporary discussions of race and ancestry.

『Abstract』 Entanglement is a key resource for quantum computing, sensing, and communication, but it is susceptible to decoherence. To address this, research in quantum optics has explored filtering techniques such as photon ancillas and Rydberg atom blockade to restore entangled states. We introduce an approach to entanglement retrieval that exploits the features of non-Hermitian systems. By designing an anti–parity-time two-state guiding configuration, we demonstrate efficient extraction of entanglement from any input state. This filter is implemented on a lossless waveguide network and achieves near-unity fidelity under single- and two-photon excitation and is scalable to higher photon levels, remaining robust against decoherence during propagation. Our results offer an approach to using non-Hermitian symmetries to address central challenges in quantum technologies.

『Abstract』 The sense of touch conveys critical environmental information, facilitating object recognition, manipulation, and social interaction, and can be engineered through haptic actuators that stimulate cutaneous receptors. An unfulfilled challenge lies in haptic interface technologies that can engage all the various mechanoreceptors in a programmable, spatiotemporal fashion across large areas of the body. Here, we introduce a small-scale actuator technology that can impart omnidirectional, superimposable, dynamic forces to the surface of skin, as the basis for stimulating individual classes of mechanoreceptors or selected combinations of them. High-bit haptic information transfer and realistic virtual tactile sensations are possible, as illustrated through human subject perception studies in extended reality applications that include advanced hand navigation, realistic texture reproduction, and sensory substitution for music perception.

『Abstract』Zorya is a recently identified and widely distributed bacterial immune system that protects bacteria from viral (phage) infections. Three Zorya subtypes have been identified, each containing predicted membrane-embedded ZorA–ZorB (ZorAB) complexes paired with soluble subunits that differ among Zorya subtypes, notably ZorC and ZorD in type I Zorya systems . Here we investigate the molecular basis of Zorya defence using cryo-electron microscopy, mutagenesis, fluorescence microscopy, proteomics and functional studies. We present cryo-electron microscopy structures of ZorAB and show that it shares stoichiometry and features of other 5:2 inner membrane ion-driven rotary motors. The ZorA 5 B 2 complex contains a dimeric ZorB peptidoglycan-binding domain and a pentameric α-helical coiled-coil tail made of ZorA that projects approximately 70 nm into the cytoplasm. We also characterize the structure and function of the soluble Zorya components ZorC and ZorD, finding that they have DNA-binding and nuclease activity, respectively. Comprehensive functional and mutational analyses demonstrate that all Zorya components work in concert to protect bacterial cells against invading phages. We provide evidence that ZorAB operates as a proton-driven motor that becomes activated after sensing of phage invasion. Subsequently, ZorAB transfers the phage invasion signal through the ZorA cytoplasmic tail to recruit and activate the soluble ZorC and ZorD effectors, which facilitate the degradation of the phage DNA. In summary, our study elucidates the foundational mechanisms of Zorya function as an anti-phage defence system.

『Abstract』The blood–brain barrier (BBB) is highly specialized to protect the brain from harmful circulating factors in the blood and maintain brain homeostasis . The brain endothelial glycocalyx layer, a carbohydrate-rich meshwork composed primarily of proteoglycans, glycoproteins and glycolipids that coats the BBB lumen, is a key structural component of the BBB . This layer forms the first interface between the blood and brain vasculature, yet little is known about its composition and roles in supporting BBB function in homeostatic and diseased states. Here we find that the brain endothelial glycocalyx is highly dysregulated during ageing and neurodegenerative disease. We identify significant perturbation in an underexplored class of densely O-glycosylated proteins known as mucin-domain glycoproteins. We demonstrate that ageing- and disease-associated aberrations in brain endothelial mucin-domain glycoproteins lead to dysregulated BBB function and, in severe cases, brain haemorrhaging in mice. Finally, we demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.

『Abstract』Phonon polaritons are quasiparticles resulting from the coherent coupling of photons with optical phonons in polar dielectrics . Owing to their exceptional ability to confine electric fields to deep-subwavelength scales with low loss, they are uniquely poised to enable a suite of applications beyond the reach of conventional photonics, such as subdiffraction imaging and near-field energy transfer . The conventional approach to exciting phonon polaritons through optical methods, however, involves costly light sources along with near-field schemes , and generally leads to low excitation efficiency owing to substantial momentum mismatch between phonon polaritons and free-space photons. Here we demonstrate that under proper conditions, phonon polaritons can be excited all-electrically by drifting charge carriers. Specifically, in hexagonal boron nitride (hBN)/graphene heterostructures, by electrically driving charge carriers in ultrahigh-mobility graphene out of equilibrium, we observe bright electroluminescence of hBN’s hyperbolic phonon polaritons (HPhPs) at mid-infrared frequencies, which shows a temperature and carrier density dependence distinct from black-body thermal emission. Moreover, the carrier density dependence of the HPhP electroluminescence spectra reveals that HPhP electroluminescence can arise from both interband transition and intraband Cherenkov radiation of charge carriers in graphene. The HPhP electroluminescence offers avenues for realizing electrically pumped mid-infrared and terahertz phonon-polariton light sources.

『Abstract』Optical amplification, crucial for modern communication, primarily relies on erbium-doped fibre amplifiers (EDFAs) . Yet, EDFAs only cover a portion of the low-loss spectrum of optical fibres. This has motivated the development of amplifiers operating beyond the erbium gain window. Pioneering work on optical parametric amplifiers (OPAs) using intrinsic third-order optical nonlinearity has led to demonstrations of increased channel capacity. OPAs offer high gain, can reach the 3-dB quantum limit for phase-preserving amplifiers and exhibit unidirectional operation. However, power requirements for highly nonlinear fibres or bulk waveguides have impeded their adoption. By contrast, OPAs based on integrated photonic circuits offer the advantages of substantially increased mode confinement and optical nonlinearity but have been limited in bandwidth . We overcome this challenge by using low-loss gallium phosphide-on-silicon dioxide photonic integrated circuits (PICs) and attain up to 35 dB of parametric gain with waveguides only a few centimetres long in a compact footprint of 0.25 square millimetres. Fibre-to-fibre net gain exceeding 10 dB across an ultra-broad bandwidth of approximately 140 nm (that is, 17 THz) is achieved, with a threefold increase in the gain window compared with C-band EDFAs. We further demonstrate a high dynamic range for input signals, spanning six orders of magnitude, while maintaining a low noise figure. We exploit these performance characteristics to amplify coherent communication signals. This marks, to our knowledge, the first ultra-broadband, high-gain, continuous-wave amplification in a photonic chip, opening up new capabilities for next-generation integrated photonics.

『Abstract』The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved over short timescales, leading to the emergence of more transmissible variants such as Alpha and Delta . The arrival of the Omicron variant marked a major shift, introducing numerous extra mutations in the spike gene compared with earlier variants . These evolutionary changes have raised concerns regarding their potential impact on immune evasion, disease severity and the effectiveness of vaccines and treatments . In this epidemiological study, we identified two distinct patterns in the protective effect of natural infection against reinfection in the Omicron versus pre-Omicron eras. Before Omicron, natural infection provided strong and durable protection against reinfection, with minimal waning over time. However, during the Omicron era, protection was robust only for those recently infected, declining rapidly over time and diminishing within a year. These results demonstrate that SARS-CoV-2 immune protection is shaped by a dynamic interaction between host immunity and viral evolution, leading to contrasting reinfection patterns before and after Omicron’s first wave. This shift in patterns suggests a change in evolutionary pressures, with intrinsic transmissibility driving adaptation pre-Omicron and immune escape becoming dominant post-Omicron, underscoring the need for periodic vaccine updates to sustain immunity.

『Abstract』Bipolar disorder is a leading contributor to the global burden of disease . Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown . We analysed data from participants of European, East Asian, African American and Latino ancestries ( n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings , and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder , highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

『Abstract』High-grade gliomas (HGGs) are the leading cause of brain cancer-related death. HGGs include clinically, anatomically and molecularly distinct subtypes that stratify into diffuse midline gliomas (DMGs), such as H3K27M -altered diffuse intrinsic pontine glioma, and hemispheric HGGs, such as IDH wild-type glioblastoma. Neuronal activity drives glioma progression through paracrine signalling and neuron-to-glioma synapses . Glutamatergic AMPA receptor-dependent synapses between neurons and glioma cells have been demonstrated in paediatric and adult high-grade gliomas, and early work has suggested heterogeneous glioma GABAergic responses . However, neuron-to-glioma synapses mediated by neurotransmitters other than glutamate remain understudied. Using whole-cell patch-clamp electrophysiology, in vivo optogenetics and patient-derived orthotopic xenograft models, we identified functional, tumour-promoting GABAergic neuron-to-glioma synapses mediated by GABA A receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 chloride transporter function and consequently elevated intracellular chloride concentration in DMG malignant cells. As membrane depolarization increases glioma proliferation , we found that the activity of GABAergic interneurons promotes DMG proliferation in vivo. The benzodiazepine lorazepam enhances GABA-mediated signalling, increases glioma proliferation and growth, and shortens survival in DMG patient-derived orthotopic xenograft models. By contrast, only minimal depolarizing GABAergic currents were found in hemispheric HGGs and lorazepam did not influence the growth rate of hemispheric glioblastoma xenografts. Together, these findings uncover growth-promoting GABAergic synaptic communication between GABAergic neurons and H3K27M -altered DMG cells, underscoring a tumour subtype-specific mechanism of brain cancer neurophysiology.

『Abstract』DNA double-strand breaks (DSBs) disrupt the continuity of the genome, with consequences for malignant transformation. Massive DNA damage can elicit a cellular checkpoint response that prevents cell proliferation . However, how highly aggressive cancer cells, which can tolerate widespread DNA damage, respond to DSBs alongside continuous chromosome duplication is unknown. Here we show that DSBs induce a local genome maintenance mechanism that inhibits replication initiation in DSB-containing topologically associating domains (TADs) without affecting DNA synthesis at other genomic locations. This process is facilitated by mediators of replication and DSBs (MRDs). In normal and cancer cells, MRDs include the TIMELESS–TIPIN complex and the WEE1 kinase, which actively dislodges the TIMELESS–TIPIN complex from replication origins adjacent to DSBs and prevents initiation of DNA synthesis at DSB-containing TADs. Dysregulation of MRDs, or disruption of 3D chromatin architecture by dissolving TADs, results in inadvertent replication in damaged chromatin and increased DNA damage in cancer cells. We propose that the intact MRD cascade precedes DSB repair to prevent genomic instability, which is otherwise observed when replication is forced, or when genome architecture is challenged, in the presence of DSBs . These observations reveal a previously unknown vulnerability in the DNA replication machinery that may be exploited to therapeutically target cancer cells.

『Abstract』Aggression is an evolutionarily conserved behaviour that controls social hierarchies and protects valuable resources. In mice, aggressive behaviour can be broken down into an appetitive phase, which involves approach and investigation, and a consummatory phase, which involves biting, kicking and wrestling . Here, by performing an unsupervised weighted correlation network analysis on whole-brain FOS expression in mice, we identify a cluster of brain regions, including hypothalamic and amygdalar subregions and olfactory cortical regions, that are highly co-activated in male but not in female aggressors. The posterolateral cortical amygdala (COApl)—an extended olfactory structure—was found to be a hub region, on the basis of the number and strength of correlations with other regions in the cluster. Our data also show that oestrogen receptor 1 ( Esr1 )-expressing cells in the COApl (COApl ) exhibit increased activity during attack behaviour and during bouts of investigation that precede an attack, in male mice only. Chemogenetic or optogenetic inhibition of COApl cells in male aggressors reduces aggression and increases pro-social investigation without affecting social reward and reinforcement behaviour. We further show that COApl projections to the ventromedial hypothalamus and central amygdala are necessary for these behaviours. Collectively, these data suggest that, in aggressive males, COApl cells respond specifically to social stimuli, thereby enhancing their salience and promoting attack behaviour.

『Abstract』Ultra-hot Jupiters, an extreme class of planets not found in our Solar System, provide a unique window into atmospheric processes. The extreme temperature contrasts between their day and night sides pose a fundamental climate puzzle: how is energy distributed? To address this, we must observe the three-dimensional structure of these atmospheres, particularly their vertical circulation patterns that can serve as a testbed for advanced global circulation models, for example, in ref. . Here we show a notable shift in atmospheric circulation in an ultra-hot Jupiter: a unilateral flow from the hot star-facing side to the cooler space-facing side of the planet sits below an equatorial super-rotational jet stream. By resolving the vertical structure of atmospheric dynamics, we move beyond integrated global snapshots of the atmosphere, enabling more accurate identification of flow patterns and allowing for a more nuanced comparison to models. Global circulation models based on first principles struggle to replicate the observed circulation pattern underscoring a critical gap between theoretical understanding of atmospheric flows and observational evidence. This work serves as a testbed to develop more comprehensive models applicable beyond our Solar System as we prepare for the next generation of giant telescopes.

『Abstract』For decades, antigen presentation on major histocompatibility complex class I for T cell-mediated immunity has been considered the primary function of proteasome-derived peptides . However, whether the products of proteasomal degradation play additional parts in mounting immune responses remains unknown. Antimicrobial peptides serve as a first line of defence against invading pathogens before the adaptive immune system responds. Although the protective function of antimicrobial peptides across numerous tissues is well established, the cellular mechanisms underlying their generation are not fully understood. Here we uncover a role for proteasomes in the constitutive and bacterial-induced generation of defence peptides that impede bacterial growth both in vitro and in vivo by disrupting bacterial membranes. In silico prediction of proteome-wide proteasomal cleavage identified hundreds of thousands of potential proteasome-derived defence peptides with cationic properties that may be generated en route to degradation to act as a first line of defence. Furthermore, bacterial infection induces changes in proteasome composition and function, including PSME3 recruitment and increased tryptic-like cleavage, enhancing antimicrobial activity. Beyond providing mechanistic insights into the role of proteasomes in cell-autonomous innate immunity, our study suggests that proteasome-cleaved peptides may have previously overlooked functions downstream of degradation. From a translational standpoint, identifying proteasome-derived defence peptides could provide an untapped source of natural antibiotics for biotechnological applications and therapeutic interventions in infectious diseases and immunocompromised conditions.

『Abstract』Antimicrobial resistance is a public health threat associated with increased morbidity, mortality and financial burden in nursing homes and other healthcare settings . Residents of nursing homes are at increased risk of pathogen colonization and infection owing to antimicrobial-resistant bacteria and fungi. Nursing homes act as reservoirs, amplifiers and disseminators of antimicrobial resistance in healthcare networks and across geographical regions . Here we investigate the genomic epidemiology of the emerging, multidrug-resistant human fungal pathogen Candida auris in a ventilator-capable nursing home. Coupling strain-resolved metagenomics with isolate sequencing, we report skin colonization and clonal spread of C. auris on the skin of nursing home residents and throughout a metropolitan region. We also report that most Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa and Entobacter species (ESKAPE) pathogens and other high-priority pathogens (including Escherichia coli , Providencia stuartii , Proteus mirabilis and Morganella morganii ) are shared in a nursing home. Integrating microbiome and clinical microbiology data, we detect carbapenemase genes at multiple skin sites on residents identified as carriers of these genes. We analyse publicly available shotgun metagenomic samples (stool and skin) collected from residents with varying medical conditions living in seven other nursing homes and provide additional evidence of previously unappreciated bacterial strain sharing. Taken together, our data suggest that skin is a reservoir for colonization by C. auris and ESKAPE pathogens and their associated antimicrobial-resistance genes.

『Abstract』Amphibians are the most threatened vertebrates, yet their resilience to rising temperatures remains poorly understood . This is primarily because knowledge of thermal tolerance is taxonomically and geographically biased , compromising global climate vulnerability assessments. Here we used a phylogenetically informed data-imputation approach to predict the heat tolerance of 60% of amphibian species and assessed their vulnerability to daily temperature variations in thermal refugia. We found that 104 out of 5,203 species (2%) are currently exposed to overheating events in shaded terrestrial conditions. Despite accounting for heat-tolerance plasticity, a 4 °C global temperature increase would create a step change in impact severity, pushing 7.5% of species beyond their physiological limits. In the Southern Hemisphere, tropical species encounter disproportionally more overheating events, while non-tropical species are more susceptible in the Northern Hemisphere. These findings challenge evidence for a general latitudinal gradient in overheating risk and underscore the importance of considering climatic variability in vulnerability assessments. We provide conservative estimates assuming access to cool shaded microenvironments. Thus, the impacts of global warming will probably exceed our projections. Our microclimate-explicit analyses demonstrate that vegetation and water bodies are critical in buffering amphibians during heat waves. Immediate action is needed to preserve and manage these microhabitat features.

『Abstract』Frictional interfaces are found in systems ranging from biological joints to earthquake faults. When and how these interfaces slide is a fundamental problem in geosciences and engineering . It is believed that there exists a threshold shear force, called static friction, below which the interface is stationary , despite many studies suggesting that this concept is outdated . By contrast, rate-and-state friction formulations predict that interfaces are always sliding , but this feature is often considered an artefact that calls for modifications . Here we show that nominally stationary interfaces subjected to constant shear and normal loads, with a driving force that is notably below the classically defined static friction for which creep is known to occur , are sliding, but with diminishingly small rates down to 10 m s . Our precise measurements directly at the interface are enabled by digital image correlation . This behaviour contradicts classical models of friction but confirms the prediction of rate-and-state friction . The diminishing slip rates of nominally stationary interfaces reflect interface healing, which would manifest itself in higher peak friction in subsequent slip events , such as earthquakes and landslides, substantially modifying their nucleation and propagation and hence their hazard .

『Abstract』The complex life cycle of the malaria parasite Plasmodium falciparum involves several major differentiation stages, each requiring strict control of gene expression. Fundamental changes in chromatin structure and epigenetic modifications during life cycle progression suggest a central role for these mechanisms in regulating the transcriptional program of malaria parasite development . P. falciparum chromatin is distinct from other eukaryotes, with an extraordinarily high AT content (>80%) and highly divergent histones resulting in atypical DNA packaging properties . Moreover, the chromatin remodellers that are critical for shaping chromatin structure are not conserved and are unexplored in P. falciparum . Here we identify P. falciparum Snf2L ( Pf Snf2L, encoded by PF3D7_1104200 ) as an ISWI-related ATPase that actively repositions P. falciparum nucleosomes in vitro. Our results demonstrate that Pf Snf2L is essential, regulating both asexual development and sexual differentiation. Pf Snf2L globally controls just-in-time transcription by spatiotemporally determining nucleosome positioning at the promoters of stage-specific genes. The unique sequence and functional properties of Pf Snf2L led to the identification of an inhibitor that specifically kills P. falciparum and phenocopies the loss of correct gene expression timing. The inhibitor represents a new class of antimalarial transmission-blocking drugs, inhibiting gametocyte formation.

『Abstract』Active systems composed of energy-generating microscopic constituents are a promising platform to create autonomous functional materials that can, for example, locomote through complex and unpredictable environments. Yet coaxing these energy sources into useful mechanical work has proved challenging. Here we engineer active solids based on centimetre-scale building blocks that perform adaptive locomotion. These prototypes exhibit a non-variational form of elasticity characterized by odd moduli , whose magnitude we predict from microscopics using coarse-grained theories and which we validate experimentally. When interacting with an external environment, these active solids spontaneously undergo limit cycles of shape changes, which naturally lead to locomotion such as rolling and crawling. The robustness of the locomotion is rooted in an emergent feedback loop between the active solid and the environment, which is mediated by elastic deformations and stresses. As a result, our active solids are able to accelerate, adjust their gaits and locomote through a variety of terrains with a similar performance to more complex control strategies implemented by neural networks. Our work establishes active solids as a bridge between materials and robots and suggests decentralized strategies to control the nonlinear dynamics of biological systems , soft materials and driven nanomechanical devices .

『Abstract』A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA–lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran (individualized neoantigen vaccine with backbone-optimized uridine mRNA–lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells ( n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells ( n = 8; median RFS 13.4 months; P = 0.007). In responders, autogene cevumeran induces CD8 T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8 T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA–lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.

『Abstract』Global ocean surface temperatures were at record levels for more than a year from April 2023 onwards, exceeding the previous record in 2015–2016 by 0.25 °C on average between April 2023 and March 2024 . The nearly global extent and unprecedented intensity of this event prompted questions about how exceptional it was and whether climate models can represent such record-shattering jumps in surface ocean temperatures . Here we construct observation-based synthetic time series to show that a jump in global sea surface temperatures that breaks the previous record by at least 0.25 °C is a 1-in-512-year event under the current long-term warming trend (1-in-205-year to 1-in-1,185-year event; 95% confidence interval). Without a global warming trend, such an event would have been practically impossible. Using 270 simulations from a wide range of fully coupled climate models, we show that these models successfully simulate such record-shattering jumps in global ocean surface temperatures, underpinning the models’ usefulness in understanding the characteristics, drivers and consequences of such events. These model simulations suggest that the record-shattering jump in surface ocean temperatures in 2023–2024 was an extreme event after which surface ocean temperatures are expected to revert to the expected long-term warming trend.

『Abstract』Entangled photon pairs from spontaneous parametric down-conversion (SPDC) are central to many quantum applications . SPDC is typically performed in non-centrosymmetric systems with an inherent second-order nonlinearity ( χ ) . We demonstrate strong narrowband SPDC with an on-chip rate of 0.8 million pairs per second in Si 3 N 4 . Si 3 N 4 is the pre-eminent material for photonic integration and also exhibits the lowest waveguide loss (which is essential for integrated quantum circuits). However, being amorphous, silicon nitride lacks an intrinsic χ , which limits its role in photonic quantum devices. We enabled SPDC in Si 3 N 4 by combining strong light-field enhancement inside a high optical Q -factor microcavity with an optically induced space-charge field. We present narrowband photon pairs with a high spectral brightness. The quantum nature of the down-converted photon pairs is verified through coincidence measurements. This light source, based on Si 3 N 4 integrated photonics technology, unlocks new avenues for quantum systems on a chip.

『Abstract』Under high electrical current, some materials can emit electromagnetic radiation beyond incandescence. This phenomenon, referred to as electroluminescence, leads to the efficient emission of visible photons and is the basis of domestic lighting devices (for example, light-emitting diodes) . In principle, electroluminescence can lead to mid-infrared emission of confined light–matter excitations called phonon polaritons , resulting from the coupling of photons with crystal lattice vibrations (optical phonons). In particular, phonon polaritons arising in the van der Waals crystal hexagonal boron nitride (hBN) present hyperbolic dispersion, which enhances light–matter coupling . For this reason, electroluminescence of hyperbolic phonon polaritons (HPhPs) has been proposed as an explanation for the peculiar radiative energy transfer within hBN-encapsulated graphene transistors . However, as HPhPs are locally confined, they are inaccessible in the far field, and as such, any hint of electroluminescence has been based on indirect electronic signatures and has yet to be confirmed by direct observation. Here we demonstrate far-field mid-infrared (wavelength approximately 6.5 μm) electroluminescence of HPhPs excited by strongly biased high-mobility graphene within a van der Waals heterostructure, and we quantify the associated radiative energy transfer through the material. The presence of HPhPs is revealed by far-field mid-infrared spectroscopy owing to their elastic scattering at discontinuities in the heterostructure. The resulting radiative flux is quantified by mid-infrared pyrometry of the substrate receiving the energy. This radiative energy transfer is also shown to be reduced in hBN with nanoscale inhomogeneities, demonstrating the central role of the electromagnetic environment in this process.

『Abstract』The breakdown of cellulose is one of the most important reactions in nature and is central to biomass conversion to fuels and chemicals . However, the microfibrillar organization of cellulose and its complex interactions with other components of the plant cell wall poses a major challenge for enzymatic conversion . Here, by mining the metagenomic ‘dark matter’ (unclassified DNA with unknown function) of a microbial community specialized in lignocellulose degradation, we discovered a metalloenzyme that oxidatively cleaves cellulose. This metalloenzyme acts on cellulose through an exo-type mechanism with C1 regioselectivity, resulting exclusively in cellobionic acid as a product. The crystal structure reveals a catalytic copper buried in a compact jelly-roll scaffold that features a flattened cellulose binding site. This metalloenzyme exhibits a homodimeric configuration that enables in situ hydrogen peroxide generation by one subunit while the other is productively interacting with cellulose. The secretome of an engineered strain of the fungus Trichoderma reesei expressing this metalloenzyme boosted the glucose release from pretreated lignocellulosic biomass under industrially relevant conditions, demonstrating its biotechnological potential. This discovery modifies the current understanding of bacterial redox enzymatic systems devoted to overcoming biomass recalcitrance . Furthermore, it enables the conversion of agro-industrial residues into value-added bioproducts, thereby contributing to the transition to a sustainable and bio-based economy.

『Abstract』Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor ( EGFR )-driven lung cancers . We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.

『Abstract』Rates of lineage diversification vary considerably across the tree of life, often as a result of evolutionary innovations . Although the ability to produce new traits can vary between clades and may drive ecological transitions , the impact of differences in the pace at which innovations evolve at macroevolutionary scales has been overlooked. Complex teeth are one innovation that contributed to the evolutionary success of major vertebrate lineages . Here we show that evolutionary lability of tooth complexity, but not complexity itself, spurs rapid diversification across ray-finned fishes. Speciation rates are five times higher when transitions between simple and complex teeth occur rapidly. We find that African cichlids are unique among all fishes; they are dominated by lineages that transition between simple and complex teeth at unparalleled rates. This innovation interacted with the ecological versatility of complex teeth to spur rapid adaptive radiations in lakes Malawi, Victoria and Barombi Mbo. The marked effect on diversification stems from the tight association of tooth complexity with microhabitat and diet. Our results show that phylogenetic variation in how innovations evolve can have a stronger effect on patterns of diversification than the innovation itself. Investigating the impact of innovations from this new perspective will probably implicate more traits in causing heterogeneous diversification rates across the tree of life.

『Abstract』Place cells in the hippocampus and grid cells in the entorhinal cortex are elements of a neural map of self position . For these cells to benefit navigation, their representation must be dynamically related to the surrounding locations . A candidate mechanism for linking places along an animal’s path has been described for place cells, in which the sequence of spikes in each cycle of the hippocampal theta oscillation encodes a trajectory from the animal’s current location towards upcoming locations . In mazes that bifurcate, such trajectories alternately traverse the two upcoming arms when the animal approaches the choice point , raising the possibility that the trajectories express available forward paths encoded on previous trials . However, to bridge the animal’s path with the wider environment, beyond places previously or subsequently visited, an experience-independent spatial sampling mechanism might be required. Here we show in freely moving rats that in individual theta cycles, ensembles of grid cells and place cells encode a position signal that sweeps linearly outwards from the animal’s location into the ambient environment, with sweep direction alternating stereotypically between left and right across successive theta cycles. These sweeps are accompanied by, and aligned with, a similarly alternating directional signal in a discrete population of parasubiculum cells that have putative connections to grid cells via conjunctive grid × direction cells. Sweeps extend into never-visited locations that are inaccessible to the animal. Sweeps persist during REM sleep. The sweep directions can be explained by an algorithm that maximizes the cumulative coverage of the surrounding manifold space. The sustained and unconditional expression of theta-patterned left–right-alternating sweeps in the entorhinal–hippocampal positioning system provides an efficient ‘look around’ mechanism for sampling locations beyond the travelled path.

『Abstract』Educational disparities remain a key contributor to increasing social and wealth inequalities. To address this, researchers and policymakers have focused on average differences between racial groups or differences among students who are falling behind . This focus potentially leads to educational triage, diverting resources away from high-achieving students, including those from racial minorities . Here we focus on the ‘racial excellence gap’—the difference in the likelihood that students from racial minorities (Black and Hispanic) reach the highest levels of academic achievement compared with their non-minority (white and Asian) peers. There is a shortage of evidence that systematically measures the magnitude of the excellence gap and how it evolves . Using longitudinal, statewide, administrative data, we document eight facts regarding the excellence gap from third grade (typically ages 8–9) to high school (typically ages 14–18), link the stability of excellence gaps and student backgrounds, and assess the efficacy of public policies. We show that excellence gaps in maths and reading are evident by the third grade and grow slightly over time, especially for female students. About one third of the gap is explained by a student’s socioeconomic status, and about one tenth is explained by the school environment. Top-achieving racial minority students are also less likely to persist in excellence as they progress through school. Moreover, state accountability policies that direct additional resources to reduce non-race-based inequality had minimal effects on the racial excellence gaps. Documenting these patterns is an important step towards eliminating excellence gaps and removing the ‘racial glass ceiling’.

『Abstract』Cosmic reionization began when ultraviolet (UV) radiation produced in the first galaxies began illuminating the cold, neutral gas that filled the primordial Universe . Recent James Webb Space Telescope (JWST) observations have shown that surprisingly UV-bright galaxies were in place beyond redshift z = 14, when the Universe was less than 300 Myr old . Smooth turnovers of their UV continua have been interpreted as damping-wing absorption of Lyman-α (Ly-α), the principal hydrogen transition . However, spectral signatures encoding crucial properties of these sources, such as their emergent radiation field, largely remain elusive. Here we report spectroscopy from the JWST Advanced Deep Extragalactic Survey (JADES ) of a galaxy at redshift z = 13.0 that reveals a singular, bright emission line unambiguously identified as Ly-α, as well as a smooth turnover. We observe an equivalent width of EW Ly-α > 40 Å (rest frame), previously only seen at z < 9 where the intervening intergalactic medium becomes increasingly ionized . Together with an extremely blue UV continuum, the unexpected Ly-α emission indicates that the galaxy is a prolific producer and leaker of ionizing photons. This suggests that massive, hot stars or an active galactic nucleus have created an early reionized region to prevent complete extinction of Ly-α, thus shedding new light on the nature of the earliest galaxies and the onset of reionization only 330 Myr after the Big Bang.