经典100 | NCS： 2025-05-12 期

『Abstract』Volcanic hotspots are thought to form by melting in an upwelling mantle plume head followed by melting of the plume tail. Plate motion then generates an age-progressive volcanic track originating from a large igneous province to a currently active hotspot. The most voluminous large igneous province, the approximately 120-million-year-old Ontong Java Nui Plateau (OJP-Nui) in the mid-Pacific, however, lacks an obvious volcanic track. Although the Louisville hotspot track was originally proposed as a candidate, limited constraints for Pacific absolute plate and plume motion before 80 million years ago (Ma) suggest a mismatch . Existing Pacific models rely on age–distance data from the continuous Hawai‘i–Emperor and Louisville tracks, but their tracks older than approximately 80 Ma are subducted. Elsewhere on the Pacific Plate, only discontinuous seamount tracks that formed before 80 Ma are documented . Currently, models require approximately 1,200 kilometres of latitudinal motion to link the Louisville plume to the OJP-Nui , but palaeolatitude estimates from about 70 Ma to today remain within error of its present location , suggesting that any substantial Louisville plume motion occurred earlier. Here, through a combination of geochemistry and geochronology , we demonstrate that Samoa and Rurutu–Arago are the longest-lived Pacific hotspots, traceable to more than 100 Ma before subducting into the Mariana Trench. These tracks better constrain plate rotation between 80 Ma and 100 Ma, allowing us to update Pacific absolute plate motion models and link the Louisville volcanic track to OJP-Nui without requiring major plume motion.

『Abstract』Abstract We present results from a randomized controlled trial in Bangladesh that introduced operational practices to improve energy efficiency and reduce emissions in 276 “zigzag” brick kilns. Of all intervention kilns, 65% adopted the improved practices. Treatment assignment reduced energy use by 10.5% ( P -value <0.001) and decreased CO 2 and PM 2.5 emissions by 171 and 0.45 metric tons, respectively, per kiln per year. Valuing the CO 2 reductions using a social cost of carbon of 185 USD per metric ton, we find that the social benefits outweigh costs by a factor of 65 to 1. The intervention, which required no new capital investment, also decreased fuel costs and increased brick quality. Our results demonstrate the potential for privately profitable, as well as publicly beneficial, improvements to address environmental problems in informal industries.

『Abstract』Abstract Integrons are genetic systems that drive bacterial adaptation by acquiring, expressing, and shuffling gene cassettes. While mobile integrons are well known for spreading antibiotic resistance genes, the functions of the hundreds of cassettes carried by sedentary integrons remain largely unexplored. We show that many of these cassettes encode small variants of known antiphage systems that favor their inclusion in the integron. We also demonstrate that nearly 10% of the integron cassettes in the pandemic Vibrio cholerae strain encode novel antiphage functions. Most of these novel systems have little or no similarity to previously known ones, with several providing defense through cell lysis or growth arrest. Our work highlights the stabilization and prevalence of small antiphage systems within integrons, making them an untapped biobank of defense mechanisms.

『Abstract』Abstract Three-dimensional printing offers promise for patient-specific implants and therapies but is often limited by the need for invasive surgical procedures. To address this, we developed an imaging-guided deep tissue in vivo sound printing (DISP) platform. By incorporating cross-linking agent–loaded low-temperature–sensitive liposomes into bioinks, DISP enables precise, rapid, on-demand cross-linking of diverse functional biomaterials using focused ultrasound. Gas vesicle–based ultrasound imaging provides real-time monitoring and allows for customized pattern creation in live animals. We validated DISP by successfully printing near diseased areas in the mouse bladder and deep within rabbit leg muscles in vivo, demonstrating its potential for localized drug delivery and tissue replacement. DISP’s ability to print conductive, drug-loaded, cell-laden, and bioadhesive biomaterials demonstrates its versatility for diverse biomedical applications.

『Abstract』Recent evidence has shown that increased levels of circulating long-chain ceramides predict atherosclerotic cardiovascular disease independently of cholesterol . Although targeting ceramide signalling may provide therapeutic benefits beyond the treatment of hypercholesterolaemia, the underlying mechanism by which circulating ceramides aggravate atherosclerotic cardiovascular disease remains elusive. Here we examine whether circulating long-chain ceramides activate membrane G-protein-coupled receptors to exacerbate atherosclerosis. We perform a systematic screen that combines G-protein-signalling quantification, bioinformatic analysis of G-protein-coupled receptor expression and functional examination of NLRP3 inflammasome activation. The results suggest that CYSLTR2 and P2RY6 are potential endogenous receptors of C16:0 ceramide-induced inflammasome activation in both endothelial cells and macrophages. Inhibition of CYSLTR2 and P2RY6 genetically or pharmacologically alleviates ceramide-induced atherosclerosis aggravation. Moreover, increased ceramide levels correlate with the severity of coronary artery disease in patients with varying degrees of renal impairment. Notably, CYSLTR2 and P2RY6 deficiency mitigates chronic-kidney-disease-aggravated atherosclerosis in mice without affecting cholesterol or ceramide levels. Structural analyses of ceramide–CYSLTR2–G q complexes reveal that both C16:0 and C20:0 ceramides bind in an inclined channel-like ligand-binding pocket on CYSLTR2. We further reveal an unconventional mechanism underlying ceramide-induced CYSLTR2 activation and the CYSLTR2–G q interface. Overall, our study provides structural and molecular mechanisms of how long-chain ceramides initiate transmembrane G q and inflammasome signalling through direct binding to CYSLTR2 and P2RY6 receptors. Therefore, blocking these signals may provide a new therapeutic potential to treat atherosclerosis-related diseases.

『Abstract』Human activities drive a wide range of environmental pressures, including habitat change, pollution and climate change, resulting in unprecedented effects on biodiversity . However, despite decades of research, generalizations on the dimensions and extent of human impacts on biodiversity remain ambiguous. Mixed views persist on the trajectory of biodiversity at the local scale and even more so on the biotic homogenization of biodiversity across space . We compiled 2,133 publications covering 97,783 impacted and reference sites, creating an unparallelled dataset of 3,667 independent comparisons of biodiversity impacts across all main organismal groups, habitats and the five most predominant human pressures . For all comparisons, we quantified three key measures of biodiversity to assess how these human pressures drive homogenization and shifts in composition of biological communities across space and changes in local diversity, respectively. We show that human pressures distinctly shift community composition and decrease local diversity across terrestrial, freshwater and marine ecosystems. Yet, contrary to long-standing expectations, there is no clear general homogenization of communities. Critically, the direction and magnitude of biodiversity changes vary across pressures, organisms and scales at which they are studied. Our exhaustive global analysis reveals the general impact and key mediating factors of human pressures on biodiversity and can benchmark conservation strategies.

『Abstract』The most dynamic and repetitive regions of great ape genomes have traditionally been excluded from comparative studies . Consequently, our understanding of the evolution of our species is incomplete. Here we present haplotype-resolved reference genomes and comparative analyses of six ape species: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang. We achieve chromosome-level contiguity with substantial sequence accuracy (<1 error in 2.7 megabases) and completely sequence 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, to provide in-depth evolutionary insights. Comparative analyses enabled investigations of the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference genome. Such regions include newly minted gene families in lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes and subterminal heterochromatin. This resource serves as a comprehensive baseline for future evolutionary studies of humans and our closest living ape relatives.

『Abstract』The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis . FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections . The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP–DH and ACP–ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics.

『Abstract』Beneath oceanic spreading centres, the lithosphere–asthenosphere boundary (LAB) acts as a permeability barrier that focuses the delivery of melt from deep within the mantle towards the spreading axis . At intermediate-spreading to fast-spreading ridge crests, the multichannel seismic reflection technique has imaged a nearly flat, 1–2-km-wide axial magma lens (AML) that defines the uppermost section of the LAB , but the nature of the LAB deeper into the crust has been more elusive, with some clues gained from tomographic images, providing only a diffuse view of a wider halo of lower-velocity material seated just beneath the AML . Here we present 3D seismic reflection images of the LAB extending deep (5–6 km) into the crust beneath Axial volcano, located at the intersection of the Juan de Fuca Ridge and the Cobb–Eickelberg hotspot. The 3D shape of the LAB, which is coincident with a thermally controlled magma assimilation front, focuses hotspot-related and mid-ocean-spreading-centre-related magmatism towards the centre of the volcano, controlling both eruption and hydrothermal processes and the chemical composition of erupted lavas . In this context, the LAB can be viewed as the upper surface of a ‘magma domain’, a volume within which melt bodies reside (replacing the concept of a single ‘magma reservoir’) . Our discovery of a funnel-shaped, crustal LAB suggests that thermally controlled magma assimilation could be occurring along this surface at other volcanic systems, such as Iceland.

『Abstract』Abstract The two-dimensional on three-dimensional (2D/3D) perovskite bilayer heterostructure can improve the stability and performance of perovskite solar cells. We show that the 2D/3D perovskite stack in a device evolves dynamically during its end-of-life decomposition. Initially phase-pure 2D interlayers can evolve differently, resulting in different device stabilities. We show that a robust 2D interlayer can be formed using mixed solvents to regulate its crystallinity and phase purity. The resulting 2D/3D devices achieved 25.9% efficiency and had good durability, retaining 91% of their initial performance after 1074 hours at 85°C using maximum power point tracking.

『Abstract』Nickel is a critical element in the shift to sustainable energy systems, with the demand for nickel projected to exceed 6 million tons annually by 2040 , largely driven by the electrification of the transport sector. Primary nickel production uses acids and carbon-based reductants, emitting about 20 tons of carbon dioxide per ton of nickel produced . Here we present a method using fossil-free hydrogen-plasma-based reduction to extract nickel from low-grade ore variants known as laterites. We bypass the traditional multistep process and combine calcination, smelting, reduction and refining into a single metallurgical step conducted in one furnace. This approach produces high-grade ferronickel alloys at fast reduction kinetics. Thermodynamic control of the atmosphere of the furnace enables selective nickel reduction, yielding an alloy with minimal impurities (<0.04 wt% silicon, approximately 0.01 wt% phosphorus and <0.09 wt% calcium), eliminating the need for further refining. The proposed method has the potential to be up to about 18% more energy efficient while cutting direct carbon dioxide emissions by up to 84% compared with current practice. Our work thus shows a sustainable approach to help resolve the contradiction between the beneficial use of nickel in sustainable energy technologies and the environmental harm caused by its production.

『Abstract』Metal-halide perovskites are promising light-emitter candidates for next-generation light-emitting diodes (LEDs) . Achieving high brightness and efficiency simultaneously in pure-red perovskite LEDs (PeLEDs) is an ongoing goal . Three-dimensional (3D) CsPbI 3- x Br x emitters have excellent carrier transport capability and high colour purity, which could allow efficient and ultrabright pure-red PeLEDs. However, such devices are prone to efficiency roll-off, resulting in low efficiency and low brightness under high current density. Here, by using electrically excited transient absorption spectroscopy, we discovered the efficiency roll-off was induced by hole leakage. Therefore, we developed a CsPbI 3- x Br x intragrain heterostructure containing narrow bandgap emitters and wide bandgap barriers to confine the injected carriers. The wide bandgap barrier was incorporated by introducing strongly bonding molecules into the [PbX 6 ] framework to expand the 3D CsPbI 3- x Br x lattice. This strategy resulted in bright and efficient pure-red PeLEDs, with a high brightness of 24,600 cd m , maximum external quantum efficiency of 24.2% and low efficiency roll-off, maintaining a 10.5% external quantum efficiency at a high luminance of 22,670 cd m .

『Abstract』Hydrogen embrittlement (HE) impairs the durability of aluminium (Al) alloys and hinders their use in a hydrogen economy . Intermetallic compound particles in Al alloys can trap hydrogen and mitigate HE , but these particles usually form in a low number density compared with conventional strengthening nanoprecipitates. Here we report a size-sieved complex precipitation in Sc-added Al–Mg alloys to achieve a high-density dispersion of both fine Al 3 Sc nanoprecipitates and in situ formed core-shell Al 3 (Mg, Sc) 2 /Al 3 Sc nanophases with high hydrogen-trapping ability. The two-step heat treatment induces heterogeneous nucleation of the Samson-phase Al 3 (Mg, Sc) 2 on the surface of Al 3 Sc nanoprecipitates that are only above 10 nm in size. The size dependence is associated with Al 3 Sc nanoprecipitate incoherency, which leads to local segregation of magnesium and triggers the formation of Al 3 (Mg, Sc) 2 . The tailored distribution of dual nanoprecipitates in our Al–Mg–Sc alloy provides about a 40% increase in strength and nearly five times improved HE resistance compared with the Sc-free alloy, reaching a record tensile uniform elongation in Al alloys charged with H up to 7 ppmw. We apply this strategy to other Al–Mg-based alloys, such as Al–Mg–Ti–Zr, Al–Mg–Cu–Sc and Al–Mg–Zn–Sc alloys. Our work showcases a possible route to increase hydrogen resistance in high-strength Al alloys and could be readily adapted to large-scale industrial production.

『Abstract』Human RAD52 is a multifunctional DNA repair protein involved in several cellular events that support genome stability, including protection of stalled DNA replication forks from excessive degradation . In its gatekeeper role, RAD52 binds to and stabilizes stalled replication forks during replication stress, protecting them from reversal by SMARCAL1 motor . The structural and molecular mechanism of the RAD52-mediated fork protection remains elusive. Here, using P1 nuclease sensitivity, biochemical and single-molecule analyses, we show that RAD52 dynamically remodels replication forks through its strand exchange activity. The presence of the single-stranded DNA binding protein RPA at the fork modulates the kinetics of the strand exchange without impeding the reaction outcome. Mass photometry and single-particle cryo-electron microscopy show that the replication fork promotes a unique nucleoprotein structure containing head-to-head arrangement of two undecameric RAD52 rings with an extended positively charged surface that accommodates all three arms of the replication fork. We propose that the formation and continuity of this surface is important for the strand exchange reaction and for competition with SMARCAL1.

『Abstract』Lymphatic capillaries continuously take up interstitial fluid and adapt to resulting changes in vessel calibre . The mechanisms by which the permeable monolayer of loosely connected lymphatic endothelial cells (LECs) maintains mechanical stability remain elusive. Here we identify dynamic cytoskeletal regulation of LEC shape, induced by isotropic stretch, as crucial for the integrity and function of dermal lymphatic capillaries. We found that the oak leaf-shaped LECs showed a spectrum of VE-cadherin-based junctional configurations at the lobular intercellular interface and a unique cytoskeletal organization, with microtubules at concave regions and F-actin at convex lobes. Multispectral and longitudinal intravital imaging of capillary LEC shape and actin revealed dynamic remodelling of cellular overlaps in vivo during homeostasis and in response to interstitial fluid volume increase. Akin to puzzle cells of the plant epidermis , LEC shape was controlled by Rho GTPase CDC42-regulated cytoskeletal dynamics, enhancing monolayer stability. Moreover, cyclic isotropic stretch increased cellular overlaps and junction curvature in primary LECs. Our findings indicate that capillary LEC shape results from continuous remodelling of cellular overlaps that maintain vessel integrity while preserving permeable cell–cell contacts compatible with vessel expansion and fluid uptake. We propose a bellows-like fluid propulsion mechanism, in which fluid-induced lumen expansion and shrinkage of LEC overlaps are countered by actin-based lamellipodia-like overlap extension to aid vessel constriction.

『Abstract』Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders . As a key modulator of brain homeostasis , it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.

『Abstract』In the course of antibody affinity maturation, germinal centre (GC) B cells mutate their immunoglobulin heavy- and light-chain genes in a process known as somatic hypermutation (SHM) . Panels of mutant B cells with different binding affinities for antigens are then selected in a Darwinian manner, which leads to a progressive increase in affinity among the population . As with any Darwinian process, rare gain-of-fitness mutations must be identified and common loss-of-fitness mutations avoided . Progressive acquisition of mutations therefore poses a risk during large proliferative bursts , when GC B cells undergo several cell cycles in the absence of affinity-based selection . Using a combination of in vivo mouse experiments and mathematical modelling, here we show that GCs achieve this balance by strongly suppressing SHM during clonal-burst-type expansion, so that a large fraction of the progeny generated by these bursts does not deviate from their ancestral genotype. Intravital imaging and image-based cell sorting of a mouse strain carrying a reporter of cyclin-dependent kinase 2 (CDK2) activity showed that B cells that are actively undergoing proliferative bursts lack the transient CDK2 ‘G0-like’ phase of the cell cycle in which SHM takes place. We propose a model in which inertially cycling B cells mostly delay SHM until the G0-like phase that follows their final round of division in the GC dark zone, thus maintaining affinity as they clonally expand in the absence of selection.

『Abstract』Abstract Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I–bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor–redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.

『Abstract』Germinal centres are specialized microenvironments where B cells undergo affinity maturation. B cells expressing antibodies whose affinity is improved by somatic hypermutation are selected for expansion by limiting numbers of T follicular helper cells. Cell division is accompanied by mutation of the immunoglobulin genes, at what is believed to be a fixed rate of around 1 × 10 per base pair per cell division . As mutagenesis is random, the probability of acquiring deleterious mutations outweighs the probability of acquiring affinity-enhancing mutations. This effect might be heightened, and even become counterproductive, in B cells that express high-affinity antibodies and undergo the greatest number of cell divisions . Here we experimentally examine a theoretical model that explains how affinity maturation could be optimized by varying the rate of somatic hypermutation such that cells that express higher-affinity antibodies divide more but mutate less per division. Data obtained from mice immunized with SARS-CoV-2 vaccines or a model antigen align with the theoretical model and show that cells producing high-affinity antibodies shorten the G0/G1 phases of the cell cycle and reduce their mutation rates. We propose that these mechanisms safeguard high-affinity B cell lineages and enhance the outcomes of antibody affinity maturation.

『Abstract』Climate extremes are escalating under anthropogenic climate change . Yet, how this translates into unprecedented cumulative extreme event exposure in a person’s lifetime remains unclear. Here we use climate models, impact models and demographic data to project the number of people experiencing cumulative lifetime exposure to climate extremes above the 99.99th percentile of exposure expected in a pre-industrial climate. We project that the birth cohort fraction facing this unprecedented lifetime exposure to heatwaves, crop failures, river floods, droughts, wildfires and tropical cyclones will at least double from 1960 to 2020 under current mitigation policies aligned with a global warming pathway reaching 2.7 °C above pre-industrial temperatures by 2100. Under a 1.5 °C pathway, 52% of people born in 2020 will experience unprecedented lifetime exposure to heatwaves. If global warming reaches 3.5 °C by 2100, this fraction rises to 92% for heatwaves, 29% for crop failures and 14% for river floods. The chance of facing unprecedented lifetime exposure to heatwaves is substantially larger among population groups characterized by high socioeconomic vulnerabilities. Our results call for deep and sustained greenhouse gas emissions reductions to lower the burden of climate change on current young generations.

『Abstract』Fast excitatory neurotransmission in the mammalian brain is mediated by cation-selective AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (AMPARs) . AMPARs are critical for the learning and memory mechanisms of Hebbian plasticity and glutamatergic synapse homeostasis , with recent work establishing that AMPAR missense mutations can cause autism and intellectual disability . AMPARs have been grouped into two functionally distinct tetrameric assemblies based on the inclusion or exclusion of the GluA2 subunit that determines Ca permeability through RNA editing . GluA2-containing AMPARs are the most abundant in the central nervous system and considered to be Ca impermeable . Here we show this is not the case. Contrary to conventional understanding, GluA2-containing AMPARs form a continuum of polyamine-insensitive ion channels with varying degrees of Ca permeability. Their ability to transport Ca is shaped by the subunit composition of AMPAR tetramers as well as the spatial orientation of transmembrane AMPAR regulatory proteins and cornichon auxiliary subunits. Ca crosses the ion-conduction pathway by docking to an extracellular binding site that helps funnel divalent ions into the pore selectivity filter. The dynamic range in Ca permeability, however, arises because auxiliary subunits primarily modify the selectivity filter. Taken together, our work proposes a broader role for AMPARs in Ca signalling in the mammalian brain and offers mechanistic insight into the pathogenic nature of missense mutations.

『Abstract』Abstract Size and shape are critical discriminators between molecular species and states. We describe a microchip-based high-throughput imaging approach offering rapid and precise determination of molecular properties under native solution conditions. Our method detects differences in molecular weight across at least three orders of magnitude and down to two carbon atoms in small molecules. We quantify the strength of molecular interactions across more than six orders of magnitude in affinity constant and track reactions in real time. Highly parallel measurements on individual molecules serve to characterize sample-state heterogeneity at the highest resolution, offering predictive input to model three-dimensional structure. We further leverage the method’s structural sensitivity for diagnostics, exploiting ligand-induced conformational changes in the insulin receptor to sense insulin concentration in serum at the subnanoliter and subzeptomole scale.

『Abstract』The preference for a particular thermal range is a key determinant of the distribution of animal species. However, we know little on how temperature preference behaviour evolves during the colonization of new environments. Here we show that at least two distinct neurobiological mechanisms drive the evolution of temperature preference in flies of the genus Drosophila . Fly species from mild climates ( D. melanogaster and D. persimilis ) avoid both innocuous and noxious heat, and we show that the thermal activation threshold of the molecular heat receptor Gr28b.d precisely matches species-specific thresholds of behavioural heat avoidance. We find that desert-dwelling D. mojavensis are instead actively attracted to innocuous heat. Notably, heat attraction is also mediated by Gr28b.d (and by the antennal neurons that express it) and matches its threshold of heat activation. Rather, the switch in valence from heat aversion to attraction correlates with specific changes in thermosensory input to the lateral horn, the main target of central thermosensory pathways and a region of the fly brain implicated in the processing of innate valence . Together, our results demonstrate that, in Drosophila , the adaptation to different thermal niches involves changes in thermal preference behaviour, and that this can be accomplished using distinct neurobiological solutions, ranging from shifts in the activation threshold of peripheral thermosensory receptor proteins to a substantial change in the way temperature valence is processed in the brain.

『Abstract』Abstract Animals achieve robust locomotion by offloading regulation from the brain to physical couplings within the body. In contrast, locomotion in artificial systems often depends on centralized processors. Here, we introduce a rapid and autonomous locomotion strategy with synchronized gaits emerging through physical interactions between self-oscillating limbs and the environment, without control signals. Each limb is a single soft tube that only requires a constant flow of air to perform cyclic stepping motions at frequencies reaching 300 hertz. Physical synchronization of several of these self-oscillating limbs enables locomotion speeds that are orders of magnitude faster than those of comparable state-of-the-art robots. Through body-environment dynamics, these seemingly simple devices exhibit autonomy, including obstacle avoidance, amphibious gait transitions, and phototaxis.

『Abstract』Abstract Saturated heterocycles are commonly adorned with groups that influence their biological properties. Synthetic methods that transpose existing substituents on saturated heterocycles to multiple peripheral positions are therefore highly valuable. In this work, we report a formal 1,2-acyl transposition through the photochemical exchange of the C 2 –C 3 positions of C 2 -acylated dihydrobenzofurans. This strategy relies on an unusual photochemical isomerization of the dihydrobenzofuran core to a highly electrophilic spiro-cyclopropane intermediate that is then intercepted by a halide nucleophile. A variety of aryl ketones are transposed using 370-nanometer centered irradiation. Additionally, carboxylic acids, esters, and amides can be transposed using 310-nanometer centered irradiation. This work highlights the power of a skeletal rearrangement to achieve a net peripheral modification.

『Abstract』Abstract The Cambrian evolutionary radiation is noted for its profusion of bizarre and unfamiliar body forms, many of which illuminate the early ancestry of major animal groups. The spine-covered fossil Shishania aculeata (Cambrian Stage 4, Yunnan, China) has been interpreted as intermediate between mollusks and their lophotrochozoan ancestors. Our new material challenges this interpretation. We propose taphonomic explanations for apparent molluscan features and instead identify prominent anatomical similarities to coeval chancelloriids from nearby strata. Our reinterpretation of Shishania as an early-diverging chancelloriid helps to consolidate a model for the early evolution of this enduringly problematic group of sponge-like metazoans.

『Abstract』Neurotropic herpesviruses may be implicated in the development of dementia . Moreover, vaccines may have important off-target immunological effects . Here we aim to determine the effect of live-attenuated herpes zoster vaccination on the occurrence of dementia diagnoses. To provide causal as opposed to correlational evidence, we take advantage of the fact that, in Wales, eligibility for the zoster vaccine was determined on the basis of an individual’s exact date of birth. Those born before 2 September 1933 were ineligible and remained ineligible for life, whereas those born on or after 2 September 1933 were eligible for at least 1 year to receive the vaccine. Using large-scale electronic health record data, we first show that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely 1 week too old to be eligible, to 47.2% among those who were just 1 week younger. Apart from this large difference in the probability of ever receiving the zoster vaccine, individuals born just 1 week before 2 September 1933 are unlikely to differ systematically from those born 1 week later. Using these comparison groups in a regression discontinuity design, we show that receiving the zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of 7 years by 3.5 percentage points (95% confidence interval (CI) = 0.6–7.1, P = 0.019), corresponding to a 20.0% (95% CI = 6.5–33.4) relative reduction. This protective effect was stronger among women than men. We successfully confirm our findings in a different population (England and Wales’s combined population), with a different type of data (death certificates) and using an outcome (deaths with dementia as primary cause) that is closely related to dementia, but less reliant on a timely diagnosis of dementia by the healthcare system . Through the use of a unique natural experiment, this study provides evidence of a dementia-preventing or dementia-delaying effect from zoster vaccination that is less vulnerable to confounding and bias than the existing associational evidence.

『Abstract』Abstract Skyrmions in noncentrosymmetric materials are believed to occur due to the Dzyaloshinskii-Moriya interaction. By contrast, the skyrmion formation mechanism in centrosymmetric materials remains elusive. Here, we reveal the intrinsic electronic structure of the centrosymmetric GdRu 2 Si 2 by selectively measuring magnetic domains using angle-resolved photoemission spectroscopy (ARPES). We found robust Fermi surface (FS) nesting, consistent with the magnetic modulation q -vector detected by the previous resonant x-ray scattering measurements. The pseudogap opens at the nested FS portions, which vary for different magnetic domains. The anomalous pseudogap disconnects the FS to generate Fermi arcs with twofold symmetry. These results indicate that the Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction plays a decisive role in generating the screw spin modulation responsible for the skyrmion formation in GdRu 2 Si 2 . Furthermore, we demonstrate the flexible nature of magnetism in GdRu 2 Si 2 by manipulating magnetic domains with magnetic field and temperature cyclings, providing potential future applications for data storage and processing devices.

『Abstract』Nuclear fission leads to the splitting of a nucleus into two fragments . Studying the distribution of the masses and charges of the fragments is essential for establishing the fission mechanisms and refining the theoretical models . It has value for our understanding of r-process nucleosynthesis , in which the fission of nuclei with extreme neutron-to-proton ratios is pivotal for determining astrophysical abundances and understanding the origin of the elements and for energy applications . Although the asymmetric distribution of fragments is well understood for actinides (elements in the periodic table with atomic numbers from 89 to 103) based on shell effects , symmetric fission governs the scission process for lighter elements. However, unexpected asymmetric splits have been observed in neutron-deficient exotic nuclei , prompting extensive further investigations. Here we present measurements of the charge distributions of fission fragments for 100 exotic fissioning systems, 75 of which have never been measured, and establish a connection between the neutron-deficient sub-lead region and the well-understood actinide region. These new data comprehensively map the asymmetric fission island and provide clear evidence for the role played by the deformed Z = 36 proton shell of the light fragment in the fission of sub-lead nuclei. Our dataset will help constrain the fission models used to estimate the fission properties of nuclei with extreme neutron-to-proton ratios for which experimental data are unavailable.

『Abstract』Long-chain fatty acids are the building blocks of fat in human bodies. In mammals, fatty acid synthase (FASN) contains multiple enzymatic domains to catalyse all chemical reactions needed for de novo fatty acid synthesis . Although the chemical reactions carried out by these enzymatic domains are well defined, how the dimeric FASN with an open architecture continuously catalyses such reactions to synthesize a complete fatty acid remains elusive. Here, using a strategy of tagging and purifying endogenous FASN in HEK293T cells for single-particle cryo-electron microscopy studies, we characterized the structural dynamics of endogenous human FASN. We captured conformational snapshots of various functional substates in the condensing cycle and developed a procedure to analyse the particle distribution landscape of FASN with different orientations between its condensing and modifying wings. Together, our findings reveal that FASN function does not require a large rotational motion between its two main functional domains during the condensing cycle, and that the catalytic reactions in the condensing cycle carried out by the two monomers are unsynchronized. Our data thus provide a new composite view of FASN dynamics during the fatty acid synthesis condensing cycle.

『Abstract』Abstract Repeated ketamine treatment to maintain a rapid antidepressant effect can lead to side effects over time, highlighting an unmet clinical need for sustaining this drug’s antidepressant action from a single administration. Ketamine-induced synaptic potentiation at CA3-CA1 synapses has been proposed to be a key synaptic substrate for antidepressant action. Here, we found that ketamine-induced CA3-CA1 synaptic potentiation could be augmented by transiently increasing extracellular signal–regulated kinase (ERK) activity through pharmacological inhibition of dual-specificity phosphatases 6 (DUSP6). The antidepressant-like behavioral effects of acute ketamine treatment were extended by DUSP6 inhibition for up to 2 months. The selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons abolished these DUSP6 inhibition–mediated synaptic and behavioral effects. These data suggest that ketamine’s rapid antidepressant effects can be sustained by selectively targeting downstream intracellular signaling.

『Abstract』Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained . We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele . Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.

『Abstract』Accumulating evidence indicates that antibiotic exposure may lead to impaired vaccine responses ; however, the mechanisms underlying this association remain poorly understood. Here we prospectively followed 191 healthy, vaginally born, term infants from birth to 15 months, using a systems vaccinology approach to assess the effects of antibiotic exposure on immune responses to vaccination. Exposure to direct neonatal but not intrapartum antibiotics was associated with significantly lower antibody titres against various polysaccharides in the 13-valent pneumococcal conjugate vaccine and the Haemophilus influenzae type b polyribosylribitol phosphate and diphtheria toxoid antigens in the combined 6-in-1 Infanrix Hexa vaccine at 7 months of age. Blood from infants exposed to neonatal antibiotics had an inflammatory transcriptional profile before vaccination; in addition, faecal metagenomics showed reduced abundance of Bifidobacterium species in these infants at the time of vaccination, which was correlated with reduced vaccine antibody titres 6 months later. In preclinical models, responses to the 13-valent pneumococcal conjugate vaccine were strongly dependent on an intact microbiota but could be restored in germ-free mice by administering a consortium of Bifidobacterium species or a probiotic already widely used in neonatal units. Our data suggest that microbiota-targeted interventions could mitigate the detrimental effects of early-life antibiotics on vaccine immunogenicity.

『Abstract』The coupling between electrons and phonons is one of the fundamental interactions in solids, underpinning a wide range of phenomena, such as resistivity, heat conductivity and superconductivity. However, direct measurements of this coupling for individual phonon modes remain a substantial challenge. In this work, we introduce a new technique for mapping phonon dispersions and electron–phonon coupling (EPC) in van der Waals (vdW) materials. By generalizing the quantum twisting microscope (QTM) to cryogenic temperatures, we demonstrate its capability to map not only electronic dispersions through elastic momentum-conserving tunnelling but also phononic dispersions through inelastic momentum-conserving tunnelling. Crucially, the inelastic tunnelling strength provides a direct and quantitative measure of the momentum and mode-resolved EPC. We use this technique to measure the phonon spectrum and EPC of twisted bilayer graphene (TBG) with twist angles larger than 6°. Notably, we find that, unlike standard acoustic phonons, whose coupling to electrons diminishes as their momentum tends to zero, TBG exhibits a low-energy mode whose coupling increases with decreasing twist angle. We show that this unusual coupling arises from the modulation of the interlayer tunnelling by a layer-antisymmetric ‘phason’ mode of the moire system. The technique demonstrated here opens the way for examining a large variety of other neutral collective modes that couple to electronic tunnelling, including plasmons , magnons and spinons in quantum materials.

『Abstract』Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments . Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity , offering a potential therapeutic option. Here we present the results of a multicentre phase 1 clinical trial evaluating VG161, an engineered oncolytic herpes simplex virus that expresses IL-12, IL-15, IL-15Rα and a PD-1–PD-L1-blocking fusion protein , for safety and efficacy in patients with advanced liver cancer. VG161 was well tolerated, with no dose-limiting toxicities observed, and it demonstrated promising efficacy by reshaping the tumour immune microenvironment and re-sensitizing tumours that were previously resistant to systemic treatments. Notably, we also found that patients who had previously been sensitive to checkpoint inhibitor therapy showed enhanced efficacy with VG161 treatment. Furthermore, we developed an efficacy-prediction model based on differentially expressed genes, which successfully identified patients who were likely to benefit from VG161 and predicted prolonged overall survival. These findings position VG161 as a promising third-line therapeutic option for refractory hepatocellular carcinoma. This provides a new avenue for treatment and advances the field of oncolytic virus-based immunotherapies. ClinicalTrials.gov registration: NCT04806464 .