前沿速递 | NCS 集萃：2025-03-03 期

『Abstract』Abstract Inferring cellular and molecular dynamics of multiple sclerosis (MS) lesions from postmortem tissue collected decades after onset is challenging. Using magnetic resonance image (MRI)–guided spatiotemporal RNA profiling in marmoset experimental autoimmune encephalitis (EAE), we mapped lesion dynamics and modeled molecular perturbations relevant to MS. Five distinct lesion microenvironments emerged, involving neuroglial responses, tissue destruction and repair, and brain border regulation. Before demyelination, MRI identified a high ratio of proton density–weighted signal to T 1 relaxation time, capturing early hypercellularity, and elevated astrocytic and ependymal senescence signals marked perivascular and periventricular areas that later became demyelination hotspots. As lesions expanded, concentric glial barriers formed, initially dominated by proliferating and diversifying microglia and oligodendrocyte precursors, later replaced by monocytes and lymphocytes. We highlight SERPINE1 astrocytes as a signaling hub underlying lesion onset in both marmoset EAE and MS.

『Abstract』Abstract Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction–associated fatty liver disease (MAFLD). This study identifies alkylation repair homolog protein 5 (ALKBH5), an RNA N -methyladenosine (m A) demethylase, as a major regulator in metabolic disease. ALKBH5 is up-regulated in the liver during obesity and also phosphorylated by protein kinase A, causing its translocation to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the glucagon receptor (GCGR) and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Targeted knockdown of hepatic Alkbh5 reverses T2DM and MAFLD in diabetic mice, highlighting its therapeutic potential. This study unveils a regulatory mechanism wherein ALKBH5 orchestrates glucose and lipid homeostasis by integrating the GCGR and mTORC1 pathways, providing insight into the regulation of metabolic diseases.

『Abstract』Abstract Although the dynamics of collisions between a molecule and a solid surface are ultimately quantum mechanical, decohering effects owing to the large number of interacting degrees of freedom typically obscure the wavelike nature of these events. However, a partial decoupling of internal molecular motion from external degrees of freedom can reveal striking interference effects despite significant momentum exchange between the molecule and the bath of surface vibrations. We report state-prepared and state-resolved measurements of methane scattering from a room-temperature gold surface that demonstrate total destructive interference between molecular states related by a reflection symmetry operation. High-contrast interference effects prevail for all processes investigated, including vibrationally excited and vibrationally inelastic collisions. The results demonstrate the distinctly quantum mechanical effect of discrete symmetries in molecular collision dynamics.

『Abstract』Abstract Materials functionalities may be associated with atomic-level structural dynamics occurring on the millisecond timescale. However, the capability of electron microscopy to image structures with high spatial resolution and millisecond temporal resolution is often limited by poor signal-to-noise ratios. With an unsupervised deep denoising framework, we observed metal nanoparticle surfaces (platinum nanoparticles on cerium oxide) in a gas environment with time resolutions down to 10 milliseconds at a moderate electron dose. On this timescale, many nanoparticle surfaces continuously transition between ordered and disordered configurations. Stress fields can penetrate below the surface, leading to defect formation and destabilization, thus making the nanoparticle fluxional. Combining this unsupervised denoiser with in situ electron microscopy greatly improves spatiotemporal characterization, opening a new window for the exploration of atomic-level structural dynamics in materials.

『Abstract』Abstract Numerous gram-negative bacterial pathogens employ the type III secretion system (T3SS), a multiprotein injectisome, to deliver virulence proteins into host cells and cause diseases. We uncover erucamide as a previously unknown phytoalexin of both dicots and monocots that blocks the T3SS function of multiple bacterial pathogens. Genetically impairing erucamide accumulation or exogenous application in Arabidopsis highlighted erucamide’s role in antibacterial immunity. Erucamide binds Hypersensitive response and conserved C (HrcC), a key T3SS component, to block injectisome assembly. Analyses of erucamide analogs and HrcC mutants indicated that the erucamide-HrcC binding is required for inhibiting T3SS in vitro and antibacterial resistance in plants, suggesting an essential role of erucamide-HrcC binding in disease resistance. This work reveals a plant chemical defense that targets major virulence machinery in bacterial pathogens.

『Abstract』Abstract Hydrogels consist of cross-linked polymers that are highly swollen with water. Water evaporation or freezing during temperature changes may lead to stiff and brittle hydrogels. We introduce a strategy called “hydro-locking,” which involves immobilizing the water molecules within the polymer network of the hydrogel. This is accomplished by establishing robust connections between water molecules and the polymer by using sulfuric acid. A sacrificial network is introduced to shield the prime polymer network from collapsing. Under the hydro-locking mode, an alginate-polyacrylamide double-network hydrogel remains soft and stretchable within a temperature range that spans from –115° to 143°C. The strategy works with a range of hydrogels and solutions and may enable the preservation and observation of materials or even living organisms at extreme temperatures.

『Abstract』Abstract Widespread use of genetically engineered maize targeting the corn rootworm complex ( Diabrotica species) has raised concerns about insect resistance. Twelve years of university field trial and farm survey data from 10 US Corn Belt states indicate that maize hybrids expressing toxins derived from the bacterium Bacillus thuringiensis (Bt maize) exhibited declining protection from rootworm feeding with increased planting while pest pressures simultaneously decreased. The analysis revealed a tendency to overplant Bt maize, leading to substantial economic losses; this was particularly striking in eastern Corn Belt states. Our findings highlight the need to go beyond the “tragedy of the commons” perspective to protect sustainable use of Bt and other crop biotechnology resources. We propose moving toward a more diversified and transparent seed supply.

『Abstract』Abstract Genomes contain mosaics of discordant evolutionary histories, challenging the accurate inference of the tree of life. Although genome-wide data are routinely used for discordance-aware phylogenomic analyses, because of modeling and scalability limitations, the current practice leaves out large chunks of genomes. As more high-quality genomes become available, we urgently need discordance-aware methods to infer the tree directly from a multiple genome alignment. In this study, we introduce Coalescence-Aware Alignment-Based Species Tree Estimator (CASTER), a theoretically justified site-based method that eliminates the need to predefine recombination-free loci. CASTER is scalable to hundreds of mammalian whole genomes. We demonstrate the accuracy and scalability of CASTER in simulations that include recombination and apply CASTER to several biological datasets, showing that its per-site scores can reveal both biological and artifactual patterns of discordance across the genome.

『Abstract』Abstract Extreme morphological disparity within Mollusca has long confounded efforts to reconstruct a stable backbone phylogeny for the phylum. Familiar molluscan groups—gastropods, bivalves, and cephalopods—each represent a diverse radiation with myriad morphological, ecological, and behavioral adaptations. The phylum further encompasses many more unfamiliar experiments in animal body-plan evolution. In this work, we reconstructed the phylogeny for living Mollusca on the basis of metazoan BUSCO (Benchmarking Universal Single-Copy Orthologs) genes extracted from 77 (13 new) genomes, including multiple members of all eight classes with two high-quality genome assemblies for monoplacophorans. Our analyses confirm a phylogeny proposed from morphology and show widespread genomic variation. The flexibility of the molluscan genome likely explains both historic challenges with their genomes and their evolutionary success.

『Abstract』Abstract Collective motion, which is ubiquitous in nature, has traditionally been explained by “self-propelled particle” models from theoretical physics. Here we show, through field, lab, and virtual reality experimentation, that classical models of collective behavior cannot account for how collective motion emerges in marching desert locusts, whose swarms affect the livelihood of millions. In contrast to assumptions made by these models, locusts do not explicitly align with neighbors. While individuals respond to moving-dot stimuli through the optomotor response, this innate behavior does not mediate social response to neighbors. Instead, locust marching behavior, across scales, can be explained by a minimal cognitive framework, which incorporates individuals’ neural representation of bearings to neighbors and internal consensus dynamics for making directional choices. Our findings challenge long-held beliefs about how order can emerge from disorder in animal collectives.

『Abstract』Abstract Interest in actinide–carbon bonds has persisted since actinide organometallics were first investigated for applications in isotope separation during the Manhattan Project. Transplutonium organometallics are rarely isolated and structurally characterized, likely owing to limited isotope inventories, a scarcity of suitable laboratory infrastructure, and intrinsic difficulties with the anaerobic conditions required. Herein, we report the discovery of an organometallic “berkelocene” complex prepared from 0.3 milligrams of berkelium-249. Single-crystal x-ray diffraction shows a tetravalent berkelium ion between two substituted cyclooctatetraene ligands, resulting in the formation of berkelium–carbon bonds. The coordination in berkelocene resembles that of uranocene, and calculations show that the berkelium 5f orbitals engage in covalent overlap with the δ-symmetry orbitals of the cyclooctatetraenide ligand π system. Charge transfer from the ligands is diminished relative to uranocene and other actinocenes, which maximizes contributions from the stable, half-filled 5f configuration of tetravalent berkelium.

『Abstract』Abstract Shape-anisotropic nanocrystals and patchy particles have been explored to construct complex superstructures, but most studies have focused on convex shapes. We report that nonconvex, dumbbell-shaped nanocrystals (nanodumbbells) exhibit globally interlocking self-assembly behaviors governed by curvature-guided depletion interactions. By tailoring the local curvature of nanodumbbells, we can precisely and flexibly adjust particle bonding directionality, a level of control rarely achievable with conventional convex building blocks. These nanodumbbells can undergo long-range ordered assembly into various intricate two-dimensional superlattices, including the chiral Kagome lattice. Theoretical calculations reveal that the Kagome lattice is a thermodynamically stable phase, with depletion interactions playing a crucial role in stabilizing these non–close-packed structures. The emergence of Kagome lattices and other unusual structures highlights the vast potential of nonconvex nanocrystals for creating sophisticated architectures.

『Abstract』Abstract Identifying the specific roles of precession, obliquity, and eccentricity in glacial-interglacial transitions is hindered by imprecise age control. We circumvent this problem by focusing on the morphology of deglaciation and inception, which we show depends strongly on the relative phasing of precession versus obliquity. We demonstrate that although both parameters are important, precession has more influence on deglacial onset, whereas obliquity is more important for the attainment of peak interglacial conditions and glacial inception. We find that the set of precession peaks (minima) responsible for terminations since 0.9 million years ago is a subset of those peaks that begin (i.e., the precession parameter starts decreasing) while obliquity is increasing. Specifically, termination occurs with the first of these candidate peaks to occur after each eccentricity minimum. Thus, the gross morphology of 100-thousand-year (100-kyr) glacial cycles appears largely deterministic.

『Abstract』Abstract Inorganic phosphate (Pi) is essential for life, and plant cells monitor Pi availability by sensing inositol pyrophosphate (PP-InsP) levels. In this work, we describe the hijacking of plant phosphate sensing by a conserved family of Nudix hydrolase effectors from pathogenic Magnaporthe and Colletotrichum fungi. Structural and enzymatic analyses of the Nudix effector family demonstrate that they selectively hydrolyze PP-InsP. Gene deletion experiments of Nudix effectors in Magnaporthe oryzae , Colletotrichum higginsianum , and Colletotrichum graminicola indicate that PP-InsP hydrolysis substantially enhances disease symptoms in diverse pathosystems. Further, we show that this conserved effector family induces phosphate starvation signaling in plants. Our study elucidates a molecular mechanism, used by multiple phytopathogenic fungi, that manipulates the highly conserved plant phosphate sensing pathway to exacerbate disease.

『Abstract』Abstract Atmospheric organic aerosols (OAs) influence Earth’s climate by absorbing sunlight. However, the link between their evolving composition and their absorptive effects is unclear. We demonstrate that brown nitrogen (BrN), the absorptive nitrogenous component of OAs, dominates their global absorption. Using a global model, we quantified BrN abundance, tracked its optical evolution with chemical aging, and assessed its radiative absorption. BrN contributes 76% of OAs’ surface light absorption over the US and 61% of their global absorptive optical depth. Moreover, the observed variability of OAs’ absorptive capacity is primarily driven by the sources and aging of BrN. BrN represents 18% of the global absorptive direct radiative effect of carbonaceous aerosols, with biomass burning being the largest contributor. Our research establishes a nitrogen-centric framework for attributing the climate impacts of OAs.

『Abstract』Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets have been approved by the FDA or are in clinical trials, highlighting the potential of this approach . Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified a new synthetic lethal target, PELO , for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 or microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD , a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required owing to MSI-H-associated mutations in TTC37 (also known as SKIC3 ), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response, a stress response to accumulation of misfolded or unfolded nascent polypeptides. Together, our findings indicate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD .

『Abstract』During motor learning, breaks in practice are known to facilitate behavioural optimizations. Although this process has traditionally been studied over long breaks that last hours to days , recent studies in humans have demonstrated that rapid performance gains during early motor sequence learning are most pronounced after very brief breaks lasting seconds to minutes . However, the precise causal neural mechanisms that facilitate performance gains after brief breaks remain poorly understood. Here we recorded neural ensemble activity in the motor cortex of macaques while they performed a visuomotor sequence learning task interspersed with brief breaks. We found that task-related neural cofiring patterns were reactivated during brief breaks. The rate and content of reactivations predicted the magnitude and pattern of subsequent performance gains. Of note, we found that performance gains and reactivations were positively correlated with cortical ripples (80–120 Hz oscillations) but anti-correlated with β bursts (13–30 Hz oscillations), which ultimately dominated breaks after the fast learning phase plateaued. We then applied 20 Hz epidural alternating current stimulation (ACS) to motor cortex, which reduced reactivation rates in a phase-specific and dose-dependent manner. Notably, 20 Hz ACS also eliminated performance gains. Overall, our results indicate that the reactivations of task ensembles during brief breaks are causal drivers of subsequent performance gains. β bursts compete with this process, possibly to support stable performance.

『Abstract』Most current strategies for carbon management require CO 2 removal (CDR) from the atmosphere on the multi-hundred gigatonne (Gt) scale by 2100 (refs. ). Mg-rich silicate minerals can remove > 10 Gt CO 2 and sequester it as stable and innocuous carbonate minerals or dissolved bicarbonate ions . However, the reaction rates of these minerals under ambient conditions are far too slow for practical use. Here we show that CaCO 3 and CaSO 4 react quantitatively with diverse Mg-rich silicates (for example, olivine, serpentine and augite) under thermochemical conditions to form Ca 2 SiO 4 and MgO. On exposure to ambient air under wet conditions, Ca 2 SiO 4 is converted to CaCO 3 and silicic acid, and MgO is partially converted into a Mg carbonate within weeks, whereas the input Mg silicate shows no reactivity over 6 months. Alternatively, Ca 2 SiO 4 and MgO can be completely carbonated to CaCO 3 and Mg(HCO 3 ) 2 under 1 atm CO 2 at ambient temperature within hours. Using CaCO 3 as the Ca source, this chemistry enables a CDR process in which the output Ca 2 SiO 4 /MgO material is used to remove CO 2 from air or soil and the CO 2 process emissions are sequestered. Analysis of the energy requirements indicates that this process could require less than 1 MWh per tonne CO 2 removed, approximately half the energy of CO 2 capture with leading direct air capture technologies. The chemistry described here could unlock Mg-rich silicates as a vast resource for safe and permanent CDR.

『Abstract』To solve problems of practical importance , quantum computers probably need to incorporate quantum error correction, in which a logical qubit is redundantly encoded in many noisy physical qubits . The large physical-qubit overhead associated with error correction motivates the search for more hardware-efficient approaches . Here, using a superconducting quantum circuit , we realize a logical qubit memory formed from the concatenation of encoded bosonic cat qubits with an outer repetition code of distance d = 5 (ref. ). A stabilizing circuit passively protects cat qubits against bit flips . The repetition code, using ancilla transmons for syndrome measurement, corrects cat qubit phase flips. We study the performance and scaling of the logical qubit memory, finding that the phase-flip correcting repetition code operates below the threshold. The logical bit-flip error is suppressed with increasing cat qubit mean photon number, enabled by our realization of a cat-transmon noise-biased CX gate. The minimum measured logical error per cycle is on average 1.75(2)% for the distance-3 code sections, and 1.65(3)% for the distance-5 code. Despite the increased number of fault locations of the distance-5 code, the high degree of noise bias preserved during error correction enables comparable performance. These results, where the intrinsic error suppression of the bosonic encodings enables us to use a hardware-efficient outer error-correcting code, indicate that concatenated bosonic codes can be a compelling model for reaching fault-tolerant quantum computation.

『Abstract』In advanced applications such as aerospace and space exploration, materials must balance lightness, functionality and extreme thermal fluctuation resistance . Shape-memory alloys show promise with strength, toughness and substantial strain recovery due to superelasticity, but maintaining low mass and effective operation at cryogenic temperatures is challenging . We hereby introduce a new shape-memory alloy that adheres to these stringent criteria. Predominantly composed of Ti and Al with a chemical composition of Ti 75.25 Al 20 Cr 4.75 , this alloy is characterized by a low density (4.36 × 10 kg m ) and a high specific strength (185 × 10 Pa m per kg) at room temperature, while showing excellent superelasticity. The superelasticity, owing to a reversible stress-induced phase transformation from an ordered body-centred cubic parent phase to an ordered orthorhombic martensite, allows for a recoverable strain exceeding 7%. This functionality persists across a broad range of temperatures, from deep cryogenic 4.2 K to above room temperature, arising from an unconventional temperature dependence of transformation stresses. Below a certain threshold during cooling, the critical transformation stress inversely correlates with temperature. We interpret this behaviour from the perspective of a temperature-dependent anomalous lattice instability of the parent phase. This alloy holds potential in everyday appliances requiring flexible strain accommodation, as well as components designed for extreme environmental conditions such as deep space and liquefied gases.

『Abstract』Single-cell RNA sequencing has profiled hundreds of millions of human cells across organs, diseases, development and perturbations to date. Mining these growing atlases could reveal cell–disease associations, identify cell states in unexpected tissue contexts and relate in vivo biology to in vitro models. These require a common measure of cell similarity across the body and an efficient way to search. Here we develop SCimilarity, a metric-learning framework to learn a unified and interpretable representation that enables rapid queries of tens of millions of cell profiles from diverse studies for cells that are transcriptionally similar to an input cell profile or state. We use SCimilarity to query a 23.4-million-cell atlas of 412 single-cell RNA-sequencing studies for macrophage and fibroblast profiles from interstitial lung disease and reveal similar cell profiles across other fibrotic diseases and tissues. The top scoring in vitro hit for the macrophage query was a 3D hydrogel system , which we experimentally demonstrated reproduces this cell state. SCimilarity serves as a foundation model for single-cell profiles that enables researchers to query for similar cellular states across the human body, providing a powerful tool for generating biological insights from the Human Cell Atlas.

『Abstract』The Atlantic Meridional Overturning Circulation (AMOC), vital for northwards heat transport in the Atlantic Ocean, is projected to weaken owing to global warming , with significant global climate impacts . However, the extent of AMOC weakening is uncertain with wide variation across climate models and some statistical indicators suggesting an imminent collapse . Here we show that the AMOC is resilient to extreme greenhouse gas and North Atlantic freshwater forcings across 34 climate models. Upwelling in the Southern Ocean, driven by persistent Southern Ocean winds, sustains a weakened AMOC in all cases, preventing its complete collapse. As Southern Ocean upwelling must be balanced by downwelling in the Atlantic or Pacific, the AMOC can only collapse if a compensating Pacific Meridional Overturning Circulation (PMOC) develops. Remarkably, a PMOC does emerge in almost all models, but it is too weak to balance all of the Southern Ocean upwelling, suggesting that an AMOC collapse is unlikely this century. Our findings reveal AMOC-stabilizing mechanisms with implications for past and future AMOC changes, and hence for ecosystems and ocean biogeochemistry. They suggest that better understanding and estimates of the Southern Ocean and Indo-Pacific circulations are urgently needed to accurately predict future AMOC change.

『Abstract』After a long-distance migration, Avars with Eastern Asian ancestry arrived in Eastern Central Europe in 567 to 568 ce and encountered groups with very different European ancestry . We used ancient genome-wide data of 722 individuals and fine-grained interdisciplinary analysis of large seventh- to eighth-century ce neighbouring cemeteries south of Vienna (Austria) to address the centuries-long impact of this encounter . We found that even 200 years after immigration, the ancestry at one site (Leobersdorf) remained dominantly East Asian-like, whereas the other site (Modling) shows local, European-like ancestry. These two nearby sites show little biological relatedness, despite sharing a distinctive late-Avar culture . We reconstructed six-generation pedigrees at both sites including up to 450 closely related individuals, allowing per-generation demographic profiling of the communities. Despite different ancestry, these pedigrees together with large networks of distant relatedness show absence of consanguinity, patrilineal pattern with female exogamy, multiple reproductive partnerships (for example, levirate) and direct correlation of biological connectivity with archaeological markers of social status. The generation-long genetic barrier was maintained by systematically choosing partners with similar ancestry from other sites in the Avar realm. Leobersdorf had more biological connections with the Avar heartlands than with Modling, which is instead linked to another site from the Vienna Basin with European-like ancestry. Mobility between sites was mostly due to female exogamy pointing to different marriage networks as the main driver of the maintenance of the genetic barrier.

『Abstract』Turnover in species composition through time is a dominant form of biodiversity change, which has profound effects on the functioning of ecological communities . Turnover rates differ markedly among communities , but the drivers of this variation across taxa and realms remain unknown. Here we analyse 42,225 time series of species composition from marine, terrestrial and freshwater assemblages, and show that temporal rates of turnover were consistently faster in locations that experienced faster temperature change, including both warming and cooling. In addition, assemblages with limited access to microclimate refugia or that faced stronger human impacts on land were especially responsive to temperature change, with up to 48% of species replaced per decade. These results reveal a widespread signal of vulnerability to continuing climate change and highlight which ecological communities are most sensitive, raising concerns about ecosystem integrity as climate change and other human impacts accelerate.

『Abstract』The oestrogen receptor (ER or ERα), a nuclear hormone receptor that drives most breast cancer , is commonly activated by phosphorylation at serine 118 within its intrinsically disordered N-terminal transactivation domain . Although this modification enables oestrogen-independent ER function, its mechanism has remained unclear despite ongoing clinical trials of kinase inhibitors targeting this region . By integration of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy with functional studies, we show that serine 118 phosphorylation triggers an unexpected expansion of the disordered domain and disrupts specific hydrophobic clustering between two aromatic-rich regions. Mutations mimicking this disruption rescue ER transcriptional activity, target-gene expression and cell growth impaired by a phosphorylation-deficient S118A mutation. These findings, driven by hydrophobic interactions, extend beyond electrostatic models and provide mechanistic insights into intrinsically disordered proteins , with implications for other nuclear receptors . This fundamental sequence–structure–function relationship advances our understanding of intrinsic ER disorder, crucial for developing targeted breast cancer therapeutics.

『Abstract』The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8 T cell response pre-emptively, in the absence of an infection . However, the scope and purpose of this anticommensal immune programme are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labelled commensal elicits high antibody titres under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a new form of topical vaccination.

『Abstract』The microbiota colonizes each barrier site and broadly controls host physiology . However, when uncontrolled, microbial colonists can also promote inflammation and induce systemic infection . The unique strategies used at each barrier tissue to control the coexistence of the host with its microbiota remain largely elusive. Here we uncover that, in the skin, host–microbiota symbiosis depends on the ability of the skin to act as an autonomous lymphoid organ. Notably, an encounter with a new skin commensal promotes two parallel responses, both under the control of Langerhans cells. On one hand, skin commensals induce the formation of classical germinal centres in the lymph node associated with immunoglobulin G1 (IgG1) and IgG3 antibody responses. On the other hand, microbial colonization also leads to the development of tertiary lymphoid organs in the skin that can locally sustain IgG2b and IgG2c responses. These phenomena are supported by the ability of regulatory T cells to convert into T follicular helper cells. Skin autonomous production of antibodies is sufficient to control local microbial biomass, as well as subsequent systemic infection with the same microorganism. Collectively, these results reveal a compartmentalization of humoral responses to the microbiota allowing for control of both microbial symbiosis and potential pathogenesis.

『Abstract』Gas samples relevant to health and the environment typically contain many molecular species that span a huge concentration dynamic range. Mid-infrared frequency comb spectroscopy with high-finesse cavity enhancement has allowed the most sensitive multispecies trace-gas detections so far . However, the robust performance of this technique depends critically on ensuring absorption-path-length enhancement over a broad spectral coverage, which is severely limited by comb–cavity frequency mismatch if strongly absorbing compounds are present. Here we introduce modulated ringdown comb interferometry, a technique that resolves the vulnerability of comb–cavity enhancement to strong intracavity absorption or dispersion. This technique works by measuring ringdown dynamics carried by massively parallel comb lines transmitted through a length-modulated cavity, making use of both the periodicity of the field dynamics and the Doppler frequency shifts introduced from a Michelson interferometer. As a demonstration, we measure highly dispersive exhaled human breath samples and ambient air in the mid-infrared with finesse improved to 23,000 and coverage to 1,010 cm . Such a product of finesse and spectral coverage is orders of magnitude better than all previous demonstrations , enabling us to simultaneously quantify 20 distinct molecular species at above 1-part-per-trillion sensitivity varying in concentrations by seven orders of magnitude. This technique unlocks next-generation sensing performance for complex and dynamic molecular compositions, with scalable improvement to both finesse and spectral coverage.

『Abstract』Foraminifera are ubiquitous marine protists that intracellularly accumulate phosphate , an important macronutrient in marine ecosystems and in fertilizer potentially leaked into the ocean. Intracellular phosphate concentrations can be 100–1,000 times higher than in the surrounding water . Here we show that phosphate storage in foraminifera is widespread, from tidal flats to the deep sea. The total amount of intracellular phosphate stored in the benthic foraminifer Ammonia confertitesta in the Wadden Sea during a bloom is as high as around 5% of the annual consumption of phosphorus (P) fertilizer in Germany. Budget calculations for the Southern North Sea and the Peruvian Oxygen Minimum Zone indicate that benthic foraminifera may buffer riverine P runoff for approximately 37 days at the Southern North Sea and for about 21 days at the Peruvian margin. This indicates that these organisms are probably relevant for marine P cycling—they potentially buffer anthropogenic eutrophication in coastal environments. Phosphate is stored as polyphosphate in cell organelles that are potentially acidocalcisomes. Their metabolic functions can range from regulation of osmotic pressure and intracellular pH to calcium and energy storage. In addition, storage of energetic P compounds, such as creatine phosphate and polyphosphate, is probably an adaptation of foraminifera to O 2 depletion.

『Abstract』Neuronal phenotypic traits such as morphology, connectivity and function are dictated, to a large extent, by a specific combination of differentially expressed genes. Clusters of neurons in transcriptomic space correspond to distinct cell types and in some cases—for example, Caenorhabditis elegans neurons and retinal ganglion cells —have been shown to share morphology and function. The zebrafish optic tectum is composed of a spatial array of neurons that transforms visual inputs into motor outputs. Although the visuotopic map is continuous, subregions of the tectum are functionally specialized . Here, to uncover the cell-type architecture of the tectum, we transcriptionally profiled its neurons, revealing more than 60 cell types that are organized in distinct anatomical layers. We measured the visual responses of thousands of tectal neurons by two-photon calcium imaging and matched them with their transcriptional profiles. Furthermore, we characterized the morphologies of transcriptionally identified neurons using specific transgenic lines. Notably, we found that neurons that are transcriptionally similar can diverge in shape, connectivity and visual responses. Incorporating the spatial coordinates of neurons within the tectal volume revealed functionally and morphologically defined anatomical subclusters within individual transcriptomic clusters. Our findings demonstrate that extrinsic, position-dependent factors expand the phenotypic repertoire of genetically similar neurons.

『Abstract』Diversity-generating retroelements (DGRs) create massive protein sequence variation (up to 10 ) in ecologically diverse microorganisms. A recent survey identified around 31,000 DGRs from more than 1,500 bacterial and archaeal genera, constituting more than 90 environment types . DGRs are especially enriched in the human gut microbiome and nano-sized microorganisms that seem to comprise most microbial life and maintain DGRs despite reduced genomes . DGRs are also implicated in the emergence of multicellularity . Variation occurs during reverse transcription of a protein-encoding RNA template coupled to misincorporation at adenosines. In the prototypical Bordetella bacteriophage DGR, the template must be surrounded by upstream and downstream RNA segments for complementary DNA synthesis to be carried out by a complex of the DGR reverse transcriptase bRT and associated protein Avd. The function of the surrounding RNA was unknown. Here we show through cryogenic electron microscopy that this RNA envelops bRT and lies over the barrel-shaped Avd, forming an intimate ribonucleoprotein. An abundance of essential interactions in the ribonucleoprotein precisely position an RNA homoduplex in the bRT active site for initiation of reverse transcription. Our results explain how the surrounding RNA primes complementary DNA synthesis, promotes processivity, terminates polymerization and strictly limits mutagenesis to specific proteins through mechanisms that are probably conserved in DGRs belonging to distant taxa.

『Abstract』Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)–LTβ receptor (LTβR) pathway , the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues , induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LTβR-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LTβR myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.

『Abstract』Growing evidence indicates that migratory animals exploit the magnetic field of the Earth for navigation, both as a compass to determine direction and as a map to determine geographical position . It has long been proposed that, to navigate using a magnetic map, animals must learn the magnetic coordinates of the destination , yet the pivotal hypothesis that animals can learn magnetic signatures of geographical areas has, to our knowledge, yet to be tested. Here we report that an iconic navigating species, the loggerhead turtle ( Caretta caretta ), can learn such information. When fed repeatedly in magnetic fields replicating those that exist in particular oceanic locations, juvenile turtles learned to distinguish magnetic fields in which they encountered food from magnetic fields that exist elsewhere, an ability that might underlie foraging site fidelity. Conditioned responses in this new magnetic map assay were unaffected by radiofrequency oscillating magnetic fields, a treatment expected to disrupt radical-pair-based chemical magnetoreception , suggesting that the magnetic map sense of the turtle does not rely on this mechanism. By contrast, orientation behaviour that required use of the magnetic compass was disrupted by radiofrequency oscillating magnetic fields. The findings provide evidence that two different mechanisms of magnetoreception underlie the magnetic map and magnetic compass in sea turtles.

『Abstract』Photonics offers a promising platform for quantum computing , owing to the availability of chip integration for mass-manufacturable modules, fibre optics for networking and room-temperature operation of most components. However, experimental demonstrations are needed of complete integrated systems comprising all basic functionalities for universal and fault-tolerant operation . Here we construct a (sub-performant) scale model of a quantum computer using 35 photonic chips to demonstrate its functionality and feasibility. This combines all the primitive components as discrete, scalable rack-deployed modules networked over fibre-optic interconnects, including 84 squeezers and 36 photon-number-resolving detectors furnishing 12 physical qubit modes at each clock cycle. We use this machine, which we name Aurora, to synthesize a cluster state entangled across separate chips with 86.4 billion modes, and demonstrate its capability of implementing the foliated distance-2 repetition code with real-time decoding. The key building blocks needed for universality and fault tolerance are demonstrated: heralded synthesis of single-temporal-mode non-Gaussian resource states, real-time multiplexing actuated on photon-number-resolving detection, spatiotemporal cluster-state formation with fibre buffers, and adaptive measurements implemented using chip-integrated homodyne detectors with real-time single-clock-cycle feedforward. We also present a detailed analysis of our architecture’s tolerances for optical loss, which is the dominant and most challenging hurdle to crossing the fault-tolerant threshold. This work lays out the path to cross the fault-tolerant threshold and scale photonic quantum computers to the point of addressing useful applications.

『Abstract』Single-cell genomic technologies enable the multimodal profiling of millions of cells across temporal and spatial dimensions. However, experimental limitations hinder the comprehensive measurement of cells under native temporal dynamics and in their native spatial tissue niche. Optimal transport has emerged as a powerful tool to address these constraints and has facilitated the recovery of the original cellular context . Yet, most optimal transport applications are unable to incorporate multimodal information or scale to single-cell atlases. Here we introduce multi-omics single-cell optimal transport (moscot), a scalable framework for optimal transport in single-cell genomics that supports multimodality across all applications. We demonstrate the capability of moscot to efficiently reconstruct developmental trajectories of 1.7 million cells from mouse embryos across 20 time points. To illustrate the capability of moscot in space, we enrich spatial transcriptomic datasets by mapping multimodal information from single-cell profiles in a mouse liver sample and align multiple coronal sections of the mouse brain. We present moscot.spatiotemporal, an approach that leverages gene-expression data across both spatial and temporal dimensions to uncover the spatiotemporal dynamics of mouse embryogenesis. We also resolve endocrine-lineage relationships of delta and epsilon cells in a previously unpublished mouse, time-resolved pancreas development dataset using paired measurements of gene expression and chromatin accessibility. Our findings are confirmed through experimental validation of NEUROD2 as a regulator of epsilon progenitor cells in a model of human induced pluripotent stem cell islet cell differentiation. Moscot is available as open-source software, accompanied by extensive documentation.

『Abstract』Synthetic lethality exploits the genetic vulnerabilities of cancer cells to enable a targeted, precision approach to treat cancer . Over the past 15 years, synthetic lethal cancer target discovery approaches have led to clinical successes of PARP inhibitors and ushered several next-generation therapeutic targets such as WRN , USP1 , PKMYT1 , POLQ and PRMT5 into the clinic. Here we identify, in human cancer, a novel synthetic lethal interaction between the PELO–HBS1L and SKI complexes of the mRNA quality control pathway. In distinct genetic contexts, including 9p21.3-deleted and high microsatellite instability (MSI-H) tumours, we found that phenotypically destabilized SKI complex leads to dependence on the PELO–HBS1L ribosomal rescue complex. PELO–HBS1L and SKI complex synthetic lethality alters the normal cell cycle and drives the unfolded protein response through the activation of IRE1, as well as robust tumour growth inhibition. Our results indicate that PELO and HBS1L represent novel therapeutic targets whose dependence converges upon SKI complex destabilization, a common phenotypic biomarker in diverse genetic contexts representing a significant population of patients with cancer.

『Abstract』The synthesis of a complex molecule begins from an initial design stage in which possible routes are triaged by strategy and feasibility, on the basis of analogy to similar reactions . However, as molecular complexity increases, predictability decreases ; inevitably, even experienced chemists resort to trial and error to identify viable intermediates en route to the target molecule. We encountered such a problem in the synthesis of picrotoxane sesquiterpenes in which pattern-recognition methods anticipated success, but small variations in structure led to failure. Here, to solve this problem but avoid tedious guess-and-check experimentation, we built a virtual library of elusive late-stage intermediate analogues that were triaged by reactivity and altered the synthesis pathway. The efficiency of this method led to concise routes to 25 naturally occurring picrotoxanes. Costly density-functional-theory transition-state calculations were replaced with faster reactant parameterizations to increase scalability and, in this case, inform the mechanism. This approach can serve as an add-on search to human or computer-assisted synthesis planning applicable to high-complexity targets and/or steps with little representation in the literature or reaction databases.

『Abstract』Identifying phase-separated structures remains challenging, and effective intervention methods are currently lacking . Here we screened for phase-separated proteins in breast tumour cells and identified forkhead (FKH) box protein M1 (FOXM1) as the most prominent candidate. Oncogenic FOXM1 underwent liquid–liquid phase separation (LLPS) with FKH consensus DNA element, and compartmentalized the transcription apparatus in the nucleus, thereby sustaining chromatin accessibility and super-enhancer landscapes crucial for tumour metastatic outgrowth. Screening an epigenetics compound library identified AMPK agonists as suppressors of FOXM1 condensation. AMPK phosphorylated FOXM1 in the intrinsically disordered region (IDR), perturbing condensates, reducing oncogenic transcription, accumulating double-stranded DNA to stimulate innate immune responses, and endowing discrete FOXM1 with the ability to activate immunogenicity-related gene expressions. By developing a genetic code-expansion orthogonal system, we demonstrated that a phosphoryl moiety at a specific IDR1 site causes electrostatic repulsion, thereby abolishing FOXM1 LLPS and aggregation. A peptide targeting IDR1 and carrying the AMPK-phosphorylated residue was designed to disrupt FOXM1 LLPS and was shown to inhibit tumour malignancy, rescue tumour immunogenicity and improve tumour immunotherapy. Together, these findings provide novel and in-depth insights on function and mechanism of FOXM1 and develop methodologies that hold promising implications in clinics.

『Abstract』Recently, the bilayer nickelate La 3 Ni 2 O 7 has been discovered as a new superconductor with transition temperature T c near 80 K under high pressure . Despite extensive theoretical and experimental work to understand the nature of its superconductivity , the requirement of extreme pressure restricts the use of many experimental probes and limits its application potential. Here we present signatures of superconductivity in La 3 Ni 2 O 7 thin films at ambient pressure, facilitated by the application of epitaxial compressive strain. The onset T c varies roughly from 26 to 42 K, with higher T c values correlating with smaller in-plane lattice constants. We observed the co-existence of other Ruddlesden–Popper phases within the films and dependence of transport behaviour with ozone annealing, suggesting that the observed low zero resistance T c of around 2 K can be attributed to stacking defects, grain boundaries and oxygen stoichiometry. This finding initiates numerous opportunities to stabilize and study superconductivity in bilayer nickelates at ambient pressure, and to facilitate the broad understanding of the ever-growing number of high temperature and unconventional superconductors in the transition metal oxides.

『Abstract』Quantum error correction provides a path to reach practical quantum computing by combining multiple physical qubits into a logical qubit, in which the logical error rate is suppressed exponentially as more qubits are added. However, this exponential suppression only occurs if the physical error rate is below a critical threshold. Here we present two below-threshold surface code memories on our newest generation of superconducting processors, Willow: a distance-7 code and a distance-5 code integrated with a real-time decoder. The logical error rate of our larger quantum memory is suppressed by a factor of Λ = 2.14 ± 0.02 when increasing the code distance by 2, culminating in a 101-qubit distance-7 code with 0.143% ± 0.003 per cent error per cycle of error correction. This logical memory is also beyond breakeven, exceeding the lifetime of its best physical qubit by a factor of 2.4 ± 0.3. Our system maintains below-threshold performance when decoding in real time, achieving an average decoder latency of 63 microseconds at distance 5 up to a million cycles, with a cycle time of 1.1 microseconds. We also run repetition codes up to distance 29 and find that logical performance is limited by rare correlated error events, occurring approximately once every hour or 3 × 10 cycles. Our results indicate device performance that, if scaled, could realize the operational requirements of large-scale fault-tolerant quantum algorithms.

『Abstract』Ultrasmall CsPbI 3 perovskite quantum dots (QDs) are the most promising candidates for realizing efficient and stable pure-red perovskite light-emitting diodes (PeLEDs) . However, it is challenging for ultrasmall CsPbI 3 QDs to retain their solution-phase properties when they assemble into conductive films, greatly hindering their device application . Here we report an approach for in situ deposit stabilized ultrasmall CsPbI 3 QD conductive solids, by constructing CsPbI 3 QD/quasi - two-dimensional (quasi-2D) perovskite heteroepitaxy. The well-aligned periodic array of edge-oriented ligands at heterointerface triggers a substantial octahedral tilting in a critical layer thickness of CsPbI 3 QDs, which heightens the Gibbs free energy difference between the tilted-CsPbI 3 and δ-CsPbI 3 leading to thermodynamic stabilization of CsPbI 3 QDs. The approach allows us to fabricate stabilized CsPbI 3 QD conductive films with tunable emission covering the entire red spectral region from 600 nm to 710 nm. Here we report the pure-red PeLEDs with narrow electroluminescence peak centred at 630 nm, matching the Rec. 2100 standard for ultrahigh-definition display. The champion device exhibits a certified external quantum efficiency of 24.6% and a half-lifetime of 6,330 min, ranking as one of the most efficient and stable pure-red PeLED reported to date. The approach is also compatible with large-area manufacturing, enabling 1 cm PeLED to exhibit the best external quantum efficiency of 20.5% at 630 nm.

『Abstract』Two-dimensional (2D) semiconductors, particularly transition metal dichalcogenides (TMDs), are promising for advanced electronics beyond silicon . Traditionally, TMDs are epitaxially grown on crystalline substrates by chemical vapour deposition. However, this approach requires post-growth transfer to target substrates, which makes controlling thickness and scalability difficult. Here we introduce a method called hypotaxy (‘hypo’ meaning downward and ‘taxy’ meaning arrangement), which enables wafer-scale single-crystal TMD growth directly on various substrates, including amorphous and lattice-mismatched substrates, while preserving crystalline alignment with an overlying 2D template. By sulfurizing or selenizing a pre-deposited metal film under graphene, aligned TMD nuclei form, coalescing into a single-crystal film as graphene is removed. This method achieves precise MoS 2 thickness control from monolayer to hundreds of layers on diverse substrates, producing 4-inch single-crystal MoS 2 with high thermal conductivity (about 120 W m K ) and mobility (around 87 cm V s ). Furthermore, nanopores created in graphene using oxygen plasma treatment allow MoS 2 growth at a lower temperature of 400 °C, compatible with back-end-of-line processes. This hypotaxy approach extends to other TMDs, such as MoSe 2 , WS 2 and WSe 2 , offering a solution to substrate limitations in conventional epitaxy and enabling wafer-scale TMDs for monolithic three-dimensional integration.