前沿速递 | NCS 集萃： 2025-02-20 期 [Up]

『Abstract』The vision of robotic materials—cohesive collectives of robotic units that can arrange into virtually any form with any physical properties—has long intrigued both science and fiction. Yet, this vision requires a fundamental physical challenge to be overcome: The collective must be strong, to support loads, yet flow, to take new forms. We achieve this in a material-like robotic collective by modulating the interunit tangential forces to control topological rearrangements of units within a tightly packed structure. This allows local control of rigidity transitions between solid and fluid-like states in the collective and enables spatiotemporal control of shape and strength. We demonstrate structure-forming and healing and show the collective supporting 700 newtons (500 times the weight of a robot) before “melting” under its own weight.

『Abstract』Keyhole instability during laser welding and laser powder bed fusion (LPBF) can cause keyhole collapse and pore formation. Using high-speed x-ray imaging, we demonstrate that the flow vortex–induced protrusion on the rear keyhole wall is crucial in initiating keyhole instability. Applying a transverse magnetic field suppresses the keyhole instability by driving a secondary thermoelectric magnetohydrodynamics (TEMHD) flow that alters the net flow vortex. This minimizes protrusions and large-amplitude keyhole oscillations. The suppression effectiveness depends on the laser scanning direction relative to the magnetic field orientation because this controls the Seebeck effect–induced Lorentz force’s direction. We show that at LPBF length scales, electromagnetic damping is weak, and for alloys with a large Seebeck coefficient, TEMHD becomes the dominant mechanism controlling flow behind the keyhole.

『Abstract』Neuronal accumulation and spread of pathological α-synuclein (α-syn) fibrils are key events in Parkinson's disease (PD) pathophysiology. However, the neuronal mechanisms underlying the uptake of α-syn fibrils remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects α-syn aggregation. Overexpressing FAM171A2 promotes α-syn fibril endocytosis and exacerbates the spread and neurotoxicity of α-syn pathology. Neuronal-specific knockdown of FAM171A2 expression shows protective effects. Mechanistically, the FAM171A2 extracellular domain 1 interacts with the α-syn C terminus through electrostatic forces, with >1000 times more selective for fibrils. Furthermore, we identified bemcentinib as an effective blocker of FAM171A2–α-syn fibril interaction with an in vitro binding assay, in cellular models, and in mice. Our findings identified FAM171A2 as a potential receptor for the neuronal uptake of α-syn fibrils and, thus, as a therapeutic target against PD.

『Abstract』Ice streams are major regulators of sea level change. However, standard viscous flow simulations of their evolution have limited predictive power owing to incomplete understanding of involved processes. On the Greenland ice sheet, borehole fiber-optic observations revealed a brittle deformation mode that is incompatible with viscous flow, over length scales similar to the resolution of modern ice sheet models: englacial ice quake cascades that are unobservable at the surface. Nucleating near volcanism-related impurities that promote grain boundary cracking, the ice quake cascades appear as a macroscopic form of crystal-scale wild plasticity. A conservative estimate indicates that seismic cascades are likely to produce strain rates that are comparable in amplitude with those measured geodetically, providing a plausible missing link between current ice sheet models and observations.

『Abstract』The reversion of vinyl polymers with carbon-carbon backbones to their monomers represents an ideal path to alleviate the growing plastic waste stream. However, depolymerizing such stable materials remains a challenge, with state-of-the-art methods relying on “designer” polymers that are neither commercially produced nor suitable for real-world applications. In this work, we report a main chain–initiated, visible light–triggered depolymerization directly applicable to commercial polymers containing undisclosed impurities (e.g., comonomers, additives, or dyes). By in situ generation of chlorine radicals directly from the solvent, near-quantitative (>98%) depolymerization of polymethacrylates could be achieved regardless of their synthetic route (e.g., radical or ionic polymerization), end group, and molecular weight (up to 1.6 million daltons). The possibility to perform multigram-scale depolymerizations and confer temporal control renders this methodology a versatile and general route to recycling.

『Abstract』Thermoelectric coolers (TECs) are pivotal in modern heat management but face limitations in efficiency and manufacturing scalability. We address these challenges by using an extrusion-based 3D printing technique to fabricate high-performance thermoelectric materials. Our ink formulations ensure the integrity of the 3D-printed structure and effective particle bonding during sintering, achieving record-high figure of merit ( zT ) values of 1.42 for p-type bismuth antimony telluride [(Bi,Sb) 2 Te 3 ] and 1.3 for n-type silver selenide (Ag 2 Se) materials at room temperature. The resulting TEC demonstrates a cooling temperature gradient of 50°C in air. Moreover, this scalable and cost-effective method circumvents energy-intensive and time-consuming steps, such as ingot preparation and subsequently machining processes, offering a transformative solution for thermoelectric device production and heralding a new era of efficient and sustainable thermoelectric technologies.

『Abstract』Over the last 80 years, chlorine (Cl) has been the primary promoter of the ethylene epoxidation reaction valued at ~40 billion USD per year, providing a ~25% selectivity increase over unpromoted silver (Ag) (~55%). Promoters such as cesium, rhenium, and molybdenum each add a few percent of selectivity enhancements to achieve 90% overall, but their codependence on Cl makes optimizing and understanding their function complex. We took a theory-guided, single-atom alloy approach to identify nickel (Ni) as a dopant in Ag that can facilitate selective oxidation by activating molecular oxygen (O 2 ) without binding oxygen (O) too strongly. Surface science experiments confirmed the facile adsorption/desorption of O 2 on NiAg, as well as demonstrating that Ni serves to stabilize unselective nucleophilic oxygen. Supported Ag catalyst studies revealed that the addition of Ni in a 1:200 Ni to Ag atomic ratio provides a ~25% selectivity increase without the need for Cl co-flow and acts cooperatively with Cl, resulting in a further 10% initial increase in selectivity.

『Abstract』Prokaryotes have evolved diverse defense strategies against viral infection, including foreign nucleic acid degradation by CRISPR-Cas systems and DNA and RNA synthesis inhibition through nucleotide pool depletion. Here, we report an antiviral mechanism of type III CRISPR-Cas–regulated adenosine triphosphate (ATP) depletion in which ATP is converted into inosine triphosphate (ITP) by CRISPR-Cas–associated adenosine deaminase (CAAD) upon activation by either cA 4 or cA 6 , followed by hydrolysis into inosine monophosphate (IMP) by Nudix hydrolase, ultimately resulting in cell growth arrest. The cryo–electron microscopy structures of CAAD in its apo and activated forms, together with biochemical evidence, revealed how cA 4 or cA 6 binds to the CRISPR-associated Rossmann fold (CARF) domain and abrogates CAAD autoinhibition, inducing substantial conformational changes that reshape the structure of CAAD and induce its deaminase activity. Our results reveal the mechanism of a CRISPR-Cas–regulated ATP depletion antiviral strategy.

『Abstract』Humans often take actions to assist others experiencing unresponsiveness, such as transient loss of consciousness. How other animals react to unresponsive conspecifics—and the neural mechanisms driving such behaviors—remain largely unexplored. In this study, we demonstrated that mice exhibit rescue-like social behaviors toward unresponsive conspecifics, characterized by intense physical contact and grooming directed at the recipient’s facial and mouth areas, which expedite their recovery from unresponsiveness. We identified the medial amygdala (MeA) as a key region that encodes the unresponsive state of others and drives this head-directed physical contact. Notably, the behavioral responses toward unresponsive conspecifics differed from those directed at awake, stressed individuals, and these responses were differentially represented in the MeA. These findings shed light on the neural mechanisms underlying prosocial responses toward unresponsive individuals.

『Abstract』Clinical diagnosis typically incorporates physical examination, patient history, various laboratory tests, and imaging studies but makes limited use of the human immune system’s own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis, an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to severe acute respiratory syndrome coronavirus 2, influenza, and human immunodeficiency virus, highlight antigen-specific receptors, and reveal distinct characteristics of systemic lupus erythematosus and type-1 diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of immune responses.

『Abstract』The introduction of a single C-atom into organic substrates typically results in the formation of flat molecules containing unsaturated C(sp)-centers. Adding a single C(sp )-atom surrounded by four σ-C–C bonds, which opens up the three-dimensional space, is an unresolved problem in synthetic chemistry. We report the synthesis and application of the diazosulfur ylide Ph 2 S=C=N 2 reagent that combines the reactivity of both sulfur ylides and diazo compounds to create carbon spiro-centers in a general fashion by the sequential or single-step installation of a C(sp )-atom. New C–C and C–X (where X is O or N) bonds can be created around the C(sp )-atom, which can ultimately be extended to four C–C σ-bonds in one step without resorting to transition metal catalysis. Ph 2 SCN 2 can also be used to access highly strained frameworks containing (oxa)spiro[2.2]pentanes as well as tricyclic spiro-compounds.

『Abstract』Evolvability—the capacity to generate adaptive variation—is a trait that can itself evolve through natural selection. However, the idea that mutation can become biased toward adaptive outcomes remains controversial. In this work, we report the evolution of enhanced evolvability through localized hypermutation in experimental populations of bacteria. The evolved mechanism is analogous to the mutation-prone sequences of contingency loci observed in pathogenic bacteria. Central to this outcome was a lineage-level selection process, where success depended on the capacity to evolve between two phenotypic states. Subsequent evolution showed that the hypermutable locus is itself evolvable with respect to alterations in the frequency of environmental change. Lineages with localized hypermutability were more likely to acquire additional adaptive mutations, revealing an unanticipated benefit.

『Abstract』Whereas humans exhibit emergency responses to assist unconscious individuals, how nonhuman animals react to unresponsive conspecifics is less well understood. We report that mice exhibit stereotypic behaviors toward unconscious or dead social partners, which escalate from sniffing and grooming to more forceful actions such as mouth or tongue biting and tongue pulling. The latter intense actions, more prominent in familiar pairs, begin after prolonged immobility and unresponsiveness and cease when the partner regains activity. Their consequences, including improved airway opening and clearance and accelerated recovery from unconsciousness, suggest rescue-like efforts. Oxytocin neurons in the hypothalamic paraventricular nucleus respond differentially to the presence of unconscious versus active partners, and their activation, along with oxytocin signaling, is required for the reviving-like actions. This tendency to assist unresponsive members may enhance group cohesion and survival of social species.

『Abstract』More than 3 billion years of evolution have produced an image of biology encoded into the space of natural proteins. Here, we show that language models trained at scale on evolutionary data can generate functional proteins that are far away from known proteins. We present ESM3, a frontier multimodal generative language model that reasons over the sequence, structure, and function of proteins. ESM3 can follow complex prompts combining its modalities and is highly responsive to alignment to improve its fidelity. We have prompted ESM3 to generate fluorescent proteins. Among the generations that we synthesized, we found a bright fluorescent protein at a far distance (58% sequence identity) from known fluorescent proteins, which we estimate is equivalent to simulating 500 million years of evolution.

『Abstract』Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by endogenous ligands. Therapeutic approaches such as lysosome-targeting chimaeras (LYTACs) and cytokine receptor-targeting chimeras (KineTACs) have used this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. Although powerful, these approaches can be limited by competition with native ligands and requirements for chemical modification that limit genetic encodability and can complicate manufacturing, and, more generally, there may be no native ligands that stimulate endocytosis through a given receptor. Here we describe computational design approaches for endocytosis-triggering binding proteins (EndoTags) that overcome these challenges. We present EndoTags for insulin-like growth factor 2 receptor (IGF2R) and asialoglycoprotein receptor (ASGPR), sortilin and transferrin receptors, and show that fusing these tags to soluble or transmembrane target protein binders leads to lysosomal trafficking and target degradation. As these receptors have different tissue distributions, the different EndoTags could enable targeting of degradation to different tissues. EndoTag fusion to a PD-L1 antibody considerably increases efficacy in a mouse tumour model compared to antibody alone. The modularity and genetic encodability of EndoTags enables AND gate control for higher-specificity targeted degradation, and the localized secretion of degraders from engineered cells. By promoting endocytosis, EndoTag fusion increases signalling through an engineered ligand–receptor system by nearly 100-fold. EndoTags have considerable therapeutic potential as targeted degradation inducers, signalling activators for endocytosis-dependent pathways, and cellular uptake inducers for targeted antibody–drug and antibody–RNA conjugates.

『Abstract』Modern humans arrived in Europe more than 45,000 years ago, overlapping at least 5,000 years with Neanderthals . Limited genomic data from these early modern humans have shown that at least two genetically distinct groups inhabited Europe, represented by Zlaty kun, Czechia and Bacho Kiro, Bulgaria . Here we deepen our understanding of early modern humans by analysing one high-coverage genome and five low-coverage genomes from approximately 45,000-year-old remains from Ilsenhohle in Ranis, Germany , and a further high-coverage genome from Zlaty kun. We show that distant familial relationships link the Ranis and Zlaty kun individuals and that they were part of the same small, isolated population that represents the deepest known split from the Out-of-Africa lineage. Ranis genomes harbour Neanderthal segments that originate from a single admixture event shared with all non-Africans that we date to approximately 45,000–49,000 years ago. This implies that ancestors of all non-Africans sequenced so far resided in a common population at this time, and further suggests that modern human remains older than 50,000 years from outside Africa represent different non-African populations.

『Abstract』The fusion of non-Abelian anyons is a fundamental operation in measurement-only topological quantum computation . In one-dimensional topological superconductors (1DTSs) , fusion amounts to a determination of the shared fermion parity of Majorana zero modes (MZMs). Here we introduce a device architecture that is compatible with future tests of fusion rules. We implement a single-shot interferometric measurement of fermion parity in indium arsenide–aluminium heterostructures with a gate-defined superconducting nanowire . The interferometer is formed by tunnel-coupling the proximitized nanowire to quantum dots. The nanowire causes a state-dependent shift of the quantum capacitance of these quantum dots of up to 1 fF. Our quantum-capacitance measurements show flux h /2 e -periodic bimodality with a signal-to-noise ratio (SNR) of 1 in 3.6 μs at optimal flux values. From the time traces of the quantum-capacitance measurements, we extract a dwell time in the two associated states that is longer than 1 ms at in-plane magnetic fields of approximately 2 T. We discuss the interpretation of our measurements in terms of both topologically trivial and non-trivial origins. The large capacitance shift and long poisoning time enable a parity measurement with an assignment error probability of 1%.

『Abstract』Rubisco is the primary CO 2 -fixing enzyme of the biosphere , yet it has slow kinetics . The roles of evolution and chemical mechanism in constraining its biochemical function remain debated . Engineering efforts aimed at adjusting the biochemical parameters of rubisco have largely failed , although recent results indicate that the functional potential of rubisco has a wider scope than previously known . Here we developed a massively parallel assay, using an engineered Escherichia coli in which enzyme activity is coupled to growth, to systematically map the sequence–function landscape of rubisco. Composite assay of more than 99% of single-amino acid mutants versus CO 2 concentration enabled inference of enzyme velocity and apparent CO 2 affinity parameters for thousands of substitutions. This approach identified many highly conserved positions that tolerate mutation and rare mutations that improve CO 2 affinity. These data indicate that non-trivial biochemical changes are readily accessible and that the functional distance between rubiscos from diverse organisms can be traversed, laying the groundwork for further enzyme engineering efforts.

『Abstract』Apolipoprotein B100 (apoB100) is a structural component of low-density lipoprotein (LDL) and a ligand for the LDL receptor (LDLR) . Mutations in apoB100 or in LDLR cause familial hypercholesterolaemia, an autosomal dominant disease that is characterized by a marked increase in LDL cholesterol (LDL-C) and a higher risk of cardiovascular disease . The structure of apoB100 on LDL and its interaction with LDLR are poorly understood. Here we present the cryo-electron microscopy structures of apoB100 on LDL bound to the LDLR and a nanobody complex, which can form a C 2 -symmetric, higher-order complex. Using local refinement, we determined high-resolution structures of the interfaces between apoB100 and LDLR. One binding interface is formed between several small-ligand-binding modules of LDLR and a series of basic patches that are scattered along a β-belt formed by apoB100, encircling LDL. The other binding interface is formed between the β-propeller domain of LDLR and the N-terminal domain of apoB100. Our results reveal how both interfaces are involved in LDL dimer formation, and how LDLR cycles between LDL- and self-bound conformations. In addition, known mutations in either apoB100 or LDLR, associated with high levels of LDL-C, are located at the LDL–LDLR interface.

『Abstract』Cumulative silicon photovoltaic (PV) waste highlights the importance of considering waste recycling before the commercialization of emerging PV technologies . Perovskite PVs are a promising next-generation technology , in which recycling their end-of-life waste can reduce the toxic waste and retain resources . Here we report a low-cost, green-solvent-based holistic recycling strategy to restore all valuable components from perovskite PV waste. We develop an efficient aqueous-based perovskite recycling approach that can also rejuvenate degraded perovskites. We further extend the scope of recycling to charge-transport layers, substrates, cover glasses and metal electrodes. After repeated degradation–recycling processes, the recycled devices show similar efficiency and stability compared with the fresh devices. Our holistic recycling strategy reduces by 96.6% resource depletion and by 68.8% human toxicity (cancer effects) impacts associated with perovskite PVs compared with the landfill treatment. With recycling, the levelized cost of electricity also decreases for both utility-scale and residential systems. This study highlights unique opportunities of perovskite PVs for holistic recycling and paves the way for a sustainable perovskite solar economy.

『Abstract』Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and, in turn, activate bespoke cellular functions. Such receptors would have extensive clinical potential to regulate the activity of engineered therapeutic cells, but so far only receptors against cell-surface targets have approached clinical translation . To address this gap, here we adapt a receptor architecture called the synthetic intramembrane proteolysis receptor (SNIPR) for activation by soluble ligands. Our SNIPR platform can be activated by both natural and synthetic soluble factors, with notably low baseline activity and high fold activation, through an endocytic, pH-dependent cleavage mechanism. We demonstrate the therapeutic capabilities of the receptor platform by localizing the activity of chimeric antigen receptor (CAR) T cells to solid tumours in which soluble disease-associated factors are expressed, bypassing the major hurdle of on-target off-tumour toxicity in bystander organs. We further apply the SNIPR platform to engineer fully synthetic signalling networks between cells orthogonal to natural signalling pathways, expanding the scope of synthetic biology. Our design framework enables cellular communication and environmental interactions, extending the capabilities of synthetic cellular networking in clinical and research contexts.

『Abstract』Despite their high relative abundance in our Universe, neutrinos are the least understood fundamental particles of nature. In fact, the quantum properties of neutrinos emitted in experimentally relevant sources are theoretically contested and the spatial extent of the neutrino wavepacket is only loosely constrained by reactor neutrino oscillation data with a spread of 13 orders of magnitude . Here we present a method to directly access this quantity by precisely measuring the energy width of the recoil daughter nucleus emitted in the radioactive decay of beryllium-7. The final state in the decay process contains a recoiling lithium-7 nucleus, which is entangled with an electron neutrino at creation. The lithium-7 energy spectrum is measured to high precision by directly embedding beryllium-7 radioisotopes into a high-resolution superconducting tunnel junction that is operated as a cryogenic sensor. Under this approach, we set a lower limit on the Heisenberg spatial uncertainty of the recoil daughter of 6.2 pm, which implies that the final-state system is localized at a scale more than a thousand times larger than the nucleus itself. From this measurement, the first, to our knowledge, direct lower limit on the spatial extent of a neutrino wavepacket is extracted. These results may have implications in several areas including the theoretical understanding of neutrino properties, the nature of localization in weak nuclear decays and the interpretation of neutrino physics data.

『Abstract』The use of reactive supports to disperse metal species is crucial for constructing highly efficient interfacial catalysts, by tuning the competitive reactant adsorption–activation pattern in supported metal catalysts into a non-competitive mechanism . However, these reactive supports are prone to deterioration during catalysis, limiting the lifespan of the catalyst and their potential practical applications . New strategies are needed to simultaneously protect reactive supports and surface metal species without compromising the inherent catalytic performance. Here we report a new strategy to augment the structural stability of highly active interfacial catalysts by using inert nano-overlays to partially shield and partition the surface of the reactive support. Specifically, we demonstrate that atomically dispersed inert oxide nano-overlays on a highly active Pt/γ-Mo 2 N catalyst can block the redundant surface sites of γ-Mo 2 N responsible for surface oxidation of this reactive support and the resulting deactivation. This strategy yields an efficient and highly durable catalyst for hydrogen production by methanol-reforming reaction with a mere 0.26 wt% Pt loading, exhibiting a record-high turnover number, to our knowledge, of 15,300,000 and a notable apparent turnover frequency of \(\mathrm{24,500}\,{\text{mol}}_{{{\rm{H}}}_{2}}\,{\text{mol}}_{{\rm{metal}}}^{-1}\,{\text{h}}^{-1}\) . This innovative approach showcases the prospects of reducing noble metal consumption and boosting longevity, which could be applied to design effective and stable heterogeneous catalysts.

『Abstract』Cis -regulatory elements (CREs) control gene expression and are dynamic in their structure and function, reflecting changes in the composition of diverse effector proteins over time . However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA–protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size. Using these multiscale footprints, we created the seq2PRINT framework, which uses deep learning to allow precise inference of transcription factor and nucleosome binding and interprets regulatory logic at CREs. Applying seq2PRINT to single-cell chromatin accessibility data from human bone marrow, we observe sequential establishment and widening of CREs centred on pioneer factors across haematopoiesis. We further discover age-associated alterations in the structure of CREs in murine haematopoietic stem cells, including widespread reduction of nucleosome footprints and gain of de novo identified Ets composite motifs. Collectively, we establish a method for obtaining rich insights into DNA-binding protein dynamics from chromatin accessibility data, and reveal the architecture of regulatory elements across differentiation and ageing.

『Abstract』Low-density lipoprotein (LDL) has a central role in lipid and cholesterol metabolism and is a key agent in the development and progression of atherosclerosis, the leading cause of mortality worldwide . Apolipoprotein B100 (apoB100), one of the largest proteins in the genome, is the primary structural and functional component of LDL, yet its size and complex lipid associations have posed major challenges for structural studies . Here we present the structure of apoB100 resolved to subnanometre resolution in most regions using an integrative approach of cryo-electron microscopy, AlphaFold2 and molecular-dynamics-based refinement . The structure consists of a large globular N-terminal domain and an approximately 61-nm-long continuous amphipathic β-sheet that wraps around the LDL particle like a belt. Distributed quasi-symmetrically across the two sides of the β-belt are nine strategically located interstrand inserts that extend across the lipid surface to provide additional structural support through a network of long-range interactions. We further compare our structure to a comprehensive list of more than 200 intramolecular cross-links and find close agreement between the two. These results suggest a mechanism for how the various domains of apoB100 act in concert to maintain LDL shape and cohesion across a range of particle sizes. More generally, they advance our fundamental understanding of LDL synthesis, form and function, and will help to accelerate the design of potential therapeutics.

『Abstract』Population studies provide insights into the interplay between the gut microbiome and geographical, lifestyle, genetic and environmental factors. However, low- and middle-income countries, in which approximately 84% of the world’s population lives , are not equitably represented in large-scale gut microbiome research . Here we present the AWI-Gen 2 Microbiome Project, a cross-sectional gut microbiome study sampling 1,801 women from Burkina Faso, Ghana, Kenya and South Africa. By engaging with communities that range from rural and horticultural to post-industrial and urban informal settlements, we capture a far greater breadth of the world’s population diversity. Using shotgun metagenomic sequencing, we identify taxa with geographic and lifestyle associations, including Treponema and Cryptobacteroides species loss and Bifidobacterium species gain in urban populations. We uncover 1,005 bacterial metagenome-assembled genomes, and we identify antibiotic susceptibility as a factor that might drive Treponema succinifaciens absence in urban populations. Finally, we find an HIV infection signature defined by several taxa not previously associated with HIV, including Dysosmobacter welbionis and Enterocloster sp. This study represents the largest population-representative survey of gut metagenomes of African individuals so far, and paired with extensive clinical biomarkers and demographic data, provides extensive opportunity for microbiome-related discovery.

『Abstract』DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment . The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours , but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium . Persistent DNA lesions occurred at increased rates, with distinctive mutational signatures, in donors exposed to tobacco or chemotherapy, suggesting that they can arise from exogenous mutagens. In haematopoietic stem cells, persistent DNA lesions, probably from endogenous sources, generated the characteristic mutational signature SBS19 ; occurred steadily throughout life, including in utero; and endured for 2.2 years on average, with 15–25% of lesions lasting at least 3 years. We estimate that on average, a haematopoietic stem cell has approximately eight such lesions at any moment in time, half of which will generate a mutation with each cell cycle. Overall, 16% of mutations in blood cells are attributable to SBS19, and similar proportions of driver mutations in blood cancers exhibit this signature. These data indicate the existence of a family of DNA lesions that arise from endogenous and exogenous mutagens, are present in low numbers per genome, persist for months to years, and can generate a substantial fraction of the mutation burden of somatic cells.

『Abstract』The abundance and sequence of satellite DNA at and around centromeres is evolving rapidly despite the highly conserved and essential process through which the centromere directs chromosome inheritance . The impact of such rapid evolution is unclear. Here we find that sequence-dependent DNA shape dictates packaging of pericentromeric satellites in female meiosis through a conserved DNA-shape-recognizing chromatin architectural protein, high mobility group AT-hook 1 (HMGA1) . Pericentromeric heterochromatin in two closely related mouse species, M. musculus and M. spretus , forms on divergent satellites that differ by both density of narrow DNA minor grooves and HMGA1 recruitment. HMGA1 binds preferentially to M. musculus satellites, and depletion in M. musculus oocytes causes massive stretching of pericentromeric satellites, disruption of kinetochore organization and delays in bipolar spindle assembly. In M. musculus × spretus hybrid oocytes, HMGA1 depletion disproportionately impairs M. musculus pericentromeres and microtubule attachment to their kinetochores. Thus, DNA shape affects both pericentromere packaging and the segregation machinery. We propose that rapid evolution of centromere and pericentromere DNA does not disrupt these essential processes when the satellites adopt DNA shapes recognized by conserved architectural proteins (such as HMGA1). By packaging these satellites, architectural proteins become part of the centromeric and pericentromeric chromatin, suggesting an evolutionary strategy that lowers the cost of megabase-scale satellite expansion.

『Abstract』Generative artificial intelligence (AI) has the potential to transform creative industries through supporting human creative ideation—the generation of new ideas . However, limitations in model capabilities raise key challenges in integrating these technologies more fully into creative practices. Iterative tweaking and divergent thinking remain key to enabling creativity support using technology , yet these practices are insufficiently supported by state-of-the-art generative AI models. Using game development as a lens, we demonstrate that we can make use of an understanding of user needs to drive the development and evaluation of generative AI models in a way that aligns with these creative practices. Concretely, we introduce a state-of-the-art generative model, the World and Human Action Model (WHAM), and show that it can generate consistent and diverse gameplay sequences and persist user modifications—three capabilities that we identify as being critical for this alignment. In contrast to previous approaches to creativity support tools that required manually defining or extracting structure for relatively narrow domains, generative AI models can learn relevant structure from available data, opening the potential for a much broader range of applications.

『Abstract』When two insulating, neutral materials are contacted and separated, they exchange electrical charge . Experiments have long suggested that this ‘contact electrification’ is transitive, with different materials ordering into ‘triboelectric series’ based on the sign of charge acquired . At the same time, the effect is plagued by unpredictability, preventing consensus on the mechanism and casting doubt on the rhyme and reason that series imply . Here we expose an unanticipated connection between the unpredictability and order in contact electrification: nominally identical materials initially exchange charge randomly and intransitively, but—over repeated experiments—order into triboelectric series. We find that this evolution is driven by the act of contact itself—samples with more contacts in their history charge negatively to ones with fewer contacts. Capturing this ‘contact bias’ in a minimal model, we recreate both the initial randomness and ultimate order in numerical simulations and use it experimentally to force the appearance of a triboelectric series of our choosing. With a set of surface-sensitive techniques to search for the underlying alterations contact creates, we only find evidence of nanoscale morphological changes, pointing to a mechanism strongly coupled with mechanics. Our results highlight the centrality of contact history in contact electrification and suggest that focusing on the unpredictability that has long plagued the effect may hold the key to understanding it.

『Abstract』Crystal symmetry guides the development of condensed matter. The unique crystal symmetry connecting magnetic sublattices not only distinguishes altermagnetism from ferromagnetism and conventional antiferromagnetism but also enables it to combine the advantages of ferromagnetism and antiferromagnetism . Altermagnetic order is essentially a magnetic crystal order , determined by the magnetic-order (Neel) vector and crystal symmetry. Previous experimental studies have concentrated on manipulating the altermagnetic symmetry by tuning the Neel vector orientations . However, manipulation of the crystal symmetry, which holds great promise for manipulating the altermagnetic order, remains challenging. Here we realize the manipulation of altermagnetic order in chromium antimonide (CrSb) films via crystal symmetry. The locking between the Dzyaloshinskii–Moriya vector and the magnetic space symmetry helps to reconstruct the altermagnetic order, from a collinear Neel vector to a canted one. It generates a room-temperature spontaneous anomalous Hall effect in an altermagnet. The relative direction between the current-induced spin polarization and the Dzyaloshinskii–Moriya vector determines the switching modes of altermagnetic order, that is, parallel for the field-assisted mode in CrSb \((1\bar{1}00)\) /Pt and non-parallel for the field-free mode in W/CrSb \((11\bar{2}0)\) . The Dzyaloshinskii–Moriya vector induces an asymmetric energy barrier in the field-assisted mode and generates an asymmetric driving force in the field-free mode. In particular, the latter is guaranteed by the emerging Dzyaloshinskii–Moriya torque in altermagnets. Reconstructing crystal symmetry adds a new twist to the manipulation of altermagnetic order. It not only underpins the magnetic-memory and nano-oscillator technology but also inspires crossover studies between altermagnetism and other research topics.

『Abstract』Clinical decision-making is driven by multimodal data, including clinical notes and pathological characteristics. Artificial intelligence approaches that can effectively integrate multimodal data hold significant promise in advancing clinical care . However, the scarcity of well-annotated multimodal datasets in clinical settings has hindered the development of useful models. In this study, we developed the Multimodal transformer with Unified maSKed modeling (MUSK), a vision–language foundation model designed to leverage large-scale, unlabelled, unpaired image and text data. MUSK was pretrained on 50 million pathology images from 11,577 patients and one billion pathology-related text tokens using unified masked modelling. It was further pretrained on one million pathology image–text pairs to efficiently align the vision and language features. With minimal or no further training, MUSK was tested in a wide range of applications and demonstrated superior performance across 23 patch-level and slide-level benchmarks, including image-to-text and text-to-image retrieval, visual question answering, image classification and molecular biomarker prediction. Furthermore, MUSK showed strong performance in outcome prediction, including melanoma relapse prediction, pan-cancer prognosis prediction and immunotherapy response prediction in lung and gastro-oesophageal cancers. MUSK effectively combined complementary information from pathology images and clinical reports and could potentially improve diagnosis and precision in cancer therapy.

『Abstract』Cancer cells require high levels of iron for rapid proliferation, leading to significant upregulation of cell-surface transferrin receptor 1 (TfR1), which mediates iron uptake by binding to the iron-carrying protein transferrin . Leveraging this phenomenon and the fast endocytosis rate of TfR1 (refs. ), we developed transferrin receptor targeting chimeras (TransTACs), a heterobispecific antibody modality for membrane protein degradation. TransTACs are engineered to drive rapid co-internalization of a target protein of interest and TfR1 from the cell surface, and to enable target protein entry into the lysosomal degradation pathway. We show that TransTACs can efficiently degrade a diverse range of single-pass, multi-pass, native or synthetic membrane proteins, including epidermal growth factor receptor, programmed cell death 1 ligand 1, cluster of differentiation 20 and chimeric antigen receptor. In example applications, TransTACs enabled the reversible control of human primary chimeric antigen receptor T cells and the targeting of drug-resistant epidermal growth factor receptor-driven lung cancer with the exon 19 deletion/T790M/C797S mutations in a mouse xenograft model. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and targeted cancer therapy.

『Abstract』Exoplanet surveys have shown a class of abundant exoplanets smaller than Neptune on close, <100-day orbits . These planets form two populations separated by a natural division at about 1.8 R ⊕ termed the radius valley. It is uncertain whether these populations arose from separate dry versus water-rich formation channels, evolved apart because of long-term atmospheric loss or a combination of both . Here we report observations of ongoing hydrogen loss from two sibling planets, TOI-776 b (1.85 ± 0.13 R ⊕ ) and TOI-776 c (2.02 ± 0.14 R ⊕ ), the sizes of which near the radius valley and mature (1–4 Gyr) age make them valuable for investigating the origins of the divided population of which they are a part. During the transits of these planets, absorption appeared against the Lyman-α emission of the host star, compatible with hydrogen escape at rates equivalent to 0.03–0.6% and 0.1–0.9% of the total mass per billion years of each planet, respectively. Observations of the outer planet, TOI-776 c, are incompatible with an outflow of dissociated steam, suggesting both it and its inner sibling formed in a dry environment. These observations support the strong role of hydrogen loss in the evolution of close-orbiting sub-Neptunes .

『Abstract』Hippocampal circuits in the brain enable two distinct cognitive functions: the construction of spatial maps for navigation, and the storage of sequential episodic memories . Although there have been advances in modelling spatial representations in the hippocampus , we lack good models of its role in episodic memory. Here we present a neocortical–entorhinal–hippocampal network model that implements a high-capacity general associative memory, spatial memory and episodic memory. By factoring content storage from the dynamics of generating error-correcting stable states, the circuit (which we call vector hippocampal scaffolded heteroassociative memory (Vector-HaSH)) avoids the memory cliff of prior memory models , and instead exhibits a graceful trade-off between number of stored items and recall detail. A pre-structured internal scaffold based on grid cell states is essential for constructing even non-spatial episodic memory: it enables high-capacity sequence memorization by abstracting the chaining problem into one of learning low-dimensional transitions. Vector-HaSH reproduces several hippocampal experiments on spatial mapping and context-based representations, and provides a circuit model of the ‘memory palaces’ used by memory athletes . Thus, this work provides a unified understanding of the spatial mapping and associative and episodic memory roles of the hippocampus.

『Abstract』Lithium (Li) ions are central to the energy storing functionality of rechargeable batteries . Present technology relies on sophisticated Li-inclusive electrode materials to provide Li ions and exactingly protect them to ensure a decent lifetime . Li-deficient materials are thus excluded from battery design, and the battery fails when active Li ions are consumed . Our study breaks this limit by means of a cell-level Li supply strategy. This involves externally adding an organic Li salt into an assembled cell, which decomposes during cell formation, liberating Li ions and expelling organic ligands as gases. This non-invasive and rapid process preserves cell integrity without necessitating disassembly. We leveraged machine learning to discover such functional salts and identified lithium trifluoromethanesulfinate (LiSO 2 CF 3 ) with optimal electrochemical activity, potential, product formation, electrolyte solubility and specific capacity. As a proof-of-concept, we demonstrated a 3.0 V, 1,192 Wh kg Li-free cathode, chromium oxide, in the anode-less cell, as well as an organic sulfurized polyacrylonitrile cathode incorporated in a 388 Wh kg pouch cell with a 440-cycle life. These systems exhibit improved energy density, enhanced sustainability and reduced cost compared with conventional Li-ion batteries. Furthermore, the lifetime of commercial LiFePO 4 batteries was extended by at least an order of magnitude. With repeated external Li supplies, a commercial graphite|LiFePO 4 cell displayed a capacity retention of 96.0% after 11,818 cycles.

『Abstract』Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis . However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule β (RELMβ) is a critical regulator of oral tolerance. RELMβ is abundant in the sera of both patients with FA and mouse models of FA. Deletion of RELMβ protects mice from FA and the development of food-antigen-specific IgE and anaphylaxis. RELMβ disrupts food tolerance through the modulation of the gut microbiome and depletion of indole-metabolite-producing Lactobacilli and Alistipes . Tolerance is maintained by the local production of indole derivatives driving FA protective RORγt regulatory T (T reg ) cells through activation of the aryl hydrocarbon receptor. RELMβ antagonism in the peri-weaning period restores oral tolerance and protects genetically prone offspring from developing FA later in life. Together, we show that RELMβ mediates a gut immune–epithelial circuit regulating tolerance to food antigens—a novel mode of innate control of adaptive immunity through microbiome editing—and identify targetable candidates in this circuit for prevention and treatment of FA.

『Abstract』Aromatic compounds are used across chemistry and materials science as a result of their stability, characteristic interactions, defined molecular shape and the numerous approaches for their synthesis by a diversity of cyclization reactions . By contrast, the cleavage of inert aromatic carbon–carbon bonds remained largely unfeasible owing to the unfavourable energetics of disrupting aromaticity on ring opening. For non-aromatic structures, alkene metathesis catalysed by transition-metal alkylidenes is established as one of the most versatile carbon–carbon bond-forming and -breaking reactions . However, despite remarkable advancements, strategies to open aromatic compounds by metathesis remain elusive . Here we report aromatic ring-opening metathesis (ArROM) for the cleavage of aromatic rings, including tetraphene, naphthalene, indole, benzofuran and phenanthrenes, by using Schrock–Hoveyda molybdenum catalysts. The reactions for each ring system proceed through unique alkylidene intermediates. We further show the possibility for stereoselective ArROM with exquisite catalyst control over the configuration of atropisomers. ArROM is, therefore, a viable and efficient approach to catalytically transform and interconvert various aromatics without the requirement for any reagents or photoexcitation.

『Abstract』Nutrient acquisition is crucial for sustaining life. Plants develop beneficial intracellular partnerships with arbuscular mycorrhiza (AM) and nitrogen-fixing bacteria to surmount the scarcity of soil nutrients and tap into atmospheric dinitrogen, respectively . Initiation of these root endosymbioses requires symbiont-induced oscillations in nuclear calcium (Ca ) concentrations in root cells . How the nuclear-localized ion channels, cyclic nucleotide-gated channel (CNGC) 15 and DOESN’T MAKE INFECTIONS1 (DMI1) are coordinated to specify symbiotic-induced nuclear Ca oscillations remains unknown. Here we discovered an autoactive CNGC15 mutant that generates spontaneous low-frequency Ca oscillations. While CNGC15 produces nuclear Ca oscillations via a gating mechanism involving its helix 1, DMI1 acts as a pacemaker to specify the frequency of the oscillations. We demonstrate that the specificity of symbiotic-induced nuclear Ca oscillations is encoded in its frequency. A high frequency activates endosymbiosis programmes, whereas a low frequency modulates phenylpropanoid pathways. Consequently, the autoactive cngc15 mutant, which is capable of generating both frequencies, has increased flavonoids that enhance AM, root nodule symbiosis and nutrient acquisition. We transferred this trait to wheat, resulting in field-grown wheat with increased AM colonization and nutrient acquisition. Our findings reveal a new strategy to boost endosymbiosis in the field and reduce inorganic fertilizer use while sustaining plant growth.

『Abstract』Zinc is emerging as a key material for next-generation biodegradable implants . However, its inherent softness limits its use in load-bearing orthopaedic implants. Although reducing the grain size of zinc can make it stronger, it also destabilizes its mechanical properties and thus makes it less durable at body temperature . Here we show that extruded Zn alloys of dilute compositions can achieve ultrahigh strength and excellent durability when their micron-scale grain size is increased while maintaining a basal texture. In this inverse Hall–Petch effect, the dominant deformation mode changes from inter-granular grain boundary sliding and dynamic recrystallization at the original grain size to intra-granular pyramidal slip and unusual twinning at the increased grain size. The role of the anomalous twins, termed ‘accommodation twins’ in this work, is to accommodate the altered grain shape in the plane lying perpendicular to the external loading direction, in contrast to the well-known ‘mechanical twins’ whose role is to deliver plasticity along the external loading direction . The strength level achieved in these dilute zinc alloys is nearly double those of biodegradable implants made of magnesium alloys—making them the strongest and most stable biodegradable alloys available, to our knowledge, for fabricating bone fixation implants.

『Abstract』Mitigating loss of genetic diversity is a major global biodiversity challenge . To meet recent international commitments to maintain genetic diversity within species , we need to understand relationships between threats, conservation management and genetic diversity change. Here we conduct a global analysis of genetic diversity change via meta-analysis of all available temporal measures of genetic diversity from more than three decades of research. We show that within-population genetic diversity is being lost over timescales likely to have been impacted by human activities, and that some conservation actions may mitigate this loss. Our dataset includes 628 species (animals, plants, fungi and chromists) across all terrestrial and most marine realms on Earth. Threats impacted two-thirds of the populations that we analysed, and less than half of the populations analysed received conservation management. Genetic diversity loss occurs globally and is a realistic prediction for many species, especially birds and mammals, in the face of threats such as land use change, disease, abiotic natural phenomena and harvesting or harassment. Conservation strategies designed to improve environmental conditions, increase population growth rates and introduce new individuals (for example, restoring connectivity or performing translocations) may maintain or even increase genetic diversity. Our findings underscore the urgent need for active, genetically informed conservation interventions to halt genetic diversity loss.

『Abstract』Transcriptional activation of the embryonic genome (EGA) is a major developmental landmark enabling the embryo to become independent from maternal control. The magnitude and control of transcriptional reprogramming during this event across mammals remains poorly understood. Here, we developed Smart-seq+5′ for high sensitivity, full-length transcript coverage and simultaneous capture of 5′ transcript information from single cells and single embryos. Using Smart-seq+5′, we profiled 34 developmental stages in 5 mammalian species and provide an extensive characterization of the transcriptional repertoire of early development before, during, and after EGA. We demonstrate widespread transposable element (TE)-driven transcription across species, including, remarkably, of DNA transposons. We identify 19,657 TE-driven genic transcripts, suggesting extensive TE co-option in early development over evolutionary timescales. TEs display similar expression dynamics across species and species-specific patterns, suggesting shared and divergent regulation. Our work provides a powerful resource for understanding transcriptional regulation of mammalian development.

『Abstract』Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.

『Abstract』The ongoing circulation of highly pathogenic avian influenza (HPAI) A (H5N1) viruses, particularly clade 2.3.4.4b strains, poses a significant threat to animal and public health. Recent outbreaks in cattle highlight concerns about cross-species transmission and zoonotic spillover. Here, we found that the hemagglutinin (HA) protein from a cattle-infecting H5N1 virus has acquired slight binding to human-like α2-6-linked receptors while still exhibiting a strong preference for avian-like α2-3-linked sialic acid receptors. Immunohistochemical staining revealed HA binding to bovine pulmonary and mammary tissues, aligning with clinical observations. HA also binds effectively to human conjunctival, tracheal, and mammary tissues, indicating a risk for human transmission, notably in cases of conjunctivitis. High-resolution cryo-electron microscopy (cryo-EM) structures of this H5 HA in complex with either α2-3 or α2-6 receptors elucidate the molecular mechanisms underlying its receptor-binding properties. These findings provide critical insights into the tropism and transmission potential of this emerging pathogen.

『Abstract』Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O 2 ). In hypoxia, ubiquinol (UQH 2 ) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O 2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O 2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo . Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.

『Abstract』Sustained lymphocyte migration from blood into lymph nodes (LNs) is important for immune responses. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that the oxysterol biosynthetic enzyme cholesterol-25-hydroxylase (Ch25h) is upregulated in LN high endothelial venules during viral infection. Lymphocytes become dependent on oxysterols, generated through a transcellular endothelial-fibroblast metabolic pathway, and the receptor EBI2 for inflamed LN entry. Additionally, Langerhans cells are an oxysterol source. Ch25h is also expressed in inflamed peripheral endothelium, and EBI2 mediates B cell recruitment in a tumor model. Finally, we demonstrate that LN CCL19 is critical in lymphocyte recruitment during inflammation. Thus, our work explains how naive precursor trafficking is sustained in responding LNs, identifies a role for oxysterols in cell recruitment into inflamed tissues, and establishes a logic for the CCR7 two-ligand system.

『Abstract』The factors shaping human microbiome variation are a major focus of biomedical research. While other fields have used large sequencing compendia to extract insights requiring otherwise impractical sample sizes, the microbiome field has lacked a comparably sized resource for the 16S rRNA gene amplicon sequencing commonly used to quantify microbiome composition. To address this gap, we processed 168,464 publicly available human gut microbiome samples with a uniform pipeline. We use this compendium to evaluate geographic and technical effects on microbiome variation. We find that regions such as Central and Southern Asia differ significantly from the more thoroughly characterized microbiomes of Europe and Northern America and that composition alone can be used to predict a sample’s region of origin. We also find strong associations between microbiome variation and technical factors such as primers and DNA extraction. We anticipate this growing work, the Human Microbiome Compendium, will enable advanced applied and methodological research.

『Abstract』Membrane contact sites (MCSs) are fundamental for intracellular communication, but their role in intercellular communication remains unexplored. We show that in plants, plasmodesmata communication bridges function as atypical endoplasmic reticulum (ER)-plasma membrane (PM) tubular MCSs, operating at cell-cell interfaces. Similar to other MCSs, ER-PM apposition is controlled by a protein-lipid tethering complex, but uniquely, this serves intercellular communication. Combining high-resolution microscopy, molecular dynamics, and pharmacological and genetic approaches, we show that cell-cell trafficking is modulated through the combined action of multiple C2 domains transmembrane domain proteins (MCTPs) 3, 4, and 6 ER-PM tethers and phosphatidylinositol-4-phosphate (PI4P) lipid. Graded PI4P amounts regulate MCTP docking to the PM, their plasmodesmata localization, and cell-cell permeability. SAC7, an ER-localized PI4P-phosphatase, regulates MCTP4 accumulation at plasmodesmata and modulates cell-cell trafficking capacity in a cell-type-specific manner. Our findings expand MCS functions in information transmission from intracellular to intercellular cellular activities.

『Abstract』The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (m A), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m A and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation. We identify a set of genes whose expression is fine-tuned by both gene-body 5mC, which promotes transcription, and m A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m A are both essential for the differentiation of embryonic stem cells into embryoid bodies and that the upregulation of key differentiation genes during early differentiation depends on the dynamic balance between increased 5mC and decreased m A. Our findings add a surprising dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development and likely other biological processes.

『Abstract』Upon infection, human immunodeficiency virus type 1 (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T cells and macrophages. The capsid enters the nuclear pore complex (NPC), driven by interactions with numerous phenylalanine-glycine (FG)-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown, however. Here, we combined super-resolution and correlative microscopy with cryoelectron tomography and molecular simulations to study the nuclear entry of HIV-1 capsids in primary human macrophages. Our data indicate that cytosolically bound cyclophilin A is stripped off capsids entering the NPC, and the capsid hexagonal lattice remains largely intact inside and beyond the central channel. Strikingly, the NPC scaffold rings frequently crack during capsid passage, consistent with computer simulations indicating the need for NPC widening. The unique cone shape of the HIV-1 capsid facilitates its entry into NPCs and helps to crack their rings.

『Abstract』Xist RNA initiates X inactivation as it spreads in cis across the chromosome. Here, we reveal a biophysical basis for its cis -limited diffusion. Xist RNA and HNRNPK together drive a liquid-liquid phase separation (LLPS) that encapsulates the chromosome. HNRNPK droplets pull on Xist and internalize the RNA. Once internalized, Xist induces a further phase transition and “softens” the HNRNPK droplet. Xist alters the condensate’s deformability, adhesiveness, and wetting properties in vitro . Other Xist-interacting proteins are internalized and entrapped within the droplet, resulting in a concentration of Xist and protein partners within the condensate. We attribute LLPS to HNRNPK’s RGG and Xist’s repeat B (RepB) motifs. Mutating these motifs causes Xist diffusion, disrupts polycomb recruitment, and precludes the required mixing of chromosomal compartments for Xist’s migration. Thus, we hypothesize that phase transitions in HNRNPK condensates allow Xist to locally concentrate silencing factors and to spread through internal channels of the HNRNPK-encapsulated chromosome.

『Abstract』ATP-binding cassette (ABC) transporter subfamily H is only identified in arthropods and zebrafish. It transports lipids and is related to insecticide resistance. However, the precise mechanisms of its functions remain elusive. Here, we report cryoelectron microscopy (cryo-EM) structures of an ABCH from Tribolium castaneum , a worldwide pest of stored grains, in complex with an HEK293 cell-ceramide lipid, a fluorescent-labeled ceramide, a carbamate insecticide, and a maltose detergent inhibitor. We revealed a narrow, long, and arched substrate-binding tunnel in the transmembrane domains of the transporter dimer with two arginine-gated cytoplasmic entries for the binding and transport of lipids or insecticides. A pair of glutamines above the tunnel acts as a gate for directing substrate to be extruded via a vent-like hydrophilic exit to the extracellular side of the membrane upon ATP binding. Our structures and biochemical data provide mechanistic understanding of lipid transport, insecticide detoxification, and the inhibition of transporter activity by branched maltose detergents.

『Abstract』Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine α1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.

『Abstract』This study investigated the cervicovaginal microbiome’s (CVM’s) impact on Chlamydia trachomatis (CT) infection among Black and Hispanic adolescent and young adult women. A total of 187 women with incident CT were matched to 373 controls, and the CVM was characterized before, during, and after CT infection. The findings highlight that a specific subtype of bacterial vaginosis (BV), identified from 16S rRNA gene reads using the molBV algorithm and community state type (CST) clustering, is a significant risk factor for CT acquisition. A microbial risk score (MRS) further identified a network of bacterial genera associated with increased CT risk. Post treatment, the CVM associated with CT acquisition re-emerged in a different subset of cases leading to reinfection. Additionally, the analysis showed a connection between post-treatment CVM and the development of pelvic inflammatory disease (PID) and miscarriage, further underscoring the CVM’s contributing role to incident CT natural history and highlighting its consideration as a therapeutic target.

『Abstract』Defining the subcellular distribution of all human proteins and their remodeling across cellular states remains a central goal in cell biology. Here, we present a high-resolution strategy to map subcellular organization using organelle immunocapture coupled to mass spectrometry. We apply this workflow to a cell-wide collection of membranous and membraneless compartments. A graph-based analysis assigns the subcellular localization of over 7,600 proteins, defines spatial networks, and uncovers interconnections between cellular compartments. Our approach can be deployed to comprehensively profile proteome remodeling during cellular perturbation. By characterizing the cellular landscape following HCoV-OC43 viral infection, we discover that many proteins are regulated by changes in their spatial distribution rather than by changes in abundance. Our results establish that proteome-wide analysis of subcellular remodeling provides key insights for elucidating cellular responses, uncovering an essential role for ferroptosis in OC43 infection. Our dataset can be explored at organelles.czbiohub.org .

『Abstract』Nanoparticle vaccines displaying combinations of SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) could protect against SARS-CoV-2 variants and spillover of zoonotic sarbecoviruses into humans. Using a computational approach, we designed variants of SARS-CoV-2 RBDs and selected 7 natural sarbecovirus RBDs, each predicted to fold properly and abrogate antibody responses to variable epitopes. RBDs were attached to 60-mer nanoparticles to make immunogens displaying two (mosaic-2 COM s), five (mosaic-5 COM ), or seven (mosaic-7 COM ) different RBDs for comparisons with mosaic-8b, which elicited cross-reactive antibodies and protected animals from sarbecovirus challenges. Naive and COVID-19 pre-vaccinated mice immunized with mosaic-7 COM elicited antibodies targeting conserved RBD epitopes, and their sera exhibited higher binding and neutralization titers against sarbecoviruses than mosaic-8b. Mosaic-2 COM s and mosaic-5 COM elicited higher antibody potencies against some SARS-CoV-2 variants than mosaic-7 COM . However, mosaic-7 COM elicited more potent responses against zoonotic sarbecoviruses and highly mutated Omicrons, supporting its use to protect against SARS-CoV-2 variants and zoonotic sarbecoviruses.