前沿速递 | NCS 集萃： 2025-03-07 期 [Up]

『Abstract』Abstract Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive. We report a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development. We show evidence for the existence of a similar program in humans and identify specific fungi and bacteria that are sufficient for β cell growth. The microbiota also plays an important role in seeding islet-resident macrophages, and macrophage depletion during development reduces β cells. Candida dubliniensis increases β cells in a macrophage-dependent manner through distinctive cell wall composition and reduces murine diabetes incidence. Provision of C. dubliniensis after β cell ablation or antibiotic treatment improves β cell function. These data identify fungi as critical early-life commensals that promote long-term metabolic health.

『Abstract』Abstract Cells have evolved mechanisms to distribute ~10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must assemble. In this study, we demonstrate that proteins with shared functions share amino acid sequence codes that guide them to compartment destinations. We developed a protein language model, ProtGPS, that predicts with high performance the compartment localization of human proteins excluded from the training set. ProtGPS successfully guided generation of novel protein sequences that selectively assemble in the nucleolus. ProtGPS identified pathological mutations that change this code and lead to altered subcellular localization of proteins. Our results indicate that protein sequences contain not only a folding code but also a previously unrecognized code governing their distribution to diverse subcellular compartments.

『Abstract』Abstract DNA G-quadruplexes (G4s) are non–B-form DNA secondary structures that threaten genome stability by impeding DNA replication. To elucidate how G4s induce replication fork arrest, we characterized fork collisions with preformed G4s in the parental DNA using reconstituted yeast and human replisomes. We demonstrate that a single G4 in the leading strand template is sufficient to stall replisomes by arresting the CMG helicase. Cryo–electron microscopy structures of stalled yeast and human CMG complexes reveal that the folded G4 is lodged inside the central CMG channel, arresting translocation. The G4 stabilizes the CMG at distinct translocation intermediates, suggesting an unprecedented helical inchworm mechanism for DNA translocation. These findings illuminate the eukaryotic replication fork mechanism under normal and perturbed conditions.

『Abstract』Abstract Methods for making high-spring-index polymer fiber or yarn muscles have required expensive fabrication by wrapping around a mandrel, which limits their practical applications. We demonstrate an inexpensive mandrel-free method for making polymer muscles that can have a spring index of >50 and a contractile tensile stroke exceeding 97%. This method enables the spring index to be varied along a muscle’s length by varying the plying twist, resulting in muscles that transition between homochiral and heterochiral when either heated or cooled. We demonstrate use of these polymer muscles for robots and environmentally driven comfort-adjusting jackets. This mandrel-free method was used to make high-spring-index carbon nanotube yarns for mechanical energy harvesters, self-powered strain sensors, and solvent-driven and electrochemically driven artificial muscles.

『Abstract』Abstract Manioc—also called cassava and yuca—is among the world’s most important crops, originating in South America in the early Holocene. Domestication for its starchy roots involved a near-total shift from sexual to clonal propagation, and almost all manioc worldwide is now grown from stem cuttings. In this work, we analyze 573 new and published genomes, focusing on traditional varieties from the Americas and wild relatives from herbaria, to reveal the effects of this shift to clonality. We observe kinship over large distances, maintenance of high genetic diversity, intergenerational heterozygosity enrichment, and genomic mosaics of identity-by-descent haploblocks that connect all manioc worldwide. Interviews with Indigenous traditional farmers in the Brazilian Cerrado illuminate how traditional management strategies for sustaining, diversifying, and sharing the gene pool have shaped manioc diversity.

『Abstract』Abstract The lattice deformation and structural evolution of perovskite films in response to electric fields, temperature, and light limit the operational endurance of solar cells. We mechanically reinforced perovskite thin films by integrating a polymer-coupled monolithic single-layer graphene interface that led to a twofold enhancement in modulus and hardness. The synergistic effect of graphene and poly(methyl methacrylate) restricted photoinduced lattice expansion and decreased the deformation ratio from 0.31 to 0.08%, which minimized the structural damage caused by dynamic lattice evolution. Solar cell devices maintained >97% of their initial power conversion efficiency after maximum power point tracking for >3670 hours under full-spectrum air mass 1.5 global (AM 1.5 G) sunlight at 90°C.

『Abstract』Abstract Understanding the capacity of forests to adapt to climate change is of pivotal importance for conservation science, yet this is still widely unknown. This knowledge gap is particularly acute in high-biodiversity tropical forests. Here, we examined how tropical forests of the Americas have shifted community trait composition in recent decades as a response to changes in climate. Based on historical trait-climate relationships, we found that, overall, the studied functional traits show shifts of less than 8% of what would be expected given the observed changes in climate. However, the recruit assemblage shows shifts of 21% relative to climate change expectation. The most diverse forests on Earth are changing in functional trait composition but at a rate that is fundamentally insufficient to track climate change.

『Abstract』Abstract Deconstructive transformation of carbon-carbon double bonds (C=C) is a pivotal strategy in synthetic chemistry and drug discovery. Despite the substantial advances in olefin metathesis and ozonolysis for natural product synthesis through C=C double-bond cleavage, the catalytic remodeling of complex molecules through C=C double-bond deconstruction has been underdeveloped. We report a heterogeneous copper-catalyzed C=C double-bond cleavage, which enables the remodeling of complex molecules by converting the carbons on either side of the C=C double bond to carbonyl and cyano groups, respectively. In particular, this method provides an efficient protocol to conveniently transform terpenoids, glycals, steroids, and bioactive molecules to privileged scaffolds with underexplored chemical space.

『Abstract』Abstract The ultrafast manipulation of molecular states by charge transfer is essential for characterizing and controlling molecular dynamics. In this study, we demonstrated exciton formation in a single molecule through ultrafast electron tunneling processes between a molecule and a metal tip of a scanning tunneling microscope (STM) using a phase-controlled terahertz (THz) pulse. The pronounced luminescence of the well-defined molecular system under the distinct carrier-envelope phase of the THz pulse revealed that sequential state-selective electron-tunneling processes to the frontier molecular orbitals promoted ultrafast exciton formation in the molecule at the STM junction. Furthermore, ultrafast control of exciton formation was achieved using phase- and delay-controlled THz pulse pairs, providing a route for the regulation of molecular dynamics and the emergence of new molecular functions.

『Abstract』Abstract Numerous declines have been documented across insect groups, and the potential consequences of insect losses are dire. Butterflies are the most surveyed insect taxa, yet analyses have been limited in geographic scale or rely on data from a single monitoring program. Using records of 12.6 million individual butterflies from >76,000 surveys across 35 monitoring programs, we characterized overall and species-specific butterfly abundance trends across the contiguous United States. Between 2000 and 2020, total butterfly abundance fell by 22% across the 554 recorded species. Species-level declines were widespread, with 13 times as many species declining as increasing. The prevalence of declines throughout all regions in the United States highlights an urgent need to protect butterflies from further losses.

『Abstract』Abstract The synthesis of nitrogen-containing molecules through carbon–nitrogen (C–N) bond formation is critical for the discovery and preparation of medicines, agrochemicals, and materials. Here, we report the direct insertion of a nitrogen atom into unactivated carbon-carbon double bonds to access aza-allenium intermediates, which can be converted either into nitriles or amidine products, depending on the initial alkene substitution pattern. This operationally simple and highly functionally compatible reaction works on a wide range of unactivated alkenes. PIFA, a commercially available and inexpensive hypervalent iodine reagent, is key to this reactivity. Our mechanistic proposal is supported by chemical trapping experiments, which concomitantly demonstrate the utility of our method to access valuable N -heterocycles. Additionally, our method can be used as a general strategy for synthesizing amides and amines, as well as N-labeled molecules.

『Abstract』Abstract The regulation of messenger RNA (mRNA) and protein abundances is well-studied, but less is known about the evolutionary processes shaping their relationship. To address this, we derived a new phylogenetic model and applied it to multispecies mammalian data. Our analyses reveal (i) strong stabilizing selection on protein abundances over macroevolutionary time, (ii) mutations affecting mRNA abundances minimally impact protein abundances, (iii) mRNA abundances evolve under selection to align with protein abundances, and (iv) mRNA abundances adapt faster than protein abundances owing to greater mutational opportunity. These conclusions are supported by comparisons of model parameters with independent functional genomic data. By decomposing mutational and selective influences on mRNA-protein dynamics, our approach provides a framework for discovering the evolutionary rules that drive divergence in gene expression.

『Abstract』Abstract Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8 dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.

『Abstract』Abstract Millions of ribosomes are packed within mammalian cells, yet we lack tools to visualize them in toto and characterize their subcellular composition. In this study, we present ribosome expansion microscopy (RiboExM) to visualize individual ribosomes and an optogenetic proximity-labeling technique (ALIBi) to probe their composition. We generated a super-resolution ribosomal map, revealing subcellular translational hotspots and enrichment of 60 S subunits near polysomes at the endoplasmic reticulum (ER). We found that Lsg1 tethers 60 S to the ER and regulates translation of select proteins. Additionally, we discovered ribosome heterogeneity at mitochondria guiding translation of metabolism-related transcripts. Lastly, we visualized ribosomes in neurons, revealing a dynamic switch between monosomes and polysomes in neuronal translation. Together, these approaches enable exploration of ribosomal localization and composition at unprecedented resolution.

『Abstract』Abstract Global change drives biodiversity shifts worldwide, but these shifts are poorly understood in highly diverse tropical regions. In tropical mountains, plants are mostly expected to migrate upslope in response to warming. To assess this, we analyze shifts in elevation ranges of species in Mesoamerican cloud forests using three decades of species’ occurrence records. Our findings reveal a mean upslope shift of 1.8 to 2.7 meters per year since 1979 driven by the upslope retreat of the less thermophilic montane species. These shifts are mostly accompanied by retreating lower and upper edges attributed to varying degrees of species’ exposure to deforestation and climate change. Our results highlight the vulnerability of cloud forests under global change and the urgency to increase monitoring of species’ responses.

『Abstract』Neurons in the hippocampus are correlated with different variables, including space, time, sensory cues, rewards and actions, in which the extent of tuning depends on ongoing task demands . However, it remains uncertain whether such diverse tuning corresponds to distinct functions within the hippocampal network or whether a more generic computation can account for these observations . Here, to disentangle the contribution of externally driven cues versus internal computation, we developed a task in mice in which space, auditory tones, rewards and context were juxtaposed with changing relevance. High-density electrophysiological recordings revealed that neurons were tuned to each of these modalities. By comparing movement paths and action sequences, we observed that external variables had limited direct influence on hippocampal firing. Instead, spiking was influenced by online action plans and modulated by goal uncertainty. Our results suggest that internally generated cell assembly sequences are selected and updated by action plans towards deliberate goals. The apparent tuning of hippocampal neuronal spiking to different sensory modalities might emerge due to alignment to the afforded action progression within a task rather than representation of external cues.

『Abstract』For nearly 450 million years, mycorrhizal fungi have constructed networks to collect and trade nutrient resources with plant roots . Owing to their dependence on host-derived carbon, these fungi face conflicting trade-offs in building networks that balance construction costs against geographical coverage and long-distance resource transport to and from roots . How they navigate these design challenges is unclear . Here, to monitor the construction of living trade networks, we built a custom-designed robot for high-throughput time-lapse imaging that could track over 500,000 fungal nodes simultaneously. We then measured around 100,000 cytoplasmic flow trajectories inside the networks. We found that mycorrhizal fungi build networks as self-regulating travelling waves—pulses of growing tips pull an expanding wave of nutrient-absorbing mycelium, the density of which is self-regulated by fusion. This design offers a solution to conflicting trade demands because relatively small carbon investments fuel fungal range expansions beyond nutrient-depletion zones, fostering exploration for plant partners and nutrients. Over time, networks maintained highly constant transport efficiencies back to roots, while simultaneously adding loops that shorten paths to potential new trade partners. Fungi further enhance transport flux by both widening hyphal tubes and driving faster flows along ‘trunk routes’ of the network . Our findings provide evidence that symbiotic fungi control network-level structure and flows to meet trade demands, and illuminate the design principles of a symbiotic supply-chain network shaped by millions of years of natural selection.

『Abstract』Since the onset of the pandemic, many SARS-CoV-2 variants have emerged, exhibiting substantial evolution in the virus’ spike protein , the main target of neutralizing antibodies . A plausible hypothesis proposes that the virus evolves to evade antibody-mediated neutralization (vaccine- or infection-induced) to maximize its ability to infect an immunologically experienced population . Because viral infection induces neutralizing antibodies, viral evolution may thus navigate on a dynamic immune landscape that is shaped by local infection history. Here we developed a comprehensive mechanistic model, incorporating deep mutational scanning data , antibody pharmacokinetics and regional genomic surveillance data, to predict the variant-specific relative number of susceptible individuals over time. We show that this quantity precisely matched historical variant dynamics, predicted future variant dynamics and explained global differences in variant dynamics. Our work strongly suggests that the ongoing pandemic continues to shape variant-specific population immunity, which determines a variant’s ability to transmit, thus defining variant fitness. The model can be applied to any region by utilizing local genomic surveillance data, allows contextualizing risk assessment of variants and provides information for vaccine design.

『Abstract』Extreme droughts generally decrease productivity in grassland ecosystems with negative consequences for nature’s contribution to people . The extent to which this negative effect varies among grassland types and over time in response to multi-year extreme drought remains unclear. Here, using a coordinated distributed experiment that simulated four years of growing-season drought (around 66% rainfall reduction), we compared drought sensitivity within and among six representative grasslands spanning broad precipitation gradients in each of Eurasia and North America—two of the Northern Hemisphere’s largest grass-dominated regions. Aboveground plant production declined substantially with drought in the Eurasian grasslands and the effects accumulated over time, while the declines were less severe and more muted over time in the North American grasslands. Drought effects on species richness shifted from positive to negative in Eurasia, but from negative to positive in North America over time. The differing responses of plant production in these grasslands were accompanied by less common (subordinate) plant species declining in Eurasian grasslands but increasing in North American grasslands. Our findings demonstrate the high production sensitivity of Eurasian compared with North American grasslands to extreme drought (43.6% versus 25.2% reduction), and the key role of subordinate species in determining impacts of extreme drought on grassland productivity.

『Abstract』In subsurface methanogenic ecosystems, the ubiquity of methylated-compound-using archaea—methylotrophic methanogens —implies that methylated compounds have an important role in the ecology and carbon cycling of such habitats. However, the origin of these chemicals remains unclear as there are no known energy metabolisms that generate methylated compounds de novo as a major product. Here we identified an energy metabolism in the subsurface-derived thermophilic anaerobe Zhaonella formicivorans that catalyses the conversion of formate to methanol, thereby producing methanol without requiring methylated compounds as an input. Cultivation experiments showed that formate-driven methanologenesis is inhibited by the accumulation of methanol. However, this limitation can be overcome through methanol consumption by a methylotrophic partner methanogen, Methermicoccus shengliensis . This symbiosis represents a fourth mode of mutualistic cross-feeding driven by thermodynamic necessity (syntrophy), previously thought to rely on transfer of hydrogen, formate or electrons . The unusual metabolism and syntrophy provide insights into the enigmatic presence of methylated compounds in subsurface methanogenic ecosystems and demonstrate how organisms survive at the thermodynamic limit through metabolic symbiosis.

『Abstract』Multijunction photovoltaics (PVs) are gaining prominence owing to their superior capability of achieving power conversion efficiencies (PCEs) beyond the radiative limit of single-junction cells , for which improving narrow-bandgap (NBG) tin–lead perovskites is critical for thin-film devices . Here, with a focus on understanding the chemistry of tin–lead perovskite precursor solutions, we find that Sn( ii ) species dominate interactions with precursors and additives and uncover the exclusive role of carboxylic acid in regulating solution colloidal properties and film crystallization and ammonium in improving film optoelectronic properties. Materials that combine these two functional groups, amino acid salts, considerably improve the semiconducting quality and homogeneity of perovskite films, surpassing the effect of the individual functional groups when introduced as part of separate molecules. Our enhanced tin–lead perovskite layer allows us to fabricate solar cells with PCEs of 23.9%, 29.7% (certified 29.26%) and 28.7% for single-junction, double-junction and triple-junction devices, respectively. Our 1-cm triple-junction devices show PCEs of 28.4% (certified 27.28%). Encapsulated triple-junction cells maintain 80% of their initial efficiencies after 860 h maximum power point tracking (MPPT) in ambient. We further fabricate quadruple-junction devices and obtain PCEs of 27.9% with the highest open-circuit voltage of 4.94 V. This work establishes a new benchmark for multijunction PVs.

『Abstract』UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal . By co-opting KBTBD4, a substrate receptor of the CUL3–RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1–CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition . However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1–HDAC1–CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3–neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST–HDAC1/2–KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1 . By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.

『Abstract』Intra-atomic orbital hybridization and interatomic bond formation are the two fundamental processes when real atoms are condensed to form matter . Artificial atoms mimic real atoms by demonstrating discrete energy levels attributable to quantum confinement . As such, they offer a solid-state analogue for simulating intra-atomic orbital hybridization and interatomic bond formation. Signatures of interatomic bond formation have been extensively observed in various artificial atoms . However, direct evidence of the intra-atomic orbital hybridization in the artificial atoms remains to be experimentally demonstrated. Here we realize the orbital hybridization in artificial atoms by altering the shape of the artificial atoms. The anisotropy of the confining potential gives rise to the hybridization between quasibound states with different orbital quantum numbers within the artificial atom. These hybridized orbits are directly visualized in real space in our experiment and are well reproduced by both numerical calculations and analytical derivations. Our study opens an avenue for designing artificial matter that cannot be accessed on real atoms through experiments. Moreover, the results obtained inspire the progressive control of quantum states in diverse systems.

『Abstract』Argonaute proteins are categorized into AGO and PIWI clades. Across most animal species, AGO-clade proteins are widely expressed in various cell types, and regulate normal gene expression . By contrast, PIWI-clade proteins predominantly function during gametogenesis to suppress transposons and ensure fertility . Both clades use nucleic acid guides for target recognition by means of base pairing, crucial for initiating target silencing, often through direct cleavage. AGO-clade proteins use a narrow channel to secure a tight guide–target interaction . By contrast, PIWI proteins feature a wider channel that potentially allows mismatches during pairing, broadening target silencing capability . However, the mechanism of PIWI-mediated target cleavage remains unclear. Here we demonstrate that after target binding, PIWI proteins undergo a conformational change from an ‘open’ state to a ‘locked’ state, facilitating base pairing and enhancing target cleavage efficiency. This transition involves narrowing of the binding channel and repositioning of the PIWI-interacting RNA–target duplex towards the MID-PIWI lobe, establishing extensive contacts for duplex stabilization. During this transition, we also identify an intermediate ‘comma-shaped’ conformation, which might recruit GTSF1, a known auxiliary protein that enhances PIWI cleavage activity . GTSF1 facilitates the transition to the locked state by linking the PIWI domain to the RNA duplex, thereby expediting the conformational change critical for efficient target cleavage. These findings explain the molecular mechanisms underlying PIWI–PIWI-interacting RNA complex function in target RNA cleavage, providing insights into how dynamic conformational changes from PIWI proteins coordinate cofactors to safeguard gametogenesis.

『Abstract』The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning . Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations . However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here we establish a mouse model that enables simultaneous genetic access to the brain’s DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signalling and decrease 5HT signalling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioural deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive the acquisition of new associations and supported reinforcement more potently than either manipulation did alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement.

『Abstract』Tropical deforestation was found to cause large reductions in precipitation using a range of observation-based datasets . However, the limitations of satellite-based space-for-time statistical analysis have hindered understanding of the roles of reshaped mesoscale atmospheric circulation and regional precipitation recycling at different scales. These effects are considered nonlocal effects, which are distinct from the local effects governed by deforestation-induced reductions in evapotranspiration (ET). Here we show reversed precipitation responses to Amazon deforestation across wet and dry seasons. During the wet season, deforested grids experienced a noteworthy increase in precipitation (0.96 mm month per percentage point forest loss), primarily attributed to enhanced mesoscale atmospheric circulation (that is, nonlocal effect). These nonlocal increases weaken with distance from deforested grids, leading to significant precipitation reductions in buffers beyond 60 km. Conversely, during the dry season, precipitation decreases in deforested grids and throughout all analysis buffers, with local effects from reduced ET dominating. Our findings highlight the intricate balance between local effects and nonlocal effects in driving deforestation–precipitation responses across different seasons and scales and emphasize the urgent need to address the rapid and extensive loss of forest in the Amazon region.

『Abstract』Cancer mutations can create neomorphic protein–protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma , the most common embryonal brain tumour in children . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST . However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1–HDAC1–CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3–neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4–HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein–protein interactions.

『Abstract』The North Pontic Region was the meeting point of the farmers of Old Europe and the foragers and pastoralists of the Eurasian steppe , and the source of migrations deep into Europe . Here we report genome-wide data from 81 prehistoric North Pontic individuals to understand the genetic makeup of its people. North Pontic foragers had ancestry from Balkan and Eastern hunter-gatherers as well as European farmers and, occasionally, Caucasus hunter-gatherers. During the Eneolithic period, a wave of migrants from the Caucasus–Lower Volga area bypassed local foragers to mix in equal parts with Trypillian farmers, forming the people of the Usatove culture around 4500 bce . A temporally overlapping wave of migrants from the Caucasus–Lower Volga blended with foragers instead of farmers to form Serednii Stih people . The third wave was the Yamna—descendants of the Serednii Stih who formed by mixture around 4000 bce and expanded during the Early Bronze Age (3300 bce ). The temporal gap between Serednii Stih and the Yamna is bridged by a genetically Yamna individual from Mykhailivka, Ukraine (3635–3383 bce ), a site of archaeological continuity across the Eneolithic–Bronze Age transition and a likely epicentre of Yamna formation. Each of these three waves of migration propagated distinctive ancestries while also incorporating outsiders, a flexible strategy that may explain the success of the peoples of the North Pontic in spreading their genes and culture across Eurasia .

『Abstract』The Casarabe culture (500–1400 ce ), spreading over roughly 4,500 km of the monumental mounds region of the Llanos de Moxos, Bolivia, is one of the clearest examples of urbanism in pre-Columbian (pre-1492 ce ) Amazonia. It exhibits a four-tier hierarchical settlement pattern, with hundreds of monumental mounds interconnected by canals and causeways . Despite archaeological evidence indicating that maize was cultivated by this society , it is unknown whether it was the staple crop and which type of agricultural farming system was used to support this urban-scale society. Here, we address this issue by integration of remote sensing, field survey and microbotanical analyses, which shows that the Casarabe culture invested heavily in landscape engineering, constructing a complex system of drainage canals (to drain excess water during the rainy season) and newly documented savannah farm ponds (to retain water in the dry season). Phytolith analyses of 178 samples from 18 soil profiles in drained fields, farm ponds and forested settings record the singular and ubiquitous presence of maize ( Zea mays ) in pre-Columbian fields and farm ponds, and an absence of evidence for agricultural practices in the forest. Collectively, our findings show how the Casarabe culture managed the savannah landscape for intensive year-round maize monoculture that probably sustained its relatively large population. Our results have implications for how we conceive agricultural systems in Amazonia, and show an example of a Neolithic-like, grain-based agrarian economy in the Amazon.

『Abstract』Antimicrobial compounds are essential for controlling bacterial infections. Stress-induced bacterial tolerance and persisters can undermine antimicrobial activities under laboratory conditions, but their quantitative effects under physiological conditions remain unclear . Here we determined constraints on clearance of Salmonella by antimicrobials in infected mice and tissue-mimicking chemostats. The antibiotics enrofloxacin and ceftriaxone exhibited poor anti- Salmonella activity under both conditions, primarily owing to severe nutrient starvation, which restricted Salmonella replication . Other infection-associated conditions, such as acidic pH, glucose, oxidative stress, nitrosative stress, antimicrobial peptides, osmolarity, oxygen limitation, carbon dioxide and carbonate, as well as drug efflux, toxin–antitoxin modules and cell size had limited effects. A subset of resilient Salmonella appeared as a key obstacle for clearance by enrofloxacin, based on the biphasic decline of Salmonella colony-forming units. However, these data were misleading, because colony formation was confounded by extensive post-exposure killing. More accurate single-cell, real-time assays showed uniformly slow damage, indicating high resilience across the entire Salmonella population. The resulting extensive survival of bulk bacteria minimized the effect of hyper-resilient persisters. Thus, starvation-induced general resilience of Salmonella was the main cause of poor antibiotic clearance. These findings highlight the importance of quantifying antibiotic activity with real-time, single-cell assays under physiological conditions.

『Abstract』Quantum networks that distribute entanglement among remote nodes will unlock transformational technologies in quantum computing, communication and sensing . However, state-of-the-art networks use only a single optically addressed qubit per node; this constrains both the quantum communication bandwidth and memory resources, greatly impeding scalability. Solid-state platforms provide a valuable resource for multiplexed quantum networking in which multiple spectrally distinguishable qubits can be hosted in nano-scale volumes. Here we harness this resource by implementing a two-node network consisting of several rare-earth ions coupled to nanophotonic cavities . This is accomplished with a protocol that entangles distinguishable Yb ions through frequency-erasing photon detection combined with real-time quantum feedforward. This method is robust to slow optical frequency fluctuations occurring on timescales longer than a single entanglement attempt: a universal challenge amongst solid-state emitters. We demonstrate the enhanced functionality of these multi-emitter nodes in two ways. First, we mitigate the bottlenecks to the entanglement distribution rate through multiplexed entanglement of two remote ion pairs . Second, we prepare multipartite W-states comprising three distinguishable ions as a resource for advanced quantum networking protocols . These results lay the groundwork for scalable quantum networking based on rare-earth ions.

『Abstract』Mergers of binary neutron stars emit signals in both the gravitational-wave (GW) and electromagnetic spectra. Famously, the 2017 multi-messenger observation of GW170817 (refs. ) led to scientific discoveries across cosmology , nuclear physics and gravity . Central to these results were the sky localization and distance obtained from the GW data, which, in the case of GW170817, helped to identify the associated electromagnetic transient, AT 2017gfo (ref. ), 11 h after the GW signal. Fast analysis of GW data is critical for directing time-sensitive electromagnetic observations. However, owing to challenges arising from the length and complexity of signals, it is often necessary to make approximations that sacrifice accuracy. Here we present a machine-learning framework that performs complete binary neutron star inference in just 1 s without making any such approximations. Our approach enhances multi-messenger observations by providing: (1) accurate localization even before the merger; (2) improved localization precision by around 30% compared to approximate low-latency methods; and (3) detailed information on luminosity distance, inclination and masses, which can be used to prioritize expensive telescope time. Additionally, the flexibility and reduced cost of our method open new opportunities for equation-of-state studies. Finally, we demonstrate that our method scales to long signals, up to an hour in length, thus serving as a blueprint for data analysis for next-generation ground- and space-based detectors.

『Abstract』Chirality is a ubiquitous and fundamental asymmetry in nature . Recently, the interaction of chiral objects with spin currents has attracted enormous attention from both scientific and technological perspectives . Of particular interest is the current-driven motion of chiral topological excitations such as chiral magnetic domain walls in chiral three-dimensional magnetic structures that could allow for high-density memory-storage devices. Here we use state-of-the-art multiphoton lithography to create three-dimensional chiral magnetic ribbons and perform current-induced motion of chiral domain walls. The ribbons are designed to have a clockwise or anticlockwise chiral twist with a variable magnitude. We find that domain walls can either pass through the ribbon or are impeded, depending on their chirality and configuration and the geometrical chiral twist of the ribbon. The interplay between the magnetic exchange energy and the geometrical twist generates a torsional field that favours chiral Bloch-type walls rather than the Neel-type wall favoured by the intrinsic magnetic properties of the magnetic ribbon itself. Furthermore, the interplay of spin chirality and chiral twist results in a non-reciprocal domain wall motion, namely, a domain wall filter or diode . Our findings show how the interplay between geometrical and spin chiralities can lead to new functionalities that could allow for innovative chiral spintronics.

『Abstract』Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more . Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity . At present, the only available treatments for snakebites consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs . Here we used deep learning methods to de novo design proteins to bind short-chain and long-chain α-neurotoxins and cytotoxins from the 3FTx family. With limited experimental screening, we obtained protein designs with remarkable thermal stability, high binding affinity and near-atomic-level agreement with the computational models. The designed proteins effectively neutralized all three 3FTx subfamilies in vitro and protected mice from a lethal neurotoxin challenge. Such potent, stable and readily manufacturable toxin-neutralizing proteins could provide the basis for safer, cost-effective and widely accessible next-generation antivenom therapeutics. Beyond snakebite, our results highlight how computational design could help democratize therapeutic discovery, particularly in resource-limited settings, by substantially reducing costs and resource requirements for the development of therapies for neglected tropical diseases.

『Abstract』The Yamnaya archaeological complex appeared around 3300 bc across the steppes north of the Black and Caspian Seas, and by 3000 bc it reached its maximal extent, ranging from Hungary in the west to Kazakhstan in the east. To localize Yamnaya origins among the preceding Eneolithic people, we assembled ancient DNA from 435 individuals, demonstrating three genetic clines. A Caucasus–lower Volga (CLV) cline suffused with Caucasus hunter-gatherer ancestry extended between a Caucasus Neolithic southern end and a northern end at Berezhnovka along the lower Volga river. Bidirectional gene flow created intermediate populations, such as the north Caucasus Maikop people, and those at Remontnoye on the steppe. The Volga cline was formed as CLV people mixed with upriver populations of Eastern hunter-gatherer ancestry, creating hypervariable groups, including one at Khvalynsk. The Dnipro cline was formed when CLV people moved west, mixing with people with Ukraine Neolithic hunter-gatherer ancestry along the Dnipro and Don rivers to establish Serednii Stih groups, from whom Yamnaya ancestors formed around 4000 bc and grew rapidly after 3750–3350 bc . The CLV people contributed around four-fifths of the ancestry of the Yamnaya and, entering Anatolia, probably from the east, at least one-tenth of the ancestry of Bronze Age central Anatolians, who spoke Hittite . We therefore propose that the final unity of the speakers of ‘proto-Indo-Anatolian’, the language ancestral to both Anatolian and Indo-European people, occurred in CLV people some time between 4400 bc and 4000 bc .

『Abstract』Hofstadter’s butterfly, the predicted energy spectrum for non-interacting electrons confined to a two-dimensional lattice in a magnetic field, is one of the most remarkable fractal structures in nature . At rational ratios of magnetic flux quanta per lattice unit cell, this spectrum shows self-similar distributions of energy levels that reflect its recursive construction. For most materials, Hofstadter’s butterfly is predicted under experimental conditions that are unachievable using laboratory-scale magnetic fields . More recently, electrical transport studies have provided evidence for Hofstadter’s butterfly in materials engineered to have artificially large lattice constants , such as those with moire superlattices . Yet, so far, direct spectroscopy of the fractal energy spectrum predicted by Hofstadter nearly 50 years ago has remained out of reach. Here we use high-resolution scanning tunnelling microscopy/spectroscopy (STM/STS) to investigate the flat electronic bands in twisted bilayer graphene (TBG) near the predicted second magic angle , an ideal setting for spectroscopic studies of Hofstadter’s spectrum. Our study shows the fractionalization of flat moire bands into discrete Hofstadter subbands and discerns experimental signatures of self-similarity of this spectrum. Moreover, our measurements uncover a spectrum that evolves dynamically with electron density, showing phenomena beyond that of Hofstadter’s original model owing to the combined effects of strong correlations, Coulomb interactions and the quantum degeneracy of electrons in TBG.

『Abstract』Soil alkalinization and global warming are predicted to pose major challenges to agriculture in the future, as they continue to accelerate, markedly reducing global arable land and crop yields . Therefore, strategies for future agriculture are needed to further improve globally cultivated, relatively high-yielding Green Revolution varieties (GRVs) derived from the SEMIDWARF 1 ( SD1 ) gene . Here we propose that precise regulation of the phytohormone gibberellin (GA) to optimal levels is the key to not only confer alkali–thermal tolerance to GRVs, but also to further enhance their yield. Endogenous modulation of ALKALI-THERMAL TOLERANCE 1/2 ( ATT1/2 ), quantitative trait loci encoding GA20-oxidases or exogenous application of GA minimized rice yield loss affected by sodic soils. Mechanistically, high GA concentrations induce reactive oxygen species over-accumulation, whereas low GA concentrations repress the expression of stress-tolerance genes by means of DELLA–NGR5-mediated H3K27me3 methylation. We further showed that ATT1 induces large fluctuations in GA levels, whereas ATT2 is the ideal candidate for fine-tuning GA concentrations to appropriate levels to balance reactive oxygen species and H3K27me3 methylation to improve alkali–thermal tolerance and yield. Thus, ATT2 is expected to be a potential new post-Green Revolution gene that could be harnessed to develop and use marginal lands for sustainable agriculture in the future.

『Abstract』Investigating glacial isostatic adjustment has been the standard method to decipher Earth’s interior viscosity structure , but such an approach has been rarely applied to other planets because of a lack of observational data . The north polar cap of Mars is the only millions-of-years-old surface feature that can induce measurable surface deformation on this planet, thereby holding clues to its present-day internal viscosity structure . Here we investigate the emplacement of this ice cap by combining thermal evolution models , viscoelastic deformation calculations and radar observations . We show that downward motion of the northern regions is ongoing and can be constrained by analyses of the time-variable gravity field and NASA’s InSight seismic moment rate . Only models with present-day high viscosities (2–6 × 10 Pa s for depths greater than 500 km), strong mantle depletion in radiogenic elements (more than 90%) and thick average crusts (thicker than 40 km) are consistent with the negligible flexure beneath the polar cap seen by radars. The northern lithosphere must deform at less than 0.13 mm per year and have a seismic efficiency less than 0.3 to satisfy gravity and seismic constraints, respectively. Our models show that the north polar cap formed over the last 1.7–12.0 Myr and that glacial isostatic adjustment can be further constrained by future gravity recovery missions to Mars .

『Abstract』Broadly neutralizing antibodies (bNAbs) show potential to prevent human immunodeficiency virus (HIV-1) infection in humans . However, there are limited data on the antibody concentrations required to prevent infection. Clinical trials of bNAb prophylaxis have demonstrated partial efficacy , but the sampling frequency typically does not allow precise timing of infection events and concurrent antibody levels. Here, using simian immunodeficiency virus (SIV) infection of rhesus macaques, we show that although potent bNAbs can delay the onset of acute viremia, subclinical infections occur while bNAb levels remain high. Serial SIV challenge of monkeys given partially and fully neutralizing bNAbs revealed that ‘viral blips’—low and transient plasma viremia—often occur while serum bNAb concentrations are well above currently accepted protective levels. To understand the precise timing of the infections resulting in such blips, we performed plasma viral sequencing on monkeys that were serially challenged with genetically barcoded SIV after bNAb administration. These analyses showed that subclinical infections occurred in most animals that were given potent bNAb prophylaxis. These subclinical infections occurred while antibody concentrations were 2- to 400-fold higher than the levels required to prevent fully viremic breakthrough infection. This study demonstrates that immunoprophylaxis can mask subclinical infections, which may affect the interpretation of prophylactic HIV-1 bNAb clinical trials.

『Abstract』Imaging inflammation holds immense potential for advancing the diagnosis, treatment and prognosis of many conditions . The lack of a specific and sensitive positron emission tomography (PET) probe to detect inflammation is a critical challenge. To bridge this gap, we present CD45-PET imaging, which detects inflammation with exceptional sensitivity and clarity in several preclinical models. Notably, the intensity of the CD45-PET signal correlates robustly with the severity of disease in models of inflammatory lung and bowel diseases, outperforming F-fluorodeoxyglucose PET, the most widely used imaging modality for inflammation globally. Longitudinal CD45-PET imaging further enables precise monitoring of dynamic changes in tissue-specific inflammatory profiles. Finally, we developed a human CD45-PET probe for clinical translation that effectively detects human immune cells in a humanized mouse model. CD45-PET imaging holds substantial clinical promise, offering a tool for guiding diagnostic and therapeutic decisions for inflammatory diseases through a precise, whole-body assessment of the inflammation profiles of individual patients.

『Abstract』Despite advancements in wearable technologies , barriers remain in achieving distributed computation located persistently on the human body. Here a textile fibre computer that monolithically combines analogue sensing, digital memory, processing and communication in a mass of less than 5 g is presented. Enabled by a foldable interposer, the two-dimensional pad architectures of microdevices were mapped to three-dimensional cylindrical layouts conforming to fibre geometry. Through connection with helical copper microwires, eight microdevices were thermally drawn into a machine-washable elastic fibre capable of more than 60% stretch. This programmable fibre, which incorporates a 32-bit floating-point microcontroller, independently performs edge computing tasks even when braided, woven, knitted or seam-sewn into garments. The universality of the assembly process allows for the integration of additional functions with simple modifications, including a rechargeable fibre power source that operates the computer for nearly 6 h. Finally, we surmount the perennial limitation of rigid interconnects by implementing two wireless communication schemes involving woven optical links and seam-inserted radio-frequency communications. To demonstrate its utility, we show that garments equipped with four fibre computers, one per limb, operating individually trained neural networks achieve, on average, 67% accuracy in classifying physical activity. However, when networked, inference accuracy increases to 95% using simple weighted voting.

『Abstract』Elastocaloric cooling using shape memory alloys (SMAs) has attracted considerable interest as an environmentally friendly, energy-efficient alternative to conventional vapour-compression refrigeration . However, the limited cooling power of existing devices (≤300 W) hampers the commercialization of this technology . Here we constructed a kilowatt-scale elastocaloric cooling device using compressive tubular NiTi in an ‘SMAs in series–fluid in parallel’ architecture, referred to as the multi-cell architecture. A large specific cooling power of 12.3 W g was achieved by the large surface-area-to-volume ratio of thin-walled tubular NiTi at high-frequency operation (3.5 Hz), complemented by graphene nanofluid as an efficient heat transfer agent. Furthermore, the multi-cell architecture ensures a sufficient elastocaloric mass for tight assembly while maintaining a low system fluid pressure. Our device achieves a cooling power of 1,284 W on the fluid side at zero temperature lift during the initial 500,000 cycles, demonstrating the potential of this green cooling technology for a decarbonized future .

『Abstract』Low temperature severely limits the growth, yield, and geographical distribution of maize ( Zea mays L.). How maize adapts to cold climates remains largely unclear. Here, we identify a basic helix-loop-helix (bHLH) transcription factor, COLD-RESPONSIVE OPERATION LOCUS 1 (COOL1), as a crucial regulator of maize cold tolerance through genome-wide association studies. Natural variations in the COOL1 promoter affect the binding affinity of ELONGATED HYPOCOTYL5 (HY5), a transcriptional factor repressing COOL1 transcription. COOL1, in turn, negatively regulates downstream cold-responsive genes, thereby modulating cold tolerance. Moreover, calcium-dependent protein kinase CPK17 translocates to the nucleus and stabilizes COOL1 in response to cold stress. Intriguingly, the cold-tolerant allele of COOL1 is predominantly distributed in northern high latitudes with cold climates. This study defines a previously unknown pathway by which the COOL1-centered module regulates cold tolerance for high latitudinal adaptation in maize.

『Abstract』Coronavirus fusion with and entry into the host cell depends on viral spike, which acts as a crucial component of viral infection. However, the lack of receptor-activated spike intermediate conformation has hindered a comprehensive understanding of spike-induced membrane fusion. Here, we captured an angiotensin-converting enzyme 2 (ACE2)-induced early fusion intermediate conformation (E-FIC) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike in which heptad repeat 1 (HR1) in S2 has ejected while S1 remains attached. This E-FIC can transition to the late FIC after S2′ cleavage. Leveraging this discovery, we designed an E-FIC-targeted dual-functional antiviral protein, AL5E. AL5E effectively inactivated ACE2-using coronaviruses and inhibited their infection, outperforming a mono-functional antiviral in protecting animals against these coronaviruses. This study has identified the E-FIC and used it as a target for the development of a dual-functional antiviral for the prevention and treatment of ACE2-using coronavirus infection.

『Abstract』Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.

『Abstract』Biocatalytic cascades with spatial proximity can orchestrate multistep pathways to form metabolic highways, which enhance the overall catalytic efficiency. However, the effect of spatial organization on catalytic activity is poorly understood, and multienzyme architectural engineering with predictable performance remains unrealized. Here, we developed a standardized framework, called iMARS, to rapidly design the optimal multienzyme architecture by integrating high-throughput activity tests and structural analysis. The approach showed potential for industrial-scale applications, with artificial fusion enzymes designed by iMARS significantly improving the production of resveratrol by 45.1-fold and raspberry ketone by 11.3-fold in vivo , as well as enhancing ergothioneine synthesis in fed-batch fermentation. In addition, iMARS greatly enhanced the in vitro catalytic efficiency of the multienzyme complexes for PET plastic depolymerization and vanillin biosynthesis. As a generalizable and flexible strategy at molecular level, iMARS could greatly facilitate green chemistry, synthetic biology, and biomanufacturing.

『Abstract』The amphipod Hirondellea gigas is a dominant species inhabiting the deepest part of the ocean (∼6,800–11,000 m), but little is known about its genetic adaptation and population dynamics. Here, we present a chromosome-level genome of H. gigas , characterized by a large genome size of 13.92 Gb. Whole-genome sequencing of 510 individuals from the Mariana Trench indicates no population differentiation across depths, suggesting its capacity to tolerate hydrostatic pressure across wide ranges. H. gigas in the West Philippine Basin is genetically divergent from the Mariana and Yap Trenches, suggesting genetic isolation attributed to the geographic separation of hadal features. A drastic reduction in effective population size potentially reflects glacial-interglacial changes. By integrating multi-omics analysis, we propose host-symbiotic microbial interactions may be crucial in the adaptation of H. gigas to the extremely high-pressure and food-limited environment. Our findings provide clues for adaptation to the hadal zone and population genetics.

『Abstract』The nervous system needs to balance the stability of neural representations with plasticity. It is unclear what the representational stability of simple well-rehearsed actions is, particularly in humans, and their adaptability to new contexts. Using an electrocorticography brain-computer interface (BCI) in tetraplegic participants, we found that the low-dimensional manifold and relative representational distances for a repertoire of simple imagined movements were remarkably stable. The manifold’s absolute location, however, demonstrated constrained day-to-day drift. Strikingly, neural statistics, especially variance, could be flexibly regulated to increase representational distances during BCI control without somatotopic changes. Discernability strengthened with practice and was BCI-specific, demonstrating contextual specificity. Sampling representational plasticity and drift across days subsequently uncovered a meta-representational structure with generalizable decision boundaries for the repertoire; this allowed long-term neuroprosthetic control of a robotic arm and hand for reaching and grasping. Our study offers insights into mesoscale representational statistics that also enable long-term complex neuroprosthetic control.

『Abstract』Systematic exploration of the hadal zone, Earth’s deepest oceanic realm, has historically faced technical limitations. Here, we collected 1,648 sediment samples at 6–11 km in the Mariana Trench, Yap Trench, and Philippine Basin for the Mariana Trench Environment and Ecology Research (MEER) project. Metagenomic and 16S rRNA gene amplicon sequencing generated the 92-Tbp MEER dataset, comprising 7,564 species (89.4% unreported), indicating high taxonomic novelty. Unlike in reported environments, neutral drift played a minimal role, while homogeneous selection (HoS, 50.5%) and dispersal limitation (DL, 43.8%) emerged as dominant ecological drivers. HoS favored streamlined genomes with key functions for hadal adaptation, e.g., aromatic compound utilization (oligotrophic adaptation) and antioxidation (high-pressure adaptation). Conversely, DL promoted versatile metabolism with larger genomes. These findings indicated that environmental factors drive the high taxonomic novelty in the hadal zone, advancing our understanding of the ecological mechanisms governing microbial ecosystems in such an extreme oceanic environment.

『Abstract』The deep sea, especially hadal zones, characterized by high-hydrostatic pressure, low temperatures, and near-total darkness, present some of the most challenging environments for life on Earth. However, teleost fish have successfully colonized these extreme habitats through complex adaptations. We generated genome assemblies of 12 species, including 11 deep-sea fishes. Our findings reconstructed the teleost deep-sea colonization history and revealed the overall impact of the deep-sea environment on fishes. Interestingly, our results question the previously assumed linear correlation between trimethylamine oxide (TMAO) content and depth. By contrast, we observed a convergent aa replacement in the rtf1 gene in most deep-sea fishes under 3,000 m, and in vitro experiments suggest that this mutation can influence transcriptional efficiency, which is likely to be advantageous in the deep-sea environment. Moreover, our study underlines the pervasive impact of human activities, as we detected the presence of persistent organic pollutants in species from the Mariana Trench.

『Abstract』Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase ( ALK )-rearranged (“ALK+”) patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ . Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo . Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.

『Abstract』The centromere is the chromosomal locus that recruits the kinetochore, directing faithful propagation of the genome during cell division. Using cryo-ET on human mitotic chromosomes, we reveal a distinctive architecture at the centromere: clustered 20- to 25-nm nucleosome-associated complexes within chromatin clearings that delineate them from surrounding chromatin. Centromere components CENP-C and CENP-N are each required for the integrity of the complexes, while CENP-C is also required to maintain the chromatin clearing. We find that CENP-C is required in mitosis, not just for kinetochore assembly, likely reflecting its role in organizing the inner kinetochore during chromosome segregation. We further visualize the scaffold of the fibrous corona, a structure amplified at unattached kinetochores, revealing crescent-shaped parallel arrays of fibrils extending >1 μm. Thus, we reveal how the organization of centromeric chromatin creates a clearing at the site of kinetochore formation as well as the nature of kinetochore amplification mediated by corona fibrils.

『Abstract』Most land plants form symbioses with microbes to acquire nutrients but also must restrict infection by pathogens. Here, we show that a single pair of lysin-motif-containing receptor-like kinases, MpaLYR and MpaCERK1, mediates both immunity and symbiosis in the liverwort Marchantia paleacea . MpaLYR has a higher affinity for long-chain (CO7) versus short-chain chitin oligomers (CO4). Although both CO7 and CO4 can activate symbiosis-related genes, CO7 triggers stronger immune responses than CO4 in a dosage-dependent manner. CO4 can inhibit CO7-induced strong immune responses, recapitulating the early response to inoculation with the symbiont arbuscular mycorrhizal fungi. We show that phosphate starvation of plants increases their production of strigolactone, which stimulates CO4/CO5 secretion from mycorrhizal fungi, thereby prioritizing symbiosis over immunity. Thus, a single pair of LysM receptors mediates dosage-dependent perception of different chitin oligomers to discern symbiotic and pathogenic microbes in M. paleacea , which may facilitate terrestrialization.

『Abstract』Industrialization adversely affects the gut microbiome and predisposes individuals to chronic non-communicable diseases. We tested a microbiome restoration strategy comprising a diet that recapitulated key characteristics of non-industrialized dietary patterns (restore diet) and a bacterium rarely found in industrialized microbiomes ( Limosilactobacillus reuteri ) in a randomized controlled feeding trial in healthy Canadian adults. The restore diet, despite reducing gut microbiome diversity, enhanced the persistence of L. reuteri strain from rural Papua New Guinea (PB-W1) and redressed several microbiome features altered by industrialization. The diet also beneficially altered microbiota-derived plasma metabolites implicated in the etiology of chronic non-communicable diseases. Considerable cardiometabolic benefits were observed independently of L. reuteri administration, several of which could be accurately predicted by baseline and diet-responsive microbiome features. The findings suggest that a dietary intervention targeted toward restoring the gut microbiome can improve host-microbiome interactions that likely underpin chronic pathologies, which can guide dietary recommendations and the development of therapeutic and nutritional strategies.

『Abstract』A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches and CRISPR perturbation. In vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve the regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.

『Abstract』Knowledge of protein-metabolite interactions can enhance mechanistic understanding and chemical probing of biochemical processes, but the discovery of endogenous ligands remains challenging. Here, we combined rapid affinity purification with precision mass spectrometry and high-resolution molecular docking to precisely map the physical associations of 296 chemically diverse small-molecule metabolite ligands with 69 distinct essential enzymes and 45 transcription factors in the gram-negative bacterium Escherichia coli . We then conducted systematic metabolic pathway integration, pan-microbial evolutionary projections, and independent in-depth biophysical characterization experiments to define the functional significance of ligand interfaces. This effort revealed principles governing functional crosstalk on a network level, divergent patterns of binding pocket conservation, and scaffolds for designing selective chemical probes. This structurally resolved ligand interactome mapping pipeline can be scaled to illuminate the native small-molecule networks of complete cells and potentially entire multi-cellular communities.

『Abstract』Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.