前沿速递 | NCS 集萃： 2025-01-13 期 [Up]

『Abstract』Abstract How populations adapt to their environment is a fundamental question in biology. Yet, we know surprisingly little about this process, especially for endangered species, such as nonhuman great apes. Chimpanzees, our closest living relatives, are particularly notable because they inhabit diverse habitats, from rainforest to woodland-savannah. Whether genetic adaptation facilitates such habitat diversity remains unknown, despite it having wide implications for evolutionary biology and conservation. By using newly sequenced exomes from 828 wild chimpanzees (388 postfiltering), we found evidence of fine-scale genetic adaptation to habitat, with signatures of positive selection in forest chimpanzees in the same genes underlying adaptation to malaria in humans. This work demonstrates the power of noninvasive samples to reveal genetic adaptations in endangered populations and highlights the importance of adaptive genetic diversity for chimpanzees.

『Abstract』Abstract Thermoelectrics have been limited by the scarcity of their constituent elements, especially telluride. The earth-abundant, wide-bandgap ( E g ≈ 46 k B T ) tin sulfide (SnS) has shown promising performance in its crystal form. We improved the thermoelectric efficiency in SnS crystals by promoting the convergence of energy and momentum of four valance bands, termed quadruple-band synglisis. We introduced more Sn vacancies to activate quadruple-band synglisis and facilitate carrier transport by inducing SnS 2 in selenium (Se)–alloyed SnS, leading to a high dimensionless figure of merit ( ZT ) of ~1.0 at 300 kelvin and an average ZT of ~1.3 at 300 to 773 kelvin in p-type SnS crystals. We further obtained an experimental efficiency of ~6.5%, and our fabricated cooler demonstrated a maximum cooling temperature difference of ~48.4 kelvin at 353 kelvin. Our observations should draw interest to earth-abundant SnS crystals for applications of waste-heat recovery and thermoelectric cooling.

『Abstract』Abstract The impacts of degradation and deforestation on tropical forests are poorly understood, particularly at landscape scales. We present an extensive ecosystem analysis of the impacts of logging and conversion of tropical forest to oil palm from a large-scale study in Borneo, synthesizing responses from 82 variables categorized into four ecological levels spanning a broad suite of ecosystem properties: (i) structure and environment, (ii) species traits, (iii) biodiversity, and (iv) ecosystem functions. Responses were highly heterogeneous and often complex and nonlinear. Variables that were directly impacted by the physical process of timber extraction, such as soil structure, were sensitive to even moderate amounts of logging, whereas measures of biodiversity and ecosystem functioning were generally resilient to logging but more affected by conversion to oil palm plantation.

『Abstract』Abstract Axions, hypothetical elementary particles that remain undetectable in nature, can arise as quasiparticles in three-dimensional crystals known as axion insulators. Previous implementations of axion insulators have largely been limited to two-dimensional systems, leaving their topological properties in three dimensions unexplored in experiment. Here, we realize an axion insulator in a three-dimensional photonic crystal and probe its topological properties. Demonstrated features include half-quantized Chern numbers on each surface that resembles a fractional Chern insulator, unidirectional chiral hinge states forming topological transport in three dimensions, and arithmetic operations between fractional and integer Chern numbers. Our work experimentally establishes the axion insulator as a three-dimensional topological phase of matter and enables chiral states to form complex, unidirectional three-dimensional networks through braiding.

『Abstract』Abstract Achieving net-zero greenhouse gas emissions likely entails not only lowering emissions but also deploying carbon dioxide (CO 2 ) removal technologies. We explored the annual potential to store CO 2 in building materials. We found that fully replacing conventional building materials with CO 2 -storing alternatives in new infrastructure could store as much as 16.6 ± 2.8 billion tonnes of CO 2 each year—roughly 50% of anthropogenic CO 2 emissions in 2021. The total storage potential is far more sensitive to the scale of materials used than the quantity of carbon stored per unit mass of materials. Moreover, the carbon storage reservoir of building materials will grow in proportion to demand for such materials, which could reduce demand for more costly or environmentally risky geological, terrestrial, or ocean storage.

『Abstract』Abstract Accurately modeling the deformation of temperate glacier ice, which is at its pressure-melting temperature and contains liquid water at grain boundaries, is essential for predicting ice sheet discharge to the ocean and associated sea-level rise. Central to such modeling is Glen’s flow law, in which strain rate depends on stress raised to a power of n = 3 to 4. In sharp contrast to this nonlinearity, we found by conducting large-scale, shear-deformation experiments that temperate ice is linear-viscous ( n ≈ 1.0) over common ranges of liquid water content and stress expected near glacier beds and in ice-stream margins. This linearity is likely caused by diffusive pressure melting and refreezing at grain boundaries and could help to stabilize modeled responses of ice sheets to shrinkage-induced stress increases.

『Abstract』Abstract How mammalian herbivores evolve to feed on chemically defended plants remains poorly understood. In this study, we investigated the adaptation of two species of woodrats ( Neotoma lepida and N. bryanti ) to creosote bush ( Larrea tridentata ), a toxic shrub that expanded across the southwestern United States after the Last Glacial Maximum. We found that creosote-adapted woodrats have elevated gene dosage across multiple biotransformation enzyme families. These duplication events occurred independently across species and substantially increase expression of biotransformation genes, especially within the glucuronidation pathway. We propose that increased gene dosage resulting from duplication is an important mechanism by which animals initially adapt to novel environmental pressures.

『Abstract』Abstract One of the primary challenges in commercializing perovskite solar cells (PSCs) is achieving both high power conversion efficiency (PCE) and sufficient stability. We integrate wafer-scale continuous monolayer MoS 2 buffers at the top and bottom of a perovskite layer through a transfer process. These films physically block ion migration of perovskite into carrier transport layers and chemically stabilize the formamidinium lead iodide phase through strong coordination interaction. Effective chemical passivation results from the formation of Pb-S bonds, and minority carriers are blocked through a type-I band alignment. Planar p-i-n PSCs (0.074 square centimeters) and modules (9.6 square centimeters) with MoS 2 /perovskite/MoS 2 configuration achieve PCEs up to 26.2% (certified steady-state PCE of 25.9%) and 22.8%, respectively. Moreover, the devices show excellent damp heat (85°C and 85% relative humidity) stability with <5% PCE loss after 1200 hours and notable high temperature (85°C) operational stability with <4% PCE loss after 1200 hours.

『Abstract』Abstract The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8 T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

『Abstract』Abstract Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells called lipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue’s stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, but not in nonmammalian tetrapods. Thus, analogous to bubble wrap, superstable lipid vacuoles confer skeletal tissue with cartilage-like properties without “packing foam–like” extracellular matrix.

『Abstract』Abstract Sociosexual preference is critical for reproduction and survival. However, neural mechanisms encoding social decisions on sex preference remain unclear. In this study, we show that both male and female mice exhibit female preference but shift to male preference when facing survival threats; their preference is mediated by the dimorphic changes in the excitability of ventral tegmental area dopaminergic (VTA ) neurons. In males, VTA projections to the nucleus accumbens (NAc) mediate female preference, and those to the medial preoptic area mediate male preference. In females, firing-pattern (phasic-like versus tonic-like) alteration of the VTA -NAc projection determines sociosexual preferences. These findings define VTA neurons as a key node for social decision-making and reveal the sexually dimorphic DA circuit mechanisms underlying sociosexual preference.

『Abstract』Abstract We explored the potential for membrane materials to reduce energy and carbon requirements for the separation of aliphatic hydrocarbon feedstocks and products. We developed a series of fluorine-rich poly(arylene amine) polymer membranes that feature rigid polymer backbones with segregated perfluoroalkyl side chains. This combination imbues the polymers with resistance to dilation induced by hydrocarbon immersion without the loss of solution-based membrane fabrication techniques. These materials exhibit good separation of liquid-phase alkane isomers at ambient temperatures. The integration of these polymeric membranes into fuel and chemical feedstock separation processes was investigated in a series of experiments. Technoeconomic analyses based on these experiments indicate that the best-performing membrane materials can substantially reduce the energy costs and associated carbon emissions of hydrocarbon separations (two to 10 times, depending on product specifications).

『Abstract』Abstract Elucidating the interaction between membrane proteins and antibodies requires whole-cell imaging at high spatiotemporal resolution. Lattice light-sheet (LLS) microscopy offers fast volumetric imaging but suffers from limited spatial resolution. DNA-based point accumulation for imaging in nanoscale topography (DNA-PAINT) achieves molecular resolution but is restricted to two-dimensional imaging owing to long acquisition times. We have developed two-dye imager (TDI) probes that enable ~15-fold faster imaging. Combining TDI-DNA-PAINT and LLS microscopy on immunological B cells revealed the oligomeric states and interaction of endogenous CD20 with the therapeutic monoclonal antibodies (mAbs) rituximab, ofatumumab, and obinutuzumab. Our results demonstrate that CD20 is abundantly expressed on microvilli that bind mAbs, which leads to an antibody concentration–dependent B cell polarization and stabilization of microvilli protrusions. These findings could aid rational design of improved immunotherapies targeting tumor-associated antigens.

『Abstract』Abstract The current understanding of primate natural action organization derives from laboratory experiments in restrained contexts (RCs) under the assumption that this knowledge generalizes to freely moving contexts (FMCs). In this work, we developed a neurobehavioral platform to enable wireless recording of the same premotor neurons in both RCs and FMCs. Neurons often encoded the same hand and mouth actions differently in RCs and FMCs. Furthermore, in FMCs, we identified cells that selectively encoded actions untestable during RCs and others that displayed mixed selectivity for multiple actions, which is compatible with an organization based on cortical motor synergies at different levels of complexity. Cross-context decoding demonstrated that neural activity in FMCs is richer and more generalizable than in RCs, which suggests that neuroethological approaches are better suited to unveil the neural bases of behavior.

『Abstract』Abstract Identifying what drove the late Pleistocene megafaunal extinctions on the continents remains one of the most contested topics in historical science. This is especially so in Australia, which lost 90% of its large species by 40,000 years ago, more than half of them kangaroos. Determining causation has been obstructed by a poor understanding of their ecology. Using dental microwear texture analysis, we show that most members of Australia’s richest Pleistocene kangaroo assemblage had diets that were much more generalized than their craniodental anatomy implies. Mixed feeding across most kangaroos pinpoints dietary breadth as a key behavioral adaptation to climate-driven fluctuations in vegetation structure, dispelling the likelihood that late Pleistocene climatic variation was a primary driver of their disappearance.

『Abstract』The role of the vertebrate retina in early vision is generally described by the efficient coding hypothesis , which predicts that the retina reduces the redundancy inherent in natural scenes by discarding spatiotemporal correlations while preserving stimulus information . It is unclear, however, whether the predicted decorrelation and redundancy reduction in the activity of ganglion cells, the retina’s output neurons, hold under gaze shifts, which dominate the dynamics of the natural visual input . We show here that species-specific gaze patterns in natural stimuli can drive correlated spiking responses both in and across distinct types of ganglion cells in marmoset as well as mouse retina. These concerted responses disrupt redundancy reduction to signal fixation periods with locally high spatial contrast. Model-based analyses of ganglion cell responses to natural stimuli show that the observed response correlations follow from nonlinear pooling of ganglion cell inputs. Our results indicate cell-type-specific deviations from efficient coding in retinal processing of natural gaze shifts.

『Abstract』A critical challenge in glioma treatment is detecting tumour infiltration during surgery to achieve safe maximal resection . Unfortunately, safely resectable residual tumour is found in the majority of patients with glioma after surgery, causing early recurrence and decreased survival . Here we present FastGlioma, a visual foundation model for fast (<10 s) and accurate detection of glioma infiltration in fresh, unprocessed surgical tissue. FastGlioma was pretrained using large-scale self-supervision (around 4 million images) on rapid, label-free optical microscopy, and fine-tuned to output a normalized score that indicates the degree of tumour infiltration within whole-slide optical images. In a prospective, multicentre, international testing cohort of patients with diffuse glioma ( n = 220), FastGlioma was able to detect and quantify the degree of tumour infiltration with an average area under the receiver operating characteristic curve of 92.1 ± 0.9%. FastGlioma outperformed image-guided and fluorescence-guided adjuncts for detecting tumour infiltration during surgery by a wide margin in a head-to-head, prospective study ( n = 129). The performance of FastGlioma remained high across diverse patient demographics, medical centres and diffuse glioma molecular subtypes as defined by the World Health Organization. FastGlioma shows zero-shot generalization to other adult and paediatric brain tumour diagnoses, demonstrating the potential for our foundation model to be used as a general-purpose adjunct for guiding brain tumour surgeries. These findings represent the transformative potential of medical foundation models to unlock the role of artificial intelligence in the care of patients with cancer.

『Abstract』Wheat is the second largest food crop with a very good breeding system and pedigree record in China. Investigating the genomic footprints of wheat cultivars will unveil potential avenues for future breeding efforts . Here we report chromosome-level genome assemblies of 17 wheat cultivars that chronicle the breeding history of China. Comparative genomic analysis uncovered a wealth of structural rearrangements, identifying 249,976 structural variations with 49.03% (122,567) longer than 5 kb. Cultivars developed in 1980s displayed significant accumulations of structural variations, a pattern linked to the extensive incorporation of European and American varieties into breeding programmes of that era. We further proved that structural variations in the centromere-proximal regions are associated with a reduction of crossover events. We showed that common wheat evolved from spring to winter types via mutations and duplications of the VRN-A1 gene as an adaptation strategy to a changing environment. We confirmed shifts in wheat cultivars linked to dietary preferences, migration and cultural integration in Northwest China. We identified large presence or absence variations of pSc200 tandem repeats on the 1RS terminal, suggesting its own rapid evolution in the wheat genome. The high-quality genome assemblies of 17 representatives developed and their good complementarity to the 10+ pan-genomes offer a robust platform for future genomics-assisted breeding in wheat.

『Abstract』The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development . Although numerous cell-intrinsic mechanisms have been revealed , little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes. Lineage tracing and depletion in mice demonstrated that delayed hepatocyte development in early fetal livers increased the chromosomal instability of newly colonizing HSPCs. In addition, HSPCs developed tolerance to genotoxins in hepatocyte-conditioned medium, suggesting that hepatocytes protect the HSPC genome in a paracrine manner. Proteomic analyses demonstrated the enrichment of fetuin-A in hepatocyte-conditioned medium but not in early fetal livers. Fetuin-A activates a Toll-like receptor pathway to prevent pathogenic R-loop accumulation in HSPCs undergoing DNA replication and gene transcription in the fetal liver. Numerous haematopoietic regulatory genes frequently involved in leukaemogenic mutations are associated with R-loop-enriched regions. In Fetua -knockout mice, HSPCs showed increased genome instability and susceptibility to malignancy induction. Moreover, low concentrations of fetuin-A correlated with the oncogenesis of childhood leukaemia. Therefore, we uncover a mechanism operating in developmental tissues that offers tissue-forming cell genome protection and is implicated in developmental-related diseases.

『Abstract』Amniote integumentary appendages constitute a diverse group of micro-organs, including feathers, hair and scales. These structures typically develop as genetically controlled units , the spatial patterning of which emerges from a self-organized chemical Turing system with integrated mechanical feedback . The seemingly purely mechanical patterning of polygonal crocodile head scales provides an exception to this paradigm . However, the nature and origin of the mechanical stress field driving this patterning remain unclear. Here, using precise in ovo intravenous injections of epidermal growth factor protein, we generate Nile crocodile embryos with substantially convoluted head skin, as well as hatchlings with smaller polygonal head scales resembling those of caimans. We then use light-sheet fluorescence microscopy to quantify embryonic tissue-layer geometry, collagen architecture and the spatial distribution of proliferating cells. Using these data, we build a phenomenological three-dimensional mechanical growth model that recapitulates both normal and experimentally modified patterning of crocodile head scales. Our experiments and numerical simulations demonstrate that crocodile head scales self-organize through compressive folding, originating from near-homogeneous skin growth with differential stiffness of the dermis versus the epidermis. Our experiments and theoretical morphospace analyses indicate that variation in embryonic growth and material properties of skin layers provides a simple evolutionary mechanism that produces a diversity of head-scale patterns among crocodilian species.

『Abstract』Pre-eclampsia is a placental disorder that affects 3–5% of all pregnancies and is a leading cause of maternal and fetal morbidity worldwide . With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic messenger RNA (mRNA) delivery to the placenta is an attractive therapeutic option for pre-eclampsia. Here we use high-throughput screening to evaluate a library of 98 LNP formulations in vivo and identify a placenta-tropic LNP (LNP 55) that mediates more than 100-fold greater mRNA delivery to the placenta in pregnant mice than a formulation based on the Food and Drug Administration-approved Onpattro LNP (DLin-MC3-DMA) . We propose an endogenous targeting mechanism based on β 2 -glycoprotein I adsorption that enables LNP delivery to the placenta. In both inflammation- and hypoxia-induced models of pre-eclampsia, a single administration of LNP 55 encapsulating vascular endothelial growth factor (VEGF) mRNA resolves maternal hypertension until the end of gestation. In addition, with our VEGF mRNA LNP 55 therapeutic, we demonstrate improvements in fetal health and partially restore placental vasculature, the local and systemic immune landscape and serum levels of soluble Fms-like tyrosine kinase-1, a clinical biomarker of pre-eclampsia . Together, these results demonstrate the potential of this mRNA LNP platform for treating placental disorders such as pre-eclampsia.

『Abstract』Frictional motion is mediated by rapidly propagating ruptures that detach the ensemble of contacts forming the frictional interface between contacting bodies . These ruptures are similar to shear cracks. When this process takes place in natural faults, these rapid ruptures are essentially earthquakes . Although fracture mechanics describe the rapid motion of these singular objects, the nucleation process that creates them is not understood . Here we fully describe the nucleation process by extending fracture mechanics to explicitly incorporate finite interface widths (which are generally ignored ). We show, experimentally and theoretically, that slow steady creep ensues at a well-defined stress threshold. Moreover, as slowly creeping patches approach the interface width, a topological transition takes place in which these creeping patches smoothly transition to the rapid fracture that is described by classical fracture mechanics . Apart from its relevance to fracture and material strength, this new picture of rupture nucleation dynamics is directly relevant to earthquake nucleation dynamics; slow, aseismic rupture must always precede rapid seismic rupture (so long as the initial defect in the interface is localized in both spatial dimensions). The theory may provide a new framework for understanding how and when earthquakes nucleate.

『Abstract』C–N bond formation is integral to modern chemical synthesis owing to the ubiquity of nitrogen heterocycles in small-molecule pharmaceuticals and agrochemicals. Alkene hydroamination with unactivated alkenes is an atom-economical strategy for constructing these bonds. However, these reactions are challenging to render asymmetric when preparing fully substituted carbon stereocentres. Here we report a photoenzymatic alkene hydroamination to prepare 2,2-disubstituted pyrrolidines by a Baeyer–Villiger mono-oxygenase. Five rounds of protein engineering afforded a mutant, providing excellent product yield and stereoselectivity. Unlike related photochemical hydroaminations, which rely on the oxidation of the amine or alkene for C–N bond formation, this work exploits a through-space interaction of a reductively generated benzylic radical and the nitrogen lone pair. This antibonding interaction lowers the oxidation potential of the radical, enabling electron transfer to the flavin cofactor. Experiments indicate that the enzyme microenvironment is essential in enabling a innovative C–N bond formation mechanism with no parallel in small-molecule catalysis. Molecular dynamics simulations were performed to investigate the substrate in the enzyme active site, which further support this hypothesis. This work is a rare example of an emerging mechanism in non-natural biocatalysis in which an enzyme has access to a mechanism that its individual components do not. Our study showcases the potential of enhancing emergent mechanisms using protein engineering to provide unique mechanistic solutions to unanswered challenges in chemical synthesis.

『Abstract』The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders . We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD) . Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.

『Abstract』Despite the fundamental role of bacterial strain variation in gut microbiota function , the number of unique strains of a species that can stably colonize the human intestine is still unknown for almost all species. Here we determine the strain richness (SR) of common gut species using thousands of sequenced bacterial isolates with paired metagenomes. We show that SR varies across species, is transferable by faecal microbiota transplantation, and is uniquely low in the gut compared with soil and lake environments. Active therapeutic administration of supraphysiologic numbers of strains per species increases recipient SR, which then converges back to the population average after dosing is ceased. Stratifying engraftment outcomes by high or low SR shows that SR predicts microbial addition or replacement in faecal transplants. Together, these results indicate that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and thereby influence strain addition and replacement in faecal microbiota transplantation and defined live biotherapeutic products.

『Abstract』High-throughput experimentation (HTE) has accelerated academic and industrial chemical research in reaction development and drug discovery and has been broadly applied in many domains of organic chemistry . However, application of HTE in electrosynthesis—an enabling tool for chemical synthesis—has been limited by a dearth of suitable standardized reactors . Here we report the development of microelectronic devices, which are produced using standard nanofabrication techniques, to enable wireless electrosynthesis on the microlitre scale. These robust and inexpensive devices are powered by visible light and convert any traditional 96-well or 384-well plate into an electrochemical reactor. We validate the devices in oxidative, reductive and paired electrolysis and further apply them to achieve the library synthesis of biologically active compounds and accelerate the development of two electrosynthetic methodologies. We anticipate that, by simplifying the way electrochemical reactions are set up, this user-friendly solution will not only enhance the experience and efficiency of current practitioners but also substantially reduce the barrier for nonspecialists to enter the field of electrosynthesis, thus allowing the broader community of synthetic chemists to explore and benefit from new reactivities and synthetic strategies enabled by electrochemistry .

『Abstract』Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH) . While increasing HCC risk , MASH triggers p53-dependent hepatocyte senescence , which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells , paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2–FBP1–AKT–p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.

『Abstract』Hypoxic cancer cells resist many antineoplastic therapies and can seed recurrence . We previously found that either deficiency or inhibition of protein-tyrosine phosphatase (PTP1B) promotes human epidermal growth factor receptor 2-positive breast cancer cell death in hypoxia by activation of RNF213 (ref. ), a large protein with multiple AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) implicated in Moyamoya disease, lipotoxicity and innate immunity . Here we report that PTP1B and ABL1/2 reciprocally control RNF213 tyrosine phosphorylation and, consequently, its oligomerization and RZ domain activation. The RZ domain ubiquitylates and induces the degradation of the major NF-κB regulator CYLD/SPATA2. Decreased CYLD/SPATA2 levels lead to NF-κB activation and induction of the NLRP3 inflammasome which, together with hypoxia-induced endoplasmic reticulum stress, triggers pyroptotic cell death. Consistent with this model, CYLD deletion phenocopies, whereas NLRP3 deletion blocks, the effects of PTP1B deficiency on human epidermal growth factor receptor 2-positive breast cancer xenograft growth. Reconstitution studies with RNF213 mutants confirm that the RZ domain mediates tumour cell death. In concert, our results identify a unique, potentially targetable PTP1B–RNF213–CYLD–SPATA2 pathway critical for the control of inflammatory cell death in hypoxic tumours, provide new insights into RNF213 regulation and have potential implications for the pathogenesis of Moyamoya disease, inflammatory disorders and autoimmune disease.

『Abstract』It is commonly believed that there are only two types of particle exchange statistics in quantum mechanics, fermions and bosons, with the exception of anyons in two dimensions . In principle, a second exception known as parastatistics, which extends outside two dimensions, has been considered but was believed to be physically equivalent to fermions and bosons . Here we show that non-trivial parastatistics inequivalent to either fermions or bosons can exist in physical systems. These new types of identical particle obey generalized exclusion principles, leading to exotic free-particle thermodynamics distinct from any system of free fermions and bosons. We formulate our theory by developing a second quantization of paraparticles that naturally includes exactly solvable non-interacting theories and incorporates physical constraints such as locality. We then construct a family of exactly solvable quantum spin models in one and two dimensions, in which free paraparticles emerge as quasiparticle excitations, and their exchange statistics can be physically observed and are notably distinct from fermions and bosons. This demonstrates the possibility of a new type of quasiparticle in condensed matter systems and—more speculatively—the potential for previously unconsidered types of elementary particle.

『Abstract』Lytic cell death culminates in plasma membrane rupture, which releases large intracellular molecules to augment the inflammatory response. Plasma membrane rupture is mediated by the effector membrane protein ninjurin-1 (NINJ1) , which polymerizes and ruptures the membrane via its hydrophilic face . How NINJ1 is restrained under steady-state conditions to ensure cell survival remains unknown. Here we describe the molecular underpinnings of NINJ1 inhibition. Using cryogenic electron microscopy, we determined the structure of inactive-state mouse NINJ1 bound to the newly developed nanobody Nb538. Inactive NINJ1 forms a face-to-face homodimer by adopting a three-helix conformation with unkinked transmembrane helix 1 (TM1), in contrast to the four-helix TM1-kinked active conformation . Accordingly, endogenous NINJ1 from primary macrophages is a dimer under steady-state conditions. Inactive dimers sequester the membrane rupture-inducing hydrophilic face of NINJ1 and occlude the binding site for kinked TM1 from neighbouring activated NINJ1 molecules. Mutagenesis studies in cells show that destabilization of inactive face-to-face dimers leads to NINJ1-mediated cell death, whereas stabilization of face-to-face dimers inhibits NINJ1 activity. Moreover, destabilizing mutations prompt spontaneous TM1 kink formation, a hallmark of NINJ1 activation. Collectively, our data demonstrate that dimeric NINJ1 is autoinhibited in trans to prevent unprovoked plasma membrane rupture and cell death.

『Abstract』Tabular data, spreadsheets organized in rows and columns, are ubiquitous across scientific fields, from biomedicine to particle physics to economics and climate science . The fundamental prediction task of filling in missing values of a label column based on the rest of the columns is essential for various applications as diverse as biomedical risk models, drug discovery and materials science. Although deep learning has revolutionized learning from raw data and led to numerous high-profile success stories , gradient-boosted decision trees have dominated tabular data for the past 20 years. Here we present the Tabular Prior-data Fitted Network (TabPFN), a tabular foundation model that outperforms all previous methods on datasets with up to 10,000 samples by a wide margin, using substantially less training time. In 2.8 s, TabPFN outperforms an ensemble of the strongest baselines tuned for 4 h in a classification setting. As a generative transformer-based foundation model, this model also allows fine-tuning, data generation, density estimation and learning reusable embeddings. TabPFN is a learning algorithm that is itself learned across millions of synthetic datasets, demonstrating the power of this approach for algorithm development. By improving modelling abilities across diverse fields, TabPFN has the potential to accelerate scientific discovery and enhance important decision-making in various domains.

『Abstract』Allergic diseases affect more than a quarter of individuals in industrialized countries, and are a major public health concern . The high-affinity Fc receptor for immunoglobulin E (FcεRI), which is mainly present on mast cells and basophils, has a crucial role in allergic diseases . Monomeric immunoglobulin E (IgE) binding to FcεRI regulates mast cell survival, differentiation and maturation . However, the underlying molecular mechanism remains unclear. Here we demonstrate that prior to IgE binding, FcεRI exists mostly as a homodimer on human mast cell membranes. The structure of human FcεRI confirms the dimeric organization, with each promoter comprising one α subunit, one β subunit and two γ subunits. The transmembrane helices of the α subunits form a layered arrangement with those of the γ and β subunits. The dimeric interface is mediated by a four-helix bundle of the α and γ subunits at the intracellular juxtamembrane region. Cholesterol-like molecules embedded within the transmembrane domain may stabilize the dimeric assembly. Upon IgE binding, the dimeric FcεRI dissociates into two protomers, each of which binds to an IgE molecule. This process elicits transcriptional activation of Egr1 , Egr3 and Ccl2 in rat basophils, which can be attenuated by inhibiting the FcεRI dimer-to-monomer transition. Collectively, our study reveals the mechanism of antigen-independent, IgE-mediated FcεRI activation.

『Abstract』Excitons, Coulomb-driven bound states of electrons and holes, are typically composed of integer charges . However, in bilayer systems influenced by charge fractionalization , a more interesting form of interlayer exciton can emerge, in which pairing occurs between constituents that carry fractional charges. Despite numerous theoretical predictions for these fractional excitons , their experimental observation has remained unexplored. Here we report transport signatures of excitonic pairing in fractional quantum Hall effect states. By probing the composition of these excitons and their impact on the underlying wavefunction, we discover two new types of quantum phases of matter. One of these can be viewed as the fractional counterpart of the exciton condensate at a total filling of 1, whereas the other involves a more unusual type of exciton that obeys non-bosonic quantum statistics, challenging the standard model of bosonic excitons.

『Abstract』A central question in biology is how macromolecular machines function cooperatively. In bacteria, transcription and translation occur in the same cellular compartment, and can be physically and functionally coupled . Although high-resolution structures of the ribosome–RNA polymerase (RNAP) complex have provided initial mechanistic insights into the coupling process , we lack knowledge of how these structural snapshots are placed along a dynamic reaction trajectory. Here we reconstitute a complete and active transcription–translation system and develop multi-colour single-molecule fluorescence microscopy experiments to directly and simultaneously track transcription elongation, translation elongation and the physical and functional coupling between the ribosome and the RNAP in real time. Our data show that physical coupling between ribosome and RNAP can occur over hundreds of nucleotides of intervening mRNA by mRNA looping, a process facilitated by NusG. We detect active transcription elongation during mRNA looping and show that NusA-paused RNAPs can be activated by the ribosome by long-range physical coupling. Conversely, the ribosome slows down while colliding with the RNAP. We hereby provide an alternative explanation for how the ribosome can efficiently rescue RNAP from frequent pausing without requiring collisions by a closely trailing ribosome. Overall, our dynamic data mechanistically highlight an example of how two central macromolecular machineries, the ribosome and RNAP, can physically and functionally cooperate to optimize gene expression.

『Abstract』Piezoelectric materials directly convert between electrical and mechanical energies. They are used as transducers in applications such as nano-positioning and ultrasound imaging. Improving the properties of these devices requires piezoelectric materials capable of delivering a large longitudinal strain on the application of an electric field. A large longitudinal strain of more than 1% is generally anticipated in suitably oriented single crystals of specific compositions of ferroelectric materials . Polycrystalline piezoceramics typically show a longitudinal strain of approximately 0.2–0.4%. We demonstrate that when the thickness of a polycrystalline piezoceramic is reduced to such an extent that a large fraction of the grains are in the triaxial–biaxal crossover regime, the domain-switching fraction increases considerably. If the positive and the negative surfaces of the piezoceramic respond to electric fields symmetrically, as in the classical PbZr x Ti x O 3 , a longitudinal strain of approximately 1% can be achieved in a 0.2 mm disc of the morphotropic phase boundary composition (a 300% increase from a thickness of 0.7 mm). We show that oxygen vacancies in piezoceramics cause asymmetrical switching at the positive and negative surfaces, which causes thin piezoceramics to bend. We expect these findings will encourage further engineering of these mechanisms across different piezoelectric material systems, opening new applications for electromechanical actuation.

『Abstract』The complete blood count (CBC) is an important screening tool for healthy adults and a common test at periodic exams. However, results are usually interpreted relative to one-size-fits-all reference intervals , undermining the precision medicine goal to tailor care for patients on the basis of their unique characteristics . Here we study thousands of diverse patients at an academic medical centre and show that routine CBC indices fluctuate around stable values or setpoints , and setpoints are patient-specific, with the typical healthy adult’s nine CBC setpoints distinguishable as a group from those of 98% of other healthy adults, and setpoint differences persist for at least 20 years. Haematological setpoints reflect a deep physiologic phenotype enabling investigation of acquired and genetic determinants of haematological regulation and its variation among healthy adults. Setpoints in apparently healthy adults were associated with significant variation in clinical risk: absolute risk of some common diseases and morbidities varied by more than 2% (heart attack and stroke, diabetes, kidney disease, osteoporosis), and absolute risk of all-cause 10 year mortality varied by more than 5%. Setpoints also define patient-specific reference intervals and personalize the interpretation of subsequent test results. In retrospective analysis, setpoints improved sensitivity and specificity for evaluation of some common conditions including diabetes, kidney disease, thyroid dysfunction, iron deficiency and myeloproliferative neoplasms. This study shows CBC setpoints are sufficiently stable and patient-specific to help realize the promise of precision medicine for healthy adults.

『Abstract』Lithium (Li) metal batteries (LMBs) are promising for high-energy-density rechargeable batteries . However, Li dendrites formed by the reaction between highly active Li and non-aqueous electrolytes lead to safety concerns and rapid capacity decay . Developing a reliable solid–electrolyte interphase is critical for realizing high-rate and long-life LMBs, but remains technically challenging . Here we demonstrate that adding excess m -Li 2 ZrF 6 (monoclinic) nanoparticles to a commercial LiPF 6 -containing carbonate electrolyte of LMBs facilitates the release of abundant ZrF 6 ions into the electrolyte driven by the applied voltage, converting to t -Li 2 ZrF 6 (trigonal) and creating a stable solid–electrolyte interphase in situ with high Li-ion conductivity. Computational and cryogenic transmission electron microscopy studies revealed that the in situ formation of the t -Li 2 ZrF 6 -rich solid–electrolyte interphase markedly enhanced Li-ion transfer and suppressed the growth of Li dendrites. As a result, LMBs assembled with LiFePO 4 cathodes (areal loading, 1.8/2.2 mAh cm ), three-dimensional Li–carbon anodes (50-µm-thick Li) and Li 2 ZrF 6 -based electrolyte displayed greatly improved cycling stability with high capacity retention (>80.0%) after 3,000 cycles (1C/2C rate). This achievement represents leading performance and, thus, delivers a reliable Li 2 ZrF 6 -based electrolyte for durable LMBs under practical high-rate conditions.

『Abstract』Mimicking the superstructures and properties of spherical biological encapsulants such as viral capsids and ferritin offers viable pathways to understand their chiral assemblies and functional roles in living systems. However, stereospecific assembly of artificial polyhedra with mechanical properties and guest-binding attributes akin to biological encapsulants remains a formidable challenge. Here we report the stereospecific assembly of dynamic supramolecular snub cubes from 12 helical macrocycles, which are held together by 144 weak C–H hydrogen bonds . The enantiomerically pure snub cubes, which have external diameters of 5.1 nm, contain 2,712 atoms and chiral cavities with volumes of 6,215 Å . The stereospecific assembly of left- and right-handed snub cubes was achieved by means of a hierarchical chirality transfer protocol , which was streamlined by diastereoselective crystallization. In addition to their reversible photochromic behaviour, the snub cubes exhibit photocontrollable elasticity and hardness in their crystalline states. The snub cubes can accommodate numerous small guest molecules simultaneously and encapsulate two different guest molecules separately inside the uniquely distinct compartments in their frameworks. This research expands the scope of artificial supramolecular assemblies to imitate the chiral superstructures, dynamic features and binding properties of spherical biomacromolecules and also establishes a protocol for construction of crystalline materials with photocontrollable mechanical properties.

『Abstract』The physical manifestations of memory formation and recall are fundamental questions that remain unresolved . At the cellular level, ensembles of neurons called engrams are activated by learning events and control memory recall . Astrocytes are found in close proximity to neurons and engage in a range of activities that support neurotransmission and circuit plasticity . Moreover, astrocytes exhibit experience-dependent plasticity , although whether specific ensembles of astrocytes participate in memory recall remains obscure. Here we show that learning events induce c-Fos expression in a subset of hippocampal astrocytes, and that this subsequently regulates the function of the hippocampal circuit in mice. Intersectional labelling of astrocyte ensembles with c-Fos after learning events shows that they are closely affiliated with engram neurons, and reactivation of these astrocyte ensembles stimulates memory recall. At the molecular level, learning-associated astrocyte (LAA) ensembles exhibit elevated expression of nuclear factor I-A, and its selective deletion from this population suppresses memory recall. Taken together, our data identify LAA ensembles as a form of plasticity that is sufficient to provoke memory recall and indicate that astrocytes are an active component of the engram.

『Abstract』The sense of taste generally shows diminishing sensitivity to prolonged sweet stimuli, referred to as sweet adaptation. Yet, its mechanistic landscape remains incomplete. Here, we report that glia-like type I cells provide a distinct mode of sweet adaptation via intercellular crosstalk with chemosensory type II cells. Using the microfluidic-based intravital tongue imaging system, we found that sweet adaptation is facilitated along the synaptic transduction from type II cells to gustatory afferent nerves, while type I cells display temporally delayed and prolonged activities. We identified that type I cells receive purinergic input from adjacent type II cells via P2RY2 and provide inhibitory feedback to the synaptic transduction of sweet taste. Aligning with our cellular-level findings, purinergic activation of type I cells attenuated sweet licking behavior, and P2RY2 knockout mice showed decelerated adaptation behavior. Our study highlights a veiled intercellular mode of sweet adaptation, potentially contributing to the efficient encoding of prolonged sweetness.

『Abstract』Underlying variation in height are regulatory changes to chondrocytes, cartilage cells comprising long-bone growth plates. Currently, we lack knowledge on epigenetic regulation and gene expression of chondrocytes sampled across the human skeleton, and therefore we cannot understand basic regulatory mechanisms controlling height biology. We first rectify this issue by generating extensive epigenetic and transcriptomic maps from chondrocytes sampled from different growth plates across developing human skeletons, discovering novel regulatory networks shaping human bone/joint development. Next, using these maps in tandem with height genome-wide association study (GWAS) signals, we disentangle the regulatory impacts that skeletal element-specific versus global-acting variants have on skeletal growth, revealing the prime importance of regulatory pleiotropy in controlling height variation. Finally, as height is highly heritable, and thus often the test case for complex-trait genetics, we leverage these datasets within a testable omnigenic model framework to discover novel chondrocyte developmental modules and peripheral-acting factors shaping height biology and skeletal growth.

『Abstract』We present replication-aware single-molecule accessibility mapping (RASAM), a method to nondestructively measure replication status and protein-DNA interactions on chromatin genome-wide. Using RASAM, we uncover a genome-wide state of single-molecule “hyperaccessibility” post-replication that resolves over several hours. Combining RASAM with cellular models for rapid protein degradation, we demonstrate that histone chaperone CAF-1 reduces nascent chromatin accessibility by filling single-molecular “gaps” and generating closely spaced dinucleosomes on replicated DNA. At cis -regulatory elements, we observe unique modes by which nascent chromatin hyperaccessibility resolves: at CCCTC-binding factor (CTCF)-binding sites, CTCF and nucleosomes compete, reducing CTCF occupancy and motif accessibility post-replication; at active transcription start sites, high chromatin accessibility is maintained, implying rapid re-establishment of nucleosome-free regions. Our study introduces a new paradigm for studying replicated chromatin fiber organization. More broadly, we uncover a unique organization of newly replicated chromatin that must be reset by active processes, providing a substrate for epigenetic reprogramming.

『Abstract』Recent reports raise concerns on the changing epidemiology of mpox in the Democratic Republic of the Congo (DRC). High-quality genomes were generated for 337 patients from 14/26 provinces to document whether the increase in number of cases is due to zoonotic spillover events or viral evolution, with enrichment of APOBEC3 mutations linked to human adaptation. Our study highlights two patterns of transmission contributing to the source of human cases. All new sequences from the eastern South Kivu province ( n = 17; 4.8%) corresponded to the recently described clade Ib, associated with sexual contact and sustained human-to-human transmission. By contrast, all other genomes are clade Ia, which exhibits high genetic diversity with low numbers of APOBEC3 mutations compared with clade Ib, suggesting multiple zoonotic introductions. The presence of multiple clade I variants in urban areas highlights the need for coordinated international response efforts and more studies on the transmission and the reservoir of mpox.

『Abstract』The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset ( n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients’ gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.

『Abstract』Understanding protein function would be facilitated by direct, real-time observation of chemical kinetics in the atomic structure. The selectivity filter (SF) of the K channel provides an ideal model, catalyzing the dehydration and transport of K ions across the cell membrane through a narrow pore. We used a “pump-probe” method called electric-field-stimulated time-resolved X-ray crystallography (EFX) to initiate and observe K conduction in the NaK2K channel in both directions on the timescale of the transport process. We observe both known and potentially new features in the high-energy conformations visited along the conduction pathway, including the associated dynamics of protein residues that control selectivity and conduction rate. A single time series of one channel in action shows the orderly appearance of features observed in diverse homologs with diverse methods, arguing for deep conservation of the dynamics underlying the reaction coordinate in this protein family.

『Abstract』The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases.

『Abstract』While apolipoprotein E ( APOE ) is the strongest genetic modifier for late-onset Alzheimer’s disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased lysosomal accumulation of tau fibrils and was elevated in the APOE4 mouse brain with exacerbation by tau pathology. Intrahippocampal injection of PUFA-CE-lipApoE4 was sufficient to induce lipofuscinosis in wild-type mice. Finally, the protective Christchurch mutation also reduced LDLR binding and phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD risk by reducing the deleterious effects of endolysosomal targeting of ApoE and associated pathogenic lipids.

『Abstract』Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body’s Pacinian corpuscle neurons, which are distinguished by their ability to entrain to high-frequency (40–1,000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high-frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.

『Abstract』Cryptochromes (CRYs) are blue-light receptors that regulate diverse aspects of plant growth. However, whether and how non-photoexcited CRYs function in darkness or non-blue-light conditions is unknown. Here, we show that CRY2 affects the Arabidopsis transcriptome even in darkness, revealing a non-canonical function. CRY2 suppresses cell division in the root apical meristem to downregulate root elongation in darkness. Blue-light oligomerizes CRY2 to de-repress root elongation. CRY2 physically interacts with FORKED-LIKE 1 (FL1) and FL3, and these interactions are inhibited by blue light, with only monomeric but not dimeric CRY2 able to interact. FL1 and FL3 associate with the chromatin of cell division genes to facilitate their transcription. This pro-growth activity is inhibited by CRY2’s physical interaction with FLs in darkness. Plants have evolved to perceive both blue-light and dark cues to coordinate activation and repression of competing developmental processes in above- and below-ground organs through economical and dichotomous use of ancient light receptors.

『Abstract』Indigenous maize varieties from eastern North America have played an outsized role in breeding programs, yet their early origins are not fully understood. We generated paleogenomic data to reconstruct how maize first reached this region and how it was selected during the process. Genomic ancestry analyses reveal recurrent movements northward from different parts of Mexico, likely culminating in at least two dispersals from the US Southwest across the Great Plains to the Ozarks and beyond. We find that 1,000-year-old Ozark specimens carry a highly differentiated wx1 gene, which is involved in the synthesis of amylose, highlighting repeated selective pressures on the starch metabolic pathway throughout maize’s domestication. This population shows a close affinity with the lineage that ultimately became the Northern Flints, a major contributor to modern commercial maize.

『Abstract』β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.

『Abstract』Stress induces aversive memory overgeneralization, a hallmark of many psychiatric disorders. Memories are encoded by a sparse ensemble of neurons active during an event (an engram ensemble). We examined the molecular and circuit processes mediating stress-induced threat memory overgeneralization in mice. Stress, acting via corticosterone, increased the density of engram ensembles supporting a threat memory in lateral amygdala, and this engram ensemble was reactivated by both specific and non-specific retrieval cues (generalized threat memory). Furthermore, we identified a critical role for endocannabinoids, acting retrogradely on parvalbumin-positive (PV+) lateral amygdala interneurons in the formation of a less-sparse engram and memory generalization induced by stress. Glucocorticoid receptor antagonists, endocannabinoid synthesis inhibitors, increasing PV+ neuronal activity, and knocking down cannabinoid receptors in lateral amygdala PV+ neurons restored threat memory specificity and a sparse engram in stressed mice. These findings offer insights into stress-induced memory alterations, providing potential therapeutic avenues for stress-related disorders.

『Abstract』Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.

『Abstract』Kernel dehydration rate (KDR) is a crucial production trait that affects mechanized harvesting and kernel quality in maize; however, the underlying mechanisms remain unclear. Here, we identified a quantitative trait locus (QTL), qKDR1 , as a non-coding sequence that regulates the expression of qKDR1 REGULATED PEPTIDE GENE ( RPG ). RPG encodes a 31 amino acid micropeptide, microRPG1, which controls KDR by precisely modulating the expression of two genes, ZmETHYLENE-INSENSITIVE3-like 1 and 3 , in the ethylene signaling pathway in the kernels after filling. microRPG1 is a Zea genus-specific micropeptide and originated de novo from a non-coding sequence. Knockouts of microRPG1 result in faster KDR in maize. By contrast, overexpression or exogenous application of the micropeptide shows the opposite effect both in maize and Arabidopsis . Our findings reveal the molecular mechanism of microRPG1 in kernel dehydration and provide an important tool for future crop breeding.

『Abstract』Synaptic configurations underpin how the nervous system processes sensory information to produce a behavioral response. This is best understood for chemical synapses, and we know far less about how electrical synaptic configurations modulate sensory information processing and context-specific behaviors. We discovered that innexin 1 (INX-1), a gap junction protein that forms electrical synapses, is required to deploy context-specific behavioral strategies underlying thermotaxis behavior in C. elegans . Within this well-defined circuit, INX-1 couples two bilaterally symmetric interneurons to integrate sensory information during migratory behavior across temperature gradients. In inx-1 mutants, uncoupled interneurons display increased excitability and responses to subthreshold sensory stimuli due to increased membrane resistance and reduced membrane capacitance, resulting in abnormal responses that extend run durations and trap the animals in context-irrelevant tracking of isotherms. Thus, a conserved configuration of electrical synapses enables differential processing of sensory information to deploy context-specific behavioral strategies.