前沿速递 | NCS 集萃：2025-01-31 期

『Abstract』Abstract We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into repetitive sequences, up to 1697 per cell line, which enables generating large-scale deletions, inversions, translocations, and circular DNA. Recombinase induction produced more than 100 stochastic megabase-sized rearrangements in each cell. We tracked these rearrangements over time to measure selection pressures, finding a preference for shorter variants that avoided essential genes. We characterized 29 clones with multiple rearrangements, finding an impact of deletions on expression of genes in the variant but not on nearby genes. This genome-scrambling strategy enables large deletions, sequence relocations, and the insertion of regulatory elements to explore genome dispensability and organization.

『Abstract』Abstract Influenza virus pandemics and seasonal epidemics have claimed countless lives. Recurrent zoonotic spillovers of influenza viruses with pandemic potential underscore the need for effective countermeasures. In this study, we show that pre-exposure prophylaxis with broadly neutralizing antibody (bnAb) MEDI8852 is highly effective in protecting cynomolgus macaques from severe disease caused by aerosolized highly pathogenic avian influenza H5N1 virus infection. Protection was antibody dose–dependent yet independent of Fc-mediated effector functions at the dose tested. Macaques receiving MEDI8852 at 10 milligrams per kilogram or higher had negligible impairment of respiratory function after infection, whereas control animals were not protected from severe disease and fatality. Given the breadth of MEDI8852 and other bnAbs, we anticipate that protection from unforeseen pandemic influenza A viruses is achievable.

『Abstract』Abstract Social animals live in groups and interact volitionally in complex ways. However, little is known about neural responses under such natural conditions. Here, we investigated hippocampal CA1 neurons in a mixed-sex group of five to 10 freely behaving wild Egyptian fruit bats that lived continuously in a laboratory-based cave and formed a stable social network. In-flight, most hippocampal place cells were socially modulated and represented the identity and sex of conspecifics. Upon social interactions, neurons represented specific interaction types. During active observation, neurons encoded the bat’s own position and head direction, together with the position, direction, and identity of multiple conspecifics. Identity-coding neurons encoded the same bat across contexts. The strength of identity coding was modulated by sex, hierarchy, and social affiliation. Thus, hippocampal neurons form a multidimensional sociospatial representation of the natural world.

『Abstract』Abstract Human-driven Arctic warming and resulting sea ice loss have been associated with declines in several polar bear populations. However, quantifying how individual responses to environmental change integrate and scale to influence population dynamics in polar bears has yet to be achieved. We developed an individual-based bioenergetic model and hindcast population dynamics across 42 years of observed sea ice conditions in Western Hudson Bay, a region undergoing rapid environmental change. The model successfully captured trends in individual morphometrics, reproduction, and population abundance observed over four decades of empirical monitoring data. Our study provides evidence for the interplay between individual energetics and environmental constraints in shaping population dynamics and for the fundamental role of a single limiting mechanism—energy—underpinning the decline of an apex Arctic predator.

『Abstract』Abstract Highly concentrated solutions of asymmetric semiconductor magic-sized clusters (MSCs) of cadmium sulfide, cadmium selenide, and cadmium telluride were directed through a controlled drying meniscus front, resulting in the formation of chiral MSC assemblies. This process aligned their transition dipole moments and produced chiroptic films with exceptionally strong circular dichroism. G -factors reached magnitudes as high as 1.30 for drop-cast films and 1.06 for patterned films, approaching theoretical limits. By controlling the evaporation geometry, various domain shapes and sizes were achieved, with homochiral domains exceeding 6 square millimeters that transition smoothly between left- and right-handed chirality. Our results uncovered fundamental relationships between meniscus deposition processes, the alignment of supramolecular filaments and their MSC constituents, and their connection to emergent chiral properties.

『Abstract』Abstract During transcription, RNA polymerase II traverses through chromatin, and posttranslational modifications including histone methylations mark regions of active transcription. Histone protein H3 lysine 36 trimethylation (H3K36me3), which is established by the histone methyltransferase SET domain containing 2 (SETD2), suppresses cryptic transcription, regulates splicing, and serves as a binding site for transcription elongation factors. The mechanism by which the transcription machinery coordinates the deposition of H3K36me3 is not well understood. Here we provide cryo–electron microscopy structures of mammalian RNA polymerase II–DSIF-SPT6-PAF1c-TFIIS-IWS1-SETD2-nucleosome elongation complexes, revealing that the transcription machinery regulates H3K36me3 deposition by SETD2 on downstream and upstream nucleosomes. SPT6 binds the exposed H2A-H2B dimer during transcription, and the SPT6 death-like domain mediates an interaction with SETD2 bound to a nucleosome upstream of RNA polymerase II.

『Abstract』Abstract Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity and regulated cell death in humans. We describe a bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule adenosine 5′-diphosphate-cyclo[N7:1′′]-ribose (N7-cADPR). This molecule specifically activates the bacterial caspase-like protease, which then indiscriminately degrades cellular proteins to halt phage replication. The TIR-caspase defense system, which we denote as type IV Thoeris, is abundant in bacteria and efficiently protects against phage propagation. Our study highlights the diversity of TIR-produced immune signaling molecules and demonstrates that cell death regulated by proteases of the caspase family is an ancient mechanism of innate immunity.

『Abstract』Abstract The mechanisms by which the brain replays neural activity sequences remain unknown. Recording from large ensembles of hippocampal place cells in freely behaving rats, we observed that replay content is strictly organized over multiple timescales and governed by self-avoidance. After movement cessation, replays avoided the animal’s previous path for 3 seconds. Chains of replays avoided self-repetition over a shorter timescale. We used a continuous attractor model of neural activity to demonstrate that neuronal fatigue both generates replay sequences and produces self-avoidance over the observed timescales. In addition, replay of past experience became predominant later into the stopping period, in a manner requiring cortical input. These results indicate a mechanism for replay generation that unexpectedly constrains which sequences can be produced across time.

『Abstract』Abstract The origins and prehistory of domestic sheep ( Ovis aries ) are incompletely understood; to address this, we generated data from 118 ancient genomes spanning 12,000 years sampled from across Eurasia. Genomes from Central Turkiye ~8000 BCE are genetically proximal to the domestic origins of sheep but do not fully explain the ancestry of later populations, suggesting a mosaic of wild ancestries. Genomic signatures indicate selection by ancient herders for pigmentation patterns, hornedness, and growth rate. Although the first European sheep flocks derive from Turkiye, in a notable parallel with ancient human genome discoveries, we detected a major influx of Western steppe–related ancestry in the Bronze Age.

『Abstract』Abstract Phase diagrams and crystallography are standard tools for studying structural phase transitions, whereas acquiring kinetic information at the atomistic level has been considered essential but challenging. The η-to-θ phase transition of alumina is unidirectional in bulk and retains the crystal lattice orientation. We report a rare example of a statistical kinetics study showing that for nanoparticles on a bulk Al(OH) 3 surface, this phase transition occurs nondeterministically through an ergodic equilibrium through the molten state, and the memory of the lattice orientation is lost in this process. The rate of the interconversion was found to be insensitive to the electron dose rate, and this process had a small Gibbs free energy of activation. These nondeterministic kinetics should be a key feature of crystal nucleation occurring in high-surface-energy regions of bulk crystals.

『Abstract』Abstract Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and whether scratching provides benefit to the host are largely unknown. We found that scratching was required for skin inflammation in mouse models dependent on FcεRI-mediated mast cell activation. Scratching-induced inflammation required pain-sensing nociceptors, the neuropeptide substance P, and the mast cell receptor MrgprB2. Scratching also increased cutaneous inflammation and augmented host defense to superficial Staphylococcus aureus infection. Thus, through the activation of nociceptor-driven neuroinflammation, scratching both exacerbated allergic skin disease and provided protection from S. aureus , reconciling the seemingly paradoxical role of scratching as a pathological process and evolutionary adaptation.

『Abstract』Abstract Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) methods to generate, map, and characterize SVs in model systems are underdeveloped. To address these challenges, we developed Genome-Shuffle-seq, a method that enables the multiplex generation and mapping of thousands of SVs (deletions, inversions, translocations, and extrachromosomal circles) throughout mammalian genomes. We also demonstrate the co-capture of SV identity with single-cell transcriptomes, facilitating the measurement of SV impact on gene expression. We anticipate that Genome-Shuffle-seq will be broadly useful for the systematic exploration of the functional consequences of SVs on gene expression, the chromatin landscape, and three-dimensional nuclear architecture, while also initiating a path toward a minimal mammalian genome.

『Abstract』Abstract Recovery of large yet ecologically important carnivores poses a formidable global challenge. Tiger ( Panthera tigris ) recovery in India, the world’s most populated region, offers a distinct opportunity to evaluate the socio-ecological drivers of megafauna recovery. Tiger occupancy increased by 30% (at 2929 square kilometers per year) over the past two decades, leading to the largest global population occupying ~138,200 square kilometers. Tigers persistently occupied human-free, prey-rich protected areas (35,255 square kilometers) but also colonized proximal connected habitats that were shared with ~60 million people. Tiger absence and extinction were characterized by armed conflict, poverty, and extensive land-use changes. Sparing land for tigers enabled land sharing, provided that socioeconomic prosperity and political stability prevailed. India’s tiger recovery offers cautious optimism for megafauna recovery, particularly in the Global South.

『Abstract』Abstract In the ancient microbial Wood-Ljungdahl pathway, carbon dioxide (CO 2 ) is fixed in a multistep process that ends with acetyl–coenzyme A (acetyl-CoA) synthesis at the bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS). In this work, we present structural snapshots of the CODH/ACS from the gas-converting acetogen Clostridium autoethanogenum , characterizing the molecular choreography of the overall reaction, including electron transfer to the CODH for CO 2 reduction, methyl transfer from the corrinoid iron-sulfur protein (CoFeSP) partner to the ACS active site, and acetyl-CoA production. Unlike CODH, the multidomain ACS undergoes large conformational changes to form an internal connection to the CODH active site, accommodate the CoFeSP for methyl transfer, and protect the reaction intermediates. Altogether, the structures allow us to draw a detailed reaction mechanism of this enzyme, which is crucial for CO 2 fixation in anaerobic organisms.

『Abstract』All-inorganic perovskites prepared by substituting the organic cations (for example, methylammonium and formamidinium) with inorganic cations (for example, Cs ) are effective concepts to enhance the long-term photostability and thermal stability of perovskite solar cells (PSCs) . Hence, inorganic perovskite tandem solar cells (IPTSCs) are promising candidates for breaking the efficiency bottleneck and addressing the stability issue, too . However, challenges remain in fabricating two-terminal (2T) IPTSCs due to the inferior film formation and deep trap states induced by tin cations . Here a ligand evolution (LE) strategy with p -toluenesulfonyl hydrazide (PTSH) is used to regulate film formation and eliminate deep traps in inorganic narrow-bandgap (NBG) perovskites, enabling the successful development of 2T IPTSCs. Accordingly, the 1.31 eV CsPb 0.4 Sn 0.6 I 3 :LE device delivers a record efficiency of 17.41%. Combined with the 1.92 eV CsPbI 2 Br top cell, 2T IPTSCs exhibit a champion efficiency of 22.57% (certified, 21.92%). Moreover, IPTSCs are engineered to deliver remarkable durability under maximum power point (MPP) tracking, maintaining 80% of their initial efficiency at 65 °C for 1,510 h and at 85 °C for 800 h. We elucidate that LE deliberately leverages multiple roles for inorganic NBG perovskite growth and anticipate that our study provides an insightful guideline for developing high-efficiency and stable IPTSCs.

『Abstract』Much of the human genome is transcribed into RNAs , many of which contain structural elements that are important for their function. Such RNA molecules—including those that are structured and well-folded —are conformationally heterogeneous and flexible, which is a prerequisite for function , but this limits the applicability of methods such as NMR, crystallography and cryo-electron microscopy for structure elucidation. Moreover, owing to the lack of a large RNA structure database, and no clear correlation between sequence and structure, approaches such as AlphaFold for protein structure prediction do not apply to RNA. Therefore, determining the structures of heterogeneous RNAs remains an unmet challenge. Here we report holistic RNA structure determination method using atomic force microscopy, unsupervised machine learning and deep neural networks (HORNET), a novel method for determining three-dimensional topological structures of RNA using atomic force microscopy images of individual molecules in solution. Owing to the high signal-to-noise ratio of atomic force microscopy, this method is ideal for capturing structures of large RNA molecules in distinct conformations. In addition to six benchmark cases, we demonstrate the utility of HORNET by determining multiple heterogeneous structures of RNase P RNA and the HIV-1 Rev response element (RRE) RNA. Thus, our method addresses one of the major challenges in determining heterogeneous structures of large and flexible RNA molecules, and contributes to the fundamental understanding of RNA structural biology.

『Abstract』Uncontrolled regeneration leads to neoplastic transformation . The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin ( Areg ), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1 , LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.

『Abstract』Quantum materials governed by emergent topological fermions have become a cornerstone of physics. Dirac fermions in graphene form the basis for moire quantum matter and Dirac fermions in magnetic topological insulators enabled the discovery of the quantum anomalous Hall (QAH) effect . By contrast, there are few materials whose electromagnetic response is dominated by emergent Weyl fermions . Nearly all known Weyl materials are overwhelmingly metallic and are largely governed by irrelevant, conventional electrons. Here we theoretically predict and experimentally observe a semimetallic Weyl ferromagnet in van der Waals (Cr,Bi) 2 Te 3 . In transport, we find a record bulk anomalous Hall angle of greater than 0.5 along with non-metallic conductivity, a regime that is strongly distinct from conventional ferromagnets. Together with symmetry analysis, our data suggest a semimetallic Fermi surface composed of two Weyl points, with a giant separation of more than 75% of the linear dimension of the bulk Brillouin zone, and no other electronic states. Using state-of-the-art crystal-synthesis techniques, we widely tune the electronic structure, allowing us to annihilate the Weyl state and visualize a unique topological phase diagram exhibiting broad Chern insulating, Weyl semimetallic and magnetic semiconducting regions. Our observation of a semimetallic Weyl ferromagnet offers an avenue towards new correlated states and nonlinear phenomena, as well as zero-magnetic-field Weyl spintronic and optical devices.

『Abstract』Electrons in topological flat bands can form new topological states driven by correlation effects. The pentalayer rhombohedral graphene/hexagonal boron nitride (hBN) moire superlattice was shown to host fractional quantum anomalous Hall effect (FQAHE) at approximately 400 mK (ref. ), triggering discussions around the underlying mechanism and role of moire effects . In particular, new electron crystal states with non-trivial topology have been proposed . Here we report electrical transport measurements in rhombohedral pentalayer and tetralayer graphene/hBN moire superlattices at electronic temperatures down to below 40 mK. We observed two more fractional quantum anomalous Hall (FQAH) states and smaller R xx values in pentalayer devices than those previously reported. In the new tetralayer device, we observed FQAHE at moire filling factors v = 3/5 and 2/3. With a small current at the base temperature, we observed a new extended quantum anomalous Hall (EQAH) state and magnetic hysteresis, where R xy = h / e and vanishing R xx spans a wide range of v from 0.5 to 1.3. At increased temperature or current, EQAH states disappear and partially transition into the FQAH liquid . Furthermore, we observed displacement field-induced quantum phase transitions from the EQAH states to the Fermi liquid, FQAH liquid and the likely composite Fermi liquid. Our observations established a new topological phase of electrons with quantized Hall resistance at zero magnetic field and enriched the emergent quantum phenomena in materials with topological flat bands.

『Abstract』Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy . Incomplete penetrance is common among IEIs despite their monogenic basis . Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele , to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11 . This study highlights the importance of considering both the genotype and the ‘transcriptotype’ in analyses of the penetrance and expressivity of monogenic disorders.

『Abstract』In a dilute two-dimensional electron gas, Coulomb interactions can stabilize the formation of a Wigner crystal . Although Wigner crystals are topologically trivial, it has been predicted that electrons in a partially filled band can break continuous translational symmetry and time-reversal symmetry spontaneously, resulting in a type of topological electron crystal known as an anomalous Hall crystal . Here we report signatures of a generalized version of the anomalous Hall crystal in twisted bilayer–trilayer graphene, whose formation is driven by the moire potential. The crystal forms at a band filling of one electron per four moire unit cells ( ν = 1/4) and quadruples the unit-cell area, coinciding with an integer quantum anomalous Hall effect. The Chern number of the state is exceptionally tunable, and it can be switched reversibly between +1 and −1 by electric and magnetic fields. Several other topological electronic crystals arise in a modest magnetic field, originating from ν = 1/3, 1/2, 2/3 and 3/2. The quantum geometry of the interaction-modified bands is likely to be very different from that of the original parent band, which enables possible future discoveries of correlation-driven topological phenomena.

『Abstract』Increasing soil salinity causes significant crop losses globally; therefore, understanding plant responses to salt (sodium) stress is of high importance. Plants avoid sodium toxicity through subcellular compartmentation by intricate processes involving a high level of elemental interdependence. Current technologies to visualize sodium, in particular, together with other elements, are either indirect or lack in resolution. Here we used the newly developed cryo nanoscale secondary ion mass spectrometry ion microprobe , which allows high-resolution elemental imaging of cryo-preserved samples and reveals the subcellular distributions of key macronutrients and micronutrients in root meristem cells of Arabidopsis and rice. We found an unexpected, concentration-dependent change in sodium distribution, switching from sodium accumulation in the cell walls at low external sodium concentrations to vacuolar accumulation at stressful concentrations. We conclude that, in root meristems, a key function of the NHX family sodium/proton antiporter SALT OVERLY SENSITIVE 1 (also known as Na /H exchanger 7; SOS1/NHX7) is to sequester sodium into vacuoles, rather than extrusion of sodium into the extracellular space. This is corroborated by the use of new genomic, complementing fluorescently tagged SOS1 variants. We show that, in addition to the plasma membrane, SOS1 strongly accumulates at late endosome/prevacuoles as well as vacuoles, supporting a role of SOS1 in vacuolar sodium sequestration.

『Abstract』Accurate goal-directed behaviour requires the sense of touch to be integrated with information about body position and ongoing motion . Behaviours such as chewing, swallowing and speech critically depend on precise tactile events on a rapidly moving tongue , but neural circuits for dynamic touch-guided tongue control are unknown. Here, using high-speed videography, we examined three-dimensional lingual kinematics as mice drank from a water spout that unexpectedly changed position during licking, requiring re-aiming in response to subtle contact events on the left, centre or right surface of the tongue. Mice integrated information about both precise touch events and tongue position to re-aim ensuing licks. Touch-guided re-aiming was unaffected by photoinactivation of tongue sensory, premotor and motor cortices, but was impaired by photoinactivation of the lateral superior colliculus (latSC). Electrophysiological recordings identified latSC neurons with mechanosensory receptive fields for precise touch events that were anchored in tongue-centred, head-centred or conjunctive reference frames. Notably, latSC neurons also encoded tongue position before contact, information that is important for tongue-to-head-based coordinate transformations underlying accurate touch-guided aiming. Viral tracing revealed tongue sensory inputs to the latSC from the lingual trigeminal nucleus, and optical microstimulation in the latSC revealed a topographic map for aiming licks. These findings demonstrate that touch-guided tongue control relies on a collicular mechanosensorimotor map, analogous to collicular visuomotor maps associated with visually guided orienting across many species.

『Abstract』Roman writers found the relative empowerment of Celtic women remarkable . In southern Britain, the Late Iron Age Durotriges tribe often buried women with substantial grave goods . Here we analyse 57 ancient genomes from Durotrigian burial sites and find an extended kin group centred around a single maternal lineage, with unrelated (presumably inward migrating) burials being predominantly male. Such a matrilocal pattern is undescribed in European prehistory, but when we compare mitochondrial haplotype variation among European archaeological sites spanning six millennia, British Iron Age cemeteries stand out as having marked reductions in diversity driven by the presence of dominant matrilines. Patterns of haplotype sharing reveal that British Iron Age populations form fine-grained geographical clusters with southern links extending across the channel to the continent. Indeed, whereas most of Britain shows majority genomic continuity from the Early Bronze Age to the Iron Age, this is markedly reduced in a southern coastal core region with persistent cross-channel cultural exchange . This southern core has evidence of population influx in the Middle Bronze Age but also during the Iron Age. This is asynchronous with the rest of the island and points towards a staged, geographically granular absorption of continental influence, possibly including the acquisition of Celtic languages.

『Abstract』The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix . Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration . Despite the important roles of the DGC in physiology and pathology, its structural details remain largely unknown, hindering a comprehensive understanding of its assembly and function. Here we isolated the native DGC from mouse skeletal muscle and obtained its high-resolution structure. Our findings unveil a markedly divergent structure from the previous model of DGC assembly. Specifically, on the extracellular side, β-, γ- and δ-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for α-sarcoglycan and dystroglycan. In the transmembrane region, sarcoglycans and sarcospan flank and stabilize the single transmembrane helix of dystroglycan, rather than forming a subcomplex as previously proposed . On the intracellular side, sarcoglycans and dystroglycan engage in assembly with the dystrophin–dystrobrevin subcomplex through extensive interaction with the ZZ domain of dystrophin. Collectively, these findings enhance our understanding of the structural linkage across the cell membrane and provide a foundation for the molecular interpretation of many muscular dystrophy-related mutations.

『Abstract』Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality . Discovery of the DMD gene encoding dystrophin both revealed the cause of DMD and helped identify a family of at least ten dystrophin-associated proteins at the muscle cell membrane, collectively forming the dystrophin–glycoprotein complex (DGC) . The DGC links the extracellular matrix to the cytoskeleton, but, despite its importance, its molecular architecture has remained elusive. Here we determined the native cryo-electron microscopy structure of rabbit DGC and conducted biochemical analyses to reveal its intricate molecular configuration. An unexpected β-helix comprising β-, γ- and δ-sarcoglycan forms an extracellular platform that interacts with α-dystroglycan, β-dystroglycan and α-sarcoglycan, allowing α-dystroglycan to contact the extracellular matrix. In the membrane, sarcospan anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, while in the cytoplasm, β-dystroglycan’s juxtamembrane fragment binds dystrophin’s ZZ domain. Through these interactions, the DGC links laminin 2 to intracellular actin. Additionally, dystrophin’s WW domain, along with its EF-hand 1 domain, interacts with α-dystrobrevin. A disease-causing mutation mapping to the WW domain weakens this interaction, as confirmed by deletion of the WW domain in biochemical assays. Our findings rationalize more than 110 mutations affecting single residues associated with various muscular dystrophy subtypes and contribute to ongoing therapeutic developments, including protein restoration, upregulation of compensatory genes and gene replacement.

『Abstract』Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment . Yet, response rates are still limited, and tumour progression commonly occurs . Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition . In a first-in-human phase 1–2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

『Abstract』The amount of methane released to the atmosphere from the Nord Stream subsea pipeline leaks remains uncertain, as reflected in a wide range of estimates . A lack of information regarding the temporal variation in atmospheric emissions has made it challenging to reconcile pipeline volumetric (bottom-up) estimates with measurement-based (top-down) estimates

『Abstract』Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs) , partly because there are immunosuppressive myeloid cells in tumours . However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts ( SPP1 -TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8 T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1 -TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1 -TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1 -TAM-mediated immunosuppression in CD8 T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1 -TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1 -TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.

『Abstract』Evaporation or freezing of water-rich fluids with dilute concentrations of dissolved salts can produce brines, as observed in closed basins on Earth and detected by remote sensing on icy bodies in the outer Solar System . The mineralogical evolution of these brines is well understood in regard to terrestrial environments , but poorly constrained for extraterrestrial systems owing to a lack of direct sampling. Here we report the occurrence of salt minerals in samples of the asteroid (101955) Bennu returned by the OSIRIS-REx mission . These include sodium-bearing phosphates and sodium-rich carbonates, sulfates, chlorides and fluorides formed during evaporation of a late-stage brine that existed early in the history of Bennu’s parent body. Discovery of diverse salts would not be possible without mission sample return and careful curation and storage, because these decompose with prolonged exposure to Earth’s atmosphere. Similar brines probably still occur in the interior of icy bodies Ceres and Enceladus, as indicated by spectra or measurement of sodium carbonate on the surface or in plumes .

『Abstract』Dielectric-based energy storage capacitors characterized with fast charging and discharging speed and reliability play a vital role in cutting-edge electrical and electronic equipment. In pursuit of capacitor miniaturization and integration, dielectrics must offer high energy density and efficiency . Antiferroelectrics with antiparallel dipole configurations have been of significant interest for high-performance energy storage due to their negligible remanent polarization and high maximum polarization in the field-induced ferroelectric state . However, the low antiferroelectric–ferroelectric phase-transition field and accompanying large hysteresis loss deteriorate energy density and reliability. Here, guided by phase-field simulations, we propose a new strategy to frustrate antipolar ordering in antiferroelectrics by incorporating non-polar or polar components. Our experiments demonstrate that this approach effectively tunes the antiferroelectric–ferroelectric phase-transition fields and simultaneously reduces hysteresis loss. In PbZrO 3 -based films, we hence realized a record high energy density among all antiferroelectrics of 189 J cm along with a high efficiency of 81% at an electric field of 5.51 MV cm , which rivals the most state-of-the-art energy storage dielectrics . Atomic-scale characterization by scanning transmission electron microscopy directly revealed that the dispersed non-polar regions frustrate the long-range antipolar ordering, which contributes to the improved performance. This strategy presents new opportunities to manipulate polarization profiles and enhance energy storage performances in antiferroelectrics.

『Abstract』RNA conformational diversity has fundamental biological roles , but direct visualization of its full conformational space in solution has not been possible using traditional biophysical techniques. Using solution atomic force microscopy, a deep neural network and statistical analyses, we show that the ribonuclease P (RNase P) RNA adopts heterogeneous conformations consisting of a conformationally invariant core and highly flexible peripheral structural elements that sample a broad conformational space, with amplitudes as large as 20–60 Å in a multitude of directions, with very low net energy cost. Increasing Mg drives compaction and enhances enzymatic activity, probably by narrowing the conformational space. Moreover, analyses of the correlations and anticorrelations between spatial flexibility and sequence conservation suggest that the functional roles of both the structure and dynamics of key regions are embedded in the primary sequence. These findings reveal the structure–dynamics basis for the embodiment of both enzymatic precision and substrate promiscuity in the RNA component of the RNase P. Mapping the conformational space of the RNase P RNA demonstrates a new general approach to studying RNA structure and dynamics.

『Abstract』Recently acquired memories are reactivated in the hippocampus during sleep, an initial step for their consolidation . This process is concomitant with the hippocampal reactivation of previous memories , posing the problem of how to prevent interference between older and recent, initially labile, memory traces. Theoretical work has suggested that consolidating multiple memories while minimizing interference can be achieved by randomly interleaving their reactivation . An alternative is that a temporal microstructure of sleep can promote the reactivation of different types of memories during specific substates. Here, to test these two hypotheses, we developed a method to simultaneously record large hippocampal ensembles and monitor sleep dynamics through pupillometry in naturally sleeping mice. Oscillatory pupil fluctuations revealed a previously unknown microstructure of non-REM sleep-associated memory processes. We found that memory replay of recent experiences dominated in sharp-wave ripples during contracted pupil substates of non-REM sleep, whereas replay of previous memories preferentially occurred during dilated pupil substates. Selective closed-loop disruption of sharp-wave ripples during contracted pupil non-REM sleep impaired the recall of recent memories, whereas the same manipulation during dilated pupil substates had no behavioural effect. Stronger extrinsic excitatory inputs characterized the contracted pupil substate, whereas higher recruitment of local inhibition was prominent during dilated pupil substates. Thus, the microstructure of non-REM sleep organizes memory replay, with previous versus new memories being temporally segregated in different substates and supported by local and input-driven mechanisms, respectively. Our results suggest that the brain can multiplex distinct cognitive processes during sleep to facilitate continuous learning without interference.

『Abstract』A central question in neuroscience is how synaptic plasticity shapes the feature selectivity of neurons in behaving animals . Hippocampal CA1 pyramidal neurons display one of the most striking forms of feature selectivity by forming spatially and contextually selective receptive fields called place fields, which serve as a model for studying the synaptic basis of learning and memory. Various forms of synaptic plasticity have been proposed as cellular substrates for the emergence of place fields. However, despite decades of work, our understanding of how synaptic plasticity underlies place-field formation and memory encoding remains limited, largely due to a shortage of tools and technical challenges associated with the visualization of synaptic plasticity at the single-neuron resolution in awake behaving animals. To address this, we developed an all-optical approach to monitor the spatiotemporal tuning and synaptic weight changes of dendritic spines before and after the induction of a place field in single CA1 pyramidal neurons during spatial navigation. We identified a temporally asymmetric synaptic plasticity kernel resulting from bidirectional modifications of synaptic weights around the induction of a place field. Our work identified compartment-specific differences in the magnitude and temporal expression of synaptic plasticity between basal dendrites and oblique dendrites. Our results provide experimental evidence linking synaptic plasticity to the rapid emergence of spatial selectivity in hippocampal neurons, a critical prerequisite for episodic memory.

『Abstract』Multicomponent reactions—those where three or more substrates combine into a product—have been highly useful in rapidly building chemical building blocks of increased complexity , but achieving this enzymatically has remained rare . This limitation primarily arises because an enzyme’s active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates . Recently, chemical catalytic radical sorting has emerged as an enabling strategy for a variety of useful reactions . However, making such processes enantioselective is highly challenging owing to the inherent difficulty in the stereochemical control of radicals . Here we repurpose a thiamine-dependent enzyme through directed evolution and combine it with photoredox catalysis to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials—aldehydes, α-bromo-carbonyls and alkenes—to give access to enantioenriched ketone products. Mechanistic investigations provide insights into how this dual photocatalyst–enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 24 out of 33 examples achieving ≥97% enantiomeric excess.

『Abstract』The integrated frequency comb generator based on Kerr parametric oscillation has led to chip-scale, gigahertz-spaced combs with new applications spanning hyperscale telecommunications, low-noise microwave synthesis, light detection and ranging, and astrophysical spectrometer calibration . Recent progress in lithium niobate (LiNbO 3 ) photonic integrated circuits (PICs) has resulted in chip-scale, electro-optic (EO) frequency combs , offering precise comb-line positioning and simple operation without relying on the formation of dissipative Kerr solitons. However, current integrated EO combs face limited spectral coverage due to the large microwave power required to drive the non-resonant capacitive electrodes and the strong intrinsic birefringence of LiNbO 3 . Here we overcome both challenges with an integrated triply resonant architecture, combining monolithic microwave integrated circuits with PICs based on the recently emerged thin-film lithium tantalate (LiTaO 3 ) . With resonantly enhanced EO interaction and reduced birefringence in LiTaO 3 , we achieve a fourfold comb span extension and a 16-fold power reduction compared to the conventional, non-resonant microwave design. Driven by a hybrid integrated laser diode, the comb spans over 450 nm (more than 60 THz) with more than 2,000 lines, and the generator fits within a compact 1-cm footprint. We additionally observe that the strong EO coupling leads to an increased comb existence range approaching the full free spectral range of the optical microresonator. The ultra-broadband comb generator, combined with detuning-agnostic operation, could advance chip-scale spectrometry and ultra-low-noise millimetre wave synthesis and unlock octave-spanning EO combs. The methodology of co-designing microwave and photonics can be extended to a wide range of integrated EOs applications .

『Abstract』Reproduction, development and homeostasis depend on motile cilia, whose rhythmic beating is powered by a microtubule-based molecular machine called the axoneme. Although an atomic model of the axoneme is available for the alga Chlamydomonas reinhardtii , structures of mammalian axonemes are incomplete . Furthermore, we do not fully understand how molecular structures of axonemes vary across motile-ciliated cell types in the body. Here we use cryoelectron microscopy, cryoelectron tomography and proteomics to resolve the 96-nm modular repeat of axonemal doublet microtubules (DMTs) from both sperm flagella and epithelial cilia of the oviduct, brain ventricles and respiratory tract. We find that sperm DMTs are the most specialized, with epithelial cilia having only minor differences across tissues. We build a model of the mammalian sperm DMT, defining the positions and interactions of 181 proteins including 34 newly identified proteins. We elucidate the composition of radial spoke 3 and uncover binding sites of kinases associated with regeneration of ATP and regulation of ciliary motility. We discover a sperm-specific, axoneme-tethered T-complex protein ring complex (TRiC) chaperone that may contribute to construction or maintenance of the long flagella of mammalian sperm. We resolve axonemal dyneins in their prestroke states, illuminating conformational changes that occur during ciliary movement. Our results illustrate how elements of chemical and mechanical regulation are embedded within the axoneme, providing valuable resources for understanding the aetiology of ciliopathy and infertility, and exemplifying the discovery power of modern structural biology.

『Abstract』Seismic tomographic models based only on wave velocities have limited ability to distinguish between a thermal or compositional origin for Earth’s 3D structure . Complementing wave velocities with attenuation observations can make that distinction, which is fundamental for understanding mantle convection evolution. However, global 3D attenuation models are only available for the upper mantle at present . Here we present a 3D global model of attenuation for the whole mantle made using whole-Earth oscillations, constraining even spherical harmonics up to degree four. In the upper mantle, we find that high attenuation correlates with low velocity, indicating a thermal origin, in agreement with previous studies . In the lower mantle, we find the opposite and observe the highest attenuation in the ‘ring around the Pacific’, which is seismically fast, and the lowest attenuation in the large low-seismic-velocity provinces (LLSVPs). Comparing our model with wave speeds and attenuation predicted by a laboratory-based viscoelastic model suggests that the circum-Pacific is a colder and small-grain-size region , surrounding the warmer and large-grain-size LLSVPs. Viscosities calculated for the inferred variations in grain size and temperature confirm LLSVPs as long-lived, stable features .

『Abstract』Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . The rapid development of highly effective vaccines against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity . Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S -adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant ( K d ) of 61 pM and a half-maximal effective concentration (EC 50 ) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir . The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.

『Abstract』Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne virus that can cause severe disease in humans with case fatality rates of 10%–40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we use structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-Gn -Gc). A cryo-electron microscopy (cryo-EM) structure of this complex provides the molecular basis for GP38’s association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-Gn -Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.

『Abstract』Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including ELFN1 and ADORA3 , demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics.

『Abstract』Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18 . Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis.

『Abstract』Condensed droplets of protein regulate many cellular functions, yet the physiological conditions regulating their formation remain largely unexplored. Increasing our understanding of these mechanisms is paramount, as failure to control condensate formation and dynamics can lead to many diseases. Here, we provide evidence that matrix stiffening promotes biomolecular condensation in vivo . We demonstrate that the extracellular matrix links mechanical cues with the control of glucose metabolism to sorbitol. In turn, sorbitol acts as a natural crowding agent to promote biomolecular condensation. Using in silico simulations and in vitro assays, we establish that variations in the physiological range of sorbitol concentrations, but not glucose concentrations, are sufficient to regulate biomolecular condensates. Accordingly, pharmacological and genetic manipulation of intracellular sorbitol concentration modulates biomolecular condensates in breast cancer—a mechano-dependent disease. We propose that sorbitol is a mechanosensitive metabolite enabling protein condensation to control mechano-regulated cellular functions.

『Abstract』The underlying mechanisms used by the intestinal microbiota to shape disease outcomes of the host are poorly understood. Here, we show that the gut commensal protozoan, Tritrichomonas musculis ( T.mu ), remotely shapes the lung immune landscape to facilitate perivascular shielding of the airways by eosinophils. Lung-specific eosinophilia requires a tripartite immune network between gut-derived inflammatory group 2 innate lymphoid cells and lung-resident T cells and B cells. This network exacerbates the severity of allergic airway inflammation while hindering the systemic dissemination of pulmonary Mycobacterium tuberculosis . The identification of protozoan DNA sequences in the sputum of patients with severe allergic asthma further emphasizes the relevance of commensal protozoa in human disease. Collectively, these findings demonstrate that a commensal protozoan tunes pulmonary immunity via a gut-operated lung immune network, promoting both beneficial and detrimental disease outcomes in response to environmental airway allergens and pulmonary infections.

『Abstract』Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an N -methyladenosine (m A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.

『Abstract』A 2°C climate-warming scenario is expected to further exacerbate average crop losses by 3%–13%, yet few heat-tolerant staple-crop varieties are available toward meeting future food demands. Here, we develop high-efficiency prime-editing tools to precisely knockin a 10-bp heat-shock element (HSE) into promoters of cell-wall-invertase genes ( CWINs ) in elite rice and tomato cultivars. HSE insertion endows CWINs with heat-responsive upregulation in both controlled and field environments to enhance carbon partitioning to grain and fruits, resulting in per-plot yield increases of 25% in rice cultivar Zhonghua11 and 33% in tomato cultivar Ailsa Craig over heat-stressed controls, without fruit quality penalties. Up to 41% of heat-induced grain losses were rescued in rice. Beyond a prime-editing system for tweaking gene expression by efficiently delivering bespoke changes into crop genomes, we demonstrate broad and robust utility for targeted knockin of cis -regulatory elements to optimize source-sink relations and boost crop climate resilience.

『Abstract』Stringent control of T cell activity in the tumor microenvironment is essential for the generation of protective antitumor immunity. However, the identity, differentiation, and functions of the cells that create critical fibroblastic niches promoting tumor-infiltrating T cells remain elusive. Here, we show that CCL19-expressing fibroblastic reticular cells (FRCs) generate interconnected T cell environments (TEs) in human non-small cell lung cancer, including tertiary lymphoid structures and T cell tracks. Analysis of the FRC-T cell interactome in TEs indicated molecular networks regulating niche-specific differentiation of CCL19-expressing fibroblasts and T cell activation pathways. Single-cell transcriptomics and cell fate-mapping analyses in mice confirmed that FRCs in TEs originate from mural and adventitial progenitors. Ablation of intratumoral FRC precursors decreased antitumor T cell activity, resulting in reduced tumor control during coronavirus vector-based immunotherapy. In summary, specialized FRC niches in the tumor microenvironment govern the quality and extent of antitumor T cell immunity.

『Abstract』Cis -regulatory elements (CREs) precisely control spatiotemporal gene expression in cells. Using a spatially resolved single-cell atlas of gene expression with chromatin accessibility across ten soybean tissues, we identified 103 distinct cell types and 303,199 accessible chromatin regions (ACRs). Nearly 40% of the ACRs showed cell-type-specific patterns and were enriched for transcription factor (TF) motifs defining diverse cell identities. We identified de novo enriched TF motifs and explored the conservation of gene regulatory networks underpinning legume symbiotic nitrogen fixation. With comprehensive developmental trajectories for endosperm and embryo, we uncovered the functional transition of the three sub-cell types of endosperm, identified 13 sucrose transporters sharing the DNA binding with one finger 11 (DOF11) motif that were co-upregulated in late peripheral endosperm, and identified key embryo cell-type specification regulators during embryogenesis, including a homeobox TF that promotes cotyledon parenchyma identity. This resource provides a valuable foundation for analyzing gene regulatory programs in soybean cell types across tissues and life stages.

『Abstract』Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.

『Abstract』Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ∼1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca channels and ER Ca -release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca homeostasis, and local activation of the Ca /calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.

『Abstract』Metastatic dissemination to distant organs demands that cancer cells possess high morphological and metabolic adaptability. However, contributions of the cellular lipidome to metastasis remain elusive. Here, we uncover a correlation between metastasis potential and ferroptosis susceptibility in multiple cancers. Metastases-derived cancer cells exhibited higher ferroptosis sensitivity and polyunsaturated fatty acyl (PUFA)-lipid contents than primary-tumor-derived cells from ovarian cancer patients. Metabolism-focused CRISPR screens in a mouse model for ovarian cancer distant metastasis established via two rounds of in vivo selection revealed the PUFA-lipid biosynthesis enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a pro-hematogenous metastasis factor. ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and cellular invasiveness. While promoting metastasis, the high PUFA-lipid state creates dependencies on abhydrolase-domain-containing 6, acylglycerol lipase (ABHD6), enoyl-CoA delta isomerase 1 (ECI1), and enoyl-CoA hydratase 1 (ECH1)—rate-limiting enzymes preparing unsaturated fatty acids (UFAs) for β-oxidation. ACSL4/ECH1 co-inhibition achieved potent suppression of metastasis. Our work establishes the dual functions of PUFA-lipids in tumor progression and metastasis that may be exploitable for therapeutic development.

『Abstract』Small nucleolar RNAs (snoRNAs) are non-coding RNAs known for guiding RNA modifications, including 2′- O -methylation (N m ) and pseudouridine (Ψ). While snoRNAs may also interact with other RNAs, such as mRNA, the full repertoire of RNAs targeted by snoRNA remains elusive due to the lack of effective technologies that identify snoRNA targets transcriptome wide. Here, we develop a chemical crosslinking-based approach that comprehensively detects cellular RNA targets of snoRNAs, yielding thousands of previously unrecognized snoRNA-mRNA interactions in human cells and mouse brain tissues. Many interactions occur outside of snoRNA-guided RNA modification sites, hinting at non-canonical functions beyond RNA modification. We find that one of these snoRNAs, SNORA73 , targets mRNAs that encode secretory proteins and membrane proteins. SNORA73 also interacts with 7SL RNA, part of the signal recognition particle (SRP) required for protein secretion. The mRNA- SNORA73 - 7SL RNA interactions enhance the association of the SNORA73 -target mRNAs with SRP, thereby facilitating the secretion of encoded proteins.

『Abstract』Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.

『Abstract』Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ.

『Abstract』Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.