前沿速递 | NCS 集萃： 2025-02-06 期 [Up]

『Abstract』Optical frequency combs have enabled distinct advantages in broadband, high-resolution spectroscopy and precision interferometry. However, quantum mechanics ultimately limits the metrological precision achievable with laser frequency combs. Quantum squeezing has led to substantial measurement improvements with continuous wave lasers, but experiments demonstrating metrological advantage with squeezed combs are less developed. Using the Kerr effect in nonlinear optical fiber, a 1-gigahertz frequency comb centered at 1560 nanometers is amplitude-squeezed by >3 decibels (dB) over a 2.5-terahertz bandwidth. Dual-comb interferometry yields mode-resolved spectroscopy of hydrogen sulfide gas with a signal-to-noise ratio nearly 3 dB beyond the shot-noise limit. The quantum noise reduction leads to a twofold quantum speedup in the determination of gas concentration, with implications for high-speed measurements of multiple species in dynamic chemical environments.

『Abstract』Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the “Kidney Disease Genetic Scorecard” for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.

『Abstract』Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by down-regulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8 T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.

『Abstract』In eukaryotes, DNA-associated protein complexes coevolve with genomic sequences to orchestrate chromatin folding. We investigate the relationship between DNA sequence and the spontaneous loading and activity of chromatin components in the absence of coevolution. Using bacterial genomes integrated into Saccharomyces cerevisiae , which diverged from yeast more than 2 billion years ago, we show that nucleosomes, cohesins, and associated transcriptional machinery can lead to the formation of two different chromatin archetypes, one transcribed and the other silent, independently of heterochromatin formation. These two archetypes also form on eukaryotic exogenous sequences, depend on sequence composition, and can be predicted using neural networks trained on the native genome. They do not mix in the nucleus, leading to a bipartite nuclear compartmentalization, reminiscent of the organization of vertebrate nuclei.

『Abstract』Fast instinctive responses to environmental stimuli can be crucial for survival but are not always optimal. Animals can adapt their behavior and suppress instinctive reactions, but the neural pathways mediating such ethologically relevant forms of learning remain unclear. We found that posterolateral higher visual areas (plHVAs) are crucial for learning to suppress escapes from innate visual threats through a top-down pathway to the ventrolateral geniculate nucleus (vLGN). plHVAs are no longer necessary after learning; instead, the learned behavior relies on plasticity within vLGN populations that exert inhibitory control over escape responses. vLGN neurons receiving input from plHVAs enhance their responses to visual threat stimuli during learning through endocannabinoid-mediated long-term suppression of their inhibitory inputs. We thus reveal the detailed circuit, cellular, and synaptic mechanisms underlying experience-dependent suppression of fear responses.

『Abstract』Humpback whale song is a culturally transmitted behavior. Human language, which is also culturally transmitted, has statistically coherent parts whose frequency distribution follows a power law. These properties facilitate learning and may therefore arise because of their contribution to the faithful transmission of language over multiple cultural generations. If so, we would expect to find them in other culturally transmitted systems. In this study, we applied methods based on infant speech segmentation to 8 years of humpback recordings, uncovering in whale song the same statistical structure that is a hallmark of human language. This commonality, in two evolutionarily distant species, points to the role of learning and cultural transmission in the emergence of properties thought to be unique to human language.

『Abstract』According to Noether’s theorem, symmetries in a physical system are intertwined with conserved quantities. These symmetries often determine the system topology, which is made ever more complex with increased dimensionality. Quasicrystals have neither translational nor global rotational symmetry, yet they intrinsically inhabit a higher-dimensional space in which symmetry resurfaces. Here, we discovered topological charge vectors in four dimensions (4D) that govern the real-space topology of 2D quasicrystals and reveal their inherent conservation laws. We demonstrate control over the topology in pentagonal plasmonic quasilattices, mapped by both phase-resolved and time-domain near-field microscopy, showing that their temporal evolution continuously tunes the 2D projections of their distinct 4D topologies. Our work provides a route to experimentally probe the thermodynamic properties of quasicrystals and topological physics in 4D and above.

『Abstract』In many species with sex chromosomes, the Y is a tiny chromosome. However, the dioecious plant Silene latifolia has a giant ~550-megabase Y chromosome, which has remained unsequenced so far. We used a long- and short-read hybrid approach to obtain a high-quality male genome. Comparative analysis of the sex chromosomes with their homologs in outgroups showed that the Y is highly rearranged and degenerated. Recombination suppression between X and Y extended in several steps and triggered a massive accumulation of repeats on the Y as well as in the nonrecombining pericentromeric region of the X, leading to giant sex chromosomes. Using sex phenotype mutants, we identified candidate sex-determining genes on the Y in locations consistent with their favoring recombination suppression events 11 and 5 million years ago.

『Abstract』Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin’s actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary blood flow and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through protein-tyrosine phosphatase 1B–mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide–synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.

『Abstract』Measures to combat the parasites that cause malaria have become compromised because of reliance on a small arsenal of drugs and emerging drug resistance. We conducted a transposon mutagenesis screen in the primate malaria parasite Plasmodium knowlesi , producing the most complete classification of gene essentiality in any Plasmodium spp. to date, with the resolution to define truncatable genes. We found conservation in the druggable genome between Plasmodium spp. and divergences in mitochondrial metabolism. Perturbation analyses with the frontline antimalarial artemisinin revealed modulators that both increase and decrease drug susceptibility. Our findings aid prioritization of drug and vaccine targets for the Plasmodium vivax clade and reveal mechanisms of resistance that can inform therapeutic development.

『Abstract』Malaria parasites are highly divergent from model eukaryotes. Large-scale genome engineering methods effective in model organisms are frequently inapplicable, and systematic studies of gene function are few. We generated more than 175,000 transposon insertions in the Plasmodium knowlesi genome, averaging an insertion every 138 base pairs, and used this “supersaturation” mutagenesis to score essentiality for 98% of genes. The density of mutations allowed mapping of putative essential domains within genes, providing a completely new level of genome annotation for any Plasmodium species. Although gene essentiality was largely conserved across P. knowlesi , Plasmodium falciparum , and rodent malaria model Plasmodium berghei , a large number of shared genes are differentially essential, revealing species-specific adaptations. Our results indicated that Plasmodium essential gene evolution was conditionally linked to adaptive rewiring of metabolic networks for different hosts.

『Abstract』Some plants have massive sex-linked regions. To test hypotheses about their evolution, we sequenced the genome of Silene latifolia , in which giant heteromorphic sex chromosomes were first discovered in 1923. It has long been known that the Y chromosome consists mainly of a male-specific region that does not recombine with the X chromosome and carries the sex-determining genes and genes with other male functions. However, only with a whole Y chromosome assembly can candidate genes be validated experimentally and their locations determined and related to the suppression of recombination. We describe the genomic changes as the ancestral chromosome evolved into the current XY pair, testing ideas about the evolution of large nonrecombining regions and the mechanisms that created the present recombination pattern.

『Abstract』The powerful strikes generated by the smasher mantis shrimp require it to possess a robust protection mechanism to withstand the resultant forces. Although recent studies have suggested that phononic bandgaps complement the mantis shrimp’s defensive suite, direct experimental evidence for this mechanism has remained elusive. In this work, we explored the phononic properties of the mantis shrimp’s dactyl club using laser ultrasonic techniques and numerical simulations. Our results demonstrate that the dactyl club’s periodic region functions as a dispersive, high-quality graded system, exhibiting Bloch harmonics, flat dispersion branches, ultraslow wave modes, and wide Bragg bandgaps in the lower megahertz range. These features effectively shield the shrimp from harmful high-frequency stress waves generated by cavitation bubble collapse events during impact.

『Abstract』Plants grow complex root systems to extract unevenly distributed resources from soils. Spatial differences in soil moisture are perceived by root tips, leading to the patterning of new root branches toward available water in a process called hydropatterning. Little is known about hydropatterning behavior and its genetic basis in crop plants. Here, we developed an assay to measure hydropatterning in maize and revealed substantial differences between tropical/subtropical and temperate maize breeding germplasm that likely resulted from divergent selection. Genetic analysis of hydropatterning confirmed the regulatory role of auxin and revealed that the gaseous hormone ethylene locally inhibits root branching from air-exposed tissues. Our results demonstrate how distinct signaling pathways translate spatial patterns of water availability to developmental programs that determine root architecture.

『Abstract』Understanding how interacting particles approach thermal equilibrium is a major challenge of quantum simulators . Unlocking the full potential of such systems towards this goal requires flexible initial state preparation, precise time evolution and extensive probes for final state characterization. Here we present a quantum simulator comprising 69 superconducting qubits that supports both universal quantum gates and high-fidelity analogue evolution, with performance beyond the reach of classical simulation in cross-entropy benchmarking experiments. This hybrid platform features more versatile measurement capabilities compared with analogue-only simulators, which we leverage here to reveal a coarsening-induced breakdown of Kibble–Zurek scaling predictions in the XY model, as well as signatures of the classical Kosterlitz–Thouless phase transition . Moreover, the digital gates enable precise energy control, allowing us to study the effects of the eigenstate thermalization hypothesis in targeted parts of the eigenspectrum. We also demonstrate digital preparation of pairwise-entangled dimer states, and image the transport of energy and vorticity during subsequent thermalization in analogue evolution. These results establish the efficacy of superconducting analogue–digital quantum processors for preparing states across many-body spectra and unveiling their thermalization dynamics.

『Abstract』Cellular identity requires the concerted action of multiple transcription factors (TFs) bound together to enhancers of cell-type-specific genes. Despite TFs recognizing specific DNA motifs within accessible chromatin, this information is insufficient to explain how TFs select enhancers . Here we compared four different TF combinations that induce different cell states, analysing TF genome occupancy, chromatin accessibility, nucleosome positioning and 3D genome organization at the nucleosome resolution. We show that motif recognition on mononucleosomes can decipher only the individual binding of TFs. When bound together, TFs act cooperatively or competitively to target nucleosome arrays with defined 3D organization, displaying motifs in particular patterns. In one combination, motif directionality funnels TF combinatorial binding along chromatin loops, before infiltrating laterally to adjacent enhancers. In other combinations, TFs assemble on motif-dense and highly interconnected loop junctions, and subsequently translocate to nearby lineage-specific sites. We propose a guided-search model in which motif grammar on nucleosome fibres acts as signpost elements, directing TF combinatorial binding to enhancers.

『Abstract』Personalized antisense oligonucleotides (ASOs) have achieved positive results in the treatment of rare genetic disease . As clinical sequencing technologies continue to advance, the ability to identify patients with rare disease harbouring pathogenic genetic variants amenable to this therapeutic strategy will probably improve. Here we describe a scalable platform for generating patient-derived cellular models and demonstrate that these personalized models can be used for preclinical evaluation of patient-specific ASOs. We describe protocols for delivery of ASOs to patient-derived organoid models and confirm reversal of disease-associated phenotypes in cardiac organoids derived from a patient with Duchenne muscular dystrophy (DMD) with a structural deletion in the gene encoding dystrophin ( DMD ) that is amenable to treatment with existing ASO therapeutics. Furthermore, we designed novel patient-specific ASOs for two additional patients with DMD (siblings) with a deep intronic variant in the DMD gene that gives rise to a novel splice acceptor site, incorporation of a cryptic exon and premature transcript termination. We showed that treatment of patient-derived cardiac organoids with patient-specific ASOs results in restoration of DMD expression and reversal of disease-associated phenotypes. The approach outlined here provides the foundation for an expedited path towards the design and preclinical evaluation of personalized ASO therapeutics for a broad range of rare diseases.

『Abstract』Asteroid discoveries are essential for planetary-defence efforts aiming to prevent impacts with Earth , including the more frequent megaton explosions from decametre impactors . Although large asteroids (≥100 kilometres) have remained in the main belt since their formation , small asteroids are commonly transported to the near-Earth object (NEO) population . However, owing to the lack of direct observational constraints, their size–frequency distribution (SFD)—which informs our understanding of the NEOs and the delivery of meteorite samples to Earth—varies substantially among models . Here we report 138 detections of some of the smallest asteroids ( ≳ 10 metres) ever observed in the main belt, which were enabled by JWST’s infrared capabilities covering the emission peaks of the asteroids and synthetic tracking techniques . Despite small orbital arcs, we constrain the distances and phase angles of the objects using known asteroids as proxies, allowing us to derive sizes through radiometric techniques. Their SFD shows a break at about 100 metres (debiased cumulative slopes of q = −2.66 ± 0.60 and −0.97 ± 0.14 for diameters smaller and larger than roughly 100 metres, respectively), suggestive of a population driven by collisional cascade. These asteroids were sampled from several asteroid families—most probably Nysa, Polana and Massalia—according to the geometry of pointings considered here. Through further long-stare infrared observations, JWST is poised to serendipitously detect thousands of decametre-scale asteroids across the sky, examining individual asteroid families and the source regions of meteorites ‘in situ’.

『Abstract』Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions . Lissencephaly (‘smooth brain’) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability . However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 ( PIDD1 ) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller–Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.

『Abstract』Freshwater ecosystems are highly biodiverse and important for livelihoods and economic development , but are under substantial stress . To date, comprehensive global assessments of extinction risk have not included any speciose groups primarily living in freshwaters. Consequently, data from predominantly terrestrial tetrapods are used to guide environmental policy and conservation prioritization , whereas recent proposals for target setting in freshwaters use abiotic factors . However, there is evidence that such data are insufficient to represent the needs of freshwater species and achieve biodiversity goals . Here we present the results of a multi-taxon global freshwater fauna assessment for The IUCN Red List of Threatened Species covering 23,496 decapod crustaceans, fishes and odonates, finding that one-quarter are threatened with extinction. Prevalent threats include pollution, dams and water extraction, agriculture and invasive species, with overharvesting also driving extinctions. We also examined the degree of surrogacy of both threatened tetrapods and freshwater abiotic factors (water stress and nitrogen) for threatened freshwater species. Threatened tetrapods are good surrogates when prioritizing sites to maximize rarity-weighted richness, but poorer when prioritizing based on the most range-restricted species. However, they are much better surrogates than abiotic factors, which perform worse than random. Thus, although global priority regions identified for tetrapod conservation are broadly reflective of those for freshwater faunas, given differences in key threats and habitats, meeting the needs of tetrapods cannot be assumed sufficient to conserve freshwater species at local scales.

『Abstract』Fossils representing Cretaceous lineages of crown clade birds (Aves) are exceptionally rare but are crucial to elucidating major ecological shifts across early avian divergences. Among the earliest known putative crown birds is Vegavis iaai , a foot-propelled diver from the latest Cretaceous (69.2–68.4 million years ago) of Antarctica with controversial phylogenetic affinities . Initially recovered by phylogenetic analyses as a stem anatid (ducks and closely related species) , Vegavis has since been recovered as a stem member of Anseriformes (waterfowl) , or outside Aves altogether . Here we report a new, nearly complete skull of Vegavis that provides new insight into its feeding ecology and exhibits morphologies that support placement among waterfowl within crown-group birds. Vegavis has an avian beak (absence of teeth and reduced maxilla) and brain shape (hyperinflated cerebrum and ventrally shifted optic lobes). The temporal fossa is well excavated and expansive, indicating that this bird had hypertrophied jaw musculature. The beak is narrow and pointed, and the mandible lacks retroarticular processes. Together, these features comprise a feeding apparatus unlike that of any other known anseriform but like that of other extant birds that capture prey underwater (for example, grebes and loons). The Cretaceous occurrence of Vegavis , with a feeding ecology unique among known Galloanserae (waterfowl and landfowl), is further indication that the earliest anseriform divergences were marked by evolutionary experiments unrepresented in the extant diversity .

『Abstract』Plants lack specialized and mobile immune cells. Consequently, any cell type that encounters pathogens must mount immune responses and communicate with surrounding cells for successful defence. However, the diversity, spatial organization and function of cellular immune states in pathogen-infected plants are poorly understood . Here we infect Arabidopsis thaliana leaves with bacterial pathogens that trigger or supress immune responses and integrate time-resolved single-cell transcriptomic, epigenomic and spatial transcriptomic data to identify cell states. We describe cell-state-specific gene-regulatory logic that involves transcription factors, putative cis -regulatory elements and target genes associated with disease and immunity. We show that a rare cell population emerges at the nexus of immune-active hotspots, which we designate as primary immune responder (PRIMER) cells. PRIMER cells have non-canonical immune signatures, exemplified by the expression and genome accessibility of a previously uncharacterized transcription factor, GT-3A, which contributes to plant immunity against bacterial pathogens. PRIMER cells are surrounded by another cell state (bystander) that activates genes for long-distance cell-to-cell immune signalling. Together, our findings suggest that interactions between these cell states propagate immune responses across the leaf. Our molecularly defined single-cell spatiotemporal atlas provides functional and regulatory insights into immune cell states in plants.

『Abstract』A particle current generated by pumping in the absence of gradients in potential energy, density or temperature is associated with non-trivial dynamics. A representative example is charge pumping that is associated with the quantum Hall effect and the quantum anomalous Hall effect . Spin pumping, the spin equivalent of charge pumping, refers to the emission of a spin current by magnetization dynamics . Previous studies have focused solely on transversal spin pumping arising from classical dynamics, which corresponds to precessing atomic moments with constant magnitude. However, longitudinal spin pumping arising from quantum fluctuations, which correspond to a temporal change in the atomic moment’s magnitude, remains unexplored. Here we experimentally investigate longitudinal spin pumping using iron–rhodium (FeRh), which undergoes a first-order antiferromagnet-to-ferromagnet phase transition during which the atomic moment’s magnitude varies over time. By injecting a charge current into a FeRh/platinum bilayer, we induce a rapid phase transition of FeRh in nanoseconds, leading to the emission of a spin current to the platinum layer. The observed inverse spin Hall signal is about one order of magnitude larger than expected for transversal spin pumping, suggesting the presence of longitudinal spin pumping driven by quantum fluctuations and indicating its superiority over classical transversal spin pumping. Our result highlights the significance of quantum fluctuations in spin pumping and holds broad applicability in diverse angular momentum dynamics, such as laser-induced ultrafast demagnetization , orbital pumping and quantum spin transfer .

『Abstract』Understanding the collective quantum dynamics of non-equilibrium many-body systems is an outstanding challenge in quantum science. In particular, dynamics driven by quantum fluctuations are important for the formation of exotic quantum phases of matter , fundamental high-energy processes , quantum metrology and quantum algorithms . Here we use a programmable quantum simulator based on Rydberg atom arrays to experimentally study collective dynamics across a (2+1)-dimensional Ising quantum phase transition. After crossing the quantum critical point, we observe a gradual growth of correlations through coarsening of antiferromagnetically ordered domains . By deterministically preparing and following the evolution of ordered domains, we show that the coarsening is driven by the curvature of domain boundaries, and find that the dynamics accelerate with proximity to the quantum critical point. We quantitatively explore these phenomena and further observe long-lived oscillations of the order parameter, corresponding to an amplitude (‘Higgs’) mode . These observations offer a viewpoint into emergent collective dynamics in strongly correlated quantum systems and non-equilibrium quantum processes.

『Abstract』The fate of the West Antarctic Ice Sheet (WAIS) is the largest cause of uncertainty in long-term sea-level projections. In the last interglacial (LIG) around 125,000 years ago, data suggest that sea level was several metres higher than today , and required a significant contribution from Antarctic ice loss, with WAIS usually implicated. Antarctica and the Southern Ocean were warmer than today , by amounts comparable to those expected by 2100 under moderate to high future warming scenarios. However, direct evidence about the size of WAIS in the LIG is sparse. Here we use sea salt data from an ice core from Skytrain Ice Rise, adjacent to WAIS, to show that, during most of the LIG, the Ronne Ice Shelf was still in place, and close to its current extent. Water isotope data are consistent with a retreat of WAIS , but seem inconsistent with more dramatic model realizations in which both WAIS and the large Antarctic ice shelves were lost. This new constraint calls for a reappraisal of other elements of the LIG sea-level budget. It also weakens the observational basis that motivated model simulations projecting the highest end of projections for future rates of sea-level rise to 2300 and beyond.

『Abstract』Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated . This renders either the maternal X (X m ) chromosome or the paternal X (X p ) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active . Parent-of-X origin can modify epigenetics through DNA methylation and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active X m chromosome influences the brain and body—and then delineated unique features of X m neurons and X p neurons. An active X m chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by X m -mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the X m chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of X m -imprinted genes improved cognition in ageing female mice. Thus, the X m chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how X m impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.

『Abstract』The robustness of the macroscopic quantum nature of a superconductor can be characterized by the superfluid stiffness, ρ s , a quantity that describes the energy required to vary the phase of the macroscopic quantum wavefunction. In unconventional superconductors, such as cuprates, the low-temperature behaviour of ρ s markedly differs from that of conventional superconductors owing to quasiparticle excitations from gapless points (nodes) in momentum space. Intensive research on the recently discovered magic-angle twisted graphene family has revealed, in addition to superconducting states, strongly correlated electronic states associated with spontaneously broken symmetries, inviting the study of ρ s to uncover the potentially unconventional nature of its superconductivity. Here we report the measurement of ρ s in magic-angle twisted trilayer graphene (TTG), revealing unconventional nodal-gap superconductivity. Utilizing radio-frequency reflectometry techniques to measure the kinetic inductive response of superconducting TTG coupled to a microwave resonator, we find a linear temperature dependence of ρ s at low temperatures and nonlinear Meissner effects in the current-bias dependence, both indicating nodal structures in the superconducting order parameter. Furthermore, the doping dependence shows a linear correlation between the zero-temperature ρ s and the superconducting transition temperature T c , reminiscent of Uemura’s relation in cuprates, suggesting phase-coherence-limited superconductivity. Our results provide strong evidence for nodal superconductivity in TTG and put strong constraints on the mechanisms of these graphene-based superconductors.

『Abstract』Io experiences tidal deformation as a result of its eccentric orbit around Jupiter, which provides a primary energy source for Io’s continuing volcanic activity and infrared emission . The amount of tidal energy dissipated within Io is enormous and has been suggested to support the large-scale melting of its interior and the formation of a global subsurface magma ocean. If Io has a shallow global magma ocean, its tidal deformation would be much larger than in the case of a more rigid, mostly solid interior . Here we report the measurement of Io’s tidal deformation, quantified by the gravitational tidal Love number k 2 , enabled by two recent flybys of the Juno spacecraft. By combining Juno and Galileo Doppler data from the NASA Deep Space Network and astrometric observations, we recover Re( k 2 ) of 0.125 ± 0.047 (1 σ ) and the tidal dissipation parameter Q of 11.4 ± 3.6 (1 σ ). These measurements confirm that a shallow global magma ocean in Io does not exist and are consistent with Io having a mostly solid mantle . Our results indicate that tidal forces do not universally create global magma oceans, which may be prevented from forming owing to rapid melt ascent, intrusion and eruption , so even strong tidal heating—such as that expected on several known exoplanets and super-Earths —may not guarantee the formation of magma oceans on moons or planetary bodies.

『Abstract』Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development , metabolism , immune responses and cognitive function . However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear . Here, using untargeted metabolomics of mouse tissues, we identified a family of BA–methylcysteamine (BA–MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA–MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA–MCY increased BA production in an FXR-dependent manner, and BA–MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA–MCYs acting as intestinal FXR antagonists. The levels of BA–MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA–MCY levels, indicating that BA–MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA–MCYs are also present in human serum. Together, our results indicate that BA–MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.

『Abstract』Lung metastases occur in up to 54% of patients with metastatic tumours . Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells . Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells . Nutrients are also primed during pre-metastatic niche formation . Yet, whether and how nutrients available in organs in which tumours metastasize confer cancer cells with aggressive traits is mostly undefined. Here we found that pulmonary aspartate triggers a cellular signalling cascade in disseminated cancer cells, resulting in a translational programme that boosts aggressiveness of lung metastases. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N -methyl- d -aspartate receptor in cancer cells, which promotes CREB-dependent expression of deoxyhypusine hydroxylase ( DOHH ). DOHH is essential for hypusination, a post-translational modification that is required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational programme with TGFβ signalling as a central hub promotes collagen synthesis in lung-disseminated breast cancer cells. We detected key proteins of this mechanism in lung metastases from patients with breast cancer. In summary, we found that aspartate, a classical biosynthesis metabolite, functions in the lung environment as an extracellular signalling molecule to promote aggressiveness of metastases.

『Abstract』Non-ribosomal peptide synthetases are assembly line biosynthetic pathways that are used to produce critical therapeutic drugs and are typically arranged as large multi-domain proteins called megasynthetases . They synthesize polypeptides using peptidyl carrier proteins that shuttle each amino acid through modular loading, modification and elongation steps, and remain challenging to structurally characterize, owing in part to the inherent dynamics of their multi-domain and multi-modular architectures . Here we have developed site-selective crosslinking probes to conformationally constrain and resolve the interactions between carrier proteins and their partner enzymatic domains . We apply tetrazine click chemistry to trap the condensation of two carrier protein substrates within the active site of the condensation domain that unites the first two modules of tyrocidine biosynthesis and report the high-resolution cryo-EM structure of this complex. Together with the X-ray crystal structure of the first carrier protein crosslinked to its epimerization domain, these structures highlight captured intermodular recognition events and define the processive movement of a carrier protein from one catalytic step to the next. Characterization of these structural relationships remains central to understanding the molecular details of these unique synthetases and critically informs future synthetic biology design of these pathways.

『Abstract』Crosslinked thermosets are highly durable materials, but overcoming their petrochemical origins and inability to be recycled poses a grand challenge . Many strategies to access crosslinked polymers that are bioderived or degradable-by-design have been proposed, but they require several resource-intensive synthesis and purification steps and are not yet feasible alternatives to conventional consumer materials . Here we present a modular, one-pot synthesis of degradable thermosets from the commercially available, biosourced monomer 2,3-dihydrofuran (DHF) . In the presence of a ruthenium catalyst and photoacid generator, DHF undergoes slow ring-opening metathesis polymerization to give a soft polymer; then, exposure to light triggers strong acid generation and promotes the cationic polymerization of the same DHF monomer to spatially crosslink and strengthen the material . By manipulating catalyst loading and light exposure, we can access materials with physical properties spanning orders of magnitude and achieve spatially resolved material domains. Importantly, the DHF-based thermosets undergo stimuli-selective degradation and can be recycled to the monomer under mild heating. The use of two distinct polymerization mechanisms on a single functional group allows the synthesis of degradable and recyclable thermoset materials with precisely controlled properties.

『Abstract』Biological ageing can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function . Mammalian brains consist of thousands of cell types , which may be differentially susceptible or resilient to ageing. Here we present a comprehensive single-cell RNA sequencing dataset containing roughly 1.2 million high-quality single-cell transcriptomes of brain cells from young adult and aged mice of both sexes, from regions spanning the forebrain, midbrain and hindbrain. High-resolution clustering of all cells results in 847 cell clusters and reveals at least 14 age-biased clusters that are mostly glial types. At the broader cell subclass and supertype levels, we find age-associated gene expression signatures and provide a list of 2,449 unique differentially expressed genes (age-DE genes) for many neuronal and non-neuronal cell types. Whereas most age-DE genes are unique to specific cell types, we observe common signatures with ageing across cell types, including a decrease in expression of genes related to neuronal structure and function in many neuron types, major astrocyte types and mature oligodendrocytes, and an increase in expression of genes related to immune function, antigen presentation, inflammation, and cell motility in immune cell types and some vascular cell types. Finally, we observe that some of the cell types that demonstrate the greatest sensitivity to ageing are concentrated around the third ventricle in the hypothalamus, including tanycytes, ependymal cells, and certain neuron types in the arcuate nucleus, dorsomedial nucleus and paraventricular nucleus that express genes canonically related to energy homeostasis. Many of these types demonstrate both a decrease in neuronal function and an increase in immune response. These findings suggest that the third ventricle in the hypothalamus may be a hub for ageing in the mouse brain. Overall, this study systematically delineates a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal ageing that will serve as a foundation for the investigation of functional changes in ageing and the interaction of ageing and disease.

『Abstract』Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack . For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses . However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.

『Abstract』Dense crowds form some of the most dangerous environments in modern society . Dangers arise from uncontrolled collective motions, leading to compression against walls, suffocation and fatalities . Our current understanding of crowd dynamics primarily relies on heuristic collision models, which effectively capture the behaviour observed in small groups of people . However, the emergent dynamics of dense crowds, composed of thousands of individuals, remains a formidable many-body problem lacking quantitative experimental characterization and explanations rooted in first principles. Here we analyse the dynamics of thousands of densely packed individuals at the San Fermin festival (Spain) and infer a physical theory of dense crowds in confinement. Our measurements reveal that dense crowds can self-organize into macroscopic chiral oscillators, coordinating the orbital motion of hundreds of individuals without external guidance. Guided by these measurements and symmetry principles, we construct a mechanical model of dense-crowd motion. Our model demonstrates that emergent odd frictional forces drive a non-reciprocal phase transition towards collective chiral oscillations, capturing all our experimental observations. To test the robustness of our findings, we show that similar chiral dynamics emerged at the onset of the 2010 Love Parade disaster and propose a protocol that could help anticipate these previously unpredictable dynamics.

『Abstract』Non-ribosomal peptide synthetases (NRPSs) are megaenzymes responsible for the biosynthesis of many clinically important natural products, from early modern medicines (penicillin, bacitracin) to current blockbuster drugs (cubicin, vancomycin) and newly approved therapeutics (rezafungin) . The key chemical step in these biosyntheses is amide bond formation between aminoacyl building blocks, catalysed by the condensation (C) domain . There has been much debate over the mechanism of this reaction . NRPS condensation has been difficult to fully characterize because it is one of many successive reactions in the NRPS synthetic cycle and because the canonical substrates are each attached transiently as thioesters to mobile carrier domains, which are often both contained in the same very flexible protein as the C domain. Here we have produced a dimodular NRPS protein in two parts, modified each with appropriate non-hydrolysable substrate analogues , assembled the two parts with protein ligation , and solved the structures of the substrate- and product-bound states. The structures show the precise orientation of the megaenzyme preparing the nucleophilic attack of its key chemical step, and enable biochemical assays and quantum mechanical simulations to precisely interrogate the reaction. These data suggest that NRPS C domains use a concerted reaction mechanism, whereby the active-site histidine likely functions not as a general base, but as a crucial stabilizing hydrogen bond acceptor for the developing ammonium.

『Abstract』The physics of superconductivity in magic-angle twisted bilayer graphene (MATBG) is a topic of keen interest in moire systems research, and it may provide an insight into the pairing mechanism of other strongly correlated materials such as high-critical-temperature superconductors. Here we use d.c. transport and microwave circuit quantum electrodynamics to directly measure the superfluid stiffness of superconducting MATBG through its kinetic inductance. We find the superfluid stiffness to be much larger than expected from conventional Fermi liquid theory. Rather, it is comparable to theoretical predictions and recent experimental indications of quantum geometric effects that are dominant at the magic angle. The temperature dependence of the superfluid stiffness follows a power law, which contraindicates an isotropic Bardeen–Cooper–Schrieffer (BCS) model. Instead, the extracted power-law exponents indicate an anisotropic superconducting gap, whether interpreted in the Fermi liquid framework or by considering the quantum geometry of flat-band superconductivity. Moreover, a quadratic dependence of the superfluid stiffness on both d.c. and microwave current is observed, which is consistent with the Ginzburg–Landau theory. Taken together, our findings show that MATBG is an unconventional superconductor with an anisotropic gap and strongly suggest a connection between quantum geometry, superfluid stiffness and unconventional superconductivity in MATBG. The combined d.c.–microwave measurement platform used here is applicable to the investigation of other atomically thin superconductors.

『Abstract』Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues . The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown. Here we describe previously unknown new hierarchical arrangements in haematopoietic stem cells (HSCs) and bone marrow niches that dictate both regenerative potential and immune privilege. High-level nitric oxide-generating (NO ) HSCs are refractory to immune attack and exhibit delayed albeit robust long-term reconstitution. Such highly immune-privileged, primitive NO HSCs co-localize with distinctive capillaries characterized by primary ciliated endothelium and high levels of the immune-checkpoint molecule CD200. These capillaries regulate the regenerative functions of NO HSCs through the ciliary protein IFT20 together with CD200, endothelial nitric oxide synthase and autophagy signals, which further mediate immunoprotection. Notably, previously described niche constituents, sinusoidal cells and type-H vessels co-localize with less immune-privileged and less potent NO HSCs. Together, we identify highly immune-privileged, late-rising primitive HSCs and characterize their immunoprotective niches comprising specialized vascular domains. Our results indicate that the niche orchestrates hierarchy in stem cells and immune tolerance, and highlight future immunotherapeutic targets.

『Abstract』Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk . Brain ageing is complex and is accompanied by many cellular changes . Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions—exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell–cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

『Abstract』Carbon–hydrogen (C–H) bonds are the foundation of essentially every organic molecule, making them an ideal place to do chemical synthesis. The key challenge is achieving selectivity for one particular C( sp )−H bond . In recent years, metalloenzymes have been found to perform C( sp )−H bond functionalization . Despite substantial progresses in the past two decades , enzymatic halogenation and pseudohalogenation of unactivated C( sp )−H—providing a functional handle for further modification—have been achieved with only non-haem iron/α-ketoglutarate-dependent halogenases, and are therefore limited by the chemistry possible with these enzymes . Here we report the discovery and characterization of a previously unknown halogenase ApnU, part of a protein family containing domain of unknown function 3328 (DUF3328). ApnU uses copper in its active site to catalyse iterative chlorinations on multiple unactivated C( sp )−H bonds. By taking advantage of the softer copper centre, we demonstrate that ApnU can catalyse unprecedented enzymatic C( sp )−H bond functionalization such as iodination and thiocyanation. Using biochemical characterization and proteomics analysis, we identified the functional oligomeric state of ApnU as a covalently linked homodimer, which contains three essential pairs—one interchain and two intrachain—of disulfide bonds. The metal-coordination active site in ApnU consists of binuclear type II copper centres, as revealed by electron paramagnetic resonance spectroscopy. This discovery expands the enzymatic capability of C( sp )−H halogenases and provides a foundational understanding of this family of binuclear copper-dependent oxidative enzymes.

『Abstract』As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep. We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain. On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.

『Abstract』In Huntington’s disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG) n in the huntingtin ( HTT ) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat’s length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40–45 to 100–500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150–500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron’s life.

『Abstract』Zinc is an essential micronutrient that regulates a wide range of physiological processes, most often through zinc binding to protein cysteine residues. Despite being critical for modulation of protein function, the cysteine sites in the majority of the human proteome that are subject to zinc binding remain undefined. Here, we develop ZnCPT, a deep and quantitative mapping of the zinc-binding cysteine proteome. We define 6,173 zinc-binding cysteines, uncovering protein families across major domains of biology that are subject to constitutive or inducible zinc binding. ZnCPT enables systematic discovery of zinc-regulated structural, enzymatic, and allosteric functional domains. On this basis, we identify 52 cancer genetic dependencies subject to zinc binding and nominate malignancies sensitive to zinc-induced cytotoxicity. We discover a mechanism of zinc regulation over glutathione reductase (GSR), which drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation of protein function.

『Abstract』The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1 . Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.

『Abstract』In vitro development relies primarily on treating progenitor cells with media-borne morphogens and thus lacks native-like spatial information. Here, we engineer morphogen-secreting organizer cells programmed to self-assemble, via cell adhesion, around mouse embryonic stem (ES) cells in defined architectures. By inducing the morphogen WNT3A and its antagonist DKK1 from organizer cells, we generated diverse morphogen gradients, varying in range and steepness. These gradients were strongly correlated with morphogenetic outcomes: the range of minimum-maximum WNT activity determined the resulting range of anterior-to-posterior (A-P) axis cell lineages. Strikingly, shallow WNT activity gradients, despite showing truncated A-P lineages, yielded higher-resolution tissue morphologies, such as a beating, chambered cardiac-like structure associated with an endothelial network. Thus, synthetic organizer cells, which integrate spatial, temporal, and biochemical information, provide a powerful way to systematically and flexibly direct the development of ES or other progenitor cells in different directions within the morphogenetic landscape.

『Abstract』Three proton-sensing G protein-coupled receptors (GPCRs)—GPR4, GPR65, and GPR68—respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues. Using deep mutational scanning (DMS), we determined the functional importance of every residue in GPR68 activation by generating ∼9,500 mutants and measuring their effects on signaling and surface expression. Constant-pH molecular dynamics simulations provided insights into the conformational landscape and protonation patterns of key residues. This unbiased approach revealed that, unlike other proton-sensitive channels and receptors, no single site is critical for proton recognition. Instead, a network of titratable residues extends from the extracellular surface to the transmembrane region, converging on canonical motifs to activate proton-sensing GPCRs. Our approach integrating structure, simulations, and unbiased functional interrogation provides a framework for understanding GPCR signaling complexity.

『Abstract』Despite recent advances in imaging- and antibody-based methods, achieving in-depth, high-resolution protein mapping across entire tissues remains a significant challenge in spatial proteomics. Here, we present parallel-flow projection and transfer learning across omics data (PLATO), an integrated framework combining microfluidics with deep learning to enable high-resolution mapping of thousands of proteins in whole tissue sections. We validated the PLATO framework by profiling the spatial proteome of the mouse cerebellum, identifying 2,564 protein groups in a single run. We then applied PLATO to rat villus and human breast cancer samples, achieving a spatial resolution of 25 μm and uncovering proteomic dynamics associated with disease states. This approach revealed spatially distinct tumor subtypes, identified key dysregulated proteins, and provided novel insights into the complexity of the tumor microenvironment. We believe that PLATO represents a transformative platform for exploring spatial proteomic regulation and its interplay with genetic and environmental factors.

『Abstract』Understanding mammalian preimplantation development, particularly in humans, at the proteomic level remains limited. Here, we applied our comprehensive solution of ultrasensitive proteomic technology to measure the proteomic profiles of oocytes and early embryos and identified nearly 8,000 proteins in humans and over 6,300 proteins in mice. We observed distinct proteomic dynamics before and around zygotic genome activation (ZGA) between the two species. Integrative analysis with translatomic data revealed extensive divergence between translation activation and protein accumulation. Multi-omic analysis indicated that ZGA transcripts often contribute to protein accumulation in blastocysts. Using mouse embryos, we identified several transcriptional regulators critical for early development, thereby linking ZGA to the first lineage specification. Furthermore, single-embryo proteomics of poor-quality embryos from over 100 patient couples provided insights into preimplantation development failure. Our study may contribute to reshaping the framework of mammalian preimplantation development and opening avenues for addressing human infertility.

『Abstract』The detection of molecular patterns associated with invading pathogens is a hallmark of innate immune systems. Prokaryotes deploy sophisticated host defense mechanisms in innate anti-phage immunity. Shedu is a single-component defense system comprising a putative nuclease SduA. Here, we report cryoelectron microscopy (cryo-EM) structures of apo- and double-stranded DNA (dsDNA)-bound tetrameric SduA assemblies, revealing that the N-terminal domains of SduA form a clamp that recognizes free DNA ends. End binding positions the DNA over the PD-(D/E)XK nuclease domain, resulting in dsDNA nicking at a fixed distance from the 5′ end. The end-directed DNA nicking activity of Shedu prevents propagation of linear DNA in vivo . Finally, we show that phages escape Shedu immunity by suppressing their recombination-dependent DNA replication pathway. Taken together, these results define the antiviral mechanism of Shedu systems, underlining the paradigm that recognition of pathogen-specific nucleic acid structures is a conserved feature of innate immunity across all domains of life.

『Abstract』Replication and genome encapsidation of many negative-sense RNA viruses take place in virus-induced membraneless organelles termed viral factories (VFs). Although liquid properties of VFs are believed to control the transition from genome replication to nucleocapsid (NC) assembly, VF maturation and interactions with the cellular environment remain elusive. Here, we apply in situ cryo-correlative light and electron tomography to follow NC assembly and changes in VF morphology and their liquid properties during Ebola virus infection. We show that viral NCs transition from loosely packed helical assemblies in early VFs to compact cylinders that arrange into highly organized parallel bundles later in infection. Early VFs associate with intermediate filaments and are devoid of other host material but become progressively accessible to cellular components. Our data suggest that this process is coupled to VF solidification, loss of sphericity, and dispersion and promotes cytoplasmic exposure of NCs to facilitate their transport to budding sites.

『Abstract』During early mammalian development, the endoderm germ layer forms the foundation of the respiratory and digestive systems through complex patterning. This intricate process, guided by a series of cell fate decisions, remains only partially understood. Our study introduces innovative genetic tracing codes for 14 distinct endodermal regions using novel mouse strains. By integrating high-throughput and high-precision single-cell RNA sequencing with sophisticated imaging, we detailed the spatiotemporal and genetic lineage differentiation of the endoderm at single-cell resolution. We discovered an unexpected multipotentiality within early endodermal regions, allowing differentiation into various organ primordia. This research illuminates the complex and underestimated phenomenon where endodermal organs develop from multiple origins, prompting a reevaluation of traditional differentiation models. Our findings advance understanding in developmental biology and have significant implications for regenerative medicine and the development of advanced organoid models, providing insights into the intricate mechanisms that guide organogenesis.

『Abstract』In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.

『Abstract』Protein assembly into functional complexes is critical to life’s processes. While complex assembly is classically described as occurring between fully synthesized proteins, recent work showed that co-translational assembly is prevalent in human cells. However, the biological basis for the existence of this process and the identity of protein pairs that assemble co-translationally remain unknown. We show that co-translational assembly is governed by structural characteristics of complexes and involves mutually stabilized subunits. Accordingly, co-translationally assembling subunits are unstable in isolation and exhibit synchronized proteostasis with their partner. By leveraging structural signatures and AlphaFold2-based predictions, we accurately predicted co-translational assembly, including pair identities, at proteome scale and across species. We validated our predictions by ribosome profiling, stoichiometry perturbations, and single-molecule RNA-fluorescence in situ hybridization (smFISH) experiments that revealed co-localized mRNAs. This work establishes a fundamental connection between protein structure and the translation process, highlighting the overarching impact of three-dimensional structure on gene expression, mRNA localization, and proteostasis.

『Abstract』Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of Xenopus tropicalis GPR4 (xtGPR4) and Mus musculus GPR4 (mmGPR4) under varying pH conditions, we identified that protonation of H and H enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular H contributed to the more acidic optimal pH range of xtGPR4. Overall, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.

『Abstract』Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is highly pathogenic in humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a promising drug target. We determined the cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L) and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase. The L protein assembles with a long P tetrameric coiled-coil that is capped by a bundle of ⍺-helices that we show are likely dynamic in solution. Docking studies with a known L inhibitor clarify mechanisms of antiviral drug resistance. In addition, we identified L protein features that are required for both transcription and RNA replication and mutations that have a greater impact on RNA replication than on transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.

『Abstract』Structural maintenance of chromosomes (SMC) complexes organize the genome via DNA loop extrusion. Although some SMCs were reported to do so symmetrically, reeling DNA from both sides into the extruded DNA loop simultaneously, others perform loop extrusion asymmetrically toward one direction only. The mechanism underlying this variability remains unclear. Here, we examine the directionality of DNA loop extrusion by SMCs using in vitro single-molecule experiments. We find that cohesin and SMC5/6 do not reel in DNA from both sides, as reported before, but instead extrude DNA asymmetrically, although the direction can switch over time. Asymmetric DNA loop extrusion thus is the shared mechanism across all eukaryotic SMC complexes. For cohesin, direction switches strongly correlate with the turnover of the subunit NIPBL, during which DNA strand switching may occur. Apart from expanding by extrusion, loops frequently diffuse and shrink. The findings reveal that SMCs, surprisingly, can switch directions.