经典100 | NCS： 2025-05-16 期

『Abstract』Abstract Two-dimensional strongly interacting electrons crystalize into a solid phase known as the Wigner crystal at low densities and form a Fermi liquid at high densities. At intermediate densities, the two-dimensional solid evolves into a strongly correlated liquid phase around a critical density. We observed this quantum melting of a disordered Wigner solid in bilayer molybdenum diselenide (MoSe 2 ) using a noninvasive scanning tunneling microscopy imaging technique. At low densities, the Wigner solid forms nanocrystalline domains pinned by local disorder. It exhibits a quantum densification behavior with increased densities in the solid phase. Above a threshold density, the Wigner solid melts locally and enters a mixed phase in which solid and liquid regions coexist. The liquid regions expand and form a percolation network at even higher densities.

『Abstract』Abstract How astrocytes regulate neuronal circuits is a fundamental question in neurobiology. Specifically, how astrocytes respond to different neurotransmitters in vivo and how they affect downstream circuit modulation are questions that remain to be fully elucidated. Here, we report a mechanism in Drosophila by which G protein–coupled adrenergic signaling in astrocytes can control—or “gate”—their ability to respond to other neurotransmitters. Further, we show that manipulating this pathway potently regulates neuronal circuit activity and animal behavior. This gating mechanism is conserved in cultured primary mammalian astrocytes, suggesting that it might be an ancient feature of astrocyte circuit function. Our work establishes a mechanism by which astrocytes dynamically respond to and modulate neuronal activity in different brain regions and in different behavioral states.

『Abstract』Abstract Mountain biodiversity reorganizes rapidly as species shift upslope to track temperatures. Pervasive species redistribution poses substantial threats to mountain ecosystems, a phenomenon sometimes described as an “escalator to extinction,” primarily through mountaintop extinctions, range shift gaps (i.e., rapid shifts of suitable temperatures getting ahead of narrow-range species’ upper limits), and lowland biodiversity attrition, yet empirical evidence remains scarce. In this study, our analysis of 8800 records of historical and modern elevational range limits for 440 animal and 1629 plant species revealed little evidence supporting the proposed threats. Observed changes largely fell within random expectations, accounting for geometric constraints. Although delayed mountaintop extinctions point to accumulating extinction debt, concurrent range expansions of both narrow-range and lowland species suggest thermal niche underfilling, processes that collectively drive biotic homogenization across biologically complex mountain ecosystems.

『Abstract』Abstract Programmable gene integration in human cells has the potential to enable mutation-agnostic treatments for loss-of-function genetic diseases and facilitate many applications in the life sciences. CRISPR-associated transposases (CASTs) catalyze RNA-guided DNA integration but thus far demonstrate minimal activity in human cells. Using phage-assisted continuous evolution (PACE), we generated CAST variants with >200-fold average improved integration activity. The evolved CAST system (evoCAST) achieves ~10 to 30% integration efficiencies of kilobase-size DNA cargoes in human cells across 14 tested genomic target sites, including safe harbor loci, sites used for immunotherapy, and genes implicated in loss-of-function diseases, with undetected indels and low levels of off-target integration. Collectively, our findings establish a platform for the laboratory evolution of CASTs and advance a versatile system for programmable gene integration in living systems.

『Abstract』Abstract Bats are important reservoirs of zoonotic pathogens, but suitable model systems for comprehensively exploring host-pathogen interactions and assessing spillover risks remain limited. To address this gap, we developed a collection of bat organoid models spanning five species and four organ types. This multispecies, multiorgan organoid panel showed species- and tissue-specific replication patterns for several viruses, offering robust pathophysiological models for studying respiratory, renal, and enteric zoonotic viruses. Using this platform, we successfully isolated and characterized bat-borne mammalian orthoreoviruses and paramyxoviruses, demonstrating the utility of these organoid panels for virome surveillance. Furthermore, we successfully tested known antiviral drugs for their efficacy against bat virus isolates.

『Abstract』Abstract Both neurons and glia communicate through diffusible neuromodulators; however, how neuron-glial interactions in such neuromodulatory networks influence circuit computation and behavior is unclear. During futility-induced behavioral transitions in the larval zebrafish, the neuromodulator norepinephrine (NE) drives fast excitation and delayed inhibition of behavior and circuit activity. We found that astroglial purinergic signaling implements the inhibitory arm of this motif. In larval zebrafish, NE triggers astroglial release of adenosine triphosphate (ATP), extracellular conversion of ATP into adenosine, and behavioral suppression through activation of hindbrain neuronal adenosine receptors. Our results suggest a computational and behavioral role for an evolutionarily conserved astroglial purinergic signaling axis in NE-mediated behavioral and brain state transitions and position astroglia as important effectors in neuromodulatory signaling.

『Abstract』Abstract Brazil, the largest Latin American country, is underrepresented in genomic research despite boasting the world’s largest recently admixed population. In this study, we generated 2723 high-coverage whole-genome sequences from the Brazilian population, including urban, rural, and riverine communities representing diverse ethnic backgrounds. We reveal the impressive genomic diversity of Brazilians, identifying >8 million previously unknown variants, including 36,637 predicted deleterious and potentially affecting population health. We found a positive correlation between these deleterious variants and ancestry. Brazilian genomes are a global haplotype mosaic shaped by nonrandom mating, with peak admixture in the 18th and 19th centuries. Within this diversity, ancestry-specific haplotypes exhibit an uneven spatiotemporal distribution. We also identified putatively selected genes in this diverse population, primarily linked to fertility, immune response, and metabolic traits.

『Abstract』Abstract The regulation of G protein–coupled receptor signaling by different orthosteric ligands is thought to occur through shifts in dynamically interconverting, conformational distributions. Such changes in dynamical distributions have been detected so far only by very sparse, often non-native experimental probes at low resolution. Using a recently developed paramagnetic nuclear magnetic resonance (NMR) method, we could assign and follow 81 H- N NMR correlations in the β 1 -adrenergic receptor β 1 AR at ambient conditions in response to various orthosteric ligands in the absence or presence of a G protein–mimicking nanobody. The comparison reveals the dynamics and mechanism of the central, highly conserved xWIPF 3 motif, contiguous regions of rigid and loose conformational coupling separated by conserved prolines during signal transmission, and the plasticity of the intracellular face in response to transducer binding.

『Abstract』Abstract Climate affects habitat, food availability, and the movement and sustainability of all life. In this work, we apply Indigenous and Western scientific methods, including genomics and isotope profiling, on fossils from across Beringia to explore the effect of climate change on horses. We find that Late Pleistocene horses from Alaska and northern Yukon are related to populations from Eurasia and crossed the Bering land bridge multiple times during the last glacial interval. We also find deeply divergent lineages north and south of the American ice sheets that genetically influenced populations across Beringia and into Eurasia. As climate warmed and horses entered the ice-free corridor connecting Beringia and midcontinental America, restricted mobility and food availability impeded population growth. Our combined Western and Indigenous framework offers critical guidance for wildlife conservation amid ongoing climate change.

『Abstract』Abstract Genome sequencing of 1537 individuals from 139 ethnic groups reveals the genetic characteristics of understudied populations in North Asia and South America. Our analysis demonstrates that West Siberian ancestry, represented by the Kets and Nenets, contributed to the genetic ancestry of most Siberian populations. West Beringians, including the Koryaks, Inuit, and Luoravetlans, exhibit genetic adaptation to Arctic climate, including medically relevant variants. In South America, early migrants split into four groups—Amazonians, Andeans, Chaco Amerindians, and Patagonians—~13,900 years ago. Their longest migration led to population decline, whereas settlement in South America’s diverse environments caused instant spatial isolation, reducing genetic and immunogenic diversity. These findings highlight how population history and environmental pressures shaped the genetic architecture of human populations across North Asia and South America.

『Abstract』Abstract Mixing electroactive materials, solid-state electrolytes, and conductive carbon to fabricate composite electrodes is the most practiced but least understood process in all-solid-state batteries, which strongly dictates interfacial stability and charge transport. We report on universal halide segregation at interfaces across various halogen-containing solid-state electrolytes and a family of high-energy chalcogen cathodes enabled by mechanochemical reaction during ultrahigh-speed mixing. Bulk and interface characterizations by multimodal synchrotron x-ray probes and cryo–transmission electron microscopy show that the in situ segregated lithium halide interfacial layers substantially boost effective ion transport and suppress the volume change of bulk chalcogen cathodes. Various all-solid-state lithium-chalcogen cells demonstrate utilization close to 100% and extraordinary cycling stability at commercial-level areal capacities.

『Abstract』Abstract Locus ceruleus (LC)–derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit functional connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is completely independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and calcium dynamics fully gate the effect of NE on synapses. Additionally, we found that NE suppression of synaptic strength results from an adenosine 5′-triphosphate (ATP)–derived and A1 adenosine receptor–mediated control of presynaptic efficacy. These findings suggest that astrocytes are a core component of neuromodulatory systems and the circuit effector through which NE produces network and behavioral adaptations.

『Abstract』Abstract Latency is a common strategy in a wide range of viral lineages, but its prevalence in giant viruses remains unknown. In this work, we describe a 617–kilo–base pairs integrated giant viral element in the model green alga Chlamydomonas reinhardtii . We resolved the integrated viral genome using long-read sequencing, identified a putative polintovirus-like integrase, and show that viral particles accumulate primarily during the stationary growth phase. A diverse array of viral-encoded selfish genetic elements is expressed during viral activity, including several Fanzor nuclease–encoding transposable elements. In addition, we show that field isolates of Chlamydomonas spp. harbor signatures of endogenous giant viruses related to the C. reinhardtii virus that exhibit similar infection dynamics, suggesting that giant virus latency is prevalent in natural host communities. Our work describes an unusually large temperate virus of a unicellular eukaryote, substantially expanding the scope of cryptic viral infections in the virosphere.

『Abstract』Abstract The search for anyons, quasiparticles with fractional charge and exotic exchange statistics, has inspired decades of condensed matter research. Quantum Hall interferometers enable direct observation of the anyon braiding phase through discrete interference phase jumps when the number of encircled localized quasiparticles changes. In this study, we observed this braiding phase in both the filling factor 1/3 and 4/3 fractional quantum Hall states by probing three-state random telegraph noise (RTN) in real time. We found that the observed RTN stems from anyon quasiparticle number n fluctuations, and we reconstructed three Aharonov-Bohm oscillation signals phase shifted by 2π/3, corresponding to the three possible interference branches from braiding around n (mod 3) anyons. Our methods can be readily extended to interference of non-abelian anyons.

『Abstract』Hilbert space dimension is a key resource for quantum information processing . Not only is a large overall Hilbert space an essential requirement for quantum error correction, but a large local Hilbert space can also be advantageous for realizing gates and algorithms more efficiently . As a result, there has been considerable experimental effort in recent years to develop quantum computing platforms using qudits ( d -dimensional quantum systems with d > 2) as the fundamental unit of quantum information . Just as with qubits, quantum error correction of these qudits will be necessary in the long run, but so far, error correction of logical qudits has not been demonstrated experimentally. Here we report the experimental realization of an error-corrected logical qutrit ( d = 3) and ququart ( d = 4), which was achieved with the Gottesman–Kitaev–Preskill bosonic code . Using a reinforcement learning agent , we optimized the Gottesman–Kitaev–Preskill qutrit (ququart) as a ternary (quaternary) quantum memory and achieved beyond break-even error correction with a gain of 1.82 ± 0.03 (1.87 ± 0.03). This work represents a novel way of leveraging the large Hilbert space of a harmonic oscillator to realize hardware-efficient quantum error correction.

『Abstract』The formation of accessible chromatin around DNA double-strand breaks is essential for their efficient repair . Although the linker histone H1 is known to facilitate higher-order chromatin compaction , the mechanisms by which H1 modifications regulate chromatin relaxation in response to DNA damage are unclear. Here we show that CTP synthase 1 (CTPS1)-catalysed deamidation of H1 asparagine residues 76 and 77 triggers the sequential acetylation of lysine 75 following DNA damage, and this dual modification of H1 is associated with chromatin opening. Mechanistically, the histone acetyltransferase p300 showed a preference for deamidated H1 as a substrate, establishing H1 deamidation as a prerequisite for subsequent acetylation. Moreover, high expression of CTPS1 was associated with resistance to cancer radiotherapy, in both mouse xenograft models and clinical cohorts. These findings provide new insights into how linker histones regulate dynamic chromatin alterations in the DNA damage response.

『Abstract』Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders . To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain . Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .

『Abstract』Sensitive methods for detection of cell-free RNA (cfRNA) could facilitate non-invasive gene expression profiling and monitoring of diseases . Here we describe RARE-seq (random priming and affinity capture of cfRNA fragments for enrichment analysis by sequencing), a method optimized for cfRNA analysis. We demonstrate that platelet contamination can substantially confound cfRNA analyses and develop an approach to overcome it. In analytical validations, we find RARE-seq to be approximately 50-fold more sensitive for detecting tumour-derived cfRNA than whole-transcriptome RNA sequencing (RNA-seq), with a limit of detection of 0.05%. To explore clinical utility, we profiled 437 plasma samples from 369 individuals with cancer or non-malignant conditions and controls. Detection of non-small-cell lung cancer expression signatures in cfRNA increased with stage (6 out of 20 (30%) in stage I; 5 out of 8 (63%) in stage II; 10 out of 15 (67%) in stage III; 80 out of 96 (83% sensitivity) in stage IV at 95% specificity) and RARE-seq was more sensitive than tumour-naive circulating tumour DNA (ctDNA) analysis. In patients with EGFR -mutant non-small-cell lung cancer who developed resistance to tyrosine kinase inhibitors, we detected both histological transformation and mutation-based resistance mechanisms. Finally, we demonstrate the potential utility of RARE-seq for determination of tissue of origin, assessing benign pulmonary conditions and tracking response to mRNA vaccines. These results highlight the potential value of ultrasensitive cfRNA analysis and provide proof of concept for diverse clinical applications.

『Abstract』Acanthocephala (thorny-headed worms), characterized by the presence of an eversible proboscis with hooks, are a diverse endoparasitic group that infect a wide range of vertebrates and invertebrates . Although long regarded as a separate phylum, they have several putative sister taxa based on morphological features, including Platyhelminthes (flatworms) , Priapulida (penis worms) and Rotifera (wheel animals) . Molecular phylogenies have instead recovered them within rotifers , suggesting acanthocephalans are derived from free-living worms with a jaw apparatus (Gnathifera). Their only fossil record is Late Cretaceous eggs , contributing limited palaeontological information to deciphering their early evolution. Here we describe an acanthocephalan body fossil, Juracanthocephalus daohugouensis gen. et. sp. nov., from the Middle Jurassic Daohugou biota of China. Juracanthocephalus shows unambiguous acanthocephalan characteristics, for example a hooked proboscis, a bursa, as well as a jaw apparatus with discrete elements that is typical of other gnathiferans. Juracanthocephalus shares features with Seisonidea (an epizoic member of Rotifera) and Acanthocephala, bridging the evolutionary gap between jawed rotifers and the obligate parasitic, jawless acanthocephalans. Our results reveal previously unrecognized ecological and morphological diversity in ancient Acanthocephala and highlight the significance of transitional fossils, revealing the origins of this highly enigmatic group of living organisms.

『Abstract』High-capacity lithium-ion batteries (LIBs) play a critical role as power sources across diverse applications, including portable electronics, electric vehicles (EVs) and renewable-energy-storage systems . However, there is growing concern about the safety of integrated LIB systems, with reports of up to 9,486 incidents between 2020 and 2024 (ref. ). To ensure the safe application of commercial LIBs, it is essential to capture internal signals that enable early failure diagnosis and warning. Monitoring non-uniform temperature and strain distributions within the jelly-roll structures of the battery provides a promising approach to achieving this goal . Here we propose a miniaturized and low-power-consumption system capable of accurate sensing and wireless transmission of internal temperature and strain signals inside LIBs, with negligible influence on its performance. The acquisition of internal temperature signals and the area ratio between initial internal-short-circuited regions and battery electrodes enables quantitative analysis of thermal fusing and thermal runaway phenomena, leading to the evaluation of the intensity of battery thermal runaway and recognition of thermal abuse behaviours. This work provides a foundation for designing next-generation smart LIBs with safety warning and failure positioning capabilities.

『Abstract』Many natural motor skills, such as speaking or locomotion, are acquired through a process of trial-and-error learning over the course of development. It has long been hypothesized, motivated by observations in artificial learning experiments, that dopamine has a crucial role in this process. Dopamine in the basal ganglia is thought to guide reward-based trial-and-error learning by encoding reward prediction errors , decreasing after worse-than-predicted reward outcomes and increasing after better-than-predicted ones. Our previous work in adult zebra finches—in which we changed the perceived song quality with distorted auditory feedback—showed that dopamine in Area X, the singing-related basal ganglia, encodes performance prediction error: dopamine is suppressed after worse-than-predicted (distorted syllables) and activated after better-than-predicted (undistorted syllables) performance . However, it remains unknown whether the learning of natural behaviours, such as developmental vocal learning, occurs through dopamine-based reinforcement. Here we tracked song learning trajectories in juvenile zebra finches and used fibre photometry to monitor concurrent dopamine activity in Area X. We found that dopamine was activated after syllable renditions that were closer to the eventual adult version of the song, compared with recent renditions, and suppressed after renditions that were further away. Furthermore, the relationship between dopamine and song fluctuations revealed that dopamine predicted the future evolution of song, suggesting that dopamine drives behaviour. Finally, dopamine activity was explained by the contrast between the quality of the current rendition and the recent history of renditions—consistent with dopamine’s hypothesized role in encoding prediction errors in an actor–critic reinforcement-learning model . Reinforcement-learning algorithms have emerged as a powerful class of model to explain learning in reward-based laboratory tasks, as well as for driving autonomous learning in artificial intelligence . Our results suggest that complex natural behaviours in biological systems can also be acquired through dopamine-mediated reinforcement learning.

『Abstract』Debris disks are exoplanetary systems that contain planets, minor bodies (asteroids, Kuiper belt objects, comets and so on) and micrometre-sized debris dust . Because water ice is the most common frozen volatile, it plays an essential role in the formation of planets and minor bodies. Although water ice has been commonly found in Kuiper belt objects and comets in the Solar System , no definitive evidence for water ice in debris disks has been obtained to date . Here we report the discovery of water ice in the HD 181327 debris disk using the near-infrared spectrograph onboard the James Webb Space Telescope. We detected the solid-state broad absorption feature of water ice at 3 µm including a distinct Fresnel peak at 3.1 µm, which is indicative of large, crystalline water-ice particles. Gradients in the water-ice feature as a function of stellocentric distance reveal a dynamic environment in which water ice is destroyed and replenished. We estimated the water-ice mass fractions as ranging from 0.1% at approximately 85 au to 21% at approximately 113 au, indicating the presence of a water-ice reservoir in the HD 181327 disk beyond the snow line. The icy bodies that release water ice in HD 181327 are probably the extra-solar counterparts of water-ice-rich Kuiper belt objects in our Solar System.

『Abstract』Flowering plant sexual reproduction requires double fertilization, yielding embryo and endosperm seed compartments: the latter supports embryo growth and seed germination. In an experiment to generate haploid embryos through inhibition of pollen phospholipase activity in sunflower ( Helianthus annus ), we serendipitously discovered that emasculated sunflowers spontaneously form parthenogenic haploid seed. Exploration of genetic, chemical and environmental factors demonstrated that a specific genotype background enabled high parthenogenesis and that full spectrum high-intensity light supplementation boosted parthenogenesis, yielding hundreds of haploid seeds per head. Induction of doubled haploid plants can greatly accelerate plant breeding efficiency; however, despite successful engineering of haploid induction in many crops, few reported systems are commercially scalable . Here we report efficient methods of chemical emasculation and genome doubling to produce fertile plants and enable a scalable sunflower doubled haploid system.

『Abstract』Pyrazoles are heterocycles commonly found as key substructures in agrochemicals and medicinally active compounds alike . Despite their pervasiveness, established methods fall notably short in delivering complex pyrazoles selectively due to issues of differentiation during either assembly or N- functionalization . This is a direct consequence of a dominant synthetic strategy that attempts to control selectivity-determining bonds between poorly differentiated starting materials. To overcome this longstanding challenge, we here describe a prototypical example of an alternative conceptual approach, ‘strategic atom replacement’, in which we synthesize N- alkyl pyrazoles from isothiazoles. The net forward transformation is a ‘swap’ of the isothiazole sulfur atom with a nitrogen atom and its associated alkyl fragment to deliver the alkylated pyrazole . Linking the two azoles is an orphaned heterocycle class, 1,2,3-thiadiazine- S -oxides, whose synthetic potential has yet to be tapped . By proceeding through these unusual heterocycles, the typical selectivity and separation challenges associated with exclusively bond-based pyrazole preparations are circumvented, and even minimally differentiated peripheral substituents can be discriminated to afford isomerically pure products.

『Abstract』Adenosine triphosphate (ATP) is the principal energy currency of all living cells . Metabolically impaired obligate intracellular parasites, such as the human pathogens Chlamydia trachomatis and Rickettsia prowazekii , can acquire ATP from their host cells through a unique ATP/adenosine diphosphate (ADP) translocator, which mediates the import of ATP into and the export of ADP and phosphate out of the parasite cells, thus allowing the exploitation of the energy reserves of host cells (also known as energy parasitism). This type of ATP/ADP translocator also exists in the obligate intracellular endosymbionts of protists and the plastids of plants and algae and has been implicated to play an important role in endosymbiosis . The plastid/parasite type of ATP/ADP translocator is phylogenetically and functionally distinct from the mitochondrial ATP/ADP translocator, and its structure and transport mechanism are still unknown. Here we report the cryo-electron microscopy structures of two plastid/parasite types of ATP/ADP translocators in the apo and substrate-bound states. The ATP/ADP-binding pocket is located at the interface between the N and C domains of the translocator, and a conserved asparagine residue within the pocket is critical for substrate specificity. The translocator operates through a rocker-switch alternating access mechanism involving the relative rotation of the two domains as rigid bodies. Our results provide critical insights for understanding ATP translocation across membranes in energy parasitism and endosymbiosis and offer a structural basis for developing drugs against obligate intracellular parasites.

『Abstract』Graphene and transition metal dichalcogenide flat-band systems show similar phase diagrams, replete with magnetic and superconducting phases. An abiding question has been whether magnetic ordering competes with superconductivity or facilitates pairing. For example, recent studies of Bernal bilayer graphene in the presence of enhanced spin–orbit coupling show a substantial increase in the observed domain and critical temperature T c of superconducting states ; however, the mechanism for this enhancement remains unknown. Here we show that introducing spin–orbit coupling in rhombohedral trilayer graphene (RTG) by substrate proximity effect generates new superconducting pockets for both electron and hole doping, with maximal T c ≈ 300 mK, which is three times larger than in RTG encapsulated by hexagonal boron nitride. Using local magnetometry, we show that superconductivity straddles a transition between a spin-canted state with a finite in-plane magnetic moment and a state with complete spin–valley locking. This transition is reproduced in our Hartree–Fock calculations, in which this transition is driven by the competition between spin–orbit coupling and the carrier-density-tuned Hund’s interaction. Our experiment suggests that the enhancement of superconductivity by spin–orbit coupling is driven by a quantitative change in the canting angle rather than a change in the ground state symmetry. These results align with a recently proposed mechanism for the enhancement of superconductivity , in which fluctuations in the spin-canting order contribute to the pairing interaction.

『Abstract』Methane is an important greenhouse gas and its atmospheric concentration has almost tripled since pre-industrial times . Atmospheric methane mixing ratios vary seasonally, with the seasonal cycle amplitude (SCA) having decreased in northern high latitudes and increased in the subtropics and tropics since the 1980s . These opposing SCA trends can help understanding of long-term changes in the global methane budget, as methane emissions and sinks have opposing effects on the SCA . However, trends in the methane SCA have not yet been explored in detail . Here we use a suite of atmospheric transport model simulations and attribute the observed trends in the seasonal amplitude of methane to changes in emissions and the atmospheric sink from reaction with the hydroxyl radical (OH). We find that the decreasing amplitude in the northern high latitudes is mainly caused by an increase in natural emissions (such as wetlands) owing to a warmer climate, adding evidence to previous studies suggesting a positive climate feedback . In contrast, the enhanced methane amplitude in the subtropics and tropics is mainly attributed to strengthened OH oxidation. Our results provide independent evidence for an increase in tropospheric OH concentration of 10 ± 1% since 1984, which together with an increasing atmospheric methane concentration suggests a 21 ± 1% increase in the atmospheric methane sink.

『Abstract』Plant absorption is important for the entry of many pollutants into food chains. Although terrestrial microplastics (MPs) can be absorbed by the roots , their upward translocation is slow . Meanwhile, atmospheric MPs are widely present , but strong evidence on their direct absorption by plants is still lacking. Here, analyses using mass spectrometry detection show the widespread occurrence of polyethylene terephthalate (PET) and polystyrene (PS) polymers and oligomers in plant leaves, and identify that their levels increase with atmospheric concentrations and the leaf growth duration. The concentrations of PET and PS polymers can reach up to 10 ng per g dry weight in leaves at the high-pollution areas studied, such as the Dacron factory and a landfill site, and 10 –10 ng per g dry weight of PET and PS can be detected in the open-air-grown leafy vegetables. Nano-sized PET and PS particles in the leaves were visually detected by hyperspectral imaging and atomic force microscopy–infrared spectroscopy. Absorption of the proactively exposed non-labelled, fluorescently labelled or europium-labelled plastic particles by maize ( Zea mays L.) leaves through stomatal pathways, as well as their translocation to the vascular tissue through the apoplastic pathway, and accumulation in trichomes was identified using hyperspectral imaging, confocal microscopy and laser-ablation inductively coupled plasma mass spectrometry. Our results demonstrate that the absorption and accumulation of atmospheric MPs by plant leaves occur widely in the environment, and this should not be neglected when assessing the exposure of humans and other organisms to environmental MPs.

『Abstract』Navigating social environments is a fundamental challenge for the brain. It has been established that the brain solves this problem, in part, by representing social information in an agent-centric manner; knowledge about others’ abilities or attitudes is tagged to individuals such as ‘oneself’ or the ‘other’ . This intuitive approach has informed the understanding of key nodes in the social parts of the brain, the dorsomedial prefrontal cortex (dmPFC) and the anterior cingulate cortex (ACC) . However, the patterns or combinations in which individuals might interact with one another is as important as the identities of the individuals. Here, in four studies using functional magnetic resonance imaging, behavioural experiments and a social group decision-making task, we show that the dmPFC and ACC represent the combinatorial possibilities for social interaction afforded by a given situation, and that they do so in a compressed format resembling the basis functions used in spatial, visual and motor domains . The basis functions align with social interaction types, as opposed to individual identities. Our results indicate that there are deep analogies between abstract neural coding schemes in the visual and motor domain and the construction of our sense of social identity.

『Abstract』Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation . This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2 ) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer’s disease , and it can induce T cell exhaustion . However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2 -deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2 -deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.

『Abstract』Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission . iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction . The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion channel helices hinging away from the pore axis in a motif that is conserved across all iGluRs. Desensitization occurs when the local dimer pairs decouple and enables closure of the ion channel below through restoring the channel hinges and refolding the channel gate. Our findings define how glutamate gates iGluRs, provide foundations for therapeutic design and demonstrate how physiological temperatures can alter iGluR function.

『Abstract』Haematopoietic stem cells maintain blood production throughout life . Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they independently self-renew in parallel over life, evenly contributing to differentiated progenitors and peripheral blood. The stem cell pool grows steadily over the mouse lifespan to about 70,000 cells, self-renewing about every 6 weeks. Aged mice did not display the profound loss of clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing showed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations, exhibiting a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.

『Abstract』Although learning in response to extrinsic reinforcement is theorized to be driven by dopamine signals that encode the difference between expected and experienced rewards , skills that enable verbal or musical expression can be learned without extrinsic reinforcement. Instead, spontaneous execution of these skills is thought to be intrinsically reinforcing . Whether dopamine signals similarly guide learning of these intrinsically reinforced behaviours is unknown. In juvenile zebra finches learning from an adult tutor, dopamine signalling in a song-specialized basal ganglia region is required for successful song copying, a spontaneous, intrinsically reinforced process . Here we show that dopamine dynamics in the song basal ganglia faithfully track the learned quality of juvenile song performance on a rendition-by-rendition basis. Furthermore, dopamine release in the basal ganglia is driven not only by inputs from midbrain dopamine neurons classically associated with reinforcement learning but also by song premotor inputs, which act by means of local cholinergic signalling to elevate dopamine during singing. Although both cholinergic and dopaminergic signalling are necessary for juvenile song learning, only dopamine tracks the learned quality of song performance. Therefore, dopamine dynamics in the basal ganglia encode performance quality during self-directed, long-term learning of natural behaviours.

『Abstract』RNA-binding proteins (RBPs) control varied processes, including RNA splicing, stability, transport and translation . Dysfunctional RNA–RBP interactions contribute to the pathogenesis of human disease ; however, characterizing the nature and dynamics of multiprotein assemblies on RNA has been challenging. Here, to address this, non-isotopic ligation-based ultraviolet-light-induced cross-linking and immunoprecipitation was combined with mass spectrometry (irCLIP-RNP) to identify RNA-dependent associated proteins (RDAPs) co-bound to RNA with any RBP of interest. irCLIP-RNP defined landscapes of multimeric protein assemblies on RNA, revealing patterns of RBP–RNA associations, including cell-type-selective combinatorial relationships between RDAPs and primary RBPs. irCLIP-RNP also defined dynamic RDAP remodelling in response to epidermal growth factor (EGF), revealing that EGF-induced recruitment of UPF1 adjacent to HNRNPC promotes splicing surveillance of cell proliferation mRNAs. To identify the RNAs simultaneously co-bound by multiple studied RBPs, a sequential immunoprecipitation irCLIP (Re-CLIP) method was also developed. Re-CLIP confirmed binding relationships observed in irCLIP-RNP and identified HNRNPC and UPF1 RBP co-binding on RND3 and DDX3X mRNAs. irCLIP-RNP and Re-CLIP provide a framework to identify and characterize dynamic RNA–protein assemblies in living cells.

『Abstract』When two massive objects (black holes, neutron stars or stars) in our universe fly past each other, their gravitational interactions deflect their trajectories . The gravitational waves emitted in the related bound-orbit system—the binary inspiral—are now routinely detected by gravitational-wave observatories . Theoretical physics needs to provide high-precision templates to make use of unprecedented sensitivity and precision of the data from upcoming gravitational-wave observatories . Motivated by this challenge, several analytical and numerical techniques have been developed to approximately solve this gravitational two-body problem. Although numerical relativity is accurate , it is too time-consuming to rapidly produce large numbers of gravitational-wave templates. For this, approximate analytical results are also required . Here we report on a new, highest-precision analytical result for the scattering angle, radiated energy and recoil of a black hole or neutron star scattering encounter at the fifth order in Newton’s gravitational coupling G , assuming a hierarchy in the two masses. This is achieved by modifying state-of-the-art techniques for the scattering of elementary particles in colliders to this classical physics problem in our universe. Our results show that mathematical functions related to Calabi–Yau (CY) manifolds, 2 n -dimensional generalizations of tori, appear in the solution to the radiated energy in these scatterings. We anticipate that our analytical results will allow the development of a new generation of gravitational-wave models, for which the transition to the bound-state problem through analytic continuation and strong-field resummation will need to be performed.

『Abstract』The relative twist angle between layers of near-lattice-matched van der Waals materials is critical for the emergent phenomena associated with moire flat bands . However, the concept of angle rotation control is not exclusive to moire superlattices in which electrons directly experience a twist-angle-dependent periodic potential. Instead, it can also be used to induce programmable symmetry-breaking perturbations with the goal of stabilizing desired correlated states. Here we experimentally demonstrate ‘moireless’ twist-tuning of superconductivity together with other correlated orders in Bernal bilayer graphene proximitized by tungsten diselenide. The precise alignment between the two materials systematically controls the strength of induced Ising spin–orbit coupling (SOC), profoundly altering the phase diagram. As Ising SOC is increased, superconductivity onsets at a higher displacement field and features a higher critical temperature, reaching up to 0.5 K. Within the main superconducting dome and in the strong Ising SOC limit, we find an unusual phase transition characterized by a nematic redistribution of holes among trigonally warped Fermi pockets and enhanced resilience to in-plane magnetic fields. The superconducting behaviour is theoretically compatible with the prominent role of interband interactions between symmetry-breaking Fermi pockets. Moreover, we identify two additional superconducting regions, one of which descends from an inter-valley coherent normal state and shows a Pauli-limit violation ratio exceeding 40, among the highest for all known superconductors . Our results provide insights into ultraclean graphene superconductors and underscore the potential of utilizing moireless-twist engineering across a wide range of van der Waals heterostructures.

『Abstract』In the future, monsoon rainfall over densely populated South Asia is expected to increase, even as monsoon circulation weakens . By contrast, past warm intervals were marked by both increased rainfall and a strengthening of monsoon circulation , posing a challenge to understanding the response of the South Asian summer monsoon to warming. Here we show consistent South Asian summer monsoon changes in the mid-Pliocene, Last Interglacial, mid-Holocene and future scenarios, characterized by an overall increase in monsoon rainfall, a weakening of the monsoon trough-like circulation over the Bay of Bengal and a strengthening of the monsoon circulation over the northern Arabian Sea, as revealed by a compilation of proxy records and climate simulations. Increased monsoon rainfall is thermodynamically dominated by atmospheric moisture following the rich-get-richer paradigm, and dynamically dominated by the monsoon circulation driven by the enhanced land warming in subtropical western Eurasia and northern Africa. The coherent response of monsoon dynamics across warm climates reconciles past strengthening with future weakening, reinforcing confidence in future projections. Further prediction of South Asian summer monsoon circulation and rainfall by physics-based regression models using past information agrees well with climate model projections, with spatial correlation coefficients of approximately 0.8 and 0.7 under the high-emissions scenario. These findings underscore the promising potential of past analogues, bolstered by palaeoclimate reconstruction, in improving future South Asian summer monsoon projections.

『Abstract』Defence from environmental threats is provided by physical barriers that confer mechanical protection and prevent the entry of microorganisms . If microorganisms overcome those barriers, however, innate immune cells use toxic chemicals to kill the invading cells . Here we examine immune diversity across tissues and identify a population of neutrophils in the skin that expresses a broad repertoire of proteins and enzymes needed to build the extracellular matrix. In the naive skin, these matrix-producing neutrophils contribute to the composition and structure of the extracellular matrix, reinforce its mechanical properties and promote barrier function. After injury, these neutrophils build ‘rings’ of matrix around wounds, which shield against foreign molecules and bacteria. This structural program relies on TGFβ signalling; disabling the TGFβ receptor in neutrophils impaired ring formation around wounds and facilitated bacterial invasion. We infer that the innate immune system has evolved diverse strategies for defence, including one that physically shields the host from the outside world.

『Abstract』Several hydrogen-rich superconductors have been found to show unprecedentedly high critical temperatures , stimulating investigations into the nature of the superconductivity in these materials. Although their macroscopic superconducting properties are established , microscopic insights into the pairing mechanism remains unclear. Here we characterize the superconducting gap structure in the high-temperature superconductor H 3 S and its deuterium counterpart D 3 S by performing tunnelling spectroscopy measurements. The tunnelling spectra reveal that H 3 S and D 3 S both have a fully gapped structure, which could be well described by a single s -wave Dynes model, with gap values 2 Δ of approximately 60 meV and 44 meV, respectively. Furthermore, we observed gap features of another likely H-depleted H x S superconducting phase in a poorly synthesized hydrogen sulfide sample. Our work offers direct experimental evidence for superconductivity in the hydrogen-rich superconductor H 3 S from a microscopic perspective. It validates the phonon-mediated mechanism of superconducting pairing and provides a foundation for further understanding the origins of high-temperature superconductivity in hydrogen-rich compounds.

『Abstract』Membranes are molecular interfaces that compartmentalize cells to control the flow of nutrients and information. These functions are facilitated by diverse collections of lipids, nearly all of which are distributed asymmetrically between the two bilayer leaflets. Most models of biomembrane structure and function include the implicit assumption that these leaflets have similar abundances of phospholipids. Here, we show that this assumption is generally invalid and investigate the consequences of lipid abundance imbalances in mammalian plasma membranes (PMs). Using lipidomics, we report that cytoplasmic leaflets of human erythrocyte membranes have >50% overabundance of phospholipids compared with exoplasmic leaflets. This imbalance is enabled by an asymmetric interleaflet distribution of cholesterol, which regulates cellular cholesterol homeostasis. These features produce unique functional characteristics, including low PM permeability and resting tension in the cytoplasmic leaflet that regulates protein localization.

『Abstract』Targeting ubiquitin E3 ligases is therapeutically attractive; however, the absence of an active-site pocket impedes computational approaches for identifying inhibitors. In a large, unbiased biochemical screen, we discover inhibitors that bind a cryptic cavity distant from the catalytic cysteine of the homologous to E6-associated protein C terminus domain (HECT) E3 ligase, SMAD ubiquitin regulatory factor 1 (SMURF1). Structural and biochemical analyses and engineered escape mutants revealed that these inhibitors restrict an essential catalytic motion by extending an α helix over a conserved glycine hinge. SMURF1 levels are increased in pulmonary arterial hypertension (PAH), a disease caused by mutation of bone morphogenetic protein receptor-2 (BMPR2). We demonstrated that SMURF1 inhibition prevented BMPR2 ubiquitylation, normalized bone morphogenetic protein (BMP) signaling, restored pulmonary vascular cell homeostasis, and reversed pathology in established experimental PAH. Leveraging this deep mechanistic understanding, we undertook an in silico machine-learning-based screen to identify inhibitors of the prototypic HECT E6AP and confirmed glycine-hinge-dependent allosteric activity in vitro . Inhibiting HECTs and other glycine-hinge proteins opens a new druggable space.

『Abstract』How genomic DNA is folded during cell division to form the characteristic rod-shaped mitotic chromosomes essential for faithful genome inheritance is a long-standing open question in biology. Here, we use nanoscale DNA tracing in single dividing cells to directly visualize how the 3D fold of genomic DNA changes during mitosis at scales from single loops to entire chromosomes. Our structural analysis reveals a characteristic genome scaling minimum of 6–8 megabases in mitosis. Combined with data-driven modeling and molecular perturbations, we can show that very large and strongly overlapping loops formed by condensins are the fundamental structuring principle of mitotic chromosomes. These loops compact chromosomes locally and globally to the limit set by chromatin self-repulsion. The characteristic length, density, and increasingly overlapping structure of mitotic loops we observe in 3D fully explain how the rod-shaped mitotic chromosome structure emerges by self-organization during cell division.

『Abstract』To maintain tissue homeostasis, many cells reside in a quiescent state until prompted to divide. The reactivation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the reactivation of quiescent cells in developmentally L1-arrested C. elegans . Utilizing a forward genetic screen in C. elegans , we discovered that macroautophagy targets protein aggregates to lysosomes in quiescent cells, leading to lysosome damage. Genetic inhibition of macroautophagy and stimulation of lysosomes via the overexpression of HLH-30 (TFEB/TFE3) synergistically reduces lysosome damage. Damaged lysosomes require IRE-1/XBP-1 for their repair following prolonged L1 arrest. Protein aggregates are also targeted to lysosomes by macroautophagy in quiescent cultured mammalian cells and are associated with lysosome damage. Thus, lysosome damage is a hallmark of quiescent cells, and limiting lysosome damage by restraining macroautophagy can stimulate their reactivation.

『Abstract』Meningeal lymphatics serve as an outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, but the neural mechanisms underlying these changes have remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene ( Il6 ). IL-6 drives inhibitory synapse phenotypes via a combination of trans - and classical IL-6 signaling. Restoring meningeal lymphatic function in aged mice reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.

『Abstract』Optical recording of intricate molecular dynamics is becoming an indispensable technique for biological studies, accelerated by the development of new or improved biosensors and microscopy technology. This creates major computational challenges to extract and quantify biologically meaningful spatiotemporal patterns embedded within complex and rich data sources, many of which cannot be captured with existing methods. Here, we introduce activity quantification and analysis (AQuA2), a fast, accurate, and versatile data analysis platform built upon advanced machine-learning techniques. It decomposes complex live-imaging-based datasets into elementary signaling events, allowing accurate and unbiased quantification of molecular activities and identification of consensus functional units. We demonstrate applications across a wide range of biosensors, cell types, organs, animal models, microscopy techniques, and imaging approaches. As exemplar findings, we show how AQuA2 identified drug-dependent interactions between neurons and astroglia, as well as distinct sensorimotor signal propagation patterns in the mouse spinal cord.

『Abstract』Neural reflexes to chemicals in the throat protect the airway from aspiration and infection. Mechanistic understanding of these reflexes remains premature, exemplified by chronic cough—a sensitized cough reflex—being a prevalent unmet clinical need. Here, in mice, a whole-body search for channel synapses—featuring CALHM1/3 channel-mediated neurotransmitter release—and single-cell transcriptomics uncovered subclasses of the Pou2f3 chemosensory cell family in the throat communicating with vagal neurons via this synapse. They express G protein-coupled receptors (GPCRs) for noxious chemicals, T2Rs, which upon stimulation trigger swallow and cough-like expulsive reflexes in the hypopharynx and larynx, respectively. These reflexes were abolished by Calhm3 and Pou2f3 knockout and could be triggered by targeted optogenetic stimulation. Furthermore, aeroallergen exposure augmented CALHM3-dependent expulsive reflex. This study identifies Pou2f3 epithelial cells with channel synapses as chemosensory end organs of airway protective reflexes and sites of their hyperresponsiveness, advancing mechanistic understanding of airway defense programs with distinct therapeutic potential.

『Abstract』Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.

『Abstract』Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.

『Abstract』Advanced gene editing methods have accelerated biomedical discovery and hold great therapeutic promise, but safe and efficient delivery of gene editors remains challenging. In this study, we present a virus-like particle (VLP) system featuring nucleocytosolic shuttling vehicles that retrieve pre-assembled Cas-effectors via aptamer-tagged guide RNAs. This approach ensures preferential loading of fully assembled editor ribonucleoproteins (RNPs) and enhances the efficacy of prime editing, base editing, trans -activators, and nuclease activity coupled to homology-directed repair in multiple immortalized, primary, stem cell, and stem-cell-derived cell types. We also achieve additional protection of inherently unstable prime editing guide RNAs (pegRNAs) by shielding the 3′-exposed end with Csy4/Cas6f, further enhancing editing performance. Furthermore, we identify a minimal set of packaging and budding modules that can serve as a platform for bottom-up engineering of enveloped delivery vehicles. Notably, our system demonstrates superior per-VLP editing efficiency in primary T lymphocytes and two mouse models of inherited retinal disease, highlighting its therapeutic potential.

『Abstract』Chimeric antigen receptor (CAR) T cell therapy for solid tumors encounters challenges such as on-target off-tumor toxicity, exhaustion, and limited T cell persistence. Here, we engineer sonogenetic EchoBack-CAR T cells using an ultrasensitive heat-shock promoter screened from a library and integrated with a positive feedback loop from CAR signaling, enabling long-lasting CAR expression upon focused-ultrasound (FUS) stimulation. EchoBack-hGD2CAR T cells, targeting disialoganglioside GD2, exhibited potent cytotoxicity and persistence in 3D glioblastoma (GBM) models. In mice, EchoBack-hGD2CAR T cells suppressed GBM without off-tumor toxicity and outperformed their constitutive counterparts. Single-cell RNA sequencing revealed enhanced cytotoxicity and reduced exhaustion in EchoBack-CAR T cells compared with the standard CAR T cells. This EchoBack design was further adapted to target prostate-specific membrane antigen (EchoBack-PSMACAR) for prostate cancer treatment, demonstrating long-lasting tumor suppression with minimal off-tumor toxicity. Thus, the sonogenetic EchoBack-CAR T cells can serve as a versatile, efficient, and safe strategy for solid tumor treatment.

『Abstract』The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.

『Abstract』The intestinal immune system maintains tolerance to harmless food proteins and gut microbiota through peripherally derived RORγt Tregs (pTregs), which prevent food intolerance and inflammatory bowel disease. Recent studies suggested that RORγt antigen-presenting cells (APCs), which encompass rare dendritic cell (DC) subsets and type 3 innate lymphoid cells (ILC3s), are key to pTreg induction. Here, we developed a mouse with reduced RORγt APCs by deleting a specific cis -regulatory element of Rorc encoding RORγt. Single-cell RNA sequencing and flow cytometry analyses confirmed the depletion of a RORγt DC subset and ILC3s. These mice showed a secondary reduction in pTregs, impaired tolerance to oral antigens, and an increase in T helper (Th)2 cells. Conversely, ILC3-deficient mice showed no pTregs or Th2 cell abnormalities. Lineage tracing revealed that RORγt DCs share a lymphoid origin with ILC3s, consistent with their similar phenotypic traits. These findings highlight the role of lymphoid RORγt DCs in maintaining intestinal immune balance and preventing conditions like food allergies.