前沿速递 | NCS 集萃： 2025-05-01 期 [Up]

『Abstract』Highly pathogenic avian influenza (HPAI) viruses cross species barriers and have the potential to cause pandemics. In North America, HPAI A(H5N1) viruses related to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected wild birds, poultry, and mammals. Our genomic analysis and epidemiological investigation showed that a reassortment event in wild bird populations preceded a single wild bird–to-cattle transmission episode. The movement of asymptomatic or presymptomatic cattle has likely played a role in the spread of HPAI within the United States dairy herd. Some molecular markers that may lead to changes in transmission efficiency and phenotype were detected at low frequencies. Continued transmission of H5N1 HPAI within dairy cattle increases the risk for infection and subsequent spread of the virus to human populations.

『Abstract』Since early 2022, highly pathogenic avian influenza (HPAI) H5N1 virus infections have been reported in wild aquatic birds and poultry throughout the USA with spillover into several mammalian species . In March 2024, HPAIV H5N1 clade 2.3.4.4b was first detected in dairy cows in Texas, USA, and continues to circulate on dairy farms in many states . Milk production and quality are diminished in infected dairy cows, with high virus titres in milk raising concerns of exposure to mammals including humans through consumption . Here we investigated routes of infection with bovine HPAIV H5N1 clade 2.3.4.4b in cynomolgus macaques, a surrogate model for human infection . We show that intranasal or intratracheal inoculation of macaques could cause systemic infection resulting in mild and severe respiratory disease, respectively. By contrast, infection by the orogastric route resulted in limited infection and seroconversion of macaques that remained subclinical.

『Abstract』Lasso peptides (biologically active molecules with a distinct structurally constrained knotted fold) are natural products that belong to the class of ribosomally synthesized and post-translationally modified peptides . Lasso peptides act on several bacterial targets , but none have been reported to inhibit the ribosome, one of the main targets of antibiotics in the bacterial cell . Here we report the identification and characterization of the lasso peptide antibiotic lariocidin and its internally cyclized derivative lariocidin B, produced by Paenibacillus sp. M2, which has broad-spectrum activity against a range of bacterial pathogens. We show that lariocidins inhibit bacterial growth by binding to the ribosome and interfering with protein synthesis. Structural, genetic and biochemical data show that lariocidins bind at a unique site in the small ribosomal subunit, where they interact with the 16S ribosomal RNA and aminoacyl-tRNA, inhibiting translocation and inducing miscoding. Lariocidin is unaffected by common resistance mechanisms, has a low propensity for generating spontaneous resistance, shows no toxicity to human cells, and has potent in vivo activity in a mouse model of Acinetobacter baumannii infection. Our identification of ribosome-targeting lasso peptides uncovers new routes towards the discovery of alternative protein-synthesis inhibitors and offers a novel chemical scaffold for the development of much-needed antibacterial drugs.

『Abstract』Structural disorder within materials gives rise to fascinating phenomena, attributed to the intricate interplay of their thermodynamic and electrochemical properties . Oxygen-redox (OR) electrochemistry offers a breakthrough in capacity limits, while inducing structural disorder with reduced electrochemical reversibility . The conventional explanation for the thermal expansion of solids relies on the Gruneisen relationship, linking the expansion coefficient to the anharmonicity of the crystal lattice . However, this paradigm may not be applicable to OR materials due to the unexplored dynamic disorder–order transition in such systems . Here we reveal the presence of negative thermal expansion with a large coefficient value of −14.4(2) × 10 °C in OR active materials, attributing this to thermally driven disorder–order transitions. The modulation of OR behaviour not only enables precise control over the thermal expansion coefficient of materials, but also establishes a pragmatic framework for the design of functional materials with zero thermal expansion. Furthermore, we demonstrate that the reinstatement of structural disorder within the material can also be accomplished through the electrochemical driving force. By adjusting the cut-off voltages, evaluation of the discharge voltage change indicates a potential for nearly 100% structure recovery. This finding offers a pathway for restoring OR active materials to their pristine state through operando electrochemical processes, presenting a new mitigation strategy to address the persistent challenge of voltage decay.

『Abstract』Given the high recurrence rates of hepatocellular carcinoma (HCC) post-resection , improved early identification of patients at high risk for post-resection recurrence would help to improve patient outcomes and prioritize healthcare resources . Here we observed a spatial and HCC recurrence-associated distribution of natural killer (NK) cells in the invasive front and tumour centre from 61 patients. Using extreme gradient boosting and inverse-variance weighting, we developed the tumour immune microenvironment spatial (TIMES) score based on the spatial expression patterns of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM and HLA-DRB1) to predict HCC recurrence risk. The TIMES score (hazard ratio = 88.2, P < 0.001) outperformed current standard tools for patient risk stratification including the TNM and BCLC systems. We validated the model in 231 patients from five multicentred cohorts, achieving a real-world accuracy of 82.2% and specificity of 85.7%. The predictive power of these biomarkers emerged through the integration of their spatial distributions, rather than individual marker expression levels alone. In vivo models, including NK cell-specific Spon2 -knockout mice, revealed that SPON2 enhances IFNγ secretion and NK cell infiltration at the invasive front. Our study introduces TIMES, a publicly accessible tool for predicting HCC recurrence risk, offering insights into its potential to inform treatment decisions for early-stage HCC.

『Abstract』Stable, nonprecious catalysts are vital for large-scale alkaline water electrolysis. Here, we report a grafted superstructure, MOF@POM, formed by self-assembling a metal-organic framework (MOF) with polyoxometalate (POM). In situ electrochemical transformation converts MOF into active metal (oxy)hydroxides to produce a catalyst with a low overpotential of 178 millivolts at 10 milliamperes per square centimeter in alkaline electrolyte. An anion exchange membrane water electrolyzer incorporating this catalyst achieves 3 amperes per square centimeter at 1.78 volts at 80°C and stable operation at 2 amperes per square centimeter for 5140 hours at room temperature. In situ electrochemical spectroscopy and theoretical studies reveal that the synergistic interactions between metal atoms create a fast electron-transfer channel from catalytic iron and cobalt sites, nickel, and tungsten in the polyoxometalate to the electrode, stabilizing the metal sites and preventing dissolution.

『Abstract』Long-range and anisotropic dipolar interactions profoundly modify the dynamics of particles hopping in a periodic lattice potential. We report the realization of a generalized t-J model with dipolar interactions using a system of ultracold fermionic molecules with spin encoded in the two lowest rotational states. We independently tuned the dipolar Ising and spin-exchange couplings and the molecular motion and studied their interplay on coherent spin dynamics. Using Ramsey spectroscopy, we observed and modeled interaction-driven contrast decay that depends strongly both on the strength of the anisotropy between Ising and spin-exchange couplings and on motion. This study paves the way for future exploration of kinetic spin dynamics and quantum magnetism with highly tunable molecular platforms in regimes that are challenging for existing numerical and analytical methods.

『Abstract』Four-wave mixing is a nonlinear optical phenomenon that can be used for wideband low-noise optical amplification and wavelength conversion. It has been extensively investigated for applications in communications , computing , metrology , imaging and quantum optics . With its advantages of small footprint, large nonlinearity and dispersion-engineering capability, optical integrated waveguides are excellent candidates for realizing high-gain and large-bandwidth four-wave mixing for which anomalous dispersion is a key condition. Various waveguides based on, for example, silicon, aluminium gallium arsenide and nonlinear glass have been studied , but suffer from considerable gain and bandwidth reductions, as conventional design approaches for anomalous dispersion result in multi-mode operation. We present a methodology for fabricating nonlinear waveguides with simultaneous single-mode operation and anomalous dispersion for ultra-broadband operation and high-efficiency four-wave mixing. Although we implemented this in silicon nitride waveguides, the design approach can be used with other platforms as well. By using higher-order dispersion, we achieved unprecedented amplification bandwidths of more than 300 nm in these ultra-low-loss integrated waveguides. Penalty-free all-optical wavelength conversion of 100 Gbit s data in a single optical channel of over 200 nm was realized. These single-mode dispersion-engineered nonlinear waveguides could become practical building blocks in various nonlinear photonics applications.

『Abstract』Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial . The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

『Abstract』Tumour cells often evade immune pressure exerted by CD8 T cells or immunotherapies through mechanisms that are largely unclear . Here, using complementary in vivo and in vitro CRISPR–Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS–STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS–STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8 T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.

『Abstract』Social grouping increases survival in many species, including humans . By contrast, social isolation generates an aversive state (‘loneliness’) that motivates social seeking and heightens social interaction upon reunion . The observed rebound in social interaction triggered by isolation suggests a homeostatic process underlying the control of social need, similar to physiological drives such as hunger, thirst or sleep . In this study, we assessed social responses in several mouse strains, among which FVB/NJ mice emerged as highly, and C57BL/6J mice as moderately, sensitive to social isolation. Using both strains, we uncovered two previously uncharacterized neuronal populations in the hypothalamic preoptic nucleus that are activated during either social isolation or social rebound and orchestrate the behaviour display of social need and social satiety, respectively. We identified direct connectivity between these two populations and with brain areas associated with social behaviour, emotional state, reward and physiological needs and showed that mice require touch to assess the presence of others and fulfil their social need. These data show a brain-wide neural system underlying social homeostasis and provide significant mechanistic insights into the nature and function of circuits controlling instinctive social need and for the understanding of healthy and diseased brain states associated with social context.

『Abstract』The electric double layer (EDL) is critical in electrochemical capacitors and transistors, on-water chemistry, and bioelectric technologies. Ion dynamics within the EDL define the limits for charging and discharging processes. Classical EDL models struggle at high electrolyte concentrations, and observing EDL dynamics has been challenging. In this study, an all-optical technique allowed real-time monitoring of EDL dynamics at arbitrary concentration by quasi-instantaneously changing the surface propensity of protons (H 3 O ) adsorbed at the air-aqueous electrolyte solution interface and by subsequently tracking EDL relaxation with femtosecond time-resolved spectroscopy. EDL reorganization occurred on picosecond timescales and was strongly concentration dependent. Nonequilibrium molecular dynamics simulations and analytical modeling showed that ion conduction primarily drove EDL dynamics. This research quantified EDL dynamics and identified its primary driver, providing insights for optimization of electrochemical applications.

『Abstract』The Saharo-Arabian Desert is one of the largest biogeographical barriers on Earth, impeding dispersals between Africa and Eurasia, including movements of past hominins. Recent research suggests that this barrier has been in place since at least 11 million years ago . In contrast, fossil evidence from the late Miocene epoch and the Pleistocene epoch suggests the episodic presence within the Saharo-Arabian Desert interior of water-dependent fauna (for example, crocodiles, equids, hippopotamids and proboscideans) , sustained by rivers and lakes that are largely absent from today’s arid landscape. Although numerous humid phases occurred in southern Arabia during the past 1.1 million years , little is known about Arabia’s palaeoclimate before this time. Here, based on a climatic record from desert speleothems, we show recurrent humid intervals in the central Arabian interior over the past 8 million years. Precipitation during humid intervals decreased and became more variable over time, as the monsoon’s influence weakened, coinciding with enhanced Northern Hemisphere polar ice cover during the Pleistocene. Wetter conditions likely facilitated mammalian dispersals between Africa and Eurasia, with Arabia acting as a key crossroads for continental-scale biogeographic exchanges.

『Abstract』Gliomas are incurable malignancies notable for having an immunosuppressive microenvironment with abundant myeloid cells, the immunomodulatory phenotypes of which remain poorly defined . Here we systematically investigate these phenotypes by integrating single-cell RNA sequencing, chromatin accessibility, spatial transcriptomics and glioma organoid explant systems. We discovered four immunomodulatory expression programs: microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumours, and systemic inflammatory and complement immunosuppressive programs, which are also expressed by non-brain tumours. The programs are not contingent on myeloid cell type, developmental origin or tumour mutational state, but instead are driven by microenvironmental cues, including tumour hypoxia, interleukin-1β, TGFβ and standard-of-care dexamethasone treatment. Their relative expression can predict immunotherapy response and overall survival. By associating the respective programs with mediating genomic elements, transcription factors and signalling pathways, we uncover strategies for manipulating myeloid-cell phenotypes. Our study provides a framework to understand immunomodulation by myeloid cells in glioma and a foundation for the development of more-effective immunotherapies.

『Abstract』Materials with a high electrocaloric effect (ECE) tend to favour a disordered yet easily tunable polar structure. Perovskite ferroelectrics stand out as ideal candidates owing to their high dielectric responses and reasonable thermal conductivity. The introduction of multielement atomic distortions induces a high-polar-entropy state that notably increases the ECE by effectively overcoming the constraints imposed by highly ordered, polar-correlated perovskite structures. Here we developed a lead-free relaxor ferroelectric with strong polar disorder through targeted multielement substitution at both the A and B sites of the perovskite, effectively distorting the lattice structure and inducing a variety of nanoscale polar configurations, polymorphic polar variants and non-polar regions. A combination of these multielement-induced features led to an increased density of interfaces, significantly enhancing the polar entropy. Remarkably, a high ECE for an entropy change of about 15 J kg K under a 10 MV m field is observed for the material across a broad temperature range exceeding 60 °C. The formation of ultrafine, dispersed, multiphase lattice configurations leads to high-polar-entropy ferroelectric oxides with a high ECE and a long lifetime of over 1 million cycles that are suitable for manufacturing multilayer ceramic capacitors for practical electrocaloric refrigeration applications.

『Abstract』The tumour-suppressor protein BRCA2 has a central role in homology-directed DNA repair by enhancing the formation of RAD51 filaments on resected single-stranded DNA generated at double-stranded DNA breaks and stimulating RAD51 activity . Individuals with BRCA2 mutations are predisposed to cancer; however, BRCA2-deficient tumours are often responsive to targeted therapy with PARP inhibitors (PARPi) . The mechanism by which BRCA2 deficiency renders cells sensitive to PARPi but with minimal toxicity in cells heterozygous for BRCA2 mutations remains unclear. Here we identify a previously unknown role of BRCA2 that is directly linked to the effect of PARP1 inhibition. Using biochemical and single-molecule approaches, we demonstrate that PARPi-mediated PARP1 retention on a resected DNA substrate interferes with RAD51 filament stability and impairs RAD51-mediated DNA strand exchange. Full-length BRCA2 protects RAD51 filaments and counteracts the instability conferred by PARPi-mediated retention by preventing the binding of PARP1 to DNA. Extending these findings to a cellular context, we use quantitative single-molecule localization microscopy to show that BRCA2 prevents PARPi-induced PARP1 retention at homologous-recombination repair sites. By contrast, BRCA2-deficient cells exhibit increased PARP1 retention at these lesions in response to PARPi. These results provide mechanistic insights into the role of BRCA2 in maintaining RAD51 stability and protecting homologous-recombination repair sites by mitigating PARPi-mediated PARP1 retention.

『Abstract』Long interspersed element–1 (LINE-1) retrotransposons are the only active autonomous transposable elements in humans. They propagate by reverse transcribing their messenger RNA into new genomic locations by a process called target-primed reverse transcription (TPRT). In this work, we present four cryo–electron microscopy structures of the human LINE-1 TPRT complex, revealing the conformational dynamics of open reading frame 2 protein (ORF2p) and its extensive remodeling of the target DNA for TPRT initiation. We observe nicking of the DNA second strand during reverse transcription of the first strand. Structure prediction identifies high-confidence binding sites for LINE-1–associated factors—namely proliferating cell nuclear antigen (PCNA) and cytoplasmic poly(A)-binding protein 1 (PABPC1)—on ORF2p. Together with our structural data, this suggests a mechanism by which these factors regulate retrotransposition and supports a model for TPRT that accounts for retrotransposition outcomes observed in cells.

『Abstract』Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. Whereas cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. In this study, we reveal a bacterial antiphage system that mediates immune signaling through nucleobase modification. Immunity is triggered by phage nucleotide kinases, which, combined with the system-encoded adenosine deaminase, produce deoxyinosine triphosphates (dITPs) as immune messengers. The dITP signal activates a downstream effector to mediate depletion of cellular nicotinamide adenine dinucleotide (oxidized form), resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular deoxyadenosine monophosphate, the precursor of dITP messengers. Our findings uncover a nucleobase modification–based antiphage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.

『Abstract』Zeolites have exceptional catalytic performance in oil refining and chemical synthesis that can be attributed to their well-defined porous structures that host active sites. This study pinpoints the exact locations of aluminum atoms in ZSM-5 structures—a key zeolite catalyst. Aluminum siting governs catalytic efficiency in acid and redox processes. Anomalous x-ray powder diffraction (AXRPD) at the aluminum K-edge probes the long-range order of aluminum atoms within the ZSM-5 frameworks, precisely quantifying both isolated aluminum atoms and Al(-O-Si-O-) x Al sequences (aluminum pairs). Supported by nuclear magnetic resonance studies, AXRPD unambiguously determines the crystallographic organization of aluminum pairs, recognized spectroscopically as α, β, and γ sites, linking their distribution to superior catalytic activity in propene oligomerization. This combined approach provides essential insights for optimizing zeolite catalysts and enhancing their performance.

『Abstract』Recent advances in quantum communications have underscored the crucial role of optical coherence in developing quantum networks. This resource, which is fundamental to the phase-based architecture of the quantum internet , has enabled the only successful demonstrations of multi-node quantum networks and substantially extended the range of quantum key distribution (QKD) . However, the scalability of coherence-based quantum protocols remains uncertain owing to the specialized hardware required, such as ultra-stable optical cavities and cryogenic photon detectors. Here we implement the coherence-based twin-field QKD protocol over a 254-kilometre commercial telecom network spanning between Frankfurt and Kehl, Germany, achieving encryption key distribution at 110 bits per second. Our results are enabled by a scalable approach to optical coherence distribution, supported by a practical system architecture and non-cryogenic single-photon detection aided by off-band phase stabilization. Our results demonstrate repeater-like quantum communication in an operational network setting, doubling the distance for practical real-world QKD implementations without cryogenic cooling. In addition, to our knowledge, we realized one of the largest QKD networks featuring measurement-device-independent properties . Our research aligns the requirements of coherence-based quantum communication with the capabilities of existing telecommunication infrastructure, which is likely to be useful to the future of high-performance quantum networks, including the implementation of advanced quantum communication protocols, quantum repeaters, quantum sensing networks and distributed quantum computing .

『Abstract』Radio-frequency (RF) accelerators providing high-quality relativistic electron beams are an important resource enabling many areas of science, as well as industrial and medical applications. Two decades ago, laser-plasma accelerators that support orders of magnitude higher electric fields than those provided by modern RF cavities produced quasi-monoenergetic electron beams for the first time . Since then, high-brightness electron beams at gigaelectronvolt (GeV) beam energy and competitive beam properties have been demonstrated from only centimetre-long plasmas , a substantial advantage over the hundreds of metres required by RF-cavity-based accelerators. However, despite the considerable progress, the comparably large energy spread and the fluctuation (jitter) in beam energy still effectively prevent laser-plasma accelerators from driving real-world applications. Here we report the generation of a laser-plasma electron beam using active energy compression, resulting in a performance so far only associated with modern RF-based accelerators. Using a magnetic chicane, the electron bunch is first stretched longitudinally to imprint an energy correlation, which is then removed with an active RF cavity. The resulting energy spread and energy jitter are reduced by more than an order of magnitude to below the permille level, meeting the acceptance criteria of a modern synchrotron, thereby opening the path to a compact storage ring injector and other applications.

『Abstract』Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer . However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81 years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR , requiring exon skipping to derive BCR::ABL1 , were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3–14 years (confidence interval 2–16 years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.

『Abstract』The phytohormone auxin (Aux) is a principal endogenous developmental signal in plants. It mediates transcriptional reprogramming by a well-established canonical signalling mechanism. TIR1/AFB auxin receptors are F-box subunits of an ubiquitin ligase complex; after auxin perception, they associate with Aux/IAA transcriptional repressors and ubiquitinate them for degradation, thus enabling the activation of auxin response factor (ARF) transcription factors . Here we revise this paradigm by showing that without TIR1 adenylate cyclase (AC) activity , auxin-induced degradation of Aux/IAAs is not sufficient to mediate the transcriptional auxin response. Abolishing the TIR1 AC activity does not affect auxin-induced degradation of Aux/IAAs but renders TIR1 non-functional in mediating transcriptional reprogramming and auxin-regulated development, including shoot, root, root hair growth and lateral root formation. Transgenic plants show that local cAMP production in the vicinity of the Aux/IAA–ARF complex by unrelated AC enzymes bypasses the need for auxin perception and is sufficient to induce ARF-mediated transcription. These discoveries revise the canonical model of auxin signalling and establish TIR1/AFB-produced cAMP as a second messenger essential for transcriptional reprograming.

『Abstract』Metamaterials with multimodal deformation mechanisms resemble machines , especially when endowed with autonomous functionality. A representative architected assembly, with tunable chirality, converts linear motion into rotation . These chiral metamaterials with a machine-like dual modality have potential use in areas such as wave manipulation , optical activity related to circular polarization and chiral active fluids . However, the dual motions are essentially coupled and cannot be independently controlled. Moreover, they are restricted to small deformation, that is, strain ≤2%, which limits their applications. Here we establish modular chiral metamaterials, consisting of auxetic planar tessellations and origami-inspired columnar arrays, with decoupled actuation. Under single-degree-of-freedom actuation, the assembly twists between 0° and 90°, contracts in-plane up to 25% and shrinks out-of-plane more than 50%. Using experiments and simulations, we show that the deformation of the assembly involves in-plane twist and contraction dominated by the rotating-square tessellations and out-of-plane shrinkage dominated by the tubular Kresling origami arrays. Moreover, we demonstrate two distinct actuation conditions: twist with free translation and linear displacement with free rotation. Our metamaterial is built on a highly modular assembly, which enables reprogrammable instability, local chirality control, tunable loading capacity and scalability. Our concept provides routes towards multimodal, multistable and reprogrammable machines, with applications in robotic transformers, thermoregulation, mechanical memories in hysteresis loops, non-commutative state transition and plug-and-play functional assemblies for energy absorption and information encryption.

『Abstract』The peripheral nervous system (PNS) orchestrates organ function in health and disease. Most cancers, including pancreatic ductal adenocarcinoma (PDAC), are infiltrated by PNS neurons, and this contributes to the complex tumour microenvironment (TME) . However, neuronal cell bodies reside in various PNS ganglia, far from the tumour mass. Thus, cancer-innervating or healthy-organ-innervating neurons are lacking in current tissue-sequencing datasets. To molecularly characterize pancreas- and PDAC-innervating neurons at single-cell resolution, we developed Trace-n-Seq. This method uses retrograde tracing of axons from tissues to their respective ganglia, followed by single-cell isolation and transcriptomic analysis. By characterizing more than 5,000 individual sympathetic and sensory neurons, with about 4,000 innervating PDAC or healthy pancreas, we reveal novel neuronal cell types and molecular networks that are distinct to the pancreas, pancreatitis, PDAC or melanoma metastasis. We integrate single-cell datasets of innervating neurons and the TME to establish a neuron–cancer–microenvironment interactome, delineate cancer-driven neuronal reprogramming and generate a pancreatic-cancer nerve signature. Pharmacological denervation induces a pro-inflammatory TME and increases the effectiveness of immune-checkpoint inhibitors. The taxane nab-paclitaxel causes intratumoral neuropathy, which attenuates PDAC growth and, in combination with sympathetic denervation, results in synergistic tumour regression. Our multi-dimensional data provide insights into the networks and functions of PDAC-innervating neurons, and support the inclusion of denervation in future therapies.

『Abstract』To circumvent CRISPR-Cas immunity, phages express anti-CRISPR factors that inhibit the expression or activities of Cas proteins. Whereas most anti-CRISPRs described to date are proteins, recently described small RNAs called RNA anti-CRISPRs (rAcrs) have sequence homology to CRISPR RNAs (crRNAs) and displace them from cognate Cas nucleases. In this work, we report the discovery of rAcrVIA1—a plasmid-encoded small RNA that inhibits the RNA-targeting CRISPR-Cas13 system in its natural host, Listeria seeligeri . We solved the cryo–electron microscopy structure of the Cas13-rAcr complex, which revealed that rAcrVIA1 adopts a fold nearly identical to crRNA despite sharing negligible sequence similarity. Collectively, our findings expand the diversity of rAcrs and reveal an example of immune antagonism through RNA structural mimicry.

『Abstract』The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability . Unravelling the complementary interplay between these pathways remains a challenge . Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.

『Abstract』The eukaryote Tree of Life (eToL) depicts the relationships among all eukaryotic organisms; its root represents the Last Eukaryotic Common Ancestor (LECA) from which all extant complex lifeforms are descended . Locating this root is crucial for reconstructing the features of LECA, both as the endpoint of eukaryogenesis and the start point for the evolution of the myriad complex traits underpinning the diversification of living eukaryotes. However, the position of the root remains contentious due to pervasive phylogenetic artefacts stemming from inadequate evolutionary models, poor taxon sampling and limited phylogenetic signal . Here we estimate the root of the eToL with unprecedented resolution on the basis of a new, much larger, dataset of mitochondrial proteins that includes all known eukaryotic supergroups. Our analyses of a 100 taxon × 93 protein dataset with state-of-the-art phylogenetic models and an extensive evaluation of alternative hypotheses show that the eukaryotic root lies between two multi-supergroup assemblages: ‘Opimoda+’ and ‘Diphoda+’. This position is consistently supported across different models and robustness analyses. Notably, groups containing ‘typical excavates’ are placed on both sides of the root, suggesting the complex features of the ‘excavate’ cell architecture trace back to LECA. This study sheds light on the ancestral cells from which extant eukaryotes arose and provides a crucial framework for investigating the origin and evolution of canonical eukaryotic features.

『Abstract』Ceria nanoparticles supported on alumina are widely used in various catalytic reactions, particularly in conjunction with platinum group metals (PGMs) . Here we found that treating these catalysts at temperatures between 750 and about 1,000 °C in the presence of CO and NO in steam (reactive treatment under reducing atmosphere) leads to the dispersion of ceria nanoparticles into high-density 2D (roughly one atomic layer thin) Ce x O y domains, as confirmed by microscopy, X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), infrared spectroscopy and density functional theory (DFT) calculations. These domains, which densely cover the alumina, exhibit substantially enhanced oxygen mobility and storage capacity, facilitating easier extraction of oxygen and the formation of Ce sites and oxygen vacancies. As a result, these catalysts—whether with or without PGMs, such as Rh and Pt—show improved activity for several industrially important catalytic reactions, including NO and N 2 O reduction, as well as CO and NO oxidation, even after exposure to harsh ageing conditions. This study shows a catalyst architecture with superior redox properties under conditions that typically cause sintering, offering a pathway to more efficient metal–ceria catalysts for enhanced general catalysis.

『Abstract』Organic farming is often considered to be more sustainable than conventional farming. However, both farming systems comprise highly variable management practices. In this study, we show that in organic and conventional arable fields, the multifunctionality of soils decreases with increasing agricultural management intensity. Soil organic carbon content and bacterial biomass, respectively, were the strongest abiotic and biotic predictors of soil multifunctionality. Greater soil multifunctionality was associated with less-frequent inversion tillage and higher frequency of grass-legume cover cropping, and organic farming did not outperform conventional farming. Our results suggest that reducing management intensity will enhance soil multifunctionality in both conventional and organic farming. This implies that, in contexts where high-yielding, high-intensity agriculture prevails, the paradigm of sustainable intensification should be replaced by “productive deintensification.”

『Abstract』Nuclear star clusters (NSCs) are the densest stellar systems in the Universe. These clusters can be found at the centre of all galaxy types but tend to favour galaxies of intermediate stellar mass around 10 M ⊙ (refs. ). At present, two main processes are under debate to explain their formation: in situ star formation from gas infall and migration and merging of globular clusters (GCs) caused by dynamical friction . Studies of NSC stellar populations suggest that the former predominates in massive galaxies, whereas the latter prevails in dwarf galaxies, and both contribute equally at intermediate mass. However, until now, no ongoing merger of GCs has been observed to confirm this scenario. Here we report the serendipitous discovery of five dwarf galaxies with complex nuclear regions, characterized by multiple nuclei and tidal tails, using high-resolution images from the Hubble Space Telescope. These structures have been reproduced in complementary N -body simulations, supporting the interpretation that they result from migrating and merging of star clusters. The small detection rate and short simulated timescales (below 100 Myr) of this process may explain why this has not been observed previously. This study highlights the need for large surveys with high resolution to fully map the migration scenario steps.

『Abstract』The search for simple principles that underlie the spatial structure and dynamics of plant communities is a long-standing challenge in ecology . In particular, the relationship between species coexistence and the spatial distribution of plants is challenging to resolve in species-rich communities . Here we present a comprehensive analysis of the spatial patterns of 720 tree species in 21 large forest plots and their consequences for species coexistence. We show that species with low abundance tend to be more spatially aggregated than more abundant species. Moreover, there is a latitudinal gradient in the strength of this negative aggregation–abundance relationship that increases from tropical to temperate forests. We suggest, in line with recent work , that latitudinal gradients in animal seed dispersal and mycorrhizal associations may jointly generate this pattern. By integrating the observed spatial patterns into population models , we derive the conditions under which species can invade from low abundance in terms of spatial patterns, demography, niche overlap and immigration. Evaluation of the spatial-invasion condition for the 720 tree species analysed suggests that temperate and tropical forests both meet the invasion criterion to a similar extent but through contrasting strategies conditioned by their spatial patterns. Our approach opens up new avenues for the integration of observed spatial patterns into ecological theory and underscores the need to understand the interaction among spatial patterns at the neighbourhood scale and multiple ecological processes in greater detail.

『Abstract』Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was indispensable for CP-A adipogenesis and visceral fat expansion. These findings uncover a fundamental mechanism of age-dependent adipose remodeling, offering critical insights into age-related metabolic diseases.

『Abstract』Chemical recycling to monomers is a key strategy for a sustainable circular polymer economy. However, most efforts have focused on polymers with carbon backbones. Recycling of silicone polymers and corresponding materials, featuring a robust inorganic backbone and tunable properties, remains in its infancy. We present a general method for depolymerization of a very wide range of silicone-based materials and postconsumer waste, including end-of-life cross-linked polydimethylsiloxane-based networks within formulated materials. The reaction proceeds at 40°C, harnessing an efficient gallium catalyst for a million-fold rate enhancement and boron trichloride as the chlorine source, to produce nearly quantitative yields of (methyl)chlorosilanes, key intermediates in the Muller-Rochow process that anchors the silicone industry.

『Abstract』Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally . Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours . There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A 2 (TXA 2 ). TXA 2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA 2 using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA 2 in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

『Abstract』Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body’s immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell–rich or a noninflamed T cell–deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

『Abstract』Protein polymer scaffolds composed of death fold (DF) proteins are critical to the formation of signalosomes in immune signaling. The biophysical properties that these polymeric scaffolds require for signal transduction are not clearly defined. Here, we engineered single-component DF signalosomes. We found that functionality depends on the stability provided by the DF polymer, which could also be achieved with a bacterial DF domain, a synthetic filament-forming domain, and amyloid-like sequences. This demonstrates the importance of polymer stability and inducibility irrespective of the motif’s origin. By varying the number of included TRAF6 interaction motifs, we demonstrate that avidity is a tunable property that can control the amplitude of signaling outputs. This work lays out a reductionist framework to elucidate the required signaling properties through polymeric scaffolds by adjusting their assembly kinetics, stability, and avidity.

『Abstract』The stability of hazardous volcanic systems is strongly influenced by the uppermost magma storage depth and volatile exsolution . Despite abundant evidence for an upper crustal magma reservoir beneath Yellowstone caldera , its depth and the properties at its top have not been well constrained. New controlled-source seismic imaging illuminates a sharp reflective cap of the magma reservoir approximately 3.8 km beneath the northeastern caldera. Magma ascent to such low pressure is expected to drive volatile exsolution and potentially localized accumulation of bubbles near the top of the reservoir , but this process typically remains hidden in contemporary volcanic systems. P-wave and P-to-S-wave reflections from the sharp top of the Yellowstone magma reservoir indicate that a mixture of supercritical fluid and magma fills the pore space at the cap of the approximately 3–8-km-deep low-shear-velocity layer imaged by seismic tomography . The results are consistent with partial retention of bubbles exsolved from an upper crustal reservoir with ongoing magma supply from a volatile-enriched mantle source. Bubble accumulation can eventually lead to reservoir instability , but the bubble volume fraction seismically estimated at the top of the reservoir today is lower than typical estimates of pre-eruptive conditions for rhyolites , and measurements of the hydrothermal system document high fluxes of magmatic volatiles escaping to the surface . We infer that the magma reservoir is in a stable state of efficient bubble ascent into the hydrothermal system on the basis of estimates that it is a crystal-rich (less than 30% porosity) reservoir for which dynamic modelling favours channelized bubble escape that prevents instability .

『Abstract』Lepidoptera is the most herbivorous of all the insect orders, with predatory caterpillars globally comprising less than 0.13% of the nearly 200,000 moth and butterfly species. Here, we report a species in which caterpillars are carnivorous inhabitants of spider’s webs, feeding on the arthropods that they find there. This Hawaiian lineage also boasts an unprecedented and macabre practice of decorating its portable larval home with the body parts of the spider prey it harvests from the web where it resides. Phylogenomic data suggest that the origin of this unique spider cohabitant is at least six million years old, more than one million years older than Hawaii’s current high islands. After decades of searching, only one species has been discovered, and it is restricted to 15 square kilometers of a single mountain range on the island of Oʻahu, meaning that other members of the lineage have disappeared from older islands. Conservation action to save this globally unique lineage is imperative and overdue.

『Abstract』Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees . HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation . However, their target genes and functional contributions to human brain development remain largely uncharacterized. Here we elucidate the cis -regulatory functions of HARs in human and chimpanzee induced pluripotent stem (iPS) cell-induced excitatory neurons. Using genomic and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologues for functional characterization via single-cell CRISPR interference, and demonstrated their species-specific gene regulatory functions. Our findings reveal diverse functional outcomes of HAR-mediated cis -regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPS cell pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we used prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons. Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.