前沿速递 | NCS 集萃： 2025-02-14 期 [Up]

『Abstract』Combinations of transcription factors govern the identity of cell types, which is reflected by genomic enhancer codes. We used deep learning to characterize these enhancer codes and devised three metrics to compare cell types in the telencephalon across amniotes. To this end, we generated single-cell multiome and spatially resolved transcriptomics data of the chicken telencephalon. Enhancer codes of orthologous nonneuronal and γ-aminobutyric acid–mediated (GABAergic) cell types show a high degree of similarity across amniotes, whereas excitatory neurons of the mammalian neocortex and avian pallium exhibit varying degrees of similarity. Enhancer codes of avian mesopallial neurons are most similar to those of mammalian deep-layer neurons. With this study, we present generally applicable deep learning approaches to characterize and compare cell types on the basis of genomic regulatory sequences.

『Abstract』Enzymes exist in ensembles of states that encode the energetics underlying their catalysis. Conformational ensembles built from 1231 structures of 17 serine proteases revealed atomic-level changes across their reaction states. By comparing the enzymatic and solution reaction, we identified molecular features that provide catalysis and quantified their energetic contributions to catalysis. Serine proteases precisely position their reactants in destabilized conformers, creating a downhill energetic gradient that selectively favors the motions required for reaction while limiting off-pathway conformational states. The same catalytic features have repeatedly evolved in proteases and additional enzymes across multiple distinct structural folds. Our ensemble-function analyses revealed previously unknown catalytic features, provided quantitative models based on simple physical and chemical principles, and identified motifs recurrent in nature that may inspire enzyme design.

『Abstract』The requirement for C 2 H 2 concentrations below 2 parts per million (ppm) in gas streams for C 2 H 4 polymerization necessitates its semihydrogenation to C 2 H 4 . We demonstrate selective chemical looping combustion of C 2 H 2 in C 2 H 4 -rich streams by Bi 2 O 3 as an alternative catalytic pathway to reduce C 2 H 2 concentration below 2 ppm. Bi 2 O 3 combusts C 2 H 2 with a first-order rate constant that is 3000 times greater than the rate constant for C 2 H 4 combustion. In successive redox cycles, the lattice O of Bi 2 O 3 can be fully replenished without discernible changes in local Bi coordination or C 2 H 2 combustion selectivity. Heterolytic activation of C–H bonds across Bi–O sites and the higher acidity of C 2 H 2 results in lower barriers for C 2 H 2 activation than C 2 H 4 , enabling selective catalytic hydrocarbon combustion leveraging differences in molecular deprotonation energies.

『Abstract』The amniote pallium contains sensory circuits that are structurally and functionally equivalent, yet their evolutionary relationship remains unresolved. We used birthdating analysis, single-cell RNA and spatial transcriptomics, and mathematical modeling to compare the development and evolution of known pallial circuits across birds (chick), lizards (gecko), and mammals (mouse). We reveal that neurons within these circuits’ stations are generated at varying developmental times and brain regions across species and found an early developmental divergence in the transcriptomic progression of glutamatergic neurons. Our research highlights developmental distinctions and functional similarities in the sensory circuit between birds and mammals, suggesting the convergence of high-order sensory processing across amniote lineages.

『Abstract』Naive CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

『Abstract』Innovations in the pallium likely facilitated the evolution of advanced cognitive abilities in birds. We therefore scrutinized its cellular composition and evolution using cell type atlases from chicken, mouse, and nonavian reptiles. We found that the avian pallium shares most inhibitory neuron types with other amniotes. Whereas excitatory neuron types in amniote hippocampal regions show evolutionary conservation, those in other pallial regions have diverged. Neurons in the avian mesopallium display gene expression profiles akin to the mammalian claustrum and deep cortical layers, while certain nidopallial cell types resemble neurons in the piriform cortex. Lastly, we observed substantial gene expression convergence between the dorsally located hyperpallium and ventrally located nidopallium during late development, suggesting that topological location does not always dictate gene expression programs determining functional properties in the adult avian pallium.

『Abstract』Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how hypertranscription might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)–cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide in FFPE sections. We demonstrate global RNAPII elevations in mouse gliomas and assorted human tumors in small clinical samples and discover regional elevations corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at S-phase-dependent histone genes correlated with WHO grade in meningiomas, accurately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneuploidy in cancer, with general implications for precision oncology.

『Abstract』High sugar–containing foods are readily consumed, even after meals and beyond fullness sensation (e.g., as desserts). Although reward-driven processing of palatable foods can promote overeating, the neurobiological mechanisms that underlie the selective appetite for sugar in states of satiety remain unclear. Hypothalamic pro-opiomelanocortin (POMC) neurons are principal regulators of satiety because they decrease food intake through excitatory melanocortin neuropeptides. We discovered that POMC neurons not only promote satiety in fed conditions but concomitantly switch on sugar appetite, which drives overconsumption. POMC neuron projections to the paraventricular thalamus selectively inhibited postsynaptic neurons through mu-opioid receptor signaling. This opioid circuit was strongly activated during sugar consumption, which was most notable in satiety states. Correspondingly, inhibiting its activity diminished high-sugar diet intake in sated mice.

『Abstract』Sequencing-based genetic tests have uncovered a vast array of BRCA2 sequence variants . Owing to limited clinical, familial and epidemiological data, thousands of variants are considered to be variants of uncertain significance (VUS). Here we have utilized CRISPR–Cas9-based saturation genome editing in a humanized mouse embryonic stem cell line to determine the functional effect of VUS. We have categorized nearly all possible single nucleotide variants (SNVs) in the region that encodes the carboxylate-terminal DNA-binding domain of BRCA2. We have generated function scores for 6,551 SNVs, covering 96.4% of possible SNVs in exons 15–26 spanning BRCA2 residues 2479–3216. These variants include 1,282 SNVs that are categorized as missense VUS in the clinical variant database ClinVar, with 77.2% of these classified as benign and 20.4% classified as pathogenic using our functional score. Our assay provides evidence that 3,384 of the SNVs in the region are benign and 776 are pathogenic. Our classification aligns closely with pathogenicity data from ClinVar, orthogonal functional assays and computational meta predictors. We have integrated our embryonic stem cell-based BRCA2 -saturation genome editing dataset with other available evidence and utilized the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for clinical classification of all possible SNVs. This classification is available as a sequence–function map and serves as a valuable resource for interpreting unidentified variants in the population and for physicians and genetic counsellors to assess BRCA2 VUS in patients.

『Abstract』Positive effects of plant diversity on productivity have been globally demonstrated and explained by two main effects: complementarity effects and selection effects . However, plant diversity experiments have shown substantial variation in these effects, with driving factors poorly understood . On the basis of a meta-analysis of 452 experiments across the globe, we show that productivity increases on average by 15.2% from monocultures to species mixtures with an average species richness of 2.6; net biodiversity effects are stronger in grassland and forest experiments and weaker in container, cropland and aquatic ecosystems. Of the net biodiversity effects, complementarity effects and selection effects contribute 65.6% and 34.4%, respectively. Complementarity effects increase with phylogenetic diversity, the mixing of nitrogen-fixing and non-nitrogen-fixing species and the functional diversity of leaf nitrogen contents, which indicate the key roles of niche partitioning, biotic feedback and abiotic facilitation in complementarity effects. More positive selection effects occur with higher species biomass inequality in their monocultures. Complementarity effects increase over time, whereas selection effects decrease over time, and they remain consistent across global variations in climates. Our results provide key insights into understanding global variations in plant diversity effects on productivity and underscore the importance of integrating both complementarity and selection effects into strategies for biodiversity conservation and ecological restoration.

『Abstract』Linear conducting polymers show ballistic transport, imposed by mobile carriers moving along the polymer chains , whereas conductance in the extended dimension, that is, between polymer strands or layers, remains weak due to the lack of intermolecular ordering and electronic coupling . Here we report a multilayer-stacked two-dimensional polyaniline (2DPANI) crystal, which shows metallic out-of-plane charge transport with high electrical conductivity. The material comprises columnar π arrays with an interlayer distance of 3.59 Å and periodic rhombohedral lattices formed by interwoven polyaniline chains. Electron spin resonance spectroscopy reveals significant electron delocalization in the 2DPANI lattices. First-principles calculations indicate the in-plane 2D conjugation and strong interlayer electronic coupling in 2DPANI facilitated by the Cl-bridged layer stacking. To assess the local optical conductivity, we used terahertz and infrared nanospectroscopy to unravel a Drude-type conductivity with an infrared plasma frequency and an extrapolated local d.c. conductivity of around 200 S cm . Conductive scanning probe microscopy showed an unusually high out-of-plane conductivity of roughly 15 S cm . Transport measurements through vertical and lateral micro-devices revealed comparable high out-of-plane (roughly 7 S cm ) and in-plane conductivity (roughly 16 S cm ). The vertical micro-devices further showed increasing conductivity with decreasing temperature, demonstrating unique out-of-plane metallic transport behaviour. By using this multilayer-stacked 2D conducting polymer design, we predict the achievement of strong electronic coupling beyond in-plane interactions, potentially reaching three-dimensional metallic conductivity .

『Abstract』Type A GABA (γ-aminobutyric acid) receptors (GABA A receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics . These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABA A receptors in the human brain have been inferred from subunit localization in tissue , functional measurements and structural analysis from recombinant expression and in mice . However, the arrangements of subunits that co-assemble physiologically in native human GABA A receptors remain unknown. Here we isolated α1 subunit-containing GABA A receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefined subunit interfaces. Drug-like densities in a subset of these interfaces led us to uncover unexpected activity on the GABA A receptor of antiepileptic drugs and resulted in localization of one of these drugs to the benzodiazepine-binding site. Proteomics and further structural analysis suggest interactions with the auxiliary subunits neuroligin 2 and GARLH4, which localize and modulate GABA A receptors at inhibitory synapses. This work provides a structural foundation for understanding GABA A receptor signalling and targeted pharmacology in the human brain.

『Abstract』Expanding the performance of field-effect devices is a key challenge of the ever-growing chip industry at the core of current technologies . Non-volatile multiferroic transistors that control atomic movements rather than purely electronic distribution are highly desired . Recently, a field-effect control over structural transitions was achieved in commensurate stacking configurations of honeycomb van der Waals (vdW) polytypes by sliding boundary strips between oppositely polarized domains . This ferroelectric hysteretic response, however, relied on pre-existing dislocation strips between relatively large micron-scale domains, severely limiting practical implementations . Here we report the robust electric switching of single-domain polytypes in nanometre-scale islands embedded in super-lubricant vdW arrays. We etch cavities into a thin layered spacer and then encapsulate it with functional flakes. The flakes above/under the lattice-mismatched spacer sag and touch at each cavity to form islands of commensurate and metastable polytype configurations. By imaging the polarization of the polytypes, we observe nucleation and annihilation of boundary strips and geometry-adaptable ferroelectric hysteresis loops. Using mechanical stress, we further control the position of boundary strips, modify marginal twist angles and nucleate patterns of polar domain. This super-lubricant arrays of polytype (SLAP) concept suggests ‘slidetronics’ device applications such as elastic-coupled neuromorphic memory cells and non-volatile multiferroic tunnelling transistors and programmable response by designing the size, shape and symmetry of the islands and of the arrays .

『Abstract』The ventrolateral pallial (VLp) excitatory neurons in the claustro-amygdalar complex and piriform cortex (PIR; which forms part of the palaeocortex) form reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that results in adaptive behaviours . Early-life disruptions in these circuits are linked to neuropsychiatric disorders , highlighting the importance of understanding their development. Here we reveal that the transcription factors SOX4, SOX11 and TFAP2D have a pivotal role in the development, identity and PFC connectivity of these excitatory neurons. The absence of SOX4 and SOX11 in post-mitotic excitatory neurons results in a marked reduction in the size of the basolateral amygdala complex (BLC), claustrum (CLA) and PIR. These transcription factors control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including in humans, identified conserved Tfap2d expression in developing excitatory neurons of BLC, CLA, PIR and the associated transitional areas of the frontal, insular and temporal cortex. Although the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat-response behaviours, differences emerge in the phenotypes at different Tfap2d dosages, particularly in terms of changes observed in BLC size and BLC–PFC connectivity. This underscores the importance of Tfap2d dosage in orchestrating developmental shifts in BLC–PFC connectivity and behavioural modifications that resemble symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial VLp excitatory neurons and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.

『Abstract』The construction of superlattices with a spatial modulation of chemical compositions allows for the creation of artificial materials with tailorable periodic potential landscapes and tunable electronic and optical properties . Conventional semiconductor superlattices with designable potential modulation in one dimension has enabled high-electron-mobility transistors and quantum-cascade lasers. More recently, a diverse set of superlattices has been constructed through self-assembly or guided assembly of multiscale building units, including zero-dimensional nanoclusters and nanoparticles , one-dimensional nanorods and nanowires , two-dimensional nanolayers and nanosheets , and hybrid two-dimensional molecular assemblies . These self-assembled superlattices feature periodic structural modulation in two or three dimensions, but often lack atomic precision owing to the inevitable structural disorder at the interfaces between the constituent units. Here we report a one-pot synthesis of multi-dimensional single-crystalline superlattices consisting of periodic arrangement of zero-, one- and two-dimensional building units. By exploiting zirconium (IV) metal–organic frameworks as host templates for directed nucleation and precise growth of metal-halide sublattices through a coordination-assisted assembly strategy, we synthesize a family of single-crystalline porous superlattices. Single-crystal X-ray crystallography and high-resolution transmission electron microscopy clearly resolve the high-order superlattice structure with deterministic atomic coordinates. Further treatment with selected amine molecules produces perovskite-like superlattices with highly tunable photoluminescence and chiroptical properties. Our study creates a platform of high-order single-crystalline porous superlattices, opening opportunities to tailor the electronic, optical and quantum properties beyond the reach of conventional crystalline solids.

『Abstract』The precise control of mechanochemical activation within deep tissues using non-invasive ultrasound holds profound implications for advancing our understanding of fundamental biomedical sciences and revolutionizing disease treatments . However, a theory-guided mechanoresponsive materials system with well-defined ultrasound activation has yet to be explored . Here we present the concept of using porous hydrogen-bonded organic frameworks (HOFs) as toolkits for focused ultrasound (FUS) programmably triggered drug activation to control specific cellular events in the deep brain, through on-demand scission of the supramolecular interactions. A theoretical model is developed to potentially visualize the mechanochemical scission and ultrasound mechanics, providing valuable guidelines for the rational design of mechanoresponsive materials to achieve programmable control. To demonstrate the practicality of this approach, we encapsulate the designer drug clozapine N-oxide (CNO) into the optimal HOF nanocrystals for FUS-gated release to activate engineered G-protein-coupled receptors in the ventral tegmental area (VTA) of mice and rats and hence achieve targeted neural circuit modulation even at depth 9 mm with a latency of seconds. This work demonstrates the capability of ultrasound to precisely control molecular interactions and develops ultrasound-programmable HOFs to non-invasively and spatiotemporally control cellular events, thereby facilitating the establishment of precise molecular therapeutic possibilities.

『Abstract』Recent discoveries from time-domain surveys are defying our expectations for how matter accretes onto supermassive black holes (SMBHs). The increased rate of short-timescale, repetitive events around SMBHs, including the recently discovered quasi-periodic eruptions , are garnering further interest in stellar-mass companions around SMBHs and the progenitors to millihertz-frequency gravitational-wave events. Here we report the discovery of a highly significant millihertz quasi-periodic oscillation (QPO) in an actively accreting SMBH, 1ES 1927+654, which underwent a major optical, ultraviolet and X-ray outburst beginning in 2018 . The QPO was detected in 2022 with a roughly 18-minute period, corresponding to coherent motion on a scale of less than 10 gravitational radii, much closer to the SMBH than typical quasi-periodic eruptions. The period decreased to 7.1 minutes over 2 years with a decelerating period evolution ( \(\ddot{P}\) greater than zero). To our knowledge, this evolution has never been seen in SMBH QPOs or high-frequency QPOs in stellar-mass black holes. Models invoking orbital decay of a stellar-mass companion struggle to explain the period evolution without stable mass transfer to offset angular-momentum losses, and the lack of a direct analogue to stellar-mass black-hole QPOs means that many instability models cannot explain all of the observed properties of the QPO in 1ES 1927+654. Future X-ray monitoring will test these models, and if it is a stellar-mass orbiter, the Laser Interferometer Space Antenna (LISA) should detect its low-frequency gravitational-wave emission.

『Abstract』Enhanced weathering (EW) with agriculture uses crushed silicate rocks to drive carbon dioxide removal (CDR) . If widely adopted on farmlands, it could help achieve net-zero emissions by 2050 . Here we show, with a detailed US state-specific carbon cycle analysis constrained by resource provision, that EW deployed on agricultural land could sequester 0.16–0.30 GtCO 2 yr by 2050, rising to 0.25–0.49 GtCO 2 yr by 2070. Geochemical assessment of rivers and oceans suggests effective transport of dissolved products from EW from soils, offering CDR on intergenerational timescales. Our analysis further indicates that EW may temporarily help lower ground-level ozone and concentrations of secondary aerosols in agricultural regions. Geospatially mapped CDR costs show heterogeneity across the USA, reflecting a combination of cropland distance from basalt source regions, timing of EW deployment and evolving CDR rates. CDR costs are highest in the first two decades before declining to about US$100–150 tCO 2 by 2050, including for states that contribute most to total national CDR. Although EW cannot be a substitute for emission reductions, our assessment strengthens the case for EW as an overlooked practical innovation for helping the USA meet net-zero 2050 goals . Public awareness of EW and equity impacts of EW deployment across the USA require further exploration and we note that mobilizing an EW industry at the necessary scale could take decades.

『Abstract』Galaxy clusters contain vast amounts of hot ionized gas known as the intracluster medium (ICM). In relaxed cluster cores, the radiative cooling time of the ICM is shorter than the age of the cluster. However, the absence of line emission associated with cooling suggests heating mechanisms that offset the cooling, with feedback from active galactic nuclei (AGNs) being the most likely source . Turbulence and bulk motions, such as the oscillating (‘sloshing’) motion of the core gas in the cluster potential well, have also been proposed as mechanisms for heat distribution from the outside of the core . Here we present X-ray spectroscopic observations of the Centaurus galaxy cluster with the X-Ray Imaging and Spectroscopy Mission satellite. We find that the hot gas flows along the line of sight relative to the central galaxy, with velocities from 130 km s to 310 km s within about 30 kpc of the centre. This indicates bulk flow consistent with core gas sloshing. Although the bulk flow may prevent excessive accumulation of cooled gas at the centre, it could distribute the heat injected by the AGN and bring in thermal energy from the surrounding ICM. The velocity dispersion of the gas is found to be only ≲ 120 km s in the core, even within about 10 kpc of the AGN. This suggests that the influence of the AGN on the surrounding ICM motion is limited in the cluster.

『Abstract』Inflammatory diseases are often chronic and recurrent, and current treatments do not typically remove underlying disease drivers . T cells participate in a wide range of inflammatory diseases such as psoriasis , Crohn’s disease , oesophagitis and multiple sclerosis , and clonally expanded antigen-specific T cells may contribute to disease chronicity and recurrence, in part by forming persistent pathogenic memory. Chronic rhinosinusitis and asthma are inflammatory airway diseases that often present as comorbidities . Chronic rhinosinusitis affects more than 10% of the general population . Among these patients, 20–25% would develop nasal polyps, which often require repeated surgical resections owing to a high incidence of recurrence . Whereas abundant T cells infiltrate the nasal polyps tissue , T cell subsets that drive the disease pathology and promote recurrence are not fully understood. By comparing T cell repertoires in nasal polyp tissues obtained from consecutive surgeries, here we report that persistent CD8 T cell clones carrying effector memory-like features colonize the mucosal tissue during disease recurrence, and these cells characteristically express the tryptase Granzyme K (GZMK). We find that GZMK cleaves many complement components, including C2, C3, C4 and C5, that collectively contribute to the activation of the complement cascade. GZMK-expressing CD8 T cells participate in organized tertiary lymphoid structures, and tissue GZMK levels predict the disease severity and comorbidities better than well-established biomarkers such as eosinophilia and tissue interleukin-5. Using a mouse asthma model, we further show that GZMK-expressing CD8 T cells exacerbate the disease in a manner dependent on the proteolytic activity of GZMK and complements. Genetic ablation or pharmacological inhibition of GZMK after the disease onset markedly alleviates tissue pathology and restores lung function. Our work identifies a pathogenic CD8 memory T cell subset that promotes tissue inflammation and recurrent airway diseases by the effector molecule GZMK and suggests GZMK as a potential therapeutic target.

『Abstract』Breast cancer is a highly heterogeneous disease whose prognosis and treatment as defined by the expression of three receptors—oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2; encoded by ERBB2 )—is insufficient to capture the full spectrum of clinical outcomes and therapeutic vulnerabilities. Previously, we demonstrated that transcriptional and genomic profiles define eleven integrative subtypes with distinct clinical outcomes, including four ER subtypes with increased risk of relapse decades after diagnosis . Here, to determine whether these subtypes reflect distinct evolutionary histories, interactions with the immune system and pathway dependencies, we established a meta-cohort of 1,828 breast tumours spanning pre-invasive, primary invasive and metastatic disease with whole-genome and transcriptome sequencing. We demonstrate that breast tumours fall along a continuum constrained by three genomic archetypes. The ER high-risk integrative subgroup is characterized by complex focal amplifications, similar to HER2 tumours, including cyclic extrachromosomal DNA amplifications induced by ER through R-loop formation and APOBEC3B-editing, which arise in pre-invasive lesions. By contrast, triple-negative tumours exhibit genome-wide instability and tandem duplications and are enriched for homologous repair deficiency-like signatures, whereas ER typical-risk tumours are largely genomically stable. These genomic archetypes, which replicate in an independent cohort of 2,659 primary tumours, are established early during tumorigenesis, sculpt the tumour microenvironment and are conserved in metastatic disease. These complex structural alterations contribute to replication stress and immune evasion, and persist throughout tumour evolution, unveiling potential vulnerabilities.

『Abstract』Glioblastoma is an incurable brain malignancy. By the time of clinical diagnosis, these tumours exhibit a degree of genetic and cellular heterogeneity that provides few clues to the mechanisms that initiate and drive gliomagenesis . Here, to explore the early steps in gliomagenesis, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging, to initiate and then closely track tumour formation. We isolated labelled and unlabelled cells at multiple stages—before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth—and subjected cells of each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogeneous clonal hierarchy that evolves with tumour growth. By exploring the injury response in wounded normal mouse brains, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response program occurs during tumorigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of glioblastoma, identifying a unique cell state and an injury response program tied to early tumour formation. These findings have implications for glioblastoma therapies and raise new possibilities for early diagnosis and prevention of disease.

『Abstract』Recent macroevolutionary studies predict a diversification of early birds during the Jurassic period , but the unquestionable Jurassic bird fossil record is limited to Archaeopteryx , which has also been referred to deinonychosaurian dinosaurs by some analyses . Although they have feathered wings, the known Jurassic birds are more similar to non-avialan theropods in having the ancestral long reptilian tail . This is in stark contrast to most Cretaceous and crownward taxa, which have a short tail that terminates in a compound bone called the pygostyle . Here we report on the oldest short-tailed avialan, Baminornis zhenghensis gen. et sp. nov., from the recently discovered Late Jurassic Zhenghe Fauna , which fills a noticeable spatio-temporal gap in the earliest branching avialan fossil record. B. zhenghensis exhibits a unique combination of derived ornithothoracine-like pectoral and pelvic girdles and plesiomorphic non-avialan maniraptoran hand, demonstrating mosaic evolution along stem avialan line. An avialan furcula collected from the same locality is referrable to ornithuromorphs on the basis of our morphometric and phylogenetic analyses. These newly discovered fossils demonstrate the early appearance of highly derived bird features, and together with an anchiornithine fossil from the same locality, they suggest an earlier origin of birds and a radiation of early birds in the Jurassic.

『Abstract』Distributed quantum computing (DQC) combines the computing power of multiple networked quantum processing modules, ideally enabling the execution of large quantum circuits without compromising performance or qubit connectivity . Photonic networks are well suited as a versatile and reconfigurable interconnect layer for DQC; remote entanglement shared between matter qubits across the network enables all-to-all logical connectivity through quantum gate teleportation (QGT) . For a scalable DQC architecture, the QGT implementation must be deterministic and repeatable; until now, no demonstration has satisfied these requirements. Here we experimentally demonstrate the distribution of quantum computations between two photonically interconnected trapped-ion modules. The modules, separated by about two metres, each contain dedicated network and circuit qubits. By using heralded remote entanglement between the network qubits, we deterministically teleport a controlled-Z (CZ) gate between two circuit qubits in separate modules, achieving 86% fidelity. We then execute Grover’s search algorithm —to our knowledge, the first implementation of a distributed quantum algorithm comprising several non-local two-qubit gates—and measure a 71% success rate. Furthermore, we implement distributed iSWAP and SWAP circuits, compiled with two and three instances of QGT, respectively, demonstrating the ability to distribute arbitrary two-qubit operations . As photons can be interfaced with a variety of systems, the versatile DQC architecture demonstrated here provides a viable pathway towards large-scale quantum computing for a range of physical platforms.

『Abstract』Discrete protein assemblies ranging from hundreds of kilodaltons to hundreds of megadaltons in size are a ubiquitous feature of biological systems and perform highly specialized functions . Despite remarkable recent progress in accurately designing new self-assembling proteins, the size and complexity of these assemblies has been limited by a reliance on strict symmetry . Here, inspired by the pseudosymmetry observed in bacterial microcompartments and viral capsids, we developed a hierarchical computational method for designing large pseudosymmetric self-assembling protein nanomaterials. We computationally designed pseudosymmetric heterooligomeric components and used them to create discrete, cage-like protein assemblies with icosahedral symmetry containing 240, 540 and 960 subunits. At 49, 71 and 96 nm diameter, these nanocages are the largest bounded computationally designed protein assemblies generated to date. More broadly, by moving beyond strict symmetry, our work substantially broadens the variety of self-assembling protein architectures that are accessible through design.

『Abstract』Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order . Infections in bats are largely asymptomatic , indicating limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species, including potential viral reservoirs. Here we describe a systematic analysis covering 115 mammalian genomes that revealed that signatures of selection in immune genes are more prevalent in bats than in other mammalian orders. We found an excess of immune gene adaptations in the ancestral chiropteran branch and in many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15 , which is an antiviral gene contributing to hyperinflammation during COVID-19 (refs. ), exhibits key residue changes in rhinolophid and hipposiderid bats. Cellular infection experiments show species-specific antiviral differences and an essential role of protein conjugation in antiviral function of bat ISG15 , separate from its role in secretion and inflammation in humans. Furthermore, in contrast to humans, ISG15 in most rhinolophid and hipposiderid bats has strong anti-SARS-CoV-2 activity. Our work reveals molecular mechanisms that contribute to viral tolerance and disease resistance in bats.

『Abstract』The zeta inhibitory peptide (ZIP) interferes with memory maintenance and long-term potentiation (LTP) when administered to mice. However, mice lacking its putative target, protein kinase PKMζ, exhibit normal learning and memory as well as LTP , making the mechanism of ZIP unclear. Here we show that ZIP disrupts LTP by removing surface AMPA receptors through its cationic charge alone. This effect requires endophilin-A2-mediated endocytosis and is fully blocked by drugs suppressing macropinocytosis. ZIP and other cationic peptides remove newly inserted AMPA receptor nanoclusters at potentiated synapses, providing a mechanism by which these peptides erase memories without altering basal synaptic function. When delivered in vivo, cationic peptides can modulate memories on local and brain-wide scales, and these mechanisms can be leveraged to prevent memory loss in a model of traumatic brain injury. Our findings uncover a previously unknown synaptic mechanism by which memories are maintained or lost.

『Abstract』Topological wave structures, such as vortices , polarization textures and skyrmions , appear in various quantum and classical wave fields, including optics and acoustics. In particular, optical vortices have found numerous applications , ranging from quantum information to astrophysics. Furthermore, both optical and acoustic structured waves are crucial in the manipulation of small particles , from atoms to macroscopic biological objects. Recently, there has been a surge of interest in structured water surface waves, which can be notable analogues of quantum, optical and acoustic wave systems . However, topological water-wave forms, especially their ability to manipulate particles, have not yet been demonstrated. Here we describe the controllable generation of topological structures, namely wave vortices, skyrmions and polarization Mobius strips, in gravity water waves. Most importantly, we demonstrate the efficient manipulation of subwavelength and wavelength-order floating particles with topologically structured water waves. This includes trapping the particles in the high-intensity field zones and controlling their orbital and spinning motion due to the orbital and spin angular momenta of the water waves. Our results reveal the water-wave counterpart of optical and acoustic manipulation, which paves the way for applications in hydrodynamics and microfluidics.

『Abstract』Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers . However, variants of uncertain significance limit the clinical utility of test results. Thus, there is a need for functional characterization and clinical classification of all BRCA2 variants to facilitate the clinical management of individuals with these variants. Here we analysed all possible single-nucleotide variants from exons 15 to 26 that encode the BRCA2 DNA-binding domain hotspot for pathogenic missense variants. To enable this, we used saturation genome editing CRISPR–Cas9-based knock-in endogenous targeting of human haploid HAP1 cells . The assay was calibrated relative to nonsense and silent variants and was validated using pathogenic and benign standards from ClinVar and results from a homology-directed repair functional assay . Variants (6,959 out of 6,960 evaluated) were assigned to seven categories of pathogenicity based on a VarCall Bayesian model . Single-nucleotide variants that encode loss-of-function missense variants were associated with increased risks of breast cancer and ovarian cancer. The functional assay results were integrated into models from ClinGen, the American College of Medical Genetics and Genomics, and the Association for Molecular Pathology for clinical classification of BRCA2 variants. Using this approach, 91% were classified as pathogenic or likely pathogenic or as benign or likely benign. These classified variants can be used to improve clinical management of individuals with a BRCA2 variant.

『Abstract』In the centres of many galaxy clusters, the hot (approximately 10 kelvin) intracluster medium can become dense enough that it should cool on short timescales . However, the low measured star formation rates in massive central galaxies and the absence of soft X-ray lines from the cooling gas suggest that most of this gas never cools. This is known as the cooling flow problem. The latest observations suggest that black hole jets are maintaining the vast majority of gas at high temperatures . A cooling flow has yet to be fully mapped through all the gas phases in any galaxy cluster. Here we present observations of the Phoenix cluster using the James Webb Space Telescope to map the [Ne vi ] λ 7.652-μm emission line, enabling us to probe the gas at 10 kelvin on large scales. These data show extended [Ne vi ] emission that is cospatial with the cooling peak in the intracluster medium, the coolest gas phases and the sites of active star formation. Taken together, these imply a recent episode of rapid cooling, causing a short-lived spike in the cooling rate, which we estimate to be 5,000–23,000 solar masses per year. These data provide a large-scale map of gas at temperatures between 10 kelvin and 10 kelvin in a cluster core, and highlight the critical role that black hole feedback has in not only regulating cooling but also promoting it .

『Abstract』Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral, octahedral or icosahedral point group symmetry to generate closed cage-like structures . Viruses access more complex higher triangulation number icosahedral architectures by breaking perfect point group symmetry , but nature appears not to have explored similar symmetry breaking for tetrahedral or octahedral symmetries. Here we describe a general design strategy for building higher triangulation number architectures starting from regular polyhedra through pseudosymmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (tetrahedral), 96 (octahedral) and 240 (icosahedral) subunits, each with 4 distinct chains and 6 different protein–protein interfaces, and diameters of 33 nm, 43 nm and 75 nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen-displaying vaccine candidates and targeted delivery vehicles .

『Abstract』During normal cellular homeostasis, unfolded and mislocalized proteins are recognized and removed, preventing the build-up of toxic byproducts . When protein homeostasis is perturbed during ageing, neurodegeneration or cellular stress, proteins can accumulate several forms of chemical damage through reactive metabolites . Such modifications have been proposed to trigger the selective removal of chemically marked proteins ; however, identifying modifications that are sufficient to induce protein degradation has remained challenging. Here, using a semi-synthetic chemical biology approach coupled to cellular assays, we found that C-terminal amide-bearing proteins (CTAPs) are rapidly cleared from human cells. A CRISPR screen identified FBXO31 as a reader of C-terminal amides. FBXO31 is a substrate receptor for the SKP1–CUL1–F-box protein (SCF) ubiquitin ligase SCF–FBXO31, which ubiquitylates CTAPs for subsequent proteasomal degradation. A conserved binding pocket enables FBXO31 to bind to almost any C-terminal peptide bearing an amide while retaining exquisite selectivity over non-modified clients. This mechanism facilitates binding and turnover of endogenous CTAPs that are formed after oxidative stress. A dominant human mutation found in neurodevelopmental disorders reverses CTAP recognition, such that non-amidated neosubstrates are now degraded and FBXO31 becomes markedly toxic. We propose that CTAPs may represent the vanguard of a largely unexplored class of modified amino acid degrons that could provide a general strategy for selective yet broad surveillance of chemically damaged proteins.

『Abstract』The assessment of research performance is widely seen as a vital tool in upholding the highest standards of quality, with selection and competition believed to drive progress. Academic institutions need to take critical decisions on hiring and promotion, while facing external pressure by also being subject to research assessment . Here we present an outlook on research assessment for career progression with specific focus on promotion to full professorship, based on 314 policies from 190 academic institutions and 218 policies from 58 government agencies, covering 32 countries in the Global North and 89 countries in the Global South. We investigated how frequently various promotion criteria are mentioned and carried out a statistical analysis to infer commonalities and differences across policies. Although quantitative methods of assessment remain popular, in agreement with what is found in more geographically restricted studies , they are not omnipresent. We find differences between the Global North and the Global South as well as between institutional and national policies, but less so between disciplines. A preference for bibliometric indicators is more marked in upper-middle-income countries. Although we see some variation, many promotion policies are based on the assumption of specific career paths that become normative rather than embracing diversity. In turn, this restricts opportunities for researchers. These results challenge current practice and have strategic implications for researchers, research managers and national governments.

『Abstract』The detection of cosmic neutrinos with energies above a teraelectronvolt (TeV) offers a unique exploration into astrophysical phenomena . Electrically neutral and interacting only by means of the weak interaction, neutrinos are not deflected by magnetic fields and are rarely absorbed by interstellar matter: their direction indicates that their cosmic origin might be from the farthest reaches of the Universe. High-energy neutrinos can be produced when ultra-relativistic cosmic-ray protons or nuclei interact with other matter or photons, and their observation could be a signature of these processes. Here we report an exceptionally high-energy event observed by KM3NeT, the deep-sea neutrino telescope in the Mediterranean Sea , which we associate with a cosmic neutrino detection. We detect a muon with an estimated energy of \(12{0}_{-60}^{+110}\) petaelectronvolts (PeV). In light of its enormous energy and near-horizontal direction, the muon most probably originated from the interaction of a neutrino of even higher energy in the vicinity of the detector. The cosmic neutrino energy spectrum measured up to now falls steeply with energy. However, the energy of this event is much larger than that of any neutrino detected so far. This suggests that the neutrino may have originated in a different cosmic accelerator than the lower-energy neutrinos, or this may be the first detection of a cosmogenic neutrino , resulting from the interactions of ultra-high-energy cosmic rays with background photons in the Universe.