Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours1. Multimodal analyses of clinical specimens reveal substantial inflammatory infiltrate in leptomeningeal metastases with enrichment of IFNγ and resulting downstream signalling. Here, to investigate and overcome this futile anti-tumour response within the leptomeninges, we developed syngeneic lung cancer, breast cancer and melanoma leptomeningeal-metastasis mouse models. We show that transgenic host mice lacking IFNγ or its receptor fail to control the growth of leptomeningeal metastases growth. Leptomeningeal overexpression of Ifng through a targeted adeno-associated-virus-based system controls cancer cell growth independent of adaptive immunity. Using a suite of transgenic hosts, we demonstrate that leptomeningeal T cells generate IFNγ to actively recruit and activate peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. Independent of antigen presentation, migratory CCR7+ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This study identifies unique, leptomeninges-specific IFNγ signalling and suggests an immune-therapeutic approach against tumours within this space.

Here we report on the nearly complete and uncrushed 14th specimen of Archaeopteryx. Exceptional preservation and preparation guided by micro-computed tomographic data make this one of the best exemplars of this iconic taxon, preserving important data regarding skeletal transformation and plumage evolution in relation to the acquisition of flight during early avian evolution. The ventrolaterally exposed skull reveals a palatal morphology intermediate between troodontids1 and crownward Cretaceous birds2,3. Modifications of the skull reflect the shift towards a less rigid cranial architecture in archaeopterygids from non-avian theropods. The complete vertebral column reveals paired proatlases and a tail longer than previously recognized. Skin traces on the right major digit of the hand suggest that the minor digit was free and mobile distally, contrary to previous interpretations4. The morphology of the foot pads indicates that they were adapted for non-raptorial terrestrial locomotion. Specialized inner secondary feathers called tertials5,6 are observed on both wings. Humeral tertials are absent in non-avian dinosaurs closely related to birds, suggesting that these feathers evolved for flight, creating a continuous aerodynamic surface. These new findings clarify the mosaic of traits present in Archaeopteryx, refine ecological predictions and elucidate the unique evolutionary history of the Archaeopterygidae, providing clues regarding the ancestral avian condition.

The human cerebral cortex is composed of six layers and dozens of areas that are molecularly and structurally distinct1-4. Although single-cell transcriptomic studies have advanced the molecular characterization of human cortical development, a substantial gap exists owing to the loss of spatial context during cell dissociation5-8. Here we used multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based nucleus segmentation, to examine the molecular, cellular and cytoarchitectural development of the human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing more than 18 million single cells, spans eight cortical areas across seven developmental time points. We uncovered the early establishment of the six-layer structure, identifiable by the laminar distribution of excitatory neuron subtypes, 3 months before the emergence of cytoarchitectural layers. Notably, we discovered two distinct modes of cortical areal specification during mid-gestation: (1) a continuous, gradual transition observed across most cortical areas along the anterior-posterior axis and (2) a discrete, abrupt boundary specifically identified between the primary (V1) and secondary (V2) visual cortices as early as gestational week 20. This sharp binary transition in V1-V2 neuronal subtypes challenges the notion that mid-gestation cortical arealization involves only gradient-like transitions6,10. Furthermore, integrating single-nucleus RNA sequencing with MERFISH revealed an early upregulation of synaptogenesis in V1-specific layer 4 neurons. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This study establishes a spatially resolved single-cell analysis paradigm and paves the way for the construction of a comprehensive developmental atlas of the human brain.

Ultra-long-range genomic contacts, which are key components of neuronal genome architecture1-3, constitute a biochemical enigma. This is because regulatory DNA elements make selective and stable contacts with DNA sequences located hundreds of kilobases away, instead of interacting with proximal sequences occupied by the exact same transcription factors1,4. This is exemplified in olfactory sensory neurons (OSNs), in which only a fraction of LHX2-, EBF1- and LDB1-bound sites interact with each other, converging into highly selective multi-chromosomal enhancer hubs5. To obtain biochemical insight into this process, here we assembled olfactory receptor (OR) enhancer hubs in vitro with recombinant proteins and enhancer DNA. Cell-free reconstitution of enhancer hubs revealed that OR enhancers form nucleoprotein condensates with unusual, solid-like characteristics. Assembly of these solid condensates is orchestrated by specific DNA motifs enriched in OR enhancers, which are likely to confer distinct homotypic properties on their resident LHX2-EBF1-LDB1 complexes. Single-molecule tracking and pulse-chase experiments in vivo confirmed that LHX2 and EBF1 assemble OR-transcription-competent condensates with solid properties in OSN nuclei, under physiological concentrations of protein. Thus, homophilic nucleoprotein interactions that are influenced by DNA sequence generate new types of biomolecular condensate, which might provide a generalizable explanation for the stability and specificity of long-range genomic contacts across cell types.

The mammalian gut harbours trillions of commensal bacteria that interact with their hosts through various bioactive molecules1,2. However, the mutualistic strategies that hosts evolve to benefit from these symbiotic relationships are largely unexplored. Here we report that mouse enterocytes secrete apolipoprotein L9a and b (APOL9a/b) in the presence of microbiota. By integrating flow cytometry sorting of APOL9-binding bacterial taxa with 16S ribosomal RNA gene sequencing (APOL9-seq), we identify that APOL9a/b, as well as their human equivalent APOL2, coat gut bacteria belonging to the order of Bacteroidales with a high degree of specificity through commensal ceramide-1-phosphate (Cer1P) lipids. Genetic abolition of ceramide-1-phosphate synthesis pathways in gut-dominant symbiote Bacteroides thetaiotaomicron significantly decreases the binding of APOL9a/b to the bacterium. Instead of lysing the bacterial cells, coating of APOL9a/b induces the production of outer membrane vesicles (OMVs) from the target bacteria. Subsequently, the Bacteroides-elicited outer membrane vesicles enhance the host's interferon-γ signalling to promote major histocompatibility complex class II expression in the intestinal epithelial cells. In mice, the loss of Apol9a/b compromises the gut major histocompatibility complex class II-instructed immune barrier function, leading to early mortality from infection by intestinal pathogens. Our data show how a host-elicited factor benefits gut immunological homeostasis by selectively targeting commensal ceramide molecules.

Imposing incommensurable periodicity on the periodic atomic lattice can lead to complex structural phases consisting of locally periodic structure bounded by topological defects1-8. Twisted trilayer graphene (TTG) is an ideal material platform to study the interplay between different atomic periodicities, which can be tuned by twist angles between the layers, leading to moiré-of-moiré lattices9-26. Interlayer and intralayer interactions between two interfaces in TTG transform this moiré-of-moiré lattice into an intricate network of domain structures at small twist angles, which can harbour exotic electronic behaviours9-26. Here we report a complete structural phase diagram of TTG with atomic-scale lattice reconstruction. Using transmission electron microscopy (TEM) combined with a new interatomic potential simulation27,28, we show several large-scale moiré lattices, including triangular, kagome and a corner-shared hexagram-shaped domain pattern. Each domain is bounded by a 2D network of domain-wall lattices. In the limit of small twist angles, two competing structural orders-rhombohedral and Bernal stackings-with a slight energy difference cause unconventional lattice reconstruction with spontaneous symmetry breaking (SSB) and nematic instability, highlighting the importance of long-range interlayer interactions across entire van der Waals layers. The diverse tessellation of distinct domains, whose topological network can be tuned by the adjustment of the twist angles, establishes TTG as a platform for exploring the interplay between emerging quantum properties and controllable nontrivial lattices.

Precision measurements using low-energy antiprotons, exclusively available at the antimatter factory (AMF) of CERN1, offer stringent tests of charge-parity-time (CPT) invariance, which is a fundamental symmetry in the Standard Model of particle physics2. These tests have been realized, for example, in antiprotonic helium3 and antihydrogen4. In our cryogenic Penning-trap experiments5, we measure the magnetic moments6,7 and charge-to-mass ratios of protons and antiprotons and now provide the most precise test of CPT invariance in the baryon sector8. Our experiments are limited by magnetic field fluctuations imposed by the decelerators in the AMF; therefore, we are advancing the relocation of antiprotons to dedicated precision laboratories. Here we present the successful transport of a trapped proton cloud from the AMF using BASE-STEP9-a transportable, superconducting, autonomous and open Penning-trap system that can distribute antiprotons into other experiments. We transferred the trapped protons from our experimental area at the AMF onto a truck and transported them across the Meyrin site of CERN, demonstrating autonomous operation without external power for 4 h and loss-free proton relocation. We thereby confirm the feasibility of transferring particles into low-noise laboratories in the vicinity of the AMF and of using a power generator on the truck10 to reach laboratories throughout Europe. This marks the potential start of a new era in precision antimatter research, enabling low-noise measurements of antiprotons, the charged antimatter ions H¯+11 and H¯2- (ref. 12), and other accelerator-produced ions, such as hydrogen-like lead or uranium ions13,14.

Mainland Southeast Asia (MSEA) has rich ethnic and cultural diversity with a population of nearly 300 million1,2. However, people from MSEA are underrepresented in the current human genomic databases. Here we present the SEA3K genome dataset (phase I), generated by deep short-read whole-genome sequencing of 3,023 individuals from 30 MSEA populations, and long-read whole-genome sequencing of 37 representative individuals. We identified 79.59 million small variants and 96,384 structural variants, among which 22.83 million small variants and 24,622 structural variants are unique to this dataset. We observed a high genetic heterogeneity across MSEA populations, reflected by the varied combinations of genetic components. We identified 44 genomic regions with strong signatures of Darwinian positive selection, covering 89 genes involved in varied physiological systems such as physical traits and immune response. Furthermore, we observed varied patterns of archaic Denisovan introgression in MSEA populations, supporting the proposal of at least two distinct instances of Denisovan admixture into modern humans in Asia3. We also detected genomic regions that suggest adaptive archaic introgressions in MSEA populations. The large number of novel genomic variants in MSEA populations highlight the necessity of studying regional populations that can help answer key questions related to prehistory, genetic adaptation and complex diseases.

The Moon undergoes periodic tidal forcing due to its eccentric and oblique orbit around the Earth1. The response to this tidal interaction drives temporal changes in the lunar gravity field and is sensitive to the satellite's internal structure2-4. We use data from the NASA GRAIL spacecraft5-9 to recover the time-varying lunar gravity field, including a degree-3 gravitational tidal Love number, k3. Here, we report our estimated value of k3 = 0.0163 ± 0.0007, which is about 72% higher than that expected for a spherically symmetric moon10. Such a large k3 can be explained if the elastic shear modulus of the mantle varies by about 2-3% between the nearside and farside4, providing an observational demonstration of lateral heterogeneities in the deep lunar interior. This asymmetric structure suggests preservation of a predominantly thermal anomaly of roughly 100-200 K in the nearside mantle that formed surface mare regions 3-4 billion years ago11 and could influence the spatial distribution of deep moonquakes12.

Choice behaviour of animals is characterized by two main tendencies: taking actions that led to rewards and repeating past actions1,2. Theory suggests that these strategies may be reinforced by different types of dopaminergic teaching signals: reward prediction error to reinforce value-based associations and movement-based action prediction errors to reinforce value-free repetitive associations3-6. Here we use an auditory discrimination task in mice to show that movement-related dopamine activity in the tail of the striatum encodes the hypothesized action prediction error signal. Causal manipulations reveal that this prediction error serves as a value-free teaching signal that supports learning by reinforcing repeated associations. Computational modelling and experiments demonstrate that action prediction errors alone cannot support reward-guided learning, but when paired with the reward prediction error circuitry they serve to consolidate stable sound-action associations in a value-free manner. Together we show that there are two types of dopaminergic prediction errors that work in tandem to support learning, each reinforcing different types of association in different striatal areas.

In quantum mechanics, empty space is not void but is characterized by vacuum-field fluctuations, which underlie phenomena such as the Lamb shift1, spontaneous emission, and the Casimir effect2. Due to their quantitatively small relative contributions in free-space atomic physics, they were traditionally overlooked in solid-state systems. Recently, however, the interplay between electronic correlations and quantum electrodynamical effects in low-dimensional systems has become a rapidly advancing area in condensed matter physics3-5, with substantial implications for quantum materials and device engineering. High-mobility two-dimensional electron gases in the quantum Hall regime6 offer an ideal platform to investigate how vacuum electromagnetic fields affect strongly correlated electronic states. Here we demonstrate that adjusting the coupling strength between a two-dimensional electron gas and the vacuum fields of a hovering split-ring resonator leads to a significant reduction in exchange splitting at odd-integer filling factors, along with an enhancement of fractional quantum Hall gaps at filling factors 4/3, 5/3 and 7/5. Theoretical analysis indicates that these effects stem from an effective long-range attractive interaction mediated by virtual cavity photons in regions with strong vacuum electric field gradients. Our findings uncover a new mechanism by which cavity vacuum fields can reshape electronic correlations in quantum Hall systems, establishing a new approach for manipulating correlated quantum phases in low-dimensional materials and paving the way for engineering tailored many-body interactions in compact devices.

The anti-tumour effect of radiotherapy beyond the treatment field-the abscopal effect-has garnered much interest1. However, the potentially deleterious effect of radiation in promoting metastasis is less well studied. Here we show that radiotherapy induces the expression of the EGFR ligand amphiregulin in tumour cells, which reprogrammes EGFR-expressing myeloid cells toward an immunosuppressive phenotype and reduces phagocytosis. This stimulates distant metastasis growth in human patients and in pre-clinical mouse tumour models. The inhibition of these tumour-promoting factors induced by radiotherapy may represent a novel therapeutic strategy to improve patient outcomes.

Electrochemical CO2 reduction into chemicals and fuels holds great promise for renewable energy storage and carbon recycling1-3. Although high-temperature CO2 electroreduction in solid oxide electrolysis cells is industrially relevant, current catalysts have modest energy efficiency and a limited lifetime at high current densities, generally below 70% and 200 h, respectively, at 1 A cm-2 and temperatures of 800 °C or higher4-8. Here we develop an encapsulated Co-Ni alloy catalyst using Sm2O3-doped CeO2 that exhibits an energy efficiency of 90% and a lifetime of more than 2,000 h at 1 A cm-2 for high-temperature CO2-to-CO conversion at 800 °C. Its selectivity towards CO is about 100%, and its single-pass yield reaches 90%. We show that the efficacy of our catalyst arises from its unique encapsulated structure and optimized alloy composition, which simultaneously enable enhanced CO2 adsorption, moderate CO adsorption and suppressed metal agglomeration. This work provides an efficient strategy for the design of catalysts for high-temperature reactions that overcomes the typical trade-off between activity and stability and has potential industrial applications.

Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment5, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders effectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell-transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efficacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy.

The known fossil record of crown-group amniotes begins in the late Carboniferous with the sauropsid trackmaker Notalacerta1,2 and the sauropsid body fossil Hylonomus1-4. The earliest body fossils of crown-group tetrapods are mid-Carboniferous, and the oldest trackways are early Carboniferous5-7. This suggests that the tetrapod crown group originated in the earliest Carboniferous (early Tournaisian), with the amniote crown group appearing in the early part of the late Carboniferous. Here we present new trackway data from Australia that challenge this widely accepted timeline. A track-bearing slab from the Snowy Plains Formation of Victoria, Taungurung Country, securely dated to the early Tournaisian8,9, shows footprints from a crown-group amniote with clawed feet, most probably a primitive sauropsid. This pushes back the likely origin of crown-group amniotes by at least 35-40 million years. We also extend the range of Notalacerta into the early Carboniferous. The Australian tracks indicate that the amniote crown-group node cannot be much younger than the Devonian/Carboniferous boundary, and that the tetrapod crown-group node must be located deep within the Devonian; an estimate based on molecular-tree branch lengths suggests an approximate age of early Frasnian for the latter. The implications for the early evolution of tetrapods are profound; all stem-tetrapod and stem-amniote lineages must have originated during the Devonian. It seems that tetrapod evolution proceeded much faster, and the Devonian tetrapod record is much less complete, than has been thought.

Depression is characterized by diverse symptom combinations that can be represented as dynamic networks. While previous research has focused on central symptoms for targeted interventions, less attention has been given to whole-network properties. Here we show that 'network temperature', a novel measure of psychological network stability, captures symptom alignment across adolescence-a critical period for depression onset. Network temperature reflects system stability, with higher values indicating less symptom alignment and greater variability. In three large longitudinal adolescent cohorts (total N = 35,901), we found that network temperature decreases across adolescence, with the steepest decline during early adolescence, particularly in males. This suggests that depression symptom networks stabilize throughout development via increased symptom alignment, potentially explaining why adolescence is a crucial period for depression onset. These findings highlight early adolescence as a key intervention window and underscore the importance of sex-specific and personalized interventions.

Schizophrenia is associated with structural and functional changes in the central nervous system, including the most distal part of it, the retina. However, the question of whether retinal atrophy is present before individuals develop schizophrenia or is a secondary consequence of the disorder remains unanswered. Here we address this question by examining the association between polygenic risk scores for schizophrenia and retinal morphologies in individuals without a schizophrenia diagnosis. We used population data for 34,939 white British and Irish individuals from the UK Biobank. Our robust regression results show that higher polygenic risk scores for schizophrenia were associated with thinner overall maculae, while controlling for confounding factors (b = -0.17, P = 0.018). Similarly, we found that greater polygenic risk scores for schizophrenia specific to neuroinflammation gene sets were associated with thinner ganglion cell inner plexiform layers (b = -0.10, self-contained P = 0.014, competitive P = 0.02). These results provide new evidence for genetic factors that could predispose individuals to heightened neuroinflammatory responses. Over time, these responses could contribute to neurodegenerative processes such as retinal thinning.