Axon regeneration is limited in the mammalian central nervous system1. Neurons must balance stress responses with regenerative demands after axonal injury2, but the mechanisms remain unclear. Here we identify aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix/PER-ARNT-SIM (bHLH-PAS) transcription factor, as a key regulator of this stress-growth switch. We show that ligand-mediated AhR signalling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models. Mechanistic studies reveal that axotomy-induced AhR activation in dorsal root ganglion neurons enforces proteostasis and stress-response programs to preserve tissue integrity. By contrast, AhR ablation redirects the neuronal response towards elevated de novo translation and pro-growth signalling, enabling axon regeneration. This growth-promoting effect requires HIF1α, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response and DNA hydroxymethylation to rewire neuronal injury-response programs. Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis and metabolic signalling to control the balance between stress adaptation and axonal repair.

The discovery of high-temperature superconductivity in bulk La3Ni2O7 under high hydrostatic pressure1-4 and biaxial compression in epitaxial thin films5-8 has ignited significant interest in understanding the interplay between atomic and electronic structure in these compounds. Subtle changes in the nickel-oxygen bonding environment are thought to be key drivers for stabilizing superconductivity, but specific details of which bonds and which modifications are most relevant remains so far unresolved. While direct, atomic-scale structural characterization under hydrostatic pressure is beyond current experimental capabilities, static stabilization of strained La3Ni2O7 films provides a platform well-suited to investigation with new picometer-resolution electron microscopy methods. Here, we use multislice electron ptychography (MEP)9,10 to directly measure the atomic-scale structural evolution of La3Ni2O7 thin films across a wide range of biaxial strains tuned via substrate choice. By resolving both the cation and oxygen sublattices, we study the strain-dependent evolution of atomic bonds, providing the opportunity to isolate and disentangle the effects of specific structural motifs for stabilizing superconductivity. We identify the lifting of crystalline symmetry through modification of the nickel-oxygen octahedral distortions under compressive strain as a key structural ingredient for superconductivity and identify in-plane lattice compression as a common attribute between bulk and thin film superconductivity. Building upon the detailed structures obtained by MEP, we introduce a theoretical framework to disentangle coupled structural distortions in corner-sharing octahedra11, which suggest that both known superconducting geometries of La3Ni2O7 (hydrostatic pressure and compressive strain) suppress local t2g orbital mixing in the low-energy Ni bands by raising the octahedral symmetry.

Cortical high gamma-band activity (HGA) is used in many scientific investigations1-18, yet its biophysical source is a matter of debate. Two leading hypotheses are that HGA predominantly represents summed postsynaptic potentials or-more commonly-that it predominantly represents summed local spikes. If the latter were true, the nearest neurons to an electrode should contribute most to HGA recorded on that electrode. To test these hypotheses, here we trained monkeys (Macaca mulatta) to decouple local spiking from HGA on a single electrode using a brain-machine interface. Their ability to decouple them suggested that HGA is probably not generated simply by summed local spiking. Instead, HGA correlated with co-firing of neuronal populations that were widely distributed across millimetres of cortex. The neuronal spikes that contributed more to this co-firing also contributed more to, and preceded, spike-triggered HGA. These results suggest that HGA arises mainly from summed postsynaptic potentials triggered by the synchronous co-firing of widely distributed neurons.

Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction1-7. Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling8. Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR-galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.

During mammalian evolution, excitatory neurons in upper cortical layer 2 and layer 3 (L2/3) have shown a disproportionate expansion compared with other layers1-4. Replicative expansion of cortical neural progenitors is associated with considerable oxidative DNA damage. Here we show that activating transcription factor 4 (ATF4) has roles as a critical regulator of the DNA damage response, directly activating components of double-stranded DNA repair, including CIRBP, UBA52 and EBF1. Notably, pan-cortical knockout (Emx1-Cre;Atf4fl/fl) demonstrates that ATF4 is required specifically for the development of upper layer 2/3 neurons, marked by the expression of cut-like homeobox 2 protein, CUX2. ATF4 functions to repair DNA damage and attenuate cell death of embryonic radial glial progenitors in a p53-dependent manner. In particular, we show that cold inducible RNA-binding protein (CIRBP) is a transcriptional target of ATF4 that is required for normal phosphorylation of the key double-strand DNA repair factor ataxia telangiectasia mutated (ATM). These findings establish that ATF4 is an essential regulator of the DNA damage response. They further indicate that there are extraordinary requirements for DNA repair after replicative stress in CUX2+ neurons during mammalian brain development.

Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease1, but the underlying mechanisms for cell-type-specific neuronal losses remain poorly understood. Previous studies have shown that upper cortical layer thinning occurs in progressive human multiple sclerosis (MS) and that cortical layer 2 and layer 3 (L2/3) excitatory neurons (L2/3ENs) that express CUT-like homeobox 2 (CUX2) are selectively vulnerable to degeneration2. Here we report that L2/3ENs within MS cortical lesions have an elevated DNA damage burden. DNA damage and selective loss of L2/3ENs were recapitulated in diverse mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability. Functions of Cux2 and activating transcription factor 4 (Atf4) were essential for resilience of L2/3ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double-strand break repair. Interferon-γ, a cytokine implicated in MS pathogenesis3,4, was sufficient to elevate levels of reactive oxygen species, leading to DNA damage-mediated neuronal death in vitro, and caused selective depletion of L2/3 neurons in mice. These findings indicate that DNA damage burden and inadequate repair in CUX2+ L2/3ENs contributes to selective vulnerability in neuroinflammatory injury.

Complex lattices that combine low- and high-order rotational symmetries underpin functional materials ranging from kagome superconductors1-3 to auxetic mechanical networks4 and photonic crystals with topologically protected states5-7. However, assembling such structures typically requires anisotropic particle shapes, directional bonding or fully imposed templates8-11, which often suffer from severe kinetic frustration and defect trapping. Here we introduce a dual-symmetry-guided (DSG) principle that exploits the geometric self-duality of a target tiling. By decomposing the structure into two mutually dual sublattices of lower symmetry and sparsely pinning only one sublattice using optical traps in a colloidal monolayer, the complementary sublattice spontaneously self-organizes through purely isotropic repulsive interactions, thereby reconstructing the full lattice. Using this minimal guidance strategy, we experimentally realize, and corroborate with simulations, a broad class of complex Archimedean lattices as well as two-dimensional quasicrystalline structures. DSG reveals lattice-dependent thermal stability while preserving interconnected free volume for mobile particles, enabling efficient defect relaxation and kinetically accessible assembly even under strong pinning conditions. We show that full pinning corresponds to a special limiting case of DSG, and that reformulating conventional templating protocols within the DSG framework systematically reduces kinetic barriers and suppresses defect formation. By decoupling structural complexity from interaction anisotropy, DSG provides a general and experimentally accessible route to complex-symmetry materials with programmable structural and physical properties.

Full-colour ultrahigh-resolution quantum dot light-emitting diodes (URQLEDs) with high efficiency and stability are required for next-generation near-eye displays1-3. However, existing quantum dot (QD) patterning techniques struggle to simultaneously achieve submicrometre pixel sizes, full-colour integration and high device performance. Here we report a dual-action force dynamics (DAFD) strategy using a hard silicon template as a nanoimprinting stamp, combined with integral inverted transfer printing. This approach enables red-green-blue (RGB) full-colour QD pixel arrays with densities in the range 9,072-25,400 pixels per inch (PPI), maintaining high-fidelity pattern replication with a conservative transfer yield >99.9%. The method is compatible with both CdSe/ZnS and perovskite QDs on rigid and flexible substrates. Beyond patterning, we identify and address a previously underappreciated bottleneck in ultrahigh-resolution devices-electric-field non-uniformity arising from pixel microstructures. Matching the dielectric constant of the leakage-current-blocking layer to that of the QDs by means of TiO2 nanoparticle incorporation yields a more uniform electric-field distribution, effectively suppressing edge effects and enhancing both efficiency and operational stability. Red URQLEDs at 12,700 PPI achieved a peak external quantum efficiency (EQE) of 26.1% and an operational lifetime T95@1,000 cd m-2 of 65,190 h. Comparable enhancements in device performance were obtained for green and blue URQLEDs, with EQE improvements of 124% and 119%, respectively. RGB-pixelated white URQLEDs reached a peak EQE of 10.1%. By integrating these URQLEDs with complementary metal-oxide-semiconductor (CMOS) integrated circuits, we demonstrated solution-processed active-matrix URQLED animated displays.

Tissue inflammation or nerve injury at the periphery can cause chronic pain. Although the spinal-cord-projecting neurons in the rostral ventromedial medulla (RVMSC neurons) can promote pain chronification1-4, the pathway by which peripheral injury signals drive these neurons is poorly understood1-3,5. Here we report a circuit loop that extends from the spinal cord to the ventral posterolateral thalamus and posterior complex of the thalamus, proceeds to the primary somatosensory cortex and returns to the spinal cord via the lateral superior colliculus, which in turn connects to μ-opioid-receptor-expressing RVMSC neurons. Silencing any node along this multisynaptic circuit has minimal effects on nociception in healthy mice, but can eliminate mechanical hypersensitization and restore normal nociceptive response thresholds in mouse models of inflammatory and neuropathic pain. In healthy mice, repetitive-but not acute-activation of each node in this circuit is sufficient to cause robust chronic mechanical hypersensitization. Our findings reveal a spino-brain-spinal cord circuit loop that links ascending and descending pathways and specifically drives chronic mechanical pain. This could enable the identification of cellular targets for treating chronic pain.

Stellar theory predicts a forbidden range of black-hole masses between approximately 50 M⊙ and 130 M⊙ owing to pair-instability supernovae1-7, but evidence for such a gap in the mass distribution from gravitational-wave astronomy has proved elusive. Early hints of a cut-off in black-hole masses at about 45 M⊙ disappeared with the subsequent discovery of more massive binary black holes8,9. Here we report evidence of the pair-instability gap in LIGO-Virgo-KAGRA's fourth Gravitational-Wave Transient Catalog (GWTC-4), with a lower boundary of 44-4+5M⊙ (90% credibility). Although the gap is not present in the distribution of primary masses m1 (the bigger of the two black holes in a binary system), it appears unambiguously in the distribution of secondary masses m2, in which m2 ≤ m1. The location of the gap lines up well with a previously identified transition in the binary black-hole spin distribution; binaries with primary components in the gap tend to spin more rapidly than those below the gap. We interpret these findings as evidence for a subpopulation of hierarchical mergers: binaries in which the primary component is the product of a previous black-hole merger and thus populates the gap. Our measurement of the location of the pair-instability gap constrains the S-factor for 12C(α, γ)16O at 300 keV to 260-108+190keVbarns .

Recent observations of superconductivity in twisted bilayer WSe2 (refs. 1,2) have extended the family of moiré superconductors beyond twisted graphene3-15. In WSe2, two different twist angles were studied, 3.65° (ref. 1) and 5.0° (ref. 2), and two seemingly distinct superconducting phase diagrams were reported, raising the question of whether the superconducting phases in the two devices share a similar origin. Here we address the question by experimentally mapping the evolution of the phase diagram across devices with twist angles spanning the range defined by the initial reports and comparing the results to twist angle-dependent theory. We find that the superconducting state evolves smoothly with twist angle and at all twist angles is proximal to a Fermi surface reconstruction with, presumably, antiferromagnetic ordering, but is neither necessarily tied to the Van Hove singularity nor to the half-band insulator. Our results connect the previously distinct phase diagrams at 3.65° and 5°, and offer new insight into the origin of the superconductivity in this system and its evolution as the correlation strength increases. More broadly, the smooth phase diagram evolution, repeatability between different devices and dynamic gate tunability within each device establish twisted transition metal dichalcogenides as a unique platform for the study of correlated phases as the ratio of interaction strength to bandwidth is varied.

Pangenomes are revolutionizing our ability to resolve genomic regions with complex variations1. However, existing human pangenomes2,3, constrained by small sample sizes, provide limited utility for medical and population genetic applications. Here we generated 1,116 diploid genome assemblies (55 de novo and 1,061 pangenome-informed) with an average size of 2.98 Gb and a mean quality value of 46 as part of the 1000 Chinese Pangenome (1KCP) project. On the basis of these assemblies, we constructed a pangenome comprising 405.3 million base pairs of sequences absent from the current references GRCh38 and CHM13, including 26.2 million base pairs of functional genic and predicted regulatory elements. We catalogued a full spectrum of genetic variation, including 35.4 million small variants, 110,530 structural variants (SVs), 485,575 tandem repeats (TRs) and 0.86 million nested variants embedded in non-reference sequences. This extensive dataset enabled detailed characterization of multiscale genic variations relevant to medical genetics, including gene-altering SVs, TR expansions, gene cluster variations and HLA gene haplotypes. Coupled with the 1KCP gene expression data, we conducted pan-variant expression quantitative trait locus (eQTL) mapping to analyse diverse variant types. We identified 3,256 eQTLs involving complex variants (SVs, TRs and nested variants) and elucidated their regulatory complexity. Finally, we developed a 1KCP pan-variant imputation reference panel, which provides multitype genetic markers to enhance the resolution of future association studies. This resource advances our understanding of complex variants and their functional implications to provide new insights into human health.

Iron-based superconductors (FeSCs) are a fascinating family of materials in which several electronic bands and strong antiferromagnetic (AFM) correlations are key ingredients for competing ground states1-6, including antiferromagnetism, electronic nematicity and unconventional superconductivity. FeTe, unlike its superconducting isostructural counterpart FeSe, has long been considered an AFM metal sans superconductivity7-9. Here we use molecular-beam epitaxy (MBE) to grow FeTe films and perform post-growth annealing under a Te flux. By performing spin-polarized scanning tunnelling microscopy and spectroscopy (STM/S), we demonstrate that the AFM order in as-grown FeTe films is induced by interstitial Fe atoms that disrupt the ideal 1:1 stoichiometry. Notably, the removal of these interstitial Fe atoms through Te annealing yields stoichiometric FeTe films that show no AFM order and instead exhibit robust superconductivity with a critical temperature of about 13.5 K. This superconducting state is further confirmed by the observation of Cooper-pair tunnelling, zero electrical resistance and the Meissner effect. Therefore, our results demonstrate that stoichiometric FeTe is inherently a superconductor, overturning a long-held view that it is an AFM metal. This work clarifies the origin of superconductivity in FeTe-based heterostructures10-15 and demonstrates the importance of stoichiometry control in understanding the competition between antiferromagnetism and superconductivity in FeSCs.

The detection of internal chemicals by interoceptive chemosensory pathways is critical for regulating metabolism and physiology1. The molecular identities of interoceptors, and the functional consequences of chemosensation by specific interoceptive neurons, remain to be fully described. The pharyngeal neuronal network of Caenorhabditis elegans is anatomically and functionally analogous to the mammalian enteric nervous system2,3. Here we show that the I3 pharyngeal enteric neuron responds to cations via an I3-specific ionotropic receptor to regulate salt stress tolerance. The GLR-9 ionotropic receptor and the GLR-7 IR25a co-receptor orthologue localize to the gut lumen-exposed sensory ending of I3, and are necessary and sufficient for salt sensation. Salt detection by I3 protects specifically against high-salt stress, as glr-9 mutants show reduced tolerance of hypertonic salt but not of sugar solutions, with or without prior acclimatization. Whereas cholinergic signalling from I3 promotes tolerance of acute high-salt stress, peptidergic signalling from I3 during acclimatization is essential for resistance to a subsequent high-salt challenge. Transcriptomic and reporter gene analyses show that I3 modulates salt tolerance in part by regulating the expression of salt stress response genes in distal tissues. Correspondingly, mutations in a subset of salt- and GLR-9-regulated genes reduce salt stress resistance. Our results describe the mechanisms by which chemosensation mediated by a defined enteric neuron regulates physiological homeostasis in response to a specific abiotic stress.

Cellular diversity is governed not only by the transcriptome but also by multiple layers of epigenomic regulation, including nucleosome occupancy, chromatin states and genome architecture1-3. Here, to comprehensively understand how these regulatory modalities converge to shape cellular identity, we developed a single-cell four-omics sequencing method that enables parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression within the same cell (CHARM). Applying CHARM to mouse embryonic stem cells and cortical tissues, we reconstructed integrated epigenome profiles, uncovering distinct cell-cycle dynamics of chromatin accessibility and histone modification, and spatial clustering of regulatory elements in three-dimensional nuclear space. Leveraging an interpretable machine learning model, we further identified thousands of enhancer-promoter linkages with high accuracy that modulate gene expression in a cell-type- and subtype-specific manner. Together, CHARM enables integrative dissection of the three-dimensional epigenome at single-cell resolution, providing a versatile platform for decoding the regulatory landscape across diverse cells in complex tissues.

Chelicerata is a megadiverse (over 120,000 species) arthropod clade that includes familiar taxa of profound ecological and economic importance, such as scorpions, spiders and mites1. Extant chelicerates share a unique anatomical character, the chelicerae-feeding first appendages terminated by a simple pincer-like chela2. The fossil record of these primarily predatory animals spans almost 500 million years3, suggesting a likely yet undocumented origin during the Cambrian Explosion. Artiopods4-6, megacheirans4,7-9, habeliids10-13 and mollisoniids14,15 have been considered Cambrian stem- or crown-group chelicerates, but they all lack unequivocal chelicerae, leaving the emergence of chelicerae-bearing arthropods unclear. Here we describe Megachelicerax cousteaui gen. et sp. nov., a large soft-bodied arthropod from the middle Cambrian of Utah featuring massive three-segmented chelicerae, along with five pairs of pseudobiramous prosomal limbs with non-foliaceous exopodal rami, and plate-like lamellae-bearing opisthosomal appendages. Bayesian and parsimony phylogenetic analyses resolve Megachelicerax as a stem-group chelicerate bridging Cambrian habeliids and post-Cambrian chelicerae-bearing synziphosurines. This finding provides unequivocal evidence of large predatory chelicerates in the Cambrian, illuminates their body plan's origin, and confirms habeliids, mollisoniids and probably megacheirans as members of total-group Chelicerata.

The seventh pandemic of cholera, caused by the seventh pandemic El Tor lineage of Vibrio cholerae, was previously shown to have emanated in three global waves from the Bay of Bengal, bordering Bangladesh and India1. However, the respective roles of the Ganges Delta and Basin regions in seeding these global pandemic waves were not known. Here we show that, although transmission events occur between Bangladesh and India, V. cholerae in the two countries has largely evolved separately over the past 20 years, apparently constrained by national borders rather than by hydrological features, such as the Ganges Delta and Basin. Evolution within Bangladesh was distinct from that seen in India, involving rapid gain and loss of genes and mobile genetic elements, particularly those involved in phage defence. The loss of these systems was associated with increased risk of severe disease and transmission outside Bangladesh. Lineage replacement in Bangladesh in 2018, resulting in a major change in phage defence systems, was accompanied by a rapid change in the lineage and anti-defence system of lytic phage ICP1. Here we show that the Ganges Basin, falling across Bangladesh and Northern India, rather than the Ganges Delta, probably acts as a global launch pad for pandemic disease. This shifts our understanding of Bangladesh as the purported global source of cholera and underscores the potential role of phage in controlling spread of lineages within the current seventh pandemic.

Cooper-pair density modulation (CPDM) states are superconducting phases in which the order parameter varies periodically in real space without breaking translational symmetry1-3. Moiré superlattices in layered materials4-18 have recently emerged as powerful platforms for engineering charge density with tunable lattice symmetry, offering a new route to creating and controlling CPDM states. Here we demonstrate moiré-induced CPDM states in a bilayer heterostructure formed by epitaxially stacking one quintuple layer (1QL) of topological insulator Sb2Te3 on a six-unit-cell (6UC) antiferromagnetic FeTe layer. Scanning tunnelling microscopy and spectroscopy (STM/S) measurements reveal a moiré superlattice formed between the hexagonal tellurium lattice of Sb2Te3 and the square tellurium lattice of FeTe, which spatially modulates the two superconducting gaps of the 1QL Sb2Te3/6UC FeTe bilayer. Our Josephson STM/S measurements provide direct real-space imaging of the CPDM states with a wavelength corresponding to the periodicity of the moiré superlattice. By substituting Sb2Te3 with Bi2Te3, we achieve control over both the periodicity and magnitude of the CPDM states. Our work demonstrates an epitaxial strategy for synthesizing moiré superlattices from materials with different crystal symmetries and reveals a new mechanism for engineering CPDM states in designer bilayer heterostructures.

Dynamic assembly of the complex I signalosome mediated by three death domain (DD)-containing proteins-TNFR1, TRADD and RIPK1-is key for transmitting extracellular TNF stimuli to intracellular NF-κB signalling in controlling 'live or die' cell fate1. This signalling hub features the rapid recruitment of TRADD and RIPK1 after engagement of TNFR1 by TNF for the formation of complex I, followed by timed disassembly for transition into downstream signalling complexes2,3, but the mechanism driving the dynamic reversibility of complex I remains unclear. Here we captured the assembly core of complex I and determined its cryo-electron microscopy structure, showing a pentameric fibre comprising 31 DDs, with a single layer of a TRADD-DD pentamer sandwiched between multiple layers of TNFR1-DD and RIPK1-DD homopentamers. Structural analysis revealed a strong opposing electric dipole moment (EDM) generated by RIPK1-DD oligomerization relative to that of TNFR1-DD and TRADD-DD. Structure-guided mutagenesis in TNFR1-TRADD-RIPK1 pentameric fibres altering the EDM without affecting DD oligomerization demonstrated the role and mechanism of EDM in driving the dynamic reversibility mediating the rapid assembly and disassembly of complex I. Our study demonstrates a role for long-range interactions mediated by protein EDMs in driving the assembly and disassembly of super-signalling complex I for promoting NF-κB signalling.

Myelin sheaths made by oligodendrocytes in the central nervous system (CNS) are critical to circuit function and neural health. The distribution of these insulating sheaths varies substantially between brain regions1, neuron subtypes2 and individual axons3-5, but the mechanisms that control this patterning are poorly understood. Although previous studies suggested that each oligodendrocyte process generates a single myelin sheath, this mode of axon ensheathment severely constrains myelination along highly branched axons within complex circuits6. Here we find that axon ensheathment by individual myelinating processes in zebrafish and mouse proceeds at different rates along axons. This enables a single oligodendrocyte process to extend past axon branch points and nodes of Ranvier before ensheathment, resulting in the formation of chains of myelin sheaths connected by thin cytoplasmic processes. In the cerebral cortex, these 'paranodal bridges' expand the myelin territory produced by individual oligodendrocytes along the highly branched axons of parvalbumin interneurons. Although flexible ensheathment reduces the need for oligodendrocytes, terminal sheaths in myelin chains degenerated more frequently in the aged brain, suggesting that they are more vulnerable to cellular and environmental stress and disproportionally contribute to myelin loss.