Brain clocks track the deviations between predicted brain age and chronological age (brain age gaps, BAGs). These BAGs can be used to measure accelerated aging, monitoring deviations from the healthy brain trajectories associated with brain diseases and different cumulative burdens. However, the underlying biophysical mechanisms associated with BAGs in aging and dementia remain unclear. Here, we combine source space connectivity (EEG) with generative brain modeling in healthy controls (HCs) from the global south and north, alongside Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) patients (N=1,399). BAGs in aging were influenced by geography (south>north), income (low>high), sex (female>male), and education (low>high), with larger BAGs in patients, especially females with AD. Biophysical modeling revealed BAGs related to hyperexcitability and structural disintegration in aging, while hypoexcitability and severe disintegration were linked to dementia. Our work sheds light on the biophysical mechanisms of accelerated aging and dementia in diverse populations.

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.