Aside from movement initiation and control, the primary motor cortex (M1) has been implicated in pain modulation mechanisms. A large body of clinical data has demonstrated that stimulation and behavioral activation of M1 result in clinically important pain relief in patients with specific chronic pain syndromes. However, despite its clinical importance, the full range of circuits for motor cortex-related analgesia (MCRA) remains an enigma. This review draws on insights from experimental and clinical data and provides an overview of the neurobiological mechanisms of MCRA, with particular emphasis on its neurocircuitry basis. Based on structural and functional connections of the M1 within the pain connectome, neural circuits for MCRA are discussed at different levels of the neuroaxis, specifically, the endogenous pain modulation system, the thalamus, the extrapyramidal system, non-noxious somatosensory systems, and cortico-limbic pain signatures. We believe that novel insights from this review will expedite our understanding of M1-induced pain modulation and offer hope for successful mechanism-based refinements of this interventional approach in chronic pain management.

Hilbert space dimension is a key resource for quantum information processing1,2. Not only is a large overall Hilbert space an essential requirement for quantum error correction, but a large local Hilbert space can also be advantageous for realizing gates and algorithms more efficiently3-7. As a result, there has been considerable experimental effort in recent years to develop quantum computing platforms using qudits (d-dimensional quantum systems with d > 2) as the fundamental unit of quantum information8-19. Just as with qubits, quantum error correction of these qudits will be necessary in the long run, but so far, error correction of logical qudits has not been demonstrated experimentally. Here we report the experimental realization of an error-corrected logical qutrit (d = 3) and ququart (d = 4), which was achieved with the Gottesman-Kitaev-Preskill bosonic code20. Using a reinforcement learning agent21,22, we optimized the Gottesman-Kitaev-Preskill qutrit (ququart) as a ternary (quaternary) quantum memory and achieved beyond break-even error correction with a gain of 1.82 ± 0.03 (1.87 ± 0.03). This work represents a novel way of leveraging the large Hilbert space of a harmonic oscillator to realize hardware-efficient quantum error correction.

When two massive objects (black holes, neutron stars or stars) in our universe fly past each other, their gravitational interactions deflect their trajectories1,2. The gravitational waves emitted in the related bound-orbit system-the binary inspiral-are now routinely detected by gravitational-wave observatories3. Theoretical physics needs to provide high-precision templates to make use of unprecedented sensitivity and precision of the data from upcoming gravitational-wave observatories4. Motivated by this challenge, several analytical and numerical techniques have been developed to approximately solve this gravitational two-body problem. Although numerical relativity is accurate5-7, it is too time-consuming to rapidly produce large numbers of gravitational-wave templates. For this, approximate analytical results are also required8-15. Here we report on a new, highest-precision analytical result for the scattering angle, radiated energy and recoil of a black hole or neutron star scattering encounter at the fifth order in Newton's gravitational coupling G, assuming a hierarchy in the two masses. This is achieved by modifying state-of-the-art techniques for the scattering of elementary particles in colliders to this classical physics problem in our universe. Our results show that mathematical functions related to Calabi-Yau (CY) manifolds, 2n-dimensional generalizations of tori, appear in the solution to the radiated energy in these scatterings. We anticipate that our analytical results will allow the development of a new generation of gravitational-wave models, for which the transition to the bound-state problem through analytic continuation and strong-field resummation will need to be performed.

The pressures humanity has been placing on the environment have put Earth's stability at risk. The planetary boundaries framework serves as a method to define a 'safe operating space for humanity'1,2 and has so far been applied mostly to highlight the currently prevailing unsustainable environmental conditions. The ability to evaluate trends over time, however, can help us explore the consequences of alternative policy decisions and identify pathways for living within planetary boundaries3. Here we use the Integrated Model to Assess the Global Environment4 to project control variables for eight out of nine planetary boundaries under alternative scenarios to 2050, both with and without strong environmental policy measures. The results show that, with current trends and policies, the situation is projected to worsen to 2050 for all planetary boundaries, except for ozone depletion. Targeted interventions, such as implementing the Paris climate agreement, a shift to a healthier diet, improved food, and water- and nutrient-use efficiency, can effectively reduce the degree of transgression of the planetary boundaries, steering humanity towards a more sustainable trajectory (that is, if they can be implemented based on social and institutional feasibility considerations). However, even in this scenario, several planetary boundaries, including climate change, biogeochemical flows and biodiversity, will remain transgressed in 2050, partly as result of inertia. This means that more-effective policy measures will be needed to ensure we are living well within the planetary boundaries.

Based on seminal work in placental species (eutherians)1-10, a paradigm of mammalian development has emerged wherein the genome-wide erasure of parental DNA methylation is required for embryogenesis. Whether such DNA methylation reprogramming is, in fact, conserved in other mammals is unknown. Here, to resolve this point, we generated base-resolution DNA methylation maps in gametes, embryos and adult tissues of a marsupial, the opossum Monodelphis domestica, revealing variations from the eutherian-derived model. The difference in DNA methylation level between oocytes and sperm is less pronounced than that in eutherians. Furthermore, unlike the genome of eutherians, that of the opossum remains hypermethylated during the cleavage stages. In the blastocyst, DNA demethylation is transient and modest in the epiblast. However, it is sustained in the trophectoderm, suggesting an evolutionarily conserved function for DNA hypomethylation in the mammalian placenta. Furthermore, unlike that in eutherians, the inactive X chromosome becomes globally DNA hypomethylated during embryogenesis. We identify gamete differentially methylated regions that exhibit distinct fates in the embryo, with some transient, and others retained and that represent candidate imprinted loci. We also reveal a possible mechanism for imprinted X inactivation, through maternal DNA methylation of the Xist-like noncoding RNA RSX11. We conclude that the evolutionarily divergent eutherians and marsupials use DNA demethylation differently during embryogenesis.

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.

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.

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.

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.

Beginning with Edward Jenner's discovery of the smallpox vaccine, the ever-expanding repertoire of vaccines against pathogens has saved many lives. During the COVID-19 pandemic, a revolutionary mRNA injectable vaccine emerged that effectively controlled the severity of disease caused by SARS-CoV-2. This vaccine induced potent antigen-specific neutralizing serum IgG antibodies, but was limited in its ability to prevent viral invasion at the respiratory surfaces. Nasal vaccines have attracted attention as a potential strategy to combat respiratory infections and prepare for future pandemics. Input from disciplines such as microbiology, biomaterials, bioengineering and chemistry have complemented the immunology to create innovative delivery systems. This approach to vaccine delivery has yielded nasal vaccines that induce secretory IgA as well as serum IgG antibodies, which are expected to prevent pathogen invasion, thereby diminishing transmission and disease severity. For a nasal vaccine to be successful, the complexity of the relevant anatomical, physiological and immunological properties, including the proximity of the central nervous system to the nasal cavity, must be considered. In this Review, we discuss past and current efforts as well as future directions for developing safe and effective nasal vaccines for the prevention of respiratory infections.

Climate extremes are escalating under anthropogenic climate change1. Yet, how this translates into unprecedented cumulative extreme event exposure in a person's lifetime remains unclear. Here we use climate models, impact models and demographic data to project the number of people experiencing cumulative lifetime exposure to climate extremes above the 99.99th percentile of exposure expected in a pre-industrial climate. We project that the birth cohort fraction facing this unprecedented lifetime exposure to heatwaves, crop failures, river floods, droughts, wildfires and tropical cyclones will at least double from 1960 to 2020 under current mitigation policies aligned with a global warming pathway reaching 2.7 °C above pre-industrial temperatures by 2100. Under a 1.5 °C pathway, 52% of people born in 2020 will experience unprecedented lifetime exposure to heatwaves. If global warming reaches 3.5 °C by 2100, this fraction rises to 92% for heatwaves, 29% for crop failures and 14% for river floods. The chance of facing unprecedented lifetime exposure to heatwaves is substantially larger among population groups characterized by high socioeconomic vulnerabilities. Our results call for deep and sustained greenhouse gas emissions reductions to lower the burden of climate change on current young generations.

Activating mutations in the rat sarcoma (RAS) genes HRAS, NRAS and KRAS collectively represent the most frequent oncogenic driver in human cancer1. They have previously been considered undruggable, but advances in the past few years have led to the clinical development of agents that target KRAS(G12C) and KRAS(G12D) mutants, yielding promises of therapeutic responses at tolerated doses2. However, clinical agents that selectively target NRAS(Q61*) mutants (* represents 'any'), the second-most-frequent oncogenic driver in melanoma, are still lacking. Here we identify SHOC2, a component of the SHOC2-MRAS-PP1C complex, as a dependency of RAS(Q61*) tumours in a nucleotide-state-dependent and isoform-agnostic manner. Mechanistically, we found that oncogenic NRAS(Q61R) forms a direct interaction with SHOC2, evidenced by X-ray co-crystal structure. In vitro high-throughput screening enabled the discovery of small molecules that bind to SHOC2 and disrupt the interaction with NRAS(Q61*). Structure-based optimization led to a cellularly active tool compound that shows inhibition of mitogen-activated protein kinase (MAPK) signalling and proliferation in RAS-mutant cancer models, most notably in NRAS(Q61*) settings. These findings provide evidence for a neomorph SHOC2-(canonical)RAS protein interaction that is pharmacologically actionable and relevant to cancer sustenance. Overall, this work provides the concept validation and foundation for developing new therapies at the core of the RAS signalling pathway.

Lysosomes catabolize lipids and other biological molecules, maintaining cellular and organismal homeostasis. Bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles, stimulates lipid-degrading enzymes and is altered in various human conditions, including neurodegenerative diseases1,2. Although lysosomal BMP synthase was recently discovered3, the enzymes mediating BMP turnover remain elusive. Here we show that lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that the resistance of BMP to lysosomal hydrolysis arises from its unique sn2, sn2' esterification position and stereochemistry, as neither feature alone confers resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes. Furthermore, PLA2G15 efficiently hydrolyses synthesized BMP stereoisomers with primary esters, challenging the long-held thought that BMP stereochemistry alone ensures resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate several BMP species, a phenotype reversible by supplementing wild-type PLA2G15 but not its inactive mutant. Targeting PLA2G15 reduces the cholesterol accumulation in fibroblasts of patients with Niemann-Pick disease type C1 and significantly ameliorates disease pathologies in Niemann-Pick disease type C1-deficient mice, leading to an extended lifespan. Our findings established the rules governing BMP stability in lysosomes and identified PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases.

Entrainment is a process in schooling migratory fish whereby routes to suitable habitats are transferred from repeat spawners to recruits over generations through social learning1. Selective fisheries targeting older fish may therefore result in collective memory loss and disrupted migration culture2. The world's largest herring (Clupea harengus) population has traditionally migrated up to 1,300 km southward from wintering areas in northern Norwegian waters to spawn at the west coast. This conservative strategy is proposed to be a trade-off between high energetic swimming costs and enhanced larval survival under improved growth conditions3. Here an analysis of extensive data from fisheries, scientific surveys and tagging experiments demonstrates an abrupt approximately 800-km poleward shift in main spawning. The new migration was established by a large cohort recruiting when the abundance of older fish was critically low due to age-selective fisheries. The threshold of memory required for cultural transfer was probably not met-a situation that was further exacerbated by reduced spatiotemporal overlap between older fish and recruits driven by migration constraints and climate change. Finally, a minority of survivors from older generations adopted the migration culture from the recruits instead of the historically opposite. This may have profound consequences for production and coastal ecology, challenging the management of migratory schooling fish.