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.

Metal-halide perovskites are promising light-emitter candidates for next-generation light-emitting diodes (LEDs)1-8. Achieving high brightness and efficiency simultaneously in pure-red perovskite LEDs (PeLEDs) is an ongoing goal9,10. Three-dimensional (3D) CsPbI3-xBrx emitters have excellent carrier transport capability and high colour purity, which could allow efficient and ultrabright pure-red PeLEDs. However, such devices are prone to efficiency roll-off, resulting in low efficiency and low brightness under high current density. Here, by using electrically excited transient absorption spectroscopy, we discovered the efficiency roll-off was induced by hole leakage. Therefore, we developed a CsPbI3-xBrx intragrain heterostructure containing narrow bandgap emitters and wide bandgap barriers to confine the injected carriers. The wide bandgap barrier was incorporated by introducing strongly bonding molecules into the [PbX6]4- framework to expand the 3D CsPbI3-xBrx lattice. This strategy resulted in bright and efficient pure-red PeLEDs, with a high brightness of 24,600 cd m-2, maximum external quantum efficiency of 24.2% and low efficiency roll-off, maintaining a 10.5% external quantum efficiency at a high luminance of 22,670 cd m-2.

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.

The relative twist angle between layers of near-lattice-matched van der Waals materials is critical for the emergent phenomena associated with moiré flat bands1-3. However, the concept of angle rotation control is not exclusive to moiré superlattices in which electrons directly experience a twist-angle-dependent periodic potential. Instead, it can also be used to induce programmable symmetry-breaking perturbations with the goal of stabilizing desired correlated states. Here we experimentally demonstrate 'moiréless' twist-tuning of superconductivity together with other correlated orders in Bernal bilayer graphene proximitized by tungsten diselenide. The precise alignment between the two materials systematically controls the strength of induced Ising spin-orbit coupling (SOC), profoundly altering the phase diagram. As Ising SOC is increased, superconductivity onsets at a higher displacement field and features a higher critical temperature, reaching up to 0.5 K. Within the main superconducting dome and in the strong Ising SOC limit, we find an unusual phase transition characterized by a nematic redistribution of holes among trigonally warped Fermi pockets and enhanced resilience to in-plane magnetic fields. The superconducting behaviour is theoretically compatible with the prominent role of interband interactions between symmetry-breaking Fermi pockets. Moreover, we identify two additional superconducting regions, one of which descends from an inter-valley coherent normal state and shows a Pauli-limit violation ratio exceeding 40, among the highest for all known superconductors4-7. Our results provide insights into ultraclean graphene superconductors and underscore the potential of utilizing moiréless-twist engineering across a wide range of van der Waals heterostructures.

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.

Methane is an important greenhouse gas1 and its atmospheric concentration has almost tripled since pre-industrial times2-4. Atmospheric methane mixing ratios vary seasonally, with the seasonal cycle amplitude (SCA) having decreased in northern high latitudes and increased in the subtropics and tropics since the 1980s5,6. These opposing SCA trends can help understanding of long-term changes in the global methane budget, as methane emissions and sinks have opposing effects on the SCA5. However, trends in the methane SCA have not yet been explored in detail5,6. Here we use a suite of atmospheric transport model simulations and attribute the observed trends in the seasonal amplitude of methane to changes in emissions and the atmospheric sink from reaction with the hydroxyl radical (OH). We find that the decreasing amplitude in the northern high latitudes is mainly caused by an increase in natural emissions (such as wetlands) owing to a warmer climate, adding evidence to previous studies suggesting a positive climate feedback7-9. In contrast, the enhanced methane amplitude in the subtropics and tropics is mainly attributed to strengthened OH oxidation. Our results provide independent evidence for an increase in tropospheric OH concentration10,11 of 10 ± 1% since 1984, which together with an increasing atmospheric methane concentration suggests a 21 ± 1% increase in the atmospheric methane sink.

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.

The primary motor cortex (M1) is central for the learning and execution of dexterous motor skills1-3, and its superficial layer (layers 2 and 3; hereafter, L2/3) is a key locus of learning-related plasticity1,4-6. It remains unknown how motor learning shapes the way in which upstream regions activate M1 circuits to execute learned movements. Here, using longitudinal axonal imaging of the main inputs to M1 L2/3 in mice, we show that the motor thalamus is the key input source that encodes learned movements in experts (animals trained for two weeks). We then use optogenetics to identify the subset of M1 L2/3 neurons that are strongly driven by thalamic inputs before and after learning. We find that the thalamic influence on M1 changes with learning, such that the motor thalamus preferentially activates the M1 neurons that encode learned movements in experts. Inactivation of the thalamic inputs to M1 in experts impairs learned movements. Our study shows that motor learning reshapes the thalamic influence on M1 to enable the reliable execution of learned movements.

Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge in paediatric neuro-oncology1. Bulk-omics approaches have identified considerable intertumoural heterogeneity in group 3/4 medulloblastoma, including the presence of clear single-gene oncogenic drivers in only a subset of cases, whereas in most cases, large-scale copy number aberrations prevail2,3. However, intratumoural heterogeneity, the role of oncogene aberrations, and broad copy number variation in tumour evolution and treatment resistance remain poorly understood. To dissect this interplay, we used single-cell technologies (single-nucleus RNA sequencing (snRNA-seq), single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing (snATAC-seq) and spatial transcriptomics) on a cohort of group 3/4 medulloblastoma with known alterations in the oncogenes MYC, MYCN and PRDM6. We show that large-scale chromosomal aberrations are early tumour-initiating events, whereas the single-gene oncogenic events arise late and are typically subclonal, but MYC can become clonal upon disease progression to drive further tumour development and therapy resistance. Spatial transcriptomics shows that the subclones are mostly interspersed across tumour tissue, but clear segregation is also present. Using a population genetics model, we estimate medulloblastoma initiation in the cerebellar unipolar brush cell lineage starting from the first gestational trimester. Our findings demonstrate how single-cell technologies can be applied for early detection and diagnosis of this fatal disease.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis1. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2-4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work5. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron-fentomycin-1-to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states10.

As the primary source of noradrenaline in the brain, the locus coeruleus (LC) regulates arousal, avoidance and stress responses1,2. However, how local neuromodulatory inputs control LC function remains unresolved. Here we identify a population of transcriptionally, spatially and functionally diverse GABAergic (γ-aminobutyric acid-producing) neurons in the LC dendritic field that receive distant inputs and modulate modes of LC firing to control global arousal levels and arousal-related processing and behaviours. We define peri-LC anatomy using viral tracing and combine single-cell RNA sequencing with spatial transcriptomics to molecularly define both LC noradrenaline-producing and peri-LC cell types. We identify several neuronal cell types that underlie peri-LC functional diversity using a series of complementary neural circuit approaches in behaving mice. Our findings indicate that LC and peri-LC neurons are transcriptionally, functionally and anatomically heterogenous neuronal populations that modulate arousal and avoidance states. Defining the molecular, cellular and functional diversity of the LC and peri-LC provides a roadmap for understanding the neurobiological basis of arousal, motivation and neuropsychiatric disorders.

In bilaterian animals, gene regulation is shaped by a combination of linear and spatial regulatory information. Regulatory elements along the genome are integrated into gene regulatory landscapes through chromatin compartmentalization1,2, insulation of neighbouring genomic regions3,4 and chromatin looping that brings together distal cis-regulatory sequences5. However, the evolution of these regulatory features is unknown because the three-dimensional genome architecture of most animal lineages remains unexplored6,7. To trace the evolutionary origins of animal genome regulation, here we characterized the physical organization of the genome in non-bilaterian animals (sponges, ctenophores, placozoans and cnidarians)8,9 and their closest unicellular relatives (ichthyosporeans, filastereans and choanoflagellates)10 by combining high-resolution chromosome conformation capture11,12 with epigenomic marks and gene expression data. Our comparative analysis showed that chromatin looping is a conserved feature of genome architecture in ctenophores, placozoans and cnidarians. These sequence-determined distal contacts involve both promoter-enhancer and promoter-promoter interactions. By contrast, chromatin loops are absent in the unicellular relatives of animals. Our findings indicate that spatial genome regulation emerged early in animal evolution. This evolutionary innovation introduced regulatory complexity, ultimately facilitating the diversification of animal developmental programmes and cell type repertoires.

The hippocampus1-6, as well as dopamine circuits7-9, coordinates decision-making in anxiety-eliciting situations. Yet, little is known about how dopamine modulates hippocampal representations of emotionally salient stimuli to inform appropriate resolution of approach versus avoidance conflicts. Here we studied dopaminoceptive neurons in the male mouse ventral hippocampus (vHipp), molecularly distinguished by their expression of dopamine D1 or D2 receptors. We show that these neurons are transcriptionally distinct and topographically organized across vHipp subfields and cell types. In the ventral subiculum where they are enriched, both D1 and D2 neurons are recruited during anxiogenic exploration, yet with distinct profiles related to investigation and behavioural selection. In turn, they mediate opposite approach-avoidance responses, and are differentially modulated by dopaminergic transmission in that region. Together, these results suggest that vHipp dopamine dynamics gate exploratory behaviours under contextual uncertainty, implicating dopaminoception in the complex computation engaged in the vHipp to govern emotional states.

Animals learn to carry out motor actions in specific sensory contexts to achieve goals. The striatum has been implicated in producing sensory-motor associations1, yet its contributions to memory formation and recall are not clear. Here, to investigate the contribution of the striatum to these processes, mice were taught to associate a cue, consisting of optogenetic activation of striatum-projecting neurons in visual cortex, with the availability of a food pellet that could be retrieved by forelimb reaching. As necessary to direct learning, striatal neural activity encoded both the sensory context and the outcome of reaching. With training, the rate of cued reaching increased, but brief optogenetic inhibition of striatal activity arrested learning and prevented trial-to-trial improvements in performance. However, the same manipulation did not affect performance improvements already consolidated into short-term (less than 1 h) or long-term (days) memories. Hence, striatal activity is necessary for trial-to-trial improvements in performance, leading to plasticity in other brain areas that mediate memory recall.

Graphene and transition metal dichalcogenide flat-band systems show similar phase diagrams, replete with magnetic1-5 and superconducting6-11 phases. An abiding question has been whether magnetic ordering competes with superconductivity or facilitates pairing. For example, recent studies of Bernal bilayer graphene in the presence of enhanced spin-orbit coupling show a substantial increase in the observed domain and critical temperature Tc of superconducting states12-14; however, the mechanism for this enhancement remains unknown. Here we show that introducing spin-orbit coupling in rhombohedral trilayer graphene (RTG) by substrate proximity effect generates new superconducting pockets for both electron and hole doping, with maximal Tc ≈ 300 mK, which is three times larger than in RTG encapsulated by hexagonal boron nitride. Using local magnetometry, we show that superconductivity straddles a transition between a spin-canted state with a finite in-plane magnetic moment and a state with complete spin-valley locking. This transition is reproduced in our Hartree-Fock calculations, in which this transition is driven by the competition between spin-orbit coupling and the carrier-density-tuned Hund's interaction. Our experiment suggests that the enhancement of superconductivity by spin-orbit coupling is driven by a quantitative change in the canting angle rather than a change in the ground state symmetry. These results align with a recently proposed mechanism for the enhancement of superconductivity15, in which fluctuations in the spin-canting order contribute to the pairing interaction.