The basal ganglia are fundamental to motor control and their dysfunction is linked to motor deficits1-8. Influential investigations on the primate oculomotor system posited that movement generally depends on transient pauses of tonically firing inhibitory basal ganglia output neurons releasing brainstem motor centres9,10. However, prominent increases in basal ganglia output neuron firing observed during other motor tasks cast doubts on the proposed mechanisms of movement regulation through basal ganglia circuitry11-22. Here we show that basal ganglia output neurons in the mouse substantia nigra pars reticulata (SNr) represent complex forelimb movements with highly granular and dynamic changes in spiking activity, tiling task execution at the population level. Single SNr neurons exhibit movement-specific firing pauses as well as increases, each occurring in concert with precise and different forelimb movements. Combining optogenetics and simultaneous recordings from basal ganglia output and postsynaptic brainstem neurons, we reveal the functional role of these dynamic firing-rate changes in releasing and suppressing movement through downstream targets. Together, our results demonstrate the existence and function of highly specific and temporally precise movement representations in basal ganglia output circuitry. We propose a model in which basal ganglia output neurons fire dynamically to provide granular and bidirectional movement-specific signals for release and suppression of motor programs to downstream circuits.

The emergence of infectious diseases, particularly those caused by fungal pathogens, poses serious threats to public health, wildlife and ecosystem stability1. Host-fungus interactions and environmental factors have been extensively examined2-4. However, the role of genetic variability in pathogens is often less well-studied, even for diseases such as white-nose in bats, which has caused one of the highest disease-driven death tolls documented in nonhuman mammals5. Previous research on white-nose disease has primarily focused on variations in disease outcomes attributed to host traits or environmental conditions6-8, but has neglected pathogen variability. Here we leverage an extensive reference collection of 5,479 fungal isolates from 27 countries to reveal that the widespread causative agent is not a single species but two sympatric cryptic species, each exhibiting host specialization. Our findings provide evidence of recombination in each species, but significant genetic differentiation across their genomes, including differences in genome organization. Both species contain geographically differentiated populations, which enabled us to identify the species introduced to North America and trace its source population to a region in Ukraine. In light of our discovery of the existence of two cryptic species of the causative agent of white-nose disease, our research underscores the need to integrate the study of pathogen variability into comprehensive disease surveillance, management and prevention strategies. This holistic approach is crucial for enhancing our understanding of diseases and implementing effective measures to prevent their spread.

Specialized immune cells that reside in tissues orchestrate diverse biological functions by communicating with parenchymal cells1. The contribution of the innate immune compartment in the meninges and the central nervous system (CNS) is well-characterized; however, whether cells of the adaptive immune system reside in the brain and are involved in maintaining homeostasis is unclear2-4. Here we show that the subfornical organ (SFO) of the brain is a nucleus for parenchymal αβ T cells in the steady-state brain in both mice and humans. Using unbiased transcriptomics, we show that these extravascular T cells in the brain are distinct from meningeal T cells: they secrete IFNγ robustly and express tissue-residence proteins such as CXCR6, which are required for their retention in the brain and for normal adaptive behaviour. These T cells are primed in the periphery by the microbiome, and traffic from the white adipose and gastrointestinal tissues to the brain. Once established, their numbers can be modulated by alterations to either the gut microbiota or the composition of adipose tissue. In summary, we find that CD4 T cells reside in the brain at steady state and are anatomically concentrated in the SFO in mice and humans; that they are transcriptionally and functionally distinct from meningeal T cells; and that they secrete IFNγ to maintain CNS homeostasis through homeostatic fat-brain and gut-brain axes.

Self-recognition is a fundamental cellular process across evolution and forms the basis of neuronal self-avoidance1-4. Clustered protocadherin (cPcdh) proteins, which comprise a large family of isoform-specific homophilic recognition molecules, have a pivotal role in the neuronal self-avoidance that is required for mammalian brain development5-7. The probabilistic expression of different cPcdh isoforms confers unique identities on neurons and forms the basis for neuronal processes to discriminate between self and non-self5,6,8. Whether this self-recognition mechanism also exists in astrocytes remains unknown. Here we report that γC3, a specific isoform in the Pcdhγ family, is enriched in human and mouse astrocytes. Using genetic manipulation, we demonstrate that γC3 acts autonomously to regulate astrocyte morphogenesis in the mouse visual cortex. To determine whether γC3 proteins act by promoting recognition between processes of the same astrocyte, we generated pairs of γC3 chimeric proteins that are capable of heterophilic binding to each other, but incapable of homophilic binding. Co-expression of complementary heterophilic binding isoform pairs in the same γC3-null astrocyte restored normal morphology. By contrast, chimeric γC3 proteins individually expressed in single γC3-null mutant astrocytes did not. These data establish that self-recognition mediated by γC3 contributes to astrocyte development in the mammalian brain.

The multicellular coordination that underlies tissue homeostasis and disease progression is of fundamental interest1-5. However, how diverse cell types are organized within tissue niches for cohesive functioning remains largely unknown. Here we systematically characterized cross-tissue coordinated cellular modules in healthy tissues, uncovering their spatiotemporal dynamics and phenotypic associations, and examined their rewiring in cancer. We first compiled a comprehensive single-cell transcriptomic atlas from 35 human tissues, revealing substantial inter-tissue variability in cellular composition. By leveraging covariance in cellular abundance, we identified 12 cellular modules with distinct cellular compositions, tissue prevalences and spatial organizations, and demonstrated coordinated intercellular communication within cellular modules using in situ spatial and in vivo perturbation data. Among them, two immune cellular modules in the spleen showed contrasting chronological dynamics with ageing. Analysis of multicellular changes in the breast revealed a menopausal trajectory associated with fibroblast dynamics. Furthermore, interrogation across cancer types uncovered simultaneous rewiring of two types of multicellular ecosystem during tumour progression, including the loss of tissue-specific healthy organization and the emergence of a convergent cancerous ecosystem. These findings reveal fundamental organizing principles of multicellular ecosystems in health and cancer, laying a foundation for further investigations into tissue-level functional coordination across diverse contexts.

Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.

Cannabis sativa is a globally important seed oil, fibre and drug-producing plant species. However, a century of prohibition has severely restricted development of breeding and germplasm resources, leaving potential hemp-based nutritional and fibre applications unrealized. Here we present a cannabis pangenome, constructed with 181 new and 12 previously released genomes from a total of 144 biological samples including both male (XY) and female (XX) plants. We identified widespread regions of the cannabis pangenome that are surprisingly diverse for a single species, with high levels of genetic and structural variation, and propose a novel population structure and hybridization history. Across the ancient heteromorphic X and Y sex chromosomes, we observed a variable boundary at the sex-determining and pseudoautosomal regions as well as genes that exhibit male-biased expression, including genes encoding several key flowering regulators. Conversely, the cannabinoid synthase genes, which are responsible for producing cannabidiol acid and delta-9-tetrahydrocannabinolic acid, contained very low levels of diversity, despite being embedded within a variable region with multiple pseudogenized paralogues, structural variation and distinct transposable element arrangements. Additionally, we identified variants of acyl-lipid thioesterase genes that were associated with fatty acid chain length variation and the production of the rare cannabinoids, tetrahydrocannabivarin and cannabidivarin. We conclude that the C. sativa gene pool remains only partially characterized, the existence of wild relatives in Asia is likely and its potential as a crop species remains largely unrealized.

Many species use a temporary decrease in body temperature and metabolic rate (torpor) as a strategy to survive food scarcity in a cool environment. Torpor is caused by preoptic neurons that express a variety of peptides and receptors1-7, but no single genetic marker has been found for this population. Here we report that expression of the prostaglandin EP3 receptor (EP3R) marks a unique population of median preoptic nucleus (MnPO) neurons that are required for both torpor and lipopolysaccharide-induced fever8. The MnPO-EP3R neurons produce persistent fever responses when inhibited and prolonged hypothermic responses when activated either chemogenetically or optogenetically, even for brief periods of time. The mechanism for these prolonged responses appears to involve increases in intracellular levels of cAMP and calcium that may persist for many minutes up to hours beyond the termination of a stimulus. These properties endow the population of MnPO-EP3R neurons with the ability to act as a two-way switch for the hypothermic and hyperthermic responses that are required for survival.

Recently, a class of long-period radio transients (LPTs) has been discovered, exhibiting emission thousands of times longer than radio pulsars1-5. These findings, enabled by advances in wide-field radio surveys, challenge existing models of rotationally powered pulsars. Proposed models include highly magnetized neutron stars6, white-dwarf pulsars7 and white-dwarf binary systems with low-mass companions8. Although some models predict X-ray emission6,9, no LPTs have been detected in X-rays despite extensive searches1-5,10. Here we report the discovery of an extremely bright LPT (10-20 Jy in radio), ASKAP J1832-0911, which has coincident radio and X-ray emission, both with a 44.2-minute period. Its correlated and highly variable X-ray and radio luminosities, combined with other observational properties, are unlike any known Galactic object. The source could be an old magnetar or an ultra-magnetized white dwarf; however, both interpretations present theoretical challenges. This X-ray detection from an LPT reveals that these objects are more energetic than previously thought and establishes a class of hour-scale periodic X-ray transients with a luminosity of about 1033 erg s-1 linked to exceptionally bright coherent radio emission.

Doping is a primary method to modulate the electrical properties of semiconductors, enabling the fabrication of various homojunctions/heterojunctions and complex devices1-8. For organic semiconductors (OSCs), the electrical performance has been extensively improved by developing doping methods and dopants9-13. However, compared with the state-of-the-art spatial resolution of inorganic semiconductor fabrication processes, OSCs lag far behind, limiting the construction of complex organic electronic devices5. Here we present a facile light-triggered doping strategy and develop a series of inactive photoactivable dopants (iPADs) for regionally controlled n-doping of OSCs. By converting iPADs into active dopants through ultraviolet (UV) exposure, controllable doping of various n-type OSCs with high electrical conductivity greater than 30 S cm-1 has been realized. Using iPADs can substantially improve the performances of OSCs in transistors, logic circuits and thermoelectrics. Also, regionally controlled doping is demonstrated in OSCs with a record resolution down to 1 μm. Overall, our strategy has achieved tunable doping levels in OSCs with high spatial resolution, which is expected to be highly suited for integrated circuits in both roll-to-roll and laboratory-scale environments.

Fast thermal dephasing limits macroscopic quantum phenomena to cryogenic conditions1-4 and hinders their use at ambient temperatures5,6. For electronic excitations in condensed media, dephasing is mediated by thermal lattice motion1,7,8. Therefore, taming the lattice influence is essential for creating collective electronic quantum states at high temperatures. Although there are occasional reports of high-Tc quantum effects across different platforms, it is unclear which lattice characteristics and electron-lattice interactions lead to macroscopically coherent electronic states in solids9. Here we studied intensity fluctuations in the macroscopic polarization during the emergence of superfluorescence in a lead halide perovskite10 and showed that spontaneously synchronized polaronic lattice oscillations accompany collective electronic dipole emission. We further developed an effective field model and theoretically confirmed that exciton-lattice interactions lead to a new electronically and structurally entangled coherent extended solitonic state beyond a critical polaron density. The analysis shows a phase transition with two processes happening in tandem: incoherent disordered polaronic lattice deformations establish an order, while macroscopic quantum coherence among excitons simultaneously emerges. Recombination of excitons in this state culminates in superfluorescence at high temperatures. Our study establishes fundamental connections between the transient superfluorescence process observed after the impulsive excitation of perovskites and general equilibrium phase transitions achieved by thermal cooling. By identifying various electron-lattice interactions in the perovskite structure and their respective role in creating collectively coherent electronic effects in solids, our work provides unprecedented insight into the design and development of new materials that exhibit high-temperature macroscopic quantum phenomena.

Scientists and inventors set the direction of their work amid evolving questions, opportunities and challenges, yet the understanding of pivots between research areas and their outcomes remains limited1-5. Theories of creative search highlight the potential benefits of exploration but also emphasize difficulties in moving beyond one's expertise6-14. Here we introduce a measurement framework to quantify how far researchers move from their existing work, and apply it to millions of papers and patents. We find a pervasive 'pivot penalty', in which the impact of new research steeply declines the further a researcher moves from their previous work. The pivot penalty applies nearly universally across science and patenting, and has been growing in magnitude over the past five decades. Larger pivots further exhibit weak engagement with established mixtures of prior knowledge, lower publication success rates and less market impact. Unexpected shocks to the research landscape, which may push researchers away from existing areas or pull them into new ones, further demonstrate substantial pivot penalties, including in the context of the COVID-19 pandemic. The pivot penalty generalizes across fields, career stage, productivity, collaboration and funding contexts, highlighting both the breadth and depth of the adaptive challenge. Overall, the findings point to large and increasing challenges in effectively adapting to new opportunities and threats, with implications for individual researchers, research organizations, science policy and the capacity of science and society as a whole to confront emergent demands.

Lentiviral vector (LV)-mediated ex vivo gene therapy for haematopoietic stem and progenitor cells (HSPCs) has delivered on the promise of a 'one-and-done' treatment for several genetic diseases1. However, ex vivo manipulation and patient conditioning before transplantation are major hurdles that could be overcome by an in vivo approach. Here we demonstrate that in vivo gene delivery to HSPCs after systemic LV administration is enabled by the substantial trafficking of these cells from the liver to the bone marrow in newborn mice. We improved gene-transfer efficiency using a phagocytosis-shielded LV, successfully reaching bona fide HSPCs capable of long-term multilineage output and engraftment after serial transplantation, as confirmed by clonal tracking. HSPC mobilization further increased gene transfer, extending the window of intervention, although permissiveness to LV transduction declined with age. We successfully tested this in vivo strategy in mouse models of adenosine deaminase deficiency, autosomal recessive osteopetrosis and Fanconi anaemia. Interestingly, in vivo gene transfer provided a selective advantage to corrected HSPCs in Fanconi anaemia, leading to near-complete haematopoietic reconstitution and prevention of bone marrow failure. Given that circulating HSPCs in humans are also most abundant shortly after birth, in vivo HSPC gene transfer holds strong translational potential across multiple diseases.

Lakes are crucial for ecosystems1, greenhouse gas emissions2 and water resources3, yet their surface-extent dynamics, particularly seasonality, remain poorly understood at continental to global scales owing to limitations in satellite observations4,5. Although previous studies have focused on long-term changes6-8, comprehensive assessments of seasonality have been constrained by trade-offs between spatial resolution and temporal resolution in single-source satellite data. Here we show that seasonality is the dominant driver of lake-surface-extent variations globally. By leveraging a deep-learning-based spatiotemporal fusion of MODIS and Landsat-based datasets, combined with high-performance computing, we achieved monthly mapping of 1.4 million lakes (2001-2023). Our approach yielded basin-level median user's and producer's accuracies of 93% and 96%, respectively, when validated against the Global Surface Water dataset7. Seasonality-dominated lakes constitute 66% of the global lake area and approximately 60% of total lake counts, with over 90% of the world's population residing in regions where such lakes prevail. During seasonality-induced extreme events, the impacts can exceed the combined magnitude of 23-year long-term changes and regular seasonal variations, doubling the contraction of 42% of shrinking lakes and fully offsetting the expansion of 45% of growing lakes. These results uncover previously hidden seasonal dynamics that are crucial for understanding hydrospheric responses to environmental changes9, protecting lacustrine systems10-12 and improving global climate models13,14. Our findings underscore the importance of incorporating seasonality into future research and suggest that advancements in the fusion of multisource remote-sensing data offer a promising path forward.

There is ongoing debate as to when oxygenic photosynthesis evolved on Earth1,2. Geochemical data from ancient sediments indicate localized or ephemeral photosynthetic O2 production before the Great Oxidation Event (GOE) approximately 2.5-2.3 billion years ago (Ga), and currently suggest Archaean origins, approximately 3 Ga or earlier3-9. However, sedimentary records of the early Earth often suffer from preservation issues, and poor control on the timing of oxidation leaves geochemical proxy data for the ancient presence of O2 open to critique10-13. Here, we report rare Earth element data from three different Archaean carbonate platforms preserved in greenstone belts of the northwest Superior Craton (Canada), which were deposited by the activity of marine photosynthetic bacteria 2.87 Ga, 2.85 Ga and 2.78 Ga. All three indicate O2 production before the GOE in the form of significant depletions in cerium (Ce), reflecting oxidative Ce removal from ancient seawater, as occurs today14. Using 138La-138Ce geochronology, we show that La/Ce fractionation, and thus Ce oxidation, occurred at the time of deposition, making these the oldest directly dated Ce anomalies. These results place the origin of oxygenic photosynthesis in the Mesoarchaean or earlier and bring an important new perspective on a long-standing debate regarding Earth's biological and geochemical evolution.

Magnetic states with zero magnetization but non-relativistic spin splitting are outstanding candidates for the next generation of spintronic devices. Their electronvolt (eV)-scale spin splitting, ultrafast spin dynamics and nearly vanishing stray fields make them particularly promising for several applications1,2. A variety of such magnetic states with non-trivial spin textures have been identified recently, including even-parity d-wave, g-wave or i-wave altermagnets and odd-parity p-wave magnets3-7. Achieving voltage-based control of the non-uniform spin polarization of these magnetic states is of great interest for realizing energy-efficient and compact devices for information storage and processing8,9. Spin-spiral type II multiferroics are optimal candidates for such voltage-based control, as they exhibit an inversion-symmetry-breaking magnetic order that directly induces ferroelectric polarization, allowing for symmetry-protected cross-control between spin chirality and polar order10-14. Here we combine photocurrent measurements, first-principles calculations and group-theory analysis to provide direct evidence that the spin polarization of the spin-spiral type II multiferroic NiI2 exhibits odd-parity character connected to the spiral chirality. The symmetry-protected coupling between chirality and polar order enables electrical control of a primarily non-relativistic spin polarization. Our findings represent an observation of p-wave magnetism in a spin-spiral type II multiferroic, which may lead to the development of voltage-based switching of non-relativistic spin polarization in compensated magnets.

Air pollution affects climate through various complex interactions1. It perturbs the Earth's radiative energy balance and alters the atmospheric oxidation capacity, which determines the lifetimes of short-lived climate forcers, such as methane1. A key mechanism in this dynamic is the impact of air pollutants on the hydroxyl radical (OH), the most important oxidant in the troposphere, which accounts for approximately 90% of the methane chemical sink2. However, a comprehensive quantification of the interactions between air pollutants, OH and methane over decadal timescales remains incomplete2. Here we develop an integrated observation-driven and model-driven approach to quantify how variations in key air pollutants influence the methane chemical sink and alter the methane budget. Our results indicate that, from 2005 to 2021, enhanced tropospheric ozone, increased water vapour and decreased carbon monoxide levels collectively contributed to a 1.3-2.0 Tg year-1 increase per year in the global methane sink, thereby buffering atmospheric methane growth rates. This increase in the methane sink was primarily concentrated in tropical regions and exhibited a north-south asymmetry. Periods of high methane growth were typically linked to abrupt OH level declines driven by fluctuations in air pollutants, especially during extreme events such as mega wildfires and the COVID-19 pandemic. Our study suggests a trade-off between O3 pollution control and methane removal mediated by OH and highlights the risk of increasing carbon monoxide emissions from widespread wildfires.

Bacteria defend themselves from viral predation using diverse immune systems, many of which target foreign DNA for degradation1. Defense-associated reverse transcriptase (DRT) systems provide an intriguing counterpoint to this strategy by leveraging DNA synthesis instead2,3. We and others recently showed that DRT2 systems use an RNA template to assemble a de novo gene that encodes an antiviral effector protein, Neo4,5. It remains unknown whether similar mechanisms of defense are employed by other related DRT families. Focusing on DRT9, here we uncover an unprecedented mechanism of DNA homopolymer synthesis. Viral infection triggers polydeoxyadenylate (poly-dA) accumulation in the cell, driving abortive infection and population-level immunity. Cryo-EM structures reveal how a noncoding RNA serves as both a structural scaffold and reverse transcription template to direct hexameric complex assembly and poly-dA synthesis. Remarkably, biochemical and functional experiments identify tyrosine residues within the reverse transcriptase itself that likely prime DNA synthesis, leading to the formation of high-molecular weight protein-DNA covalent adducts. Synthesis of poly-dA by DRT9 in vivo is regulated by the competing activities of phage-encoded triggers and host-encoded silencers. Collectively, our work unveils a novel nucleic acid-driven defense system that expands the paradigm of bacterial immunity and broadens the known functions of reverse transcriptases.

The shale gas revolution has shifted propylene production from naphtha cracking to on-purpose production with propane dehydrogenation (PDH) as the dominant technology1-9. Because PDH is endothermic and requires high temperatures that favour sintering and coking, the challenge is to develop active and stable catalysts1-3 that are sufficiently stable10,11. Zeolite-supported Pt-Sn catalysts have been developed to balance activity, selectivity and stability12,13, and more recent work documented a PDH catalyst based on zeolite-anchored single rhodium atoms with exceptional performance and stability14. Here we show for silicalite-1 (S-1) that migration of encapsulated Pt-Sn2 clusters and hence agglomeration and anchoring within the zeolite versus agglomeration on the external surface can be controlled by adjusting the length of the S-1 crystals' b-axis. We find that when this axis is longer than 2.00 μm, migration of Pt-Sn2 monomers during PDH results in intra-crystalline formation of (Pt-Sn2)2 dimers that are securely locked in the channels of S-1 and capable of converting pure propane feed to propylene at 550 °C for more than 6 months with 98.3% selectivity at 91% equilibrium conversion. This performance exceeds that of other Pt-based PDH catalysts and approaches that of the Rh-based catalyst. While synthesis requirements and cost are currently prohibitive for industrial use, we anticipate that our approach to controlling the migration and lockup of metals in zeolites may enable to development of other noble metal catalysts that offer extended service lifetimes in industrial applications15-17.

Electrochemistry is undergoing a resurgence in synthetic chemistry and boasts compelling advantages1. Repurposing natural enzymes through synthetic chemical strategies holds significant promise for exploring new chemical space2-6. Elegant strategies, including directed evolution7-10, artificial enzymes11, and photoenzymatic catalysis12,13 have demonstrated their capacities for expanding the applications of enzymes in both academia and industry. However, the integration of electrochemistry with enzymes has primarily been limited to replicating previously established enzyme functions14-16. Key challenges in achieving new enzyme reactivity with electricity include compatibility issues and difficulties in heterogeneous electron transfer. Here we report the reshaping of thiamine-dependent enzymes with ferrocene-mediated electrocatalysis to unlock an unnatural dynamic kinetic oxidation of α-branched aldehydes. This robust electroenzymatic approach yields various bioactive (S)-profens with up to 99% enantiomeric excess, is applicable with whole cells overexpressing the enzyme and using down to 0.05 mol% enzyme loadings. Mechanistic investigations reveal multiple functions of the electroenzyme in the precise substrate discrimination, accelerating racemization, and facilitating kinetically matched electron transfer events.