Publications in Nature

Bats are extraordinary among mammals, having uniquely evolved powered flight and laryngeal echolocation, along with disease resistance, extended healthspans and the ability to hibernate1. However, the evolutionary history of bats and the understanding of these adaptations remain unresolved. We analysed chromosome-level, long-read genome assemblies from 103 bat species, including 42 new assemblies, representing all 21 bat families. This dataset, expanded in scope and assembly quality, yielded a new bat phylogeny. We placed Myzopodidae as the earliest branch within Vespertilionoidea, and resolved yangochiropteran relationships, identifying Emballonuroidea and Vespertilionoidea as sister groups. Our analysis revealed a mosaic evolutionary history across bats and explained why previous phylogenetic studies were misled. Chromosomal ancestral-state reconstructions supported 26 ancestral bat chromosomes. We integrated a morphological dataset of 699 characters for 65 species, including 44 pre-Quaternary fossils and representatives of most living bat families, with neutrally evolving genomic sites. Fossilized birth–death and dispersal–extinction cladogenesis analyses showed that bats, and thus powered flight, probably originated in Europe in the late Palaeocene, refuting African and North American origins. Placement of the fossil †Vielasia in the oldest ‘Eochiroptera’ clade indicates that laryngeal echolocation predates crown-bat diversification. Total evidence dating, including the fossil taxa, significantly reduced unrepresented basal branch lengths compared with molecular-only divergence estimates. By integrating comprehensive genomic and morphological datasets, analysed using innovative methods, we resolve long-standing controversies in bat biology and provide new insights into the evolutionary history and trait diversification of bats.

Fucoidans, a class of complex polysaccharides produced by brown algae and diatoms, contribute to long-term carbon sequestration owing to their resistance to microbial degradation1,2. Although individual microorganisms can break down portions of these polysaccharides3, 4–5, it remains unclear whether complete breakdown is possible in nature and, if so, by what mechanisms. Here we show that fucoidans are degraded through synergistic interactions between specialized bacteria with complementary metabolic functions. Using metabolomic analysis of a reconstructed marine consortium, we uncovered metabolic guilds of bacteria that preferentially degrade either the sulfated fucose backbone or the side branches of rare monomers. This functional division of labour leads to an unexpectedly high number of synergistic interactions between different degraders that enhanced degradation efficiency up to 97.1%. Despite varying fucoidan structures across different types of algae6, the metabolic functions of degraders remained conserved, enabling quantitative prediction of degradation outcomes based on community and substrate composition. The frequent co-occurrence of functionally complementary fucoidan degraders in ocean metagenomes suggests that synergistic degradation is a globally relevant strategy. Our findings suggest that the environmental turnover of complex biopolymers depends not only on individual metabolic capabilities of degraders but also on ecological interactions shaped by substrate architecture. This work provides a mechanistic framework for understanding carbon cycling in the ocean and for engineering synthetic microbial consortia to degrade recalcitrant polysaccharides.

Games have long been a microcosm for studying planning and reasoning in both natural and artificial intelligence, often focusing on expert-level or even super-human play1, 2, 3, 4, 5–6. But real life also pushes human intelligence along a different frontier, requiring people to flexibly navigate decision-making problems that they have never thought about before. Here we use novice gameplay to study how people reason about new problem settings. Through a series of large-scale behavioural studies with over 1,000 participants and 121 two-player strategic board games (almost all novel to our participants), we show that people are systematic and adaptively rational in how they play a game for the first time or evaluate a game (for example, how fair or how fun it is likely to be) before they have played it even once. We explain these capacities via a computational cognitive model that we call the ‘Intuitive Gamer’: a model based on mechanisms of fast and flat (depth-limited) goal-directed probabilistic simulation. Our work offers insights into how people rapidly evaluate, act and make suggestions when encountering novel problems, and could inform the design of more flexible and human-like artificial intelligence systems that can determine not just how to solve new tasks but also whether a task is worth thinking about at all.

Stimulator of interferon genes (STING) is an evolutionary conserved immune signalling protein with key roles in host defence, cancer, senescence and inflammation1, 2–3. Downstream of STING, type I interferon, inflammatory cytokine signalling and non-canonical autophagy are governed by a multilayered mechanism integrating ligand-induced structural transitions, protein–protein interactions and coordinated intracellular trafficking4, 5, 6, 7, 8, 9, 10, 11, 12–13. Despite its central role in immunity and relevance as therapeutic target14, the sequence elements that govern STING (in)activation in cells remain incompletely understood. Here we developed a massively parallel assay to systematically chart the sequence-function landscape of STING. Profiling thousands of single amino-acid variants, we identified structural and functional determinants that shape the immunostimulatory capacity of STING and its ability to translate ligand recognition into distinct signalling outputs. Cryogenic-electron microscopy structures of select STING hyperactive variants revealed new regulatory principles dictating conformational transition from inactive to signalling-competent states of STING. Mutational effects are widespread across the functional landscape and can sensitize STING towards the natural ligand 2′3′-cGAMP15, 16, 17–18 or decouple interferon induction from non-canonical autophagy, demonstrating a diversity of possible responses that can be accessed through single point substitutions. Finally, our data showed the clinical and evolutionary relevance of naturally occurring STING protein variants. Collectively, these findings define molecular principles that tune STING activity and chart the landscape of its functional potential across immune contexts.

Many diseases, including obesity, have systemic effects that perturb multiple organ systems throughout the body1,2. However, tools for comprehensive, high-resolution analysis of disease-associated changes at the whole-body scale have been lacking. Here we developed MouseMapper, a suite of foundation-model-based deep-learning algorithms enabling multi-system analysis of disease across the entire mouse body. MouseMapper enables whole-body quantitative analysis of nerves and immune cells, resolving fine axonal branches and immune-cell clusters while automatically segmenting 31 organs and tissues. We used MouseMapper to study diet-induced obesity, and identified structural alterations of the infraorbital branch of the trigeminal ganglia. This structural impairment in infraorbital nerves was associated with functional sensory deficits in whisker sensing. Furthermore, we identified proteomic changes in the trigeminal ganglion affecting axon remodelling and complement pathways both in mice and humans. MouseMapper also generated detailed three-dimensional inflammation maps by characterizing immune cell cluster compositions across tissues. The MouseMapper framework demonstrates robust generalizability across different imaging resolutions and datasets. Our study provides a powerful, scalable approach for identifying and quantifying systemic pathologies, bridging molecular insights from animal models to human conditions.

Disease tolerance is a defence strategy essential for survival of infections, limiting physiological damage without killing the pathogen^1,2. The disease course and pathology an infection may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Because successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defence strategy would change with age. Animals infected with a 50% lethal dose  (LD₅₀) of a pathogen often show distinct health and sickness trajectories due to differences in disease tolerance^1,3 and can be used to define tolerance mechanisms. Here, using a polymicrobial sepsis model, we found that, despite having the same LD₅₀, aged and young susceptible mice showed distinct disease courses. In young survivors, cardiac Foxo1 and its downstream effector Trim63 (MuRF1) protected from sepsis-induced cardiac remodelling, multi-organ injury and mortality. Conversely, in aged hosts, Foxo1 and Trim63 acted as drivers of sepsis pathogenesis and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and indicate that disease tolerance genes show antagonistic pleiotropy.

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide¹, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden^2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.

Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells^1,2. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis^3,4. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity⁵. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.