Science Advances

Vampire bats are the only tetrapods that feed exclusively on blood. To uncover the molecular basis of this extreme dietary specialization, we generated six new reference genomes, including genomes of all three vampire bat species, and integrated comparative analyses of gene sequence evolution (selection signatures, duplications, and losses) with transcriptomic data from six major organs to identify shifts in gene expression. Our integrative analyses reveal sequence or expression changes in 150 genes that illuminate the genetic mechanisms underlying sanguivory. Through comparative analyses and experiments, we show that the enlarged vampire bat stomach has increased connective tissue content enabling extreme expansion, is pH-neutral, and exhibits reduced mucus production, together providing molecular insights into its shift from a digestive to an absorptive organ for water, electrolytes, and vitamins. We further uncover pathway-level molecular changes underlying altered gastrointestinal motility; trypsin-dependent protein digestion; upregulated amino acid catabolism with key aspects diverging from other mammals; impaired dietary fat digestion counterbalanced by increased fatty acid synthesis; defective sugar metabolism and natural insulin deficiency; enhanced heme iron absorption; and adult splenic erythropoiesis. Together, these findings reveal the molecular adaptations that enable one of the most extreme dietary transitions among vertebrates.

Postmenopausal osteoporosis is a highly prevalent disease characterized by low bone mass and structural deterioration of bone tissue leading to increased bone fragility and fracture risk. Osteocytes orchestrate local bone (re)modeling and therefore, characterizing their 3D morphological and spatial distribution across distinct (re)modeling microenvironments is essential for understanding the cellular mechanisms underlying divergent tissue-level responses. To address this, we used a 3D-3D multiscale registration framework mapping endpoint osteocyte lacunae onto dynamic, time-lapsed in vivo (re)modeling sites. Ovariectomized 15-week-old mice were subjected to 4 weeks of anabolic parathyroid hormone (PTH) or anti-catabolic bisphosphonate (BIS) treatment as monotreatment or combined with cyclic mechanical loading (ML). Biweekly in vivo micro-computed tomography (micro-CT) to identify (re)modeling sites and endpoint ultra-high resolution (ultra-HR) micro-CT to characterize osteocyte lacunae was performed. Osteocyte lacunae were characterized by lacunar density, volume and sphericity. Our findings showed that physical and pharmacological therapies differentially regulate the osteocyte lacunar network through distinct perilacunar adaptations across functional microenvironments. While BIS stabilizes local lacunar architecture, PTH drives asymmetrical lacunar expansion (increased volume with reduced sphericity) through perilacunar remodeling that supersedes any added ML effects. Crucially, estrogen loss disrupts the natural spatial maturation gradient by inducing rounding of lacunae in newly formed bone. Therapies counteract this disruption, restoring the healthy gradients in lacunar morphometry between spatially distinct microenvironments. Additionally, despite restoring tissue-level bone volume, physical and pharmacological osteoporosis therapies do not fully recover persistent lacunar density deficits. The overall lacunar morphological spatial signatures confirm active osteocytic tuning to endocrine, physical and matrix cues.

Background: Pro-inflammatory and high-environmental-impact diets both threaten population and planetary health, but whether the two objectives align or conflict across countries is unresolved. We tested whether a supply-based dietary inflammatory index (sDII) is coupled to greenhouse-gas (GHG), land and freshwater footprints, and whether a nutrition-feasible reallocation can lower both simultaneously. Methods: From FAO Food Balance Sheets we built sDII (12 inflammatory-weighted components; construct validity r=0.9999) and five per-capita footprints using three independent life-cycle inventories for 182 national food-supply series. For each country, constrained optimisation reallocated 13 food-group supplies under isoenergetic, protein-preserving and food-group-bound constraints, minimising sDII and GHG jointly (Pareto frontier). Health burden was estimated via pooled relative-risk meta-analysis and 2023 World Bank population data. Results: sDII was only weakly associated with GHG (Spearman rho=0.14), land (rho=0.13) and freshwater (rho=0.28) in 2023. The balanced-Pareto reallocation lowered both sDII and GHG in 182/182 series (100% synergy): population-weighted delta sDII=-0.235, GHG -37.5%, land -49.3%, water -17.2%, i.e. 4.28 Gt CO2e/yr avoided. The associated reduction in metabolic-syndrome burden was directionally consistent but modest (~1.1% of the prevalent pool, ~2.84 million cases). Results were robust to three life-cycle inventories and three feasibility-bound regimes. Conclusions: Anti-inflammatory and low-carbon goals are decoupled rather than conflicting, and an isoenergetic, protein-preserving reallocation reconciles them in every country. Environmental gains are large and robust; health gains are directionally consistent but modest--triangulation, not a causal claim.

In cells, ESCRT-III is unique in mediating fission of membrane necks from inside, a process called reverse-topology fission. Yet, in vitro, the complex primarily assembles outside membrane necks and mediates fission with normal topology. Here, we show that the direction of ESCRT-mediated membrane deformation emerges from bilayer asymmetry rather than being intrinsically encoded by the ESCRT machinery alone. Using genetic perturbations in budding yeast, we find that disruption of phospholipid asymmetry and sphingolipid homeostasis does not abolish ESCRT-dependent trafficking but renders ILV formation highly sensitive to membrane physical state, leading to inefficient cargo sorting and accumulation of stalled endosomal intermediates. In vitro reconstitution experiments and synthetic in vivo cargo systems demonstrate that asymmetric protein distribution across the membrane is sufficient to bias curvature directionality, with luminal leaflet crowding promoting efficient ILV incorporation and cytosolic crowding inhibiting inward budding. Together, these results support a model in which ESCRT-mediated membrane bending directionality emerges from the intrinsic tension difference between the bilayer leaflets. This tension difference arises from both lipid and cargo crowding-encoded asymmetries within the bilayer, rather than being solely encoded by ESCRT polymer properties.

Mechanical stability critically influences bone fracture healing, yet how the early mechanical environment directs the transition from inflammation to regeneration remains unclear. Using a murine femoral osteotomy model, we compared rigid, semirigid, and dynamically adjusted semirigid-to-rigid fixation. Semirigid fixation delayed healing on day 21, whereas a strategy of early compliance followed by increased stiffness after 7 days restored bridging and improved bone regeneration beyond constant rigid fixation, pointing to a critical early mechanosensitive window after fracture. Single-cell RNA sequencing across the first week, comparing semirigid with rigid fixation, showed that fixation stiffness altered intercellular signaling within one day of injury. Signaling among myeloid populations was more broadly increased under semirigid fixation, with monocytes the single exception, and signaling associated with resolution of inflammation was reduced. From day 5, periosteal and skeletal progenitor populations increasingly directed cartilage-associated matrix and growth factor signaling toward macrophages and chondrocytes, accompanied by increased Sox9 regulon activity and increased COL10+ hypertrophic cartilage matrix by day 7. Reduced fixation stiffness therefore promotes a chondrogenic trajectory of repair, but increasing stiffness is required to redirect this response toward bone formation. Piezo1 was expressed across the responding populations and shifted between compartments as healing progressed. PIEZO1 activation with Yoda1 under rigid fixation enhanced bone formation but provided no additional benefit under semirigid or dynamically adjusted fixation, whereas inhibition of mechanosensitive signaling with GsMTx4 impaired repair across all conditions. Together, these findings establish the early mechanical environment as a determinant of fracture-healing trajectory, shaping the transition from inflammation to regeneration, and show that successful repair depends not on maximal stability but on when stiffness is applied. Increasing either early mechanical stimulation or cellular mechanosensitivity enhanced regeneration, supporting mechanosensitive signaling as a key component of the early healing response.

Competing lipid kinases and phosphatases are critical for organizing cellular membranes, but whether a minimal system can autonomously organize proteins and lipids into dynamic spatiotemporal patterns is unknown. Here, we report the in vitro reconstitution of the Legionella phosphatidylinositol (PI) 3-kinase MavQ and PI 3-phosphatase SidP. Together with their lipid substrates, PI and PI 3-phosphate (PI3P), these enzymes form a minimal self-organizing system that generates ATP-dependent spatiotemporal patterns, including traveling waves, on model membranes. These behaviors arise from MavQs cooperative membrane binding, SidPs phosphatase activity, and the continual interconversion and redistribution of PI and PI3P within a conserved membrane pool. A reaction-diffusion model reproduces the observed dynamics and predicts that lipid conservation prevents patterns from propagating across membrane discontinuities, which we verify experimentally. Together, these findings establish enzymatic modification of membrane lipids as a distinct molecular strategy for biological pattern formation.

Regeneration after spinal cord injury requires progenitor cells to convert injury-associated signals into coordinated remodeling of gene regulatory programs. Mammalian spinal progenitors show limited neurogenic output after injury, whereas zebrafish regenerate spinal neurons and recover motor function. To investigate the regulatory changes that allow ependymo-radial glia (ERG) cells, the progenitor cells of the zebrafish spinal cord, to generate new neurons, we combined single-nucleus gene expression and chromatin accessibility profiling across embryonic, larval, and adult stages with topic-based gene regulatory network (GRN) inference. We found that larval and adult ERGs enter the injury response from distinct regulatory baselines: larval progenitors are characterized by a gliogenic program, whereas adult progenitors maintain a comparatively quiescent state. Following injury, both populations gradually change their baseline programs and shift towards a lesion-associated module marked by stress-responsive and chromatin-associated regulators, including jun, hmga1a, hmga2, ybx1, and foxj1a. The shift away from homeostatic states is supported by decreased expression of the Notch-associated regulators nuclear factor I A (nfia) and hey1 in larvae, while in adults, downregulation of the same nuclear factor and other TFs such as bhlhe41 is associated with quiescence exit. Pathway analysis showed stage-specific alterations after injury, characterized predominantly by extracellular signaling and cytoskeletal reorganization in larvae and by metabolic and translational remodeling in adults. Despite divergence from the homeostatic states, injury-induced larval and adult GRNs remain distinct from embryonic hERG regulatory programs. Thus, larval and adult progenitors follow different trajectories from their baselines towards a related lesion-reactive state, in which shared regeneration-associated features are acquired within respective contexts.

Marine heatwaves cause massive, but often patchy coral bleaching. Why neighboring colonies often respond differently remains unresolved. Here, we show that interactions between metabolic demand and flow-mediated resupply generate heterogeneous oxygen microenvironments inside branching corals under heat stress. During the 2023 and 2024 Red Sea heatwaves, high-frequency in situ measurements revealed hypoxic to near-anoxic interbranch conditions despite well-oxygenated surrounding seawater. In 2023, neighboring colonies developed divergent oxygen regimes preceding paling and bleaching; in 2024, stronger and earlier thermal stress was associated with recurrent nighttime near-anoxia before tissue disintegration and mortality. A physics-based three-dimensional fluid-metabolism model reproduced these patterns. Oxygen depletion and coral impacts emerged when metabolic oxygen demand exceeded flow-mediated resupply. Organism-scale variability in oxygen regimes may explain divergent coral fate under shared heatwave exposure.

Studying the role of individual neurons in behavior and disease requires tools for controlling neural activity with high spatiotemporal resolution. Implantable nanophotonic neural probes are capable of delivering targeted photostimulation to enable genetically distinct neurons to be selectively controlled, yet face barriers to achieving scalable emitter densities and lack sensors for monitoring feedback signals relevant to device operation. To address this, we developed laser-integrated nanophotonic neural probes, which feature hybrid-integrated laser diodes (LD) and thermo-optic photonics switches for scalable emitter addressing and on-chip sensors for monitoring optical power and temperature during photo-stimulation. Devices were fabricated at a commercial silicon photonics foundry on 200-mm diameter silicon-on-insulator (SOI) wafers in an active visible-light platform and were controlled using a custom-developed electronic circuit board. Each device features a hybrid-integrated InGaN LD which couples 450-nm light into a reconfigurable photonic switching tree for delivering spatially resolved photostimulation through 16 emitters along a 3-mm implantable shank. Using the on-chip photodetectors, we demonstrate how devices can enable switching tree calibration as well as output power monitoring during photostimulation. Furthermore, using the on-chip temperature sensors, we show how device temperature perturbations resulting from LD and thermo-optic switch activation can be directly monitored during photostimulation to ensure temperature fluctuations remain below 1 {degrees}C. We validate our design by delivering high spatiotemporal photostimulation during an in vivo optogenetic experiment with simultaneous Neuropixels recording to monitor evoked responses. Overall, these scalable integrated devices offer a pathway for neuroscientists to conduct fiberless optogenetic experiments with greater control and precision.

COMPASS (Complex of proteins associated with Set1) are highly conserved chromatin regulatory complexes responsible for all methylation marks on histone H3 lysine 4 (H3K4). The COMPASS protein SET1A is upregulated in metastatic breast cancer, and its H3K4 methyltransferase activity promotes metastasis in a palmitic acid diet setting. We identify and characterize FCD-11, a first-in-class small molecule inhibitor of COMPASS activity designed to disrupt the termolecular interface between COMPASS SET domains, ASH2L, and RBBP5. FCD-11 significantly inhibited the H3K4me3 methyltransferase activity of SET1A/COMPASS and MLL1/COMPASS in vitro. ChIP-seq and CETSA indicated that FCD-11 selectively inhibits SET1A/COMPASS activity in mouse embryonic stem cells and breast cancer cell lines. FCD-11 significantly reduced tumor size and extended survival in mouse models of breast cancer. Our findings establish FCD-11 as a potent, COMPASS-specific inhibitor lead compound with preclinical efficacy in breast cancer models and therapeutic potential for cancers with abnormal dependence on SET1A/COMPASS activity.

The Ocean sustains planetary health through climate regulation, biodiversity, and essential ecosystem services. Plankton underpins these processes by driving primary production, sustaining food webs, and mediating carbon sequestration. Yet the spatial organization of plankton-based ecosystem services remains poorly understood. The High Seas Treaty and the 30% Ocean protection target by 2030 create an urgent need for science-based guidance for global ocean governance. Here, we aim to identify key planktonic areas associated with functional diversity, net primary productivity, and carbon export globally. We used machine learning to integrate omics-derived plankton functions and satellite observations with diversity metric and ecosystem services. Leveraging metagenomic data, we identified molecular functions strongly linked to ecosystem functioning and project their global distributions across seasons. We reveal putative hotspots of functional diversity, net primary productivity, and carbon export. Our analysis pinpoints areas where all three indicators converge synchronously, predominantly along oceanographic structures such as polar fronts and principal current systems. By relying on satellite data as core input, our approach captures the temporal variability of these hotspots, providing a global, dynamic protocol for projections of plankton-based ecosystem services. These findings establish a foundation for developing integrative conservation tools based on ecosystem functioning and inform adaptive management under climate change.

Species differ in longevity, physiology, and social organization, and these properties expose them to distinct endogenous and environmental mutagens. Mutational spectra generated by these processes can shape downstream molecular evolution, influencing synonymous nucleotide composition, codon usage, and even amino acid composition. Tracing this signal from life history to proteome through mutagenesis could reveal how mutational pressure interacts with the fitness landscape, including the direction of molecular change and the extent to which proteins remain functional while following mutational biases. Here, building on the recently identified age-associated mitochondrial A>G mutational signature in mammals, we test the universality of this signature and its downstream effects on genome and proteome evolution by comparing long-lived termites with short-lived non-termite cockroaches. We find that termite mtDNA exhibits a stronger A>G mutational signature than that of non-termite cockroaches, accompanied by coordinated shifts in synonymous nucleotide composition, codon usage, and amino acid composition. Our results show that ecological and life-history-associated mutational pressures can be transmitted through a hierarchy from mutational spectra to nucleotide composition and ultimately to proteome evolution. Mitochondrial genomes may therefore function not only as records of ancestry but also as molecular archives of the biological conditions under which species evolve.

Mites and ticks (Acari) constitute one of the most species-rich and ecologically diverse arachnid radiations, yet their interrelationships and genomic mechanisms underlying their diversification remain poorly resolved. Here, we reconstructed the evolutionary relationships and trajectory of Parasitiformes using phylogenetics and comparative genomics to test the phylogenetic signal in rare genomic changes. Maximum likelihood and macrosynteny analysis revealed multiple shared chromosomal fusion-with-mixing events that unite Opilioacaridae and Ixodida as sister taxa, with Mesostigmata as a derived sister clade, overturning the prior basal placement of Opilioacaridae as a slowly evolving "living fossil" lineage. We show that major parasitiform lineages diversified through asymmetric, large-scale genome and regulatory rewiring. Opilioacaridae genome retains ancestral chelicerate genomic features, including an intact, contiguous Hox gene cluster, high repetitive-element content, and a conserved microRNA repertoire, all shared with Ixodida. By contrast, the hyperdiverse Mesostigmata shows marked genome compaction, with shortened introns, disrupted and fragmented Hox clusters, and widespread loss of microRNA families, despite retention of developmentally essential miRNAs. Comparative analysis of gene-family evolution further identifies lineage-specific expansions in Ixodida associated with blood feeding and immune evasion, alongside independent, convergent expansion of cuticle-protein gene families in ectoparasitic Mesostigmata. These findings demonstrate that contrasting modes of genome evolution, long-term structural stasis versus rapid compaction, together with convergent gene-family expansion linked to independent origins of parasitism, can coexist within a single arachnid radiation, offering new insight into the molecular basis of developmental regulatory evolution and adaptive diversification in Acari.

Comparative embryology has revealed that early animal development is based on highly conserved genetic programs. Beyond embryogenesis however, animals undergo remarkably diverse post-embryonic developmental transitions such as metamorphosis. Whether these transitions are also organised into conserved genetic programs remains largely unexplored. To identify conserved genetic programs underlying post-embryonic development, we examine metamorphic remodelling in five teleost fishes, spanning 200 million years of evolution. By integrating comparative co-expression networks, evolutionary genomics, phylogenetic modelling, and functional data in zebrafish, we uncovered a conserved post-embryonic developmental network. This conserved network comprises components involved in core cellular processes, and involved in development and physiology, both of which are under the control of thyroid hormone during metamorphosis. Despite evolutionary conservation at the coding sequence level, this network exhibits significant turnover in gene family copy number following the teleost-specific whole-genome duplication as well as lineage-specific expansions and contractions. The variation in gene copy numbers is associated with macroevolutionary variation in a number of ecological and morphological traits, including swimming performance, and trophic level. Cross-species tissue expression, zebrafish single-cell transcriptomics, and zebrafish perturbation phenotypes placed the implicated genes in biological contexts relevant to these traits. Together, our results provide evidence of an ancient, functionally partitioned post-embryonic developmental network that has diversified throughout teleost evolution. The heterochronic variation in network function, changes in endocrine activity, and gene-family turnover provide potential routes through which a shared developmental architecture contributed to the evolution of phenotypic diversity in teleosts.

Orsay virus (OrV), infecting Caenorhabditis elegans, is a valuable model for studying host-virus interactions, yet its bipartite RNA genome packaging and assembly mechanisms remain unclear. To investigate these mechanisms, we combine infection assays, single-molecule imaging, and cryo-electron microscopy. We find that the two RNA segments accumulate asymmetrically, and that productive infection depends on coinfection by multiple particles. We therefore asked whether unequal segment availability generates heterogeneous virions. Cryo-EM analysis of OrV, including symmetric and asymmetric reconstructions to 2.5 [A] resolution, unveils uniform internal density, excluding large populations of empty or semi-empty particles. We show the genome forms a semi-ordered network contacting the electropositive capsid interior through sequence-independent interactions with the N-terminus and penton region. We also resolve the capsid-8 linker, identifying the penton as a likely site coordinating capsid assembly. Together, we propose a model in which stochastic genome assortment emerges during assembly modulated by segment-specific replication dynamics.

Mate-seeking during peak sexual receptivity is tightly coupled with exploratory movement, a process made more efficient by transient suppression of excretion. Here, we define a functional hypothalamic-hindbrain circuit in mice that promotes locomotion while eliminating urination and defecation for hours. Chemogenetic stimulation of excitatory estrogen-melanocortin-responsive MC4R+ neurons in the ventrolateral ventromedial hypothalamus (VMHvl) effectively silences bladder and colonic visceral reflexes, even at noxious distension pressures, underscoring the potency of this anti-excretion circuit. Pelvic sensations and excretion are restored only after ablating inhibitory GABAergic neurons in the Barringtons nucleus/locus coeruleus (BAR/LC) hindbrain region or after antagonizing endogenous endorphin signaling. Our study illustrates how a hormone-responsive brain node prioritizes movement over excretion and blunts pelvic discomfort, thereby optimizing an essential voluntary behavior for evolutionary fitness.

The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.

How animals perform odor-guided search across the broad range of dynamic flow conditions they encounter in nature is not well understood. Prior work treats established strategies such as circling and zigzagging as discrete, context-dependent behaviors. Here, we propose a parsimonious mathematical framework that unites these motifs into a continuum. We show that free flying Drosophila exhibit this continuum by smoothly reshaping search behavior between circling and zigzagging across unsteady flow, still air, and a range of wind speeds. Strikingly, a flow-invariant rhythmic course progression underlies this behavioral spectrum. Available data from moths and sharks across different flow regimes suggest a similarly preserved rhythm, while the rate of this rhythm varies across taxa. Together, these results support a common conceptual basis for olfactory search behavior and explain how search geometry can adapt automatically to local flow.

How stochastic molecular events are converted into ordered cellular machines that perform mechanical work remains a central question in biology. Cryo-electron tomography enables visualization of macromolecular assemblies inside cells at molecular resolution, but static tomograms are generally interpreted as structural snapshots, with limited access to assembly state and temporal progression. Here, we show that cellular tomograms retain interpretable information about the assembly of a force-generating actin network. Using human macrophage podosomes as a physiologically relevant system, we combine spatial mapping of actin filaments (F-actin) and Arp2/3-mediated branch junctions, orientation analysis of deep-learning-based filament segmentations and Markov-chain modeling to infer actin-network assembly in situ. We identify favored membrane-directed actin polymerization and Arp2/3-mediated branching, establishing a local growth axis for podosome network organization. At the network scale, podosomes display layered helical order: filament-orientation classes recur at intervals of approximately 33 nm along the membrane-normal axis, forming a three-class cycle that returns to an approximately equivalent non-polar orientation. Markov modeling identifies preferred mother-to-daughter filament-orientation transitions and yields a stationary composition of branch-orientation states that closely matches that observed in structurally more advanced network regions. Together, these results link local actin nucleation, network-scale architecture and structural assembly state in a native cellular machine. Our study advances cryo-electron tomography from structural description toward temporal inference and 4D in situ structural biology.

Denisovans, originally identified from ancient genome from Denisova Cave in Altai, were a sister group to the Neanderthals and were once widely distributed across diverse terrains in the north and south of eastern Asia1-5. Genomic studies suggest that there were multiple events of interbreeding between modern humans (Homo sapiens) and Denisovans somewhere in Asia6. However, little is known about Denisovan living environments, diet, ecological niche, the timing of their disappearance, and the possible coexistence with modern humans in different regions. Here we report the radiocarbon age and stable isotopic signature of Penghu 3, a large Denisovan tibia from Penghu Channel, Taiwan7. The results showed that Penghu 3 dates to approximately 45,000 years ago, the time when modern humans were already widespread in southern parts of Asia. This Denisovan individual inhabited a C4-dominated ecosystem, open environments such as savannahs and floodplains, or a mixture of both, and consumed a high proportion of animal protein similar to some European Neanderthals8-10, with no clear evidence for the use of aquatic resources. These findings have implications for the behavioral flexibility, large body size7, and eventual disappearance of the Denisovans.