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Endogenous ATP–powered nanomotors directing neural stem cell differentiation for Parkinson’s disease treatment

Transplantation-free neuron regeneration remains attractive yet unsolved for reversing Parkinson’s disease (PD). Here, we present enzyme-driven mesoporous gold nanomotors (Apyrase@Au) that leverage endogenous biochemical energy for spatiotemporally controlled promotion of neural stem cell (NSC) differentiation, without exogenous stem cell transplantation. By catalyzing endogenous adenosine triphosphate (ATP) hydrolysis, Apyrase@Au nanomotors simultaneously generate directional propulsion and localized signaling messenger protons. These protons induce calcium influx and activate quiescent NSCs within the ventricular-subventricular zone of PD mice, directing their differentiation into functional neurons and alleviating moving dysfunction. The bioenergy-converting system imparts dual functionality to active matter, propelling while concurrently yielding bioactive products. This work demonstrates the potential of ATP-powered nanomachines as a self-sustaining and targeted biointerface, offering a promising strategy for promoting NSC differentiation and alleviating moving dysfunction in degenerative diseases.

HairTime: A noninvasive assay for estimating circadian phase from a single hair sample

Circadian clocks govern daily physiological and behavioral processes and are crucial for health; disruptions can lead to various diseases. The circadian phase of entrainment—the phase of the internal circadian clock in relation to external environmental cycles—is influenced by both genetic and environmental factors, varies between individuals, and is reflected in daily behaviors such as sleep–wake patterns, cognitive performance, and physical activity. While circadian phase may also fluctuate within individuals, the dynamics and extent of such variation in daily life remain largely unexplored. The gold standard for circadian phase assessment, dim-light melatonin onset (DLMO), is impractical for large-scale studies, and blood-based molecular biomarkers, while promising, are limited in feasibility. To address these challenges, we developed HairTime, a noninvasive assay that estimates circadian phase from a single daytime hair sample. Developed and evaluated in two steps—a training and a validation study—HairTime demonstrated strong predictive power compared to DLMO. Suitable for large-scale studies, it was assessed using over 4,000 samples. Circadian phase estimations showed a normal distribution and were associated with age, sex, and notably, work schedules, with earlier timing on workdays, suggesting that societal factors can modulate internal rhythms. Together, these findings establish HairTime as a promising tool for assessing circadian phase in research and lay the foundation for future applications in personalized chronotherapy.

Sparse spatial scaffolding for visual working memory

When holding information ‘in mind’, it is vital to keep individual representations separated and selectively accessible for guiding behaviour. Space is known to serve as a foundational scaffold for mnemonic individuation, yet the format and flexibility of spatial scaffolding for working memory remain elusive. We hypothesised that information in working memory can be re-coded from its native format at encoding to organise and retain internal representations sparsely. To test this, we presented to-be-memorised visual items at distinct directions and distances and leveraged gaze biases during mnemonic selection as an implicit read-out of spatial scaffolding for working memory. We report how male and female humans abstract away over incidental item distance when direction alone suffices as a scaffold, but incorporate distance when it aids mnemonic individuation. This suggests the flexible use of a sparse spatial scaffold for working memory, resorting to the minimal spatial scaffold required for the individuation of internal representations. Significance statement A foundational task faced by the brain is to not only maintain relevant information ‘in mind’ but also to keep maintained representations separate from each other and selectively accessible for guiding behaviour. It has long been known that spatial configurations serve as a foundational scaffold for working-memory organisation, but the nature and flexibility of such spatial scaffolding have remained unclear. By probing biases in fixational gaze behaviour during mnemonic selection, we could uniquely uncover spatial coding for working memory through the eyes – without ever asking about memory for location. Doing so, we uncover the flexible nature of spatial scaffolding for memory: retaining those spatial properties that aid memory organisation while abstracting away over spatial properties that are obsolete.

Dynamic translocation of Inside-Out proteins to the cell surface underlies cellular adaptation to cancer-induced stress

Inside-Out (I-O) protein display, the noncanonical surface localization of intracellular proteins, represents an underexplored feature of tumor cell biology. Here, we map the molecular landscape and trafficking mechanisms that control the presentation of I-O proteins on cancer cell membranes. Employing APEX2-mediated proximity biotinylation and a custom antibody generation and validation platform, we identified approximately 140 high-confidence I-O proteins, primarily ribosomal, proteasomal, chaperone, and translation factors, notably enriched in protein families associated with stress-response pathways. Validation of 500 antibodies encompassing 40 I-O targets across seven tumor cell lines confirmed selective and robust surface localization, while in vivo imaging in mouse xenografts demonstrated pronounced and tumor-specific antibody accumulation. I-O proteins were absent on peripheral blood mononuclear cells (PBMCs) and in normal tissues, indicating cancer cell selectivity. Functional analyses revealed that I-O protein tethering to the membrane is dependent on heparan sulfate interactions; enzymatic removal of these glycans led to the clearance of I-O proteins from the cell surface. Notably, the removed proteins returned to baseline levels within 6 h, indicating a dynamic balance related to Endoplasmic Reticulum (ER)-Golgi trafficking and cellular stress. Nearly half of these I-O proteins overlapped with known stress granule (SG) components; however, stress elements that promote SG formation do not similarly affect surface display of I-O proteins. Furthermore, I-O proteins are present on standard cancer cell lines under lower stress levels needed to induce SG formation, suggesting parallel yet mechanistically distinct aspects of the stress response. These findings position I-O display as a paradigm in protein trafficking, different from traditional secretion pathways and closely linked to stress response.

Disruption of Glomerular Map Formation in the Accessory Olfactory System Impairs Chemosensory Processing and Social Behavior

Chemosensory signals play a fundamental role in guiding innate behaviors in mice, including mating, territoriality, and aggression, through specialized olfactory subsystems, such as the vomeronasal system. Chemosignals activate distinct subsets of glomeruli in the accessory olfactory bulb (AOB), suggesting that glomerular maps may contribute to the interpretation of chemosensory information driving these behaviors. Here, we investigate the consequences of altering glomerular map organization on sensory processing and social behavior in male and female mice by ablating the expression of the cell adhesion receptor Kirrel3 in basal vomeronasal sensory neurons (VSNs). Conditional ablation of Kirrel3 in VSNs led to a marked reorganization of the posterior AOB, characterized by altered specificity of VSN innervation and enlarged glomeruli. Despite retaining the ability to discriminate male from female urine, Kirrel3 -deficient mice exhibited significantly reduced vomeronasal acuity to chemosignals, which is associated with a loss of male-directed aggression in both male and postpartum female mice. Functional mapping of neural activity revealed attenuated responses in mitral cells of the AOB, as well as in aggression-related brain regions, including the medial amygdala and ventromedial hypothalamus. These findings underscore the critical role of glomerular map integrity in the vomeronasal system for maintaining chemosensory acuity and regulating social behaviors. Furthermore, this study provides insight into how molecular disruptions in sensory neuron connectivity can reshape neural circuits and behavioral outputs. Significance statement The accessory olfactory system detects chemosignals that guide social and reproductive behaviors. Vomeronasal sensory neurons that detect these chemosignals innervate the accessory olfactory bulb in spatially conserved synaptic units, termed glomeruli. Although urine chemosignals activate spatially-conserved subsets of glomeruli, the functional role of these activation maps remained unclear. By selectively disrupting glomerular map formation in the accessory olfactory bulb, we observed profound deficits in the ability of mice to interpret social chemosignals, leading to aberrant patterns of neuronal activation and aggression. This study reveals that precise glomerular mapping is essential for translating chemosignal detection into appropriate innate behaviors, bridging a key gap in our understanding of neural encoding in this system.

Unique structural and ligand-binding properties of the <i>Staphylococcus aureus</i> serine hydrolase FphE

Staphylococcus aureus is a human pathogen capable of forming biofilms that complicate treatment and facilitate chronic infections. A family of S. aureus serine hydrolases are important regulators of virulence and biofilm formation. Among these, FphE is highly specific to S. aureus and therefore a viable target for both imaging and therapy. Here, we present bioinformatic and structural evidence that FphE may be involved in aromatic compound metabolism. In addition, 12 distinct crystal forms reveal that FphE exists as a highly unusual but stable and flexible, cross-subunit homodimer, unique to the large alpha/beta hydrolase superfamily. Substrate engagement favors retention of the dimeric state, which is a more catalytically active form of the enzyme, and small-angle X-ray scattering confirms that the dimeric architecture occurs in solution. High-resolution cocrystal structures of FphE covalently bound to two chemically distinct ligands reveal different modes of active site engagement, supporting an atypical structural plasticity of the dimer interface. Together, these findings establish FphE as a structurally unique alpha/beta hydrolase and provide a foundation for structure-guided development of S. aureus –specific inhibitors and imaging probes.

NLRP1B is an integrated decoy that subverts <i> <i>Shigella</i> flexneri </i> E3 ligase activity to promote effector-triggered immunity

Inflammasomes are cytosolic immune complexes that recognize pathogen-associated stimuli to initiate a potent inflammatory response. While some inflammasomes directly recognize pathogen-associated molecules, others, such as the NLRP1B inflammasome, respond to pathogen-associated activities. Specifically, the NLRP1B inflammasome senses the enzymatic activity of pathogen-secreted proteases and E3 ligases through a mechanism of “functional degradation”—effectors that promote the proteasomal degradation of NLRP1B induce activation of this inflammasome. However, why pathogens would target NLRP1B for degradation when doing so promotes a robust inflammatory response is unclear. We propose that NLRP1 acts as an integrated decoy receptor by mimicking other host proteins targeted for degradation by pathogens. Specifically, we hypothesize that NLRP1B encodes sequences and features such that these pathogen effectors are unable to distinguish between NLRP1B and their other targets. To test this hypothesis, we determine how the Shigella flexneri E3 ligase IpaH7.8 is recognized by NLRP1B and whether these interactions are equivalent to those between IpaH7.8 and its other substrates, the Gasdermin (GSDM) family of proteins. Here, we show that IpaH7.8 recognizes both the GSDMs and NLRP1B through a single shared interface and that NLRP1B presents a surface similar to that recognized by IpaH7.8 on the GSDMs. In this way, NLRP1B acts as a decoy for the GSDMs to subvert the activity of IpaH7.8 to promote inflammasome activation. These data demonstrate that NLRP1B acts as an integrated decoy receptor and establish the use of integrated decoy receptors by the vertebrate immune system.

Visual awareness of stimulus features shapes motor control through action end-state comfort

Inorganic phosphate and the rapid mobilization of metabolic energy in neurons

Neurons experience brief, intense periods of energy demand when they are excited, but how they rapidly coordinate energy expenditure with production is incompletely understood. Part of the difficulty has been measuring the levels of molecules involved in this metabolic response with spatiotemporal precision in single live cells. Here, we engineered a quantitative fluorescent biosensor to monitor cytosolic inorganic phosphate (P i ), a fundamental component of energy metabolism that has a classically proposed but largely neglected role in activating glycolysis. Using two-photon fluorescence lifetime imaging, we observed millimolar increases in P i within seconds of stimulating mouse neurons both ex vivo and in vivo. Drawing on results from metabolic modeling, biosensor imaging, and enzymology, we argue that P i is a sensitive reporter of energy usage that potently links metabolic energy supply with demand in neurons. Quantitative live-cell imaging of P i should be a valuable approach for studying bioenergetics more generally.

Spatiotemporal evolution and drivers of grassland ecosystem service value in Inner Mongolia

Convergent motifs of early olfactory processing are recapitulated by layer-wise efficient coding

The architecture of early olfactory processing is a striking example of convergent evolution. Typically, a panel of broadly tuned receptors is selectively expressed in sensory neurons (each neuron expressing only one receptor), and each glomerulus receives projections from just one neuron type. Taken together, these three motifs—broad receptors, selective expression, and glomerular convergence—constitute “canonical olfaction,” since a number of model organisms including mice and flies exhibit these features. The emergence of this distinctive architecture across evolutionary lineages suggests that it may be optimized for information processing, an idea known as efficient coding. In this work, we show that by maximizing mutual information one layer at a time, efficient coding recovers several features of canonical olfactory processing under realistic biophysical assumptions. We also explore the settings in which noncanonical olfaction may be advantageous. Along the way, we make several predictions relating olfactory circuits to features of receptor families and the olfactory environment.

A deep reinforcement learning approach for dynamic transaction fee adjustment in Ethereum

Abstract Blockchain users pay transaction fees to miners or block proposers who validate and add transactions to the distributed ledger. Ethereum introduces the concept of gas to decouple transaction costs from Ether’s price volatility, calculating fees based on gas units. The current mechanism defined by Ethereum Improvement Proposal (EIP) 1559 dynamically adjusts the base fee according to block gas usage. However, its rule-based adjustment can lead to unstable gas consumption when demand fluctuates within a narrow range and struggles to respond efficiently to sudden demand spikes, such as during non-fungible token (NFT) drops. To address these limitations, we propose a deep reinforcement learning-based transaction fee mechanism that learns an adaptive base-fee update policy. Our approach maintains gas consumption close to the target level across various demand scenarios and stabilizes transaction fees and gas usage per block even under abrupt demand shifts. These results demonstrate that the proposed method provides a more adaptive and resilient fee adjustment mechanism compared to the current EIP-1559 model.

The psychology of offensive and defensive intergroup violence: Preregistered insights from 58 countries

Evolutionary theory and historical evidence suggest humans possess distinct psychological tendencies for defensive and offensive violence, which have insufficiently been considered in research. In a large-scale preregistered study across 58 countries ( N = 18,128), we demonstrate that violent extremist intentions manifest along two distinct psychological phenomena: defensive extremism, motivated by protecting one’s group from (perceived) threats, and offensive extremism, driven by establishing group dominance. We show that these dimensions a) can be reliably differentiated across diverse cultural contexts, b) are distinctively associated with psychological dispositions, and c) systematically differentiate countries varying in macrolevel sociopolitical functioning and violence. Across nations, a two-factorial structure was observed that was invariant at the scalar level. Defensive extremist intentions were consistently higher than offensive extremism in 56 out of 58 countries, suggesting greater moral acceptance of protective violence. While psychopathy was positively related to both types of violent extremist intentions, those high in Machiavellianism and narcissism demonstrated particularly higher levels of defensive extremist intentions. By contrast, those scoring high on religious fundamentalism and social dominance orientation demonstrated particularly higher levels of offensive extremist intentions. Unexpectedly, liberal political group identification was associated with higher offensive but lower defensive extremist intentions. Crucially, offensive (but not defensive) intentions were associated with macrolevel societal dysfunction, including political terror and internal conflict. These findings establish that defensive and offensive violent extremist intentions represent two conceptually different forms of extremism across a large and diverse range of countries, with consequences for research and practice.

Investigating uncharacterised genes in Saccharomyces cerevisiae using robot scientists

Abstract Despite extensive research on Saccharomyces cerevisiae functional genomics, approximately 880 out of ~6,000 open reading frames (ORFs) remain uncharacterised. In this study we propose a method for characterising genes with limited prior functional knowledge using an automated laboratory platform, in conjunction with several hypothesis instantiation methods. We demonstrate this method by investigating YGR067C , an uncharacterised ORF hypothesised to regulate respiration during the diauxic shift. Predictions of the first-order effects of deletion were obtained by curating a list of pathways relevant to the hypothesis. Higher-order effects were predicted using simulation models based on the GEM Yeast9. The predictions were tested using empirical data from biological experiments performed in the Robot Scientist Eve, which generated OD 560 , transcriptomics, and metabolomics data. We observed that YGR067C deletion led to downregulation of transcripts in some ethanol consuming respiratory pathways during the glucose phase During the ethanol phase we observed that NAD+, NADP+ and NADH accumulated, and several amino acid biosynthesis pathways were enriched for the ygr067c∆ strain, suggesting longer term consequences of YGR067C mediated regulation. Based on these observations we propose that the role of YGR067C during the diauxic shift is to regulate genes related to ethanol consumption and respiration in the glucose phase.

Phages drive the dissemination of antibiotic resistance genes by facilitating host adaptation to heavy metal stress

Heavy metals are increasingly recognized as major drivers of antibiotic resistance gene (ARG) dissemination in soil ecosystems. However, the role of phages in heavy metal–driven ARG dissemination and the underlying mechanisms remain poorly understood. Here, through integrative metagenomic, viromics, and metabolomic analyses of paddy soils across China, we reveal that soil phages promote ARG dissemination under heavy metal stress, likely through two potential mechanisms. First, phage-encoded auxiliary metabolic genes (AMGs) reprogram host metabolism to enhance bacterial survival and adaptation, thereby facilitating the cotransfer of adjacent ARGs and indirectly promoting horizontal dissemination. Second, phage-encoded heavy metal detoxification genes (HDGs) directly mediate metal detoxification, driving the cotransfer of neighboring ARG fragments and inducing lipid peroxidation–associated increases in membrane permeability, which collectively enhance ARG mobilization. We further identify a significant enrichment of lysogenic phages coharboring ARGs with AMGs or HDGs (AMG–ARG and HDG–ARG fragments), underscoring their contribution to ARG dissemination. Phage transplantation experiments confirm that elevated heavy metal stress triggers lysogenic phage-mediated ARG transduction to bacterial hosts. Cumulatively, our experiments highlight the pivotal role of phages in mediating ARG transfer under heavy metal pressure and underscore the necessity of incorporating phage dynamics into ARG risk assessments.

Biarticular energy transfer mechanisms of the gastrocnemii muscles are associated with managing body energy during hole negotiation gait

Abstract In this study, the energy transfer potential between the ankle and knee joints via the biarticular gastrocnemius medialis and lateralis muscles was investigated, as well as its association with changes in total centre of mass (CoM) energy during hole negotiation - a common task in daily life locomotion - and level walking. Whole-body kinematics and activation patterns of the gastrocnemii and vasti muscles were measured during the preparation, hole, and recovery steps in 18 participants. During hole negotiation, we found a significant ( p  &lt; 0.001) increase in the peak-to-peak range of total CoM energy, providing evidence for an increased challenge in managing CoM energy. We observed significantly ( p  &lt; 0.001) increased potential for energy transfer between the ankle and knee joints via the biarticular gastrocnemii muscles, accompanied by the gastrocnemii and vasti muscles being active during the energy transfer phases. Finally, we found that the increase in energy transfer potential from the ankle to the knee joint was associated with a decrease in total CoM energy, and the increase in energy transfer potential from the knee to the ankle joint was associated with an increase in total CoM energy. Our findings demonstrate increased involvement of biarticular mechanisms in the management of total CoM energy during hole negotiation compared to level walking.

Cell type diversification and phenotype convergence underlying white fin-ornamentation of cyprinid fishes

Neural crest–derived cells offer valuable opportunities to dissect mechanisms of cell fate specification and differentiation and the underpinnings of cell type diversification over evolutionary time. Particularly useful for such analyses are pigment cells of ectothermic vertebrates that arise from neural crest cells or via latent neural crest–derived stem cells. Among these are white cells, leucophores, present in a variety of species that contribute to patterns on the body or ornamentation on the fins. To better understand developmental and evolutionary origins of these cells, we examined leucophores harboring deposits of yellow/orange carotenoids—xantholeucophores—of zebrafish and leucophores of white cloud minnow. We show that white phenotypes of both cell types require sepiapterin reductase and an accumulation of pale and colorless pteridines. We further demonstrate that xantholeucophores of zebrafish develop from yellow, sepiapterin-rich xanthophore-like cells and that this transition requires both gap junctional communication and the aquaglyceroporin/peroxiporin channel Aquaporin 3, revealing similarities and differences in differentiation and patterning compared to pigment cells on the body. These findings identify xantholeucophores of zebrafish and leucophores of white cloud minnow as distinct developmentally, genetically, and biochemically from other white cells of zebrafish—melanoleucophores—that develop directly from melanophores and depend on guanine crystals, as well as white cells of medaka fish and anemonefish. Our results highlight remarkable convergences and parallelisms in the acquisition of white cell phenotypes within and between phylogenetic lineages and identify this as a rich system for enquiries into the evolutionary individuation of novel cell types.

Cloud assisted blockchain-enabled split federated learning framework for security and privacy-preserving of IoMT in healthcare 5.0

Biologically grounded on-chip model identifies selective topographic reorganization within hyperexcitable corticostriatal networks

The mammalian cerebral cortex projects to the striatum in a precise, hierarchical topography, forming parallel loops that underlie sensorimotor, associative, and limbic processing. Despite the striatum’s lack of clear anatomical boundaries, these projections remain functionally segregated, suggesting the existence of intrinsic organizing principles. Disruptions in corticostriatal connectivity and excitability are common in neurodevelopmental disorders, but it remains unclear whether such abnormalities are a cause or a consequence of circuit dysfunction. Here, we hypothesized that the excitability state of cortical neurons plays a direct role in shaping the topographic organization of their striatal projections. To test this, we engineered a biologically faithful in vitro platform inspired by the Tesla valve, enabling adjacent corticostriatal territories to be modeled under controlled excitability regimes. We found that cortical hyperexcitability disrupted the normal developmental transition from axonal growth to stabilization, leading to premature invasion of neighboring territories and the formation of ectopic convergence zones. As a result, the segregation between parallel pathways was lost, while local connectivity patterns remained unaffected. These findings reveal that intrinsic, activity-sensitive mechanisms constrain long-range axonal growth to shape the wiring diagram of the corticostriatal projectome. They also highlight the power of biologically grounded on-chip models to uncover how early circuit vulnerabilities can lead to connectivity defects characteristic of disorders such as autism spectrum disorder, schizophrenia, epilepsy, and obsessive-compulsive disorder.

Incidence of autism spectrum disorder in children in Kazakhstan and risk factors associated with all-cause hospitalizations