Biology subjects

Yao, L.

Publications and source records attributed to Yao, L..

At least 19 recordsLinked to original sources

bioRxiv2026

APLNR regulates directed migration to spatially pattern mesoderm in human gastruloids

During human gastrulation, mesoderm progenitors migrate while acquiring distinct identities. Whether this movement contributes to subsequent patterning remains unclear. Here, we identify the apelin receptor (APLNR) as a regulator of directed migration of mesoderm in human gastruloids. TBXT+ cells ingress basally and disperse from the PS-like region toward epiblast-like cells. Tracking reveals that this dispersal reflects a directional bias rather than increased speed. APLNR is enriched in nascent mesoderm, while its ligand APELA is expressed in adjacent epithelial cells. Control gastruloids exhibit fourfold greater dispersal than APLNR-depleted gastruloids despite modest speed differences, consistent with a model of chemotaxis by an epithelial ligand field. Paraxial and lateral mesoderm differentiation competence is preserved following APLNR depletion, while signaling programs and central FOXC2+ paraxial organization are altered. These findings support a role for APLNR-dependent guidance in positioning competent mesoderm progenitors for subsequent patterning.

developmental biology↗

bioRxiv2026

A conservative moving-boundary multiphysics framework reveals nonlinear coupling between osmotic flow and actin-driven cell migration

Cell migration couples membrane transport, intracellular fluid motion, and actin remodeling on a boundary that deforms with the cell. Quantitative interpretation of this coupling requires accurate one-sided membrane solute transport and conservative transfer between the G-actin and F-actin pools, because these fields determine the osmotic pressure and polymerization flux that enter the force balance. We develop an implicit immersed-boundary Stokes--Brinkman solver coupled to a sharp interface Cartesian grid advection--diffusion solver that enforces Robin conditions on the evolving membrane and advances F-actin/G-actin exchange through paired interface fluxes on the same accepted geometry. The framework resolves membrane mechanics, osmotic water permeation, solute transport, actin turnover, substrate drag, and intracellular advection in one calculation. Long-duration tests show excellent conservation of total actin and total solute under sustained interface motion and transport. The actin calculations recover biphasic dependencies on both depolymerization and substrate coupling, while pump-induced migration generates a rearward cell-relative cytosolic flow. In the fully coupled system, this flow redistributes G-actin more strongly than F-actin, reorganizes membrane polymerization and F-actin stress, and changes cell migration. Matched controls show that the coupled actin--osmotic system travels farther than the baseline-corrected sum of the isolated actin- and pump-driven responses. The calculations identify cytosolic convection as a physical route through which polarized membrane transport reorganizes the force-generating actin system and produces a nonlinear migration response.

biophysics↗

bioRxiv2026

Age-Adjusted Cerebellar Volumetry and Developmental Outcomes in Extremely Low Birth Weight Infants

Background: Infants with extremely low birth weight (ELBW) are at high risk for neurodevelopmental impairment, but the relationship between cerebellar structure and later developmental outcome remains incompletely defined. Methods: In this retrospective single-center study, we examined total cerebellar volume on clinically acquired brain magnetic resonance imaging (MRI) in ELBW infants while accounting for postmenstrual age (PMA) at imaging. Results: Of 65 infants screened, 42 were included. Mean gestational age at birth was 25.54 {+/-} 1.68 weeks, mean birth weight was 733.2 {+/-} 118.7 g, and mean PMA at MRI was 43.02 {+/-} 6.53 weeks (range, 31.57--68.00). Mean cerebellar volume was 22.17 {+/-} 9.63 cm. Independently adjudicated developmental outcomes comprised normal development in 16 infants, isolated or specific impairment in 12, and moderate/severe impairment in 14. Unadjusted cerebellar volumes did not differ across developmental groups (P = 0.490) or qualitative MRI categories (P = 0.875). However, the PMA-by-developmental-category interaction was significant (P = 0.002), with estimated cross-sectional slopes of 1.72, 1.56, and 0.39 cm per week, respectively. The interaction remained significant within 36--46 weeks PMA (n = 29; P = 0.011) and after adjustment for small-for-gestational-age (SGA) status. Sensitivity analyses indicated uncertainty in the stability of the interaction. Conclusions: These findings suggest that age-informed cerebellar volumetric patterns may provide developmental information not evident from average volumes alone and support prospective validation with standardized imaging and developmental assessments. As a result, cerebellar volumes obtained early in life may hold prognostic information for ELBW infants.

neuroscience↗

bioRxiv2026

Neuropeptides NLP-10 and FLP-18 stimulate lipid catabolism in chronically diet-restricted Caenorhabditis elegans

Neuropeptides mediate inter-tissue communication in energy metabolism, yet most remain functionally uncharacterized. Using C. elegans, we uncover a neuropeptide signaling cascade that drives lipid catabolism under chronic dietary restriction. We show that impaired pharyngeal function leads to dyspepsia and nutrient insufficiency, which activates a signaling axis comprising two peptide-receptor pairs, NLP-10-NPR-35 and FLP-18-NPR-4. This cascade originates in ADL sensory neurons, relays through multiple interneurons, and enhances triglyceride hydrolysis in the intestine. Genetic disruption of any component of this axis restores fat accumulation in diet-restricted mutants, whereas overexpression of individual components in well-fed animals is insufficient to drive fat mobilization. Importantly, the same neuropeptide axis is engaged in starved wild-type animals, indicating a general response toward energy deficit rather than mutant-specific effects. These findings reveal a conserved neuroendocrine circuit that senses internal energy shortage and orchestrates systemic metabolic adaptation, providing a conceptual framework for how neuropeptide networks integrate nutritional status with energy balance in animals.

neuroscience↗

bioRxiv2026

Hygrochastic Seedpods: Engineering Microclimates for Forest Restoration

Forest restoration at scale depends on sowing seeds directly onto the land, yet seedling establishment is often poor and inconsistent. Seed enhancement technologies, such as priming, coating, and pelleting, improve germination under water, temperature, and salinity stress by supplying polymers, nutrients, or microorganisms at the seed surface. Being mainly conformal films, they act continuously once wetted and cannot gate when a seed is exposed to the soil. They also enclose no air volume, so the microenvironment they create is inseparable from the surrounding soil and has been inferred from plant performance rather than measured directly. Whether an engineered carrier can instead set both the state and the duration of the post-dispersal microenvironment, and how such an effect can be directly quantified, remains unexplored. Here we show that hygrochastic seedpods hold seeds in a timed, directly measurable microclimate and accelerate seedling emergence. The pods are programmable, responsive conical shells enclosing an air cavity around the seed. Two design solutions were investigated in parallel: wooden seedpods that crack open upon hydration, and poly(vinyl alcohol)/boric acid seedpods that gradually disintegrate after sustained wetting. In both, wax coatings act as a programmable diffusion-limited timer that sets activation from hours to days. The pod cavity permits direct sensing and monitoring, which no coating geometries allow. As directly measured during the initial phase after deployment, seedpod interiors ran 2 - 3 C warmer and drier than the surrounding soil, and these differences persisted after opening. Across indoor and field trials in several tree species, pods accelerated early seedling emergence without penalizing subsequent growth. These results identify artificial hygrochastic seedpods as a transient ecological mediator that regulates both the timing of seed exposure and the microclimate around the seed, offering a strategy for improving forest restoration under variable environmental conditions.

bioengineering↗

bioRxiv2026

PlantRegMoD: An integrative and AI-driven multi-omics database for plant regeneration research

Plant regeneration underpins plant developmental plasticity, tissue culture, genetic transformation and crop improvement. Although numerous related omics datasets have been generated, specialized multi-omics databases for this field are still scarce. Here, we constructed PlantRegMoD, an AI-powered integrated database dedicated to plant regeneration. This platform hosts 20.54 TB standardized multi-omics data from 147 projects across 32 plant species and 2,593 samples. We established a unified hierarchical classification system covering five major categories and nine regeneration models, and curated 236 regeneration genes as well as their 28,190 homologs across 58 representative plant species. It contains extensive transcriptomic resources across all regeneration models, together with 196,423 single cells and over 8.81 million epigenetic peaks to dissect cellular heterogeneity and multi-layered epigenetic regulation. Equipped with nine online omics-related tools and a RAG-based intelligent Q&A system, PlantRegMoD greatly reduces bioinformatic barriers and serves as a robust resource for mechanistic, functional and evolutionary studies of plant regeneration.

plant biology↗

bioRxiv2026

Structures of MeCP2 bound to nucleosomes reveal distinct mechanisms of Rett syndrome mutations

Methyl-CpG binding protein 2 (MeCP2) is a chromatin-associated regulator essential for neuronal gene regulation, and pathogenic mutations in MeCP2 cause Rett syndrome (RTT). However, the mechanisms governing MeCP2 engagement on chromatin and the effects of RTT mutations on nucleosome interactions remain poorly understood. We determined cryo-EM structures of MeCP2 bound to mono-nucleosomes with or without linker DNA methylation. In the absence of linker DNA methylation, the methyl-CpG binding domain (MBD) engages nucleosomal DNA near superhelical location +/- 7, whereas a methylated linker CpG redirects MBD to the linker methylation site. Quantitative EMSA, MNase footprinting, and fluorescence polarization show that both MBD and AT-hook regions cooperate to stabilize nucleosome binding, and that six common RTT variants (R133C, T158M, R306C, R168X, R255X, R270X) fall into four mechanistic classes. Loss-of-function truncations progressively weaken binding, whereas missense variants show near-WT DNA affinity. Among the variants, R133C shows near wild-type affinity for naked DNA but loses methylation-directed nucleosome engagement. Our analysis of human neuronal transcriptomic and chromatin occupancy datasets showed that RTT variants R133C and R168X lose CpG-island specificity and redistribute in the genome through distinct biochemical routes. Together, this work establishes a framework linking variant-specific defects in nucleosome binding to chromatin-targeting failure and transcriptional dysregulation in RTT.

biochemistry↗

bioRxiv2026

Transcription-specific synaptic plasticity mediates engram computations

Memory is encoded by sparse ensembles of neurons. While activity-dependent transcription and learning-induced synaptic plasticity are causally related to memory formation and recall, the link between the transcriptional regulation of synaptic plasticity and memory computations remains elusive. In particular, even though transcriptionally defined neuronal ensembles within a memory engram exhibit specific forms of synaptic plasticity and support distinct behavioral outputs, it is still unclear whether transcription-specific synaptic plasticity drives ensemble computations, rather than merely serving as a marker of ensemble identity. Here, we demonstrate that transcription-specific synaptic plasticity enables ensemble computations essential for learning-induced adaptive behaviors. In the mouse dentate gyrus (DG), we found that neuronal ensembles genetically defined by Fos-dependent transcription engage plasticity in feedforward excitatory synapses, whereas those defined by Npas4-dependent transcription engage plasticity in recurrent inhibitory synapses. We modeled spiking neural networks with transcription-specific synaptic plasticity and observed that Fos- and Npas4-dependent ensembles emerged following learning and stabilized with memory consolidation. Our computational model predicted that blocking Fos- or Npas4-dependent synaptic plasticity disrupts memory generalization and discrimination, respectively. By acutely deleting Fos or Npas4 in the DG to selectively block Fos- or Npas4-dependent synaptic plasticity, we conducted contextual fear conditioning experiments whose results supported our computational model's prediction. Our study provides causal evidence that specific transcriptional programs induced in distinct neuronal ensembles differentially engage synaptic plasticity and thereby regulate memory computations.

neuroscience↗

bioRxiv2026

Phagocytic activity of perivascular cell promotes CNS injury pathology

Injury, stroke, and neurological diseases cause persistent accumulation of cellular debris that deteriorates lesion microenvironment and impedes central nervous system (CNS) repair. Debris clearance in the injured CNS has long been attributed primarily to microglia and infiltrating macrophages. Here, we identify perivascular cells as previously unrecognized phagocytes that expand after injury and exhibit robust phagocytic activity. Perivascular cell phagocytosis is conserved across multiple mouse models of CNS injury and human stroke lesions. These cells exhibit key hallmarks of phagocytosis, including LC3-associated phagocytosis for efficient lysosomal degradation. Mechanistically, phosphatidylserine serves as the eat-me signal and Axl mediates myelin debris uptake. Myelin phagocytosis drives perivascular cell proliferation, fibrosis and lesion progression. Genetic deletion of Axl in perivascular cells or pharmacological inhibition with the FDA-approved Axl inhibitor Gilteritinib reduces pathology and improves functional recovery after spinal cord injury. Together, these findings establish Axl-dependent perivascular cell phagocytosis as a therapeutic target for CNS repair.

neuroscience↗

bioRxiv2026

Assembly of the ATP-driven cobalt chelatase

Nature has evolved two distinct chelatase families to catalyze the insertion of metal ions into tetrapyrrole macrocycles. Whereas the single-subunit ATP-independent chelatases have been widely investigated, little is known about the three-subunit ATP-driven chelatases. Here we show step-wise assembly of the ATP-driven cobalt chelatase CobSTN that is essential for aerobic vitamin B12 biosynthesis. The motor subunit CobS fits into a hexameric or dodecameric spiral, and forms complex with the adaptor subunit CobT. Upon binding to adenine nucleotide, the spiral transforms to an asymmetrical ring and CobT synergistically rotates and inserts a distinctive shaft into the ring hole. The largest subunit CobN interacts with the opposite side of CobT from the CobS ring, and hence the holoenzyme is assembled.

biochemistry↗

bioRxiv2026

IgGM2: An All-Atom Foundation Model for Adaptive Immune Receptor Design

Accurate immune receptor design requires modeling the coupled variation of aminoacid sequence, full-atom conformation, and target-binding geometry across antibodies, nanobodies, and T-cell receptors (TCRs). Existing methods often address only part of this problem, either by separating structure generation from sequence design, relying on fixed-backbone inverse folding, or focusing on a single receptor class. We introduce IgGM2, a unified all-atom generative framework for immune receptor structure prediction and CDR sequence-structure co-design. IgGM2 follows a structure-to-design strategy: it first learns how immune receptors are positioned around fixed target structures, and then transfers this target-conditioned structural prior to CDR design. Unlike modular design pipelines, IgGM2 jointly generates CDR residue identities and full-atom receptor structures, allowing frame-work geometry to adapt to designed CDRs without separate inverse folding or external sidechain packing. Unlike continuous residue encodings based on virtualatom geometry, IgGM2 keeps sequence prediction explicit while using atom14 placeholders only for full-atom representation. On structure prediction benchmarks, IgGM2 better captures receptor-target spatial relationships than AlphaFold3 on FoldBench and achieves strong performance on TCR-pMHC modeling. On sequence design benchmarks, IgGM2 achieves competitive amino-acid recovery and improves Rosetta-based interface preference metrics, suggesting more favorable generated binding interfaces. These results support IgGM2 as a unified all-atom framework for adaptive immune receptor structure prediction and design.

bioinformatics↗

bioRxiv2026

MDA5 and the integrated stress response control sex-specific type 1 diabetes onset in NOD mice

Type I diabetes (T1D) is an autoimmune disorder in which the insulin producing cells of the pancreas are attacked and destroyed by autoreactive T cells. The innate immune mechanisms that contribute to T1D remain incompletely defined. Genome-wide association studies in humans have identified alleles of the IFIH1 gene, which encodes the intracellular RNA sensor MDA5, that are strongly associated with development of T1D. We previously found that MDA5 signaling drives disease and mortality in a mouse model of Aicardi-Goutieres Syndrome (AGS) caused by mutations in the ADAR1 RNA editing enzyme. Genetic dissection of disease in this ADAR1 mutant mouse model revealed that the double stranded RNA-activated kinase PKR and the RNA sensor ZBP1 are also essential for disease. To test the role of intracellular RNA detection in T1D in the nonobese diabetic (NOD) mouse model, we used CRISPR targeting to generate NOD mice targeted for Ifih1, Eif2ak2 (PKR) and Zbp1. We found that haploinsufficiency for Ifih1 resulted in modest but significant protection from T1D only in male NOD mice, but neither PKR nor ZBP1 contributed to T1D onset or incidence. Moreover, treatment of NOD mice with a pharmacological inhibitor of the integrated stress response (ISR) had no effect on T1D incidence in female NOD mice, but accelerated and exacerbated disease in male NOD mice. Together, our findings demonstrate that MDA5 and the ISR contribute to sex-specific disease incidence in NOD mice.

immunology↗

bioRxiv2026

Hepatic Acetate is an Essential Fuel for the Heart during Energy-Deprived States

Energy supply is fundamental to cardiac performance, yet the mechanisms by which the heart adapts to nutrient scarcity remain incompletely understood. Here, we identify acetate as a pivotal metabolic substrate that sustains cardiac contractile function during fasting-induced energy deficiency. Fasted mice reveal significant elevation of circulating acetate derived from hepatic fatty acid catabolism. Physiological concentrations of acetate alone can maintain ex vivo beating and electrical stability in Langendorff-perfused hearts. Primary mouse cardiomyocytes preferentially utilize acetate under energy-restricted conditions, which is abolished by knockdown of mitochondrial Acss1, the enzyme responsible for converting acetate to acetyl-CoA. Isotopic tracing with 13C-acetate demonstrated selective cardiac uptake during fasting. In vivo, acetate supplementation preserved heart rate and systolic function in fasted wild-type mice but not in Acss1-deficient hearts. These findings reveal an Acss1-dependent metabolic pathway enabling the heart to harness hepatic acetate as an endogenous fuel, representing a nutrient stress-responsive adaptation based on inter-organ crosstalk and implying therapeutic potential of acetate to energy-deficient heart diseases.

biochemistry↗

bioRxiv2026

Quantitative Imaging and Characterization of Ganglioside Diversity in Mouse and Human Brain Tissues

Our understanding of how ganglioside species are spatially and quantitatively distributed within regions in mammalian remains limited. Studies are typically translated from rodents, assuming that gangliosides species contents within brain regions reflect the human condition. Herein, we provide a rich spatial ganglioside brain atlas describing the content, compositional differences, and concentrations of 48 ganglioside species across different regions in mouse and humans with no clinically known neurodegeneration. Our quantitative mass spectrometry imaging (MSI) approach allows non-rigid co-registration of mass spectrometry and microscopy images to allow precise spatial alignment and extraction of normalised ganglioside concentration data to reference mouse brain tissue anatomy and neuropathological annotated tissues for flexible downstream lipidomics analysis. Considerable differences and similarities are observed permitting region-specific ganglioside maps across twelve brain regions in wild type mouse. Gangliosides in mouse brain tissue generally preferred Cer 36:1;O2 configurations whereas human gangliosides in corresponding anatomically-annotated regions tended to favour Cer 38:1;O2 and longer backbones. Notably, this observation is more pronounced in gray matter compared to white matter. Collectively, this study defines the precise and quantitative ganglioside atlases across mice and human brains to guide and accelerate the discovery of biomarkers and therapeutic targets for brain diseases.

neuroscience↗

bioRxiv2026

Structure of the human HIRA histone chaperone with a nucleosome suggests a stepwise nucleosome assembly mechanism

The restoration of chromatin in the wake of a DNA or RNA polymerase is essential to maintain the integrity of eukaryotic genomes. Human HIRA is a 1.8-megadalton, three-subunit histone chaperone that mediates all replication-independent deposition of the histone variant H3.3 at active chromatin regions1-6. Disruption of HIRA perturbs active-chromatin organization and has wide-ranging consequences for development, cellular senescence, and genome integrity7-11. Despite its central biological role in reassembling nucleosomes post-transcription, the structure of native human HIRA and the mechanism by which it organizes histones and DNA during nucleosome assembly remain unknown. In particular, the function of the largest HIRA subunit CABIN1 is enigmatic. Here, we show that HIRA is not simply a passive histone hand-off factor but remains engaged across multiple stages of nucleosome assembly, including a close interaction with the nucleosome. Cryo-EM structures reveal that HIRA forms an extended arch-like structure that binds the nucleosome primarily through extensive CABIN1 contacts with histones, histone tails, nucleosomal DNA, and linker DNA, during the final stage of nucleosome assembly. Together, our results suggest a testable mechanism for HIRA-mediated nucleosome assembly and product release and provide the basis for elucidating the molecular details of this fundamental biological process.

biochemistry↗

bioRxiv2026

Prevotella copri alleviates hyperuricemia via uricolysis and gut microbiota reconstruction

Despite the therapeutic promise of uric acid-metabolizing microbes for hyperuricemia, their application is hindered by the scarcity of highly efficacious strains. To identify uric acid-metabolizing microbes, we enriched gut microbiota from cynomolgus monkeys under uric acid-supplemented conditions. This selection increased the abundance of Prevotellaceae_UCG-001 and norank_f_Prevotellaceae, implicating Prevotella species as key uric acid degraders. In vitro validation confirmed efficient uric acid consumption by two new Prevotella isolates and the reference strain Prevotella copri DSM 18205 (P. copri). Oral administration of P. copri in hyperuricemic mice reduced uric acid levels in serum and kidney tissues and alleviated renal fibrosis by suppressing the TGF-{beta}/Smad pathway and downstream fibrogenic genes. Moreover, P. copri administration restored the depleted population of Faecalibaculum, and further assays demonstrated that Faecalibaculum rodentium directly metabolizes uric acid. Collectively, P. copri alleviates hyperuricemia via a dual mechanism: direct uric acid catabolism and enrichment of commensal uric acid-consuming bacteria. These findings establish P. copri as a promising live biotherapeutic agent for hyperuricemia and highlight microbial collaboration as a therapeutic strategy for metabolic diseases.

microbiology↗

bioRxiv2026

Assessing the affinity spectrum of an antigen-specific memory B cell repertoire by inverted ImmunoSpot

The biological efficacy of an antibody is largely defined by its affinity. Moreover, because the binding affinity of an antibody can span orders of magnitude, each antigen-specific B cell would not be expected to contribute equally to humoral defense: high-affinity antibodies are likely to possess increased potency in comparison to those with lower affinities. Hence, assessing the affinity spectrum of a persons antigen-specific B cell repertoire would provide valuable information on their immune competence. Currently, cloning and expression of large numbers of monoclonal antibodies (mAbs) per test subject would be required to gain such insights, but this is impractical in the context of large-scale immune monitoring efforts. Here, we introduce a variant of the B cell ImmunoSpot assay that can simultaneously assess the relative affinity distribution of hundreds of individual B cells in a test sample. Additionally, we also demonstrated its suitability for high-throughput assay workflows that require minimal labor and exploit machine-assisted image analysis software tools. Specifically, as proof of principle, we verified that B cell hybridomas secreting mAbs of different affinities for the SARS-CoV-2 Spike protein could readily be distinguished through simple titration of the soluble antigen detection probe. Furthermore, using this assay methodology we provide evidence for affinity maturation within the Spike-specific memory B cell repertoire following a second COVID-19 mRNA vaccination. Collectively, we introduce a high-throughput suitable and scalable methodology with the potential of filling a major gap in the immune monitoring field: characterizing the affinity distribution of antigen-specific B cells in large study cohorts.

immunology↗

bioRxiv2026

Geometry-enhanced protein language modeling enables discovery of novel antibiotic resistance genes

The global antibiotic resistome remains largely unexplored, not because antibiotic resistance genes (ARGs) are rare in the environment, but because many are evolutionarily distant from known ARGs. Current computational approaches primarily rely on sequence homology, and thus miss distant homologues. We develop GeoARG, a geometry-enhanced framework that integrates structural features with protein language models through knowledge distillation, enabling efficient large-scale screening using sequence input alone. Across multiple benchmarks, GeoARG substantially improves the detection of remotely homologous ARGs, particularly under low sequence identity and fragmented conditions. Large-scale metagenomic analysis uncovers 1,485 high-confidence ARG candidates that are highly divergent from known ARGs, expanding the phylogenetic and functional landscape of the resistome. Structural analyses further show that these candidates preserve active-site geometry and maintain stable ligand-binding configurations consistent with known resistance mechanisms. These results demonstrate that geometric constraints enable systematic expansion of the resistome and facilitate the discovery of evolutionarily distant yet functionally conserved genes. A public web server is available at https://ycclab.cuhk.edu.cn/GeoARG/.

bioinformatics↗