Biology subjects

Yu, Y.

Publications and source records attributed to Yu, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Interspecific hybrids reveal a deeply conserved nuclear role of EIF1A-family proteins in zygotic genome activation

Zygotic genome activation (ZGA) launches inaugural gene expression and autonomous development of the embryo. Yet, conserved regulators of ZGA among different mammals remain poorly defined. Here, we generated interspecific hybrid embryos to place distant mammalian genomes in a shared maternal cytoplasm. These hybrids undergo cleavage and transcriptional activation from divergent parental genomes. Comparative transcriptomics identifies a core set of zygotic genes reproducibly activated across different hybrid contexts, including the Eif1a-like family. Depletion of EIF1A-like proteins disrupts ZGA and preimplantation development in mouse, pig and cattle embryos. Although best known for translation initiation, these proteins contain a conserved nuclear localization signal and translocate to the nucleus at the onset of major ZGA. Further studies revealed that they occupy promoters of nearly all ZGA genes and MERVL/MT2 retrotransposons, required for local chromatin accessibility. These findings uncover a conserved nuclear licensing function for EIF1A-family proteins in zygotic genome activation among divergent mammalian embryos.

developmental biology↗

bioRxiv2026

VenusGenome: Genome-Aware Masked Autoencoding for Microbial Genome Representation Learning

Genomic-context models have shown that contextualizing protein embeddings can improve predictions of microbial function. We observe that a gene's protein embedding is partially predictable from the embeddings of neighboring genes in the genome, motivating high-ratio masking that requires reconstruction from sparser genomic context. Genomic modeling must also distinguish biological relationships from assembly conventions, since the ordering of separate contigs does not imply adjacency and strand labels depend on the reference orientation. We therefore introduce VenusGenome, a gene-resolution masked autoencoder that combines visible-only encoding with genome-aware attention incorporating contig boundaries, relative strand orientations, and gene positions. We pretrain this model on a curated corpus of over 1.7 million microbial genome assemblies from isolate and metagenomic sources, using frozen protein embeddings as gene-level inputs. Across genome-level phenotype prediction and gene-level tasks, the resulting frozen representations achieve the highest mean performance among the evaluated models on nine of eleven primary metrics. An exploratory gene-input perturbation analysis further links representation sensitivity to experimentally measured fitness defects. Ablations support the contribution of genome-aware attention and show the benefits of masked autoencoding over BERT-style masked modeling, with further gains from higher masking ratios.

bioinformatics↗

bioRxiv2026

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.

neuroscience↗

bioRxiv2026

Defense-associated reverse transcriptases synthesize DNA in a telomerase-like manner

Defense-associated reverse transcriptases (DRTs) constitute an emerging class of bacterial defense systems that harness reverse-transcriptase activity to generate cDNA products and counter phage infection. A distinct subset of DRT10 systems evolutionarily related to telomerase generates tandem-repeat DNA to confer antiphage immunity. Here, we biochemically characterize the reverse transcription activity of DRT10 and determine cryo-EM structures of DRT10-ncRNA complex in three functional states, revealing an unanticipated 2:1 RT:ncRNA assembly mode. Two DRT10 protomers dimerize through a central pair of interlocked {beta}-hairpins and are further embraced by a single ncRNA. This architecture distinguishes DRT10 from previously characterized DRT complexes, which either lack an ncRNA component or exhibit an equivalent stoichiometry of RT:ncRNA. Strikingly, despite the nearly identical conformations of the two DRT10 protomers, cDNA product density was resolved in only one catalytic pocket, revealing different product occupancy within the dimer. Moreover, along with flanking linkers, the stem loops of the ncRNA as fixed points to supply steric barriers help define the template boundary. These findings reveal a distinctive ncRNA-mediated DRT10 dimeric assembly and establish a mechanistic framework for protein-primed reverse transcription constrained by the length of the RNA flanking linker.

biochemistry↗

bioRxiv2026

Genetic accessibility, not superior fitness, determines which anti-HBs antibody escape variants are selected in patients

Background and Aims: Genetic diversity within the hepatitis B virus (HBV) surface antigen (HBsAg) drives the emergence of immune escape variants, but studying this diversity in vivo has been limited by the difficulty of establishing infection from patient isolates. We aimed to perform unbiased in vivo screening of variants in the HBs antigenic loop for antibody escape and fitness, using synthetic DNA launch of HBV in human hepatocyte chimeric mice. Approach and Results: Direct intrahepatic injection (IHI) of barcoded, recombinant cccDNA established infection from up to 32,000 independent launch events of a genotype A strain and successfully launched clinical consensus sequences across the major genotypes. Using IHI, we performed deep mutational scanning of 4,608 codon variants across the HBs antigenic loop. Under control antibody treatment, diverse variants expanded, revealing differences in variant fitness in the absence of adaptive immune pressure. Anti-HBs monoclonal antibody treatment suppressed wild-type viremia while permitting breakthrough of resistant variants from the library. Sequencing identified strong enrichment for substitutions at G145 (G145Q, G145H, G145R). Notably, G145Q, rather than the clinically dominant G145R, showed the greatest fitness advantage, indicating that G145R's clinical prevalence does not reflect superior intrinsic fitness. Conclusions: Unbiased in vivo screening reveals that clinically observed HBV escape mutations reflect which substitutions are genetically accessible by single nucleotide change and compatible with the overlapping polymerase reading frame, rather than which confer optimal fitness. This approach establishes a platform for high-resolution mapping of viral variant fitness under antiviral selection pressure.

microbiology↗

bioRxiv2026

YGEP: An Integrated Web Platform for Genomic Evaluation and Intelligent Breeding in Yak

Background: The yak (Bos grunniens) is an essential livestock species in high-altitude alpine ecosystems, serving key roles in meat, milk, and wool production as well as ecological maintenance. However, traditional yak breeding systems face several limitations, including fragmented herd data management, inefficient phenotypic collection, missing pedigree records, and high technical barriers to applying genomic technologies. These factors constrain the widespread application of modern genetic evaluation methods in yak breeding programs. Description: We developed the Yak Genomic Evaluation Platform (YGEP, https://yakbreeding.swun.edu.cn/en/), an integrated digital system for yak genetic selection and herd management. YGEP integrates three core analytical modules: pedigree reconstruction, genotype imputation and genomic breeding value estimation. Benchmarking on 706 yaks showed that GBLUP achieved a prediction accuracy of r = 0.96 for cannon bone circumference (CCB), and KBeagle reached 84.0% imputation accuracy with the combined reference panel. Conclusion: YGEP bridges the gap between advanced genomic analytics and practical yak breeding. By integrating pedigree reconstruction, genotype imputation, and GEBV estimation into a user-friendly cloud platform, YGEP effectively eliminates technical and data bottlenecks. Overall, it provides an accessible, scalable, and standardized solution to advance digital herd management and precision genetic improvement in alpine livestock.

bioinformatics↗

bioRxiv2026

Spatial transcriptomics reveals tumour cell-intrinsic and microenvironmental features associated with survival in high-grade serous ovarian carcinoma

High-grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian carcinoma and accounts for the majority of deaths from the disease, with fewer than half of patients surviving five years after diagnosis. Bulk transcriptomic profiling has identified molecular subtypes and gene-expression signatures associated with shorter or longer survival. However, because bulk profiling measures a composite of tumour and microenvironmental gene expression, the cellular origins of these signatures and their relationship to the tumour microenvironment remain unresolved. To address this, we applied Xenium spatial transcriptomics to treatment-naive HGSOC tumours from 122 patients using a custom 480-gene panel designed to measure tumour-intrinsic gene expression and distinguish immune and stromal cell populations in the surrounding microenvironment. Analysis of tumour-intrinsic gene expression identified 61 genes nominally associated with overall survival, from which Elastic-Net modelling prioritised five genes associated with longer survival and nine associated with shorter survival. Notably, 46 of the 61 associations did not reach the nominal significance threshold when expression was instead aggregated across all cells from the same patients, highlighting how whole-tissue expression can obscure tumour-cell-specific survival associations. Complementary analysis of tumour-proximal cell populations revealed that multiple immune populations were associated with longer survival, whereas two fibroblast populations were associated with shorter survival. Integrating these analyses revealed that survival-associated tumour-intrinsic gene expression was correlated with the abundance of neighbouring immune and stromal populations that were themselves associated with survival. Pairwise Cox regression demonstrated substantial overlap in the prognostic information captured by these features, while analysis of individual gene-cell combinations showed that survival associations differed according to the abundance of neighbouring populations. Consensus clustering further identified four patient groups with distinct combinations of tumour-intrinsic expression and microenvironmental composition, broadly separating patients with longer and shorter survival. Together, this cohort-scale spatial analysis identifies tumour-intrinsic and microenvironmental features associated with HGSOC survival and reveals how their correlated patterns and combined associations relate to patient outcome.

cancer biology↗

bioRxiv2026

Spontaneous eye behavior is an objective marker of parkinsonian severity

Eye behavior disruption is reported in Parkinson's disease (PD), but its correlation with disease severity has not been well examined. Here, in a nonhuman primate model of PD, we show that spontaneous eye behavior is impaired in parkinsonism and correlates with clinical rating scores and subthalamic beta oscillatory activity. These findings suggest that spontaneous eye behavior could serve as an objective, non-invasive biomarker of parkinsonian severity.

neuroscience↗

bioRxiv2026

DisenTE: Sparse Pattern-Context Modeling for Interpretable Translation-Efficiency Matrix Completion

Partially observed object-by-context matrices arise across data-rich science, where dominant object effects can obscure smaller but informative context-dependent variation. We study this problem in a translation-efficiency atlas of 9,494 5' UTRs across 78 cellular and tissue contexts. We present DisenTE, a sequence-conditioned neural model that combines separate sequence and context branches with a sparse low-rank pattern-context channel. Each module pairs a sequence-derived activation with context-specific deployment weights, forming a dictionary whose sequence and context components can be examined separately. Under five-fold within-panel entry masking, DisenTE achieves a UTR-centered residual Spearman correlation of 0.641 +/- 0.005, compared with 0.304 +/- 0.003 for the strongest reference model. The learned dictionary retains 11 of 20 candidate modules. CTM 6 has the largest overlap with an external TOP set and a cap-proximal pyrimidine pattern; CTMs 5 and 7 also overlap the set but have purine-containing consensuses. The evidence supports CTM 6 as a TOP sequence anchor and CTMs 5 and 7 as TOP-set-associated factors. On this dataset, DisenTE improves completion over the evaluated references and provides module-level summaries of its fitted context-dependent variation.

bioinformatics↗

bioRxiv2026

Loss of DNA Demethylase Enhances Arsenic Resistance Via Reducing of PIN2 Antisense Long Noncoding RNA

DNA methylation dynamics regulate diverse plant stress responses, but the mechanisms governing arsenic (As) tolerance through epigenetic pathways remain largely unknown. Here we report that Arabidopsis mutants lacking the DNA demethylase, REPRESSOR OF SILENCING (ROS1), show substantially enhanced As resistance. Integrating transcriptome and methylome data, we found that PIN-FORMED 2 (PIN2), encoding an auxin efflux carrier that also transports As out of cells, represents a key ROS1 target. In ros1, we observed increased methylation in the last exon of PIN2, a region functioning as the promoter for an antisense long non-coding RNA (lncRNA). Hypermethylation of the promoter suppresses the antisense lncRNA, which follows reduction of sense PIN2 transcription. As a result, PIN2 expression increases in ros1 mutants during As exposure, enhancing As tolerance. Analysis of ros1 pin2 double mutants confirmed that PIN2 acts downstream of ROS1 in As tolerance. Our study demonstrates an epigenetic pathway in which ROS1 regulates As tolerance by controlling PIN2 expression through antisense lncRNA-mediated transcriptional interference, offering new epigenetic strategies using plants in heavy metal contaminated environments.

plant biology↗

bioRxiv2026

Brain state shapes the polarity of pulsed infrared neural stimulation responses in individual cortical neurons

Pulsed infrared neural stimulation (INS, 1875nm the peak of energy absorption by water) is a non-viral method developed to activate single submillimeter sites in the brain. When used in ultrahigh-field fMRI, it reveals functionally specific brain-wide columnar networks comprising synaptically activated nodes. INS is non-damaging and effective for use in the human cortex and is useful for neural and behavioral neuromodulation in primates. To investigate how physiological state influences its cellular effects, we performed in vivo two-photon calcium imaging with GCaMP6s in mice and tracked identified cortical neurons in awake vs anesthetized states. Across the tested radiant exposures, INS-evoked responses differed markedly between states: under anesthesia, stimulation produced predominantly positive-going calcium responses, whereas during wakefulness the same identified neurons exhibited negative-going responses. Pharmacological manipulation of this baseline level by GABAergic signaling shifted response polarity in opposite directions: picrotoxin under anesthesia produced awake-like negative responses, whereas muscimol during wakefulness produced anesthetized-like positive responses. Trial-by-trial analyses further showed that the relationship between pre-stimulus baseline level and INS-evoked response depended on physiological state. Because INS relies on transient tissue heating, we also developed an in situ EGFP-based calibration approach to estimate temperature-related fluorescence changes. These fluoro-thermal contributions were modest at lower radiant exposures and became increasingly important at higher exposures, particularly near the fiber pathway. The low-intensity results are consistent with, but do not establish, a state-dependent feed-forward inhibitory framework. Together, these findings show that the neuronal response to focal INS is shaped by ongoing brain state and provide a practical framework for separating state-dependent calcium responses from temperature-related fluorescence effects, making INS a potentially versatile tool for neuroscience and clinical applications.

neuroscience↗

bioRxiv2026

Xenon improves autism-like behaviors in mice through potentiation of PVT-CeA glutamatergic neurotransmission

Autism spectrum disorder (ASD) is a common neurodevelopmental disease with no currently effective treatments. In this study, Xenon (Xe), a noble gas used clinically as an anesthetic and a neuroprotectant, has been investigated for its potential therapeutic effects in ASD. Two genetic ASD mouse models (Mef2c mutant and Shank3-/- mice) were exposed to a low concentration of xenon (25%) mixed with oxygen (30%) and balanced with nitrogen for a single exposure of 30 min or for 10 min per day for 10 days. These Xe exposure paradigms rescued ASD-like behaviors in both male and female mice. The behavioral improvements persisted for up to 10 days following termination of the 10-day exposure paradigm. Mechanistically, Xe reduced glutamic acid decarboxylase expression in the inhibitory neurons (verified with RNAseq) of the paraventricular thalamic nucleus (PVT) and decreased GABA release during social interaction. Targeted infusion of the GABAA receptor agonist muscimol into the PVT abolished the Xe-mediated behavioral improvements. Reduced GABAergic transmission following Xe exposure increased PVT glutamatergic neuronal activity. Chemogenetic inhibition of these neurons eliminated the therapeutic effects of Xe, whereas chemogenetic activation mimicked the Xe-induced behavioral improvements. Furthermore, opto-inhibition of PVT glutamatergic projections to the central amygdala (CeA) blocked Xe-mediated behavioral improvement. Opto-activation of the PVT-CeA glutamatergic circuit reversed ASD-like behaviors. These findings demonstrate that Xe ameliorates ASD-like phenotypes in mouse models by modulating the PVT Glu-CeA circuit, supporting Xe as a novel potential therapy for ASD.

animal behavior and cognition↗

bioRxiv2026

Somatic differentiation evolves rapidly and repeatedly through the modification of developmental plasticity

Plasticity has been proposed to facilitate the evolution of novelty, but it's unclear if it can drive a transition to a novel kind of individual. We report the experimental evolution of obligate somatic differentiation in Eudorina, a predominantly undifferentiated species that develops plastic somatic cells in response to cold stress. Eudorina is a species of volvocine algae, a clade in which cellular differentiation has evolved repeatedly. We exposed Eudorina from 2 lab lines and 46 course-based undergraduate research experience lines to repeated cold shock. Somatic differentiation evolved rapidly, with 21 of 48 lines (44%) exhibiting a larger proportion of differentiated colonies in baseline conditions. We also identified a lineage with obligate somatic differentiation; this is the first published example of the experimental evolution of obligate somatic differentiation. 11 lines, including the obligately differentiated one, also exhibited changes in the proportion of somatic cells per differentiated colony. The proportion of somatic cells in these lines converged with that of Pleodorina, a polyphyletic soma-differentiated volvocine algae genus. Genome sequencing revealed that 93% of genes mutated in the obligately differentiated line and not in the control had at least one homolog with soma-specific expression in obligately differentiated Volvox carteri or Astrephomene gubernaculifera and/or cold-induced expression in unicellular Chlamydomonas reinhardtii. Moreover, 72% of genes mutated in the obligately differentiated line and not in the control had homologs with both soma-specific expression and cold-induced expression. These genes all have regulatory mutations and lie at the intersection of cold shock and somatic differentiation regulatory modules. Our results provide the first empirical demonstration that the modification of plastic responses to the environment can drive the evolution of somatic differentiation, a key step in the evolution of a new kind of evolutionary individual.

evolutionary biology↗

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

The HBV basal core promoter mutation confers a replicative advantage and transcriptionally reprograms hepatocytes toward HCC subtypes

Background: Hepatitis B virus (HBV) basal core promoter (BCP) and precore (PC) mutations occur during chronic HBV infection with the BCP-mutant being associated with increased hepatocellular carcinoma (HCC) risk. Objectives: The effects of these mutants on viral replication, hepatocyte biology, and carcinogenesis remain poorly defined. To address this, we characterized BCP- and PC-mutants using human hepatocyte chimeric mice and asked whether the resulting infection-induced transcriptomes correspond to subsets of human HBV-related hepatocellular carcinomas (HBV-HCCs). Design: Isogenic wild-type (WT), BCP- and PC-mutants of HBV genotypes A, C, and D (HBV-A, -C, -D) were generated from recombinant covalently-closed circular DNA to infect chimeric mice. HBV-HCC transcriptomic datasets from The Cancer Genome Atlas (TCGA) were used to stratify association of HBV variants with HCC subtypes. Results: WT, BCP-mutant, and PC-mutant HBV sequences remained genetically stable. The BCP mutation, but not the PC mutation, accelerated the rise in serum viremia in HBV-D- and HBV-A-infected chimeras; in HBV-C, acceleration required both (PC+BCP) mutations. Further comparisons of HBV-D variants revealed that the BCP-mutant increased intrahepatic viral DNA, viral protein expression, and upregulated cancer-related pathways, including transcripts associated with a subset of HBV-HCCs. Analysis of HBV-HCC samples from the TCGA revealed that tumors often harbor a mixture of WT and mutant transcripts, and that WT- and BCP-mutant-associated HCCs exhibit distinct transcriptional profiles. Conclusions: The HBV BCP-mutant directly perturbs hepatocyte homeostasis via virus-intrinsic mechanisms, selectively activating cancer-related pathways and defining a molecularly distinct subset of HBV-HCC. These findings suggest that HBV variants form distinct subcategories of HBV-HCCs.

molecular biology↗

bioRxiv2026

Spatiotemporal atlas resolves the mesenchymal-epithelial stem cell axis governing human hair follicle aging and pathology

How adult stem cell populations coordinate tissue regeneration across physiological and pathological states remains unclear. Hair follicles contain epithelial and mesenchymal stem cells that codetermine hair regeneration. Here, we integrate a multimodal spatiotemporal atlas with functional validation to define the mesenchymal-epithelial stem cell dynamics governing human hair follicle homeostasis, aging, and androgenetic alopecia. Aging is characterized by passive depletion of hDSC-derived regenerative cues, whereas AGA involves a shift of hDSC toward an inhibitory signaling hub that promotes HFSC dysfunction. We further pinpoint hDSC-secreted PTN as a key regenerative factor that promotes hair growth and counteracts androgen-induced growth suppression. This study provides a holistic framework of adult stem cell crosstalk across physiological and pathological states, offering a mechanistic roadmap to reinstate tissue regeneration.

cell biology↗

bioRxiv2026

Global proteomic analysis of sea urchin embryos reveals dynamic changes throughout embryogenesis

The sea urchin is a long-studied model used to study fertilization and various developmental processes. While its genome and transcriptomics data are well documented, the global quantitative proteomic dynamics that complement mRNA expression during development are not available. Here we utilize an "in-cell proteomics" strategy to profile the proteomic changes in 5 developmental time points (egg, 32-cell, blastula, gastrula and larva) of the purple sea urchin, Strongylocentrotus purpuratus. This strategy bypasses cell lysis needed in conventional proteomic experiments and detects over 6,000 protein groups using only 50 eggs/embryos. Over 3,000 proteins have significant changes throughout development that cluster into 6 unique expression patterns. Analysis of signaling proteins and some transcription factors involved in cell specification and differentiation align well with published literature, supporting that proteomes obtained reflect biology of the organism. Furthermore, a majority of mRNA and their corresponding protein levels are discordantly correlated across development. Overall, this study provides a comprehensive analysis of proteomic changes occurring throughout sea urchin development and establishes a powerful and sensitive high-throughput approach suitable for detecting proteomic changes with a small number of embryos.

developmental biology↗

bioRxiv2026

Parallel Arg/N-degron recognition systems regulate coenzyme A biosynthesis

Coenzyme A (CoA) is an essential metabolic cofactor whose biosynthesis is controlled by pantothenate kinases (PANKs), the rate-limiting enzymes in CoA synthesis. Although CoA production is extensively regulated, whether PANK abundance is controlled by selective protein degradation remains unknown. Here, we identify PANK1{beta} and PANK3 as substrates of the Arg/N-degron pathway. Two mechanistically distinct E3 ligase systems, UBR4-KCMF1 and MKLN1-CTLH, independently converge on a common N-terminal MK Arg/N-degron to promote PANK degradation and restrict CoA biosynthesis. UBR4-KCMF1 recognizes the MK Arg/N-degron through KCMF1 ZZ domain, whereas CTLH complex employs the B30.2-domain proteins RanBP9 and RanBP10 as previously unrecognized Arg/N-degron recognins. Structural, biochemical, and cellular analyses demonstrate that RanBP9 and RanBP10 recognize both Met-X and canonical Arg/N-degrons through their B30.2 domains, using a mechanism distinct from canonical UBR proteins. Together, these findings establish a new branch of the mammalian Arg/N-degron pathway and reveal ubiquitin-dependent control of PANK abundance in CoA homeostasis.

molecular biology↗