Biology subjects

Gao, Y.

Publications and source records attributed to Gao, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Maleic acid adjuvates BCG to induce CD4+CD8+ T cells and sterilize tuberculosis

Anti-tuberculosis (TB) immunity typically emphasizes CD4+ T and CD8+ T cells that only provide limited protection against Mycobacterium tuberculosis (Mtb) infection. The anti-TB function of CD4+CD8+ T cells remains unexplored, mostly due to the dogma that ThPOK and Runx3 antagonize each other to block their development and their scarcity. Here, we show that immunization of BCG (Bacillus Calmette-Gu&eacuterin) with Complete Freund's Adjuvant (CFA) markedly induced CD4+CD8+ T cells through the gut microbiota Clostridium butyricum or its metabolite maleic acid. Mtb-specific CD4+CD8+ T cells exhibited a broad T-cell receptor repertoire and sterilized Mtb infection by inducing SLAMF1 and neutrophil responses. Mechanistically, maleic acid interacted with PAK2 to promote STAT5 phosphorylation at Ser127, thus upregulating Ets1 expression. Direct binding of Ets1 to the Runx3 and ThPOK promoters orchestrated their expression to redirect the CD8+ T cell differentiation towards the CD4+CD8+ lineage. Moreover, immunization of BCG plus Clostridium butyricum or maleic acid sterilized Mtb infection in mouse models. These findings establish CD4+CD8+ T cells as superior immune effectors against Mtb, a concept that could fundamentally redirect the current paradigm for anti-TB vaccine development.

microbiology↗

bioRxiv2026

Discrete synaptic states and context-modulated readouts support continual learning

Biological neural systems learn new behaviors while retaining earlier ones, whereas sequentially trained artificial networks often overwrite parameters and forget previously learned behaviors. We introduce the Context-modulated Synaptic-states Recurrent Neural Network (CoSyn-RNN), a new continual-learning model inspired by heterogeneous synaptic states and neuromodulatory control. CoSyn-RNN combines sparse recurrent allocation with a discrete protection rule: after each task, recurrent neurons whose synaptic weights cross a fixed threshold form a task-specific neuron group, and their associated parameters enter a protected state during later learning. A neuron-specific gain and a task-cued mask over a fixed base readout control how recurrent activity contributes to behavior. Across various task sequences consisting of many cognitive tasks, training and validation losses and accuracies were maintained throughout learning. The protection rule produced modular, task-ordered recurrent structure compatible with forward reuse of earlier computations. Pairwise recruitment measurements further defined minimum- and maximum-cost curricula that produced markedly different final recurrent structures and different remaining capacity for future learning. Thus, CoSyn-RNN provides a biologically inspired model in which protected synaptic states, sparse allocation, and context-dependent modulation support continual learning.

neuroscience↗

bioRxiv2026

Genetic regulation of circulating metabolome in cattle

The circulating metabolome is a vital intermediate layer linking genetics to complex phenotypes, yet existing genome-wide studies-even in humans-rarely capture dynamic physiological contexts or cellular regulatory mechanisms. Here, we present the Cattle Metabolome Atlas (https://cattlema.farmgtex.org/), a comprehensive resource of 3,436 plasma metabolites and 4,851 serum metabolites from 4,651 animals with matched sequence-level genotypes across highly dynamic parity and lactation stages. We mapped 728 plasma and 622 serum metabolite quantitative trait loci (mQTL), revealing widespread context-dependent regulatory architectures. Integrating these mQTL with the multi-tissue expression quantitative trait loci (eQTL) and single-cell atlas of 59 tissues demonstrates that 74-79% of mQTL colocalize with eQTL across 29 tissues, prioritizing the liver as the primary systemic hub and resolving metabolic programs at single-cell resolution. Furthermore, we charted 538 causal gene-tissue-metabolite-trait cascades across 11 complex traits in cattle. Finally, cross-species analyses demonstrate partial evolutionary conservation of genetic metabolism between cattle and humans, establishing this atlas as a powerful asset for cattle genetics and genomics, selective breeding, and comparative biology.

genetics↗

bioRxiv2026

Opposing Experiences Shape Parvalbumin Interneuron Plasticity through Distinct Molecular Programs

Life experiences profoundly influence brain function, yet how opposing experiences are encoded remains unclear. Here, we show that opposing experiences, chronic stress (CS) and voluntary running (VR), induce largely distinct molecular programs rather than a simple bidirectional modulation of a shared molecular program in parvalbumin interneurons (PVIs). PVI-specific translational profiling across frontal cortex and dorsal and ventral hippocampus reveals that experience-dependent gene expression is organized into brain region-specific architectures, which are further structured into distinct co-expression modules. We uncovered CS-induced upregulation of histone acetyltransferase KAT6A and H3K23 acetylation specifically in PVIs of the frontal cortex accompanied by altered genome-wide redistribution of acetylated H3K23, including genes implicated in neuropsychiatric disorders. Targeted elevation of KAT6A in PVIs recapitulates CS-induced morphological and behavioral alterations. Together, our findings reveal that opposing experiences engage distinct and region-specific molecular programs in PVIs and identify a stress-responsive epigenetic pathway underlying inhibitory circuit plasticity.

neuroscience↗

bioRxiv2026

Feasibility of Using Functional Near-Infrared Spectroscopy for Characterizing Misophonia-Related Brain Activity

Significance: Misophonia is characterized by decreased tolerance to specific sounds ("triggers") that evoke negative emotional, physiological, and behavioral responses. To understand the neural mechanisms underlying misophonia, functional neuroimaging has been proposed such as functional magnetic resonance imaging (fMRI). However, the fMRI environment introduces substantial noise that increases anxiety, which is one of the comorbidities of misophonia, confounds auditory stimuli, and is costly. We therefore propose an alternative, functional near-infrared spectroscopy (fNIRS) to detect misophonia-related responses. Aim: We evaluated the feasibility of fNIRS to detect misophonia-related sound-evoked responses. Approach: We measured fNIRS, electrodermal activity (EDA), and photoplethysmography (PPG) data from ten adults with minimal to mild misophonia symptoms while they listened to trigger, unpleasant, and neutral sounds. Participants rated their annoyance and antisociality after each sound. Results: Compared with neutral sounds, trigger and unpleasant sounds received higher subjective ratings and evoked greater neural response in the orofacial area. Neural responses tended to increase with annoyance ratings. Significantly lower heart rate (HR) was observed during unpleasant sounds than during neutral and trigger sounds, with no significant difference in EDA features. Conclusions: fNIRS can measure misophonia responses in a quiet setting. Both brain and physiological responses have the same trend observed in prior fMRI studies, verifying its feasibility.

neuroscience↗

bioRxiv2026

Ancient tandem duplication of CYCLOIDEA is associated with the evolution of capitulum development in Asteraceae

Asteraceae is one of the largest and most diverse families of flowering plants. Much of their evolutionary success is attributed to their unique inflorescence structure-the capitulum. Despite their profound adaptive and taxonomic significance, the evolutionary genetic mechanisms underlying Asteraceae capitulum diversification remains poorly understood. We integrated comparative genomic analyses of 35 Asteraceae genomes with developmental transcriptome profiling of ray and disc florets. Our results uncovered a deeply conserved CYC2e-CYC2c-CYC2d-CYC2g-CYC2b tandem gene cluster that is prevalent across the Asteraceae family. We demonstrated that this tandem cluster arose during the early evolutionary diversification of Asteraceae. Subsequent lineage-specific gene retention and loss events have reshaped the composition of this cluster across different Asteraceae lineages. Notably, key members of this cluster, particularly CYC2c, CYC2d, and CYC2g, are preferentially retained in lineages with ray florets, which is consistent with their roles in regulating the ray floret development. Collectively, our findings establish a mechanistic link between the evolutionary divergence, spatiotemporal expression differentiation of the CYC2 tandem cluster as a key genetic driver underlying the morphological diversification and evolutionary success of Asteraceae.

evolutionary biology↗

bioRxiv2026

Multi-kingdom microbial diversity and interaction landscapes in mosquitoes revealed by 5,163 individual meta-transcriptomes

Mosquitoes are pathogen vectors embedded within diverse microbial ecosystems. However, the nature and interactions among their multi-kingdom microbiome remain poorly understood. We conducted a nationwide single-mosquito meta-transcriptomic survey of 5,163 mosquitoes representing 100 species across China, integrating viral discovery with marker-gene profiling of bacteria, archaea, fungi, and other eukaryotic microbes. From this, we identified 1,606 microbial species-level taxa, including extensive novel diversity, and revealed pronounced host species-specific organization of mosquito-associated communities. We detected 34 pathogens or potential pathogens of human or animal relevance, whose prevalence, abundance, host range, and geographic distribution defined distinct epidemiological patterns. Network analysis uncovered pervasive cross-kingdom microbial associations, including candidate antiviral relationships involving Wolbachia and other microbial taxa. Our study establishes a detailed view of the full-spectrum microbiome and provides a resource and conceptual framework for studying vector competence, pathogen emergence, and microbiome-informed mosquito-borne disease control.

microbiology↗

bioRxiv2026

Dynamic Control of Prokaryotic Chromosome Ploidy Rewires Metabolic Networks to Enhance Product Biosynthesis

Building high-performance microbial cell factories requires dynamic coordination of resource allocation among cellular growth, target-product biosynthesis, and endogenous host metabolism. However, existing polyploid engineering strategies rely primarily on static manipulation of chromosome copy number. Although increasing gene dosage can enhance biosynthetic capacity, static designs cannot readily accommodate the changing metabolic demands encountered during fermentation. Here, we developed a metabolite-responsive dynamic polyploid engineering strategy that couples chromosome ploidy to the cellular metabolic state. We first constructed a high-performance L-threonine biosensor and used it to sense intracellular L-threonine levels and regulate ftsZ expression, a key cell-division gene, thereby establishing a dynamic polyploid system that requires neither exogenous inducers nor antibiotics. This system enabled engineered cells to progressively transition from polyploid to haploid during fermentation, accompanied by stage-specific remodeling of cellular physiology and metabolism. Physiological characterization revealed a marked increase in cell size and alterations in cell-envelope properties during the polyploid phase, followed by a gradual decrease in chromosome copy number as fermentation progressed. Transcriptomic and metabolomic analyses further demonstrated that dynamic ploidy transitions induced global metabolic network rewiring, remodeling the tricarboxylic acid cycle and amino acid metabolism while redirecting carbon flux toward the biosynthesis of aspartate-family amino acids. Ultimately, dynamic polyploid engineering substantially enhanced L-threonine production, enabling the engineered strain to achieve an L-threonine titer of 183.1 g/L and a yield of 0.67 g/g glucose in 5-L fed-batch fermentation without antibiotics or exogenous inducers. These findings show that dynamic regulation of chromosome ploidy can couple gene-dosage control with remodeling of cellular physiology and metabolic networks, providing a new engineering strategy to overcome the limitations of static polyploid designs and build high-performance microbial cell factories.

synthetic biology↗

bioRxiv2026

Structural basis for nutrient-activated channel opening in bacterial spore germination receptors

GerA-family germinant receptors were recently identified as ion channels that initiate germination of dormant bacterial spores in response to nutrients. Here we report 2.0-[A] cryo-electron microscopy structures of apo, agonist-bound, and antagonist-bound GerA, revealing a symmetric pentamer of heterotrimers. Signaling relies on two allosteric switches that radiate from the LeuT-type ligand-binding subunit in opposite directions, one away from the channel subunit and one directly toward it. A lipoprotein subunit reroutes the first switch and allosterically activates the second, promoting their convergence on the channel. Together, these rearrangements comprise a multipronged, cooperative signal transduction pathway that connects nutrient binding to pore opening in this new class of ligand-gated ion channels.

biophysics↗

bioRxiv2026

A biologically supported global RNA architecture of cucumber mosaic virus satellite RNA

Satellite RNAs (satRNAs) are parasitic subviral agents whose biological activities are mediated largely by specific sequence determinants and structured RNA elements. Establishing biologically supported global RNA structures is therefore essential for understanding how RNA architecture underlies satRNA functions. Cucumber mosaic virus (CMV) satRNA is one of the best-characterized models for investigating satRNA structure-function relationships; however, a biologically supported global RNA architecture of CMV satRNA has yet to be established. Here, we applied AlphaFold3 modeling to predict the global structure of CMV satRNA T1 (sat-T1). Initial full-length structure modeling generated multiple long-distance interactions that lacked biological support. We therefore used fragment-based modeling, combined with chemical probing, evolutionary covariation, and compensatory mutagenesis, to derive a biologically supported global secondary structure. To determine whether structurally distant regions could interact in the context of the full-length RNA, we engineered a structure-guided T1-ZD mutant that preserved the supported secondary structure while reducing alternative base-pairing possibilities. Full-length AlphaFold3 modeling of T1-ZD largely recapitulated the proposed architecture, while one predicted model revealed a long-distance interaction that was subsequently supported by compensatory mutagenesis analysis. These findings suggest that the 3' terminus of sat-T1 may undergo conformational switching between alternative structural states. Together, our work establishes a biologically supported global RNA architecture for CMV sat-T1 and provides a structural framework for investigating the molecular basis of satRNA function.

microbiology↗

bioRxiv2026

A pharmacokinetics-informed ODE extrapolates long-term fenofibrate transcriptomic responses

Long-term in vivo transcriptomic time courses are costly, limiting assessment of chronic molecular responses from short studies. We developed a pharmacokinetics-informed transcriptomic ordinary differential equation model (PKT-ODE) that links an oral pharmacokinetic profile and Hill drug-effect function to first-order turnover of co-expression modules. The model was fitted to rat liver responses to fenofibrate at three doses in Open TG-GATEs through day 8. At the held-out day-29 endpoint, PKT-ODE achieved Pearson r = 0.960 and mean squared error (MSE) = 0.148. In this dataset, these values achieved lower prediction error and higher correlation than four statistical baselines and validation-selected linear and multilayer-perceptron transition models. Literature-curated peroxisome proliferator-activated receptor target genes occurred only in modules with positive fitted drug effects. These results provide a proof of concept for pharmacokinetics-informed transcriptomic extrapolation; cross-compound, cross-organ and alternative-regimen performance remain to be tested.

systems biology↗

bioRxiv2026

Paralemmin 2 is a shared, alternatively-spliced regulator of axon initial segments and paranodal junctions in oligodendrocytes

Nervous system function depends on highly specialized axonal membrane domains. For example, axon initial segments (AIS), nodes of Ranvier, and paranodal junctions are essential for action potential initia-tion and saltatory conduction. These domains use shared molecular machinery converging on the master scaffolding protein AnkyrinG (AnkG). Using endogenous AnkG-TurboID proximity proteomics, we identify Paralemmin 2 (Palm2), a previously uncharacterized CNS protein, as a shared component of the AIS and nodes of Ranvier in neurons, and paranodes in oligodendrocytes. Palm2 localizes transiently to the AIS and nodes during development, but is found at paranodes throughout life, reflecting cell type-specific splicing of a lipid-modified domain both necessary and sufficient for AnkG interaction. Mice lacking oli-godendroglial Palm2 assemble normal paranodes during development, but aged mice lose paranode in-tegrity due to loss of paranodal AnkG and Neurofascin-155. Our findings identify Palm2 as a lipid raft-associated regulator of axonal and oligodendroglial membrane domains and reveal cell type-specific pro-tein variants as a recurring principle for specializing axonal and glial membrane architectures.

neuroscience↗

bioRxiv2026

MOLECULAR BASIS FOR PINK1 MATURATION

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a key regulator of mitophagy, has been linked to the pathogenesis of Parkinson's disease (PD). PINK1 recruits Parkin, an E3 ubiquitin ligase, triggering mitophagy in response to mitochondrial damage. During mitophagy, the quantity, stability, and activity of PINK1 must be strictly regulated; however, the mechanisms governing these parameters under cellular stress are still unclear. Herein, we determined the structural basis for PINK1 maturation mediated by heat shock protein 90/cell division cycle 37/FK506-binding protein 51 (HSP90/CDC37/FKBP51) chaperone complex. We identified PINK1-associated proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and determined the structures of the complexes using Cryo-Electron Microscopy (Cryo-EM). Results showed that FKBP51 potentially interacts with a conserved leucine-proline-phenylalanine (LPF) motif on the activation loop of PINK1 and negatively regulates PINK1 functions in mitophagy. A PINK1 mutation located at the FKBP51 recognition site is linked to mitophagy deficiency, which can be partially rescued by specific inhibition of FKBP51. These findings reveal a general mechanism for PINK1 recognition by the HSP90/CDC37/FKBP51 chaperone complex and suggest a potential approach for upregulating PINK1 activity, which is impaired in PD.

biophysics↗

bioRxiv2026

Pressure-induced membrane tension mechanically opens the germinant receptor GerA ion channel to trigger bacterial spore germination

High pressure (HP) can trigger bacterial spore germination, acting either through germinant receptors (GRs) or the SpoVA channel. However, the mechanism by which HP activates these membrane-embedded proteins remains elusive. Here, using Bacillus subtilis, we demonstrate that the GerA germinant receptor (GR) is the primary target of moderate HP (50-300 MPa). Mutagenesis reveals that pore-lining residues within the GerA ion channel are essential for the pressure response, whereas canonical ligand-binding and intramembrane signaling residues are dispensable. We then propose a s tretch- t o- o pen (STO) model, in which HP differentially compresses the more compliant inner membrane (IM) relative to the rigid spore core, generating lateral membrane tension that promotes opening of the GerA channel. In situ membrane tension measurements indicate HP-induced compression of IM phospholipids and elevated membrane tension. This tension-dependent gating is further supported by the pressure-dependent phenotypic rescue of GerA channel mutants. Consistently, HP increases IM permeability to water-soluble and membrane-impermeable agents (propidium iodide and formaldehyde), an effect potentiated by GerA, indicating concomitant opening of GerA by HP. Furthermore, modulating IM fluidity via heat activation or decoating altered membrane physical properties and delayed HP-induced germination, establishing the IM as the critical mechanical transducer. Additionally, computational modeling and calculations support faster compression of the IM than of the core under HP, rationalizing the source of tensile stress. Together, our findings establish a novel mechanism of HP-induced GerA activation via the STO model: HP compresses the IM, generates lateral tension, and promotes opening of the GerA ion channel to trigger bacterial spore germination.

microbiology↗

bioRxiv2026

Plasma titration provides a physical ruler for cross-platform proteomics

Plasma proteomics is expanding across platforms and cohorts, and integrating these data for AI demands comparability at the protein level, not merely concordant associations1,2. Affinity and MS platforms use distinct probes (antibodies, aptamers, or peptides) and signal readouts, yielding contradictory cross-platform results3,4. Without a known quantitative truth, we cannot distinguish biology from measurement distortion, leaving no gold standard for integration. Here we introduce Plasmix--a plasma reference suite with predefined male:female ratios (M, 1:0; Y, 3:1; P, 1:1; X, 1:3; F, 0:1)--and show that preserving this quantitative titration gradient, not just technical repeatability, predicts cross-platform concordance and identifies protein measurements suitable for integration. Profiling Plasmix across five platforms (Olink, SomaScan, NULISA, AAgAtlas, and MS-DIA) and 12 protocols across 17 batches, we found discordance is dominated by signal generation, not sample identity, and platforms distort signals in a protein-specific manner. Crucially, proteins retaining the titration response showed stronger agreement in an independent cohort; anchoring to the Plasmix midpoint (P) via sample-to-reference ratios reduced distortions, extending harmonizable coverage by 10-20%. Plasmix thus provides a physical ruler to benchmark accuracy, identifying genuinely integrable measurements before pooling datasets or training AI models--a critical bottleneck for plasma proteomics.

molecular biology↗

bioRxiv2026

Fermentation-Derived Metabolites Shape Host Biology to Attenuate Severity of Inflammatory and Metabolic Disease

Fermented foods are among the few dietary interventions shown to increase gut microbiome diversity and reduce systemic inflammation in healthy adults, yet the underlying mechanisms remain poorly defined. Metabolites produced during food fermentation, termed fermentation-derived metabolites (FDMs), represent a largely uncharacterized pool of bioactive compounds that may directly mediate the physiological effects of fermented food consumption. Here, we characterize the metabolite landscape of ten vegetable-based fermented foods using metabolomics, identifying conserved enrichment of aromatic and branched-chain amino acid derivatives across diverse substrates. Using sauerkraut as a chemically representative model system, we show that metabolite extracts from wild green sauerkraut (wGS-FDMs) remodel intestinal and systemic immune populations and shift gut microbiome composition in healthy mice. wGS-FDMs suppressed NF-{kappa}B activation and pro-inflammatory cytokine secretion in vitro and decreased colitis severity in vivo. In a chronic high-fat diet model, wGS-FDMs attenuated weight gain and improved glucose and insulin tolerance, consistent with stimulation of GLP-1 secretion in vitro. Collectively, these findings establish FDMs as biologically potent dietary components capable of simultaneously modulating immune, microbial, and metabolic homeostasis across multiple physiological systems, positioning metabolites from fermented foods as an important and underappreciated class of dietary effectors in the context of chronic disease.

microbiology↗

bioRxiv2026

The Live Concert of Brains: Performer-Audience Neural Coupling Links Ensemble Coordination to Shared Audience Integration

Collective social events often require coordinated action by one group to become shared experience in another, yet how this transformation is organized across multiple brains remains unclear. Live music provides a tractable model of this problem because ensemble coordination, performer-audience alignment, and shared audience integration unfold within the same event. Here we tested whether performer-audience neural coupling acts as a cross-role neural interface linking ensemble coordination to shared audience integration. We recorded brain activity from a nine-person live performance system, consisting of a fixed three-performer ensemble and four independent audience groups, using synchronized multi-device functional near-infrared spectroscopy hyperscanning across live trio performance sessions. Inter-brain neural coupling was analyzed across three relational layers: performer-performer (PP), performer-audience (PA), and audience-audience (AA) coupling. Behavioral ratings showed strong affective engagement and shared evaluative alignment. Neural coupling during live performance was not expressed as a diffuse increase across channel pairs, but was organized into task-sensitive relational components with interpretable PC-corr network modules. Crucially, path-based mediation analyses revealed that PA components statistically bridged PP coordination and AA coupling, yielding multiple complete and partial PP [->] PA [->] AA pathways. Brain-behavior analyses further suggested that mediation-related PA components were linked to shared performance evaluation and emotional alignment. These findings identify performer-audience coupling as a cross-role neural interface through which coordinated production becomes linked to shared collective reception. Significant StatementHow coordinated actions become shared experiences is a major problem in social neuroscience, yet most studies examine pairs of people. Using live music as a model of group interaction, we found that brain-to-brain alignment was organized across social roles rather than arising as a uniform response to the same event. Performer-audience alignment occupied a bridging position between coordination within the ensemble and integration within the audience. This identifies a systems-level architecture through which collective action may become linked to collective experience. The framework moves multi-brain research beyond dyads and offers a general approach for studying classrooms, public speaking, theater, rituals, and team events, where one group generates structured behavior that another group jointly receives and interprets.

neuroscience↗

bioRxiv2026

Dynamic Temporal Changes in Urinary Proteome of Pregnant Wild-Type Mice Carrying Heterozygous 3xTg-AD Fetuses

Alzheimers disease (AD) is a progressive neurodegenerative disorder with insidious onset. At present, effective early diagnostic biomarkers are scarce, and few studies have explored ultra-early molecular alterations during embryonic development. Urinary proteomics boasts unique strengths including complete non-invasiveness, repeatable sequential sampling and high detection sensitivity, which provides a potential technical strategy for prenatal monitoring of congenital disorders. In this study, we constructed an experimental group by mating wild-type female mice with 3xTg transgenic male mice to obtain pregnant dams carrying heterozygous AD-susceptible fetuses, while wild-type male-female mating was set as the blank control. Urine samples were consecutively collected at 10 time points from gestational day 1 (D1) to D19. Label-free quantitative proteomics was adopted to screen differentially expressed proteins, and Gene Ontology (GO) enrichment analysis was carried out to interpret temporal biological processes. The results showed that stable intergroup differential proteins could be detected as early as the implantation stage (D1), and differential protein profiles existed throughout the whole gestation period. The quantity and expression trend of differential proteins exhibited obvious temporal dynamics, and permutation tests verified that the intergroup differences were not random noise. Paternally inherited AD-causing mutations could trigger systematic molecular responses in maternal mice at the early embryonic stage. This study for the first time characterized the dynamic urinary proteomic landscape of maternal mice that reflects fetal AD susceptibility. It demonstrates that maternal urine can mirror molecular signatures related to fetal AD development, offering fundamental animal experimental data for subsequent screening of prenatal non-invasive monitoring biomarkers and research on the embryonic origin of AD.

neuroscience↗