Biology subjects

Wang, F.

Publications and source records attributed to Wang, F..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Context-dependent genetic regulation of gene expression in pigs

Production livestock provide a natural system for studying gene regulation under physiologically demanding conditions shaped by rapid growth, environmental exposure, and immune challenges. Using farm pigs from the PigGTEx resource as a model, we applied quantile regression to uncover latent, context-dependent genetic effects on gene expression across tissues. This approach identifies quantile-specific expression quantitative trait loci (eQTLs) that are not detected by standard linear regression and are enriched in distal regulatory elements and three-dimensional genome architectural features rather than promoter-proximal regions. Genes with quantile-dependent eQTLs are more intolerant to loss-of-function variants and exhibit stronger enrichment in GO functional categories, indicating their likely functional significance. Cross-species comparisons reveal substantial overlap between pig and human eGenes across tissues, indicating conservation of regulatory architecture. Notably, many quantile-specific eQTLs influence tail expression states and involve genes relevant to human disease. For example, we identify a cis-eQTL affecting the conserved transcriptional regulator BCL6B in pig blood that modulates enhancer activity and reduces expression at lower quantiles. In contrast, BCL6B is minimally expressed in resting human blood and lacks detectable cis-regulatory variation under baseline conditions, consistent with its reported induction during immune activation. These findings demonstrate that pig eQTL maps can reveal context-dependent regulatory variation at loci that remain silent or weakly variable in human cohorts.

bioinformatics↗

bioRxiv2026

A foundation AI model enhances electron microscopy image analysis

Electron microscopy (EM) and advanced volume EM have extensive applications in deciphering cellular ultrastructures for life sciences. However, quality issues of EM images significantly impede the precise analysis and discovery of nanoscale biological structures. Here, we present an unsupervised Foundation Model for Five Tasks (DF5T) model for image enhancement through denoising, deblurring, super-resolution, two-dimensional (2D) inpainting, and three-dimensional (3D) isotropic restoration. DF5T was trained on an extensive dataset of multi-source membrane-bound organelle EM images, consisting of a total of over 2.25 million images. On unseen data, DF5T outperformed the existing state-of-the-art models in all five tasks. Furthermore, DF5T substantially compensates for missing three-dimensional structural information and reveals significant ultrastructural alterations in organelle geometry following chemical treatment. We demonstrate that DF5T significantly enhances electron microscopy images quality by improving the accuracy of downstream organelle segmentation and 3D structural restoration, thereby contributing to future advances in biological research.

cell biology↗

bioRxiv2026

A human gut-BBB-brain microphysiological model for studying neurodegenerative diseases

The gut-brain axis has emerged as a crucial factor in neurodegeneration, with growing evidence linking gut dysbiosis and metabolic dysfunction to Alzheimers disease (AD) progression. Unfortunately, the lack of human-relevant in vitro models limits our ability to effectively explore the mechanism of this axis. To address this gap, we have developed a human induced pluripotent stem cell (iPSC)-derived gut-blood-brain barrier (BBB)-brain microphysiological system that enables systematic investigation of gut-brain interaction in the context of AD under controlled conditions. Our findings reveal that the interaction between gut and brain organoids can promote the maturation of brain organoids, making them more similar to their physiological characteristics in vivo. Additionally, co-culture gut and brain organoids better recapitulates the pathological features of AD. We also discovered that gut organoids of AD can trigger neurodegenerative disease manifestations in healthy brain organoids. In summary, our microphysiological system provides a novel and versatile in vitro platform for studying the interaction between the gut and brain in neurodegenerative diseases.

neuroscience↗

bioRxiv2026

Drosophila melanogaster Nepl15 regulates lifespan, motor function, aging, heart rate, and cellular health in a sex-specific manner

Aging and obesity are characterized by comorbidities like declines in fertility, lifespan, gut barrier integrity, cardiac function, and motor activity, and an increase in oxidative stress due to altered nutrient and energy homeostasis. A study on Drosophila Neprilysin-like 15 (Nepl15) demonstrated that loss of Nepl15 gene significantly reduced glycogen and glycerolipid reserves in adult males and increased glycogen storage in adult females despite similar food consumption as controls. Therefore, we investigated the sex- and age-specific consequences of Nepl15 loss on cellular and physiological parameters associated with aging and obesity. We observed that egg production, rate of pupariation, and rate of adult fly eclosion were slightly better in the mutant flies. Interestingly, mutant females, but not males, exhibited significantly extended lifespan. Both sexes demonstrated improved locomotor performance, exercise endurance, gut barrier integrity, and preserved heart rate during progressive aging. At the cellular level, female mutants displayed reduced oxidative stress, elevated Sod2 expression, and increased ATP levels, all indicative of enhanced cellular health. Mutant males exhibited an increased mitochondrial membrane potential, indicating an enhanced capacity for rapid ATP production in response to enforced activity. Consistently, the energy-sensing kinase AMPK expression was reduced in the mutants. The lifespan extension of mutant females was supported by downregulation of mTOR and upregulation of Sirt6 expression. However, in mutant males, both mTOR and Sirt6 were downregulated, potentially contributing to improved physiological health without changing their lifespan. Collectively, our findings establish Nepl15 knockout mutation promotes anti-aging and anti-obesity health benefits, with stronger effects in female flies.

cell biology↗

bioRxiv2026

The archaic CUP pilus SMF-1 uses an antiparallel bundling mechanism to initiate biofilm formation

Bacterial biofilms represent a survival strategy that enables microbial communities to withstand environmental stress. Stenotrophomonas maltophilia is an emerging, antibiotic-resistant, Gram-negative, opportunistic pathogen that frequently colonizes the lungs of individuals with cystic fibrosis. Its chaperone-usher pathway (CUP) pilus, SMF-1, is present in nearly all clinical isolates and is essential for biofilm development; however, its molecular architecture has remained unknown. Here, we present a 4.0 [A] cryo-EM structure revealing that SMF-1 is an archaic, rather than a classic, CUP pilus. SMF-1 forms thin, zigzag filaments that assemble into defined antiparallel "pili-couples," which further aggregate into thick bundles. These bundles act as robust intercellular tethers, facilitating the rapid cell-to-cell aggregation required for biofilm initiation. Despite high sequence and structural similarity to classic CUP systems, SMF-1 lacks the interfaces required to form a rod-like architecture, suggesting it may represent an evolutionary intermediate between the CUP classes. Finally, we demonstrate that SMF-1 producing bacteria initiate biofilm formation within 24 hours and that flagella can further accelerate this process. Together, these findings uncover a conserved bundling mechanism that promotes bacterial colonization and may contribute to pathogenicity.

microbiology↗

bioRxiv2026

Histone H2BK120 ubiquitination modulates PRC1 activity and H2AK119ub deposition on nucleosomes

Polycomb group and Trithorax group complexes antagonistically regulate developmental gene expression, yet the mechanisms coordinating their interplay remain poorly understood. Here, we uncover a synergistic histone crosstalk in which H2BK120ub (histone H2B ubiquitination at lysine 120), a Trithorax-associated active mark, enhances Polycomb repressive complex 1 (PRC1) activity by directly binding specific PCGF subunits of PRC1 on the nucleosome surface, as shown in cryo-electron microscopy (cryo-EM) analysis. Beyond regulating enzymatic activity, H2BK120ub also modulates the competitive binding between the catalytic RNF2-BMI1 module and the RYBP subunit of noncanonical PRC1.4 complexes to nucleosomes, potentially restricting H2AK119ub (histone H2A ubiquitination at lysine 119) spreading to neighboring nucleosomes. In mouse embryonic stem cells, H2BK120ub directs the deposition of H2AK119ub within the gene bodies of a subset of developmental genes, which exhibit more rapid activation compared to canonical H3K4me3/H3K27me3 bivalent genes. These findings reveal a previously unrecognized mechanism that links active and repressive histone modifications, providing new insights into the intricate chromatin regulation of gene expression during development.

molecular biology↗

bioRxiv2026

Ecological and evolutionary dynamics of the oral microbiome across childhood

Childhood represents a critical period for oral microbiome development, yet evolutionary trajectories and the relative roles of host and environment remain unclear. Using a large longitudinal metagenomic dataset of 920 samples from a twin cohort spanning the first decade of life, we characterised microbial shifts and population dynamics of key bacterial groups. Microbiome diversity was initially reduced and highly heterogeneous and became increasingly complex and convergent with age. Microbial community state was associated with developmental age, environment and in late childhood was surprisingly strongly associated with host genotype. Strain-level analyses revealed species-specific temporal patterns of genetic variation particularly within Streptococcus, reflecting adaptive responses to host and environmental pressures. Fusobacterium exhibited consistently high replication rates, indicating sustained growth dynamics. Phylogenetic reconstruction further revealed host and niche specific genomic diversification of Saccharibacteria lineages. These findings establish childhood as a decisive period of oral microbial evolution and highlight the role of host-microbiome and epithelial interactions in shaping community structure, providing guidance for oral management strategies that promote lifelong oral health.

ecology↗

bioRxiv2026

MATR3 is essential for oocyte growth and maturation quality through a dual molecular mechanism

The molecular mechanisms governing mRNA accumulation during oocyte growth, essential for developmental competence, remain poorly understood. This study investigates the role of Matrin-3 (MATR3), a highly expressed RNA-binding protein in growing oocytes (GOs), using oocyte-specific knockout mouse models and human oocyte maturation arrest (OMA) samples. The results showed that MATR3 was more abundant in GOs than fully-grown oocytes (FGOs), highly expressed in the nucleus of non-surrounded nucleolus (NSN) oocytes, and exited the nucleus during the NSN-to-surrounded nucleolus (SN) transition. In OMA patients, MATR3 nuclear localization was missed, with smaller oocytes than FGOs. Further, Matr3 deletion in mouse GOs caused restricted oocyte growth, global transcription disorders, follicle development failure, blocked GO-granulosa cell communication (via reduced Gdf9 and Radixin expression), and infertility. Mechanistically, MATR3 regulated transcription by recruiting H3K9me2-demethylating lysine-specific demethylase 3B or binding target gene promoters, like Radixin. These findings reveal a critical role of MATR3 in orchestrating transcription and paracrine signaling during oogenesis and suggest its potential as a diagnostic and therapeutic target for OMA.

physiology↗

bioRxiv2026

Hierarchy in neuronal representations of multiple tasks in prefrontal cortex

The ability to perform multiple tasks is one of the fundamental hallmarks of general intelligence in the brain. However, the underlying neural mechanisms remain largely unknown. We trained macaque monkeys to perform four tasks with identical spatial layouts but different cognitive demands, and recorded activities of thousands of prefrontal neurons using two-photon calcium imaging. Within the same neuronal population, we identified a multitask neural geometry composed of multiple low-dimensional subtask spaces, each encoding spatial information within a specific subtask. These subtask spaces shared a ring-like representational structure, forming a generalized spatial code across different subtasks. Task separation arose from separable bases and offsets of subtask spaces, modulated primarily by meta-task features. Thus, the neural geometry is organized by a three-level hierarchical structure: location codes are nested within subtask spaces, which are grouped as different meta-tasks. This hierarchy supported generalization across both locations and tasks, and explained monkeys error behaviors. Together, the hierarchically organized neural geometry underlies flexible multitask behavior.

neuroscience↗

bioRxiv2026

The genome of an aneuploid cultivar facilitates elucidating the genetic bases of trait polymorphisms in Phalaenopsis orchids

As an important ornamental crop, Phalaenopsis orchids exhibit extraordinary trait diversity with unclear genetic bases. Here, we present a haplotype-resolved, chromosome-level genome for an aneuploid cultivar Santiago. We reveal pervasive variation in the number and sequence among homoeologous genes. When serving as a reference, this genome facilitates the genetic understanding of trait variation in a hybrid population that is highly representative in trait polymorphisms. Specifically, nucleotide polymorphisms in a potential long-distance enhancer and the consequential expression variation of PsAGL6-2, presence/absence of PsMYB12 and b-type homoeologous gene of PsMYB2 determine lip morphology variation, presence/absence of venation-associated stripes and background pink color, respectively. Diverse functions of PsMYBx1 in repressing anthocyanin accumulation across different cultivars further enhances the color patterning diversity in Phalaenopsis. Our study provides a practical framework for using a highly heterogeneous, haplotype-resolved genome to decode phenotypic diversity and has the potential to promote marker-assisted breeding in Phalaenopsis.

genomics↗

bioRxiv2026

Insight into the scaffolding function of USP18 from a high resolution cryo-EM structure of STAT2-USP18-ISG15 ternary complex

USP18 is a primary negative regulator of the type I interferon (IFN-I) signaling which regulates hundreds of IFN-stimulated genes for viral protection and anti-cancer immunity. USP18 plays dual roles in the IFN-I signaling: 1) deubiquitinase enzymatic function which cleaves ISG15 from its substrates and 2) scaffolding function through forming a complex with STAT2 to suppress IFN-I signaling. Targeting the scaffolding function of USP18, instead of its enzyme activity, is crucial for reducing cancer cell fitness and boosting anti-tumor immunity. However, the molecular basis of USP18s scaffolding function remains unclear due to the lack of structural information. Here, using a fusion tag strategy, we captured the transient USP18-STAT2 complex and determined a ternary complex structure of STAT2-USP18-ISG15 at 3.05 [A] resolution by cryogenic electron microscopy (cryo-EM) that delineated detailed USP18-STAT2 interactions. Remarkably, the ternary complex impairs USP18s enzymatic function by STAT2-mediated disruption of its catalytic triad. Structural analysis and mutagenesis identify specific USP18 point mutations, facilitating further investigation into the role of USP18 in IFN-I signaling. Taken together, our findings suggest that USP18s scaffolding function could present an untapped opportunity for cancer therapy.

molecular biology↗

bioRxiv2026

PlantMDCS: A code-free, modular toolkit for rapid deployment of plant multi-omics databases

With the rapid accumulation of diverse omics datasets, achieving efficient management and integrative analysis of plant multi-omics data remains a major challenge. Conventional solutions rely on constructing web-based databases, which often demand substantial programming expertise and long-term financial support. To address these limitations, we developed the Plant Multi-omics Database Construction System (PlantMDCS)-a locally deployable, user-friendly, and collaborative platform that unifies database construction and downstream multi-omics analysis within a graphical environment. PlantMDCS adopts a decoupled front-end/back-end architecture. The back end serves as the core engine for data management and computation, and is responsible for the storage, preprocessing, integration, and hierarchical association of multi-omics data. Once initialized, the front end supports the complete research workflow, including data import, querying, integrative analysis and visualization. All operations can be performed without programming, while local resource usage is dominated by disk storage required for user-provided datasets rather than sustained computational overhead. Benchmarking across plant species ranging from Arabidopsis to hexaploid wheat demonstrated that database construction can be completed within minutes, independent of genome size or data complexity. PlantMDCS is designed for local deployment to ensure data security, while allowing multi-user collaboration within local networks and supporting controlled remote access for teams distributed across different regions. Overall, PlantMDCS offers a secure and sustainable framework that integrates data management and analysis within a unified system. This design shifts multi-omics research away from fragmented file-based processing toward persistent, database-driven exploration, thereby enhancing analytical efficiency and reproducibility.

bioinformatics↗

bioRxiv2026

Disruption of the NTCP-EGFR receptor complex as a strategy for selective inhibition of hepatitis B and D virus entry

Hepatitis B and D virus (HBV, HDV) enter hepatocytes through a coordinated process mediated by a receptor complex consisting of sodium taurocholate co transporting polypeptide (NTCP) and its entry cofactors, including epidermal growth factor receptor (EGFR). Here, we established an in vitro assay to evaluate the NTCP-EGFR interaction and identified Oxy229, an oxysterol-based compound that disrupted this molecular interaction. Oxy229 selectively inhibited HBV and HDV infection to HepG2-NTCP cells and primary human hepatocytes. Mechanistic analysis revealed that Oxy229 impaired the relocalization of the HBV-NTCP complex from plasma membrane to intracellular vesicles. Notably, Oxy229 did not compromise the physiological functions of NTCP and EGFR, i.e., bile acid transport and activation of downstream EGFR signaling pathways including Ras-MAPK and PI3K-Akt pathways, indicating selective inhibition of viral entry. Compound derivative analysis identified Oxy283, which acquired dual inhibitory activity against both NTCP-EGFR interaction and NTCP multimerization, resulting in enhanced anti-HBV potency. These findings establish the functional significance of the NTCP-receptor complex formation in HBV/HDV entry and highlight this machinery as a potential target for antiviral intervention.

microbiology↗

bioRxiv2026

Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling

Mitochondria catabolize nutrients by generating sequentially-ordered organic acid intermediates that are oxidized through the tricarboxylic acid cycle. Pathogenic accumulation of metabolic organic acids manifests as devastating organic acidemias/acidurias and other severe diseases, but the underlying mechanisms are largely unknown. Using unbiased C. elegans genetic screening, we here reveal that mutations in the phosphoenolpyruvate carboxykinases PCK-1 and PCK-2 cause buildup of oxaloacetate, a key tricarboxylic acid cycle intermediate, leading to severe mitochondrial damage. Depletion of mitochondrial GOT-2.1 or GOT-2.2, which catalyze oxaloacetate conversion to aspartate, also causes oxaloacetate accumulation and defective mitochondria with disrupted cristae. We demonstrate that oxaloacetate binds the MICOS complex subunit CHCH-3/MIC19 and inhibits its function of promoting IMMT-1/MIC60-dependent membrane shaping and remodeling. In mammalian cells, aberrant OAA buildup similarly causes mitochondrial impairment through MIC19 and MIC60. These findings not only provide important mechanistic insights into mitochondrial damage in the context of defective oxaloacetate metabolism, but also suggest therapeutic strategies for oxaloacetate-related mitochondriopathies.

cell biology↗

bioRxiv2026

Circuit-Specific Resting-State fMRI Signatures for Stratifying First-Episode Major Depressive Disorder and Predicting Recurrence Risk

BackgroundDepression is biologically heterogeneous, and first-episode depression (FED) carries a high risk of recurrence that is poorly captured by symptom-based assessment. Early identification of patients likely to relapse, as well as reliable identification of those unlikely to relapse, is needed to support personalized intervention and efficient allocation of care. MethodsWe developed a neurocomputational framework to infer recurrence risk from resting-state fMRI functional connectivity. The framework combines a Convolutional Filtering Autoencoder (CFAE) with a k-medoids clustering algorithm (FED-kMC) to derive neurofunctional FED subtypes, followed by a Manifold Sheaves-based Ensemble Support Vector Machine (MST-LVSVM) to estimate individual-level recurrence risk and define an interpretable decision boundary. Circuit-level analyses were then used to localize connectivity pathways associated with high relapse risk. ResultsThe framework identified two neurofunctionally distinct FED subtypes with divergent recurrence trajectories and achieved an external validation accuracy of 82.61% for recurrence risk prediction. Circuit analyses highlighted dysfunction within the Medial Superior Frontal Gyrus-Hippocampus and Angular Gyrus-Precuneus pathways as neural correlates of high relapse risk, together with a decision boundary enabling early-stage risk stratification. ConclusionsIntegrating connectome-derived, circuit-level information with subtype-aware machine learning may support proactive identification of FED patients at elevated recurrence risk and facilitate targeted early interventions, bridging connectome-level analysis and clinical decision-making.

neuroscience↗

bioRxiv2026

A neuronal pathway for the supraspinal relay of warm and cool sensation

Cutaneous thermosensation is a fundamental sense allowing discrimination of external temperature changes and driving adaptive responses essential for survival and well-being. This sensory process begins with the activation of peripheral thermoreceptors, which encode the quality and intensity of thermal stimuli into neuronal activity that is further integrated by spinal cord circuits and relayed to supraspinal centres through the anterolateral tract (ALT). While classical experiments identified thermal responsive ALT neurons in the superficial spinal dorsal horn, the functional logic of innocuous temperature relay remains poorly understood. We show that, in mice, the majority of Phox2a-lineage lamina I ALT are selectively tuned to innocuous warming or cooling, and receive direct inputs from peripheral thermoreceptors. Their genetic ablation, chemogenetic or optogenetic manipulation impaired temperature discrimination. Our findings contrast with the previous finding that the majority of ALT neurons being mechano- and thermo-nociceptive and provide novel evidence for the existence of a large ensemble of genetically defined warming- and cooling- responsive ALT neurons. The large representation of innocuous temperature in supraspinal-relaying ALT neurons indicates substantial spinal amplification of thermal information and underscores the importance of innocuous thermosensation in the ascending sensory pathway.

neuroscience↗

bioRxiv2026

Medial Olivocochlear Activity Modulates Central Auditory Synapse Structure and Function

In many mammals, the auditory system is immature at birth and undergoes activity-dependent refinement. The medial olivocochlear system (MOC) contributes to the maturation of central auditory connectivity by shaping spontaneous activity in the developing inner ear. Although altered MOC activity has been linked to electrical and synaptic dysfunctions in different central auditory nuclei, an in-depth analysis of the same synapse under conditions of absent versus enhanced MOC activity is lacking. In this work, we set out a physiological and structural analysis of the calyx of Held and the principal neurons of the medial nucleus of the trapezoid body (CH-MNTB) synapse at postnatal days 12-14 in three mouse models of either sex: wild-type (WT), 9 knock-in (9KI; with enhanced MOC activity), and 9 knock-out (9KO; which lacks MOC activity). Electrophysiological recordings in brain slices revealed a reduced synaptic strength efficacy in 9KI compared to WT, including smaller excitatory postsynaptic current (EPSC) amplitudes, stronger short-term depression during repetitive stimulation and a decrease readily releasable pool size. In contrast, 9KO mice showed minimal synaptic differences relative to WT. Serial block-face electron microscopy (SBEM) reconstructions demonstrated morphological alterations of the CH in both MOC-manipulated mouse models. However, 9KI mice exhibited the largest deviations, including fewer morphologically complex CHs and increased poly-innervation of MNTB cells. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Moreover, the enhancement of MOC activity drives more pronounced developmental changes in brainstem auditory circuitry than its absence. Significance StatementBefore hearing onset, inner hair cells in altricial mammals show spontaneous electrical activity crucial for proper auditory pathway development. This activity is finely regulated by descending efferent nerves from the central nervous system during a critical developmental period, ensuring precise auditory circuit formation. Our study shows that genetically manipulating efferent function --either by eliminating it or enhancing it-- leads to structural alterations and severe synaptic dysfunction within the auditory brainstem. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Importantly, enhancing efferent peripheral activity causes more pronounced central synaptic changes than its absence, highlighting the importance of balanced efferent modulation during early auditory system development for normal brainstem auditory function.

neuroscience↗

bioRxiv2026

Dopamine signatures of excessive and compulsive cocaine and fentanyl use

Excessive and compulsive drug use despite adverse consequences is a hallmark of substance use disorder, yet individuals differ markedly in their vulnerability to develop these behaviors. Drugs of abuse are long known to alter endogenous dopamine (DA) signaling, but shared principles for how DA dynamics impact compulsive use among individuals and across drug classes are lacking. Here, we monitored DA release in the medial shell of nucleus accumbens (NAc) during cocaine and fentanyl self-administration, with or without coincident punishment, in large cohorts of mice. Contingent cocaine and fentanyl self-administration evoked complex and individually distinct DA dynamics; nevertheless, a robust negative correlation held across both drugs, such that high takers exhibited lower drug-evoked DA signals. During punished drug taking, cocaine and fentanyl cases were associated with distinct DA signatures of compulsivity. For cocaine, punishment-resistant mice showed lower sustained DA responses during the post-shock, drug-associated cue period, whereas for fentanyl, punishment-resistant mice displayed larger phasic DA at the co-occurrence of footshock and drug infusion. To identify common principles underlying these observations, we developed a computational model grounded in an Actor-Critic temporal-difference (TD) learning framework that incorporates internal states, agents uncertainty, and drug-specific effects. Remarkably, this model captures the observed diversity in DA dynamics across drug classes and among mice with variable drug taking propensities, hereby providing a unified interpretation of NAc DA signals as encoding TD reward prediction errors.

neuroscience↗