Biology subjects

Yan, J.

Publications and source records attributed to Yan, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)P2 activation

Mammalian two-pore channels (TPCs) are endolysosomal cation channels that regulate membrane trafficking and ionic homeostasis and have been strongly implicated in nicotinic acid adenine dinucleotide phosphate (NAADP) signaling. We previously identified Lsm12 as an NAADP receptor and TPC-interacting protein required for NAADP-evoked Ca2+ mobilization from acidic organelles; however, how NAADP-Lsm12 coupling regulates TPC gating has remained unclear. Here, we show that Lsm12 acts as a potent antagonist of phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2]-dependent TPC activation. Purified Lsm12 strongly inhibited PI(3,5)P2-evoked currents of TPC1 and TPC2, and endogenous Lsm12 similarly suppressed TPC2 activity in cells. Mechanistically, Lsm12 reduces the apparent sensitivity of TPC2 to PI(3,5)P2 through a competitive mechanism that depends on the concentrations of both Lsm12 and PI(3,5)P2, as well as on Lsm12-TPC interaction. Importantly, NAADP specifically and dose-dependently reverses Lsm12-mediated inhibition, restoring TPC currents only in the presence of PI(3,5)P2 or an intact PI(3,5)P2-binding site on TPCs. Consistently, acute sequestration of endogenous PI(3,5)P2 reduces NAADP-evoked cytosolic Ca2+ signals. These findings support a model in which Lsm12 tonically restrains PI(3,5)P2-dependent TPC gating, whereas NAADP binding to Lsm12 relieves this inhibition to permit channel activation. Our study therefore establishes a mechanistic link between NAADP signaling and phosphoinositide-dependent TPC gating and provides a working model for understanding NAADP-evoked Ca2+ release from acidic stores.

cell biology↗

bioRxiv2026

BioClaw: Human-Bot Research Collaboration Ecosystems in Group Chats

Day-to-day research discussions in group chats often generate hypotheses, analysis requests, and interpretation decisions, yet executing those analyses still requires researchers to leave the conversation and rely on fragmented local tools, databases, visualization software, and literature search engines. In this work, we present BioClaw, a human-bot research collaboration ecosystem that converts natural-language requests in group conversations into tool-grounded analyses executed within isolated Docker containers. Deployed across 8 messaging platforms, BioClaw turns each group chat into a persistent execution workspace. Its design combines multi-channel orchestration, per-group state and workspace management, and isolated containerized execution for reliable shared use over long-lived conversations. To support practical research workflows, BioClaw combines containerized execution with preinstalled 31 biomedical tools and 95+ skills. The application of BioClaw spans various biomedical domains (e.g., genomics, clinics, structural biology) and data modalities (e.g., sequencing data, EHR data, protein structure data). These results establish the viability of embedding executable, tool-rich agent workflows within shared digital workspaces, positioning group chats as a transformative paradigm for collaborative scientific discovery and innovation.

bioinformatics↗

bioRxiv2026

Detergent-Free Nuclear-Cytoplasmic Fractionation Enables Spatially Resolved PELSA for Enhanced Nuclear Drug Target Identification

Accurate identification of drug target proteins remain major challenges in proteomics-based target discovery, particularly for low-abundance nuclear proteins that are difficult to detect because of the complexity of whole-cell lysates. Here, we developed a detergent-free nuclear-cytoplasmic fractionation strategy compatible with peptide-centric local stability analysis (PELSA), which markedly improves detection of nuclear drug targets. Using K562 cells, we demonstrated that mild detergent-free fractionation enables high-fidelity nuclear-cytoplasmic separation with minimal cross-contamination. When coupled with PELSA, this workflow significantly increases the number of detected nuclear targets relative to whole-cell analysis. Benchmarking with well-characterized nuclear drugs, including the histone deacetylase inhibitor panobinostat and the RNA polymerase II inhibitor -amanitin, our results showed improved identification of canonical nuclear targets. Broad profiling of staurosporine target further revealed expanded kinase target coverage by combining the results of nuclear and cytoplasmic fraction, with the CLK family kinases detected exclusively in the nuclear fractions. Additionally, we showed that PELSA can also be performed on intact nucleus level. Collectively, these findings establish detergent-free nuclear-cytoplasmic fractionation-PELSA as a robust and scalable strategy for spatially resolved drug target identification, improving sensitivity for nuclear and low-abundance proteins.

biochemistry↗

bioRxiv2026

Reduced precipitation alters microbial availability and redistribution of rhizosphere carbon

Climate change intensifies grassland drying, which is predicted to decrease soil organic carbon (SOC) storage. Yet how reduced soil water affects the transport and processing of carbon in the rhizosphere -- a major source of SOC supporting microbial activities -- remains poorly resolved under field conditions. We traced living root-derived carbon (rhizodeposit C) into soils and microbes using {superscript 1}3CO2 labeling in a multi-year precipitation manipulation experiment in a California Mediterranean annual grassland dominated by Avena barbata. Under halved precipitation, season-averaged soil water content was 20% lower and soil matric potential more than threefold lower, without inducing detectable signs of plant stress. Quantitative stable isotope probing (qSIP) of rhizosphere microbial DNA revealed that up to 68% more bacterial and 13% more fungal taxa incorporated rhizodeposit C, and that microbial uptake of rhizodeposit C increased more over time under reduced precipitation, even as total microbial biomass and community composition were unchanged. {superscript 1}3C-informed co-occurrence networks of these consumers were larger and more connected under reduced precipitation. The surrounding soils contained less 13C, and modeled solute transport by soil water was 32-40% lower, implying that rhizodeposit C was retained and intensively processed nearer to roots rather than transported to the wider soil matrix. Our evidence supports that reduced precipitation concentrates rhizodeposit C near roots, increasing the number of distinct consumers and intensifying associations among them. This represents an overlooked mechanism linking precipitation reduction to rhizodeposit C cycling. These findings show that precipitation reduction may reshape rhizosphere C processing before apparent plant stress response, with potential consequences for the fate of rhizodeposit C in grassland soils.

microbiology↗

bioRxiv2026

Separable Brain Maturation Patterns Mediate Exposome Influences on Cognitive Development: A Longitudinal Study

Adolescent cognitive ability develops within a complex landscape of environmental exposures, yet the patterns of brain maturation through which these exposures relate to cognitive development remain poorly understood. Resolving this requires an integrated longitudinal view of the multidimensional exposome, multimodal brain change, and cognitive growth. Here, we examined whether brain maturation mediates the relationship between the exposome and cognitive development in a large longitudinal cohort of 1,112 adolescents, using 4,882 multimodal brain features and 112 exposome variables spanning six domains. Brain maturation patterns associated with cognitive development showed moderate yet consistent spatial correspondence with those associated with the exposome, with the family environment domain showing the strongest correspondence. We identified four latent brain patterns associated with distinct components of the exposome-cognition relationship. Collectively, these results indicate that distinct exposome domains relate to cognitive development through distinct brain maturation pathways, which also exhibit different molecular annotation profiles.

neuroscience↗

bioRxiv2026

HalluCodon enables species-specific codon optimization using multimodal language models

Codon optimization is widely used in transgenic crop development, plant synthetic biology, and molecular farming to improve heterologous protein expression in plant cells. Increasing availability of plant omics data now enables optimization strategies that account for species-specific sequence features. We developed HalluCodon, a customizable framework that uses multimodal language models to design coding sequences tailored to individual plant species. The framework allows users to fine tune pre-trained protein and RNA language models with their own datasets to build species-specific codon optimization models. The current implementation includes base models trained on coding sequences and proteomes from fifteen plant species. HalluCodon generates coding sequences through a hallucination-based design strategy guided by two predictive modules that evaluate coding sequence naturalness (CodonNAT) and expression potential (CodonEXP). Benchmark tests using representative proteins show that the generated sequences reproduce host-specific codon usage patterns and support high expression levels in plant systems.

bioinformatics↗

bioRxiv2026

Mouse behavioral genomics identifies Creld1 as a gatekeeper of somatosensation

Somatosensation enables the perception of touch, temperature, pain, and itch. These sensory modalities are mediated by primary sensory neurons in the dorsal root ganglion (DRG), which convert physical and chemical stimuli into electrical signals using specialized molecular sensors, including the touch sensor PIEZO2 (Ref1,2) and temperature sensors such as TRPV1 (Ref3,4), coupled with downstream voltage-gated sodium channels (Nav) like Nav1.7 (Ref5,6). However, the full repertoire of molecular components involved in somatosensory processing remains incompletely identified. Here, we developed an efficient postnatal CRISPR-Cas9 knockout platform to screen DRG-expressed genes via AAV9-sgRNA delivery. Combining this approach with behavioral assays of somatosensory responses, we validated the roles of PIEZO2 and TRPV1 in sensing gentle touch and noxious heat, respectively, and the broad involvement of Nav1.7 in distinct somatosensory modalities. Remarkably, a targeted screen of 20 DRG-expressed genes identified the Cysteine-rich with EGF-like domains 1 (Creld1) as a master regulator of somatosensation. Either sgRNA-mediated postnatal knockout or tamoxifen-induced Cre-mediated deletion of Creld1 in DRG neurons resulted in profound behavioral deficits in touch, temperature, pain, and itch perception, while its overexpression enhanced touch and thermal responses. Mechanistically, Creld1 functions as a novel auxiliary regulator of Nav for controlling the excitability of DRG neurons. The biochemical interaction and functional modulation of Nav by mouse Creld1 are mediated via its C-terminal transmembrane region. Notably, this domain is conserved in mouse Creld1 and some isoforms of human CRELD1, resulting in an isoform-dependent regulation of Nav1.7. Together, this work establishes a robust postnatal screening platform for somatosensory genomics and identifies Creld1 as a master regulator of somatosensory function, and provides novel therapeutic strategy for pain and itch treatment.

neuroscience↗

bioRxiv2026

Sustained Delivery of a Shingles Subunit Vaccine Overcomes Age-Related Declines in Humoral and Cellular Immunity Relative to Shingrix

The global aging population faces heightened vulnerability to infectious diseases due to immunosenescence, which diminishes the potency, durability, and breadth of vaccine-induced immunity. While the leading shingles vaccine, Shingrix(R), provides protection against herpes zoster virus for adults aged 50 and older, it is often associated with severe local and systemic reactogenicity, which limits vaccine compliance. Here, we report an injectable polymer-nanoparticle (PNP) hydrogel platform for the sustained delivery of a shingles subunit vaccine to enhance immune responses while mitigating reactogenicity in aged mice. Hydrogel-based vaccination elicited significantly more potent and durable humoral immune responses than Shingrix(R), while inflammatory cytokine levels remained below the limit of detection. Moreover, aged mice vaccinated with the hydrogel-based vaccine exhibited robust antigen-specific cellular immune responses. These findings demonstrate that controlling the temporal presentation of vaccine components can overcome age-associated declines in immune responsiveness without inducing excessive inflammatory signaling. By decoupling immunogenicity from reactogenicity, our hydrogel-based delivery strategy offers a promising approach to improve both the efficacy and tolerability of subunit vaccines for the elderly and may be broadly applicable to other vaccines targeting aging populations.

immunology↗

bioRxiv2026

FourC: identifying significant and differential contacts in 1D chromatin conformation data

4C-seq is a cost-effective 3C-based assay that measures the interactions between a single genomic element and all other genomic elements. However, 4C-seq data remains semi-quantitative because it cannot be deduplicated without UMIs. To address this, we developed an open source method, FourC, based on a Bayesian Bernoulli regression model, that overcomes the duplication problem and models spatial patterns with Gaussian processes to identify significantly enriched and differential contacts. We demonstrate the utility of FourC on 4C-seq data that profiles the local chromatin structure at key genes necessary for pancreatic differentiation and under CRISPR perturbation of enhancers.

bioinformatics↗

bioRxiv2026

Diffusion-ACP39: A Decoder-Adaptive Latent Diffusion Framework for Generative Anticancer Peptide Discovery

Cancer remains a major global health threat, with its incidence and mortality rates consistently rising in recent years. Anticancer peptides (ACPs) are short amino acid chains that can inhibit the growth or spread of cancer cells. Compared to traditional treatments, ACPs are a promising class of potential cancer therapies due to their multiple mechanisms, potential for combination cancer therapy, enhanced immune function, lower toxicity to normal tissues, fewer side effects, and less drug resistance. Although it is necessary to explore novel ACPs, traditional wet-lab methods for selecting them are labor-intensive, time-consuming, and expensive. To accelerate the discovery of novel ACPs, we proposed Diffusion-ACP39, a latent diffusion-based generative model with synchronized seed autoencoder for anticancer peptide design, capable of generating novel peptides with lengths ranging from 5 to 39 amino acids. Furthermore, we developed RF-ACP39, a random forest classifier model to assess the generative power of Diffusion-ACP39. Finally, Diffusion-ACP39 achieved an accuracy of 94.5% when generating 10,000 peptides with RF-ACP39. We also qualitatively analyzed the differences among true ACPs, random sequences, random peptides, and generated ACPs, demonstrating that the generated ACPs are most similar to true ACPs.

bioinformatics↗

bioRxiv2026

c-Fos enhances influenza virus replication by stabilizing the M2 protein and promoting autophagosome accumulation

The influenza A virus (IAV) employs multiple strategies to hijack host cellular machinery for efficient replication. While autophagosome accumulation is known to promote IAV replication, and the viral matrix protein 2 (M2) ion channel protein plays essential roles in viral uncoating, assembly, and autophagy induction, the mechanisms regulating M2 stability remain incompletely understood. Furthermore, although c-Fos participates in the replication of various viruses, its function in IAV infection has not been characterized. Here, we identify c-Fos as a critical proviral host factor that enhances IAV replication through stabilizing M2 protein and promoting autophagosome accumulation. We demonstrate that IAV infection triggers M2-mediated cytosolic calcium elevation, which upregulates c-Fos expression. The induced c-Fos physically interacts with M2 and prevents its proteasome and lysosomal degradation, thereby increasing M2 accumulation. This stabilized M2 protein as a viral protein directly facilitates viral replication while simultaneously promoting autophagosome accumulation to further enhance the process. Our findings reveal a novel positive feedback loop in IAV infection, establishing c-Fos as a key regulator of IAV replication through M2 stabilization, and highlighting these interactions as potential therapeutic targets for antiviral intervention. IMPORTANCEInfluenza A virus (IAV) remains a significant global health threat, causing substantial morbidity and mortality. Understanding virus-host interactions is crucial for developing antiviral strategies. Here, we uncover a previously unrecognized positive feedback loop in which IAV exploits the host transcription factor c-Fos to enhance its own replication. We demonstrate that IAV infection upregulates c-Fos through M2-mediated calcium signaling, and the induced c-Fos in turn stabilizes the viral M2 protein. This stabilized M2 not only directly supports viral replication but also promotes autophagosome accumulation, further facilitating virus production. Our findings establish c-Fos as a critical proviral host factor and reveal a mechanism by which IAV hijacks host cellular machinery to create a favorable environment for efficient replication. The identification of this c-Fos-M2 axis not only advances our understanding of IAV-host interactions but also opens new avenues for therapeutic intervention targeting this vulnerability in the viral life cycle.

cell biology↗

bioRxiv2026

Potential risk for hearing from prolonged exposure to sound at conversation levels

Prolonged exposure to loud and moderate noise impairs hearing; the lower the noise level, the lower risk of hearing loss is. To date, little is known about how low the noise level can be safe to hearing. This study investigated the risk of exposure to tone at typical conversational levels by measuring auditory brainstem response (ABR). We show that exposing C57 mice to continuous pure tone at 65 dB SPL for 1 hour (TE65) leads to an increase in ABR threshold that is specific to the exposure frequency. Tone exposure also increased the latencies and decreased the amplitude in Waves I and II but not in Waves III and V. Significantly, the changes in amplitude and latency were highly correlated in Wave I and such correlation gradually degraded from Wave I through to Wave V. Our findings suggest that exposure to low level sound can impair hearing and alter the auditory information process in the brain if it is persistent and presented over a sufficient period of time. Significant StatementOur findings established the risk of hearing impairment following the exposure to continuous tone at normal or conversational voice levels. This finding challenges current public health guidelines for hearing protection. Although further clarification is required, our studies prompt that the regular use of ABR testing is a potential protocol for diagnosing hearing impairment in patients experiencing hidden hearing loss (HHL).

neuroscience↗

bioRxiv2026

ABCG transporter knockouts alter integument and eye pigmentation with gene-specific effects on viability in butterflies and moths

Insects possess remarkable diversity in pigmentation across life stages, generated from a limited number of pigment precursors. ABCG transporters play central roles in pigmentation by mediating the intracellular transport of these precursors, yet their functions outside a few model systems remain poorly characterized. Here, we investigate the roles of the ABCG transporter genes white (w), scarlet (st), and oily kinshiryu (ok) across five lepidopteran species representing both butterflies and moths. CRISPR-Cas9 knockouts reveal conserved, tissue-specific functions of ABCG transporters throughout development, affecting larval and pupal integuments as well as adult eyes, but not scale coloration. Notably, our data indicate that both ommochrome and uric acid deposition underlie the coloration and opacity of Lepidoptera larvae and pupae, with the relative contributions of these pathways differing across species and stages. We also reveal that the vivid orange coloration of Gulf fritillary caterpillars arises from the interplay of ommochromes and urate granules, providing a clear example of how these pathways combine to produce diverse integument pigmentation. Loss of white was deleterious in four species examined, whereas scarlet knockouts produced viable individuals with easily detectable pigmentation phenotypes, identifying scarlet mutant backgrounds as a practical genetic marker for functional studies. Together, these findings show that conserved ABCG transporter complexes are differentially deployed across tissues and life stages, providing a mechanistic basis for the evolutionary diversification of pigmentation in Lepidoptera and enabling expanded functional genomics and transgenesis in emerging model species. Research HighlightsCRISPR-Cas9 disruption of ABCG transporters across Lepidoptera reveals conserved, tissue-specific roles in pigmentation. Interactions between ommochrome and uric acid deposition generate stage-specific coloration in larval and pupal integument.

genetics↗

bioRxiv2026

Learning a Continuous Progression Trajectory of Amyloid in Alzheimer's disease

BACKGROUNDUnderstanding of early Alzheimer progression is critical for timely diagnosis and treatment evaluation, but traditional diagnostic groups often lack sensitivity to subtle early-stage changes. METHODSWe developed SLOPE, an unsupervised dimensionality reduction method that models the amyloid progression in AD on a continuous scale which preserves the temporal sequence of follow-up visits. Applied to longitudinal amyloid PET data, SLOPE generated a two-dimensional trajectory capturing global amyloid accumulation across the AD continuum. RESULTSSLOPE-derived pseudotime scores better preserved temporal consistency across diagnostic groups and longitudinal follow-up visits and can be generalized to held-out subjects. The learned trajectory revealed biologically consistent amyloid spreading patterns and greater sensitivity to early progression than global amyloid SUVR. DISCUSSIONSLOPE provides a continuous staging of amyloid pathology that complements global amyloid measures by capturing early localized progression.

bioinformatics↗

bioRxiv2026

Ophiuchus-Ab: A Versatile Generative Foundation Model for Advanced Antibody-Based Immunotherapy

Antibodies exhibit extraordinary specificity and diversity in antigen recognition and have become a central class of therapeutics across a wide range of diseases. Despite this clinical success, antibody design remains fundamentally challenging. Antibody function emerges from intricate and highly coupled interactions between heavy and light chains, which complicate sequence-function relationships and limit the rational design of developable antibodies. Here, we reveal that modeling antibody sequence space at the level of paired heavy and light chains is essential to faithfully capture inter-chain dependencies, enabling a deeper understanding of antibody function and facilitating antibody discovery. We present Ophiuchus-Ab, a generative foundation model pre-trained on largescale paired antibody repertoires within a diffusion language modeling framework, unifying antibody generation and representation learning in a single probabilistic formulation. This framework excels diverse antibody design tasks, including CDR infilling, antibody humanization, and light-chain pairing. Beyond generation, diffusion-based pre-training yields transferable representations that enable accurate prediction of antibody properties, including developability, binding affinity, and specificity, even in low-data regimes. Together, these results establish Ophiuchus-Ab as a versatile foundation model for modeling antibodies, providing a foundation for next-generation antibody-based immunotherapy.

bioinformatics↗

bioRxiv2026

Geometric Fragility in Alzheimer's Disease: Probing the Loss of Hippocampal Hierarchical Abstraction via Contrastive Point Cloud Modeling

While human spatial cognition relies on hierarchical abstraction to integrate local features, Alzheimers disease (AD) pathology is often reduced to local volumetric atrophy. We propose geometric fragility as a distinct failure of global topological integrity within the hippocampus rather than a mere accumulation of local errors. Using a texture-invariant point cloud framework, we contrasted local feature aggregation with global hierarchical attention as computational probes for structural perception. The global paradigm demonstrated enhanced diagnostic sensitivity and exhibited cognitive resilience under simulated neuronal sparsity by maintaining structural recognition where local models suffered pattern collapse. Global modeling effectively unfolded the pathological manifold, revealing a linear trajectory of geometric degradation consistently correlated with clinical cognitive decline. These findings indicate that AD progression may be characterized as a systemic topological dissolution and suggest that effective biomarkers should prioritize hierarchical shape abstraction to accurately map the continuous transition from healthy cognition to dementia.

neuroscience↗

bioRxiv2026

LRRC55 modulates BK channels to support Purkinje cell plasticity and motor coordination

Large-conductance Ca2+- and voltage-activated K+ (BK) channels are widely expressed, including in the brain where they shape neuronal excitability. Their physiological functions are strongly influenced by cell-type-specific auxiliary subunits. The auxiliary {gamma}3 subunit (LRRC55) enhances BK-channel activation by shifting voltage-dependent gating toward more negative potentials; however, its protein distribution and in vivo function remain unclear. Here, we generated knock-in mice carrying a C-terminal epitope tag on endogenous LRRC55 to map its expression, and Lrrc55 knockout mice to test its function. LRRC55 protein was selectively enriched in cerebellar Purkinje cells. Lrrc55 deletion produced ataxia-like impairments in gait, balance, and coordination. In acute slices, pharmacological BK-channel block with paxilline altered Purkinje cell simple- and complex-spike firing in wild-type mice, whereas these BK-dependent effects were largely absent in Lrrc55 knockouts, indicating that LRRC55 is required for BK channels to shape Purkinje cell firing under these conditions. Moreover, LRRC55 loss disrupted cerebellar synaptic plasticity, abolishing parallel fiber-Purkinje cell long-term potentiation and eliminating climbing fiber-Purkinje cell long-term depression, phenocopying paxilline in wild-type cells. Together, these results identify LRRC55 as a Purkinje-cell-enriched auxiliary subunit that is essential for BK-dependent excitability and plasticity and that supports normal cerebellar motor function.

neuroscience↗

bioRxiv2026

OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA/CREB pathway

Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a glycosylated, membrane-integral protein that regulates lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Through a whole-genome CRISPR/Cas9 screen, we identified OSTM1 as a previously unrecognized tumor suppressor in B-cell malignancies. Consistent with this role, OSTM1 is frequently deleted or downregulated across a broad spectrum of human B-cell cancers. In mice, B-cell-specific monoallelic or biallelic ablation of Ostm1 cooperates with Cdkn2a loss to drive lymphomagenesis with near-complete penetrance. Mechanistically, we uncover a cytosolic, non-glycosylated fraction of OSTM1 that functions as a ubiquitin E3 ligase to promote proteasomal degradation of phosphodiesterase 3B (PDE3B). As PDE3B hydrolyzes cAMP and suppresses the tumor-protective PKA/CREB/CREBBP signaling axis, loss of OSTM1 leads to PDE3B stabilization, attenuation of cAMP signaling, and enhanced oncogenic transformation. Together, our findings establish OSTM1 as a critical suppressor of B-cell lymphomagenesis through regulation of the cAMP/PKA/CREB pathway.

cancer biology↗