Biology subjects

Yuan, Z.

Publications and source records attributed to Yuan, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Inflammatory memory disables a DDR1 degradation checkpoint to enable pancreatic cancer growth

Inflammation and stroma remodeling regulate pancreatic ductal adenocarcinoma (PDAC), but how or if these cues are integrated at the molecular level remains unclear. Here, we identify a metabolic checkpoint that controls the stability of the collagen receptor DDR1, and subsequent tumorigenesis. We show that defective Col-I remodeling deprives PDAC cells of the high affinity DDR1 ligand, [3/4]Col-I, resulting in reduced ATP and activation of AMPK. AMPK phosphorylates DDR1 at T519, promoting its recognition by the E3 ubiquitin ligase adaptor FBXW2 and subsequent degradation. Importantly, this degradation pathway can be disabled by inflammatory signaling. Exposure to inflammatory cytokines induces methylation-dependent silencing of FBXW2, which establishes an inflammatory memory that preserves DDR1 stability, enabling sustained ligand-triggered receptor oligomerization and downstream NF-{kappa}B-NRF2 signaling even in restrictive stromal environments. Together, these findings identify regulated receptor turnover as a mechanism through which stromal architecture, metabolic state, and inflammatory memory are integrated to control PDAC progression.

cancer biology↗

bioRxiv2026

Sustained Relief of Chronic Pain via a Nav1.7_Targeting ASO_siRNA Conjugate

Chronic pain affects billions globally, yet safe, long-lasting, and non-addictive analgesics remain lacking. Nav1.7 is a genetically validated pain target, but traditional small molecules have repeatedly failed. Therapeutic oligonucleotides-antisense oligonucleotides (ASOs) and siRNAs-offer selective, durable silencing. We developed N02C0702, an ASO-siRNA conjugate (ASC), achieving robust Nav1.7 knockdown and sustained analgesia without additional delivery vehicles. N02C0702 outperformed individual ASO (N02A114) and siRNA (N02S154) moieties at mRNA and protein levels and in pain relief. In CFA-induced inflammatory pain, a single intrathecal dose exceeded naproxen and suzetrigine, while in SNL neuropathic pain, efficacy persisted up to 56 days, comparable to or surpassing pregabalin. Genome-wide RNA sequencing confirmed minimal off-target effects. N02C0702 highlights Nav1.7 as a key analgesic target and demonstrates the ASC platforms potential for chronic pain and other CNS-related pathologies, offering durable, selective, and safe therapeutic effects.

neuroscience↗

bioRxiv2026

Metformin Stabilizes the Abdominal Aorta in Aneurysm by Restoring VSMC Mitochondrial Homeostasis via the AMPK-SIRT1-PGC-1α Axis

BACKGROUNDAbdominal aortic aneurysm (AAA) is a life-threatening condition with >80% mortality upon rupture and no effective pharmacotherapy available. Despite epidemiological evidence linking metformin use to reduced AAA progression, its mechanism remains elusive. Notably, peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1, encoded by Ppargc1a) is downregulated in human AAA, yet its functional role in metformins protection is unknown. METHODSWe employed porcine pancreatic elastase (PPE)-induced murine AAA, VSMC-specific Ppargc1a knockout (Ppargc1aVSMC-KO), primary VSMC senescence models, and pharmacological inhibition (Compound C for AMPK; Ex-527 for SIRT1) to define the AMPK-SIRT1-PGC-1 axis. RESULTSMetformin significantly inhibited AAA expansion, suppressed VSMC senescence (p53/p21{downarrow}, SA-{beta}-gal{downarrow}), and preserved contractile phenotype (SMTN{uparrow}, IL-6/TNF-{downarrow}). Crucially, all benefits were abrogated in Ppargc1aVSMC-KO mice, which exhibited accelerated aneurysm growth, mitochondrial fragmentation, ATP depletion, and ROS accumulation. Mechanistically, metformin activated AMPK/SIRT1 to upregulate PGC-1; AMPK or SIRT1 inhibition blocked this cascade and reversed protection. CONCLUSIONMetformin restrains AAA by restoring VSMC mitochondrial homeostasis via the AMPK/SIRT1[->]PGC-1 axis, positioning PGC-1 as a non-redundant, cell-autonomous guardian against vascular degeneration. These findings provide a mechanistic foundation for repurposing metformin and developing PGC-1-targeted therapies in AAA.

cell biology↗

bioRxiv2026

A lightweight, ultrafast and general embedding framework for large-scale spatial omics data

Deciphering ultra-large-scale omics data with minimal resources while maintaining high computational efficiency is a longstanding challenge in biology. Here, we present Local Pooling (LP), a lightweight, ultrafast and general framework that leverage neighbor-indexing strategy and local pooling module to generate omics embedding and compatible with variety of downstream analyses. We developed its adaptation for spatial omics, SpaLP, and evaluated it on over 20 large-scale datasets spanning 9 technology platforms. SpaLP consistently outperformed baseline methods across multiple benchmarks, including niche identification, expression reconstruction, multiple slices integration, 3D organ construction, multi-omics integration and cross-platform generalization. Notably, SpaLP processed a 1.35-million-cell mouse embryo slice in just 47 seconds, achieving up to 300-fold increase in computational efficiency compared to Graph Neural Network (GNN)-based methods. Meanwhile, SpaLP increased the average adjusted rand index (ARI) by over 30% for niche identification in simulated and realistic settings. Furthermore, we applied SpaLP to integrate 8.4 million mouse brain cells within 4 minutes on a single GPU and constructed a 3D spatial atlas. Finally, we explored SpaLPs ability of cross-platform generalization and potential for developing an omics foundation model. As a novel and general framework, we believe that LP could help more researchers develop new model on large-scale data and overcome the research barriers caused by computing resources in more fields.

bioinformatics↗

bioRxiv2026

PRISM: Niche-informed Deciphering of Incomplete Spatial Multi-Omics Data

Spatial multi-omics data, characterizing the knowledge of diverse molecular layers, have become indispensable for the in situ analysis of tissue architecture and complex biological processes. Nevertheless, current spatial multi-omics sequencing protocols are often hindered by incompatible protocols, resulting in incomplete spatial multi-omics pairing due to inconsistent field-of-view or spatial resolution. To address this, we present PRISM, a novel computational method tailored for this scenario. PRISM leverages a niche-informed graph to propagate information from paired to unpaired regions, jointly achieving the spatial domain identification and spatial omics imputation. Extensive benchmarking on five diverse simulated and real experimental datasets demonstrated that PRISM outperformed existing methods in spatial multi-omics analysis tasks. Application to the human Parkinsons disease data revealed that PRISM accurately recovered dopamine-associated spatial domains and metabolite distributions masked by incomplete data gaps. PRISM offers a robust solution for bridging the integration gap inherent in incompatible sequencing protocols, thereby facilitating more accurate downstream biological interpretation.

bioinformatics↗

bioRxiv2026

TRPV4 Inhibition by a Natural Product Mediates Analgesia

The transient receptor potential vanilloid 4 (TRPV4) channel, a polymodal calcium-permeable cation channel, is activated by diverse stimuli, including hyposmolarity, moderate heat, mechanical stress, and acidic pH. TRPV4 plays a critical role in the onset and progression of pain and is implicated in multiple pathological conditions, positioning it as an attractive therapeutic target. However, the development of TRPV4-targeted therapeutics has been hindered by limited mechanistic understanding of its inhibition. Here, the natural product (R)-1-(3-ethylphenyl)ethane-1,2-diol (AH001) is identified as a potent, subtype-selective TRPV4 inhibitor. A potential gating mechanism of TRPV4 inhibition is proposed through a combination of structural analyses and site-directed mutagenesis. Electrophysiological studies and cryo-electron microscopy (cryo-EM) further reveal that AH001s glucuronide metabolite, AHP, retains robust TRPV4 inhibitory activity, providing a critical structural basis for rational optimization of AH001 as a lead compound. Notably, AH001 demonstrated significant efficacy in reducing neuronal hyperexcitability in dorsal root ganglia (DRGs) and produced pronounced analgesic effects across multiple pain models, highlighting its therapeutic potential in pain relief. This study offers critical structural and mechanistic insights into TRPV4 inhibition and lays the groundwork for the structure-based design of TRPV4-targeted therapeutics.

biochemistry↗

bioRxiv2025

Pulmonary mRNA-LNP Vaccines for Rapid and Durable Protection Against Bacterial Infection

Pulmonary bacterial infections remain a major clinical challenge. Although vaccination reduces infection rates and mortality, the vulnerable post-vaccination immunity gap can still result in infection and vaccine failure. In addition, effective vaccines are unavailable for many clinically important bacterial pathogens. Here, we report a pulmonary mRNA-lipid nanoparticle (mRNA-LNP) vaccine incorporating a novel ionizable lipid engineered for localized high-level expression, which elicits both rapid and durable protections against bacterial lung infections, effectively bridging this critical window of vulnerability. Intratracheal delivery of mRNA-LNP rapidly primes lung neutrophils and macrophages into a transcriptionally pre-activated state, enhancing their phagocytic activity and enabling rapid, antigen-independent bacterial clearance during the early post-vaccination period (approximately 1-7 days). Subsequently, vaccination induces potent antigen-specific adaptive responses, conferring sustained protection against both laboratory and clinical drug-resistant Pseudomonas aeruginosa strains. Single-cell transcriptomics and immune profiling reveal coordinated activation of innate and adaptive immune programs. This dual-phase immune response exemplifies a paradigm-shifting vaccine design that integrates innate and adaptive immunity to confer both immediate and long-term protection. Our findings establish a mechanistic basis for rapid antibacterial defense and highlight pulmonary mRNA-LNP vaccination as a promising strategy for combating respiratory infections.

bioengineering↗

bioRxiv2025

Silicon Micropillar-Enhanced CRISPR Biosensor for Rapid and Sensitive Detection of Drug-Resistant Bacteria

1The growing threat of antibiotic-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), underscores the urgent need for rapid, sensitive, and field-deployable diagnostic technologies. Here, we present a silicon micropillar-enhanced CRISPR biosensor that integrates high-aspect-ratio microstructures with a one-pot RPA/CRISPR-Cas12a assay for ultrasensitive and specific detection of MRSA. Micropillar arrays with fixed diameters and varying heights (100 {micro}m, 300 {micro}m, and 500 {micro}m) were fabricated via deep reactive ion etching and functionalized for surface probe immobilization. Suboptimal crRNA design was employed to modify Cas12a activation kinetics, enabling declined trans-cleavage and enhanced end-point signal accumulation. The 500 {micro}m micropillar configuration demonstrated a tenfold improvement in sensitivity compared to the 100 {micro}m array, with a limit of detection reaching 103 CFU mL-1. The platform also showed high specificity against non-target bacterial strains. These findings highlight the potential of combining microstructured chips with one-pot CRISPR diagnostics to advance next-generation point-of-care tools for infectious disease monitoring. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/694528v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@5f5f7corg.highwire.dtl.DTLVardef@175cb35org.highwire.dtl.DTLVardef@7043e5org.highwire.dtl.DTLVardef@79aa15_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Global Mapping of circRNA-Target RNA Interactions Reveals P-Body-Mediated Translational Repression

Circular RNAs (circRNAs) are primarily produced through pre-mRNA back-splicing, yet their target repertoire and functional mechanisms remain elusive. Here, we present circTargetMap, a computational framework for globally mapping circRNA targets using RNA-RNA interactomes obtained via RNA in situ conformation sequencing (RIC-seq) in the hippocampus and ten human cell lines. This approach identified 117,163 high-confidence circRNA-target RNA interactions, with 83% of target mRNAs bound by multiple circRNAs. Functionally, CDR1as and circRMST repress target mRNA translation by sequestering them into processing bodies (P-bodies)--membraneless granules--through sequence-specific base-pairing, probably independent of AGO2, DICER, and miRNAs. To directly capture granule-associated interactions, we developed granule RIC-seq (GRIC-seq) method, revealing the broad role of circRNA-target RNA interactions in translational repression. Moreover, pathogenic variants are significantly enriched around circRNA-target RNA interaction sites, suggesting potential roles in disease. Our study provides valuable resources for circRNA functional exploration and a framework for investigating RNA-RNA interactions within membraneless organelles.

molecular biology↗

bioRxiv2025

Modular mRNA lipid nanoparticle platform rescues diverse genetic male infertility

Genetic male infertility arises from diverse mutations that disrupt spermatogenesis, yet therapeutic strategies capable of restoring germ-cell function remain limited. Messenger RNA (mRNA) therapeutics offer a programmable and non-integrating approach, but their functional compatibility in structured and immune-privileged tissues remains unclear. Here we identify a temporal mismatch between mRNA delivery kinetics and the progression of spermatogenesis as a key barrier to functional rescue. We show that delivery efficiency does not predict outcome: formulations with high peak expression but short duration fail to support spermiogenesis, whereas sustained expression aligned with developmental timing enables recovery. Guided by this principle, we establish a testis-targeted mRNA delivery platform that restores spermatogenesis across multiple genetic models and generates functional sperm capable of supporting embryo development and multigenerational inheritance. The approach is modular, extends to human seminiferous tubules ex vivo, and is supported by comprehensive safety analyses. Together, these findings define a design constraint for RNA therapeutics in structured tissues: functional rescue requires temporal alignment between delivery kinetics and the therapeutic window defined by tissue-specific biological programs.

bioengineering↗

bioRxiv2025

Structural and Functional Insights into HBx-Smc6 Targeting for HBV Inhibition

The hepatitis B virus (HBV) X protein (HBx) is a multifunctional regulator essential for HBV replication and HBV-associated hepatocarcinogenesis. Despite its central role, the molecular basis of HBx function has remained elusive. Here, we present the first cryo-electron microscopy structure of the human HBx-CRL4-Smc5/6 complex at 3.1 [A] resolution. In this reconstituted ten-subunit assembly, HBx adopts a Zn2 {square}-stabilized Y-shaped architecture that simultaneously engages the DDB1 and the Smc6 subunit. A composite helix-turn-helix (HTH) pocket in HBx accommodates a conserved "Leucine Key" motif (LRCKL) on Smc6, forming a critical interface essential for complex stability and function. Molecular docking and biochemical validation reveal that the compound Tranilast binds this HTH pocket, disrupts the HBx-Smc6 interaction, and suppresses HBV replication. These findings define the structural mechanism by which HBx counteracts host restriction and establish the HBx-Smc6 interface as a previously unrecognized and druggable target for antiviral intervention.

cell biology↗

bioRxiv2025

A TCR-mimic bispecific antibody reduces HIV-1 provirus and delays viral rebound in HLA-matched humanized mice

Bispecific antibodies that reroute cytotoxic effectors toward infected cells are promising HIV-1 cure agents, yet existing formats bind Env and are limited by antigenic variation and Env down-regulation. We engineered a TCR-mimic single-chain diabody, HI12, that recognizes a conserved Pol-derived peptide presented by HLA-A*02:01 and evaluated its effect in HLA-matched, HIV-infected humanized mice. When administered during early antiretroviral therapy (ART), HI12 was well tolerated, activated HIV-specific CD8+ T cells and accelerated plasma virus decay. Treatment produced four-to six-fold reductions in intact and total proviral DNA within lymph-node and splenic CD4+ T cells, indicating substantive reservoir clearance. After ART interruption, HI12-treated animals showed a significant delay in viral rebound compared with controls, linking reservoir reduction to improved post-therapy control. These findings provide the first in-vivo evidence that a peptide-HLA-directed bispecific antibody can both shrink the intact HIV reservoir and defer viral recrudescence, supporting further development of TCR-mimic bispecific antibodies for cure strategies. Significance StatementAn HIV-1 cure strategy will require novel therapeutics to facilitate immune-mediated elimination of infected cells and reduction of blood and tissue reservoirs. Here, we demonstrate that an TCR-mimic bispecific antibody that recognizes a conserved Pol epitope can promote CD8+ T cell-mediated clearance of infected cells in HLA-matched, HIV-infected humanized mice. The bispecific antibody therapy reduced HIV-1 proviral DNA in lymph node and splenic tissues and improved post-therapy viral control. This study highlights the potential of developing novel TCR-mimic bispecific antibodies in HIV cure-directed strategies.

immunology↗

bioRxiv2025

Distinct functional potential of bacterial extracellular vesicles across biogeographic provinces of the South Pacific Ocean

Bacterial extracellular vesicles (BEVs) are nanoscale membranous structures released by diverse types of bacteria. Laboratory model systems indicate that these nanoparticles may play several roles in the ecophysiology of marine bacteria. However, their actual functionality in the environment remains unclear. Here we describe the proteomic composition of marine BEVs over more than 5,000 nautical miles of surface waters in the South Pacific, linking BEV cargoes to the bacterial communities producing them. BEVs were consistently present across a range of biogeochemical conditions, with an overall abundance comparable to that of bacterial cells. However, the protein content of the BEVs varied significantly between different ocean regions. The BEVs were enriched in carbohydrate transporters under phytoplankton bloom conditions, and contained iron and phosphate uptake-related proteins in nutrient-limited waters. This suggests that BEVs could enable cells to perform key extracellular functions in the marine environment. Our observations further highlight the prevalence of BEVs and the biogeographic patterns of their functional potential across oceanic scales.

microbiology↗

bioRxiv2025

Predicting Spatial Transcriptomics from H&E Image by Pretrained Contrastive Alignment Learning

The intricate molecular landscape within tissues holds crucial information about cellular behavior and disease progression, yet capturing this complexity at a spatial level remains challenging. While Spatial transcriptomics (ST) offers valuable insights into gene expression patterns within their native tissue context, its widespread adoption is hindered by high costs and limited gene detection capabilities. Here we introduce CarHE (Contrastive Alignment of gene expRession for hematoxylin and eosin image), a method that overcomes these limitations by accurately predicting high-dimensional ST data (over 10,000 genes) solely from readily available H&E (Hematoxylin and Eosin) stained images. This novel pre-trained architecture employs contrastive learning through two mechanisms: cell-type-based transcriptomics information transfer and image-based histology information transfer. These mechanisms precisely align image features with spatial single-cell gene expressions, achieving prediction accuracies exceeding 0.7 (up to 1.7 folds compared to second best) across diverse tissue types and species. CarHEs superior performance extends to identifying subtle pathological features such as tertiary lymphoid structures in various cancers, including breast cancer, lung cancer, melanoma and ccRCC (clear cell renal cell carcinoma), and reconstructing 3D spatial transcriptomics from images alone, offering a cost-effective and robust alternative for large-scale spatial transcriptomics. We further validated CarHEs effectiveness by predicting DFS (Disease-Free Survival) from >1,600 lung cancer patients HE images, achieving a significantly higher AUC (Area Under the Receiver Operating Characteristic Curve) of 0.73 compared to state-of-the-art alternatives (0.58-0.64).

bioinformatics↗

bioRxiv2025

Population-specific brain charts reveal Chinese-Western differences in neurodevelopmental trajectories

Human brain charts provide unprecedented opportunities for decoding neurodevelopmental milestones and establishing clinical benchmarks for precision brain medicine 1-7. However, current lifespan brain charts are primarily derived from European and North American cohorts, with Asian populations severely underrepresented. Here, we present the first population-specific brain charts for China, developed through the Chinese Lifespan Brain Mapping Consortium (Phase I) using neuroimaging data from 43,037 participants (aged 0-100 years) across 384 sites nationwide. We establish the lifespan normative trajectories for 296 structural brain phenotypes, encompassing global, subcortical, and cortical measures. Cross-population comparisons with Western brain charts (based on data from 56,339 participants aged 0-100 years) reveal distinct neurodevelopmental patterns in the Chinese population, including prolonged cortical and subcortical maturation, accelerated cerebellar growth, and earlier development of sensorimotor regions relative to paralimbic regions. Crucially, these Chinese-specific charts outperform Western-derived models in predicting healthy brain phenotypes and detecting pathological deviations in Chinese clinical cohorts. These findings highlight the urgent need for diverse, population-representative brain charts to advance equitable precision neuroscience and improve clinical validity across populations.

neuroscience↗

bioRxiv2025

Inhibiting RhoA Activation via GDP-state Stabilization to Relieve Heart Failure

High rates of heart failure (HF) morbidity and mortality have made targeting myocardial remodeling--particularly hypertrophy and fibrosis--a key therapeutic focus. RhoA, which regulates cytoskeletal reorganization and cell migration, plays a role in this process. However, RhoA has long been considered "undruggable", due to its strong binding to its endogenous substrates, GDP/GTP, and the lack of well-defined pockets for drug targeting. Here, we discovered a cryptic pocket proximate to GDP within RhoA and identified a natural product, AH001, binds here and interacts with GDP, stabilizing RhoAs interaction with its endogenous inhibitor, RhoGDI. AH001 reduced the downstream MRTFA nuclear translocation and downregulated fibrosis/hypertrophy proteins. Consequently, AH001 mitigated myocardial remodeling in multiple HF animal models, and in the 3D myocardial tissue model. Our findings highlight the therapeutic potential of inhibiting RhoA activation in myocardial remodeling, ultimately targeting HF, and offer a promising avenue for developing reversible inhibitors against undruggable GTPases.

pharmacology and toxicology↗

bioRxiv2025

Integrating Multimodal Data for a Comprehensive Knowledge Graph to Advance Infectious Disease Research

Infectious diseases remain a formidable threat to global public health, with their escalating morbidity and mortality rates compounded by recurrent epidemics and the alarming rise of antimicrobial resistance (AMR). These challenges have intensified the urgent demand for innovative therapeutic strategies that can accelerate drug development cycles and overcome traditional research bottlenecks. To address these critical needs, we present IDKG (Infectious Disease Knowledge Graph), a specialized large-scale biomedical knowledge network designed to bridge data fragmentation through multimodal data integration. The IDKG constructs comprehensive associations from 345 infectious diseases and 708 pathogens across heterogeneous biomedical sources systematically. The graph architecture comprises nearly 50,000 nodes (8 types, including Pathogen, Protein, etc.) and over 1.2 million edges (11 types, including treats, contains, etc.), establishing an interconnected framework that enables systematic interrogation of cross-disciplinary knowledge. The integrative approach effectively dismantles conventional data silos while preserving biological contextuality. We validated the IDKGs potential by applying graph neural network-based approaches for drug repurposing prediction in human metapneumovirus (hMPV) infection, a common acute respiratory infection for which effective specific antiviral drugs are currently absent. The successfully identification of established antiviral agents, such as ribavirin and emetine, by our M1 model demonstrated its predictive accuracy and biological relevance. IDKG unifies multimodal biomedical data into a network to accelerate drug discovery and bolster outbreak response. This establishes a data-driven, knowledge-based paradigm for infectious disease research. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/657361v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@f5dc24org.highwire.dtl.DTLVardef@147d584org.highwire.dtl.DTLVardef@113083corg.highwire.dtl.DTLVardef@81d523_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Distinct Bomanins at the Drosophila 55C locus function in resistance and resilience to infections

Host defense against many Gram-positive bacteria and fungal pathogens is mainly provided by the Toll-dependent systemic immune response in Drosophila. While antimicrobial peptides active against these categories of pathogens contribute only modestly to protection, Bomanin peptides are major effectors of the Toll pathway. Remarkably, flies deleted for the 55C locus that contains 10 Bomanin genes are as sensitive as Toll pathway mutant flies to these infections. Yet, the exact functions of single Bomanins in resistance or resilience to infections remain poorly characterized. Here, we have extensively studied the role of these Bomanin genes. BomT1 functions in resistance to Enterococcus faecalis while playing a role in resilience against Metarhizium robertsii infection, like BomS2. BomT1 and BomT2 prevent the dissemination of Candida albicans throughout the host, even though they are not sufficient to confer protection to immunodeficient flies against this pathogen in survival experiments. Furthermore, BomT1 and BomBc1 mutants are sensitive to an Aspergillus fumigatus ribotoxin. We conclude that 55C Bomanins have defined albeit sometimes overlapping roles in the different facets of host defense against infections.

immunology↗