Biology subjects

Lyu, X.

Publications and source records attributed to Lyu, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Development of CYP8B1-specific inhibitors for metabolic diseases

Changes in bile acids (BAs) balance lead to various metabolic diseases, yet current treatment options targeting these changes remain severely limited. CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) is a liver-exclusive enzyme that controls the synthesis of 12-hydroxylated (12-OH) BAs. Inhibiting CYP8B1 is an attractive therapeutic strategy for attenuating 12-OH BA levels, remodeling the gut microbiota and thereby ameliorating metabolic diseases. CYP8B1-specific inhibitors are currently lacking due to structural similarities between the active site of CYP8B1 and other CYPs, and the lack of suitable high-throughput screening (HTS) assays. Herein, we developed a highly sensitive, and specific enzyme-coupled fluorescence assay to detect CYP8B1 activity, making it ideal for HTS. Employing this assay, structure-based drug design by protein X-ray crystallography, structure-activity relationship (SAR) analyses, and in vitro and in vivo validation, we developed novel CYP8B1-specific small molecule inhibitors. The lead candidate alters BA composition, favorably remodels the gut microbiota, and corrects metabolic disease in a metabolic dysfunction-associated steatotic liver disease (MASLD) mouse model. These findings reveal that pharmacologically inhibiting CYP8B1 is able to reshape the BA and gut microbiota profiles and effectively ameliorates metabolic diseases. Overall, CYP8B1-specific inhibitors represent a first-in-class promising, safe and effective therapeutic strategy against metabolic disorders.

pharmacology and toxicology↗

bioRxiv2026

MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable system, we identify the orphan transporter MCT6 (SLC16A5) as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.

physiology↗

bioRxiv2026

Research on Intelligent Optimization of Farm Planting Strategies Driven by Crop Simulation Models: A Case Study of Farm X

To meet the growing demand for precision and intelligent agricultural management, crop simulation models offer substantial potential for optimizing farm planting strategies. By simulating crop growth processes and assessing the effects of different management practices, these models provide a scientific basis for planting decision-making. In this study, the DSSAT model was first used to optimize the planting strategies of Farm X in 2023. Based on the optimized plans, the model was further applied to predict crop yields per unit area for 2024 and to establish the relationships among yield, planting density, and fertilizer application rate. Subsequently, SPSS was employed to develop a regression model describing the relationship among net profit per unit area, planting density, and fertilizer application rate. A genetic algorithm was then used to identify the optimal solutions under different scenarios, generating prescription maps for the optimal planting density and fertilizer application rate for each plot of Farm X in 2024. The results provide a scientific reference for the mechanized and automated implementation of field management practices and support the dual optimization of economic returns and resource use efficiency. This study not only conducted a systematic optimization of Farm X planting strategies for 2023, but also provided detailed predictions and optimized prescriptions for 2024 in a visual and practical form. The proposed approach offers a scientific decision-support tool for farm planting strategy formulation and lays a foundation for the intelligent and automated development of modern agriculture.

plant biology↗

bioRxiv2026

Structural basis for the broad recognition specificity of an Arabidopsis immune receptor

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors typically confer resistance through recognition of specific pathogen effectors. The Arabidopsis NLR WRR4A defies this paradigm by recognizing multiple sequence-divergent effectors from Albugo candida, conferring resistance to multiple pathogen races. Despite minimal sequence similarity, these effectors share a conserved N-terminal ferredoxin-like fold. Through cryo-EM structure determination of two WRR4A resistosomes bound to sequence-distinct effectors, combined with AlphaFold modelling, we reveal a shape-based recognition mechanism: WRR4A engages structurally conserved backbone features of the effectors in a mostly side chain-independent manner, enabling recognition of diverse effectors with similar three-dimensional architectures. These insights guided successful engineering of WRR4A to acquire novel recognition specificity. In addition, analysis of the monomeric WRR4A resting state reveals a distinct domain architecture characteristic of C-JID-containing TIR-NLRs and informs their activation mechanism. This work provides insights into NLR-mediated broad-spectrum recognition and the potential for structure-informed engineering of improved crop resistance.

plant biology↗

bioRxiv2026

A small molecule PTER-selective inhibitor reduces food intake and body weight

PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic taurine metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remain unknown, limiting our ability to harness this pathway therapeutically. Here we solve crystal structures of a eukaryotic PTER in apo and product-bound forms. These structures uncover an unexpected pocket homology between PTER and histone deacetylase (HDAC) enzymes. We exploit this similarity to engineer a first-in-class substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs in vitro. Administration of PTERi to diet-induced obese mice reduces feeding, enhances GLP1-RA (glucagon like peptide 1 receptor agonist)-induced weight loss, and prevents weight regain after GLP1-RA discontinuation. The structure of PTER connects histone and metabolite deacetylation into a parallel conceptual framework and enables proof-of-concept data for pharmacological inhibition of PTER in obesity.

biochemistry↗

bioRxiv2025

An activated wheat CCG10-NLR immune receptor forms an octameric resistosome

Nucleotide-binding and leucine-rich repeat (LRR) receptors (NLRs) are widespread intracellular immune sensors across kingdoms. In plants, the G10-type coiled-coil (CCG10)-NLRs form a distinct phylogenetic clade that remains poorly characterized. Here, we identified a gain-of-function (GOF) mutant of Wheat Autoimmunity 3 (WAI3), designated WAI3GOF, which encodes a constitutively activated CCG10-NLR protein due to an amino acid substitution. Cryo-EM structural analysis revealed that activated WAI3 assembles into a distinctive octameric resistosome. Arabidopsis RPS2, another CCG10-NLR, also forms an octamer, indicating a conserved structural property across monocot and dicot plants. The WAI3 resistosome mediates a prolonged and sustained increase in cytosolic calcium influx, facilitated by a unique channel architecture arising from its divergent CC domain configuration. Notably, this domain arrangement may be shared by many plant NLRs that lack the conserved EDVID motif in their CC domains. Our findings uncover a previously uncharacterized resistosome structure and provide insights into plant immune receptor plasticity.

plant biology↗

bioRxiv2024

Detecting mtDNA effects with an Extended Pedigree Model: An Analysis of Statistical Power and Estimation Bias

Mitochondrial DNA (mtDNA) plays a crucial role in numerous cellular processes, yet its impact on human behavior remains underexplored. The current paper proposes a novel covariance structure model with seven parameters to specifically isolate and quantify mtDNA effects on human behavior. This approach uses extended pedigrees to obtain estimates of mtDNA variance while controlling for other genetic and environmental influences. Our Monte-Carlo simulations indicate that a sample size of approximately 5,000 individuals is sufficient to detect medium mtDNA effects (mt2 = 5%), while a more substantial cohort of around 30,000 is required for small effects (mt2 = 1%). We show that deeper pedigrees increase power to detect the mtDNA effect while wider pedigrees decrease power, given the equal total sample size. We evaluated how missing kinship records and mtDNA mutations impact bias. Both lead to underestimation of mtDNA variance, and an overestimation of the interaction between nuclear DNA and mtDNA. In addition, the false positive rate of mtDNA effect estimation is low when fitting the model with data generated without mtDNA effects. Collectively, we demonstrate that using extended pedigrees to quantify the influence of mtDNA on human behavior is robust and powerful.

genetics↗

bioRxiv2024

Ethylene Modulates the Phenylpropanoid Pathway by Enhancing VvMYB14 Expression via the ERF5-Melatonin-ERF104 Pathway in Grape Seeds

Ethylene plays a crucial role in regulating polyphenol metabolism, however the underlying mechanism remains largely unknown. This work demonstrated that ethylene release occurred earlier than melatonin during seed ripening. Ethylene treatment increased the VvASMT expression and melatonin content. VvERF5 was elucidated to bind to the ERE element in the VvASMT promoter. VvERF5 overexpression increased ASMT expression and melatonin content while its suppression generated the opposite results in grape seeds, calli and/or Arabidopsis seeds. Using the promoter of VvMYB14, which was strongly induced by melatonin, a melatonin responsive element (MTRE) was identified. VvERF104 was revealed not only to be strongly induced by melatonin but to bind to the MTRE of the VvMYB14. VvERF104 overexpression and suppression largely increased and decreased the MYB14 expression, respectively, in grape seeds, calli and/or Arabidopsis seeds. VvMYB14 overexpression widely modified the expression of genes in phenylpropanoid pathway and phenolic compound content in grape seeds. DAP-seq revealed that the MEME-1 motif was the most likely binding sites of VvMYB14. VvPAL, VvC4H and VvCHS were verified to be the target genes of VvMYB14. Additionally, the roles of VvERF5, VvASMT and VvERF104 in mediating ethylene-induced changes in phenylpropanoid pathway were elucidated using their suppressing seeds. Collectively, ethylene increased the VvMYB14 expression via the pathway of ERF5-melatonin-ERF104 and thereby modified phenylpropanoid pathway.

plant biology↗

bioRxiv2024

Structural Basis for the Activation of Proteinase-Activated Receptors (PARs) by Endogenous Ligands

The proteinase-activated receptor (PAR) subfamily of G protein-coupled receptors (GPCRs) include four members, PAR1-PAR4, that play critical roles in hemostasis, thrombosis, embryonic development, wound healing, inflammation, and cancer progression. The PARs share a unique activation mechanism driven by proteinase cleavage at a specific site within the extracellular amino-terminus, exposing a tethered ligand that self-activates the receptor. Subsequent activation allows PAR family members to initiate complex intracellular signaling networks via traditional G protein-mediated pathways and beta-arrestin signaling and, in this way, the PARs link extracellular protease signaling molecules to cellular functions. Despite a primary reliance on biochemical studies for understanding tethered ligand recognition, direct structural visualization of these ligand-receptor complexes has been elusive. Here, we present structural snapshots of activated PAR1 and PAR2 bound to their endogenous tethered ligands, revealing, for the first time, shallow and constricted orthosteric binding pockets and highlighting critical residues involved in ligand recognition and receptor activation. Surprisingly, comparisons with antagonist-bound structures show minimal conformational changes in the TM6 helix, a typical signature of GPCR activation, with large movements of TM7 observed upon activation. These insights lead to the identification of a common mechanism for PAR1 and PAR2 activation and provide a structural template for designing novel antagonists targeting the orthosteric binding site, potentially opening new avenues for therapeutic interventions.

biochemistry↗

bioRxiv2024

The microtubule regulator EFA-6 forms spatially restricted cortical foci dependent on its intrinsically disordered region and interactions with tubulins

Microtubules (MTs) are dynamic components of the cytoskeleton and play essential roles in morphogenesis and maintenance of tissue and cell integrity. Despite recent advances in understanding MT ultrastructure, organization, and growth control, how cells regulate MT organization at the cell cortex remains poorly understood. The EFA-6/EFA6 proteins are recently identified membrane-associated proteins that inhibit cortical MT dynamics. Here, combining visualization of endogenously tagged C. elegans EFA-6 with genetic screening, we uncovered tubulin-dependent regulation of EFA-6 patterning. In the mature epidermal epithelium, EFA-6 forms punctate foci in specific regions of the apical cortex, dependent on its intrinsically disordered region (IDR). We further show the EFA-6 IDR is sufficient to form biomolecular condensates in vitro. In screens for mutants with altered GFP::EFA-6 localization, we identified a novel gain-of-function (gf) mutation in an -tubulin tba-1 that induces ectopic EFA-6 foci in multiple cell types. tba-1(gf) animals exhibit temperature-sensitive embryonic lethality, which is partially suppressed by efa-6(lf), indicating the interaction between tubulins and EFA-6 is important for normal development. TBA-1(gf) shows reduced incorporation into filamentous MTs but has otherwise mild effects on cellular MT organization. The ability of TBA-1(gf) to trigger ectopic EFA-6 foci formation requires {beta}-tubulin TBB-2 and the chaperon EVL-20/Arl2. The tba-1(gf)-induced EFA-6 foci display slower turnover, contain the MT-associated protein TAC-1/TACC, and require the EFA-6 MTED. Our results reveal a novel crosstalk between cellular tubulins and cortical MT regulators in vivo. HighlightsO_LIThe MT regulator EFA-6 forms spatially restricted punctate cortical foci C_LIO_LIThe EFA-6 N-terminal intrinsically disordered region (IDR) is essential for the formation of cortical foci in vivo and is sufficient for droplet formation in vitro C_LIO_LITubulins regulate formation of EFA-6 foci via the EFA-6 MT elimination domain C_LIO_LIEFA-6 foci induced by altered tubulin heterodimer function display reduced turnover and recruit TAC-1/TACC C_LI

cell biology↗

bioRxiv2024

MGPfactXMBD: A Model-Based Factorization Method for scRNA Data Unveils Bifurcating Transcriptional Modules Underlying Cell Fate Determination

Manifold-learning is particularly useful to resolve the complex cellular state space from single-cell RNA sequences. While current manifold-learning methods provide insights into cell fate by inferring graph-based trajectory at cell level, challenges remain to retrieve interpretable biology underlying the diverse cellular states. Here, we described MGPfactXMBD, a model-based manifold-learning framework and capable to factorize complex development trajectories into independent bifurcation processes of gene sets, and thus enables trajectory inference based on relevant features. MGPfactXMBD offers more nuanced understanding of the biological processes underlying cellular trajectories with potential determinants. When bench-tested across 239 datasets, MGPfactXMBD showed advantages in major quantity-control metrics, such as branch division accuracy and trajectory topology, outperforming most established methods. In real datasets, MGPfactXMBD recovered the critical pathways and cell types in microglia development with experimentally valid regulons and markers. Furthermore, MGPfactXMBD discovered evolutionary trajectories of tumor-associated CD8+ T cells and yielded new subtypes of CD8+ T cells with gene expression signatures significantly predictive of the responses to immune checkpoint inhibitor in independent cohorts. In summary, MGPfactXMBD offers a manifold-learning framework in scRNA-seq data which enables feature selection for specific biological processes and contributing to advance our understanding of biological determination of cell fate.

bioinformatics↗

bioRxiv2024

A PTER-dependent pathway of taurine metabolism linked to energy balance

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. One such taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise7, nutritional taurine supplementation8, and alcohol consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

biochemistry↗

bioRxiv2024

Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP's role as an immunotransmitter

cGAMP is a second messenger that is synthesized in the cytosol upon detection of cytosolic dsDNA and passed between cells to facilitate downstream immune signaling. ENPP1, an extracellular enzyme, was the only metazoan cGAMP hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from that of ENPP1 and accounts for all remaining cGAMP hydrolysis activity in mice lacking ENPP1. Importantly, we also show that as with ENPP1, selectively abolishing ENPP3s cGAMP hydrolase activity results in diminished cancer growth and metastasis of certain tumor types. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work clearly shows that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a new target for cancer immunotherapy.

biochemistry↗

bioRxiv2023

Neutrophil extracellular traps drive lupus flares with acute skin and kidney inflammation triggered by ultraviolet irradiation

Neutrophil extracellular traps (NETs) are major pathogenic effectors in chronic systemic lupus erythematosus (SLE) pathogenesis, but how they mediate acute, UVB-triggered skin inflammation and subsequent systemic injury remains poorly defined. Using UVB-irradiated lupus-prone mice, we identified an acute NETosis-driven skin-kidney inflammatory axis linking photosensitivity to renal inflammation. UVB induced concurrent skin and kidney inflammation with neutrophil infiltration, NETosis, and release of NET-associated effector cytokines/complement C3 and proteinuria. Mechanistically, PKC-dependent nuclear envelope rupture licensed NETosis, whereas Pkc deletion markedly suppressed NET formation and inflammation in both organs. Interestingly, only a subset of skin-infiltrating neutrophils underwent local NETosis. Spatiotemporal photoconversion tracking revealed that surviving, CXCR4-expressing neutrophils disseminated from UVB-irradiated skin to kidneys, where they underwent secondary NETosis, delivering cytokines/C3 to drive renal inflammation. Genetic or pharmacological CXCR4 inhibition blocked this dissemination, attenuating renal inflammation and proteinuria. These findings identify an acute NETosis-driven skin-kidney axis, highlighting PKC-dependent NETosis and CXCR4-mediated neutrophil dissemination as therapeutic targets in photosensitive lupus.

pathology↗

bioRxiv2023

Lac-Phe mediates the anti-obesity effect of metformin

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformins effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformins anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformins effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

physiology↗

bioRxiv2023

Surface-engineered extracellular vesicles to modulate antigen-specific T cell expansion for cancer immunotherapy

Extracellular vesicles (EVs), including exosomes, are emerging as novel mediators of cell-cell communications, involved in various processes such as immune activation and immunosuppression. Despite the recent development of several EVs-based cancer immunotherapies, their clinical efficacy remained limited. Here, using fusion with tetraspanin as one of the EV engineering techniques, we created antigen-presenting extracellular vesicles (AP-EVs) to reproduce the functional characteristics of professional antigen-presenting cells (APCs). AP-EVs were also equipped with surface-bound IL-2, a feature not inherent to APCs, which facilitated selective delivery of IL-2 to antigen-specific CD8+ T cells. AP-EVs were engineered to express a peptide-major histocompatibility class I (pMHCI) complex, a costimulatory CD80 molecule, and IL-2, allowing the simultaneous presentation of multiple immune modulators to antigen-specific CD8+ T cells. This promoted the clonal expansion and differentiation of antigen-specific cytotoxic T lymphocytes, leading to potent anticancer immune responses. Combination therapy with AP-EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumors compared with anti-PD-1 monotherapy. Our engineered EVs represent a novel effective strategy for cancer immunotherapy.

bioengineering↗

bioRxiv2023

Chrombus-XMBD: A Graph Generative Model Predicting 3D-Genome, ab initio from Chromatin Features

AbstractsThe landscape of 3D-genome is crucial for transcription regulation. But capturing the dynamics of chromatin conformation is costly and technically challenging. Here we described "Chrombus-XMBD", a graph generative model capable of predicting chromatin interactions ab inito based on available chromatin features. Chrombus employes dynamic edge convolution with QKV attention setup, which maps the relevant chromatin features to a learnable embedding space thereby generate genomewide 3D-contactmap. We validated Chrombus predictions with published databases of topological associated domains (TAD), eQTLs and gene-enhancer interactions. Chrombus outperforms existing algorithms in efficiently predicting long-range chromatin interactions. Chrombus also exhibits strong generalizability across different cell lineage and species. Additionally, the parameter sets of Chrombus inform the biological processes underlying 3D-genome. Our model provides a new perspective towards interpretable AI-modeling of the dynamics of chromatin interactions and better understanding of cis-regulation of gene expression.

bioinformatics↗

bioRxiv2023

Transcriptome brings variations of gene expression, alternative splicing, and structural variations into gene-scale trait dissection in soybean

Genome-wide association study (GWAS) identifies trait-associated loci, but due in part to slow decay of linkage disequilibrium (LD), identifying the causal genes can be a bottleneck. Transcriptome-wide association study (TWAS) addresses this by identifying gene expression-phenotype associations or integrating gene expression quantitative trait loci (eQTLs) with GWAS results. Here, we used self-pollinated soybean as a model to evaluate the application of TWAS in the genetic dissection of traits in plant species that exhibit slow LD decay. The first RNA-Seq analysis of a soybean diversity panel was conducted, which identified the genetic regulation of 29,286 genes. Different TWAS solutions were less affected by LD and robust with source of expression that identified known genes related to traits from different development stages and tissues. A novel gene named pod color L2 was identified via TWAS and functionally validated by genome editing. Our introduction of the new exon proportion feature significantly improves the capture of expression variations resulting from structural variations and alternative splicing. As a result, the genes identified by our TWAS approach exhibited a diverse range of causal variations, including SNP, insertion/deletion, gene fusion, copy number variation, and alternative splicing. Using our TWAS approach, we identified genes associated with flowering time, including both previously known candidates and novel genes that had not been linked to this trait before, providing complementary insights with GWAS. In summary, this study supports the application of TWAS for candidate gene identification in species with low rates of LD decay.

genetics↗