Biology subjects

Ye, Q.

Publications and source records attributed to Ye, Q..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

A neuroendocrine principle: Pancreatic islets actively shape sympathetic innervation

Survival critically depends on maintaining blood glucose levels to provide essential energy, especially during emergencies such as the fight-or-flight response, when timely glucose control via neural integration is vital. However, pancreatic islets constitute only a small fraction of the pancreas and are dispersed throughout the organ, raising the fundamental question of how the nervous system coordinates synchronized control of multiple islets. Using whole-organ clearing and 3D imaging, we mapped pancreatic sympathetic innervation, revealing specialized anatomical integration between sympathetic nerves and islets. Transplanted islets intrinsically attracted sympathetic nerves independent of their native environment. Chronic islet injury disrupted sympathetic innervation and markedly impaired nerve regeneration after denervation. Sympathetic denervation markedly elevated islet-derived Reg2 and Reg3{beta}; administration of these proteins accelerated sympathetic regeneration and improved islet graft function. Our findings identify an islet-sympathetic architecture actively maintained by islets, uncovering an endocrine-driven mechanism for neural regulation, highlighting Reg2 and Reg3{beta} as therapeutic candidates for diabetes management.

neuroscience↗

bioRxiv2025

Single-cell transcriptome sequencing for opening the blood-brain barrier through specific mode electroacupuncture stimulation

BackgroundThe blood-brain barrier (BBB) interferes with the treatment of central nervous system disorders owing to the complexity of its structure and restrictive function. Thus, it is challenging to develop central nervous system drug delivery strategies. Specific mode electroacupuncture (EA) stimulation can effectively open the BBB in rats. MethodsHere, we used single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell population in the Sprague-Dawley rat cerebral cortex. ResultsWe identified 23 cell subsets and eight types of cells in the brain by cell annotation. scRNA-seq revealed transcriptional changes in the cerebral cortex under EA. ConclusionsOur findings offer valuable insights into the molecular and cellular modifications in the brain resulting from EA intervention and serve as a resource for drug delivery across healthy and diseased states. Innovative approaches to enhance BBB opening will lead to more effective therapeutic plans and enhanced drug delivery.

neuroscience↗

bioRxiv2025

An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial import

Tom70 mediates mitochondrial protein import by coordinating the transfer of cytosolic preproteins from Hsp70/Hsp90 to the translocase of the outer membrane (TOM) complex. In humans, the cytosolic domain of Tom70 (HsTom70c) is entirely -helical and comprises modular TPR motifs divided into an N-terminal chaperone-binding domain (NTD) and a C-terminal preprotein-binding domain (CTD). However, the mechanisms linking these functional regions remain poorly understood. Here, we present the 2.04 [A] crystal structure of unliganded HsTom70c, revealing two distinct conformations - open and closed - within the asymmetric unit. These states are stabilized in part by interdomain crystal contacts and are supported in solution by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Principal component and dynamical network analyses reveal a continuum of motion linking the NTD and CTD via key structural elements, notably residues in helices 7, 8, and 25. Engagement of the CTD by the viral protein Orf9b interrupts this network, stabilizing a partially-closed intermediate conformation and dampening dynamics at distal NTD sites. Collectively, our findings lay the groundwork for understanding Tom70 allostery and provide a framework for dissecting its mechanistic roles in chaperone engagement, mitochondrial import, and viral subversion.

biophysics↗

bioRxiv2025

Bipartite chromatin recognition by Hop1 from two diverged holozoa

In meiosis, ploidy reduction is driven by a complex series of DNA breakage and recombination events between homologous chromosomes, orchestrated by meiotic HORMA domain proteins (HORMADs). Meiotic HORMADs possess a central chromatin binding region (CBR) whose architecture varies across eukaryotic groups. Here, we determine high-resolution crystal structures of the meiotic HORMAD CBR from two diverged aquatic holozoa, Schistosoma mansoni and Patiria miniata, which reveal tightly-associated PHD and winged helix-turn-helix (wHTH) domains. We show that PHD-wHTH CBRs bind duplex DNA through their wHTH domains, and identify key residues that disrupt this interaction. Combining experimental and predicted structures, we show that the CBRs PHD domains likely interact with the tail of histone H3, and may discriminate between unmethylated and trimethylated H3 lysine 4. Finally, we show that holozoa Hop1 CBRs bind nucleosomes in vitro in a bipartite manner involving both the PHD and wHTH domains. Our data reveal how meiotic HORMADs with PHD-wHTH CBRs can bind chromatin and potentially discriminate between chromatin states to drive meiotic recombination to specific chromosomal regions.

biochemistry↗

bioRxiv2025

Towards Unraveling Biomolecular Conformational Landscapes with a Generative Foundation Model

Recent advances in deep learning have revolutionized biomolecular structure prediction, yet a significant challenge remains: biological function emerges from dynamic equilibria across multiple conformational states rather than a single molecular structure. Here, we present OpenComplex2 (OC2), a generative model that efficiently sample biomolecular conformational ensembles. OC2 integrates a unified graph representation capturing diverse molecular inputs with diffusion-based sampling through our FloydNetwork architecture, which operates simultaneously across atomic, residue, and motif hierarchies. This multi-level approach balances fine-grained precision with computational efficiency, enabling conformational landscape sampling in hours rather than the weeks required by traditional simulations. Through comprehensive evaluation, we demonstrate that OC2 accurately reproduces experimentally determined protein and RNA ensembles, generates conformational distributions comparable to millisecond-scale molecular dynamics simulations, and captures functionally relevant transitions in important biological scenarios including allostery, induced-fit mechanisms, and cryptic pocket formation. OC2 also effectively models small molecule conformations with high validity, identifies multiple binding sites, and maintains competitive accuracy on structure prediction benchmarks, while scaling to ultra-large molecular assemblies exceeding 15,000 residues. By bridging static structure prediction and dynamic ensemble characterization, OC2 advances our understanding of how biomolecular dynamics give rise to biological function.

molecular biology↗

bioRxiv2025

Predicting Three-Dimensional Atomic-Level Structures of Biomolecular Complexes

OpenComplex1 is an open-source platform for comprehending and developing biomolecular models. Based on the architectures of AlphaFold2 and AlphaFold-Multimer, the current version of OpenComplex realizes end-to-end predictions of the biomolecular three-dimensional (3D) structures including protein, RNA, and protein-RNA complexes. OpenComplex makes it able to infer and train models of biomolecular complexes in a unified framework and supports encoders that use both MSAs and protein language models (pLM). Through extensive training on both structure and sequence databases such as the Protein Data Bank (PDB) and RNA families (Rfam) database, OpenComplex is able to generate models with equivalent or better accuracy for a wide range of biomolecules including monomers or multimers of protein and RNA as well as protein-RNA complexes. In summary, OpenComplex is a powerful tool for predicting accurate biomolecular structures in diverse application scenarios.

molecular biology↗

bioRxiv2025

Kinetic investigation of calcium-induced Sorcin aggregation by stopped-flow light scattering

Sorcin, a penta-EF hand calcium-binding protein, is implicated in multidrug resistance (MDR) in various cancers and has roles in neurodegenerative diseases. It regulates cellular calcium homeostasis by interacting with calcium channels, pumps, and exchangers in a calcium-dependent manner. Calcium binding induces a conformational change in Sorcin, exposing hydrophobic surfaces that mediate protein interactions and calcium flux between the cytosol and endoplasmic reticulum (ER). These exposed surfaces can also drive Sorcin aggregation in the absence of binding partners. Here, we exploited calcium-induced conformational changes and aggregation of Sorcin as a model to study its calcium sensitivity and aggregation mechanisms. Stopped-flow light scattering revealed that Sorcin aggregation is reversible, cooperative, and primarily influenced by Sorcin concentration rather than physiological calcium levels. Our findings suggest that calcium sensitivity of Sorcin is finely tuned by its expression level, highlighting its role as an intracellular calcium sensor. This work establishes Sorcin as a model system for studying protein aggregation mechanisms with implications for MDR and neurodegenerative diseases.

biophysics↗

bioRxiv2025

Literature-scaled immunological gene set annotation using AI-powered immune cell knowledge graph (ICKG)

Large scale application of single-cell and spatial omics in models and patient samples has led to the discovery of many novel gene sets, particularly those from an immunotherapeutic context. However, the biological meaning of those gene sets has been interpreted anecdotally through over-representation analysis against canonical annotation databases of limited complexity, granularity, and accuracy. Rich functional descriptions of individual genes in an immunological context exist in the literature but are not semantically summarized to perform gene set analysis. To overcome this limitation, we constructed immune cell knowledge graphs (ICKGs) by integrating over 24,000 published abstracts from recent literature using large language models (LLMs). ICKGs effectively integrate knowledge across individual, peer-reviewed studies, enabling accurate, verifiable graph-based reasoning. We validated the quality of ICKGs using functional omics data obtained independently from cytokine stimulation, CRISPR gene knock-out, and protein-protein interaction experiments. Using ICKGs, we achieved rich, holistic, and accurate annotation of immunological gene sets, including those that were unannotated by existing approaches and those that are in use for clinical applications. We created an interactive website (https://kchen-lab.github.io/immune-knowledgegraph.github.io/) to perform ICKG-based gene set annotations and visualize the supporting rationale.

bioinformatics↗

bioRxiv2025

Molecular basis of vitamin K-dependent protein γ-glutamyl carboxylation

Gamma-glutamyl carboxylase (GGCX) in human is the sole enzyme responsible for catalyzing the carboxylation of glutamate (Glu) to {gamma}-carboxyglutamate (Gla), a process that relies on the deprotonation of reduced vitamin K. This post-translational modification of vitamin K-dependent proteins (VKDPs) plays a pivotal role in numerous biological processes. Mutations in GGCX are responsible for multiple clinical phenotypes; however, the molecular mechanisms of GGCX activity and its pathology remain poorly understood. In this study, we reported the cryo-electron microscopy (cryo-EM) structures of GGCX bound with the either FIX or FX, two VKDPs and vitamin K, and employed the biochemical and cellular assays as well as molecular dynamics simulations to elucidate its dual-catalytic properties. The enzyme comprises a transmembrane domain that anchors the vitamin K-binding site, along with an ER luminal domain that facilitates binding of coagulation factor IX (FIX) at the exosite. The catalytic center orchestrates the oxidation of vitamin K and the carboxylation of Glu residues through a Cap-H2 coupling mechanism, along where disease-associated mutations in GGCX are predominantly clustered. These findings offer a comprehensive molecular framework for understanding the allosteric regulation of GGCXs dual enzymatic activities and provide valuable insights for developing strategies to monitor and therapeutically target vitamin K metabolism in related diseases.

biochemistry↗

bioRxiv2024

Mechanistic basis for protein conjugation in a diverged bacterial ubiquitination pathway

Ubiquitination is a fundamental and highly conserved protein post-translational modification pathway, in which ubiquitin or a ubiquitin-like protein (Ubl) is typically conjugated to a lysine side chain of a target protein. Ubiquitination is a multistep process initiated by adenylation of the Ubl C-terminus, followed by sequential formation of 2-3 Ubl[~]cysteine thioester intermediates with E1, E2, and E3 proteins before formation of the final Ubl-lysine isopeptide bond1. Ubiquitination is conserved across eukaryotes, and recent work has also revealed at least two related bacterial pathways that perform protein conjugation in the context of antiphage immunity2-5. Bioinformatics analysis has hinted at the existence of additional, as-yet uncharacterized, pathways in bacteria that could perform protein conjugation using ubiquitination-like machinery6-8. Here we describe the architecture and biochemical mechanisms of Bub (bacterial ubiquitination-like) pathways, revealing strong structural parallels along with striking mechanistic differences when compared to eukaryotic ubiquitination pathways. We show that Bub operons encode functional E1, E2, and Ubl proteins that are related to their eukaryotic counterparts but function entirely through oxyester, rather than thioester, intermediates. We also identify a novel family of serine proteases in Bub operons with a conserved serine-histidine catalytic dyad. The genomic context of Bub operons suggests that, like other bacterial ubiquitination-related pathways, they also function in antiphage immunity. Overall, our results reveal a new family of bacterial ubiquitination-related pathways with unprecedented biochemical mechanisms in both protein conjugation and deconjugation.

biochemistry↗

bioRxiv2024

Structural diversity and oligomerization of bacterial ubiquitin-like proteins

Bacteria possess a variety of operons with homology to eukaryotic ubiquitination pathways that encode predicted E1, E2, E3, deubiquitinase, and ubiquitin-like proteins. Some of these pathways have recently been shown to function in anti-bacteriophage immunity, but the biological functions of others remain unknown. Here, we show that ubiquitin-like proteins in two bacterial operon families show surprising architectural diversity, possessing one to three {beta}-grasp domains preceded by diverse N-terminal domains. We find that a large group of bacterial ubiquitin-like proteins possess three {beta}-grasp domains and form homodimers and helical filaments mediated by conserved Ca2+ ion binding sites. Our findings highlight a distinctive mode of self-assembly for ubiquitin-like proteins, and suggest that Ca2+-mediated ubiquitin-like protein filament assembly and/or disassembly enables cells to sense and respond to stress conditions that alter intracellular metal ion concentration.

biochemistry↗

bioRxiv2024

Siglec-F Deficiency Prevents Fibrosis After Bleomycin-Induced Acute Lung Injury

Injury to the lungs causes acute inflammation that can lead to pathological lung fibrosis. Airspace macrophages (AMs) are critical for repair of injured tissue, but they can contribute fibrosis through mechanisms that are incompletely understood. Siglecs are expressed by immune cells. In mice, Siglec-F is chiefly expressed AMs where it is considered inflammosuppressive. We hypothesized that its deletion would worsen lung injury and fibrosis in response to intratracheal bleomycin challenge. We evaluated Siglec-F expression and function in mice challenged with bleomycin on days 7, 14, and 21 post-challenge (2.5 U/kg). AMs were the predominant inflammatory cells at all timepoints, and they included resident (RAM) and recruited (RecAM) subsets. Siglec-F deficiency prevented fibrosis than in Siglecf-/- mouse lungs, as evident from biochemical and histologic readouts. We performed RNAseq on pooled RAMs and RecAMs from wild type and Siglec-F deficient mice. Lung fibrosis 21 d after bleomycin challenge was associated with differentially expressed genes (DEGs) related to cholesterol synthesis and metabolism. In AMs from healthy lung lavage fluid and idiopathic pulmonary fibrosis patient tissues, the human paralogs Siglec-7 and Siglec-9 were expressed. Findings here identify novel mechanisms that control protective and detrimental functions of AMs after lung injury.

physiology↗

bioRxiv2024

3D Molecular Pretraining via Localized Geometric Generation

Self-supervised learning on 3D molecular structures is gaining importance in data-driven scientific research and applications due to the high costs of annotating bio-chemical data. However, the strategic selection of semantic units for modeling 3D molecular structures remains underexplored, despite its crucial role in effective pre-training--a concept well-established in language processing and computer vision. We introduce Localized Geometric Generation (LEGO), a novel approach that treats tetrahedrons within 3D molecular structures as fundamental building blocks, leveraging their geometric simplicity and widespread presence across chemical functional patterns. Inspired by masked modeling, LEGO perturbs tetrahedral local structures and learns to reconstruct them in a self-supervised manner. Experimental results demonstrate LEGO consistently enhances molecular representations across biochemistry and quantum property prediction benchmarks. Additionally, the tetrahedral modeling and pretraining generalize from small molecules to larger molecular systems, validating by protein-ligand affinity prediction. Our results highlight the potential of selecting semantic units to build more expressive and interpretable neural networks for scientific AI applications.

bioinformatics↗

bioRxiv2024

Cross-Tissue Comparison of Epigenetic Aging Clocks in Humans

Epigenetic clocks are a common group of tools used to measure biological aging - the progressive deterioration of cells, tissues and organs. Epigenetic clocks have been trained almost exclusively using blood-based tissues but there is growing interest in estimating epigenetic age using less-invasive oral-based tissues (i.e., buccal or saliva) in both research and commercial settings. However, differentiated cell types across body tissues exhibit unique DNA methylation landscapes and age-related alterations to the DNA methylome. Applying epigenetic clocks derived from blood-based tissues to estimate epigenetic age of oral-based tissues may introduce biases. We tested the within-person comparability of common epigenetic clocks across five tissue types: buccal epithelial, saliva, dry blood spots, buffy coat (i.e., leukocytes), and peripheral blood mononuclear cells. We tested 284 distinct tissue samples from 83 individuals aged 9-70 years. Overall, there were significant within-person differences in epigenetic clock estimates from oral-based versus blood-based tissues, with average differences of almost 30 years observed in some age clocks. In addition, most epigenetic clock estimates of blood-based tissues exhibited low correlation with estimates from oral-based tissues despite controlling for cellular proportions and other technical factors. Our findings indicate that application of blood-derived epigenetic clocks in oral-based tissues may not yield comparable estimates of epigenetic age, highlighting the need for careful consideration of tissue type when estimating epigenetic age.

genomics↗

bioRxiv2024

Digital pathology assessment of kidney glomerular filtration barrier ultrastructure in an animal model of podocytopathy

BackgroundTransmission electron microscopy (TEM) images can visualize kidney glomerular filtration barrier ultrastructure, including the glomerular basement membrane (GBM) and podocyte foot processes (PFP). Podocytopathy is associated with glomerular filtration barrier morphological changes observed experimentally and clinically by measuring GBM or PFP width. However, these measurements are currently performed manually. This limits research on podocytopathy disease mechanisms and therapeutics due to labor intensiveness and inter-operator variability. MethodsWe developed a deep learning-based digital pathology computational method to measure GBM and PFP width in TEM images from the kidneys of Integrin-Linked Kinase (ILK) podocyte-specific conditional knockout (cKO) mouse, an animal model of podocytopathy, compared to wild-type (WT) control mouse. We obtained TEM images from WT and ILK cKO littermate mice at 4 weeks old. Our automated method was composed of two stages: a U-Net model for GBM segmentation, followed by an image processing algorithm for GBM and PFP width measurement. We evaluated its performance with a 4-fold cross-validation study on WT and ILK cKO mouse kidney pairs. ResultsMean (95% confidence interval) GBM segmentation accuracy, calculated as Jaccard index, was 0.73 (0.70-0.76) for WT and 0.85 (0.83-0.87) for ILK cKO TEM images. Automated and manual GBM width measurements were similar for both WT (p=0.49) and ILK cKO (p=0.06) specimens. While automated and manual PFP width measurements were similar for WT (p=0.89), they differed for ILK cKO (p<0.05) specimens. WT and ILK cKO specimens were morphologically distinguishable by manual GBM (p<0.05) and PFP (p<0.05) width measurements. This phenotypic difference was reflected in the automated GBM (p<0.05) more than PFP (p=0.06) widths. ConclusionsThese results suggest that certain automated measurements enabled via deep learning-based digital pathology tools could distinguish healthy kidneys from those with podocytopathy. Our proposed method provides high-throughput, objective morphological analysis and could facilitate podocytopathy research and translate into clinical diagnosis. Key pointsO_LIWe leveraged U-Net architecture in an algorithm to measure the widths of glomerular basement membrane and podocyte foot processes. C_LIO_LIDeep learning-based automated measurement of glomerular filtration barrier morphology has promise in podocytopathy research and diagnosis. C_LI

pathology↗

bioRxiv2024

Molecular Mechanism of Huanglian Jiedu Decoction in Treatment of Alzheimer's Disease based on Network Pharmacology

PurposeThe aim of this study was to investigate the pharmacological mechanism of Huanglian Jiedu Decoction (HLJDD) in treating Alzheimers disease through network pharmacology. HLJDD is a classic Chinese medicine prescription that is recommended in the Chinese Alzheimers disease diagnosis and treatment guidelines. However, the mechanism of HLJDD treatment for Alzheimers disease (AD) remains unclear because of its complicated components. MethodsThe related ingredients and targets of HLJDD in treating AD were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis platform (TCMSP), TTD, OMIM, GeneCards, and DrugBank. The data of the protein-protein interaction (PPI) network was constructed using STRING. The Metascape database was adopted for Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. AutoDockTools was used for molecular docking verification. ResultsIn the treatment of AD, HLJDD demonstrated strong efficacy with its core active components including were quercetin, {beta}-sitosterol, stigmasterol, targeting key proteins such as AKT1, TNF, and IL6. Molecular docking tests confirmed the significant binding affinity between these components and the aforementioned targets. The biological pathway of HLJDD in treating AD primarily involves the modulation of IL-17, TNF, and other inflammatory cytokines to regulate their impact on nerve functions. ConclusionsHLJDD may treat AD by inhibiting neuroinflammation through a comprehensive, multi-component, multi-target, and multi-pathway method.

pharmacology and toxicology↗

bioRxiv2024

Human calpain-3 and its structural plasticity: dissociation of a homohexamer into dimers on binding titin

Calpain-3 is an intracellular Ca2+-dependent cysteine protease abundant in skeletal muscle. Its physiological role in the sarcomere is thought to include removing damaged muscle proteins after exercise. Loss-of-function mutations in its single-copy gene cause a dystrophy of the limb-girdle muscles. These mutations, of which there are over 500 in humans, are spread all along this 94-kDa multi-domain protein that includes three 40+-residue sequences (NS, IS1, and IS2). The latter sequences are unique to this calpain isoform and are hypersensitive to proteolysis. To investigate the whole enzyme structure and how mutations might affect its activity, we produce the proteolytically more stable 85-kDa calpain-3 {Delta}NS {Delta}IS1 form with a C129A inactivating mutation as a recombinant protein in E. coli. During size-exclusion chromatography, this calpain-3 was consistently eluted as a much larger 0.5-MDa complex rather than the expected 170-kDa dimer. Its size, which was confirmed by SEC-MALS, Blue Native PAGE, and AUC, made the complex amenable to single-particle cryo-EM analysis. From two data sets, we obtained a 3.85-[A] reconstruction map that shows the complex is a trimer of calpain-3 dimers with six penta-EF-hand domains at its core. Calpain-3 has been reported to bind the N2A region of the giant muscle protein titin. When this 37-kDa region of titin was co-expressed with calpain-3 the multimer was reduced to a 320-kDa particle, which appears to be the calpain dimer bound to several copies of the titin fragment. We suggest that newly synthesized calpain-3 is kept as an inactive hexamer until it binds the N2A region of titin in the sarcomere, whereupon it dissociates into functional dimers.

biochemistry↗

bioRxiv2024

Global variation in the ratio of sapwood to leaf area explained by optimality principles

The sapwood area supporting a given leaf area (vH) reflects a coordinated coupling between carbon uptake, water transport and loss at a whole plant level. Worldwide variation in vH reflects diverse plants strategies adapt to prevailing environments, and impact the evolution of global carbon and water cycles. Why such a variation has not been convincingly explained yet, thus hinder its representation in Earth System Models. Here we hypothesize that optimal vH tends to mediate between plant hydraulics and leaf photosynthesis so that leaf water loss matches water supply. By compiling and testing against two extensive datasets, we show that our hypothesis explains nearly 60% of vH variation responding to light, vapour pressure deficit, temperature, and sapwood conductance in a quantitively predictable manner. Sapwood conductance or warming-enhanced hydraulic efficiency reduces the demand on sapwood area for a given total leaf area and, whereas brightening and air dryness enhance photosynthetic capacities consequently increasing the demand. This knowledge can enrich Earth System Models where carbon allocation and water hydraulics play key roles in predicting future climate-carbon feedback.

ecology↗