Biology subjects

Pan, Y.

Publications and source records attributed to Pan, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Magnetosome organelles are organized through interactions between McaA and McaB that alter the dynamics of the bacterial actin-like protein MamK

Magnetotactic bacteria (MTB) are a group of Gram-negative species that produce a lipid-bounded organelle, the magnetosome, in which a magnetic crystal is biomineralized. MTB use magnetosomes to align with the geomagnetic field for improved navigation of their environment. To optimize this alignment, these species organize their magnetosomes in a linear fashion using a handful of factors including the bacterial actin-like protein MamK. Despite these shared features, there is a broad diversity of species-specific linear magnetosome chain arrangements within MTB, but the molecular mechanisms behind these phenotypic variations are unclear. Recently, genetic analyses showed that two proteins McaA and McaB interface with the chain organization machinery of Magnetospirillum magneticum AMB-to arrange magnetite crystals in a series of subchains rather than the single cohesive chains found in closely related MTB. Here, we use in vivo co-immunoprecipitation in AMB-1 to demonstrate protein-protein interactions between McaA, McaB, and MamK. Experiments with McaA truncation mutants and conditional control of McaB localization determined that McaA-McaB interactions are dependent on amino acids 530-665 of McaA and McaB localization to the magnetosome chain. We further show that disrupting the McaA-McaB interaction alters the spatial dynamics of MamK in vivo We present a model in which protein-protein interactions between McaA, McaB, and MamK drive changes in MamK behavior to establish AMB-1s magnetosome chain organization. IMPORTANCEMagnetosomes model for understanding the cell biology of bacterial organelles and the mechanisms of bacterial cell organization. MamK, one of the best-studied bacterial actins, is a notable player in magnetosome chain assembly. This work explores how MamK dynamics are altered by two potential bacterial actin binding proteins, McaA and McaB. This system illustrates how changes in bacterial cytoskeleton regulation result in different organization of subcellular compartments. The conclusions from this research also have implications for understanding the broader evolutionary strategies for regulation of actin-like proteins and compartment organization diversification in bacteria.

microbiology↗

bioRxiv2025

A novel allele of Sh1 underlines the conversion of waxy corn to wx-sweet corn

AbstractWaxy corn and sweet corn are two major types of fresh-eating corn. Each has significant market value due to its unique sensory and nutritional profiles. Developing a variety that combines both traits would meet growing consumer demand and create new market opportunities. From a fast neutron-mutagenized population of the waxy corn inbred line HB522, we identified a mutant, wx-sweet, whose kernels exhibit both waxy and sweet properties at the filling stage. Using bulked segregant analysis (BSA) and fine mapping, we localized the causal locus to SHRUNKEN1 (Sh1) on chromosome 9, which was confirmed by an allelic test with a known Mu-insertion mutant. PCR and sequencing indicated a putative large structural variation in the second and third exons of Sh1 in wx-sweet, likely disrupting the reading frame. This novel sh1 allele significantly reduced sucrose synthase activity. The sh1 and waxy1 mutant genes act synergistically to remodel carbohydrate metabolism in wx-sweet endosperms. This remodeling, revealed by integrated transcriptomic and metabolomic analyses, drives transcriptional reprogramming and restructures metabolic flux. These changes thereby enhance sucrose and raffinose accumulation, which underlies the unique waxy-sweet texture in fresh-eating maize endosperm. In summary, our work not provides valuable genetic resources for fresh-eating corn breeding, but also elucidates, for the first time, the molecular mechanism underlying the synergistic formation of waxy and sweet texture. Key messageThe novel allele of Sh1 acts synergistically with waxy1 to regulate carbohydrate metabolism, which elucidates the molecular mechanism for the unique waxy-sweet texture in fresh-eating corn endosperm. Our work provides new strategies for sweet-waxy maize breeding.

genetics↗

bioRxiv2025

Intrinsic electrophysiological activity maps a latent dimension of poor sleep quality and reduced cognitive performance: a magnetoencephalography study using Cam-CAN data.

Sleep quality and cognition vary as functions of lifestyle, genetics, and health. However, poor sleep quality is prevalent, reportedly affecting approximately 38% of the adult population. Poor sleep quality is a significant risk factor for mood disorders, a predictive factor in cognitive decline in later life, and sleep disturbance is a putative precursor to severe cognitive impairment and is predictive of dementia onset. The direct relationship between these factors and intrinsic neural function is poorly understood. Integrating neurophysiology, cognition, and sleep quality to reveal latent factors would help understand the neurophysiology of sleep disturbances and their relation to cognitive performance. Here, we used data from the Cam-CAN dataset with a partial least squares (PLS) approach, producing a multivariate cross-decomposition model to map resting-state magnetoencephalography (MEG) data and cognitive/sleep scores of healthy controls (n = 490, age 18-86). Normative modelling was applied to MEG data, correcting for effects of age, sex, and handedness. We identify a significant relationship between poorer self-reported sleep quality and lower cognitive performance across multiple domains, characterised by excess low-frequency neural activity and reduced high-frequency activity, particularly in the alpha band. Moreover, globally increased low frequency and decreased alpha-beta functional connectivity - the dominant frequency channel in neural connectivity at rest across the brain - contribute significantly to this relationship. Our multivariate mapping approach enabled us to parse the electrophysiological signatures directly related to sleep quality and cognitive performance, independent of the confounding effects of age, and show that neural slowing and dysconnectivity are intrinsically linked to self-reported sleep quality and cognitive performance.

neuroscience↗

bioRxiv2025

A Druggable Tumor Suppressor and Leukemic Stem Cell Marker

Withdrawal StatementThe authors have withdrawn this preprint because the co-authors were not in agreement about posting the work in its current form. The authors request that this work not be cited. Please contact the corresponding author (Dr. Xunlei Kang, kangxu@health.missouri.edu) with questions.

cancer biology↗

bioRxiv2025

Atlas of Breast Cancer in Chinese Young Women Revealed by Single-cell RNA and ATAC Sequencing

Young women with breast cancer (YBC, age[<=]40) are particularly prevalent in Asian. YBCs usually show more aggressive pathology and poorer outcomes than non-young patients. However, YBCs are underrepresented in current BC risk models, with their tumor intrinsic subtypes and microenvironments lacking a systematic elucidation at the single-cell level, thereby limiting the young-specific therapies. We established a single-cell Chinese YBC landscape baseline, including 246,659 cells, by applying scRNA-seq and scATAC-seq on untreated patients. We developed a cross-modal feature selection algorithm to construct a young-intrinsic subtype classifier BCYtype, outperforming existing classifiers in pseudobulk, cellular, and external cohorts. Comparative analyses with non-young samples revealed a direct differentiation trajectory from mammary stem cells to mature luminal cells. Pseudotemporal analysis also demonstrated that tumor cells in younger patients undergo earlier carcinogenesis. Mechanistically, we found that CDH1 interacts with pTex and NKT cells, serving as a young-specific marker and a potential therapeutic target for HR+ young patients. The interaction between exhausted T cells and antigen-presenting cells revealed NKG2A as a candidate therapeutic target for triple-negative breast cancer in young patients.

cancer biology↗

bioRxiv2025

De Novo Design of Anti-Aging Peptides

Aging, a universal biological process in complex organisms, is increasingly recognized to be driven by progressive loss of epigenetic information, as proposed in the Information Theory of Aging (ITOA). However, research on anti-aging peptides remains scarce, with most existing efforts confined to derivatives of natural proteins, while systematic design attempts are virtually absent. This limitation not only restricts discovery within the evolutionary sequence space but also hampers the identification of candidates with novel mechanisms and improved efficacy. Here, we present ElixirSeeker2, the first computational framework for de novo design of anti-aging peptides. By integrating modeling of known anti-aging peptides, activity scoring from the IC50 database, and penalty constraints from toxic peptides, ElixirSeeker2 enables large-scale virtual screening and identification of novel peptide candidates. Several lead peptides demonstrated significant effects in delaying cellular senescence, restoring cellular functions in vitro and in enhancing locomotor activity of aged Caenorhabditis elegans. This study not only validates the feasibility of de novo design in anti-aging interventions but also establishes a strategy for the development of next-generation biologics.

bioinformatics↗

bioRxiv2025

Pocket-based molecule generation with an SE(3)-equivariant language model leads to a potent and selective HPK1 inhibitor with in vivo efficacy

Deep learning shows promise in structure-based drug discovery, yet challenges persist in generating pharmacologically plausible molecules with valid 3D conformation and decent binding mode in the pocket. We introduce SE3-BiLingoMol, an SE(3)-equivariant Transformer for pocket-based 3D molecule generation, addressing two key limitations of existing language-model approaches. First, it uses Geometric Algebra Transformers for SE(3)-equivariant handling of continuous 3D coordinates. Second, a bidirectional attention mechanism mitigates conformational errors accumulated during autoregressive sampling. These innovations enable SE3-BiLingoMol to generate 2D drug-like, 3D geometrically valid molecules with superior binding modes. Validated on DUD-E dataset containing over 100 targets, the model achieved state-of-the-art performance in de novo design and optimization. We applied SE3-BiLingoMol to design potent and selective inhibitors for HPK1, a promising immunotherapy target. Through an iterative human-AI workflow, integrating AI generation with experimental validations (X-ray crystallography, bioassays), we identified Cmpd. 6. This novel tetracyclic compound demonstrates potent HPK1 inhibition, excellent cellular activity, favorable pharmacokinetics, and robust anti-tumor in vivo efficacy as monotherapy and with PD-1 blockade. Our work establishes a sophisticated generative AI framework for 3D molecule design and demonstrates its application in developing cancer immunotherapy. Highlights[bullet] SE(3)-Equivariant Language Model for Molecule Generation: We introduce a dual-channel SE(3)-equivariant language model that supports de novo molecule design and optimization, addressing key challenges in prior language model-based 3D molecule generation approaches. [bullet]Discovery of Potent HPK1 Inhibitors: Application of this model led to the discovery of highly selective HPK1 inhibitors with robust in vivo efficacy, resulting in a promising lead compound. [bullet]AI-Guided Rational Drug Development Paradigm: This work establishes a paradigm for AI-guided rational drug development, showcasing AI as a "co-pilot" that inspires drug designers with novel ideas in an "evidence-based context".

bioinformatics↗

bioRxiv2025

Polyelectrolyte domains in intrinsically disordered regions differentially regulate intracellular biomolecular condensation

Intracellular condensation is a hallmark of many proteins containing intrinsically disordered regions (IDRs). Decoding the regulatory mechanisms of condensation encoded within the amino acid sequences of condensate-forming proteins is essential for understanding both how intracellular condensates assemble and how they contribute to various disease pathologies. Here, we investigated the budding yeast P-body proteins Nst1 and Edc3, which exhibit pronounced intracellular self-condensation, and identified charged amino acid clusters in the low complexity regions (LCRs) that modulate their phase behavior. Guided by the stickers-and-spacers framework, we hypothesized that clusters of charged residues within IDRs function in promoting intracellular condensation process. Using a sliding-window approach, we designated and dissected the polyelectrolyte (PE) domains of Nst1 and Edc3 and established their essential contributions to condensate coalescence. In Nst1, the polyanionic (PA) subdomain enhances intermolecular attraction and promotes coalescence, whereas the polyampholyte (PAM) subdomain imparts rigidity to the condensate as a distinct modulatory element and functions as a platform in condensation process of other P-body components. PA of Edc3 also regulates coalescence. Extending these findings to the neurodegenerative disease-associated protein TDP-43, we show that its PA regions are critical for coalescence, consistent with the presence of negatively charged amino acid clusters as potent molecular stickers functioning in condensate coalescence in cells. These results highlight charged-residue clusters as important sequence determinants of protein phase behavior and suggest that they represent promising novel regulatory targets for modulating TDP-43 condensation in cells.

cell biology↗

bioRxiv2025

Structural insights and engineering of deep-sea halophilic PET hydrolytic enzymes

Pervasive use of polyethylene terephthalate (PET) poses tremendous challenges for global waste management and environmental sustainability, fueling growing interests in enzymatic degradation as an eco-friendly solution. While PET hydrolases hold significant promise, their industrial deployment is hindered by insufficient performance, particularly under high-salinity conditions raised from high substrate loads. Building on our previous discovery of three deep-sea PET hydrolases (dsPETase01, dsPETase05 and dsPETase06) with exceptional halophilicity and PET-degrading activity, we here present their three-dimensional structures and mechanistic characterization. Structural comparison, site-directed mutagenesis, and domain swapping reveal key structural features and the essential role of C-terminal acidic residues in salt tolerance. Integrating semi-rational protein design, Transformer-based modeling, and disulfide bond engineering, we synergistically enhance the thermostability and catalytic efficiency of dsPETase05. These findings elucidate the unique structural features and salt adaptation mechanisms of deep-sea halophilic PET hydrolases, and inform the future engineering of biocatalysts for application in harsh industrial environments.

molecular biology↗

bioRxiv2025

Higher baseline alpha power is associated with faster responses in visual search

Visual search models have long emphasised that task-relevant items must be prioritized for optimal performance. While it is known that search efficiency also benefits from active distractor inhibition, the underlying neuronal mechanisms are debated. Neuronal alpha oscillations (7-14 Hz) have been associated with functional inhibition of cortical excitability, as well as distractor suppression in spatial attention and visual working memory tasks. We therefore hypothesised that alpha oscillations similarly support the deselection of distractors in visual search. Using Magnetoencephalography (MEG), we here show that high alpha power before the onset of a complex search display is associated with faster search performance. Crucially, we used a General Linear Model (GLM) approach to control for confounds between alpha power and task duration, ruling out that this result was merely driven by practice effects paired with increased fatigue over time. In addition to spontaneous oscillatory activity, we quantified the cortical excitability to colours of the search stimuli based on Rapid Invisible Frequency Tagging (RIFT) responses. In contrast to our initial hypothesis, increased pre-search alpha power did not correlate with the RIFT response, providing no direct evidence for feature-specific inhibition of distracting stimuli by alpha. Our findings challenge the traditional view of alpha oscillations reducing visual processing, showing instead that increased occipital alpha power can enhance performance in a visual task. We propose that the increase in alpha power may reflect increased top-down control supporting visual search

neuroscience↗

bioRxiv2025

VO: The Vaccine Ontology

With the widespread use of vaccines in research and clinical settings, there is an urgent need to standardize vaccine representation, integrate information across diverse vaccine types, and support computer-assisted reasoning. Accordingly, we have since 2007 developed the community-based Vaccine Ontology (VO), which aligns with the Basic Formal Ontology and adheres to OBO Foundry principles. VO models ontologically vaccines, vaccine components, vaccine immune responses, vaccine investigation studies and other vaccine-related topics. VO represents more than 10,000 vaccines targeting 289 infectious pathogens and cancers in humans and over 30 nonhuman animal species. VO provides mappings to external resources such as RxNorm, CVX, FDA, and USDA. Various VO use cases exist. VO facilitates vaccine standardization in resources such as the VIOLIN vaccine database, ImmPort, and the Vaccine Adjuvant Compendium (VAC). Semantic queries can be made to query VO. VO has been shown to enhance experimental and clinical vaccine data analysis and vaccine literature mining. Overall, VO standardizes vaccine modeling and representation and greatly supports vaccine AI research in the Semantic Web era.

bioinformatics↗

bioRxiv2025

HomRank: Homogeneous RNA Ranking for 3D Structure Evaluation

Leveraging rigorously curated RNA sequences and a novel ranking-based evaluation paradigm, we propose an improved pipeline for RNA 3D structure assessment. To enhance generalization, we construct a dataset comprising non-redundant single-chain RNA sequences from the PDB and apply unsupervised clustering to minimize data leakage. Based on this, we retrain the previous state-of-the-art method, ARES, to develop ARES+, which improves the top-1 success rate by 21% on the RNA Puzzles benchmark. To further boost near-native identification, we introduce HomRank, a homogeneous RNA ranking method that directly optimizes the selection of near-native conformations from candidate sets, resembling expert evaluation strategies. HomRank achieves 95% and 100% top-1 and top-5 success rates, respectively, significantly outperforming ARES+. These results demonstrate that carefully designed datasets and the expert-like selection paradigm can substantially improve the accuracy and robustness of RNA 3D structure assessment, offering a promising direction for deep learning-based RNA evaluation and near-native conformation selection.

bioinformatics↗

bioRxiv2025

ETS1 Orchestrates a Hybrid EMT Program Driving in vivo Metastasis and Immune Evasion

Transcriptional Intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers, yet how transcriptional ITH programs drive tumor metastasis and immune evasion in upper aerodigestive squamous cell carcinoma (UASCC) remains unclear. Through single-cell RNA sequencing analysis of UASCC cells and patient tumors, we uncovered a hybrid epithelial mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating both STAT1 and PD-L1 (CD274) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, ETS1-high tumors strongly correlated with poor survival and resistance to immune checkpoint blockade across multiple cohorts. Leveraging drug screens, we discovered that ETS1-high cancers are vulnerable to HSP90 inhibitors (e.g., Alvespimycin), which suppress ETS1 by disrupting HIF1A-mediated transcriptional activation. Together, our work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.

cancer biology↗

bioRxiv2025

Mapping and Harmonization of CVX vaccine terms tothe Vaccine Ontology

BackgroundWith many vaccines developed and used, it is critical to standardize vaccine information. The OHDSI OMOP Common Data Model (CDM), widely used to support EHR data integration and analysis, leverages CVX, RxNorm, and RxNorm Extension codes to standardize vaccine-related records. However, these terminologies lack robust semantic relations, making the vaccine classification ineffective in OMOP CDM. To address this issue, our OHDSI Vaccine Vocabulary Working Group proposes to use the Vaccine Ontology (VO) to map these standards and build up its own semantic relations. As a first study of the work, we performed the mapping and alignment of the Vaccine Administered (CVX) codes with the VO using a combination of semi-automatic and manual mapping methods. ResultsA total of 273 CVX terms were first collected and classified. A high-level VO design pattern and an exact one-to-one mapping strategy were developed to guide the CVX-to-VO term mapping. To facilitate the manual mapping and harmonization process, we also developed and evaluated three semi-automated mapping approaches utilizing lexical and semantic information of vaccine concepts to map CVX to VO. These approaches suggested candidate VO mappings for CVX terms and also indicated CVX terms that were unmappable to VO and required new term additions to VO. The application of the best approach to the 2022-10-05 release of VO achieved an accuracy of 85.55% for its suggestions. The suggestions made by the semi-automated approaches were taken into account to further enhance the mappings, which led to our eventual mapping of all CVX terms to the latest version of VO. We innovatively proposed the inclusion of the passive vaccine branch in VO, which includes 24 immunoglobulins and antitoxins from CVX as passive vaccines. A specific CVX-VO OWL file was developed and added to the VO GitHub. Use case queries were developed to demonstrate its support for computer-assisted queries of vaccine groups based on CVX-VO hierarchies. ConclusionAll CVX terms were mapped to the VO using our combined semi-automatic and manual mapping methods. The mapped results enhanced semantic vaccine classification, providing a basis for further OMOP vaccine classification and EHR data analysis.

bioinformatics↗

bioRxiv2025

Neuroligin-3 interaction with CSPG4 regulates normal and malignant glial precursors through PIEZO1

Glioma pathophysiology is robustly regulated by interactions with neurons. Key to these interactions is the role of neuroligin-3 (NLGN3), a synaptic adhesion molecule shed in response to neuronal activity1-5 that functions as a paracrine factor crucial for glioma growth. Here, we elucidate the mechanistic pathway whereby shed NLGN3 interacts with glioma and their normal glial counterpart. NLGN3 interacts with Chondroitin Sulfate Proteoglycan 4 (CSPG4) on both glioma and healthy oligodendrocyte precursor cells (OPCs)6-9, facilitating CSPG4 shedding by ADAM10. NLGN3-CSPG4 interactions and consequent shedding alter membrane tension, thereby activating PIEZO1 mechanosensitive channels and causing membrane depolarization. The NLGN3-CSPG4-PIEZO1 axis maintains OPCs in an undifferentiated, stem-like state and promotes glioma proliferation, underscoring important functional roles for the NLGN3-CSPG4-PIEZO1 axis in both healthy and malignant glial precursors.

neuroscience↗

bioRxiv2025

Cell-free DNA fragmentomic characteristics in transposon elements inform molecular regulators and enhance cancer diagnosis

Fragmentomics of plasma cell-free DNA (cfDNA) are emerging diagnostic biomarkers in cancer liquid biopsy, while the molecular regulations of cfDNA fragmentation remain elusive. In this study, we investigated the cfDNA fragmentomics in transposon elements (TEs), a special category of sequences accounting for around half of human genome. We discovered dynamics in fragmentomic features across various types of TEs in human cfDNA, including size, ending patterns and coverage, which were validated in mice and dogs. These dynamics highly correlate with epigenomic features associated with chromatin states, including DNA methylation and histone modification signals, demonstrating fundamental regulatory roles of chromatin state in cfDNA production. Furthermore, fragmentomic features within TEs were significantly altered in cancer samples, offering improved diagnostic performance compared to genome-wide fragmentomic measurements. Additionally, cfDNA coverage in TEs showed frequent imbalances between cancer and control samples in a TE- and cancer type-dependent manner, presenting a promising biomarker for cancer diagnosis. Leveraging artificial intelligence (AI) on cfDNA fragmentomic features within TEs, we developed high-performance models, named TEANA (TE Analysis in cell-free DNA), for cancer diagnosis and tumor-origin prediction. The models were validated across two pan-cancer datasets with more than 1600 samples. Hence, dynamics of cfDNA fragmentomics within TEs, which is highly correlated with cfDNA epigenomics, shed light on the regulatory mechanism of cfDNA biology and highlight translational potential in cancer liquid biopsy.

cancer biology↗

bioRxiv2025

Pentose Sugars Encode Sequence-Dependent DNA-RNA Segregation for Biomimetic Multiphase Condensates

The nucleus segregates DNA and RNA with high precision to safeguard genome stability and gene regulation despite their homologous structures, yet the underlying molecular principles have long evaded both understanding and synthetic translation. Here we show that a single atomic difference between the pentose sugars, a 2-OH in RNA versus a 2-H in DNA, suffices to drive their phase segregation with cationic peptides. This subtle chemical distinction makes RNA bind peptides more strongly than sequence-identical DNA, generating an asymmetry that, when modulated by sequence-encoded homotypic interactions, drives the formation of core-shell multiphase condensates. Using a supervised machine-learning approach, we distill these molecular principles into a predictive design rule and harness it to program a library of oligonucleotide pairs, termed SEGREGamers, that self-assemble into droplets with coexisting DNA- and RNA-rich domains. These synthetic condensates recapitulate nuclear compartment functions, including selective molecular partitioning and enhanced RNA catalysis. Our results establish a chemically encoded platform for engineering synthetic nuclear mimics and programmable biomolecular condensates, and suggest that sugar identity may have served as an ancient physical mechanism for organizing nucleic acids.

biophysics↗

bioRxiv2025

Aromatic Patch in WhiB-Like Transcription Factors Facilitates Primary Sigma Factor Interaction in Mycobacterium tuberculosis

WhiB-like (Wbl) family proteins are a unique family of iron-sulfur ([4Fe-4S]) cluster-bound transcription factors found exclusively in Actinobacteria and actinobacteriophages, including the notoriously persistent pathogen Mycobacterium tuberculosis (Mtb). Despite their critical roles in cell development, stress response and antibiotic resistance, the mechanisms of gene regulation by the Wbl family proteins are not fully understood due to the lack of a canonical DNA-binding motif in most Wbl proteins. Here, we present structural and biochemical evidence demonstrating that all Mtb Wbl proteins bind to the same site in the conserved region 4 of the primary sigma 70 factor facilitated by a previously unrecognized structural motif, the aromatic patch, in the Wbl family. Our phylogenetic findings provide compelling evidence for a complex evolutionary relationship of Wbls between actinobacteria and the associated phages. Together, this work fills a critical gap in our understanding of the function, mechanism and evolutionary origin of Wbls.

biochemistry↗