Biology subjects

Gao, C.

Publications and source records attributed to Gao, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Voltage-dependent anion channels are mitophagy receptors mediating the recycling of depolarized mitochondria in Arabidopsis

The mitochondrion is an essential organelle in eukaryotic cells, playing crucial roles in cellular respiration and intracellular signaling pathways. To maintain a healthy population of mitochondria, dysfunctional and excess mitochondria are selectively removed through an autophagic process known as mitophagy. Over the past few decades, various autophagy-related (ATG) proteins involved in mitophagy have been well characterized in yeast and mammalian cells since it has significance to the survival of eukaryotes. While the core autophagy machinery responsible for autophagosome formation is conserved among eukaryotes, the homologs of key regulators of mammalian system is absent in plant. In this study, we identified a unique mitophagy mechanism in plant, that three voltage-dependent anion channel (VDAC) family proteins in the mitochondria outer membrane -- specifically VDAC1, VDAC2, and VDAC3 -- as mitophagy receptors in Arabidopsis. These proteins were required for translocation of ATG8 from the cytosol to the mitochondria surface, when Arabidopsis cells were treated with an uncoupler, 2,4-dinitrophenol (DNP). The VDACs interacted directly with ATG8 through an ATG8-interacting motif (AIM) located in their amino (N) termini. Furthermore, vdac mutants exhibited impaired uncoupler-induced mitophagy and accumulated damaged mitochondria. These mitophagy-related phenotypes were more pronounced in vdac double and triple mutant lines. Altogether, our results indicated that VDAC1, 2, and 3 recruit ATG8 to depolarized mitochondria, facilitating the formation of mitophagosomes, presenting a distinguishing mitophagy pathway with mammalian system.

plant biology↗

bioRxiv2025

White matter microstructure and macrostructure brain charts across the human lifespan

Normative reference charts are widely used in healthcare, especially for assessing the development of individuals by benchmarking anatomic and physiological features against population trajectories across the lifespan. Recent work has extended this concept to gray matter morphology in the brain, but no such reference framework currently exists for white matter (WM) even though WM constitutes the essential substrate for neuronal communication and large-scale network integration. Here, we present the first comprehensive WM brain charts, which describe how microstructural and macrostructural features of WM evolve across the lifespan, by leveraging over 35,120 diffusion MRI scans from 50 harmonized studies. Using generalized additive models for location, scale, and shape (GAMLSS), we estimate age- and sex-stratified trajectories for 72 individual white matter pathways, quantifying both tract-specific microstructural and morphometric features. We demonstrate that these WM brain charts enable four important applications: (1) defining normative trajectories of WM maturation and decline across distinct pathways, (2) identifying previously uncharacterized developmental milestones and spatial gradients of tract maturation, (3) detecting individualized deviations from normative patterns with clinical relevance across multiple neurological disorders, and (4) facilitating standardized, cross-study centile scoring of new datasets. By establishing a unified, interpretable reference framework for WM structure, these brain charts provide a foundational metric for research and clinical neuroscience. The accompanying open-access trajectories, centile scoring tools, and harmonization methods facilitate precise mapping of WM development, aging, and pathology across diverse populations. We release the brain charts and provide an out-of-sample alignment process as a Docker image: https://zenodo.org/records/17561821.

neuroscience↗

bioRxiv2025

Rapid optimization of protein function in mammalian cells via microbe-independent deep assembly and screening

Random mutagenesis and deep mutational scanning (DMS) are widely used to optimize proteins by oversampling large libraries in microbial cells, selecting cells expressing favorable variants, and sequencing to identify enriched variants. However, these methods are slow and costly, require effort to establish selection methods for a given protein function, and do not yield data on lower-performing variants. Here, we describe Microbe-Independent Deep Assembly and Screening (MIDAS), a rapid, high-throughput method for optimizing protein function directly in mammalian cells. As a demonstration, we applied MIDAS to improve a newly designed neurotransmitter bioluminescent indicator (NeuBI) for acetylcholine (ACh). MIDAS systematically optimized interdomain linkers, identified mutational hotspots, and exhaustively scanned amino acid combinations, in each case relating specific sequences to protein performance. MIDAS-optimized variants exhibited improved performance in vivo, highlighting the potential of MIDAS for improving protein function in mammalian systems.

bioengineering↗

bioRxiv2025

Spatial Transcriptomics Identifies Immune-Stromal Niches Associated with Cancer in Adult Dermatomyositis

Adult-onset dermatomyositis (DM) is an autoimmune inflammatory myopathy with distinct cutaneous manifestations and a strong malignancy association. Through comparative analysis with cutaneous lupus erythematosus (CLE), our integrated spatial and single-cell transcriptomics analysis revealed unique immune and stromal niches associated with DM subtypes. Unexpectedly, we found an association between cancer-associated DM skin lesions and the presence of dispersed immune infiltrates enriched with macrophages, CD8+ T cells, plasma cells, and B cells with preserved vascular architecture. In contrast, non-cancer associated DM skin exhibited dense myeloid cell infiltrates, including neutrophils, monocytes, and macrophages, with elevated expression of IL1B and CXCL10 localized near injured vascular endothelia. Cytokines produced by these myeloid infiltrates together with local tissue hypoxia triggered dramatic stromal remodeling, leading to loss of vascular-associated fibroblasts. In addition to the CXCL10+ myeloid signature, non-cancer-associated DM skin with pDC presence showed the emergence of specific cellular pairs: PD-L1-expressing mregDCs and activated Tregs expressing NFKB2 and TNF receptors. While both DM and CLE showed strong interferon signatures, DM uniquely displayed IFN-{beta} expression. Together, our study provides the first comprehensive spatial mapping of immune and stromal cells in adult-onset DM.

immunology↗

bioRxiv2025

Hemodynamic traveling waves transport musical codes faster than language codes via shared bilateral streams

What takes precedence in our brain: music or language? Here we used rapid phase-encoded fMRI to explore spatiotemporal brain dynamics during naturalistic music and language tasks, seeking to track down the entire perception-to-production process and compare the speed of information transfer between the two domains. We found largely shared streams of traveling waves bilaterally, along which musical codes were transported faster than language codes for identical visual input.

neuroscience↗

bioRxiv2025

High-throughput 3D super-resolution imaging in deep tissue

Fluorescence images obtained with optical microscopes intrinsically suffer from blur and noise, which can be partially reversed by the deconvolution process. However, the deconvolution process is ill-conditioned, leading to a trade-off between detail preservation and noise suppression. Here, we develop 3D-FUDIP to fully decouple the deconvolution process into two parts: deblurring and denoising, achieving an 8-fold improvement in spatial resolution. By adopting the Poisson model, which obeys the quantum nature of photons, our 3D-FUDIP can be successfully applied to various noise conditions, especially low-light conditions where the photon number is generally extremely small. The results show that our 3D-FUDIP improves the SNR by up to 6-fold with only a one-fifth photon budget. Besides, 3D-FUDIP boosts the spatial bandwidth product (SBP) by one order of magnitude, allowing more spine details to be resolved within a larger imaging volume. By synergizing deep learning with these advances, we propose 3D-FUDIPn to further improve the imaging resolution. We demonstrate 3D-FUDIPs performance in various imaging systems, including confocal, two-photon, and light-sheet microscopes, showing compatibility and potential applications in biological science.

neuroscience↗

bioRxiv2025

Object representations drive emotion schemas across a large and diverse set of daily-life scenes

The rapid emotional evaluation of objects and events is essential in daily life. While visual scenes reliably evoke emotions, it remains unclear whether emotion schemas evoked by daily-life scenes depend on object processing systems or are extracted independently. To explore this, we collected emotion ratings for 4913 daily-life scenes from 300 participants, and predicted these ratings from representations in deep neural networks and fMRI activity patterns in visual cortex. AlexNet, an object-based model, outperformed EmoNet, an emotion-based model, in predicting emotion ratings for everyday scenes, while EmoNet excelled for explicitly evocative stimuli. Emotion information was processed hierarchically within the object recognition system, consistent with the visual cortexs organization. Activity patterns in the lateral occipital complex (LOC), an object-selective region, reliably predicted emotion ratings and outperformed other visual regions. These findings suggest that emotion processing in everyday scenes follows visual object recognition, with additional mechanisms engaged when object content is uninformative.

neuroscience↗

bioRxiv2025

TF2TG: an online resource mining the potential gene targets of transcription factors in Drosophila

Sequence-specific transcription factors (TFs) are key regulators of many biological processes, controlling the expression of their target genes through binding to the cis-regulatory regions such as promoters and enhancers. Each TF has unique DNA binding site motifs, and large-scale experiments have been conducted to characterize TF-DNA binding preferences. However, no comprehensive resource currently integrates these datasets for Drosophila. To address this need, we developed TF2TG ("transcription factor to target gene"), a comprehensive resource that combines both in vitro and in vivo datasets to link transcription factors (TFs) to their target genes based on TF-DNA binding preferences along with the protein-protein interaction data, tissue-specific transcriptomic data, and chromatin accessibility data. Although the genome offers numerous potential binding sites for each TF, only a subset is actually bound in vivo, and of these, only a fraction is functionally relevant. For instance, some TFs bind to their specific sites due to synergistic interactions with other factors nearby. This integration provides users with a comprehensive list of potential candidates as well as aids users in ranking candidate genes and determining condition-specific TF binding for studying transcriptional regulation in Drosophila.

bioinformatics↗

bioRxiv2025

A novel virus vB_PshM_Y4 with low similarity to both cultured and uncultured viruses

Viruses are the abundant and diverse biological entities on the Earth. During past decades, our knowledge about genomic diversity of viruses has been greatly expanded through high-throughput sequencing. However, whether traditional isolation method could detect virus that could not be identified by high-throughput sequencing is still unknown. In this study, a novel virus, vB_PshM_Y4, infecting Pseudoalteromonas shioyasakiensis, which is an opportunistic pathogen of economically important marine species, was isolated. After comparing vB_PshM_Y4 with the over 15 million genomes of both cultivated and uncultivated viruses in the NCBI and IMG/VR v4 datasets, no similar genome was identified. This suggests that viral isolation methods can detect novel viruses that may not be identified through high-throughput sequencing. Transmission electron microscopy showed that vB_PshM_Y4 exhibits the myoviral morphology. The virus possesses a double-stranded DNA genome that is 158,231 bp in length, with a G+C content of 30.92%, and contains 226 open reading frames (ORFs). Six ORFs were identified as putative auxiliary metabolic genes (AMGs). Phylogenetic tree and gene content-based network analyses indicated that vB_PshM_Y4 may represent a novel viral species within an unknown family of the Caudoviricetes class. Additionally, biogeographical distribution analysis showed that vB_PshM_Y4 were mainly detected in the Arctic and temperate and tropical epipelagic zones with low abundance. ImportanceThis study suggests that viral isolation could detect novel virus that could not be identified through high-throughput sequencing, contributed to a deeper understanding of the genetic diversity and distribution of Pseudoalteromonas viruses, and offered valuable insights into the prevention and control of opportunistic pathogenic bacteria affecting economically important marine organisms.

microbiology↗

bioRxiv2025

MiRNA Locker: A Modularized DNA Assembly As miRNA Inhibitors

MicroRNAs (miRNAs) are vital post-transcriptional regulators that govern key cellular processes such as proliferation, migration, and apoptosis. Current loss-of-function approaches, including chemically modified antisense oligonucleotides (ASOs), face significant challenges, including high costs, limited scalability, and off-target effects. To overcome these limitations, we developed "miRNA Locker", a novel miRNA inhibition platform created using the Overlapped Oligo Assembly (OOA) method. This innovative platform constructs highly stable dumbbell-shaped single-stranded DNA structures, offering improved target specificity, scalability, and cost-effectiveness. Using miR-214 as a proof-of-concept target, we demonstrated that miRNA Lockers effectively bind Argonaute-miRNA complexes, reduce miRNA levels, and induce downstream changes in gene expression and cellular phenotypes, surpassing the performance of commercial antagomirs. Furthermore, applying miRNA Lockers to miR-654 validated the regulatory role of miR-654 in modulating RNF8 expression and promoting epithelial-mesenchymal transition (EMT) in lung cancer cells. Our results highlight the potential of miRNA Lockers as a versatile tool for studying miRNA function and advancing miRNA-based therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/632138v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@c6ac1eorg.highwire.dtl.DTLVardef@14e2698org.highwire.dtl.DTLVardef@1c7d84aorg.highwire.dtl.DTLVardef@148f9c1_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

CESA: Cross-species Epitope Sequence Analysis for discovery of existing antibodies useful for phospho-specific protein detection in model species

Signaling pathways play key roles in many important biological processes such as cell division, differentiation, and migration. Phosphorylation site-specific antibodies specifically target proteins phosphorylated on a given tyrosine, threonine, or serine residue. Use of phospho-specific antibodies facilitates analysis of signaling pathway regulation and activity. Given the usefulness of phospho-specific antibodies, a number of collections of these antibodies have been generated, typically for detection of phosphorylated mammalian proteins. Anecdotal evidence shows that some of these are also useful for detection of phosphorylated forms of orthologous proteins in model organisms. We propose that anti-phospho-mammalian protein antibody collections comprise an untapped resource for research in other species. To systematically analyze the potential utility of anti-phospho-mammalian protein antibodies in other species, we developed the Cross-species Epitope Sequence Analysis software tool (CESA). CESA identifies and aligns orthologous proteins in model species, then analyzes conservation of antibody target sites. We used CESA to predict what phospho-specific antibodies in a collection from Cell Signaling Technology (CST) might be useful for studies in Drosophila melanogaster and other species. CESA predicts that more than 232 sites on 116 Drosophila proteins can potentially be targeted by the antibodies initially developed at CST to detect human, mouse, or rat phosphoproteins.

bioinformatics↗

bioRxiv2024

The RING-finger domain of Arabidopsis RMR functions as an E3 ligase essential for post-Golgi trafficking

Receptor-homology-transmembrane-RING-H2 (RMR) sorting receptors are essential for directing soluble cargo proteins to protein storage vacuoles in plants. These type I integral membrane proteins comprise a single transmembrane domain, an N-terminal lumenal region containing a protease-associated domain for cargo recognition, and a C-terminal cytoplasmic region (CT) with a Really-Interesting-New-Gene-H2 (RING-H2) domain. Here, we determined the crystal structure of the RING-H2 domain of Arabidopsis RMR isoform-1 (AtRMR1-RING), where the conserved C3H2C3 motif coordinates two Zn ions, a feature typical of RING-type E3 ligases. AtRMR1-RING was shown to interact with Arabidopsis E2 ubiquitin-conjugating enzyme, and exhibits E3 ligase activity in an in vitro ubiquitination assay. Biochemical analysis reveals that I234Y substitution disrupted the E2/E3 interaction and greatly reduced E3 ligase activity. Furthermore, we showed that the conserved RING-H2 domains of AtRMR isoform 2, 3 and 4 are also E3 ligases. Inactivation of E3 ligase activity by the I234Y mutation resulted in Golgi retention of AtRMR1-CT and AtRMR2. These findings suggest that the E3 ligase activity is essential for post-Golgi trafficking of RMR receptors, providing new insights into receptor-mediated protein sorting in plants.

plant biology↗

bioRxiv2024

Museum insights for conservation: Unraveling the Extinction Factors in the Jambato Harlequin Frog, Atelopus ignescens

Natural history museums harbor invaluable resources for conserving endangered species by providing insights into the mechanism of historical population declines. Here we conducted data synthesis to better understand the extinction factors of the iconic Jambato Harlequin frog, Atelopus ignescens, which was widespread in the Ecuadorian Andes before 1985 but vanished in 1988. The mechanism of extinction remains elusive, as it was uncertain whether Batrachochytrium dendrobatidis (Bd) fungus infection, climate change, or the interaction of the two factors primarily contributed to the rapid population decline. Here we synthesize historical data from natural history museums, the Global Biodiversity Information Facility (GBIF), and mitochondrial DNA sequences to uncover the factors that have potentially contributed to the extinction of the Jambato Harlequin frog. We found excessive rare alleles reflected in the negative Tajimas D estimated from the mitochondrial DNA samples collected in 1984, which indicates a selective sweep or bottleneck in the population shortly before the historical extinction. There was a marginal effect of the time before versus during Bd epizootics on the body sizes of the adult males, which was relatively weaker than the sex effect and geographic effect. The body size of adult males, but not the females form a geographic cline where the individuals in the northeast were larger than the males in the southwest. Species distribution modeling based on temperature and precipitation accurately predicted the occupancy of A. ignescens in 1960-69 (R2 = 0.72, accuracy = 0.9). This model further predicted the rapid decline in species distribution over decades of climate change between 1970-2020, which could have contributed to the rapid population decline in the 1980s. Collectively, our data synthesis revealed a strong climate effect and a weak epizootics effect on A. ignescens extinction, which unravels the mysterious rapid population decline and informs ongoing conservation efforts. This investigation inspires future museum genomic studies to dissect the potential climatic maladaptation behind one of the most dramatic extinction events in modern history.

evolutionary biology↗

bioRxiv2024

Heat Acclimation in Mice Requires Preoptic BDNF Neurons and Postsynaptic Potentiation

Heat acclimation (HA) is a key adaptive response in mammals to repeated heat exposure, essential for fitness and survival1-3. HA improves cardiovascular function, thermal comfort, and exercise capacity4, 5. However, the lack of a genetically tractable model has hindered understanding of the molecular and neural mechanisms underlying HA. Here, we show that 10 days of daily 38{degrees}C exposure lowers core body temperature (Tcore) and reduces anxiety during subsequent heat exposures in mice. HA increases brain-derived neurotrophic factor (BDNF) expression in the medial preoptic area (MPO). BDNF-expressing MPO neurons (MPOBDNF) show increased intrinsic heat sensitivity after HA. These neurons orchestrate downstream targets in the dorsomedial hypothalamus (DMH) and rostral raphe pallidus (rRPa) to mediate HA effects. BDNF, acting through its receptor tropomyosin-related kinase B (TrkB) in the DMH, facilitates the anxiolytic effect of HA by enhancing excitatory synaptic connections between MPOBDNF and DMH neurons. This study provides new insights into HA mechanisms, setting the stage for future research on heat stress reduction and exercise optimization.

neuroscience↗

bioRxiv2024

The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion

The mechanisms that regulate cancer dormancy remain poorly understood. Using a mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified Dec2 as a gene that was upregulated in metastatic dormant tumor cells. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism as the survival benefit was abrogated in immunodeficient conditions. Dec2 promoted immune evasion by repressing multiple components of the MHC-I dependent antigen presentation pathway in tumor cells. Dec2 is a regulator of circadian rhythms, and we found several components of the antigen presentation pathway oscillated in a circadian manner that was lost upon deletion of Dec2. Moreover, T-cell mediated tumor cell killing varied depending on the time of day. We suggest that lowered MHC-I presentation of antigens during rest phase is a natural effect of the circadian clock, which is exploited by Dec2-overexpressing pancreatic tumors to evade the immune system.

cancer biology↗

bioRxiv2024

Social Experience Shapes Fighting Strategies for Reproductive Success

Social isolation generally increases aggression but decreases mating competition, resulting in an intricate and ambiguous relationship between social experience, aggression, and reproductive success. In male Drosophila, aggression is often characterized by lunging, a frequent and comparatively low-intensity combat behavior. Here, we provide a behavioral paradigm for studying a less frequent but more vigorous fighting form known as tussling. While social enrichment decreases lunging, aligning with past observations, it heightens the more forceful tussling behavior. These two forms of aggression rely on different olfactory receptor neurons, specifically Or67d for lunging and Or47b for tussling. We further identify three pairs of central pC1 neurons that specifically promote tussling. Moreover, shifting from lunging to tussling in socially enriched males is accompanied with better territory control and mating success. Our findings identify distinct sensory and central neurons for two fighting forms and suggest that social experience may shape fighting strategies to optimize reproductive success.

neuroscience↗

bioRxiv2024

Multi-Modal Large Language Model Enables All-Purpose Prediction of Drug Mechanisms and Properties

Accurately predicting the mechanisms and properties of potential drug molecules is essential for advancing drug discovery. However, traditional methods often require the development of specialized models for each specific prediction task, resulting in inefficiencies in both model training and integration into work-flows. Moreover, these approaches are typically limited to predicting pharmaceutical attributes represented as discrete categories, and struggle with predicting complex attributes that are best described in free-form texts. To address these challenges, we introduce DrugChat, a multi-modal large language model (LLM) designed to provide comprehensive predictions of molecule mechanisms and properties within a unified framework. DrugChat analyzes the structure of an input molecule along with users queries to generate comprehensive, free-form predictions on drug indications, pharmacodynamics, and mechanisms of action. Moreover, DrugChat supports multi-turn dialogues with users, facilitating interactive and in-depth exploration of the same molecule. Our extensive evaluation, including assessments by human experts, demonstrates that DrugChat significantly outperforms GPT-4 and other leading LLMs in generating accurate free-form predictions, and exceeds state-of-the-art specialized prediction models.

pharmacology and toxicology↗

bioRxiv2024

Bergeyella cardium variant induces unique cytoplasmic vacuolization cell death

Bacterial pathogens have evolved multiple mechanisms to modulate host cell death, evade host immunity, and establish persistent infection. Here, we show that an emerging pathogen Bergeyella cardium variant (BCV) survives serum killing, inducing unique cytoplasmic vacuolization cell death in the majority of cells and apoptosis in a small number of bystanders. The cytoplasmic vacuolization cell death triggered by BCV is characterized by fused lysosome-associated termination and is inhibited by the sodium channel inhibitor amiloride. Endosomal solute carrier family 9 member A9 (SLC9A9) was identified as a critical regulator in the process of BCV-triggered cytoplasmic vacuolization cell death. Moreover, outer membrane vesicles (OMVs) or transfection of barrel-like membrane proteins lipocalin, {beta}-barrel, and PorV dramatically induced cytoplasmic vacuolization. BCV hijacked SLC9A9 by maintaining its high expression, increasing cytoplasmic vacuolization, and enhancing pathogenicity. These findings contribute to the development of novel approaches to modulate cytoplasmic vacuolization cell death and treat infectious diseases. HighlightsO_LIBCV triggers unique cytoplasmic vacuolization cell death. C_LIO_LISLC9A9 is essential for BCV-induced cytoplasmic vacuolization cell death. C_LIO_LIOMVs and the transfection of barrel-like proteins derived from BCV induce cytoplasmic vacuolization cell death. C_LIO_LIBCV increases pathogenicity via cytoplasmic vacuolization cell death. C_LI

cell biology↗