Biology subjects

Cao, Z.

Publications and source records attributed to Cao, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Visual Analysis of Cell Death in Bladder Cancer -- A Bibliometrics-Based Comprehensive Study

Cell death mechanisms offer therapeutic strategies for bladder cancer, yet lack comprehensive bibliometric analysis. Map global research trends and hotspots in bladder cancer cell death mechanisms via bibliometrics. We analyzed 5,392 publications (1991-2024) from Web of Science using VOSviewer (co- authorship/keyword clustering), CiteSpace (citation bursts), and GraphPad Prism (statistics). Metrics included: (1) Temporal trends, (2) Country/institution contributions, (3) Journal impact, (4) Citation dynamics, (5) Collaboration networks, (6) Conceptual hotspots. China and the US led research output. Top institutions:University of Texas System (USA; 178 publications), UTMD Anderson Cancer Center (USA; 123), Nanjing Medical University (China; 122), Journal of Urology had the highest output (106 publications); Cancer Research (IF:12.5) the highest impact. Kim Wun-Jae was the most productive author (37 articles); Jemal A the most co-cited (446 citations). Keyword and citation analyses revealed emerging integration of cell death mechanisms with immunotherapy (IT) and photodynamic therapy (PDT) to overcome chemoresistance. This study delineates the evolution of bladder cancer cell death research and identifies IT/PDT as promising resistance-overcoming strategies grounded in targeted cell death pathways.

cancer biology↗

bioRxiv2025

Unbiased recording of clonal potency reveals species-specific regulation of mammalian intestine

The mammalian intestine regenerates rapidly after damage, yet the clonal dynamics and species-specific regulation of different populations remain poorly understood. Here we used synthetic or naturally occurring DNA alterations to reconstruct clonal histories of the mouse and human intestinal epithelium at single-cell resolution. In mice, we uncovered the clonal architecture of different cell types and their roles in regeneration, supporting a hierarchical regenerative response model. We identified a rare embryonic precursor population that persisted in the adult and was crucial for regeneration after irradiation. This population was marked by Tob2, which is required for nuclear transport of Ascl2. A parallel clonal analysis of 65 human colonic biopsies revealed secretory lineage bias and an age-associated decline in clonal diversity in the distal colon. Unlike highly proliferative murine Lgr5+ stem cells, human LGR5+ cells were found largely quiescent, revealing species-specific difference in clonal potency, and suggesting a distinct regulation of intestinal stemness.

genomics↗

bioRxiv2025

Cholesterol-Responsive Interaction of NFE2L1-INSIG1 Controls VLDL Secretion and MASH Pathogenesis

Cholesterol overload drives metabolic dysfunction-associated steatohepatitis (MASH). While the liver maintains homeostasis by exporting cholesterol via very low-density lipoprotein (VLDL) secretion, this process is paradoxically suppressed under cholesterol excess by insulin-induced gene 1 (INSIG1), which inhibits sterol regulatory element-binding protein 1 (SREBP1) activity. How VLDL secretion persists during cholesterol overload to prevent lipotoxicity remains unresolved. We identify a cholesterol-responsive interaction between nuclear factor erythroid 2 related factor-1 (NFE2L1) and INSIG1 that sustains cholesterol balance. Hepatic NFE2L1 deficiency elevates INSIG1 levels, suppressing SREBP1 activation and impairing VLDL secretion, leading to cholesterol accumulation and liver injury. Mechanistically, NFE2L1 binds to INSIG1 via its N-terminal homology box 2 (NHB2) domain, with cholesterol enhancing this interaction to drive INSIG1 degradation and SREBP1 activation. In NFE2L1-deficient mice, wild-type NFE2L1 restores SREBP1 activity and VLDL secretion, while the NHB2-deleted mutant ({Delta}NHB2) fails. Lipidomics reveal that NFE2L1 deficiency reduces serum triglyceride composition, restored exclusively by wild-type NFE2L1. In a murine MASH model, NFE2L1 overexpression activates SREBP1/2, enhances cholesterol secretion, and alleviates liver injury, inflammation and fibrosis, without elevating atherogenic lipoproteins due to compensatory LDL receptor upregulation. Our findings resolve the paradox of cholesterol-driven VLDL secretion and establish the NFE2L1-INSIG1 axis as a therapeutic target for metabolic diseases.

physiology↗

bioRxiv2025

AlphaFold3 for Non-canonical Cyclic Peptide Modeling: Hierarchical Benchmarking Reveals Accuracy and Practical Guidelines

Despite the revolutionary impact of AlphaFold3 on structural biology, this models capability in predicting non-canonical cyclic peptides remains unexplored. Given the clinical significance of cyclic peptides containing unnatural residues as a therapeutic modality, we present the first systematic evaluation of AlphaFold3 for this class of molecules. To facilitate benchmarking, we developed an automated input pipeline to streamline AlphaFold3 predictions for cyclic peptides. Our study aims to: (1) quantify the hierarchical accuracy (all-atoms, C atoms, and atoms of unnatural residue levels) of AlphaFold3 in predicting both non-canonical cyclic peptide monomers and complexes; (2) assess the reliability of AlphaFold3s confidence metrics; (3) evaluate the influence of multiple sequence alignment (MSA) and structural templates; and (4) identify systematic biases in AlphaFold3s predictions. Based on these analyses, we provide practical guidelines for applying AlphaFold3 in cyclic peptide structure prediction for facilitating the related research of bioactive cyclic peptides.

bioinformatics↗

bioRxiv2025

From Noise to Models to Numbers: Evaluating Negative Binomial Models and Parameter Estimations in Single-Cell RNA-seq

The Negative Binomial (NB) distribution is widely used to approximate transcript count distributions in single-cell RNA sequencing (scRNA-seq) data, yet the reason for its ubiquity is not fully understood. Here, we employ a computationally efficient model selection technique to map the relationship between the best-fit models - Beta-Poisson (Telegraph), NB, and Poisson - and the kinetic parameters that govern gene expression stochasticity. Our findings reveal that the NB distribution closely approximates simulated data (incorporating both biological and technical noise) within an intermediate range of the sum of the gene activation and inactivation rates normalized by the mRNA degradation rate. This range expands with decreasing mean expression, increasing technical noise, and larger sample sizes. The results imply that: (i) good NB fits occur in diverse parameter regimes without exclusively indicating transcriptional bursting; (ii) for small sample sizes, biological noise predominantly shapes the NB profile even when technical noise is present; (iii) under steady-state conditions, gene-specific parameters (burst size and frequency) estimated in regions where the NB model fits well, typically show large relative errors, even after corrections for technical noise, and (iv) gene ranking by burst frequency remains reliably accurate, suggesting that burst parameters are most informative in a relative sense. Finally, applying technical-noise-corrected model fitting to scRNA-seq data confirms that a substantial fraction of mammalian genes fall within these NB-fitting regimes, despite lacking transcriptional bursting.

systems biology↗

bioRxiv2025

Sialin2 Senses Nitrate to Activate Endosomal PI3K-AKT-NOS Signaling

Nitrate functions as a signaling molecule beyond its metabolic intermediate role. Despite progress in plants, the mechanisms underlying mammalian nitrate sensing and signaling remain unclear. The accompanying study identifies Sialin2--a proteolytic fragment of nitrate transporter Sialin--as a mammalian nitrate sensor mediating cellular responses. Here, we demonstrate that nitrate triggers endocytosis, inducing Sialin proteolysis and Sialin2 generation. Nitrate-induced Sialin2 scaffolds Lyn kinase with epidermal growth factor receptor (EGFR) at endosomes, activating phosphatidylinositol 3-kinase (PI3K)-AKT-nitric oxide synthase (NOS) pathway to stimulate localized nitric oxide (NO) production, enhancing angiogenesis and cell survival. In hypertensive rats, nitrate supplementation restores endothelial function and reduces blood pressure through AKT/eNOS-dependent signaling. Unlike the classical nitrate-nitrite-NO pathway, the Sialin2-PI3K-AKT-NOS axis confines NO synthesis to endosomal microdomains, enabling spatiotemporally precise vasodilation. By establishing Sialin2 as a mammalian nitrate sensor, this study unveils a novel paradigm in nitrogen homeostasis and provides targeted therapeutic strategies for vascular disorders.

cell biology↗

bioRxiv2025

Sialin2 Functions as a Mammalian Nitrate Sensor to Sustain Mitochondrial Homeostasis

Nitrogen homeostasis is fundamental for cellular physiology, yet mammalian nitrate (NO3-) sensing mechanisms remain elusive. Here, we identify Sialin2--a proteolytic fragment of the nitrate transporter Sialin generated by cathepsin B (CTSB) cleavage-- as the first mammalian nitrate sensor. Microscale thermophoresis (MST) reveals Sialin2 as a high-affinity nitrate sensor, while Cryo-Electron Microscopy (Cryo-EM) uncovers its structural basis for signaling. We show that Sialin2 localizes to mitochondria and scaffolds liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) complexes to drive organelle-specific metabolic adaptation via spatiotemporally controlled AMPK activation, enhancing mitochondrial biogenesis, ATP production, and cell survival. Real-time tracking using the sCiSiNiS biosensor demonstrates nitrate signaling dynamics at physiological levels. This signaling axis redefines nitrate as a direct ligand activating receptor-like cascades, independent of classical nitric oxide synthesis. Our findings establish a paradigm of "inorganic salt signaling biology", wherein anions co-opt trafficking systems to achieve signaling specificity, offering therapeutic avenues for mitochondrial disorders.

cell biology↗

bioRxiv2025

How Bacterial Vesicles Trigger Hearing Loss: The Role of Pyroptosis in Cochlear Damage

Withdrawal StatementThe authors have withdrawn this manuscript because [After submitting my article, I discovered some important missing data that is crucial for supporting my viewpoint and research findings. Although I tried to supplement this data through other means, I was unable to complete it before the deadline. Therefore, I believe the best approach is to withdraw the article so that I can further refine and present my research findings in a complete manner.]. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

immunology↗

bioRxiv2025

Miniaturized and accessible functional ultrasound imaging system for freely moving mice

Functional ultrasound (fUS) imaging provides brain-wide activity maps with high spatiotemporal resolution and deep penetration, positioning it as a key technology for future non-invasive brain-computer interfaces (BCIs). Realizing this potential, particularly for chronic BCI applications requiring long-term monitoring in naturalistic settings, critically depends on significant system miniaturization to overcome the cost and complexity limitations of current platforms. Addressing this challenge, we present mini-fUS, a miniaturized, cost-effective fUS platform engineered for accessibility without compromising core performance for demanding neuroscience research. The system features a compact transmit-receiver, low-noise power supply, and high-speed data transfer, achieving pulse repetition frequencies up to 5 kHz with negligible jitter. Real-time GPU-accelerated beamforming and singular value decomposition (SVD) enable whole-brain activity mapping, demonstrated here in freely moving mice at up to 3.57 Hz with [~]100 {micro}m spatial resolution and 15 mm penetration depth. Validated through recordings of brain activity during sensory stimulation, anesthesia, and behavior, this design defines a practical hardware-software framework for fUS. By significantly improving accessibility and enabling robust monitoring in mobile subjects, this work advances the development of fUS for both fundamental research and future BCI technologies, while clarifying essential fUS operational principles.

neuroscience↗

bioRxiv2025

Mesoscopic SCAPE Microscope with a Rescanned, Super-oblique Illumination Plane

Investigating structural and functional dynamics across large spatial scales in living organisms calls for volumetric microscopy that combines a wide field of view (FOV), high spatial resolution, and sufficient temporal resolution. Swept confocally-aligned planar excitation (SCAPE) microscopy offers a compelling balance of optical sectioning, cellular resolution, and high-speed volumetric imaging. However, extending SCAPE to mesoscopic scales has been hindered by the limited tilting angle of the oblique illumination light sheet achievable with commercial low-magnification objectives. Here, we present a mesoscopic SCAPE microscope that overcomes this constraint by implementing a super-oblique light sheet--tilted up to ~60{degrees} relative to the optical axis of a 0.5-NA primary objective--enabled by an air-to-water bridging reflector. In addition, we introduce a single-galvanometer, self-conjugating rescanning strategy that allows arbitrary customization of the optical-to-mechanical angle ratio. This innovation accommodates the reversed and modulated scan displacement of the reflected light sheet and preserves descanned epi-fluorescence detection. Together, these advancements enable our mesoscopic SCAPE microscope to achieve a lateral FOV of 5.0 mm x 2.9 mm, cellular-level spatial resolution (~9.4 m x ~5.9 m lateral, and ~6.0 m axial), and a volumetric imaging rate of 9 volumes per second.

bioengineering↗

bioRxiv2025

MeDCycFold: A Rosetta Distillation Model to Accelerate Structure Prediction of Cyclic Peptides with Backbone N-methylation and D-amino Acids

Cyclic peptides with backbone N-methylated amino acids(BNMeAAs) and D-amino acids(D-AAs) have gained attention for their stability, membrane permeability, and other therapeutic potentials. Currently, Rosetta can predict their structures using energy calculations, but this method is heavily time-consuming. Moreover, structural data for cyclic peptides containing BNMeAAs and D-AAs are extremely insufficient to build a data-driven structure prediction model. To address these problems, we propose MeDCycFold, a deep learning-based Rosetta distillation model by fine-tuning the AlphaFold model. First, a cyclic peptide structure dataset is constructed using Rosetta by sampling massive conformations for cyclic peptides with BNMeAAs and D-AAs and evaluating their energy scores. Then, the AlphaFold model is fine-tuned with the extended 56 BNMeAAs and D-AAs. Besides, a relative position cyclic matrix is introduced for head-to-tail cyclization in the cyclic peptides. Finally, a force field is employed to reduce clashes in the predicted structures. Empirical experiments show that our proposed MeDCycFold speeds up structure prediction by 49 times while maintaining the prediction accuracy comparable to Rosetta, which can greatly accelerate the development of cyclic peptide drugs.

bioinformatics↗

bioRxiv2025

Palmdelphin facilitates R-spondin2 secretion to activate Wnt signaling and promote colorectal cancer stemness and tumorigenesis

The Wnt signaling pathway is a key driver of stemness and progression which contributes to mortality in colorectal cancer (CRC). R-spondins bind to LGR receptors to inhibit ubiquitin E3 ligases, thus protecting Frizzled from degradation and activating downstream Wnt signaling. Herein, we identify Palmdelphin (PALMD) as a functional marker of CRC stem cells, interspersed between intestinal and colonic crypt base epithelial cells, and predictive of aggressive CMS4 CRC and poor survival. Gene knockdown and overexpression studies revealed that PALMD initiates paracrine activation of Wnt/{beta}-catenin signaling via interacting with and facilitating the secretion of R-spondin2 (RSPO2), resulting in enhanced stemness and tumor growth in vitro and in vivo. Physiologic or pharmacologic inhibition of the PALMD-RSPO2 axis using R-spondin2-specific antibody or 6-methyl-1,3,8-trihydroxyanthraquinone (emodin), respectively, attenuates PALMD- mediated Wnt reporter activation, self-renewal, and tumorigenesis in cell and patient-derived organoid models. Together, these findings identify PALMD as a previously unknown player in Wnt signaling in CRC, and underscore the pro-tumorigenic role of R-spondin2 in this context.

cancer biology↗

bioRxiv2025

QuickProt: A Fast and Accurate Homology-Based Protein Annotation Tool for Non-Model Organism Genomes

Despite the increasing number of genomes, the annotation of protein-coding genes is still lacking. In some genomes where transcriptome data is not available, various tools have been developed to annotate genes based on homologous proteins, but each tool has its limitations. Here, we propose quickprot, a user-friendly command-line tool that constructs a set of redundancy-free gene models from the target genome based on the homologous protein sequences of a set of closely related species. We tested its applicability in stonefish, and the results showed that it has high accuracy and runs faster than existing tools. This low-cost, high-precision annotation method is expected to become a useful tool for genome annotation, which will contribute to the research of comparative genomics. The software is implemented in Python and licensed under the MIT License. The source code, documentation, and tutorials can be obtained at https://github.com/thecgs/quickprot.

bioinformatics↗

bioRxiv2025

The lysine side chain's swing motion in AapA1 toxin promotes water transport through transmembrane pores

The rising antibiotic resistance of Helicobacter pylori and the emergence of multi-drug-resistant strains pose significant challenges to its eradication. Understanding the molecular mechanisms driving this resistance is critical. This study investigates how AapA1, a toxin protein, may inhibit H. pylori growth and cause morphological changes by forming transmembrane pores in its inner membrane. Using experimental data and molecular dynamics simulations, we analyzed the pore structure and its formation mechanism. Results show that AapA1 forms pores on liposomes and exists stably in the membrane as -helices through different multimers, creating hydrophilic pores of varying sizes. Dynamic oscillation of K16/23 side chains in the membrane affects water transport through these pores, and restricting their movement significantly reduces transport. AapA1 monomers adopt three distinct conformations, with the K16/23 residues showing an up-down swing motion, potentially facilitating accelerated transport of substances. This study provides a new perspective on the dynamic structure-function relationship of AapA1-membrane interaction and highlights the role of positively charged residues in AapA1. Understanding the multimeric AapA1-membrane structure and the mechanism underlying AapA1-induced transmembrane pores is particularly crucial to develop new drugs and treatment options to reduce drug resistance emergence and combat any new emergence development.

biophysics↗

bioRxiv2025

DiNovo: high-coverage, high-confidence de novo peptide sequencing using mirror proteases and deep learning

Despite the recent advancements driven by deep learning, de novo peptide sequencing is still constrained by incomplete peptide fragmentation and insufficient protein digestion in current single protease-based proteomic experiments. Here, we present a software system, named DiNovo, for high-coverage and confidence de novo peptide sequencing by leveraging the complementarity of mirror proteases. DiNovo is empowered by several innovative algorithms, including a mirror-spectra recognition algorithm independent of pre-sequencing, two sequencing algorithms based on deep learning and graph theory, respectively, and target-decoy mapping, a method for sequencing result evaluation free of prior peptide identification. Compared with the trypsin protease used alone, DiNovo using two pairs of mirror proteases led to two to three times high-confidence amino acids sequenced. Compared with previous single-protease de novo sequencing algorithms, DiNovo achieved much higher sequence coverages. DiNovo also showed great potential as a powerful complement or alternative to database search for peptide identification with quality control.

bioinformatics↗

bioRxiv2025

Sky islands of Southwest China. II: Unraveling hidden species diversity of talpid moles using phylogenomics and skull-based deep learning

The sky islands of Southwest China, characterized by dramatic topographical and climatic variations, are prominent hotspots of biodiversity and endemism. Organisms inhabiting middle-to-high elevation habitats in this region are geographically isolated within distinct mountain chains, which over geological time have been subjected to isolation-by-distance and isolation-by-environment. These processes have led to profound allopatric diversification and strong phylogeographic structuring, resulting in a plethora of genetically distinct cryptic species, as is becoming increasingly evident for many small mammal families. However, morphological conservatism can pose significant challenges in delineating these clades within species complexes. In this study, we leverage artificial intelligence technologies to unravel the hidden species diversity of moles (family Talpidae) in Southwest Chinas sky islands. We first employed ultraconserved elements (UCEs) to investigate the evolutionary history of talpid moles, conducted molecular species delimitation using mitochondrial and multi-locus genes, and utilized both traditional and geometric morphometrics to examine their morphological disparity. To address the challenges of morphology based cryptic species identification, we developed a deep learning Hierarchical Identification of Species NETwork (HIS-NET) to create an image-based model that analyzes four different views of the skull/mandible to distinguish genera and species hierarchically. HIS-NET not only achieved expert-level accuracy in species identification but also effectively distinguished between cryptic and known species, aiding in the identification of key morphological variation intervals. Our results support the recognition of allopatrically distributed taxa in Euroscaptor and Parascaptor as full species, thereby confirming that species diversity in this region remains underestimated. Beyond advancing our understanding of speciation in this unique and fragile ecosystem, our study serves as a proof-of-concept, demonstrating the power of deep learning in unraveling hidden biodiversity within this and other species complexes.

zoology↗

bioRxiv2025

Integrative Analysis of Single-cell and Bulk RNA Sequencing Reveals Macrophage Heterogeneity in Lyme Arthritis

IntroductionLyme arthritis (LA) is a common late-stage manifestation of Lyme disease caused by Borrelia burgdorferi (Bb) infection. Macrophages play a crucial role in LA pathogenesis, yet their heterogeneity and functional states within the arthritic microenvironment remain poorly understood. MethodsWe integrated single-cell RNA sequencing data from ankle joint tissues of Bb-infected C57BL/6 mice with bulk RNA sequencing data from both infected ankle joints and bone marrow-derived macrophages. We developed a LA mouse model and validated key findings through histopathological examination and RT-qPCR analysis. ResultsWe identified nine distinct cell types in the joint microenvironment with significant compositional shifts during disease progression. Analysis of 16,617 Macrophages/Monocytes revealed seven functionally distinct subpopulations with differential responses to infection. Pseudo-time trajectory analysis demonstrated three principal differentiation pathways from monocyte-derived macrophages toward anti-inflammatory, TNF+, and IL1b+ inflammatory phenotypes. Cell-cell communication analysis revealed significantly altered TGF-{beta} signaling networks in LA, with the Tgfb1-(Tglbr1+TgIbr2) axis playing a critical role. GSVA and pathway analyses showed metabolic reprogramming from oxidative phosphorylation toward glycolysis in macrophages during infection. Through integrated analysis and LASSO regression, we identified four characteristic genes (SIRPB1C, FABP5, MMP14, and EGR1) as potential LA biomarkers and developed a diagnostic nomogram with high predictive accuracy. ConclusionOur integrative analysis provides comprehensive insights into macrophage heterogeneity and functional plasticity in LA, identifying characteristic biomarkers and potential therapeutic targets. The metabolic reprogramming and altered TGF-{beta} signaling networks we identified may contribute to disease pathogenesis and offer new avenues for intervention strategies.

genomics↗

bioRxiv2024

Single-nucleus multi-omics identifies shared and distinct pathways in Pick's and Alzheimer's disease

The study of transcriptomic and epigenomic variations in neurodegenerative diseases, particularly tauopathies like Picks disease (PiD) and Alzheimers disease (AD), offers insights into their underlying regulatory mechanisms. Here, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched non-coding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine-mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell-types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database, scROAD, to visualize predicted single-cell TF occupancy and regulatory networks. TeaserComparative studies in AD and PiD reveal critical regulatory changes and identify risk gene associations for PiD.

neuroscience↗