Biology subjects

Shi, M.

Publications and source records attributed to Shi, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Targeted delivery of niclosamide to FRβ-expressing macrophages with engineered 2-deoxy glucose dendrimer alleviates endometriosis progression and associated hyperalgesia

Endometriosis is a chronic, incurable disease. Due to limited efficacy, high recurrence rates, and serious side effects of current treatments, development of new, targeted, non-hormonal therapies is urgently needed. We previously reported that niclosamide, an FDA-approved anthelmintic drug, attenuates endometriotic lesion growth. We further identified folate receptor-{beta} (FR{beta})-positive macrophages as contributors to disease progression. Significantly, niclosamide inhibits FR{beta}+ macrophages and reduces inflammation, innervation, and angiogenesis. To develop niclosamide as a non-hormonal and selective immune cell-targeted therapy for endometriosis, we engineered a folic acid-conjugated 2-deoxyglucose dendrimer (FA-2DG-D) using click chemistry to enable selective FR{beta}-mediated uptake. Conjugation of niclosamide to FA-2DG-D yielded a targeted nanotherapeutic (FA-2DG-D-Niclo) with enhanced aqueous solubility, controlled intracellular release, and excellent batch-to-batch reproducibility. In a mouse model of endometriosis, FA-2DG-D demonstrated lesion-specific accumulation and selective internalization by FR{beta} macrophages with minimal off-target organ retention. A single intraperitoneal dose of FA-2DG-D-Niclo (25 or 50 mg/kg/bw of niclosamide) significantly reduced FR{beta} macrophage burden, suppressed lesion number and volume, and markedly improved endometriosis-associated hyperalgesia at two weeks post-treatment. Together, these findings establish FR{beta} macrophages as a potential target in endometriosis and present FA-2DG-D-Niclo as a non-hormonal, macrophage-focused nanomedicine for precise and effective endometriosis treatment. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/704463v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@d0101corg.highwire.dtl.DTLVardef@1d1a0bborg.highwire.dtl.DTLVardef@18f9271org.highwire.dtl.DTLVardef@d76bc7_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Exploring Multi-Scale Local and Global Features in Whole Slide Images Using State Space Models

Whole slide image (WSI) classification is crucial in computational pathology, yet the gigapixel scale of WSIs makes it challenging to extract discriminative and compact WSI-level features for disease diagnosis. In this paper, we propose MambaWSI, a novel method that leverages the state space model (SSM) for WSI classification by exploring multi-scale local and global features. Unlike existing approaches that sequentially traverse WSI tiles and rely on vanilla SSMs for long-range dependency modeling, we exploit a traversal strategy in a higher-dimensional discrete space that preserves spatial proximity, enabling a first-local-then-global feature extraction process. Furthermore, to align with the clinical workflow of pathologists when examining WSIs at multiple scales, we propose a two-stage hierarchical fusion strategy: inter-scale feature alignment and aggregation, followed by attention-based fusion across magnifications, integrating complementary information from multiple magnifications. Experiments on two datasets demonstrate that MambaWSI outperforms state-of-the-art methods in classification performance.1

pathology↗

bioRxiv2025

Longitudinal Identification of Zebrafish Individuals by Deep Learning

The zebrafish (Danio rerio) is a critical vertebrate model organism in biomedical research. Accurate identification and longitudinal tracking of individual fish within cohorts enable linking genotype to complex phenotypes, essential for elucidating the molecular mechanisms underlying disease pathogenesis and trait formation. Nevertheless, the establishment of reliable long-term individual identification remains a significant challenge, primarily due to their diminutive size and minimal interindividual morphological variations. We developed ESC-IDNet, a dual-stage deep learning cascade architecture deployed on the FishIndivID platform (http://bioinfo.ihb.ac.cn/fishindivid), enabling high-precision identification. Trained and tested on [~]300,000 images from 450 zebrafish (31-122 dpf), our lateral body-based identification maintained >95% accuracy with updates only every 20 days, significantly outperforming dorsal head identification (requiring [~]13-day updates). Both views achieved 100% accuracy in 1-2 day tasks. ESC-IDNet surpassed alternatives in segmentation, alignment, feature extraction, and feature matching. This framework provides a robust, transferable paradigm for individual identification in fish species.

bioinformatics↗

bioRxiv2025

Amyloid-β 42-carrying extracellular vesicles are associated with neurodegeneration and neuroinflammation in Alzheimer's disease

Alzheimers disease (AD) is the most common form of dementia, characterized by progressive amyloid-{beta} (A{beta}) accumulation and neurodegeneration. Extracellular vesicles (EVs) have been implicated in AD pathology, but their relationship to disease progression and the cerebrospinal fluid (CSF) proteome remains poorly understood. In this study, we analysed plasma-derived A{beta}42-containing EVs from participants of the Alzheimers Disease Neuroimaging Initiative (ADNI) and calculated the ratio between the percentage of A{beta}42-positive peripheral EVs and CSF A{beta}42 (rA{beta}42). This ratio was elevated in AD and positively correlated with amyloid pathology as measured by PET. Longitudinal analyses revealed that higher rA{beta}42 values predicted accelerated hippocampal atrophy and cognitive decline, independent of CSF A{beta}42 concentrations. Proteomic profiling of CSF using the SomaScan platform showed that rA{beta}42 was associated with an inflammatory signature characterized by myeloid activation and type II interferon-related signalling pathways. Together, these findings indicate that A{beta}42-carrying EVs reflect an active and inflammatory component of AD pathology and may represent a novel class of biomarkers for disease progression. Understanding the mechanisms that link A{beta}42-positive EVs to neuroinflammatory signalling could open new avenues for pathway-specific diagnostics and therapeutic strategies in AD.

neuroscience↗

bioRxiv2025

RNA viruses in water shape the viromes of shrimp and fish in aquaculture systems

Aquatic environments host immense RNA viral diversity, yet the extent to which waterborne viruses influence the virome of aquatic animals remains unclear. Here, we conducted a comprehensive longitudinal metatranscriptomic analysis of water, shrimp, and fish across multiple culture stages in aquaculture systems. We identified 3,211 RNA viruses spanning 21 viral supergroups, with 97.4% representing novel species. Water exhibited the greatest viral diversity (3,093 species), followed by shrimp (1,280) and fish (398), with most viruses detected in shrimp and fish also detected in water. Diversity analyses revealed increasing richness and significant compositional shifts in 92 high-abundance viruses (>1,000 RPM) across culture stages. Viral abundance in aquatic animals was strongly correlated with that in water, and the temporal trajectories of the 16 most abundant viruses were closely synchronized between water and shrimp. Furthermore, 337 virus species were shared among shrimp and two fish species, of which 309 were present in water. These findings demonstrated that RNA viruses in water shape the composition and dynamics of aquatic animal viromes, underscoring the importance of water virome surveillance and management for disease prevention in shrimp aquaculture.

microbiology↗

bioRxiv2025

Ergothioneine and a new food supplement product protectagainst cyclophosphamide-induced premature ovarianfailure in rats

Premature ovarian failure (POF) is characterized by disrupted estrous cycles and impaired folliculogenesis due to oxidative stress and inflammation. In this study, a cyclophosphamide (CTX)-induced POF rat model was used to evaluate the protective effects of ergothioneine (EGT) and a nutraceutical formula (FineNutri Cellular Vitality Capsules) containing EGT. CTX treatment markedly prolonged the estrous cycle, reduced estrus duration, decreased ovarian weight, impaired follicular development, and increased granulosa cell apoptosis. Serum estradiol (E2) and anti-Mullerian hormone (AMH) levels decreased, whereas luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increased, reflecting disruption of the hypothalamic-pituitary-ovarian axis by CTX. CTX treatment induced oxidative stress, with reduced catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content, and increased malondialdehyde (MDA) in ovarian tissue. The EGT and the nutraceutical formula restored estrous cycles, increased ovarian weight, improved primordial follicle counts, and reduced atretic follicles and granulosa cell apoptosis. Hormonal balance was partially restored, with increased E2 and AMH and reduced LH and FSH levels. Oxidative stress was alleviated with higher CAT, SOD, and GSH levels and reduced MDA concentrations. In addition, EGT and the formula reduced inflammation in skin tissue. These findings suggest that EGT and the nutraceutical formula could protect against CTX-induced POF and help preserve ovarian function, probably by mitigating oxidative stress.

pharmacology and toxicology↗

bioRxiv2025

Methionine γ-lyase Traps Cofactor Pyridoxal-5'-phosphate through Specific Serine-Mediated Affinity

Pyridoxal-5'-phosphate (PLP), the ubiquitous and ancient cofactor, plays important roles in enzymatic elimination, transamination and other reactions. The catalytic efficiency of PLP-dependent enzymes is significantly higher than that of free PLP. The recruitment of PLP from the environment by the enzymes, particularly through interactions outside the active site, is the key step determining the occurrence of PLP-mediated catalysis. However, the precise mechanism by which enzymes recruit PLP remains elusive. Methionine {gamma}-lyase (MGL), a PLP-dependent enzyme, catalyzes the degradation of L-methionine, thereby suppressing cancer cell proliferation through serum or dietary methionine depletion. Here, we report the crystal structure of yMGL, which belongs to a newly identified subgroup of cystathionine {gamma}-lyases, in complex with L-methionine and PLP. Through truncating the C-terminal domain of yMGL both in vitro and in vivo, we demonstrated that this domain, outside the canonical PLP-binding domain, is essential for the specific interaction between yMGL and PLP, as well as for efficient L-methionine catabolism. A conserved Ser in the C-terminal domain, positioned at the active-site entrance of MGLs, confers specificity for PLP. These findings elucidate a previously uncharacterized mechanism of PLP recruitment by MGLs and promote rational design of MGLs with tailored cofactor selectivity and catalytic performance.

biochemistry↗

bioRxiv2025

Deficiency in POLE exonuclease causes synthetic lethality in highly aneuploid cancer cells

Aneuploidy is a hallmark of cancer and is associated with drug resistance and poor clinical outcomes across diverse cancer types. However, no therapies have been clinically established to target highly aneuploid tumors. By analyzing a real-world dataset comprising nearly half a million tumor samples subjected to comprehensive genomic profiling, we identified a striking mutual exclusivity between POLE exonuclease domain mutations and high aneuploidy burden. This observation was independently validated using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Probabilistic modeling revealed that the elevated quantity and unique spectrum of mutations induced by POLE exonuclease deficiency increase the likelihood of inactivating essential genes on chromosome arms harboring losses, leading to a synthetic lethal phenotype in highly aneuploid cells. Functional experiments demonstrated that POLE exonuclease activity is essential for the viability of highly aneuploid cancer cell lines but is dispensable in diploid cells. These findings suggest that selective inhibition of POLE exonuclease may represent a promising therapeutic strategy for targeting highly aneuploid tumors.

cancer biology↗

bioRxiv2025

Using Artificial Intelligence to Assess Cross-Species Transmission Potential of Influenza A Virus

Influenza A viruses (IAVs) pose pandemic threats through cross-species transmission, yet predicting their adaptive evolution remains challenging. We introduced Influenza A virus Adaptability to host X (FluAdaX), a deep learning framework that integrates a moving average-equipped gated attention mechanism using full-genome sequences. FluAdaX demonstrated robust host classification performance across endemic IAV strains, and outperformed traditional models in detecting avian-to-human transmission. Spillover score and adaptability score were introduced to evaluate host shift risk, which prioritized variants with elevated human adaptation potential, such as H7N9, H9N2 avian IAVs, and H1N1 swine IAVs. Besides HA and NA genes, PB2 and NS genes were found critical for zoonosis. Potential molecular markers associated with avian/human tropism were identified across PB2 and NS genes using XGBoost. FluAdaX provided a dynamic framework to decode IAV host adaptation, enabling real-time risk assessment of cross-species transmission of emerging IAV variants.

bioinformatics↗

bioRxiv2025

Predicting the Evolutionary and Functional Landscapes of Viruses with a Unified Nucleotide-Protein Language Model: LucaVirus

Predicting viral evolution and function remains a central challenge in biology, hindered by high sequence divergence and limited knowledge compared to cellular organisms. Here, we introduce LucaVirus, a multi-modal foundation model for viruses, trained on 25.4 billion nucleotide and amino acid tokens covering nearly all known viruses. LucaVirus learns biologically meaningful representations capturing relationships between sequences, protein/gene homology, and evolutionary divergence. Using these embeddings, we developed downstream models that address key virology tasks: identifying hidden viruses in genomic "dark matter", annotating enzymatic activities of uncharacterized proteins, predicting viral evolvability, and identifying antibody candidates for emerging viruses. LucaVirus achieves state-of-the-art results in three tasks and matches leading models in the fourth with one-third the parameters. Together, these findings demonstrate the power of a unified foundation model to comprehensively decode the viral world and establish LucaVirus as an efficient and versatile platform for AI-driven virology, from virus discovery to functional and therapeutic predictions.

bioinformatics↗

bioRxiv2025

Inhibitory activities of monoclonal antibodies against Staphylococcus aureus Clumping factor A

Staphylococcus aureus infection is a frequent cause of sepsis in humans, a disease associated with high mortality and without specific intervention. Clumping factor A (ClfA) displayed on the bacterial surface plays a key role in promoting S. aureus replication during invasive disease. Decades of research have pointed to a wide array of ligands engaged by ClfA. The sum of these interactions supports the unique ability of this pathogen to survive and replicate in the blood stream. One such ligand is fibrin. ClfA acts as the key agglutinating factor of S. aureus by promoting the shielding of bacteria in fibrin cables and their physical escape from phagocytes. Here, we compare a series of monoclonal antibodies elicited against the ligand binding domain of ClfA following immunization of mice. We analyze these antibodies for their ability to neutralize ClfA interactions and to promote the uptake of staphylococci in whole blood. We find that while all the antibodies promoted opsonophagocytic uptake, only those that also inhibited ClfA interactions with ligands, reduced bacterial burdens in animals following blood stream challenge with S. aureus. IMPORTANCEAntibody-based approaches to fight bacterial pathogens have been modeled on toxin-producing or encapsulated pathogens for which correlates of protection can be reduced to measuring antibody neutralization or complement-fixing activities using tissue cultured cells. Such approaches have failed against Staphylococcus aureus raising uncertainty about the value of antibodies. Here, we use a series of mouse monoclonal antibodies directed against ClfA, a surface protein that allows S. aureus to thrive in the blood stream, to query how antibodies may be exploited against a pathogen endowed with a formidable array of virulence factors.

microbiology↗

bioRxiv2025

Longitudinal single-cell analysis reveals RUNX1T1 as an early driver in treatment-induced neuroendocrine transdifferentiation

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal form of advanced prostate cancer that can emerge from adenocarcinoma under androgen receptor pathway inhibition, but the tumor-cell states and regulators underlying this transition remain incompletely defined. Here, we analyzed longitudinal single-cell RNA sequencing data from the LTL331/331R patient-derived xenograft model across seven disease stages, comprising 32,269 tumor-cell transcriptomes from treatment-naive adenocarcinoma, post-castration regression, and relapsed NEPC. We identified an AR-low/NE-low intermediate state that emerged after castration and before overt relapse, as well as two transcriptionally distinct terminal NEPC states marked by ASCL1high/FOXA2low and ASCL1low/FOXA2high programs. RUNX1T1 was induced in the intermediate state and remained elevated across both terminal states. RUNX1T1 enhanced NE-associated features and cell viability during enzalutamide treatment in adenocarcinoma cells, whereas its knockdown in NCI-H660 cells reduced NE-associated transcriptional programs, proliferation, and survival and shifted the transcriptome toward an intermediate-like state. Chromatin interactome analysis and co-immunoprecipitation linked RUNX1T1 to G9A/LASP1-containing chromatin repressor complexes. These findings define a temporal framework for treatment-induced NEPC progression and identify RUNX1T1 as an early-induced and sustained regulator of NE lineage transition and maintenance of established NEPC.

cancer biology↗

bioRxiv2025

scDenorm: a denormalisation tool for integrating single-cell transcriptomics data

Integrating single-cell omics data at an atlas scale enhances our understanding of cell types and disease mechanisms. However, the integration of data processed by different normalisation methods can lead to biases, such as unexpected batch effects and gene expression distortion, leading to misinterpretations in downstream analysis. To address these challenges, we present scDenorm, an algorithm that reverts normalised single-cell omics data to raw counts, preserving the integrity of the original measurements and ensuring consistent data processing during integration. We evaluated scDenorms performance on large-scale datasets and benchmarked its impact on data integration and downstream analysis across three datasets.

bioinformatics↗

bioRxiv2025

A real-time detection and non-destructive warning method for zebrafish body surface anomalies based on improved YOLOv8 framework

The detection of anomalies on fish surfaces is of critical importance for assessing fish health status, preventing fish disease outbreaks, predicting changes in water quality, enhancing fish welfare. The zebrafish (Danio rerio), a key model organism, has been increasingly utilized in various fields, including medicine, genetics and environmental toxicology. This has led to a corresponding increase in demand for intelligent management and detection systems. However, traditional methods of fish disease detection may have irreversible effects on fish, particularly small species, and often fail to meet the precision, non-destructive warning, and real-time requirements for zebrafish detection. To address this issue, this study proposes a novel method based on the YOLOv8 framework, designated ESC-YOLOv8-seg. This method significantly enhances the precision and speed of detecting surface abnormalities on small fish in complex settings by integrating the EMA the SPPELAN and C2f-Faster modules, and adding a detection head tailored for small targets. Furthermore, the integration of positional information and surface features enables the method to achieve real-time monitoring and non-destructive early warning of fish surface abnormalities. The proposed method enhances precision in small target detection and achieves high accuracy in discerning subtle differences among detection targets. In real aquaculture settings, it can reach an average speed of 106 FPS with a detection accuracy of 98%. Although this study has been designed to meet the specific needs of zebrafish scientific research, it is highly generalisable and can be applied to the real-time detection of underwater surface abnormalities in a range of fish species in aquaculture.

bioinformatics↗

bioRxiv2025

ZMS-6659, a selective Polθ helicase inhibitor, demonstrates anti-tumor activity as monotherapy and synergy effect with PARP inhibitors and topoisomerase inhibitors

The repair of DNA double strand break (DSB) is crucial for genome stability. Homologous recombination (HR) is a high-fidelity, error-free DSB repair pathway, and its dysfunction leads to genome instability and can result in tumorigenesis. In HR deficient contexts, microhomology-mediated end joining (MMEJ), dependent on DNA polymerase theta (Pol{theta}), is up-regulated to serve as a backup pathway for DSB repair. Several studies have proved that Pol{theta} inhibition causes synthetic lethality with HR deficiency, and Pol{theta} emerges as a potential DNA damage repair (DDR) target for the treatment of HR deficient tumors both as single agent or in combination with PARP inhibitors (PARPi). In addition, evidences show that the blockage of Pol{theta} can enhance the sensitivity to DNA damage agents. Herein, we characterized ZMS-6659, a highly potent small-molecule Pol{theta} inhibitor targeting the helicase domain. ZMS-6659 induces synthetic lethality in HR deficient models, elicits synergistic effects with even low dose of PARPi and delays PARPi resistance without additional hematotoxicity. Besides, ZMS-6659 also enhance the sensitivity to topoisomerase inhibitors in HR proficient cell lines. These findings support the clinical exploration of ZMS-6659 in combination with PARPi in HR deficient tumors, and suggest a potential application expansion beyond HR deficiency.

cancer biology↗

bioRxiv2025

Genetic architecture of the S-locus supergene revealed in a tetraploid distylous species

SummaryO_LIHeterostyly is a polymorphic floral adaptation controlled by supergenes and maintained in populations by disassortative mating. The molecular basis of distyly has been investigated in several unrelated families. Previous studies have been limited to diploid species and have not included Rubiaceae, which has the highest number of heterostylous species. C_LIO_LIHere, we investigate the genetic architecture of tetraploid Schizomussaenda henryi (Rubiaceae) to identify candidate style-length genes, evidence for hemizygosity and the potential role of gene duplication in the evolution of the S-locus. Chromosome-level genome assemblies and transcriptomic approaches identified the S-locus region comprised of four hemizygous genes. C_LIO_LIThe candidate gene SchzAUX22 may regulate style length and filament growth by acting in the auxin signaling pathway. Comparative studies of the two sub-genomes of S. henryi indicated strong similarities and no significant sub-genome dominance, as expected from autotetraploidy. Evidence from haplotype-resolved assemblies of a short-styled plant indicated that it possessed the ssSS genotype, consistent with autotetraploidy, which was estimated to have originated [~]3.6 Mya. Analysis of Ks values between S-locus genes and their paralogs indicated that the S-locus likely originated through stepwise duplication. C_LIO_LIOur study provides comprehensive genomic analysis of distyly in a polyploid and demonstrates that despite whole genome doubling the S-locus supergene remains intact and functional as an outbreeding mechanism. Our results contrast with many other heterostylous lineages where polyploidy is associated with breakdown of the polymorphism and transitions to self-fertilization. C_LI

plant biology↗

bioRxiv2025

Human Body Single-Cell Atlas of 3D Genome Organization and DNA Methylation

Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multi-omic profiling of 3D genome structure and DNA methylation for 86,689 single nuclei across 16 human tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across almost all cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Intriguingly, extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, indicating that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers an extensive reference for exploring gene regulation in human health and disease.

genomics↗

bioRxiv2025

NeoAtlas and NeoBert: A Database and A Predictive Model for Canonical and Noncanonical Tumor Neoantigens

Neoantigens are classified into canonical and noncanonical types. Noncanonical neoantigens include those derived from noncoding regions, transposable elements (TE), and intron retention events, and they have recently gained considerable attention in cancer immunity. We curated 35,574 non-redundant neoantigen-HLA pairs from 14 immunopeptidomes studies, by analyzing unique features and differences across various sources of neoantigens. This knowledge enabled us to develop machine learning models for the prediction of different types of neoantigens. Our data and models are available at a public portal (https://ngdc.cncb.ac.cn/neoatlas) to facilitate broad access and future research. This resource offers advanced functionalities, including integration with epigenome browsers which allow easy navigation of epigenomic datasets to support and confirm the expression of neoantigens. We further demonstrate that combining our database with mass spectrometry analysis can identify noncanonical neoantigens. The resource we constructed holds significant value and promise for the development of neoantigen-based vaccines.

systems biology↗