Biology subjects

Bai, W.

Publications and source records attributed to Bai, W..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatiotemporal coordination of specialized cerebellar networks supports episodic memory in older adults

Episodic memory decline in ageing is typically attributed to the cortico-hippocampal system, yet the cerebellums specific contribution via cerebellar-cerebral circuits remains underexplored. We analysed task-based fMRI data from 821 older adults, including a longitudinal subset of 78 participants followed for four years. Using sparse dictionary learning on task-responsive activity, we identified three non-motor networks: a bilateral lobule VI/Crus I mnemonic-monitoring network, a right lobule Crus I/II default-mode-aligned network, and a right lobule VIIb/VIIIa evidence-evaluation network. While network recruitment varied with task demands and associated with memory performance, phase-specific static cerebellar-cerebral functional connectivity showed stable organization but limited behavioural specificity. In contrast, dynamic functional connectivity patterns effectively distinguished memory-performance groups. Crucially, greater instability in dynamic functional connectivity during encoding predicted longitudinal retrieval slowing. These findings suggest that preserved episodic memory in older adults is supported by the spatiotemporal coordination of specialized cerebellar networks with distributed cerebral networks.

neuroscience↗

bioRxiv2026

M&uumlllerian duct maintenance at the cranial region is promoted by Gata2

The paradigm of sexual differentiation holds that female embryos retain Mullerian ducts (the precursor to female reproductive tract) by default in the absence of anti-Mullerian hormone (AMH). However, whether Mullerian duct maintenance requires active signaling has remained unclear. Here, we discover that the deletion of mesenchymal Gata2 induces selective regression of the cranial Mullerian duct (future oviduct). This regression is not driven by ectopic AMH signaling, but rather by the loss of region-specific NRG1 signaling. In contrast, the caudal Mullerian duct (future uterus) is retained and displays disrupted epithelial differentiation upon Gata2 deletion in either the mesenchymal or epithelial compartments. Our findings reveal a region-specific, GATA2-dependent program that actively maintains the cranial Mullerian duct, reshaping our understanding of female reproductive tract development.

developmental biology↗

bioRxiv2026

AMPBAN: A Deep Learning Framework Integrating Protein Sequence and Structural Features for Antimicrobial Peptide Prediction

The escalating crisis of antimicrobial resistance poses a devastating and immediate threat to human life. Antimicrobial peptides (AMPs) are a promising antibiotic substitute to combat antimicrobial resistance. Compared with the traditional wet-lab screening approaches, computational models have largely improved the efficiency of predicting antimicrobial peptide. However, most computational models overlook or underutilize the evolution and structural information of peptides, which is crucial for understanding the peptide functions. Here, we proposed a sophisticated deep learning model to predict AMPs, Antimicrobial Peptide Bilinear Attention Network (AMPBAN), which incorporates peptide evolution features from ESM3 protein language model, structure features from ESMFold predicted with equivariant graph neural network (EGNN), and the joint information from sequence and structure learned via Bilinear Attention Network. AMPBAN consistently demonstrated superior accuracy and generalization compared to nine state-of-the-art AMP prediction models across multiple independent benchmarks. Furthermore, an ablation study confirms that our multimodal fusion strategy significantly refines the integration of sequence and structural signals, yielding superior predictive balance over single-modality models. This framework provides a robust tool for the accelerated discovery of novel AMPs and the advancement of next-generation antimicrobial drug development. The datasets, source code and models are available at https://github.com/baiwenhuim/ampban.

bioinformatics↗

bioRxiv2025

Integrated analysis implicates novel insights of NMB into lactate metabolism and immune response prediction in primary glioblastoma

BackgroundGlioblastoma (GBM), the most aggressive primary brain tumor in adults, exhibits profound treatment resistance and poor prognosis. Despite advances in immunotherapy for other cancers, GBM remains refractory, potentially due to its lactate-rich, immunosuppressive tumor microenvironment (TME). While aerobic glycolysis-driven lactate accumulation is known to acidify the TME and impair immune function, the precise mechanisms linking lactate metabolism to immune evasion in GBM remain elusive. MethodsWe integrated multi-omics analyses with machine learning to identify - gene signatures associated lactate metabolism (LM) and Tumor Immune Dysfunction and Exclusion (TIDE) through weighted gene co-expression network analysis (WGCNA). Multiple bioinformatic tools were employed to determine the association of key genes with TME remodeling, immunotherapy response and drug sensitivities. ResultsNeuromedin B (NMB) emerged as a pivotal regulator of lactate-mediated immunosuppression, correlating strongly with LM and TIDE. We found that NMB expression was remarkably correlated with clinical characteristics, immune response, TME remodeling and drug sensitivities. ConclusionThis study demonstrates that NMB is a key cross-factor in metabolic and immune regulation in GBM. It breaks through the traditional perception that metabolism and immunity are mutually exclusive in cancer by promoting oxidative phosphorylation (OXPHOS) metabolism and enhancing anti-tumor immunity through its dual functions. It provides a new direction for the combined intervention of metabolic targeting and immunotherapy, and the strong predictive value of NMB expression for drug response further highlights its clinical application potential in the formulation of personalized treatment strategies for GBM patients.

neuroscience↗

bioRxiv2025

Targeting USP2 induces degradation of PML-RARα with or without drug-resistant mutations in acute promyelocytic leukemia

Despite the high efficacy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL), approximately 10-20% of patients develop drug resistance due to mutations in PML-RAR and other factors. Here, it is demonstrated that inhibiting USP2 with ML364 or silencing USP2 reduces PML-RAR protein levels in both ATRA-sensitive and -resistant APL cells, an effect reversed by proteasome inhibition. Conversely, USP2 overexpression enhances PML-RAR stability. Mechanistically, USP2 interacts with and deubiquitinates PML-RAR, including drug-resistant mutants. Consistent with PML-RAR degradation, ML364 treatment significantly induces apoptosis in APL cell lines and primary leukemia cells. In conclusion, this study identifies USP2 as a novel deubiquitinating enzyme for PML-RAR and highlights USP2 inhibition as a potential therapeutic strategy for APL with PML-RAR mutations.

cell biology↗

bioRxiv2025

VPS35/Retromer-dependent MT1-MMP regulation confers melanoma metastasis

Retromer is a conserved endosomal trafficking complex responsible for recycling transmembrane protein cargoes. Membrane-type I matrix metalloproteinase (MT1-MMP), a well-studied membrane-type metalloprotease, is highly expressed in metastatic melanomas. Previously, we reported that inducing MT1-MMP perinuclear localization and inhibiting MT1-MMP membrane localization significantly reduce melanoma metastasis. However, the regulation of MT1-MMP subcellular localization and recycling is still largely unknown. Here, we performed target gene shRNA screening and found that shRNA targeting the retromer complex subunit vacuolar protein sorting 35 (VPS35) inhibited MT1-MMP membrane localization and induced its perinuclear localization. We found that inhibiting VPS35/retromer decreased MT1-MMP recycling and increased MT1-MMP-lysosome localization, which significantly affected the stability of MT1-MMP. Furthermore, our results indicated that VPS35/retromer regulates the transcription of MT1-MMP through the activation of the IL6/STAT3 inflammatory signaling pathway. Tissue microarray analysis indicated that VPS35/retromer positively correlated with MT1-MMP levels and distant metastasis. Xenograft experiments showed that targeting VPS35/retromer significantly inhibited melanoma lung metastasis, which is dependent on MT1-MMP. Our results implicate the importance of VPS35/retromer in metastatic dissemination. Our study suggests that targeting the VPS35/retromer-MT1-MMP axis will contribute to inhibiting the metastasis of melanoma.

cancer biology↗

bioRxiv2025

scWGBS-GPT: A Foundation Model for Capturing Long-Range CpG Dependencies in Single-Cell Whole-Genome Bisulfite Sequencing to Enhance Epigenetic Analysis

Single-cell DNA methylomes are challenging to interpret because of sparse CpG coverage and the complexity of genome-wide sequences. We present scDNAm-GPT, a universal foundation model that uses context-aware CpG tokenization, a Mamba backbone, and cross-attention to capture both local and global DNA methylation patterns. Trained on over one million single cells from 35 human and mouse tissues, scDNAm-GPT enables accurate cell clustering, zero-shot prediction of CpG effects on gene expression, improved trajectory inference, and reference-free deconvolution of cell types from cell-free DNA. The model hierarchically learns regulatory features, and its attention maps highlight functionally relevant regions, demonstrating high biological interpretability. These results establish scDNAm-GPT as a scalable and generalizable framework for single-cell epigenomic analysis, offering new opportunities to dissect epigenetic regulation in health and disease. Code is available at GitHub (https://github.com/ChaoqiLiang/scDNAm-GPT).

bioinformatics↗

bioRxiv2024

KIF18A in HCC Metastasis: Dual Role in Anoikis Resistance and Chromosome Instability

The study explores the role of KIF18A, a gene linked to whole-genome doubling (WGD) and chromosomal instability (CIN), in the metastatic progression of hepatocellular carcinoma (HCC). We found that KIF18A is a critical link between CIN and anoikis resistance, key factors in HCC metastasis. Through the bulk-seq analysis, we identified the pressures of anoikis and CIN faced by tumor cells during HCC metastasis and identified hub genes central to this process. Our results reveal that E2F activation during HCC progression leads to the transcription of KIF18A, promoting the survival and metastasis of CIN tumors. Overexpression of KIF18A leads to longer tumor life, more micronuclei, and increased survival and metastasis through non-canonical NF-kB activation. Deletion of KIF18A stabilizes the nuclear membrane of the micronucleus, silences cGAS-STING and PI3K-AKT pathways, and inhibits classical NF-kB. The studys limitations include the need for further animal studies to validate the findings and explore the transient activation of the cGAS-STING pathway. Additionally, future research could focus on the potential therapeutic implications of targeting KIF18A in cancer treatment.

cancer biology↗

bioRxiv2024

Genomics-FM: Universal Foundation Model for Versatile andData-Efficient Functional Genomic Analysis

Artificial intelligence (AI) plays a crucial role in functional genomic analysis, offering great potential for comprehending biological phenomena such as heredity, development, diseases, and evolution. However, the development of AI models needs substantial labeled data, and these models are typically task-specific with limited generalizability to various applications. Here, we develop Genomics-FM, a genomic vocabulary driven foundation model that enables versatile and label-efficient functional genomic analysis. Specifically, Genomics-FM is first pretrained with ensemble genomic vocabulary on vast unlabelled data to learn comprehensive and generalizable representations and then finetuned with specific genomic vocabulary on limited labeled data to selectively activate and adapt the pretraining knowledge for specific tasks. We show that Genomics-FM significantly reduces the dependence on labeled data, and demonstrates the capability to outperform existing models across a comprehensive suite of tasks including genome annotation, epigenomic and expression profile prediction, and variant effect assessment. Remarkably, Genomics-FM even shows impressive zero-shot predictive capabilities across diverse species and tissues and exhibits noticeable adaptability to RNA-related tasks. With feasibility in data scarcity and even cross-domain biological scenarios, Genomics-FM will promote the broad application of AI and empower researchers to tackle previously insurmountable challenges, paving the way for groundbreaking research and discoveries.

bioinformatics↗

bioRxiv2024

Multi-step engineered adeno-associated virus enables whole-brain mRNA delivery

Adeno-associated viruses (AAVs) are commonly used vectors for DNA delivery in gene therapy. Here we developed a system that enables the AAV shell to package mRNAs by multi-step introduction of RNA-packaging components and modification of AAV Rep proteins. The resultant mRNA-carrying AAVs (RAAVs) retained most properties of conventional AAVs, including capsid composition, virus morphology, and tissue tropism. These RAAVs could mediate mRNA transfer into target cells and tissues, leading to transient expression of the functional protein. Importantly, intravenously injected RAAVs efficiently crossed the blood-brain barrier (BBB) and infected the whole mouse brain. Thus, the DNA viral vector could be modified for RNA delivery, and our RAAV represents the first highly efficient BBB-crossing mRNA delivery system that could be used for therapeutic purposes via whole-brain infection.

bioengineering↗

bioRxiv2024

HNF&alpha is a target of the Wnt/beta-catenin pathway and regulates colorectal carcinogenesis

Hepatocyte nuclear factor 4alpha (HNF4) is a transcription factor involved in liver function. Dysregulation of HNF4 leads to hepatocarcinogenesis. However, the role and mechanism of HNF4 in colorectal cancer is still unknown. Here we demonstrate that HNF4 is upregulated in colorectal cancers. and HNF4 upregulation promotes colorectal tumorigenesis. Notably, expression levels of HNF4 are positively correlated with the Wnt/{beta}-catenin signaling pathway in colorectal cancer patients. Further, we showed that HNF4 is transcriptionally activated by Wnt/{beta}-catenin/TCF3 and is at least partially responsible for the oncognesis activity of the Wnt signaling in colorectal cancer. Our findings indicate that HNF4 is a direct target of that Wnt/{beta}-catenin pathway and could play an important role in colorectal carcinogenesis. Author SummaryHere we demonstrate that HNF4 is upregulated in colorectal cancers and HNF4 upregulation promotes colorectal tumorigenesis. Notably, expression level of HNF4 are positively correlated with the Wnt/{beta}-catenin pathway in colorectal cancer patients. Further, we showed that HNF4 is transcriptionally activated by Wnt/{beta}-catenin/TCF3 and is at least partially responsible for the oncognesis activity of the Wnt signaling pathway in colorectal cancer.

cancer biology↗

bioRxiv2024

The EGF/EGFR-YAP1/TEAD2 axis-mediated BRAF inhibitor vemurafenib resistance upregulates STIM1 in melanoma

STIM1 is the endoplasmic reticulum (ER) Ca2+ sensor for store-operated entry (SOCE) and closely correlated to carcinogenesis and tumor progression. Previously we found that STIM1 is upregulated in melanoma cells resistant to the BRAF inhibitor vemurafenib, but the regulation mechanism is unknown. Here, we show that vemurafenib resistance upregulates STIM1 through an EGF/EGFR-YAP1/TEAD2 axis. Vemurafenib resistance can lead to the increase of EGF and EGFR levels to activate the EGFR signaling pathway. Reactivated EGFR signal promotes YAP1 nuclear localization to increase the expression of STIM1. Our finding not only demonstrates the mechanism by which vemurafenib resistance promotes STIM1 expression, but also provides combined targeting EGF/EGFR-YAP1/TEAD2-STIM1 to improve the therapeutic efficiency of BRAF inhibitor in melanoma patients.

cancer biology↗

bioRxiv2023

Study on the preparation of bovine milk exosomes and the stability of lyophilized powder

Bovune milk exosomes (MK-exo) have bioactive effects on the health of consumers and can also serve as excellent drug delivery vehicles. However, long-term preservation and transportation remain major challenges at present. In this report, high-quality MK-exo are prepared on a large scale. We then developed a lyophilization method belonging to MK-exo, and performed acceleration and long-term stability experiments on the lyophilized MK-exo to evaluate the effect of lyophilization. The results showed that the lyophilized MK-exo can be stored at room temperature for at least 3 months and 2-8{degrees}C for 15 months. These findings provide data support for further understanding of the properties and applications of MK-exo.

bioengineering↗

bioRxiv2023

Mechanical Force Imprints Neutrophils to Orchestrate Pulmonary Homeostasis

Neutrophils are the most abundant immune cells that constantly patrol and marginate into the vascular beds of multiple tissues to support immune homeostasis. The extent to which neutrophils undergo adaptation in response to diverse tissue microenvironments, and the resultant biological implications of such adaptation, remains unclear. Here, we performed intravital imaging, transcriptional, and functional analyses of neutrophils in different tissues. Our findings showed that the lung harbors a transcriptionally distinct neutrophil population with unique migratory behaviors. These resident-like neutrophils guarantee a rapid response upon infection and play an important role in maintaining the homeostasis of pulmonary vasculature. Notably, pulmonary neutrophils are imprinted by mechanical cues via the mechanosensitive ion channel Piezo1. Mice with conditional Piezo1 ablation lost lung-specific neutrophil signatures, and showed impaired lung capillary angiogenesis. Furthermore, these mice displayed increased susceptibility to airway infection. Collectively, these data identify mechanical sensing via Piezo1 as an important driver for tissue-specialized neutrophils that support pulmonary homeostasis.

immunology↗

bioRxiv2023

Improving bioplastic production by Rhodopseudomonas palustris TIE-1 using synthetic biology and metabolic engineering

With the increasing demand for sustainably produced renewable resources, it is important to look towards microorganisms capable of producing bioproducts such as biofuels and bioplastics. Though many systems for bioproduct production are well documented and tested in model organisms, it is essential to look beyond to non-model organisms to expand the field and take advantage of metabolically versatile strains. This investigation centers on Rhodopseudomonas palustris TIE-1, a purple, non-sulfur autotrophic, and anaerobic bacterium capable of producing bioproducts that are comparable to their petroleum-based counterparts. To induce bioplastic overproduction, genes that might have a potential role in the PHB biosynthesis such as the regulator, phaR, and phaZ known for its ability to degrade PHB granules were deleted using markerless deletion. Mutants in pathways that might compete with polyhydroxybutyrate (PHB) production such as glycogen and nitrogen fixation previously created to increase n-butanol production by TIE-1 were also tested. In addition, a phage integration system was developed to insert RuBisCO (RuBisCO form I and II genes) driven by a constitutive promoter PaphII into TIE- 1 genome. Our results show that deletion of the phaR gene of the PHB pathway increases PHB productivity when TIE-1 was grown photoheterotrophically with butyrate and ammonium chloride (NH4Cl). Mutants unable to make glycogen or fix dinitrogen gas show an increase in PHB productivity under photoautotrophic growth conditions with hydrogen. In addition, the engineered TIE-1 overexpressing RuBisCO form I and form II produces significantly more polyhydroxybutyrate than the wild type under photoheterotrophy with butyrate and photoautotrophy with hydrogen. Inserting RuBisCO genes into TIE-1 genome is a more effective strategy than deleting competitive pathways to increase PHB production in TIE-1. The phage integration system developed for TIE-1 thus creates numerous opportunities for synthetic biology in TIE-1.

microbiology↗

bioRxiv2023

The novel roles of bovine milk-derived exosomes on skin anti-aging

Exosomes are small vesicles released from cells and present in various mammal biological fluids, such as bovine milk, which worked for skin care for many years besides dairy. In addition, Exosomes were regarded as a vehicle for intercellular communication. Therefore, we aimed to investigate the novel roles of bovine milk-derived exosomes (MK-Exo) on human skin anti-aging. Purified MK-Exo can be directly uptake by the keratinocytes and fibroblast in vitro and upregulate the expression of the natural factors related to skin moisturizing, including Filaggrin (FLG), Aquaporin 3 (AQP3), CD44 in the keratinocytes and hyaluronidase (HAS2) in the fibroblast, and MK-Exo promoted the cell migration of the fibroblast, while rescue its expression of type I collagen (Col I), type III collagen (Col III) after ultraviolet radiation. Furthermore, the phototoxicity test, photoallergy test, repeated skin irritation test, skin allergy test, and patch test confirm the safety of MK-Exo on the skin. Finally, the roles of MK-Exo in preserving moisture and anti-wrinkle were also identified in humans. Then, MK-Exo was smeared on the facial skin of 31 female volunteers twice a day for 28 days, and the functions were evaluated following the safety assessment in vivo. These studies reveal the novel roles of bovine milk-derived exosomes in human skin aging, which opens a new way of skin care.

cell biology↗

bioRxiv2023

Designed Transmembrane Proteins Inhibit the Erythropoietin Receptor in a Custom Binding Topology

Transmembrane (TM) domains as simple as a single span can perform complex biological functions using entirely lipid-embedded chemical features. Computational design has potential to generate custom tool molecules directly targeting membrane proteins at their functional TM regions. Thus far, designed TM domain-targeting agents have been limited to mimicking binding modes and motifs of natural TM interaction partners. Here, we demonstrate the design of de novo TM proteins targeting the erythropoietin receptor (EpoR) TM domain in a custom binding topology competitive with receptor homodimerization. The TM proteins expressed in mammalian cells complex with EpoR and inhibit erythropoietin-induced cell proliferation. In vitro, the synthetic TM domain complex outcompetes EpoR homodimerization. Structural characterization reveals that the complex involves the intended amino acids and agrees with our designed molecular model of antiparallel TM helices at 1:1 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom designed topologies.

bioengineering↗

bioRxiv2021

Genomic analyses of 10,376 individuals provides comprehensive map of genetic variations, structure and reference haplotypes for Chinese population

Here, we initiated the Westlake BioBank for Chinese (WBBC) pilot project with 4,535 whole-genome sequencing individuals and 5,481 high-density genotyping individuals. We identified 80.99 million SNPs and INDELs, of which 38.6% are novel. The genetic evidence of Chinese population structure supported the corresponding geographical boundaries of the Qinling-Huaihe Line and Nanling Mountains. The genetic architecture within North Han was more homogeneous than South Han, and the history of effective population size of Lingnan began to deviate from the other three regions from 6 thousand years ago. In addition, we identified a novel locus (SNX29) under selection pressure and confirmed several loci associated with alcohol metabolism and histocompatibility systems. We observed significant selection of genes on epidermal cell differentiation and skin development only in southern Chinese. Finally, we provided an online imputation server (https://wbbc.westlake.edu.cn/) which could result in higher imputation accuracy compared to the existing panels, especially for lower frequency variants.

genetics↗