Biology subjects

Liu, B.

Publications and source records attributed to Liu, B..

At least 127 records · Page 7Linked to original sources

bioRxiv2025

A piece of evidence for pathogenesis of cerebral small vessel disease caused by blood-brain barrier dysfunction

BackgroundBlood-brain barrier (BBB) dysfunction caused by endothelial cell injury is one of the widely accepted pathogenesis of small cerebral vessel disease (CSVD). However, the early microcirculation studies were notably deficient in providing compelling imaging evidence, which has hampered a comprehensive understanding of the pathophysiological processes underlying BBB dysfunction in CSVD. The onset of CSVD is insidious and the clinical manifestations are diverse, diagnosis of CSVD relies primarily on neuroimaging information currently. These MRI imaging features mainly represent the end-stage brain parenchyma injury, rather than the vascular lesion itself. Therefore, clarifying the pathophysiological processes related to cerebral microcirculation in CSVD is of great significance for early treatment intervention of CSVD. MethodsTwenty rats were used to prepare CSVD animal model by ultrasound combined with ultrasonic microbubble contrast agent. MRI, functional ultrasound (fUS) imaging and ultrasound localization microscopy (ULM) were used to evaluate microcirculation changes in acute and chronic models. ResultsCurrently, our research has successfully validated that the imaging characteristics of this model align with the four established criteria outlined in the STRIVE-2 classification. FUS shows increased microflow velocity in the molding area, which can be used for initial evaluation of CSVD models in the acute phase. ULM has revealed a progressive reduction in the density of both the short cortical arteries and the long medullary arteries, along with their respective branches, over time. Concurrently, there has been a noted deviation in blood flow velocity. ConclusionThis model offers compelling evidence at the microvascular level, suggesting that blood-brain barrier (BBB) dysfunction is a central pathophysiological mechanism in the etiology of CSVD. Then it provides a straightforward, efficient, and widely applicable tool and continuous monitoring method for the further investigation of CSVD from the macroscopic to the microscopic circulation level, with significant long-term implications for CSVD diagnosis and treatment.

neuroscience↗

bioRxiv2025

Concurrent selection of internal goals and external sensations during visual search

Flexible goal-directed behaviour relies on the selective processing of internal goal representations and external sensations. Yet, internal and external selection processes have classically been studied in isolation, leaving us in the dark how internal and external selection processes are coordinated in time to support behaviour. To address this, we developed a novel visual-search task in which we could simultaneously track selection among internal search goals held in working memory and external search targets in the environment. Capitalising on sensitive gaze and neural markers of internal and external visual selection, we provide proof-of-principle evidence in humans that internal and external selection processes do not necessarily take turns in a strictly serial manner, but can develop concurrently. We further show how concurrent internal and external selection processes are associated with largely non-overlapping neural activity patterns in the human brain, and how these processes can be performed effectively even when engaging opposite spatial locations in working memory and perception. These findings challenge views portraying brain states as being either internally or externally focused and bring new insight into how internal and external selection processes work together to yield efficient search behaviour.

neuroscience↗

bioRxiv2025

Title: Engineering Plasmids with Synthetic Origins of Replication

Plasmids remain by far the most common medium for delivering engineered DNA to microorganisms. However, the reliance on natural plasmid replication mechanisms limits their tunability, compatibility, and modularity. Here we refactor the natural pMB1 origin and create plasmids with customizable copy numbers by tuning refactored components. We then create compatible origins that use synthetic RNA regulators to implement independent copy control. We further demonstrate that the synthetic origin of replication (SynORI) can be engineered modularly to respond to various signals, allowing for multiplexed copy-based reporting of environmental signals. Lastly, a library of 6 orthogonal SynORI plasmids is created and co-maintained in E. coli for a week. This work establishes the feasibility of creating plasmids with SynORI that can serve as a new biotechnology for synthetic biology.

synthetic biology↗

bioRxiv2025

gcSV: a unified framework for comprehensive structural variant detection

The characterization of structural variants (SVs) is fundamental to genomic studies and advanced computational approaches are on demand to exert the ability of the ubiquitous high-throughput sequencing data. Herein, we propose gcSV, a read-length agnostic alignment-based approach to well-handle the issues of genome repeats, SV breakpoints and read alignments/assemblies for comprehensive, cost-effective and versatile SV calling. For long reads, its yield is 20-38% higher than state-of-the-art tools in HG002 benchmark. For hybrid sequencing, it provides a cost-effective solution (2-4x long plus 30-60x short reads) to achieve even higher yield than that of state-of-the-art tools using 30x long reads. For short reads, gcSV also achieves over 8% higher precision without any loss of sensitivity. Furthermore, gcSV confidently brings over 93,000 novel SVs comparing to the official callset of 1000 Genomes Project Phase4. The results suggest that gcSV is promising to make valuable SV discoveries in many cutting-edge studies.

bioinformatics↗

bioRxiv2025

Amyloid-β precursor protein promotes tumor growth by establishing an immune-exclusive tumor microenvironment

During initiation and progression, cancerous tissue hijacks a series of elaborate tissue homeostatic mechanisms to avoid immune surveillance, including neuro-immune interactions. Here, we show that amyloid-{beta} precursor protein (APP) and its {beta}-cleavage product amyloid-{beta}1-42 (A{beta}1-42), well-known in the pathogenesis of Alzheimers disease (AD), are expressed in multiple cancer tissues. However, the oncogenic activity of APP is due to its E1 domain, instead of A{beta}1-42. Mechanistically, APP restricts immune cells influx into tumor microenvironment (TME) and impairs CD8+ T cell and NK cell-based immunity, by dampening type I interferon (IFN) response in TME. We also provide proof-of-concept that vaccination targeting APP is effective for cancer prevention. Our current study reveals a previously unrecognized role of APP in cancer immune surveillance, and provides a new strategy for cancer prevention and treatment by targeting APP.

cancer biology↗

bioRxiv2025

B-cell-Specific Wwox Deletion Promotes Plasmablastic Tumor Development and Pro-Inflammatory Signatures in a Myeloma Mouse Model

Deletions and translocations affecting WWOX accompanied by loss of expression are frequently observed in B cell neoplasms and are linked to poor prognosis. Our previous research showed that Wwox deletion early in B cell development induces genomic instability, neoplastic transformation, and monoclonal gammopathies in mice. In this study, by crossing Cd19 Wwox knockout (KO) with Vk*MYC myeloma model mice, we generated a model with concurrent Wwox deletion and MYC activation, reproducing two common oncogenic alterations in B and plasma cell cancers. We observed that Vk*MYC:Wwox KO mice exhibited significantly reduced survival rates primarily due to the development of plasmablastic plasmacytomas and lymphomas. Transcriptome profiling from bone marrow derived Cd138+ plasma cells and plasmablastic tumors revealed enrichment of biofunctions related to tumorigenic phenotype and inflammation activation upon Wwox deletion in Vk*MYC mice. Wwox KO plasmablastic tumors displayed mutations affecting classical cancer genes, DNA damage response (DDR) genes, as well as overexpression of Aid/Apobec family members associated to hypermutation and DDR mutational signatures. These findings illustrate the significant pathobiological effects of B cell specific Wwox deletion and support a relevant role for WWOX loss of function in B cell neoplastic progression towards more aggressive phenotypes.

cancer biology↗

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2025

TransBrain: A computational framework for translating brain-wide phenotypes between humans and mice

Despite remarkable advances in whole-brain imaging technologies, the lack of quantitative approaches to bridge rodent preclinical and human studies remains a critical challenge. Here we present TransBrain, a computational framework enabling bidirectional translation of brain-wide phenotypes between humans and mice. TransBrain improves human-mouse homology mapping accuracy through: (1) a novel detached region-specific deep neural network trained on integrated multi-modal human transcriptomics to improve cortical correspondence (89.5% improvement over the original transcriptome), which revealed two evolutionarily conserved gradients explaining >50% of cortical organizational variance, and (2) random walk-based graph representation learning to construct a unified cross-species latent space incorporating anatomical hierarchies and structural connectivity. We demonstrated TransBrains utility through three cross-species applications: quantitative assessment of resting-state brain organizational features, inferring human cognitive functions from mouse optogenetic circuits, and translating molecular insights from mouse models to individual-level mechanisms in autism. TransBrain enables quantitative cross-species comparison and mechanistic investigation of both normal and pathological brain functions.

neuroscience↗

bioRxiv2025

Spacer Extension Reconciles Specificity and Activity in High-Fidelity Cas9 Genome Editing

AbstractEngineering high-fidelity CRISPR enzymes often leads to reduced cleavage activity, creating a significant hurdle in balancing nuclease specificity and efficiency for clinical applications. Here, we demonstrate that extending the spacer to 21 or 22 nucleotides restores the impaired cleavage activity of SuperFi-Cas9, an engineered high-fidelity Cas9 variant with seven mutations at the PAM-distal region. Structural and mutational analyses reveal that the spacer extension strengthens additional interactions at the PAM-distal end, stabilizing the nuclease- sgRNA-DNA complex, which appears to be disturbed due to the seven mutations. This approach not only provides a high-fidelity Cas9 with uncompromised efficiency but also introduces a novel strategy to enhance CRISPR complex stability. Our findings offer a promising avenue for precise and efficient genome editing, crucial for advancing CRISPR technologies toward clinical translation.

genomics↗

bioRxiv2024

Multiscale single-cell assessment of the fibrotic niche in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterised by excessive extracellular matrix deposition within the lung. Recent advances in single-cell RNA sequencing have identified distinct fibrotic populations, yet their origins and spatial relationships remain incompletely understood. MethodsUsing spatial transcriptomics and Hyperion imaging mass cytometry we compared the cellular composition in formalin fixed paraffin embedded fibrotic lesions (n=9 patients) with control lung (n=9), and cellular interactions were inferred using CellChat V2 ligand-receptor analysis. Monolayers of airway epithelial cells were used to identify changes in keratin (KRT) expression following cell detachment and cyclical mechanical stretch. ResultsSpatial multiomics profiling of human lung cells confirmed the in situ localisation of previously described IPF-enriched populations, and identified a previously unrecognized KRT5low/KRT17 epithelial population derived from airway basal cells that progressively acquiring molecular features of aberrant basaloid cells, forming a unique fibrotic niche enriched with the Secreted Phosphoprotein 1 (SPP1) positive macrophages. Functional studies demonstrated that epithelial detachment and cyclical mechanical stretch drive KRT5 reduction, providing a mechanism for the emergence of this transitional state. In addition, we also identified distinct immune-stromal niches enriched in lymphocytes and alveolar fibroblasts. ConclusionThese findings delineate distinct fibrotic epithelial niches in IPF and support a model in which epithelial loss induces aberrant basaloid differentiation and fibroblast activation, with subsequent airway traction and epithelial detachment generating a secondary niche enriched in basal-derived KRT5low/KRT17 cells and SPP1 macrophages.

molecular biology↗

bioRxiv2024

Structural and functional interrelationship of histone H2A and its variants H2A.Z and H2A.W in Arabidopsis

Multiple histone H2A variants are known in eukaryotes. However, the functional relationship between H2A and its variants in plants remains largely obscure. Using CRISPR/Cas9 editing, we generated a mutant lacking four H2A isoforms in Arabidopsis and analyzed the functional and structural relationship between H2A and its variants H2A.Z and H2A.W. RNA-sequencing and phenotype analyses revealed mild changes in gene transcription and plant development in the mutants lacking H2A, H2A.Z, or H2A.W compared with the wild-type plants. Chromatin immunoprecipitation sequencing analysis showed that H2A is able to substitute for both H2A.Z and H2A.W across the genome, including in euchromatin and heterochromatin regions. However, H2A.Z replaced both H2A and H2A.W primarily within the euchromatin regions. By using DNA and histones derived from Arabidopsis, we constructed nucleosomes containing H2A, H2A.Z, or H2A.W and resolved their cryogenic electron microscopy structures at near-atomic resolution. Collectively, the results reveal the structural similarity and functional redundancy of H2A and H2A variants in Arabidopsis.

plant biology↗

bioRxiv2024

Dynamic interplay between RNA N6-methyladenosine modification and porcine reproductive and respiratory syndrome virus infection

N6-methyladenosine (m6A) has attracted significant attention for its role in various biological processes, including RNA stability, translation, and the immune response. Understanding the role of m6A in viral infections is crucial to deep the complex interaction between virus and host cells. Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a significant pathogen affecting swine health worldwide. Here, we firstly identified the m6A peaks in the PRRSV genome by m6A RNA immunoprecipitation sequencing (m6A-seq). Seven m6A-enriched regions within the PRRSV genome were detected, with one located in the N protein-coding region and the others distributed across nonstructural protein-coding regions. Notably, the Nsp2-coding region contained the highest m6A peak, spanning approximately 178 nucleotides. Functional analyses demonstrated a positive correlation between m6A modification levels and PRRSV replication in porcine alveolar macrophages (PAMs), as modulating the expression of m6A methyltransferases and demethylases significantly influenced viral replication. Moreover, treatment with the universal methylation inhibitor 3-deazaadenosine (3-DAA) effectively suppressed PRRSV replication, suggesting its potential as a novel anti-PRRSV therapeutic. To further elucidate the role of m6A in PRRSV infection, we analyzed the m6A landscape in PAMs infected with pandemic and highly pathogenic PRRSV strains. Among the 4,677 transcripts exhibiting altered m6A modification levels, the MAPK14 gene as well as other genes in p38/MAPK signaling pathway potentially emerged as the preliminary targets of m6A-mediated epigenetic regulation during PRRSV infection. These findings provide new insights into the epigenetic mechanisms underlying PRRSV infection and may facilitate the development of targeted anti-PRRSV strategies and therapeutics. IMPORTANCEThe involvement of m6A in viral genome has broader implications for our understanding of virus evolution and pathogenicity. The ability of viruses to adapt to their hosts and exploit host cellular mechanisms is a critical factor in their success as pathogens. As m6A is a modification that can be manipulated by both host and virus, studying its role in viral infections may reveal new insights into viral evolution. Understanding how different viruses utilize m6A could inform strategies for developing antiviral therapies that target these interactions. Such therapies could disrupt the ability of viruses to exploit m6A modifications, potentially reducing their virulence and enhancing host defenses.

microbiology↗

bioRxiv2024

Design of high specificity binders for peptide-MHC-I complexes

Class I MHC molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance, and specific targeting of these peptide-MHC (pMHC) complexes could have considerable utility for treating diseases. Such targeting is challenging as it requires readout of the few outward facing peptide antigen residues and the avoidance of extensive contacts with the MHC carrier which is present on almost all cells. Here we describe the use of deep learning-based protein design tools to de novo design small proteins that arc above the peptide binding groove of pMHC complexes and make extensive contacts with the peptide. We identify specific binders for ten target pMHCs which when displayed on yeast bind the on-target pMHC tetramer but not closely related peptides. For five targets, incorporation of designs into chimeric antigen receptors leads to T-cell activation by the cognate pMHC complexes well above the background from complexes with peptides derived from proteome. Our approach can generate high specificity binders starting from either experimental or predicted structures of the target pMHC complexes, and should be widely useful for both protein and cell based pMHC targeting.

immunology↗

bioRxiv2024

Discovery of alternative stable states in a synthetic human gut microbial community

AbstractSeveral human-associated microbial communities exist in multiple configurations and can change their composition in response to perturbations, remaining in an altered state even after the perturbation ends. Multistability has been previously proposed to explain this behavior for gut microbiota in particular, but has not been clearly demonstrated experimentally. Here, we first investigated the life history strategies of three common human gut bacteria to identify mechanisms driving alternative states. We then used this data to build and parameterize a kinetic model, which predicted that alternative states emerge due to phenotype switching between subpopulations of the same species. Perturbation experiments supported these predictions, and confirmed the existence of alternative states. Finally, simulations showed that phenotype switching can also explain alternative states in larger communities. Thus, a transient perturbation combined with metabolic flexibility is sufficient for alternative communities to emerge, implying that they are not necessarily explained by differences between individuals. One-Sentence SummaryWe demonstrate the existence of alternative states in a human gut microbial community and propose phenotype switching as a mechanism explaining their emergence.

microbiology↗

bioRxiv2024

CD40 ligation-induced ERK activation promotes autophagy which leads to enhanced radiosensitivity in cervical carcinoma cells

CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, plays an important role not only in the immune system, but also in tumor progression. CD40 ligation reportedly promotes autophagy in immune cells. However, the effects of CD40 ligation on autophagy and its mechanism in solid tumor cells are still unclear. In this study, we find that CD40 ligation promotes autophagosome formation, and consequently promotes autophagic flux in cervical cancer cells. Mechanically, this effect relies on that ERK contributes to CD40 ligation-induced ATG13 upregulation by p53. Furthermore, we demonstrates that CD40 ligation-induced autophagy increases the radiosensitivity of cervical cancer cells. Taken together, our results provide new evidence for involvement of the CD40 pathway in autophagy and radiotherapy in cervical cancer cells.

cell biology↗

bioRxiv2024

scPrediXcan integrates advances in deep learning and single-cell data into a powerful cell-type-specific transcriptome-wide association study framework

Transcriptome-wide association studies (TWAS) help identify disease causing genes, but often fail to pinpoint disease mechanisms at the cellular level because of the limited sample sizes and sparsity of cell-type-specific expression data. Here we propose scPrediXcan which integrates state-of-the-art deep learning approaches that predict epigenetic features from DNA sequences with the canonical TWAS framework. Our prediction approach, ctPred, predicts cell-type-specific expression with high accuracy and captures complex gene regulatory grammar that linear models overlook. Applied to type 2 diabetes and systemic lupus erythematosus, scPrediXcan outperformed the canonical TWAS framework by identifying more candidate causal genes, explaining more genome-wide association studies (GWAS) loci, and providing insights into the cellular specificity of TWAS hits. Overall, our results demonstrate that scPrediXcan represents a significant advance, promising to deepen our understanding of the cellular mechanisms underlying complex diseases.

genetics↗

bioRxiv2024

Older is Order: Entropy reduction in cortical spontaneous activity marks healthy aging

Entropy trajectories remain unclear for the aging process of human brain system due to the lacking of longitudinal neuroimaging resource. We used open data from an accelerated longitudinal cohort (PREVENT-AD) that included 24 healthy aging participants followed by 4 years with 5 visits per participant to establish cortical entropy aging curves and distinguish with the effects of age and cohort. This reveals that global cortical entropy decreased with aging, while a significant cohort effect was detectable that people who were born earlier showed higher cortical entropy. Such entropy reductions were also evident for large-scale cortical networks, although with different rates of reduction for different networks. Specifically, the primary and intermediate networks reduce their entropy faster than the higher-order association networks. We conclude two specific characteristics of the entropy of the human cortex with aging: the shift of the complexity hierarchy and the diversity of complexity strengthen.

neuroscience↗

bioRxiv2024

Blocking SHP2 benefits FGFR2 inhibitor and overcomes its resistance in FGFR2-amplified gastric cancer

Fibroblast growth factor receptor 2 (FGFR2) is an important member of receptor tyrosine kinase (RTK) family. FGFR2 amplification occurs at a high frequency in gastric cancer (GC) and has been proven to be closely associated with poor prognosis and insensitivity to chemotherapy or immunotherapy. Current FGFR2-targeted therapies have limited efficacy. Hence, how to enhance efficacy and reverse resistance are urgent problems clinically. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) serves as the shared downstream mediator of all RTKs and a prominence immunosuppressive molecule. In this study, we identified FGFR2 amplification in 6.2% (10/161) of GC samples in our center. Then we showed that dual blocking SHP2 and FGFR2 enhanced the effects of FGFR2 inhibitor (FGFR2i) in FGFR2-amplified GC both in vitro and in vivo via suppressing RAS/ERK and PI3K/AKT pathways. We further showed that it overcame FGFR2i resistance by reversing the feedback activation mediated by other RTKs and continuously suppressing FGFR2-initiated downstream pathways. Notably, SHP2 blockade could suppress PD-1 expression and promoted IFN-{gamma} secretion of CD8+ T cells, enhancing the cytotoxic functions of T cells in tumor immune microenvironment. Overall, our findings suggest that dual blocking SHP2 and FGFR2 is a compelling rationale with both targeted treatment and immune regulation for FGFR2-amplified GC. Impact statementDual blocking SHP2 and FGFR2 can not only promote the targeted tumor-killing effects and overcome FGFR2 inhibitor resistance caused by feedback activation, but also activate T cell-mediated anti-tumor immunity by inhibiting PD-1 pathway in FGFR2-amplified GC. Funding informationThis work was funded by Grants from National Natural Science Foundation of China (82403862, 82403835), Jiangsu Provincial Natural Science Foundation Youth Project (BK20230151, BK20240247), Jiangsu Provincial Major Science and Technology Program (BG2024026), the Wu Jieping Medical Foundation Special Fund for Targeted Cancer Therapy (Youth Research Project) (320.6750.2023-11-30), Jiangsu Provincial Youth Science and Technology Talent Support Project (JSTJ-2025-715) and General Project of Nanjing Health Science and Technology Development Program (YKK24084).

cancer biology↗