Biology subjects

Jiang, Y.

Publications and source records attributed to Jiang, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

A Priming Circuit Controls the Olfactory Response and Memory in Drosophila

Priming is a process by which exposure to a stimulus affects the response to a subsequent stimulus in humans. In this study we found that in Drosophila, a prior encounter with an aversive stimulus results in enhanced preference for a following novel odor, while an appetitive stimulus leads to reduced preference for a new odor. This priming behavior of flies relies on the well-studied olfactory memory circuits including Kenyon cells (KC), dopaminergic neurons (DANs), and mushroom body output neurons (MBONs). Aversive stimulus results in increased odor responses in reward DANs that innervate the {gamma}4 lobe of the mushroom body (MB) and decreased odor responses in a {gamma}4{gamma}5-innvervating repulsive MBON. We concluded that these neurons are required for the priming effects in flies. These results characterized the newly found priming behavior in flies and demonstrated the sheer influence of unconditioned stimulus on odor perception during associative learning.

neuroscience↗

bioRxiv2025

Bacillus velezensis 9912 enhances rice growth by triggering plant hormone modulation and complex miRNA-mRNA regulatory networks

Bacillus velezensis, a prominent member of plant growth-promoting bacteria, effectively suppresses pathogens and promotes plant growth. Despite its well-recognized efficacy, the intricate molecular mechanisms of its growth-promoting attributes remain largely unexplored. In this study, a commercial biopesticide B. velezensis 9912 significantly enhanced leaf photosynthesis and improved rice root development in the field experiment. And then, a rigorous hydroponic experiment was performed to investigate its underlying mechanism in plant growth promotion. High-throughput sequencing and bioinformatics analysis revealed 2,938 rice genes and 30 miRNAs responsive to strain 9912. Notably, differentially expressed genes encompassed key transcription factors like ERF, WRKY, and AP2. Remarkably, auxin-and ethylene-related genes were up-regulation significantly at day 1 and pectinesterase-related genes were up-regulation considerably at day 3, which revealed an unusual growth mechanism for strain 9912 to promote rice root development. In addition, DNA replication, cell cycle, cell division, and cytoskeleton organization were significantly enriched in GO and KEGG pathways. Biosynthetic pathways of secondary metabolites, such as carotenoid, lipid, diterpenoid, and brassinosteroid were also significantly enriched. An integrated analysis of the transcriptome and miRNAome identified several miRNA-mRNA regulatory networks, including miR166-Os08g14940, miR396-Os07g9320, miR529-Os12g31540, and miR6249-Os05g07880, which are involved in the process of growth promotion. In conclusion, our investigation offers insightful thoughts into the dynamic responses of rice genes and miRNAs to B. velezensis 9912, unveiling plant hormone modulation and potential miRNA-mRNA regulatory networks that are imperative in the growth promotion mechanism.

microbiology↗

bioRxiv2025

Berberrubine Inhibits Helicobacter pylori by Inducing Oxidative Stress

Helicobacter pylori is a prevalent pathogen that colonizes the pylorus and contributes to the pathogenesis of gastric cancer. The increasing antibiotic resistance in H. pylori presents a substantial challenge for effective eradication, making the development of more effective therapeutic strategies imperative. In this study, we screened 37 pure compounds (purity >95%), 3 ethanol extracts, and 6 aqueous extracts from 6 different medicinal herbs for their potential inhibitory effects against H. pylori in vitro. Among the tested compounds, 15 exhibited inhibitory activity, with berberrubine demonstrating the strongest effect, characterized by a minimum inhibitory concentration (MIC) of 0.011 mg/ml. The comparative transcriptome analysis revealed a significant upregulation of the oxidative stress response related genes, such as fumC and sodB, in H. pylori treated with berberrubine. Further in vitro assays confirmed that berberrubine exerted antibacterial activity by stimulating oxidative stress, as evidenced by increased reactive oxygen species (ROS) production and impaired cell membrane integrity. Additionally, similar inhibitory tests were applied to Escherichia coli, a common gut opportunistic pathogen. The results showed that berberrubine inhibited E. coli through the same mechanism observed for H. pylori. In conclusion, berberrubine is a potent antibacterial agent against gastrointestinal pathogens, including H. pylori and E. coli, making it a promising candidate for further development as an antimicrobial therapeutic ImportanceThis study identified berberrubine as a potent antibacterial agent against gastrointestinal pathogens, including Helicobacter pylori and Escherichia coli by inducing cellular oxidative stress. Through increased reactive oxygen species (ROS) production and disruption of bacterial cell membrane integrity, berberrubine demonstrated strong efficacy in inhibiting drug-resistant pathogens. These findings highlight its potential as a promising therapeutic candidate for eradicating drug-resistant gastrointestinal pathogens.

microbiology↗

bioRxiv2025

Context-Dependent and Gene-Specific Role of Chromatin Architecture Mediated by Histone Modifiers and Loop-extrusion Machinery

Loop-extrusion machinery, comprising the cohesin complex and CCCTC-binding factor CTCF, organizes the interphase chromosomes into topologically associating domains (TADs) and loops, but acute depletion of components of this machinery results in variable transcriptional changes in different cell types, highlighting the complex relationship between chromatin organization and gene regulation. Here, we systematically investigated the role of 3D genome architecture in gene regulation in mouse embryonic stem cells under various perturbation conditions. We found that acute depletion of cohesin or CTCF disrupts the formation of TADs, but affects gene regulation in a gene-specific and context-dependent manner. Furthermore, the loop extrusion machinery was dispensable for transcription from most genes in steady state, consistent with prior results, but became critical for a large number of genes during transition of cellular states. Through a genome-wide CRISPR screen, we uncovered multiple factors that can modulate the role of loop extrusion machinery in gene regulation in a gene-specific manner. Among them were the MORF acetyltransferase complex members (Kat6b, Ing5, Brpf1), which could antagonize the transcriptional insulation mediated by CTCF and cohesin complex at developmental genes. Interestingly, inhibition of Kat6b partially rescues the insulator defects in cells lacking the cohesin loader Nipbl, mutations of which are responsible for the developmental disorder Cornelia de Lange syndrome. Taken together, our findings uncovered interplays between the loop extrusion machinery and histone modifying complex that underscore the context-dependent and gene-specific role of the 3D genome.

genomics↗

bioRxiv2025

ZEB2 signaling is essential for ureteral smooth muscle cell differentiation and maintenance

Mowat-Wilson Syndrome (MWS) is a multiple congenital anomaly syndrome caused by mutations in the ZEB2, which plays a critical role in cell fate determination and differentiation during development. Congenital anomalies of the kidney and urinary tract (CAKUT) have been reported in MWS patients. However, the role of ZEB2 in urinary tract development and the cellular and molecular mechanism underlining the CAKUT phenotypes in MWS remains unknown. We performed ZEB2 protein expression analysis in the developing mouse ureter. We generated Zeb2 ureteral mesenchyme-specific conditional knockout mice by crossing Zeb2 floxed mice with Tbx18Cre mice (Zeb2 cKO) and analyzed the urinary tract phenotypes in Zeb2 cKO mice and wild-type littermate controls by gross and histological examination. Ureteral cellular and molecular phenotypes were studied using TAGLN, ACTA2, FOXD1, POSTN, CDH1, TBX18, and SOX9 ureteral cell-specific markers. We found that ZEB2 is expressed in TBX18+ ureteral mesenchymal cells during mouse ureter development. Deletion of Zeb2 in developing ureteral mesenchymal cells causes hydroureter and hydronephrosis phenotypes, leading to obstructive uropathy, kidney failure, and early mortality. Cellular and molecular marker analyses showed that the TAGLN+ACTA2+ ureteral smooth muscle cells (SMCs) layer is not formed in Zeb2 cKO mice at E15.5, but the FOXD1+ and POSTN+ tunica adventitia cells layer is significantly expanded compared to wild-type controls. CDH1+ urothelium cells are reduced considerably in the Zeb2 cKO ureters at E15.5. Mechanistically, we found that Zeb2 cKO mice have significantly decreased TBX18 expression but an increased SOX9 expression in the developing ureter at E14.5 and E15.5 compared to wild-type littermate controls. Our results show that ZEB2 is essential for ureter development by maintaining ureteral mesenchymal cell differentiation into normal ureteral SMCs. Our study also shed new light on the pathological mechanism underlying the developmental abnormalities of the urinary tract phenotypes in MWS patients. Author SummaryHydroureter and hydronephrosis are common congenital anomalies with high incidence (1:100 to 1:500) that can lead to obstructive uropathy and renal failure in the pediatric population. Mowat-Wilson Syndrome (MWS), caused by heterozygous mutations in the ZEB2 gene, is a genetic disease with multiple congenital developmental defects, including hydroureter and hydronephrosis. However, the molecular function of ZEB2 in ureter development and pathogenesis of hydroureter and hydronephrosis remains unknown. Here, we show that ZEB2 is expressed in the developing ureteral mesenchymal cells, and deletion of ZEB2 in ureteral mesenchymal cells leads to ureteral smooth muscle cell loss, which is replaced by tunica adventitia cells causing hydroureter and hydronephrosis phenotype. Hence, our work not only demonstrates the critical role of ZEB2 in ureter development but also provides molecular mechanisms of urinary tract anomalies in MWS patients.

developmental biology↗

bioRxiv2025

NtLLG4-mediated unconventional polar exocytosis of NtPPME1 coordinates cell wall rigidity and membrane dynamics to control pollen tube integrity

Plant fertilization relies on controlled pollen tube growth that integrates membrane dynamics and cell wall expansion. We previously identified an unconventional exocytic pathway wherein Golgi-derived secretory vesicles (GDSVs) bypass the trans-Golgi network to deliver Nicotiana tabacum pectin methylesterase 1 (NtPPME1), thereby modulating cell wall rigidity. However, the mechanisms linking this patwhay with membrane dynamics and signaling remain elusive. Here, we used cryo-FIB-SEM and 3D tomography to identified GDSVs as a distinct vesicle population at the pollen tube tip. We further demonstrated that tobacco LORELEI-like-GPI-anchored protein 4 (NtLLG4), a key signaling molecule controlling membrane dynamics and integrity, functions as a receptor for NtPPME1, regulating its polar exocytosis via GDSVs to control cell wall stiffness. Furthermore, we identified trafficking signals which direct the unconventional exocytosis of NtPPME1 across intracellular organelles. Our findings reveal a crucial mechanism coupling cell wall rigidity with membrane signaling to control pollen tube growth and integrity during fertilization. TeaserWe reveal a mechanism coupling cell wall rigidity with member signaling to control pollen tube growth and integrity during plant fertilization.

plant biology↗

bioRxiv2025

Genome-wide mapping of 5'-aldehyde terminus induced by reactive oxygen species

DNA single strand breaks (SSBs) are abundant lesions due to cell metabolism and reactive oxygen species (ROS) and can lead to replication folk collapse, double strand break formation, genome rearrangements, cell death and disease. Among numerous chemical forms of SSBs, 5'-aldehyde terminus are the most abundant generated by hydroxyl radicals and pose significant challenge for cellular repair machinery due to the lack of specific end processing process, potentially leading to more severe biological consequences than other readily repairable SSBs. Herein we developed a new strategy to locate 5'-aldehyde terminus in genomic DNA at single-nucleotide resolution. The principle involves labelling the 5'-aldehyde terminus with an aminooxy-functionalized oligonucleotide, giving rise to a biocompatible altered DNA linkage and allowing labelled sites to be amplified by polymerase chain reaction. We sequenced the 5'-aldehyde terminus distribution in genomic DNA, nuclei, and cells following activation of the Fenton reaction. The results revealed a significant preference for adenine bases in DNA lesions and provided insights into the genome-wide distribution of such DNA damage, correlating with genomic features and chromatin accessibility. This method provide a new strategy for studies aiming to understand the biological and toxicological impacts of 5'-aldehyde termini in DNA as the form species of single strand break induced by reactive oxygen species from a human genome.

genomics↗

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↗

bioRxiv2025

Immunogenic Cell Death: the Key to Unlocking the Potential for Combined Radiation and Immunotherapy

Immunogenic cell death (ICD) enhances anti-tumor immunity by releasing tumor-associated antigens and activating the anti-tumor immune system response. However, its potential remains understudied in combination therapies. Here, we develop a mathematical model to quantify the role of ICD in optimizing the efficacy of combined radiotherapy (RT) and macrophage-based immunotherapy. Using preclinical murine data targeting the SIRP-CD47 checkpoint, we show that RT alone induces minimal ICD, whereas disrupting the SIRP-CD47 axis significantly enhances both phagocytosis and systemic immune activation. Our model predicts an optimal RT dose (6-8 Gy) for maximizing ICD, a dose-dependent abscopal effect, and a hierarchy of treatment efficacy, with SIRP-knockout macrophages exhibiting the strongest tumoricidal activity. These findings provide a quantitative framework for designing more effective combination therapies, leveraging ICD to enhance immune checkpoint inhibition and radiotherapy synergy.

cancer biology↗

bioRxiv2025

Phosphoproteomics Uncovers Tumor Heterogeneity and Therapeutic Opportunities in Early-Stage Hepatocellular Carcinoma

Mechanisms driving progression and metastasis in early-stage hepatocellular carcinoma (HCC) remain poorly clarified. Although phosphoproteomics has been applied to broader HCC cohorts, the heterogeneity of phosphorylation signaling in early-stage HCC remains unexplored. Here, we conducted integrated phosphoproteomic and proteomic analysis on early-stage HCC tumors and paired non-tumor tissues. By comparing tumor and non-tumor tissues, we identified markedly reduced phosphorylation of EGFR-mediated canonical ERK/MAPK signaling, alongside elevated atypical MAPK signaling in HCC. To further explore the signaling heterogeneity within tumors, we applied nonnegative matrix factorization (NMF) and consensus-clustering, and identified three distinct phosphoproteomic subtypes with unique phosphorylation signatures and clinical characteristics. Interrogating the most malignant subtype, we found markedly high abundance of phosphorylation of mRNA splicing regulators, and an enrichment of epithelial-mesenchymal transition (EMT) pathways in the proteome, with phosphorylation of the splicing factor SRSF3 emerging as a critical feature. Mechanistically, we show that SRSF3 hyperphosphorylation, driven by SRPK1/CLKs and potential PP1 phosphatase suppression, promotes metastasis and proliferation. Critically, SRPK1/CLKs inhibitors effectively suppressed SRSF3 hyperphosphorylation-mediated migration and invasion of HCC cells. Our study uncovers a new dimension of signaling-driven tumor heterogeneity in early-stage HCC and identifies the SRPK1/CLKs-SRSF3 hyperphosphorylation axis as a key metastatic driver, suggesting a potential therapeutic target for early intervention in HCC.

cancer biology↗

bioRxiv2025

EndoMAPV1, a Structural Protein Complex Landscape of Human Endosomes

Early/sorting endosomes are dynamic organelles that play key roles in proteome control by triaging plasma membrane proteins for either recycling or degradation in the lysosome1,2,3. These events are coordinated by numerous transiently-associated regulatory complexes and integral membrane components that contribute to organelle identity during endosome maturation4. While a subset of the several hundred protein components and cargoes known to associate with endosomes have been studied at the biochemical and/or structural level, interaction partners and higher order molecular assemblies for many endosomal components remain unknown. Here, we combine cross-linking and native gel mass spectrometry5-8 of purified early endosomes with AlphaFold9,10 and computational analysis to create a systematic human endosomal structural interactome. We present dozens of structural models for endosomal protein pairs and higher order assemblies supported by experimental cross-links from their native subcellular context, suggesting structural mechanisms for previously reported regulatory processes. Using induced neurons, we validate two candidate complexes whose interactions are supported by crosslinks and structural predictions: TMEM230 as a subunit of ATP8/11 lipid flippases11 and TMEM9/9B as subunits of CLCN3/4/5 chloride-proton antiporters12. This resource and its accompanying structural network viewer provide an experimental framework for understanding organellar structural interactomes and large-scale validation of structural predictions.

cell biology↗

bioRxiv2025

Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions

HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map the transcriptomic and epigenetic landscapes of postmortem human brains from 13 healthy individuals and 20 individuals with HIV who have a history of treatment with ART. Our study spanned three distinct regions--the prefrontal cortex, insular cortex, and ventral striatum--enabling a comprehensive exploration of region-specific and cross-regional perturbations. We found widespread and persistent HIV-associated transcriptional and epigenetic alterations across multiple cell types. Detailed analyses of microglia revealed state changes marked by immune activation and metabolic dysregulation, while integrative multiomic profiling of astrocytes identified multiple subpopulations, including a reactive subpopulation unique to HIV-infected brains. These findings suggest that cells from people with HIV exhibit molecular shifts that may underlie ongoing neuroinflammation and CNS dysfunction. Furthermore, cell-cell communication analyses uncovered dysregulated and pro-inflammatory interactions among glial populations, underscoring the multifaceted and enduring impact of HIV on the brain milieu. Collectively, our comprehensive atlas of HIV-associated brain changes reveals distinct glial cell states with signatures of pro-inflammatory signaling and metabolic dysregulation, providing a framework for developing targeted therapies for HIV-associated neurological dysfunction.

bioinformatics↗

bioRxiv2025

IQI: Individualized Quantitative trait loci (QTL) Index

There is currently no standard efficient method to precisely detecting and characterizing the difference of quantitative trait loci (QTL) effect among groups and/or populations at individual level. The main reason is that the traditional global regression based QTL analyses can only derive an overall effect of genetic variants on the quantitative trait in a specific group. It is a big challenge to obtain the individual-level QTL effect, which is necessary for accurate testing and precise characterization. Here, we first proposed an individualized QTL index (IQI) that represents the degree of regulation between genetic variants and the trait for each individual. Based on IQI, Differential QTL (DQ) analysis framework was presented to accurately detect the case-control differences in more detail. In addition, IQI can be a new feature/biomarker applied to various accurate bioinformatics analysis, such as differential analysis, disease prediction, and survival analysis. Overall, IQI affords a new perspective on pathogenic mechanisms and will facilitate the study of genetic regulation more detailedly and precisely.

bioinformatics↗

bioRxiv2025

Collective biosynthesis of plant spirooxindole alkaloids through enzyme discovery and engineering

Collective synthesis is a well-established strategy to produce natural product collections from common intermediates. Extending this concept to enzymatic systems, collective biosynthesis offers a sustainable approach to diverse molecular collections but faces distinct challenges, including incomplete pathway knowledge and narrow substrate specificity of biosynthetic enzymes. Here, we overcome these limitations through enzyme discovery and protein engineering to achieve collective biosynthesis of spirooxindole alkaloids, an important class of natural products with diverse biological activities. We identified two key enzymes that catalyze enzymatic epimerization, working sequentially with a previously discovered cytochrome P450 enzyme to fully elucidate the biosynthetic pathway of pentacyclic spirooxindole alkaloids. Structure-guided engineering expanded substrate scope, enabling collective biosynthesis of 12 tetracyclic and pentacyclic spirooxindole natural products. We also generated new-to-nature fluorinated and deuterated derivatives through precursor-directed biosynthesis. This work provides crucial insights into plant spirooxindole alkaloid biosynthesis while establishing a powerful approach for sustainable production of complex natural products.

biochemistry↗

bioRxiv2025

Loss of signaling fidelity between astrocyte endfeet and adjacent cerebral arterioles in an amyloid mouse model of Alzheimer's disease

While cerebrovascular dysfunction and reactive astrocytosis are extensively characterized hallmarks of Alzheimers disease (AD) and related dementias, the dynamic relationship between reactive astrocytes and cerebral vessels remains poorly understood. Here, we used jGCaMP8f and two photon microscopy to investigate Ca2+ signaling in multiple astrocyte subcompartments, concurrent with changes in cerebral arteriole activity, in fully awake eight-month-old male and female 5xFAD mice, a model for AD-like pathology, and wild-type (WT) littermates. In the absence of movement, spontaneous Ca2+ transients in barrel cortex occurred more frequently in astrocyte somata, processes, and perivascular regions of 5xFAD mice. However, evoked arteriole dilations (in response to air puff stimulation of contralateral whiskers) and concurrent Ca2+ transients across astrocyte compartments were reduced in 5xFAD mice relative to WTs. Synchronous activity within multi-cell astrocyte networks was also impaired in the 5xFAD group. Using a custom application to assess functional coupling between astrocyte endfeet and immediately adjacent arteriole segments, we detected deficits in Ca2+ response probability in 5xFAD mice. Moreover, endfeet Ca2+ transients following arteriole dilations exhibited a slower onset, reduced amplitude, and lacked relative proportionality to vasomotive activity compared to WTs. The results reveal nuanced alterations in 5xFAD reactive astrocytes highlighted by impaired signaling fidelity between astrocyte endfeet and cerebral arterioles. The results have important implications for the mechanistic underpinnings of brain hypometabolism and the disruption of neurophysiological communication found in AD and other neurodegenerative conditions. Significance StatementAstrocytes are an essential component of the neurovascular unit. Chronically reactive astrocyte phenotypes are mechanistically linked to deleterious features of Alzheimers disease (AD) including impaired cerebral blood flow, hypometabolism, and synapse dysfunction/loss. Here, we show that reactive astrocytes in a fully awake mouse model of AD-like amyloid pathology are spontaneously hyperactive, exhibit impaired functional connectivity, and respond to dilations in immediately adjacent arterioles with poor fidelity. The results reveal a key point of communication breakdown between the brain and the cerebrovasculature.

neuroscience↗

bioRxiv2025

Elucidation of the biosynthetic pathway of reserpine

Reserpine is a landmark natural product that has profoundly influenced our understanding of neurotransmitter biology and cardiovascular medicine. Its complex structure, featuring a unique C3 {beta}-configuration and five consecutive chiral centers, has inspired generations of synthetic chemists to develop innovative strategies for its construction. However, the biosynthetic logic underlying natures assembly of this intricate molecule has remained elusive. Here, we decipher the biosynthetic pathway of reserpine in Rauvolfia verticillata, revealing that -configured strictosidine serves as the biosynthetic precursor. The crucial C3 {beta}-configuration is established through a two-step enzymatic epimerization, orchestrated by a flavin-dependent oxidase and a NADPH-dependent reductase. The consecutive chiral centers are constructed through coordinated action of distinct enzyme families. Through the identification of eight biosynthetic enzymes, including those catalyzing late-stage methoxylation, we successfully reconstituted the biosynthesis of rauvomitorine G, a key intermediate in reserpine formation. This work unveils natures elegant approach to stereoselective synthesis of complex alkaloids and provides valuable biocatalytic tools for molecular functionalization.

biochemistry↗

bioRxiv2025

Immunogenomic profiling of circulating T cells in pediatric cancer patients during standard-of-care

While pediatric cancer patients receive intensive chemotherapy, its impact on peripheral T cells and subsequently to disease outcomes are not fully characterized. Here, we assessed T-cell dynamics during treatment, identifying associations with outcomes through immune phenotyping and T-cell Receptor (TCR) sequencing in pediatric solid and hematologic malignancies. We show that while levels of immune checkpoint proteins (PD-1, LAG3, and TIM3) at baseline were highest in lymphomas compared to other cancer groups, they increased significantly in response to therapy in all cancers. Levels of Central Memory (CM) T cells increased in leukemias and solid tumors, while naive T cells and cell-free TCR diversity decreased in lymphomas. By combining immune cell and TCR repertoire features across all timepoints, we proposed the Dynamic Immunogenomic Score (DIS) to measure patient-specific effects of therapy on the peripheral T-cell population. Higher DIS was associated with high-risk cancer types and logistic regression analysis revealed it may predict incidence of relapse in leukemia patients. TCR specificity analysis revealed patient-specific clonal dynamics and differential detection of virally-associated TCRs in cancer patients compared to healthy individuals. Our results highlight the potential of early upfront immunogenomic profiling in identifying high-risk patients that may be predictive in light of emerging cellular immunotherapies.

cancer biology↗

bioRxiv2025

Modeling mucociliary mixing and transport at tissue scale

Mucociliary clearance is the primary defense mechanism in our respiratory system against aerosol pathogens and allergens. The rhythmic movement of cilia on airway-lining cells propels mucus flow, driving the movement of trapped particles. We want harmful particles, e.g., pathogens and allergens to be transported rapidly out of the airway and beneficial particles, e.g. vaccines and medicine, to stay and disperse. However, the impact of cilia density and distribution on mucociliary mixing and transport at the tissue scale remains poorly understood. We present three-dimensional (3D) simulations of mucociliary mixing and transport at the tissue scale. We investigate the influence of ciliary cluster spacing, metachronal wave, and ciliary density on mucus mixing and transport. Our findings reveal that: (i) cilia clusters produce swirls of mucus flow, their size scales with ciliary density; (ii) a single cilia cluster generates horizontal and upward transport with horizontal mixing; (iii) for three aligned cilia clusters, an optimal cluster spacing exists for achieving maximum horizontal transport; (iv) asynchronous beating among clusters enhances mixing but hinders transport; and (v) the diffusion of particles exhibits spatial inhomogeneity, leading to particle aggregation into discrete groups over time. These discoveries have implications for understanding particle distributions in the airway and contribute to drug delivery design considerations. Author summaryOur airways are exposed to various foreign particles, including allergens, pathogens, and aerosolized vaccines or medications. The mucus coating the airway surface traps these particles, and the beating cilia extending from the ciliated epithelial cells play a crucial role in propelling the flow of mucus to transport the particles out of the airway. This mucociliary clearance process is closely associated with the initiation and progression of airway tissue response, such as allergic responses, infections, and treatment effects. Changes in ciliated cell density or mucus production can significantly impact this process. Conversely, achieving a homogeneous distribution of aerosol drug particles within the airway is essential for optimizing treatment outcomes. We simulate cilia-mucus coupled flow to examine how the motion of cilia influences the transport and mixing of particles in the mucus. Our key findings suggest that an optimal spacing for ciliated cell clusters that enhances directional transport. Intriguingly, while the metachronal wave promotes mixing, it also tends to hinder the overall transport of particles.

systems biology↗