Biology subjects

Qiu, A.

Publications and source records attributed to Qiu, A..

8 recordsLinked to original sources

bioRxiv2026

A Time-Resolved Single-Cell Atlas Reveals Infection-Status, Age-, and Sex-Dependent Immune Responses Drive Viral Disease Severity

The majority of mortality during viral infections occurs in older males; however, underlying mechanisms by which age and sex shape antiviral immunity and pathological inflammatory responses remain incompletely understood. Here, we performed time-resolved single-cell RNA sequencing across 16 conditions spanning age, sex, and four stages of influenza infection in mice, generating a high-resolution atlas. Aged mice demonstrate delayed antiviral and inflammatory responses in multiple myeloid cells, impairing viral clearance, which delays recovery. Similarly, endothelial cells from aging mice show prolonged inflammatory and antiviral gene signatures. Altered gene signatures in immune and endothelial cells result in a shift in endothelial-immune interactions in the aged lung. Further, the infection status of the cell is a major driver of transcriptional state, with infected myeloid cells exhibiting broad upregulation of genes, including interferon-stimulated, inflammatory, complement, and oxidative stress-related genes. To assess whether these age-associated transcriptional patterns are conserved in humans, we examined BAL cells obtained from healthy individuals and COVID-19 patients, and found that immune cells from aged COVID-19 patients had elevated antiviral and pro-inflammatory gene expression compared to cells from young patients. Our analyses of sex differences identified that multiple myeloid cell types in aged male mice, but not in young male mice, show persistent inflammatory responses at later stages of infection, a likely mechanism contributing to elevated mortality in older males. These data reveal how infection status of the cell, age, and sex interact to drive persistent inflammation and impaired resolution, providing a foundational resource for designing age- and sex-specific therapeutic strategies.

immunology↗

bioRxiv2025

Causal Modeling Reveals Cell-Cell Communication Dynamics in the Tumor Microenvironment During Anti-PD-1 Therapy in Breast Cancer Patients

BackgroundImmune checkpoint blockade (ICB) targeting PD-1/PD-L1 plays a crucial role in breast cancer treatment. Despite clinical success, how ICB reshapes the tumor microenvironment (TME) to enhance anti-tumor activity remains unclear. Anti-PD-1 therapy alters TME cells beyond PD-1+ T cells, with extensive cell-cell communication (CCC) playing a key role. Understanding the dynamic CCC changes upon anti-PD-1 treatment can illuminate ICB mechanisms of action and TME dynamics. MethodsWe analyzed single-cell RNA-seq data from 31 breast cancer patients before and after anti-PD-1 (pembrolizumab) treatment (Bassez et al., 2021). We identified differentially expressed genes (DEGs) induced by treatment in major cell types. We then applied an instrumental variable approach to uncover causal relationships between T-cell and non-T-cell DEGs. We further mapped ligand-receptor interactions mediating signal transduction between cells and constructed a CCC network from T to non-T cells. ResultsAnti-PD-1 therapy induced widespread transcriptional changes across multiple cell populations. Key pathways modulated in T cells included NF-{kappa}B, interferon-{gamma}, and interleukin signaling. CD4+ and CD8+ exhausted T cells engaged in distinct ligand-receptor interactions with tumor-associated macrophages (TAMs) and other types of cells, reshaping the TME. Our results indicated CD4+ exhausted T cells activated M1-like TAMs via TNF-TNFRSF1A and TNFSF14-LTBR, while CD8+ exhausted T cells engaged M1-like TAMs through ICAM1-ITGAL/ITGB2 and CCL8-CCR2, promoting anti-tumor immunity. Conversely, immunosuppressive interactions were also observed, such as TNF-TNFRSF1B (TNFR2) and TNFSF14-TNFRSF14 (HVEM) from CD4 T cells, as well as CSF1-CSF1R and RPS19-C5AR1 from CD8 T cells, which likely promote M2-like tumor-associated macrophage (TAM) polarization and contribute to pro-tumor immune regulation and resistance to therapy. Notably, key receptors in the causal CCC networks, such as C5AR1, TNFR2, and CSF1R, emerged as potential targets to enhance anti-PD-1 efficacy. ConclusionsThese findings elucidate TME remodeling during anti-PD-1 therapy and underscore the pivotal role of CCC in treatment response. Our study identifies critical communication networks that may be biomarkers for immunotherapy responsiveness and highlights novel therapeutic targets, including C5AR1 and HVEM. Furthermore, our application of causal inference methodologies provides a robust framework for dissecting CCC mechanisms in immunotherapy.

bioinformatics↗

bioRxiv2025

Inferring Personalized Cell-Cell Communication Networks in Colorectal Cancer with Individualized Causal Discovery

Understanding tumor heterogeneity at the resolution of individualized cell-cell communication networks (CCCNs) remains a major computational challenge in precision oncology. Existing inference methods largely rely on population-level correlation and thus fail to capture patient-specific signaling patterns across diverse cell types. To address this limitation, we developed an integrative computational framework combining the nested hierarchical Dirichlet process (nHDP) model for identifying hierarchically structured gene expression modules, with instance-specific Greedy Fast Causal Inference (iGFCI) for inferring individualized CCCNs (iCCCNs) in colorectal cancer (CRC). Applied to large-scale single-cell RNA-seq data from over 625,000 cells, our model successfully decomposed complex gene expression modules GEMs, potentially representing the cell lineage and cellular signaling states, and uncovered iCCCNs across detailed cell subtypes. We further used TCGA bulk RNA-seq data with survival data to validate the clinical relevance of these individualized gene expression module causal interactions, demonstrating their potential as robust prognostic signatures in CRC. Finally, we used principled causal inference methods to search for ligand-receptor pairs that mediate cell-cell communication. This framework enables mechanistic insights into immune evasion. Our computational method represents a significant advance toward realizing personalized oncology, enabling precise patient stratification and identification of actionable biomarkers for improved therapeutic targeting in cancers.

bioinformatics↗

bioRxiv2025

Epigenetic regulation of cilia stability and kidney by the chromatin remodeling SWI/SNF complexes

Cilia are important subcellular organelles, whose assembly are regulated by master regulator transcription factors including Foxj1 and Rfx proteins. However, whether and how cilia are regulated at epigenetic level remains unknown. We addressed this question by knocking down or knocking out of chromatin remodeling genes. Notably, depletion of multiple components of the switch/sucrose non-fermentable (SWI/SNF) complexes led to ciliopathy-like phenotypes in zebrafish embryos. Specifically, loss of Actl6a, an essential components of the SWI/SNF complexes, resulted in cilia disassembly and cystic kidney, without affectting cilia motility. Omics analyses revealed that in Actl6a-depleted pronephros or embryos, a set of cilia genes--including master regulators foxj1a and rfx2--were downregulated at transcriptional level, chromatin accessibility level and SWI/SNF binding level. Depletion of foxj1a or rfx2 in zebrafish also caused cilia disassembly and cystic kidney. Furthermore, overexpression of foxj1a or rfx2 mRNA partially rescued the cystic kidney and cilia disassembly phenotypes in actl6a mutants. Taken together, our study reveals that the SWI/SNF complexes maintain cilia stability and kidney homeostasis by directly modulating the expression of foxj1a or rfx2.

developmental biology↗

bioRxiv2024

Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming

Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. To examine the epigenomic state of SyS we performed comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumours. Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. We identify cell-of-origin signatures defined by enhancer states and reveal unexpected relationships between H2AK119Ub1 and active marks. The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype. We explore these distinctive features as potential vulnerabilities in SyS and identify H3K4me3 inhibition as a promising therapeutic strategy.

cancer biology↗

bioRxiv2023

Population genomic analyses reveal extensive genomic regions within selective sweeps associated with adaptation and demographic history of a wheat fungal pathogen

Plant pathogens can quickly evolve in response to the changing host and environment, resulting in destructive epidemics. The fungus Puccinia striiformis f. sp. tritici (Pst), causing wheat stripe rust disease worldwide, is one such pathogen. In the arms race between pathogens and hosts, changes in host populations exerted continuous selective forces on the dynamics of pathogens. However, the footprints of these selection forces and the demography of Pst remain poorly explored, limited our understanding the evolutionary processes that shape the spread and evolution of pathogens. In this study, we revealed several features of worldwide Pst populations through population genomic analyses. There might be limited gene flow between Pst populations from China and other countries. A slower rate of linkage disequilibrium decay was detected comparing to rust fungi with known sexual reproduction. Furthermore, we detected extensive hard and soft sweeps associated with Pst adaptation. Genes within the selective sweeps were enriched in secreted proteins and effectors and showed functions related to pathogenicity or virulence, temperature tolerance, and fungicide resistance implying that Chinese Pst populations suffered positive selection pressures from host and abiotic factors. Moreover, demographic history indicated Pst populations experienced strong bottlenecks at the beginning of the wheat domestication around 10,000 years ago and during modern agriculture around 100 years ago, suggesting that the crop domestication and breeding programs could continuously contribute to the decline of pathogen effective population sizes. Our results provided insights into the evolution of the Pst genome and highlighted the role of modern agriculture on pathogen demography. Author SummaryWheat stripe rust, as a pathogen of wheat, is capable of inducing significant yield reduction on a global scale. Traditional epidemiological investigations have elucidated the causative agent behind this disease, the wheat stripe rust pathogen, as an organism exhibiting swift adaptive evolution in response to its environment. However, the precise mechanisms underpinning its adaptive strategies and the ensuing alterations in population dynamics remain relatively unexplored. In our research, we have undertaken an analysis encompassing wheat stripe rust samples throughout the world. Employing population genomics methods, we have sought to discern the genomic footprints corresponding to the adaptive process within the pathogen. These genomic footprints have illuminated the operation of positive selection pressures caused by both the host plant and the ecological context. Concurrently, it have provided insights into the population size that the wheat stripe rust pathogen has undergone over millennia. Notably, its change in population size revealed the demographic history associated with wheat domestication.

microbiology↗

bioRxiv2023

Reticulocytes in donor RBC units enhance RBC alloimmunization

Although red blood cell (RBC) transfusions save lives, some patients develop clinically-significant alloantibodies against donor blood group antigens, which then have adverse effects in multiple clinical settings. Few effective measures exist to prevent RBC alloimmunization and/or eliminate alloantibodies in sensitized patients. Donor-related factors may influence alloimmunization; thus, there is an unmet clinical need to identify which RBC units are immunogenic. Repeat volunteer blood donors and donors on iron supplements have elevated reticulocyte counts compared to healthy non-donors. Early reticulocytes retain mitochondria and other components, which may act as danger signals in immune responses. Herein, we tested whether reticulocytes in donor RBC units could enhance RBC alloimmunization. Using a murine model, we demonstrate that transfusing donor RBC units with increased reticulocyte frequencies dose-dependently increase RBC alloimmunization rates and alloantibody levels. Transfusing reticulocyte-rich RBC units was associated with increased RBC clearance from the circulation and a robust proinflammatory cytokine response. As compared to previously reported post-transfusion RBC consumption patterns, erythrophagocytosis from reticulocyte-rich units was increasingly performed by splenic B cells. These data suggest that reticulocytes in a donated RBC unit impact the quality of blood transfused, are targeted to a distinct compartment, and may be an underappreciated risk factor for RBC alloimmunization.

immunology↗

bioRxiv2020

Spatio-Temporal Correlates of Gene Expression and Cortical Morphology across Life Course and Aging

Evidence from independent neuroimaging and genetic studies supports the concept that brain aging mirrors development. However, it is unclear whether mechanisms linking brain development and aging provide new insights to delay aging and potentially reverse it. This study determined biological mechanisms and phenotypic traits underpinning brain alterations across the life course and in aging by examining spatio-temporal correlations between gene expression and cortical volumes (n=3391) derived from the life course dataset (3-82 years) and the aging dataset (55-82 years). We revealed that a large proportion of genes whose expression was associated with cortical volume across the life course were in astrocytes. These genes, which showed up-regulation during development and down-regulation during aging, contributed to fundamental homeostatic functions of astrocytes crucial, in turn, for neuronal functions. Included among these genes were those encoding components of cAMP and Ras signal pathways, as well as retrograde endocannabinoid signaling. Genes associated with cortical volumes in the aging dataset were also enriched for the sphingolipid signaling pathway, renin-angiotensin system (RAS), proteasome, and TGF-beta signaling pathway, which is linked to the senescence-associated secretory phenotype. Neuroticism, drinking, and smoking were the common phenotypic traits in the life course and aging, while memory was the unique phenotype associated with aging. These findings provide biological mechanisms and phenotypic traits mirroring development and aging as well as unique to aging.

neuroscience↗