Biology subjects

Guan, Y.

Publications and source records attributed to Guan, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Deciphering the Sequence Basis and Application of Transcriptional Initiation Regulation in Plant Genomes Through Deep Learning

Transcription initiation is a critical regulatory step in plant gene expression, yet its sequence determinants remain largely elusive. Here we introduce GenoRetriever, an interpretable deep learning model that deciphers the sequence basis of transcriptional initiation regulation across plant genomes. Trained on STRIPE-seq data from 16 soybean tissues and six other crop species, GenoRetriever identifies 27 core sequence motifs that govern transcription start site (TSS) selection and usage. The model predicts TSS locations and usage levels with high accuracy, as validated by in silico motif insertions, saturation mutagenesis, and CRISPR-Cas9 promoter editing. It further reveals that 31.85% of natural variation between wild and domesticated soybean drives shifts in promoter motif usage during domestication, and uncovers lineage-specific motif effects between monocots and dicots. This interpretable model and its user-friendly web server for promoter analysis and design make GenoRetriever both a methodological innovation and practical tool for plant functional genomics and crop improvement.

plant biology↗

bioRxiv2025

Convergent strigolactone perception via independent horizontal gene transfer of pre-adapted α/β-hydrolases

Strigolactones (SLs) are not only phytohormones that influence multiple aspects of plant growth and development, but also signaling molecules for interactions between plants and certain fungi or bacteria. In plants, the SL receptor is an /{beta}-hydrolase (ABH) encoded by the D14/KAI2 gene family, which is known to be derived from proteobacterial RsbQ through horizontal gene transfer (HGT). Here we show that the CpD14-like (CDL) gene family, which encodes another ABH exhibiting SL receptor functions in fungi, was acquired from actinobacteria via an independent HGT event. X-ray crystallographic experiments reveal that CDL and D14/KAI2/RsbQ (DKR) proteins have distinctive lid structures but maintain the same core /{beta} fold and catalytic triad. Biochemical assays further show that both actinobacterial CDL and proteobacterial RsbQ can recognize and hydrolyze SLs, suggesting that they are pre-adapted for SL perception. This work demonstrates that independent HGT of pre-adapted genes can trigger convergent evolution of key innovations and provides insights into how SLs are sensed by organisms across kingdoms.

evolutionary biology↗

bioRxiv2025

Lipocalins are versatile regulators of development and stress response in mosses

Major physiological and developmental innovations, such as stress tolerance strategies and three-dimensional growth, are key to land plant adaptation and evolution, but their genetic basis remains to be fully understood. Although lipocalins are known for their role to optimize adaptation and development in animals, they are heavily understudied in plants. Here we show that lipocalins in the moss Physcomitrium patens are versatile regulators of miscellaneous key physiological and developmental processes. Phylogenetics analyses revealed three major groups of plant lipocalins, including a newly identified group that is restricted to seedless plants. The temperature-induced lipocalin gene in P. patens (PpTIL) is functionally conserved with flowering plants in response to various abiotic stresses (e.g., heat, cold, salt, and dehydration). We demonstrate that PpTIL not only regulates protonemal development and the transition from two-dimensional to three-dimensional growth, but also affects many other processes such as lipid transport and metabolism, auxin biosynthesis and transport, and chlorophyll catabolism. These findings provide major insights into the role of lipocalins in land plant evolution.

evolutionary biology↗

bioRxiv2025

Reflection Knockoffs via Householder Reflection: Applications in Proteomics and Genetic Fine Mapping

We present a novel knockoff construction method, and demonstrate its superior performance in two applications: identifying proteomic signatures of age and genetic fine mapping. Both applications involve datasets of highly correlated features, but they differ in the abundance of driver associations. Our primary contribution is the invention of the reflection knockoff, which is constructed from mirror images - obtained via Householder reflection - of the original features. The reflection knockoffs substantially outperform Model-X knockoffs in feature selection, particularly when features are highly correlated. Our secondary contribution is a simple method to aggregate multiple sets of identically distributed knockoff statistics to improve the consistency of knockoff filters. In the study of proteomic signatures of age, single feature tests showed overly abundant proteomic association with age. Knockoff filters using reflection knockoffs and aggregation, however, revealed that a majority of these associations are hitchhikers instead of drivers. When applied to genetic fine mapping, knockoff filters using reflection knockoffs and aggregation outperform a state-of-the-art method. We discuss a potentially exciting application of reflection knockoffs: sharing genetic data without raising concerns about privacy and regulatory violations.

bioinformatics↗

bioRxiv2024

Enalapril mitigates aging by targeting antioxidative genes via phosphorylated Smad1/5/9

Aging increases the risk of a myriad of chronic diseases, which are expensive and difficult to treat owing to their various risk factors. Repurposing existing medications has accelerated the development of therapies aimed at slowing aging. In this study, we revealed that enalapril, a drug widely prescribed for hypertension, can improve both cellular senescence and individual health. Mechanistically, phosphorylated Smad1/5/9 act as pivotal mediators of the anti-senescence properties of enalapril. It stimulates downstream genes involved in cell cycle regulation and antioxidative defense, facilitating cell proliferation and diminishing the production of reactive oxygen species (ROS), thus increasing the antioxidative ability of enalapril. At the organismal level, enalapril has been shown to bolster the physiological performance of various organs; it notably enhances memory capacity and renal function and relieves lipid accumulation. Our work highlights the potential of enalapril to augment antioxidant defenses and combat the effects of aging, thereby indicating its promise as a treatment strategy for aging-associated diseases and its use for healthy aging.

cell biology↗

bioRxiv2024

Nanoscale Optical Imaging, Reconstruction, and Spatial Analysis of Whole Mouse Glomeruli

Renal glomeruli have traditionally been studied by micrometer-scale optical microscopy to interrogate overall physiology or molecular distributions and by nanoscale electron microscopy to interrogate the ultrastructure of thin sections. While these approaches are powerful, they have been limited in their ability to obtain detailed views of the glomeruli as holistic 3D functional units. To fill this knowledge gap, we have developed a novel pipeline for imaging, reconstructing, and analyzing whole mouse glomeruli at 100 nm resolution using super-resolution fluorescence microscopy. This pipeline integrates both manual and machine learning approaches to annotate and analyze glomerular structures. Using this method, we created 18 detailed glomerulus models, from a range of healthy, aged, and model diseased mice, that outline all major structures and cell types. These models have been made publicly accessible in an online repository, providing a valuable resource for further studies. Our results also uncovered a diverse set of novel phenotypes including nuclear enlargement in all glomerular cell types in aging and disease, as well as an aging-related pattern of regional thickening of the Bowmans capsule basement membrane near the tubular-glomerular junction.

physiology↗

bioRxiv2024

Cross-Tissue Coordination between SLC Nucleoside Transporters Regulates Reproduction in Caenorhabditis elegans

Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed as metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. Together, these studies support guanosine as a rate limiting factor in the control of reproduction, uncover the previously unknown nucleoside/nucleotide communication between the soma and the germline essential for reproductive success, and highlight the significance of SLC-mediated cell-nonautonomous metabolite coordination in regulating organism physiology. Author SummaryMetabolism is essential for life, involving a complex network of chemical reactions that requires a well-organized system to maintain efficiency. This includes the optimal allocation of resources and the dynamic exchange of metabolic products between various compartments within an organism. Solute carriers (SLCs) are the largest family of transporters for metabolic products across the animal kingdom. In our research, we investigated how specific SLC transporters collaborate to move key metabolic products between different tissues. We identified two SLC transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, which are vital for transporting guanosine, a purine nucleoside, to support successful reproduction in the nematode Caenorhabditis elegans. We discovered that ENT-2 acts in the gut to export guanosine to the surrounding body cavity, while ENT-1 functions in the germline to import guanosine from the body cavity. When both transporters are disrupted, the animals experience significant reproductive defects. Our study underscores the importance of coordinated activity between SLC transporters in different tissues to maintain organism health. A breakdown in this communication can result in metabolic imbalances and physiological dysfunction.

genetics↗

bioRxiv2024

Linking microbial community structure with function using functional amplicon sequencing of the NRPS genes around wheat roots during drought stress

Secondary metabolites are bioactive compounds, diverse in structure with versatile ecological functions including key roles in mediating interactions between microorganisms and plants. Importantly, these compounds can promote the colonization of plant surfaces, such as roots, or modulate root exudates to enhance microbial recruitment and establishment. However, owing to the vast diversity of secondary metabolites, their importance in plant root colonization and in particular under stress conditions such as drought, remains unclear. To determine the involvement in root colonization of some of these secondary metabolites, we used amplicon sequencing targeting the adenylation domain of the NRPSs and the 16S rRNA gene from the rhizoplane of wheat grown in soil under normal and drought stress conditions. Results showed that drought transiently affected the bacterial community composition and the NRPS composition in the rhizoplane. We observed that drought selected for distinct groups of siderophores from different taxonomical groups, enriching for Streptomyces and depleting Pseudomonas siderophores. In addition, drought enriched Pseudomonas-derived NRPS genes encoding viscosin, a cyclic lipopeptide with biosurfactant properties, indicating that compounds linked to motility and colonization provide a competitive advantage during rhizoplane colonization under drought stress condition. This observation was experimentally confirmed using the viscosin producing P. fluorescens SBW25 and its viscosin-deficient mutant. A higher abundance of SBW25 colonized the roots under drought stress conditions compared to the viscosin-deficient mutant. In summary, our work demonstrates the potential for amplicon sequencing of NRPS genes coupled with in planta experiments to elucidate the importance of secondary metabolites in root colonization. ImportanceTo harness beneficial plant-microbe interactions for improved plant resilience, we need to advance our understanding of key factors required for successful root colonization. Bacterial produced secondary metabolites are important in plant-microbe interactions, and thus, targeting these genes generate new knowledge that is essential for leveraging bacteria for sustainable agriculture. We used amplicon sequencing of the NRPS A domain on the rhizoplane of wheat exposed to drought stress to identify important secondary metabolites in plant-microbe interactions during drought. We show that the siderophores respond differently to drought stress depending on taxonomic affiliation and that the potential to synthesize viscosin increases root colonization. Importantly, this study demonstrates the potential of amplicon sequencing of NRPS genes to reveal specific secondary metabolites involved in root colonization, particularly in relation to drought stress, and highlights how the resolution provided by this approach can link specific compounds to a specific stress condition in a soil system.

microbiology↗

bioRxiv2024

A biodegradable and restorative peripheral neural interface for the interrogation of neuropathic injuries

Monitoring the early-stage healing of severe traumatic nerve injuries is essential to gather physiological and pathological information for timely interventions and optimal clinical outcomes. While implantable peripheral nerve interfaces provide direct access to nerve fibers for precise interrogation and modulation, conventional non-degradable designs pose limited utilization in nerve injury rehabilitation. Here, we introduce a biodegradable and restorative neural interface for wireless real-time tracking and recovery of long-gap nerve injuries. Leveraging machine learning techniques, this electronic platform deciphers nerve recovery status and identifies traumatic neuroma formation at the early phase, enabling timely intervention and significantly improved therapeutic outcomes. The biodegradable nature of the device eliminates the need for retrieval procedures, reducing infection risks and secondary tissue damage. This research sheds light on bioresorbable multifunctional peripheral nerve interfaces for probing neuropathic injuries, offering vital information for early diagnosis and therapeutic intervention.

bioengineering↗

bioRxiv2024

scCancerExplorer: a comprehensive database for interactively exploring single-cell multi-omics data of human pan-cancer

Genomic, epigenomic, and transcriptomic alterations are hallmarks of cancer cells, and are closely connected. Especially, epigenetic regulation plays a critical role in tumorigenesis and progression. The growing single-cell epigenome data in cancer research provide new opportunities for data mining from a more comprehensive perspective. However, there is still a lack of databases designed for interactively exploring the single-cell multi-omics data of human pan-cancer, especially for the single-cell epigenome data. To fill in the gap, we developed scCancerExplorer, a comprehensive and user-friendly database to facilitate the exploration of the single-cell genome, epigenome (chromatin accessibility and DNA methylation), and transcriptome data of 50 cancer types. Five major modules were provided to explore those data interactively, including "integrated multi-omics analysis", "single-cell transcriptome", "single-cell epigenome", "single-cell genome", and "TCGA analysis". By simple clicking, users can easily investigate gene expression features, chromatin accessibility patterns, transcription factor activities, DNA methylation states, copy number variations, and TCGA survival analysis results. Taken together, scCancerExplorer is distinguished from previous databases with rich and interactive functions for exploring the single-cell multi-omics data of human pan-cancer. It bridges the gap between single-cell multi-omics data and the end-users, and will facilitate progress in the field of cancer research. scCancerExplorer is freely accessible via https://bianlab.cn/scCancerExplorer.

cancer biology↗

bioRxiv2024

Integrated single-cell RNA-seq analysis revealed PTN secreted by fibroblasts acting on itself and macrophages via SDC4 ligand in myocardial hypertrophy

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by massive myocardial hypertrophy, which is the most frequent cause of sudden death and can lead to heart failure (HF) or stroke. The objective of this study was to explore the communication network among various cells in the heart of pathological HCM derived from transverse aortic constriction (TAC) mouse model, and investigate the potential mechanism through data mining, biological informatics analysis, and experimental validation. Methods and ResultsThe integrated analyses including CellChat, Seurat, gene ontology (GO), pseudo-time trajectory analysis, and weighted gene co-expression network analysis (WGCNA) were performed based on the single-cell RNA-seq data (scRNA-seq). In vitro tests were conducted to verify bioinformatic analysis findings through enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (RT-qPCR), Edu staining, and transwell assay. In vivo tests were also performed to further verify bioinformatic analysis findings by western blot and immunofluorescence assays based on our established TAC mouse model with myocardial hypertrophy. Our results showed that in the heart of TAC mouse, the interaction between cardiac fibroblasts and macrophages was most common, and the increasing pleiotrophin (PTN) secreted by cardiac fibroblasts could promote themselves proliferation or invasion as well as stimulate macrophage activation to release inflammatory cytokines, such as TNF-, IL-6, Cox-2, Cd83, Egr2, and IL-10 through acting on its ligand recombinant Syndecan 4 (SDC4), which may affect cardiomyocyte normal function and eventually cause HCM. This study first demonstrated that PTN derived from cardiac fibroblasts may act on SDC4 to play crucial role in myocardial hypertrophy, which may be a potential therapeutic targets for patients with pathological HCM. ConclusionsIn this study, the complex interaction network between cardiac fibroblasts and macrophages of TAC mice based on the scRNA-seq data was investigated, and we found that the increasing PTN secreted by cardiac fibroblasts under cardiac pressure overload could promote themselves proliferation or invasion as well as stimulate macrophage activation to release inflammatory cytokines through acting on SDC4 ligand, which may affect cardiomyocyte normal function and eventually cause HCM. In addition, our study suggested that PTN derived from cardiac fibroblasts may act on SDC4 ligand to play crucial role in myocardial hypertrophy, which may be a potential therapeutic targets for patients with pathological HCM.

cell biology↗

bioRxiv2024

TrkA+ sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

cancer biology↗

bioRxiv2024

Pseudomonas taxonomic and functional microdiversity in the wheat rhizosphere is cultivar-dependent and links to disease resistance profile and root diameter

Diversity within lower taxonomic units in microbial communities is a key trait, giving rise to important ecological functions. In the rhizosphere, these functions include disease suppression and pathogen inhibition. However, limited effort has been given to exploring intragenus microdiversity in an increasingly homogenous agricultural system. Through an integrative approach combining culture-dependent and -independent methods, we explore the rhizosphere Pseudomonas pangenome and demonstrate cultivar-dependent taxonomic and functional microdiversity between two closely related modern winter wheat cultivars. A Fusarium-resistant cultivar demonstrated increased Pseudomonas taxonomic diversity but not biosynthetic diversity when compared to the susceptible cultivar, coinciding with a thinner root diameter of the resistant cultivar. We found enrichment of Pseudomonas isolates capable of antagonizing Fusarium as well as chitinase-encoding genes and pyoverdine gene clusters in the resistant cultivar. Across closely related Pseudomonas isolates from the two cultures, there were differences in genomic content and biosynthetic gene clusters. Ultimately, we highlight the need for fine-scale analysis to uncover the hidden microdiversity within rhizosphere Pseudomonas.

microbiology↗

bioRxiv2024

Abundant Parent-of-origin Effect eQTL in Humans: The Framingham Heart Study

Parent-of-origin effect (POE) is a phenomenon whereby an alleles effect on a phenotype depends both on its allelic identity and parents gender from whom the allele is inherited, as exemplified by the polar overdominance in the ovine callypyge locus and the human obesity DLK1 locus. Systematic studies of POE of expression quantitative trait loci (eQTL) are lacking. In this study we use trios among participants in the Framingham Heart Study to examine to what extend POE exists for gene expression of whole blood using whole genome sequencing and RNA sequencing. For each gene and the SNPs in cis, we performed eQTL analysis using genotype, paternal, maternal, and joint models, where the genotype model enforces the identical effect sizes on paternal and maternal alleles, and the joint model allows them to have different effect sizes. We compared models using Bayes factors to identify paternal, maternal, and opposing eQTL, where paternal and maternal effects have opposite directions. The resultant variants are collectively called POE eQTL. The highlights of our study include: 1) There are more than 2, 000 genes harbor POE eQTL and majority POE eQTL are not in the vicinity of known imprinted genes; 2) Among 180 genes harboring opposing eQTL, 99 harbor exclusively opposing eQTL, and 58 of the 99 are phosphoprotein coding genes, reflecting significant enrichment; 3) Paternal eQTL are enriched with GWAS hits, and genes harboring paternal eQTL are enriched with drug targets. Our study demonstrates the abundance of POE in gene expression, illustrates the complexity of gene expression regulation, and provides a resource that is complementary to existing resources such as GTEx. We revisited two previous POE findings in light of our POE results. A SNP residing in KCNQ1 that is maternally associated with diabetes is a maternal eQTL of CDKN1C, not KCNQ1. A SNP residing in DLK1 that showed paternal polar overdominance for human obesity is a maternal eQTL of MEG3, offering an explanation for the baseline risk of homozygous samples through association between MEG3 expression and obesity. Finally, we advised caution on conducting Mendelian randomization using gene expression as the exposure.

genetics↗

bioRxiv2024

Potent and broadly neutralizing antibodies against sarbecoviruses elicited by single ancestral SARS-CoV-2 infection

Monoclonal antibody (mAb) therapeutics hold promise for both preventing and treating infectious diseases, especially among vulnerable populations. However, the emergence of various variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges for current mAb treatments, emphasizing the need for more potent and broadly neutralizing antibodies. In this study, we employed an unbiased screening approach to discover broadly neutralizing antibodies and successfully isolated two mAbs from individuals with only exposure to ancestral SARS-CoV-2. One of these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum of SARS-CoV-2 variants, including the latest JN.1 and KP.2 variants, with consistent IC50 values ranging from [~]1 to 5 ng/mL. Notably, it also displayed broad neutralization activity against SARS-CoV and related sarbecoviruses, such as WIV1, SHC014, RaTG13, and GD-Pangolin. Structural analysis revealed that these mAbs target shared hotspot but mutation-resistant epitopes, with their Fabs locking the RBD in the "down" conformation through interactions with adjacent Fabs and RBDs, and cross-linking Spike trimers into di-trimers to block viral infection. In vivo studies conducted in a JN.1-infected hamster model validated the protective efficacy of CYFN1006-1, emphasizing its therapeutic potential. These findings suggest that, through meticulous approaches, rare antibodies with cross-neutralization activities against SARS-CoV-2 and related sarbecoviruses can be identified from individuals with exclusively ancestral virus exposure.

microbiology↗

bioRxiv2024

Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing

The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration following fracture. Surprisingly, the precise neuroanatomical circuitry mediating skeletal nociception and regeneration remains incompletely understood. Here, we characterized somatosensory dorsal root ganglia (DRG) afferent neurons innervating murine long bones before and after experimental long bone fracture in mice. Retrograde labeling of DRG neurons by an adeno-associated virus with peripheral nerve tropism showed AAV-tdT signal. Single cell transcriptomic profiling of 6,648 DRG neurons showed highest labeling across CGRP+ neuron clusters (6.9-17.2%) belonging to unmyelinated C fibers, thinly myelinated A{delta} fibers and A{beta}-Field LTMR (9.2%). Gene expression profiles of retrograde labeled DRG neurons over multiple timepoints following experimental stress fracture revealed dynamic changes in gene expression corresponding to the acute inflammatory (S100a8, S100a9) and mechanical force (Piezo2). Reparative phase after fracture included morphogens such as Tgfb1, Fgf9 and Fgf18. Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated innervation. Finally, multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding compatible with in vitro assessments of neuron-to-skeletal mesenchyme interactions.

cell biology↗

bioRxiv2024

Single-cell dissection of prognostic architecture and immunotherapy response in Helicobacter pylori infection associated gastric cancer

Most of the gastric cancer (GC) worldwide are ascribed to Helicobacter pylori (H. pylori) infections, which have a detrimental effect on the immunotherapys efficacy. Comprehensively dissecting the key cell players and molecular pathways associated with cancer immunotherapies is critical for developing novel therapeutic strategies against H. pylori infection associated GC. We performed a comprehensive single-cell transcriptome analysis of nine GC with current H. pylori infection (HpGC), three GC with previous H. pylori infection (ex-HpGC), six GC without H. pylori infection (non-HpGC), and six healthy controls (HC). We also investigated key cell players and molecular pathways associated with GC immunotherapy outcomes. We revealed the molecular heterogeneity of different cell components in GC including epithelium, immune cells, and cancer-associated fibroblasts (CAFs) at the single-cell level. The malignant epithelium of HpGC exhibited high expression level of inflammatory and epithelial-mesenchymal transition (EMT) signature, HpGC and ex-HpGC were enriched with VEGFA+ angiogenic tumor-associated macrophages (Angio-TAM) and IL11+ inflammatory CAF (iCAF), characterized by high expression levels of NECTIN2 and VEGFA/B. Additionally, we found significant correlations between the abundance of iCAF with Angio-TAM and TIGIT+ suppressive T cells, and iCAF interacted with Angio-TAM through the VEGF and ANGPTL angiogenic pathways. We also developed an immune signature and angiogenic signature and demonstrated that the iCAF abundance and angiogenic signature could predict poor immunotherapy outcomes in GC. We revealed the transcriptome characteristics and heterogeneity of various cellular constituents of HpGC and demonstrated that a synergistic combination of immunotherapy and anti-angiogenic targeted therapy may be an effective therapeutic modality for HpGC.

cancer biology↗

bioRxiv2024

Bayes factor for linear mixed model in genetic association studies

Bayes factor has advantages over p-value as test statistics for association, particularly when comparing multiple non-nested alternative models. An efficient method to compute Bayes factor for linear mixed model in the context of genetic association studies is lacking. In this study, we transform the standard linear mixed model to a Bayesian linear regression by substituting the random effect with fixed effects, where the covariates of the fixed effects are eigenvectors of the genetic relatedness matrix and their respective prior effect sizes are proportional to the corresponding eigenvalues. Using conjugate normal inverse gamma priors on regression parameters, Bayes factors can be computed in a closed form. We demonstrate numerically the known relationship between Bayes factors and p-values for the linear mixed model. We then show that predictions based on the transformed Bayesian linear regression are identical to those of the best linear unbiased prediction (BLUP) of the standard linear mixed model. Our results provided a new perspective and derivation to a known connection between BLUP and Bayesian estimates. Methods described in this note are implemented in the software IDUL as two new functionalities: computing Bayes factors and residuals for the linear mixed model. IDUL and its source code are freely available at https://github.com/haplotype/idul.

bioinformatics↗