Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 541 records · Page 30Linked to original sources

bioRxiv2023

The colocatome as a spatial -omic reveals shared microenvironment features between tumour-stroma assembloids and lung cancer specimens

Computational frameworks to quantify and compare microenvironment spatial features of in-vitro patient-derived models and clinical specimens are needed. Here, we acquired and analysed multiplexed immunofluorescence images of human lung adenocarcinoma (LUAD) alongside tumour- stroma assembloids constructed with organoids and fibroblasts harvested from the leading edge (Tumour-Adjacent Fibroblasts;TAFs) or core (Tumour Core Fibroblasts;TCFs) of human LUAD. We introduce the concept of the "colocatome" as a spatial -omic dimension to catalogue all proximate and distant colocalisations between malignant and fibroblast subpopulations in both the assembloids and clinical specimens. The colocatome expands upon the colocalisation quotient (CLQ) through a nomalisation strategy that involves permutation analysis and thereby allows comparisons of CLQs under different conditions. Using colocatome analysis, we report that both TAFs and TCFs protected cancer cells from targeted oncogene treatment by uniquely reorganising the tumour-stroma cytoarchitecture, rather than by promoting cellular heterogeneity or selection. Moreover, we show that the assembloids colocatome recapitulates the tumour-stroma cytoarchitecture defining the tumour microenvironment of LUAD clinical samples and thereby can serve as a functional spatial readout to guide translational discoveries. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/557278v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@a79aa3org.highwire.dtl.DTLVardef@199582forg.highwire.dtl.DTLVardef@6c7fb6org.highwire.dtl.DTLVardef@134a2aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

CREBBP lysine acetyltransferase domain mutations create zombie enzymes that alter chromatin loading dynamics and prevent EP300 redundancy

Epigenetic regulation of gene expression is fundamental to cell state transitions. A prominent example of this is the epigenetically-regulated generation of transitory cells states within the germinal center (GC) reaction that are required for humoral immunity. The deregulation of these processes through somatic mutations can give rise to B-cell lymphoma, thus studying these mutations can provide insight into fundamental mechanisms underlying epigenetic regulation of gene expression as well as GC B-cell and lymphoma biology. Here we show that classes of mutations in the CREBBP lysine acetyltransferase gene result in different structure, catalytic activity and function. We discover that CREBBP and its paralog EP300 are dynamically and reciprocally loaded onto chromatin during a signal-responsive cell state transitions within the GC. Mutation of CREBBP in GC-derived lymphoma interrupt signal-responsive CREBBP loading onto chromatin, while also inhibiting EP300 redundancy. These observations lead to a model in which CREBBP or EP300 loss of function through acetyltransferase domain mutations, which occur frequently in both hematopoietic and solid tumors, create a zombie enzyme that retards the function of the active paralog by binding limiting concentrations of transcription factor substrate and preventing signal-responsive enhancer activation.

cancer biology↗

bioRxiv2023

Machine learning general transcriptional predictors of plant disease

Plants utilize an innate immune system to defend against all classes of microbial invaders. While we understand specific genetic determinants of host-pathogen interactions, it remains less clear how generalized the immune response is to diverse pathogens. Using a data-driven approach, and utilizing feature selection based on network science and topology, we developed machine learning models that could predict host disease development across diverse pathosystems. These machine learning models identified early transcriptional responses predictive of later disease development, regardless of pathogen class, using a fraction of the host transcriptome. The identified gene sets were not enriched for canonical defense genes, but where statistically enriched for genes previously identified from independent data sets, including those described as representing a general plant stress response. These results highlight novel components of a general plant immune response, and demonstrate the application of machine learning to address biological hypotheses of a complex multigenic outcome. TeaserA machine learning approach can predict plant disease development caused by diverse microbial invaders, and newly identified genes may represent novel components of a general plant response to infection.

plant biology↗

bioRxiv2023

Natural genomic variation in rice blast genomes is associated with specific heterochromatinmodifications

Genome organization in eukaryotes exhibits non-random patterns tied to transcription, replication, and chromatin. However, the driving forces across these processes, and their impacts on genome evolution remain unclear. To address this, we analyzed sequence data from 86 Magnaporthe oryzae isolates, a globally important plant pathogenic fungus, alongside new reference genomes, to investigate DNA sequence variation and the epigenome. Histone modification profiles were obtained through genome-wide chromatin immunoprecipitation-sequencing of the four new reference strains, which revealed that repressive histone marks (H3K27me3, H3K9me3) were associated with SNP and INDEL frequency. Densely grouped SNPs were found to reside in heterochromatin, often outside transposable elements, highlighting the link between heterochromatin and DNA variation. Even when controlling for selection, silent SNP frequency/kb was higher in H3K27me3-associated genes. Effector genes, key to pathogenicity, also displayed this trend. Comparing the reference strains, euchromatic regions were often syntenic, while heterochromatic regions trended towards non-syntenic. Heterochromatin emerged as a major factor associated with diverse DNA variations in M. oryzae populations, even when accounting for selective pressure. This underscores heterochromatins pivotal role in shaping genetic diversity in these mainly asexually reproducing fungi.

evolutionary biology↗

bioRxiv2023

Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted IL-22 production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells (DCs) and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

physiology↗

bioRxiv2023

Machine learning-based investigation of regulated cell death for predicting prognosis and immunotherapy response in glioma patients

BackgroundGlioblastoma is a highly aggressive and malignant type of brain cancer that originates from glial cells in the brain, with a median survival time of 15 months and a 5-year survival rate of less than 5%. Regulated cell death (RCD) is the autonomous and orderly cell death under genetic control, controlled by precise signaling pathways and molecularly defined effector mechanisms, modulated by pharmacological or genetic interventions, and plays a key role in maintaining homeostasis of the internal environment. The comprehensive and systemic landscape of the RCD in glioma is not fully investigated and explored. MethodAfter collecting 18 RCD-related signatures from the opening literatures, we comprehensively explored the RCD landscape, integrating the multi-omics data, including large-scale bulk data, single-cell level data, glioma cell lines, and proteome level data. We also provided a machine learning framework for screening the potentially therapeutic candidates. ResultHere, we explored RCD-related phenotypes, investigated the profile of the RCD, and developed a RCD gene pair scoring system, named RCD.GP signature. Using the machine learning framework consisting of Lasso, RSF, XgBoost, Enet, CoxBoost and Boruta, we identified seven RCD genes as potential therapeutic targets in glioma and verified the SLC43A3 by q-PCR in glioma grades and glioma cell lines. ConclusionOur study provided comprehensive insights into the RCD roles in glioma, developed a robust RCD gene pair signature for predicting the prognosis of glioma patients, constructed a machine learning framework for screening the core candidates and identified the SLC43A3 as an oncogenic role and a prediction biomarker in glioblastoma.

bioinformatics↗

bioRxiv2023

Integration of Multiple Spatial-Omics Modalities Reveals Unique Insights into Molecular Heterogeneity of Prostate Cancer

Recent advances in spatial omics methods are revolutionising biomedical research by enabling detailed molecular analyses of cells and their interactions in their native state. As most technologies capture only a specific type of molecules, there is an unmet need to enable integration of multiple spatial-omics datasets. This, however, presents several challenges as these analyses typically operate on separate tissue sections at disparate spatial resolutions. Here, we established a spatial multi-omics integration pipeline enabling co-registration and granularity matching, and applied it to integrate spatial transcriptomics, mass spectrometry-based lipidomics, single nucleus RNA-seq and histomorphological information from human prostate cancer patient samples. This approach revealed unique correlations between lipids and gene expression profiles that are linked to distinct cell populations and histopathological disease states and uncovered molecularly different subregions not discernible by morphology alone. By its ability to correlate datasets that span across the biomolecular and spatial scale, the application of this novel spatial multi-omics integration pipeline provides unprecedented insight into the intricate interplay between different classes of molecules in a tissue context. In addition, it has unique hypothesis-generating potential, and holds promise for applications in molecular pathology, biomarker and target discovery and other tissue-based research fields.

cancer biology↗

bioRxiv2023

Zebrafish Drug Screening Identifies Erlotinib as an Inhibitor of Wnt/β-Catenin Signaling and Self-Renewal in T-cell Acute Lymphoblastic Leukemia

The Wnt/{beta}-catenin pathways significance in cancer initiation, progression, and stem cell biology underscores its therapeutic potential, yet clinical application of Wnt inhibitors remains limited due to challenges posed by off-target effects and complex crosstalk with other pathways. In this study, we leveraged the zebrafish model to perform a robust and rapid drug screening of 773 FDA-approved compounds to identify Wnt/{beta}-catenin inhibitors with minimal toxicity. Utilizing zebrafish expressing a Wnt reporter, we identified several drugs that suppressed Wnt signaling without compromising zebrafish development. The efficacy of the top hit, Erlotinib, extended to human cells, where it blocked Wnt/{beta}-catenin signaling downstream of the destruction complex. Notably, Erlotinib treatment reduced self-renewal in human T-cell Acute Lymphoblastic Leukemia cells, which are known to rely on active {beta}-catenin signaling for maintenance of leukemia-initiating cells. Erlotinib also reduced leukemia-initiating cell frequency and delayed disease formation in zebrafish models. This study underscores zebrafishs translational potential in drug discovery and repurposing, and highlights a new use for Erlotinib as a Wnt inhibitor for cancers driven by aberrant Wnt/{beta}-catenin signaling. HighlightsO_LIZebrafish-based drug screening offers an inexpensive and robust platform for identifying compounds with high efficacy and low toxicity in vivo. C_LIO_LIErlotinib, an Epidermal Growth Factor Receptor (EGFR) inhibitor, emerged as a potent and promising Wnt inhibitor with effects in both zebrafish and human cell-based Wnt reporter assays. C_LIO_LIThe identification of Erlotinib as a Wnt inhibitor underscores the value of repurposed drugs in developing targeted therapies to disrupt cancer stemness and improve clinical outcomes C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=42 SRC="FIGDIR/small/555200v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@150e0a0org.highwire.dtl.DTLVardef@cb3455org.highwire.dtl.DTLVardef@d8d8a8org.highwire.dtl.DTLVardef@780535_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Extended toolboxes enable efficient biosynthesis of valuable chemicals directly from CO2 in fast-growing Synechococcus sp. PCC 11901

CO2 recycle is crucial to the global carbon neutrality. Though cyanobacteria are known to be photoautotrophic cell factories capable of converting CO2 into valuable chemicals, their slower growth rate and lower biomass accumulation compared to those of the heterotrophic organisms significantly restrict their application at commercial scale. The newly discovered marine cyanobacterium, Synechococcus sp. PCC 11901 (hereafter PCC 11901) offers several advantages like rapid growth, high biomass and high salinity tolerance, and could become a new generation of cyanobacterial chassis. To promote its application, in this study we developed genetic toolboxes applicable to PCC11901. First, a cobalamin (VB12)-independent chassis was constructed, allowing for its cheaper cultivation. Second, genome copy numbers and transformation methods were respectively measured and optimized. The 14 neutral sites were identified and characterized within the genome PCC 11901, providing locations for genetic integration of exogenous cassettes. Subsequently, libraries were developed, reaching an expression range of approximately 800 folds for constitutive promoters and an induction fold of up to approximately 400 for inducible promotor, respectively. As a proof of concept of its utilization, we engineered the synthetic pathways of glucosylglycerol (GG) into PCC 11901 using the established toolboxes, yielding 590.41 {+/-} 21.48 mg/L for GG production. Notably, we found the cobalamin-independent PCC 11901 chassis exhibited superior self-sedimentation ability compared to the wild-type chassis. Our work here made it possible to develop the fast-growing PCC 11901 as efficient carbon-neutral cell factory in the future.

synthetic biology↗

bioRxiv2023

Cell cycle progression mechanisms: slower cyclin-D/CDK4 activation and faster cyclin-E/CDK2

Dysregulation of cyclin-dependent kinases (CDKs) impacts cell proliferation, driving cancer. Here, we ask why the cyclin-D/CDK4 complex governs cell cycle progression through the longer G1 phase, whereas cyclin-E/CDK2 regulates the short G1/S phase transition. We consider the experimentally established high-level bursting of cyclin-E, and sustained duration of elevated cyclin-D expression in the cell, available experimental cellular and structural data, and comprehensive explicit solvent molecular dynamics simulations to provide the mechanistic foundation of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in the G1 phase and G1/S transition of the cell cycle, respectively. These lead us to propose slower activation of cyclin-D/CDK4 and rapid activation of cyclin-E/CDK2. Importantly, we determine the mechanisms through which this occurs, offering innovative CDK4 drug design considerations. Our insightful mechanistic work addresses the compelling cell cycle regulation question and illuminates the distinct activation speeds in the G1 versus G1/S phases, which are crucial for cell function. StatementOur work provides an unprecedented mechanistic understanding of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in cell cycle regulation, underpinning the slower activation of cyclin-D/CDK4 in the more extended G1 phase and the rapid activation of cyclin-E/CDK2 in the brief G1/S transition. Our findings address a long-standing question in cell cycle biology and suggest the design of targeted CDK4 inhibitors.

molecular biology↗

bioRxiv2023

Surface-active antibiotic production is a multifunctional adaptation for postfire microbes

Wildfires affect soils in multiple ways, leading to numerous challenges for colonizing microbes. While it is thought that fire-adapted microbes lie at the forefront of postfire ecosystem recovery, the specific strategies that these microbes use to thrive in burned soils remain largely unknown. Through bioactivity screening of bacterial isolates from burned soils, we discovered that several Paraburkholderia spp. isolates produced a set of unusual rhamnolipid surfactants with a natural methyl ester modification. These rhamnolipid methyl esters (RLMEs) exhibited enhanced antimicrobial activity against other postfire microbial isolates, including pyrophilous Pyronema fungi and Amycolatopsis bacteria, compared to the typical rhamnolipids made by organisms such as Pseudomonas spp. RLMEs also showed enhanced surfactant properties and facilitated bacterial motility on agar surfaces. In vitro assays further demonstrated that RLMEs improved aqueous solubilization of polycyclic aromatic hydrocarbons, which are potential carbon sources found in char. Identification of the rhamnolipid biosynthesis genes in the postfire isolate, Paraburkholderia caledonica str. F3, led to the discovery of rhlM, whose gene product is responsible for the unique methylation of rhamnolipid substrates. RhlM is the first characterized bacterial representative of a large class of integral membrane methyltransferases that are widespread in bacteria. These results indicate multiple roles for RLMEs in the postfire lifestyle of Paraburkholderia isolates, including enhanced dispersal, solubilization of potential nutrients, and inhibition of competitors. Our findings shed new light on the chemical adaptations that bacteria employ in order to navigate, grow, and outcompete other soil community members in postfire environments. Significance StatementWildfires are increasing in frequency and intensity at a global scale. Microbes are the first colonizers of soil after fire events, but the adaptations that help these organisms survive in postfire environments are poorly understood. In this work, we show that a bacterium isolated from burned soil produces an unusual rhamnolipid biosurfactant that exhibits antimicrobial activity, enhances motility, and solubilizes potential nutrients derived from pyrolyzed organic matter. Collectively, our findings demonstrate that bacteria leverage specialized metabolites with multiple functions to meet the demands of life in postfire environments. Furthermore, this work reveals the potential of probing perturbed environments for the discovery of unique compounds and enzymes.

microbiology↗

bioRxiv2023

Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions

CRISPR prime editing (PE) requires a Cas9 nickase-reverse transcriptase fusion protein (known as PE2) and a prime editing guide RNA (pegRNA), an extended version of a standard guide RNA (gRNA) that both specifies the intended target genomic sequence and encodes the desired genetic edit. Here we show that sequence complementarity between the 5 and the 3 regions of a pegRNA can negatively impact its ability to complex with Cas9, thereby potentially reducing PE efficiency. We demonstrate this limitation can be overcome by a simple pegRNA refolding procedure, which improved ribonucleoprotein-mediated PE efficiencies in zebrafish embryos by up to nearly 25-fold. Further gains in PE efficiencies of as much as 6-fold could also be achieved by introducing point mutations designed to disrupt internal interactions within the pegRNA. Our work defines simple strategies that can be implemented to improve the efficiency of PE.

genomics↗

bioRxiv2023

Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy

An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti- cancer immune responses and offers a new avenue for treating various types of cancer.

cancer biology↗

bioRxiv2023

Large-scale population genomics of Malayan pangolins reveals deep diversification and a new species

BackgroundArchipelagos and oceanic islands often present high percentage of endemism due to rapid speciation. The Malayan pangolin is a species distributing at both mainland (southern Yunnan, China) and oceanic islands via Malayan peninsula, which may result in deep differentiation among populations. In-depth investigation of population structure and genetic consequences for such species is of vital importance for their protection and conservation, practically for the critically endangered Malayan pangolin that is suffering from poaching, illegal trade, and habitat loss. ResultsHere we carried out a large-scale population genomic analysis for Malayan pangolins, and revealed three highly distinct genetic populations in this species, two of which are now being reported for the first time. Based on multiple lines of genomic and morphological evidence, we postulate the existence of a new pangolin species (Manis_1). Genetic diversity and recent inbreeding were both at a moderate level for both Malayan pangolins and Manis_1, but mainland Malayan pangolins presented relatively lower genetic diversity, higher inbreeding and fitness cost than island populations. ConclusionsWe found extremely deep and graded differentiation in Malayan pangolins, with two newly discovered genetic populations and a new pangolin species that is closely related to the Philippine pangolin than the typical Malayan pangolin, but a distant relative of the Indian pangolin. Anthropogenic factors did not significantly weaken the basis of genetic sustainability for Malayan pangolins, but mainland Malayan pangolins should be paid more attention for conservation due to higher genetic risks than island populations.

genomics↗

bioRxiv2023

NaV1.6 inhibition drives the efficacy of voltage-gated sodium channel inhibitors to prevent electrically induced seizures in both wild type and Scn8aN1768D/+ gain-of-function mice

Inhibitors of voltage-gated sodium channels (NaVs) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are nonselective. We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. Mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) responded with a tonic-clonic seizure to a mild 6 Hz stimulus that was innocuous to wild-type mice. Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and better tolerated treatments for idiopathic epilepsies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/551823v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@39c09borg.highwire.dtl.DTLVardef@19413b8org.highwire.dtl.DTLVardef@9aa226org.highwire.dtl.DTLVardef@b9207_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro

BackgroundCharacterizing genetic effect heterogeneity across subpopulations with different environmental exposures is useful for identifying exposure-specific pathways, understanding biological mechanisms underlying disease heterogeneity and further pinpointing modifiable risk factors for disease prevention and management. Classical gene-by-environment interaction (GxE) analysis can be used to characterize genetic effect heterogeneity. However, it can have a high multiple testing burden in the context of genome-wide association studies (GWAS) and requires a large sample size to achieve sufficient power. MethodsWe adapt a colocalization method, SharePro, to account for effect heterogeneity in finemapping and subsequently improve power for GxE analysis. Through joint fine-mapping of exposure stratified GWAS summary statistics, SharePro can greatly reduce multiple testing burden in GxE analysis. ResultsThrough extensive simulation studies, we demonstrated that accounting for effect heterogeneity can improve power for fine-mapping. With efficient joint fine-mapping of exposure stratified GWAS summary statistics, SharePro alleviated multiple testing burden in GxE analysis and demonstrated improved power with well-controlled false discovery rate. Through analyses of smoking status stratified GWAS summary statistics, we identified genetic effects on lung function modulated by smoking status mapped to the genes CHRNA3, ADAM19 and UBR1. Additionally, using sex stratified GWAS summary statistics, we characterized sex differentiated genetic effects on fat distribution and provided biologically plausible candidates for functional follow-up studies. ConclusionsWe have developed an analytical framework to account for effect heterogeneity in finemapping and subsequently improve power for GxE analysis. The SharePro software for GxE analysis is openly available at https://github.com/zhwm/SharePro_gxe.

genetics↗

bioRxiv2023

Inflammation plays a critical role in damage to the bronchiolar epithelium induced by Trueperella pyogenes in vitro and in vivo

Trueperella pyogenes can cause severe pulmonary disease in swine, but the mechanism of pathogenesis is not well defined. T. pyogenes-induced damage to porcine bronchial epithelial cells (PBECs), porcine precision-cut lung slices (PCLS) and respiratory epithelium of mice remains unknown. In this study, we used T. pyogenes 20121 to infect PBECs in air-liquid interface conditions and porcine PCLS. T. pyogenes could adhere to, colonize and induce cytotoxic effect on PBECs and the luminal surface of bronchi in PCLS, which damaged the bronchiolar epithelium. Moreover, bronchiolar epithelial cells showed extensive degeneration in infected mice lungs. Furthermore, western blot showed the NOD-like receptor (NLR)/ C-terminal caspase recruitment domain (ASC)/caspase-1 axis and nuclear factor-kappa B (NF-{kappa}B) pathway were involved in inflammation in PCLS and lungs of mice, which also confirms PCLS provide a platform to analyze pulmonary immune response. Meanwhile, the levels of p-c-Jun N-terminal kinase (JNK), p-extracellular signal-regulated kinase (ERK) and p-protein kinase B (AKT) were increased significantly, which indicated the mitogen-activated protein kinase (MAPK) and Akt pathways were also involved of inflammation in T. pyogenes-infected mice. In addition, we used T. pyogenes 20121 to infect tumour necrosis factor alpha (TNF-)-/- mice, the results indicated apoptosis and injury in respiratory epithelium of infected TNF--/- mice were alleviated. Thus, pro-inflammatory cytokine TNF- played a role in apoptosis and respiratory epithelium injury of mice lungs. Collectively, our study provides an insight into the inflammatory injury induced by T. pyogenes, and suggests that blocking NLR or TNF- may be a potential therapeutic strategy against T. pyogenes infection.

immunology↗

bioRxiv2023

SharePro: an accurate and efficient genetic colocalization method accounting for multiple causal signals

MotivationColocalization analysis is commonly used to assess whether two or more traits share the same genetic signals identified in genome-wide association studies (GWAS), and is important for prioritizing targets for functional follow-up of GWAS results. Existing colocalization methods can have suboptimal performance when there are multiple causal variants in one genomic locus. ResultsWe propose SharePro to extend the COLOC framework for colocalization analysis. Share-Pro integrates linkage disequilibrium (LD) modelling and colocalization assessment by grouping correlated variants into effect groups. With an efficient variational inference algorithm, posterior colocalization probabilities can be accurately estimated. In simulation studies, SharePro demonstrated increased power with a well-controlled false positive rate at a low computational cost. Through a challenging case of the colocalization analysis of the circulating abundance of R-spondin 3 (RSPO3) GWAS and estimated bone mineral density GWAS, we demonstrated the utility of SharePro in identifying biologically plausible colocalized signals. Availability and ImplementationThe SharePro software for colocalization analysis is openly available at https://github.com/zhwm/SharePro_coloc and the analysis conducted in this study is available at https://github.com/zhwm/SharePro_coloc_analysis.

genetics↗