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Generation of a Litopenaeus vannamei hepatopancreas cell atlas from single nuclei transcriptomics using a new nuclei isolation method.
BACKGROUND: Crustacean aquaculture is one of the most important food sectors globally and projected to grow. It is a source of nutritious and economic animal protein in many countries. As the global demand for sea food increases, and with an increase in climatic and pathogenic threats to the industry, curating our current knowledge about crustaceans, as well as generating new tools and resources to help minimise the impact of various diseases on the sustainability of the industry is of the utmost importance to increase the resilience of the farmed animal stocks. The main aim of this pilot study was to create a new cell atlas for Pacific whiteleg shrimp (Litopenaeus vannamei) hepatopancreas which encapsulates both the different hepatocyte cell states as well as the various supporting cells found throughout the hepatopancreas, while developing a new method for nuclei isolation and data analysis in the species. RESULTS: We developed new protocols for TST-based nuclei isolation which could be used to successfully isolate and process crustacean-derived nuclei for single nuclei RNA-sequencing analysis with minimal nuclei degradation using frozen hepatopancreas tissue from healthy L. vannamei adults. The bioinformatic analysis that followed allowed us to create a new cell atlas for the hepatopancreas which details the different hepatocyte cell states. Additionally, we built up on the existing knowledge by also analysing the multiple supporting cell clusters such as IECs, fibroblasts and myocytes, which helps improve our understanding of the characteristics of this immune-related organ. CONCLUSION: Overall, 4005 cells were assigned to nine different clusters. Distinct marker genes suggest unique functions of each hepatocyte subtypes and adjacent supportive cells. The new TST-based isolation method for frozen or archived nuclei is particularly useful for processing difficult samples, such as the hepatopancreas, minimise stress and dissociation bias while allowing for greater flexibility between tissue sampling and processing times. Combining the knowledge gained through this study with past and future work in other penaeid shrimp species will allow us to create a powerful resource that will help uncover new knowledge about these important species, especially in the field of stress and immunity.
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Integrated analysis of tumor-associated macrophage infiltration and prognosis in ovarian cancer.
Ovarian cancer (OC) is a frequently lethal gynecologic malignancy, characterized by a poor prognosis and high recurrence rate. The immune microenvironment has been implicated in the progression of OC. We characterized the immune landscape in primary and malignant OC ascites using single-cell and bulk transcriptome raw OC data acquired from the Gene Expression Omnibus and The Cancer Genome Atlas databases. We then used the CIBERSORT deconvolution algorithm, weighted gene co-expression network analysis, univariate and multivariate Cox analyses, and the LASSO algorithm to develop a tumor-associated macrophage-related gene (TAMRG) prognostic signature, which enabled us to stratify and predict overall survival (OS) of OC patients. In addition, inter- and intra-patient heterogeneity of infiltrating immune cells was characterized at single-cell resolution. Tumor-infiltrating macrophages with an M2 phenotype exhibited immunosuppressive activity. M1 macrophages positively correlated with OS, whereas activated mast cells, neutrophils, M2 macrophages, and activated memory CD4+ T cells were all negatively correlated with OS. A total of 219 TAMRGs were identified, and a novel 6-gene signature (TAP1, CD163, VSIG4, IGKV4-1, CD3E, and MS4A7) with independent prognostic value was established. These results show that a TAMRG-based signature may be a promising prognostic and therapeutic target in OC.
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Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis.
Glioblastoma multiforme (GBM) is characterized by rapid progression, therapeutic resistance, and a profoundly immunosuppressive tumor microenvironment. Emerging evidence suggests that endoplasmic reticulum (ER)-associated macromolecules play critical roles in tumor adaptation. In this study, we performed a multi-omics investigation of orosomucoid-like protein 2 (ORMDL2), a conserved ER membrane protein involved in sphingolipid biosynthesis and ER stress regulation, and uncovered its regulatory functions in GBM progression. Transcriptomic analyses across The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) revealed elevated ORMDL2 expression in GBM tissues which causes poor prognosis. The MetaCore pathway and Gene Set Enrichment Analysis (GSEA) identified ORMDL2's involvement in antigen presentation via a major histocompatibility complex I (MHC class I), unfolded protein response (UPR), and mitochondrial apoptotic signaling. Single-cell RNA-sequencing data and the Human Protein Atlas showed ORMDL2 enrichment in tumor stromal cells. Pharmacogenomic correlation via the Genomics in Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) database suggested that ORMDL2 expression was associated with resistance to DNA damage response inhibitors such as etoposide, doxorubicin, talazoparib, and might interact with sphingolipid-targeting compounds. Collectively, our findings establish ORMDL2 as a multi-functional macromolecular regulator of immune suppression and therapeutic resistance in GBM, providing new mechanistic insights and potential targets for translational medicines.
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Cellular and molecular atlas of the placenta from a COVID-19 pregnant woman infected at midgestation highlights the defective impacts on foetal health.
OBJECTIVES: The impacts of the current COVID-19 pandemic on maternal and foetal health are enormous and of serious concern. However, the influence of SARS-CoV-2 infection at early-to-mid gestation on maternal and foetal health remains unclear. MATERIALS AND METHODS: Here, we report the follow-up study of a pregnant woman of her whole infective course of SARS-CoV-2, from asymptomatic infection at gestational week 20 to mild and then severe illness state, and finally cured at Week 24. Following caesarean section due to incomplete uterine rupture at Week 28, histological examinations on the placenta and foetal tissues as well as single-cell RNA sequencing (scRNA-seq) for the placenta were performed. RESULTS: Compared with the gestational age-matched control placentas, the placenta from this COVID-19 case exhibited more syncytial knots and lowered expression of syncytiotrophoblast-related genes. The scRNA-seq analysis demonstrated impaired trophoblast differentiation, activation of antiviral and inflammatory CD8 T cells, as well as the tight association of increased inflammatory responses in the placenta with complement over-activation in macrophages. In addition, levels of several inflammatory factors increased in the placenta and foetal blood. CONCLUSION: These findings illustrate a systematic cellular and molecular signature of placental insufficiency and immune activation at the maternal-foetal interface that may be attributed to SARS-CoV-2 infection at the midgestation stage, which highly suggests the extensive care for maternal and foetal outcomes in pregnant women suffering from COVID-19.
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The prognostic biomarker TPGS2 is correlated with immune infiltrates in pan-cancer: a bioinformatics analysis.
BACKGROUND: Tubulin polyglutamylase complex subunit 2 (TPGS2) is an element of the neuronal polyglutamylase complex that plays a role in the post-translational addition of glutamate residues to C-terminal tubulin tails. Recent research has shown that TPGS2 is associated with some tumors, but the roles of TPGS2 in tumor immunity remain unclear. METHODS: The research data were mainly sourced from The Cancer Genome Atlas. The data were analyzed to identify potential correlations between TPGS2 expression and survival, gene alterations, the tumor mutational burden (TMB), microsatellite instability (MSI), immune infiltration, and various immune-related genes across various cancers. The Wilcoxon rank-sum test was used to identify the significance. A log-rank test and univariate Cox regression analysis were performed to assess the survival state of the patients. Spearman's correlation coefficients were used to show the correlations. RESULTS: TPGS2 exhibited abnormal expression patterns in most types of cancers, and has promising prognostic potential in adrenocortical carcinoma and liver hepatocellular carcinoma. Further, TPGS2 expression was significantly correlated with molecular and immune subtypes. Moreover, the single-cell analyses showed that the expression of TPGS2 was associated with the cell cycle, metastasis, invasion, inflammation, and DNA damage. In addition, the immune cell infiltration analysis and gene-set enrichment analysis demonstrated that a variety of immune cells and immune processes were associated with TPGS2 expression in various cancers. Further, immune regulators, including immunoinhibitors, immunostimulators, the major histocompatibility complex, chemokines, and chemokine receptors, were correlated with TPGS2 expression in different cancer types. Finally, the TMB and MSI, which have been identified as powerful predictors of immunotherapy, were shown to be correlated with the expression of TPGS2 across human cancers. CONCLUSIONS: TPGS2 is aberrantly expressed in most cancer tissues and might be associated with immune cell infiltration in the tumor microenvironment. TPGS2 could serve not only as a biomarker for predicting clinical outcomes, but also as a promising biomarker for evaluating and developing new approaches to immunotherapy in many types of cancers, especially colon adenocarcinoma and stomach adenocarcinoma.
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Cuproptosis-Related Ferroptosis Gene Signature: A Prognostic Tool for Colon Cancer Patients.
BACKGROUND: Ferroptosis and cuprotosis, two distinct mechanisms of programmed cell death, play key roles in colon cancer development. This study aimed to construct a prognostic model for predicting colon adenocarcinoma (COAD) prognosis based on the differential expression of cuproptosis-related ferroptosis genes (CFRGs). METHODS AND RESULTS: Transcriptomic data and clinical data of COAD patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. A combination of methods, including analysis of variance, Pearson correlation analysis, Least absolute shrinkage and selection operator (LASSO) algorithm, and Cox regression was used to construct the CFRGs signatures. In addition, multiple algorithmic strategies were employed to explore the potential association between risk scores and immune infiltration features. Single-cell datasets were used to analyze model genes. Somatic mutations and drug sensitivities were compared across risk groups. Immunohistochemical analysis was performed to verify the expression of the main characterized genes. We identified eight pivotal genes in constructing the CFRGs signature. Single-cell RNA sequencing revealed differential expression of CFRGs in the COAD tumor microenvironment. The nomogram confirmed that risk scoring serves as an independent prognostic factor for COAD. The high-risk group exhibited higher immune cell and stromal cell infiltration, as well as immune checkpoint expression. Patients in the high-risk group may benefit from olanzapine administration. Both RT-PCR and immunohistochemistry have confirmed that the expression levels of GLS and YAP1 in COAD tissues are significantly higher than those in adjacent non-cancerous tissues. CONCLUSIONS: The CFRGs risk prognosis model can effectively predict patients' immune infiltration and immunotherapy response, providing a new reference basis for individualized treatment plans for COAD patients.
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Single cell map of the adult female mouse urethra reveals epithelial and stromal macrophages with distinct functional identities.
Epithelial linings at mucosal sites act in concert with resident immune cells to direct host defense. The epithelial lining of the urethra is an understudied mucosal barrier with emerging roles in antimicrobial defense during urinary tract infections. Here, we present a comprehensive cellular atlas of the adult female mouse urethra, focusing on epithelial and resident immune cells. Single cell RNA-sequencing revealed two distinct macrophage populations compartmentalized within the epithelium and stroma. Epithelial-associated macrophages display a highly dendritic morphology and populate the urethral lining in increasing numbers over the course of development. Epithelial-associated macrophages express Cx3cr1, MHCII genes, Cd74 and Aif1/Iba-1, representing an activated macrophage type (Mac-Activated) enriched for pathways involved in antigen presentation and the inflammatory response. In contrast, stromal macrophages express the scavenging receptors Mrc1/Cd206, Lyve1, Cd163 and Mgl2/Cd301b and display a signature enriched for endocytic function (Mac-Endocytic), vasculature development and tissue homeostasis. We identified epithelial cells in the urethral lining and associated glands expressing the monocyte chemoattractant genes Cx3cl1 and Cxcl17. Chemoattractant gene expression in the urethral epithelium follows a proximal-distal gradient which correlates with the increasing density of epithelial-associated macrophages expressing the receptor Cx3cr1 along the proximal-distal axis of the urethra. The study delineates spatially compartmentalized macrophage subsets in the urethra and implicates epithelial-derived chemokines in the establishment of macrophage positioning and functional specialization along the urethral axis.
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Analysis of Nucleoporin 107 Overexpression and Its Association with Prognosis and Immune Infiltration in Lung Adenocarcinoma by Bioinformatics Methods.
BACKGROUND: Lung adenocarcinoma (LUAD) has high morbidity and mortality. Current studies indicate nucleoporin 107 (NUP107) is involved in the construction of nuclear pore complex, and NUP107 overexpression contributes to the growth and development in most types of cancers, but its effect in LUAD has not been elucidated. METHODS: Differences in NUP107 expression were investigated using the Cancer Genome Atlas (TCGA) and multiple Gene Expression Omnibus (GEO) data sets. Enrichment analysis were implemented to probe the NUP107 function. The association of NUP107 with the degree of immune cell infiltration was investigated by the TIMER database, single-sample gene set enrichment analysis (ssGSEA), and ESTIMATE. The association of NUP107 expression with tumor mutation burden (TMB), TP53, and immune checkpoint was analyzed. Single-cell RNA sequencing data were used to detect NUP107 expression in different cell clusters. Finally, we performed real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) to prove the difference of NUP107 expression. RESULTS: NUP107 was overexpressed in LUAD and mainly expressed in cancer stem cell (CSC). Overexpression of NUP107 in LUAD suggested a poorer prognosis. Functional enrichment analysis pointed out that NUP107 was mainly linked to the regulation of cell cycle. Both immune cell infiltration and TMB were found to be in connection with NUP107. Cases in the group with high NUP107 expression had poorer immune infiltration, but had higher expression of immune checkpoints, TMB, and proportion of TP53 mutations. CONCLUSION: NUP107 is a sensitive diagnostic and prognostic factor for LUAD and may be involved in tumor progression through its effects on cell cycle and immune infiltration.
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Exploring the role of CDCA4 in liver hepatocellular carcinoma using bioinformatics analysis and experiments.
Liver hepatocellular carcinoma (LIHC) encompasses diverse therapeutic approaches, among which targeted therapy has gained significant prominence in recent years. The identification of numerous targets and the increasing clinical application of targeted drugs have greatly improved LIHC treatment. However, the precise role of CDCA4 (Cell Division Cycle Associated 4), as well as its underlying mechanisms and prognostic implications in LIHC, remains unclear. CDCA4 expression levels in LIHC were analyzed using multiple databases including the cancer genome atlas (TCGA), gene expression profiling interactive analysis (GEPIA), and ULCAN, as well as the datasets E_TABM_36, GSE144269, GSE14520, and GSE54236. The prognostic value of CDCA4 was then evaluated. Subsequently, the association between CDCA4 and immune cells was investigated. Enrichment analysis (GSEA) was utilized to investigate the functional roles and pathways linked to CDCA4. Additionally, the methylation patterns and drug sensitivity of CDCA4 were examined. A predictive model incorporating immune genes related to CDCA4 was developed. The TISCH dataset was used to investigate the single-cell expression patterns of CDCA4. Finally, validation of CDCA4 expression levels was conducted through RT-PCR, Western blotting, and immunohistochemistry. CDCA4 exhibited significant overexpression in LIHC and demonstrated significant correlations with clinical features. High expression of CDCA4 is associated with a poorer prognosis. Analysis of immune infiltration and enrichment revealed its association with the immune microenvironment. Furthermore, its expression is correlated with methylation and mutation patterns. CDCA4 is associated with 19 drugs. Prognostic models utilizing CDCA4 demonstrate favorable effectiveness. T cell subtypes were found to be associated with CDCA4 through single-cell analysis. The conclusive experiment provided evidence of significant upregulation of CDCA4 in LIHC. The high expression of CDCA4 in LIHC is associated with prognostic significance and is highly expressed in T cell subtypes, providing a new therapeutic target and potential therapeutic strategy for LIHC.
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Fibroblast reprogramming in the dura mater of NTG-induced migraine-related chronic hypersensitivity model drives monocyte infiltration via Angptl1-dependent stromal signaling.
BACKGROUND: Migraine, characterized by recurrent episodes of severe headache, remains mechanistically enigmatic. While traditional theories emphasize trigeminovascular activation, the role of meningeal stromal-immune crosstalk in disease chronicity is poorly understood. METHODS: A migraine-related chronic hypersensitivity model was utilized via intermittent intraperitoneal nitroglycerin (NTG, 10 mg/kg, every other day for 9 days) and peripheral mechanical hypersensitivity was assessed using von Frey filaments. Single-cell RNA sequencing (scRNA-seq) was performed on dura tissues to construct a cellular atlas of NTG-induced remodeling. These data were then integrated with migraine genome-wide association study (GWAS) risk genes, cell-cell interaction networks, and transcriptional regulation analysis to dissect NTG-driven meningeal remodeling. RESULTS: The NTG-induced migraine-related chronic hypersensitivity model demonstrated sustained mechanical allodynia, as evidenced by significantly decreased paw withdrawal thresholds (p < 0.0001). Single-cell profiling of the dura mater revealed a 2.4-fold expansion of a pro-inflammatory fibroblast subpopulation (Fibro_c5: 1.9% in Vehicle vs. 4.6% in NTG group), which exhibited marked activation of TNF-α/NF-κB signaling pathways (normalized enrichment score [NES] = 1.83). Concomitantly, we observed an 82% increase in meningeal monocytes (5.7-10.4%) that showed preferential interaction with Fibro_c5 fibroblasts through Angptl1-mediated stromal-immune crosstalk (log2 fold change = 1.41). Regulatory network analysis identified Mafk as the upstream transcriptional regulator orchestrating Angptl1 expression in this pathological communication axis. CONCLUSION: Our study reveals that NTG reprograms meningeal fibroblasts to expand a pro-inflammatory fibroblast subtype, which drives migraine-related chronic hypersensitivity through TNF-α/NF-κB signaling and Angptl1-mediated monocyte crosstalk. The identified Mafk-Angptl1 axis presents a potential therapeutic target, though human validation remains essential.