Potential Biological Pathways Research Articles

Screening of Diagnostic Biomarkers and Immune Infiltration Characteristics Linking Rheumatoid Arthritis and Rosacea Based on Bioinformatics Analysis.

Both rheumatoid arthritis (RA) and rosacea represent common chronic systemic autoimmune conditions. Recent research indicates a heightened RA risk among individuals with rosacea. However, the molecular mechanisms linking these diseases remain largely unknown. This study aims to uncover shared molecular regulatory networks and immune cell infiltration patterns in both rosacea and RA. The gene expression profiles of RA (GSE12021, GSE55457), and the rosacea gene expression profile (GSE6591), were downloaded from Gene Expression Omnibus (GEO) databases, and obtained to screen differentially expressed genes (DEGs) by using "limma" package in R software. Various analyses including GO, KEGG, protein-protein interaction (PPI) network, and weighted gene co-expression network analyses (WGCNA) were conducted to explore potential biological functions and signaling pathways. CIBERSORT was used to assess the abundance of immune cells. Pearson coefficients were used to calculate the correlations between overlapped genes and the leukocyte gene signature matrix. Flow cytometry (FCM) analysis confirmed the most abundant immune cells detected in rheumatoid arthritis and rosacea. Receiver operator characteristic (ROC) analysis, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR were used to confirm biomarkers and functions. Two hundred seventy-seven co-expressed DEGs were identified from these datasets. Functional enrichment analysis indicated that these DEGs were associated with immune processes and chemokine-mediated signaling pathways. Fourteen and 17 hub genes overlapped between cytoHubba and WGCNA were identified in RA and rosacea, respectively. Macrophages and dendritic cells were RA and rosacea's most abundant immune cells, respectively. The ROC curves demonstrated potential diagnostic values of CXCL10 and CCL27, showing higher levels in the serum of patients with RA or rosacea, and suggesting possible regulation in the densities and functions of macrophages and dendritic cells from RA and rosacea, which were validated by FCM and qRT-PCR. Importantly, our findings may contribute to the scientific basis for biomarkers and therapeutic targets for patients with RA and rosacea in the future.

Exploring causal correlations between plasma proteins and peripheral neuropathy: a Mendelian randomization.

Peripheral neuropathy (PN) is a common neurological disorder, and circulating plasma proteins with causal genetic evidence are a major source of therapeutic targets. This study identifies several potential plasma proteins that are causally related to PN risk, providing new insights into protein-mediated pathogenesis of PN and potential targets for novel therapies. To identify potential therapeutic targets for PN, we employed two-sample Mendelian randomization (MR) to identify plasma proteins associated with six common PN. First, we screened for proteins related to PN using genome-wide association studies (GWAS), obtaining genetic data on plasma proteomes from 35,559 Icelanders. Summary data for six common PN, including Carpal Tunnel Syndrome (CTS), Trigeminal Neuralgia (TN), Alcoholic Neuropathy (AIP), Drug-induced Neuropathy (DIP), Diabetic Neuropathy (DP), and Guillain-Barré syndrome (GBS), were obtained from the FinnGen database. Two-sample MR and colocalization analyses were then conducted to further identify protein-PN pairs with presumed causal relationships. Enrichment analysis of positive proteins revealed potential biological processes and pathways. Based on drug-gene interaction analysis, we ultimately identified causal proteins associated with PN that could serve as potential drug targets for treating PN. Through MR analysis, we identified eight proteins (UBC12, SEM4C, IL23R, Prothrombin, CBS, Microglobulin, MATN4, COLEC12) with causal relationships to PN. We found that UBC12 is a protective factor for DP and CTS, while the remaining proteins are risk factors. Further colocalization analysis showed a posterior probability of hypothesis 4 (PPH4) less than 0.75, indicating no positive colocalization results were found. From the pathway enrichment analysis, we discovered that the proteins were mainly concentrated in pathways related to defense response to bacterium, receptor signaling pathway via STAT, cell killing, negative regulation of cytokine production, and leukocyte mediated immunity. Finally, in Drug-Gene Interaction database (DGIdb), we identified three protein-coding genes (IL23R, F2, CBS) as potential drug targets for PN. Mendelian randomization studies confirm the causal relationship between genetically predicted PN-related risk and genetically predicted plasma protein abundance. Plasma proteins, as biomarkers associated with PN, can provide potential drug targets for etiological intervention research in PN.

PCMT1 confirmed as a pan-cancer immune biomarker and a contributor to breast cancer metastasis.

Protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT, gene name PCMT1) is an enzyme that repairs proteins with altered aspartate residues by methylation, restoring their normal structure and function. This study conducted a comprehensive analysis of PCMT1 in pan-cancer. The Cancer Genome Atlas, Human Protein Atlas website, and the Genotype-Tissue Expression were utilized in analysis of PCMT1 expression. We examined the association between PCMT1 expression and various factors, including gene modifications, DNA methylation, immune cell infiltration, immunological checkpoints, drug susceptibility, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analyses determined the potential biological roles and pathways involving PCMT1. Our focus then shifted to the role of PCMT1 in breast invasive carcinoma (BRCA). We found that PCMT1 expression was aberrant in many tumors and significantly influenced the prognosis across several cancer types. Gene alterations in PCMT1 predominantly involved deep deletions and amplifications. A negative correlation was observed between DNA methylation and PCMT1 expression across all studied cancer types except thyroid carcinoma PCMT1 exhibited positive correlations with common lymphoid progenitor and CD4(+) T helper 2 cells, whereas it was inversely correlated with central and effector memory T cells, memory CD8(+) T cells, and CD4(+) T helper 1 cells. In many cancer types, PCMT1 expression closely correlated with immunological checkpoint inhibitors, TMB, and MSI. It was also significantly linked to pathways involved in epithelial-mesenchymal transition (EMT), highlighting its role in cancer metastasis. PCMT1 emerged as a significant predictor of breast cancer progression. In vitro experiments demonstrated that reducing PCMT1 expression decreased BRCA cell migration and invasiveness. Additionally, animal studies confirmed that inhibition of PCMT1 slowed tumor growth.

Actin filament-associated protein 1-antisense RNA1 promotes the development and invasion of tongue squamous cell carcinoma via the AFAP1-AS1/miR-133a-5p/ZIC2 axis.

The present study aimed to explore the biological role and underlying mechanism of the long non-coding RNA actin filament-associated protein 1-antisense RNA1 (lncRNA AFAP1-AS1) in the progression of tongue squamous cell carcinoma (TSCC). A quantitative reverse transcriptase-PCR (RT-qPCR) was conducted to assess relative levels of the miR-133a-5p, lncRNAs AFAP1-AS1 and zinc finger family member 2 (ZIC2) in TSCC cell lines and specimens, whereas ZIC2 protein levels were measured using western blotting. After modifying the levels of expression of lncRNA AFP1-AS1, miR-133a-5p and ZIC2 using lentivirus or plasmid transfection, we examined AKT/epithelial-mesenchymal transition signaling pathway alterations, in vivo carcinogenesis of TSCC in nude mice and in vitro malignant phenotypes. A dual-luciferase reporter assay was conducted to confirm the targeting relationship between ZIC2 and miR-133a-5p, as well as between miR-133a-5p and lncRNA AFAP1-AS1. Based on The Cancer Genome Atlas (TCGA) database, we additionally validated AFP1-AS1. The potential biological pathway for AFP1-AS1 was investigated using gene set enrichment analysis (GSEA). We also evaluated the clinical diagnostic capacities of AFP1-AS1 and clustered the most potential biomarkers with the Mfuzz expression pattern. Finally, we also made relevant drug predictions for AFP1-AS1. In TSCC cell lines and specimens, lncRNA AFAP1-AS1 was upregulated. ZIC2 was upregulated in TSCC cells as a result of lncRNA AFAP1-AS1 overexpression, which also promoted TSCC cell migration, invasion, viability, and proliferation. Via the microRNA sponge effect, it was found that lncRNA AFAP1-AS1 could upregulate ZIC2 by competitively inhibiting miR-133a-5p. Interestingly, knockdown of ZIC2 reversed the biological roles of lncRNA AFAP1-AS1 with respect to inducing malignant phenotypes in TSCC cells. In addition, in vivo overexpression of lncRNA AFAP1-AS1 triggered subcutaneous tumor growth in nude mice implanted with TSCC cells and upregulated ZIC2 in the tumors. The TCGA database findings revealed that AFAP1-AS1 was significantly upregulated in TSCC specimens and had good clinical diagnostic value. The results of GSEA showed that peroxisome proliferator-activated receptor signaling pathway was significantly correlated with low expression of AFP1-AS1. Finally, the results of drug prediction indicated that the group with high AFAP1-AS1 expression was more sensitive to docetaxel, AZD4547, AZD7762 and nilotinib. The upregulation of lncRNA AFAP1-AS1, which increases TSCC cell viability, migration, proliferation and invasion via the AFAP1-AS1/miR-133a-5p/ZIC2 axis, aids in the progression of TSCC.

Relative brain age is associated with socioeconomic status and anxiety/depression problems in youth.

Brain age, a measure of biological aging in the brain, has been linked to psychiatric illness, principally in adult populations. Components of socioeconomic status (SES) associate with differences in brain structure and psychiatric risk across the lifespan. This study aimed to investigate the influence of SES on brain aging in childhood and adolescence, a period of rapid neurodevelopment and peak onset for many psychiatric disorders. We reanalyzed data from the Healthy Brain Network to examine the influence of SES components (occupational prestige, public assistance enrollment, parent education, and household income-to-needs ratio [INR]) on relative brain age (RBA). Analyses included 470 youth (5-17 years; 61.3% men), self-identifying as White (55%), African American (15%), Hispanic (9%), or multiracial (17.2%). Household income was 3.95 ± 2.33 (mean ± SD) times the federal poverty threshold. RBA quantified differences between chronological age and brain age using covariation patterns of morphological features and total volumes. We also examined associations between RBA and psychiatric symptoms (Child Behavior Checklist [CBCL]). Models covaried for sex, scan location, and parent psychiatric diagnoses. In a linear regression, lower RBA is associated with lower parent occupational prestige (p = .01), lower public assistance enrollment (p = .03), and more parent psychiatric diagnoses (p = .01), but not parent education or INR. Lower parent occupational prestige (p = .02) and lower RBA (p = .04) are associated with higher CBCL anxious/depressed scores. Our findings underscore the importance of including SES components in developmental brain research. Delayed brain aging may represent a potential biological pathway from SES to psychiatric risk. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Integrated analysis of TCGA data identifies endoplasmic reticulum stress-related lncRNA signature in stomach adenocarcinoma

Abstract Objectives To investigaed the role of endoplasmic reticulum stress (ERS)-related long non-coding RNAs (lncRNAs) in stomach adenocarcinoma (STAD) using TCGA data. Methods This study integrated clinical, transcriptomic, and tumor data from the Cancer Genome Atlas (TCGA). The expression of ERS genes was evaluated, alongside their association with identified lncRNAs. Gene set enrichment analysis and immune cell infiltration analysis were performed to elucidate the biological pathways influenced by these lncRNAs. Results The study identified five lncRNAs – AC012055.1, LINC01235, LINC00571, LINC02073, and CFAP61-AS1 – strongly correlated with ERS pathways and cancer prognosis. A prognostic model based on these lncRNAs was developed and validated across low- and high-risk groups. Potential biological pathways associated with these lncRNAs were uncovered through immune cell infiltration and GSEA. Additionally, screening identified drugs potentially effective against STAD, highlighting co-expressed genes as probable therapeutic targets. Conclusions This research offers detailed insights into the molecular mechanisms of STAD, enhancing understanding of potential therapeutic targets and showing promise for clinical applications.

GDF-15 levels in patients with polycystic ovary syndrome treated with metformin: a combined clinical and in silico pathway analysis.

Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by metabolic, reproductive, and psychological manifestations. Growth and differentiation factor 15 (GDF-15) is a cytokine associated with metabolic and inflammatory disorders. Metformin is commonly used for the treatment of PCOS. We investigated the relationship between GDF-15 levels and PCOS, the effect of metformin on GDF-15 levels, and potential biologic pathways related to GDF-15. The study included 35 women with PCOS and 32 women without PCOS (controls). Both groups were compared in terms of GDF-15 levels. Additional analysis was conducted on samples from 22 women with PCOS who were treated with either metformin (n = 7) or placebo (n = 15), retrieved from a previous randomized, controlled trial. Levels of GDF-15 were measured using MILLIPLEX. The biologic pathways related to GDF-15 were evaluated using the databases STRING, SIGNOR, and Pathway Commons. The statistical analysis was conducted using the software SPSS. Levels of GDF-15 were higher in the PCOS group compared with the non-PCOS group (p = 0.039). Among women with PCOS, GDF-15 levels were higher in those treated with metformin compared with placebo (p = 0.007). The proteins related to GDF-15 overlapped between the databases, and a significant interaction was found between GDF-15 and proteins related to PCOS and its complications, including those related to estrogen response, oxidative stress, ovarian infertility, interleukin (IL)-18, IL-4, the ratio of advanced glycation end products to their receptor (AGE/RAGE), leptin, transforming growth factor beta (TGF-β), adipogenesis, and insulin. The findings of the present study suggest a relationship between GDF-15 and PCOS and a potential increase in GDF-15 levels with metformin treatment. An additional finding was that GDF-15 could be involved in biologic pathways related to PCOS complications.

LINKAGE ANALYSIS OF PERCEIVED PHYSICAL FATIGABILITY IN THE LONG LIFE FAMILY STUDY

Abstract Fatigability, whole-body fatigue anchored to specific tasks, is a highly prevalent characteristic in older adults, but the biological mechanisms underlying perceived physical fatigability are unclear. Genetic studies may identify potential biological pathways contributing to physical fatigability. The family study design of the LLFS provides a unique opportunity to explore variants associated with fatigability using whole-genome linkage analysis. Whole genome sequencing (WGS) was available for N=2462, 496 families (age 73.6±10.5 years, 54.8% women, 99% white. Perceived physical fatigability was measured with the Pittsburgh Fatigability Scale (PFS, 0-50, lower=less severe). Prevalence of lower PFS scores (<15) was 57.9%. Multipoint linkage analysis employing likelihood-based variance components analyses were performed to identify families and genetic loci showing strong evidence for linkage. Based on linkage analysis results, a series of association analyses were performed in the subsets of linked families for PFS Physical scores. Association analyses were conducted using linear mixed models adjusted for age, field center, principal components and familial relatedness. For all families the LOD was 2.13 at chr17:79,549,108. The HLOD of the top 27 families (n=225) was 8.97. There were 8 single nucleotide polymorphisms (SNPs) identified under the linkage peak on chromosome 17. These variants were mapped to 8 different genes involved in regulation of transcription and metabolism, cellular proliferation, signal transduction, protein trafficking, and membrane structure; all important in maintenance of cellular health. Results suggest fatigability in older adults may have multiple molecular etiologies and identified variants may allude to molecular mechanisms to target in future interventions to promote healthy aging.

Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

Identification and validation of eight lysosomes-related genes signatures and correlation with immune cell infiltration in lung adenocarcinoma

Lung cancer is the leading cause of cancer-related death. Lysosomes are key degradative compartments that maintain protein homeostasis. In current study, we aimed to construct a lysosomes-related genes signature to predict the overall survival (OS) of patients with Lung Adenocarcinoma (LUAD). Differentially expressed lysosomes-related genes (DELYs) were analyzed using The Cancer Genome Atlas (TCGA-LUAD cohort) database. The prognostic risk signature was identified by Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression and multivariate Cox analysis. The predictive performance of the signature was assessed by Kaplan–Meier curves and Time-dependent receiver operating characteristic (ROC) curves. Gene set variant analysis (GSVA) was performed to explore the potential molecular biological function and signaling pathways. ESTIMATE and single sample gene set enrichment analysis (ssGSEA) were applied to estimate the difference of tumor microenvironment (TME) between the different risk subtypes. An eight prognostic genes (ACAP3, ATP8B3, BTK, CAV2, CDK5R1, GRIA1, PCSK9, and PLA2G3) signature was identified and divided patients into high-risk and low-risk groups. The prognostic signature was an independent prognostic factor for OS (HR > 1, p < 0.001). The molecular function analysis suggested that the signature was significantly correlated with cancer-associated pathways, including angiogenesis, epithelial mesenchymal transition, mTOR signaling, myc-targets. The low-risk patients had higher immune cell infiltration levels than high-risk group. We also evaluated the response to chemotherapeutic, targeted therapy and immunotherapy in high- and low-risk patients with LUAD. Furthermore, we validated the expression of the eight gene expression in LUAD tissues and cell lines by qRT-PCR. LYSscore signature provide a new modality for the accurate diagnosis and targeted treatment of LUAD and will help expand researchers’ understanding of new prognostic models.

Relationship of peripheral inflammation and discrimination with memory: a study of Black and Latinx middle‐aged adults

AbstractBackgroundMinoritized groups experience higher stress due to structural racism and discrimination. These exposures have been linked to lower cognitive test scores and inflammation is a potential biological pathway underlying this association. Yet studies with multiple inflammatory markers in diverse populations remain limited.MethodWe assessed 635 community‐dwelling adults (mean age = 54.5, SD = 11; 66% women; 67% Latinx, 33% non‐Latinx Black) from the Offspring Cohort. We characterized peripheral inflammation using principal component analysis on 33 serum inflammatory markers. Discrimination was ascertained by the Everyday and Major Discrimination Scales. Episodic memory was measured using the Selective Reminding Test and working memory by the Digit Span Test. Linear models stratified by racialized/ethnic group tested the cross‐sectional relationship between inflammation and memory adjusting for age, sex, and diabetes. Further, we examined if relationship between discrimination and memory (adjusted for age, gender, and education) was attenuated when inflammation was added. Due to smaller sample size, the magnitude of associations corresponding to change in cognitive score associated with &gt;1 year of chronological age, rather than statistical significance, was used to highlight important associations.ResultTwo inflammatory factors were derived, with component 1 including FGF2, Fractalkine, GM‐CSF, IFNg, IL13, MCP3, TNFa, and TNFb, and Component 2 including IFNa2, IL1b, IL1ra, IL5, IL9, and MIP1a. Among Spanish‐speaking participants racialized as Latinx, both inflammatory factors were associated with lower memory scores. Only the first factor was associated with lower memory for English‐speaking participants racialized as Latinx. For participants racialized as Black, only the second factor associated with lower memory. Among Spanish‐speaking Latinx, Everyday Discrimination was associated with lower working memory. Everyday Discrimination was associated with lower episodic memory among Black respondents; this association was attenuated by 20% with inclusion of the inflammatory factor 1 in the models. Several associations that were opposite to hypothesized relationships were observed.ConclusionElevated peripheral inflammation was associated with worse memory among individuals racialized as Black and Latinx. Our results indicate peripheral inflammation may contribute to disparities in cognition and may be one of the ways in which disadvantage due to structural racism and discrimination is embodied among minoritized groups in the United States.

Assessing the Biological Mechanisms Linking Smoking Behavior and Cognitive Function: A Mediation Analysis of Untargeted Metabolomics.

(1) Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which have both been linked to the development of Alzheimer's disease and related dementias (ADRD). This study identified potential mechanisms of the smoking-cognitive function relationship using metabolomics data from the longitudinal Wisconsin Registry for Alzheimer's Prevention (WRAP). (2) 1266 WRAP participants were included to assess the association between smoking status and four cognitive composite scores. Next, untargeted metabolomic data were used to assess the relationships between smoking and metabolites. Metabolites significantly associated with smoking were then tested for association with cognitive composite scores. Total effect models and mediation models were used to explore the role of metabolites in smoking-cognitive function pathways. (3) Plasma N-acetylneuraminate was associated with smoking status Preclinical Alzheimer Cognitive Composite 3 (PACC3) and Immediate Learning (IMM). N-acetylneuraminate mediated 12% of the smoking-PACC3 relationship and 13% of the smoking-IMM relationship. (4) These findings provide links between previous studies that can enhance our understanding of potential biological pathways between smoking and cognitive function.

Abstract 14613: Sex Differences in Protein Biomarkers and Measures of Fat Distribution

Background: Sex differences in obesity and fat distribution have been well described and may explain differences in subsequent cardiovascular risk in men vs women. Underlying mechanisms are not fully elucidated and warrant further investigation. Objective: This study aims to examine sex differences in the associations of obesity and fat distribution measures with cardiovascular disease (CVD) protein biomarkers reflecting key pathways including inflammation, adiposity, fibrosis, and neurohormonal regulation. Methods: We measured 71 circulating protein biomarkers in 3,143 participants with available computed tomography measures of adiposity in the Framingham Heart Study. We examined whether sex modified the association of obesity (body mass index [BMI] and waist circumference [WC]) and fat distribution measures (visceral adipose tissue [VAT]) with protein biomarkers using multiplicative interaction terms in multivariable linear regression models. Sex-stratified analyses were performed as appropriate. Results: Among 3,143 participants (mean age 50 years, 48.7% women), we found that sex modified the association of BMI with 8 protein biomarkers including AGP-1, adipsin, IGFBP-1, IGFBP-2, ADM, KLKB1, MCP-1, and ucMGP (FDR-q int &lt; 0.05 for all, Figure 1 ). For example, BMI was associated with higher MCP-1 levels in women, but not in men (ß 0.132, SE 0.025, p &lt; 0.0001 in women vs ß 0.036, SE 0.028, p = 0.20 in men, FDR-q int 0.03). We found that sex also modified the association of WC and VAT with key CVD protein biomarkers including AGP-1 and A1M. Conclusions: We found that sex modified the association of obesity and adipose traits with cardiovascular risk as ascertained using biomarkers of CVD. These findings highlight potential biological pathways that may contribute to obesity-related cardiometabolic disease uniquely in men versus women.

PSI-10 Prioritizing Fertility-Related Genes in Cattle Through Systems Genomics Data Integration

Abstract Female fertility significantly affects the efficiency of cow-calf production. Despite the collective efforts to understand the complex regulation of reproductive traits, causative genes and/or mutations have yet to be reported. Using omics technologies, such as gene expression, may unveil potential regulatory mechanisms and provide opportunities that link genotype to phenotype. Among them, expression quantitative trait loci (eQTL) are a powerful tool to identify biological mechanisms and potential markers for improving fertility. This study aimed to identify eQTLs underlying fertility-related traits and their co-localization with previously annotated QTLs. RNA-Seq from uterine epithelial cells (GSE171577) from crossbreed cows (n = 18 non-pregnant – NP and n = 25 pregnant – P) were used for gene expression analysis and SNP calling. Raw data quality control was performed, and read mapping was carried out using STAR. Genes were normalized to counts per million (CPM) and then the CPM values were log2 transformed using edgeR. Next, uniquely mapped reads were used for variant detection using the GATK software. Significant eQTLs were compared with the Animal Genome cattle database (QTLdb) to identify overlapping QTL regions. After quality control, 43 samples, 203,404 SNPs, and 15,029 genes were used for eQTL analysis. Using an additive linear model from the Matrix eQTL R-package, we identified 3,989 cis- and 7,683 trans-eQTLs for 1,120 and 2,503 genes, respectively (FDR &amp;lt; 0.05). A total of 50 cis-eQTLs were previously reported as differentially expressed genes, including CD37, CXCL3, PILRA, and PPP6R1 genes. The QTLs from QTLdb overlapping with our eQTLs were associated with traits such as age at puberty, conception rate, fertility index, and luteal activity (FDR &amp;lt; 0.05). Additionally, QTLs for production traits, such as milk production and body weight gain, were over-represented by the eQTLs we have identified. Significant biological processes underlying cis-regulated genes retrieved from ShinyGO were related to antigen processing and presentation. Likewise, trans-eQTLs genes were involved with transcription cis-regulatory region binding and transcription regulator activity. Our study provides novel regulatory and potential causative genetic variants, biological pathways, and genes underlying fertility in cows. Annotation and co-localization of detected eQTLs retrieved genomic regions previously reported as QTLs for production and reproduction-related traits. Further investigation, however, is required to untangle the mechanisms modulating gene expression and its effects on fertility-related traits.

Bioinformatics analysis and experimental validation of tumorigenic role of PPIA in gastric cancer

Gastric cancer (GC) is a malignant tumor with high incidence rate and mortality. Due to the lack of effective diagnostic indicators, most patients are diagnosed in late stage and have a poor prognosis. An increasing number of studies have proved that Peptidylprolyl isomerase A (PPIA) can play an oncogene role in various cancer types. However, the precise mechanism of PPIA in GC is still unclear. Herein, we analyzed the mRNA levels of PPIA in pan-cancer. The prognostic value of PPIA on GC was also evaluated using multiple databases. Additionally, the relationship between PPIA expression and clinical factors in GC was also examined. We further confirmed that PPIA expression was not affected by genetic alteration and DNA methylation. Moreover, the upstream regulator miRNA and lncRNA of PPIA were identified, which suggested that LINC10232/miRNA-204-5p/PPIA axis might act as a potential biological pathway in GC. Finally, this study revealed that PPIA was negatively correlated with immune checkpoint expression, immune cell biomarkers, and immune cell infiltration in GC.

Identification of key genes and regulatory networks involved in the Comorbidity of atrial fibrillation and chronic obstructive pulmonary disease

BackgroundThe underlying molecular processes of atrial fibrillation (AF) and chronic obstructive pulmonary disease (COPD) are frequently linked to increased morbidity and mortality when they co-occur. However, their underlying molecular mechanisms are questioned due to their incomplete analysis. ObjectiveThis study aimed to identify common differentially expressed genes (DEGs) in AF and COPD patients and investigate their potential biological functions and pathways. We hope to complement and update previous research through clearer figure presentation and different bioinformatic analysis methods with different datasets. MethodsWe used statistical analysis to identify DEGs in the expression profiles of AF and COPD patients using datasets from the Gene Expression Omnibus database. To ascertain whether the common DEGs were functionally enriched, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used. In addition, we generated protein‒protein interaction networks and identified significant hub genes. Furthermore, the hub genes were used to analyze transcription factor (TF)-gene interactions and TF-miRNA coregulatory networks, and their expression levels were validated in additional datasets. ResultsWe identified a total of 15 DEGs that were upregulated, whereas 36 were downregulated in AF and COPD patients. The DEGs were commonly expressed in both AF and COPD patients, with functional enrichment analysis revealing their involvement in metabolic processes and neuron-to-neuron synapses. We identified significant hub genes, including TGM2, ITPR1, CHL1, ALDOC, RPS3, FBLN2, NDUFS2, ITGA5, CTNNB1, RBP1, CLSTN2, FABP5, EPHA4, LDHA, and HNRNPL, and analyzed their coexpression and biological functions. TF-gene interaction and TF-miRNA coregulatory network analyses revealed the regulatory relationships of the hub genes. Additional datasets were analyzed to validate hub gene expression, and ALDOC, HNRNPL, and NDUFS2 displayed similar processes in AF and COPD patients. ConclusionsIn our study, we demonstrate that metabolic processes and neuron-to-neuron synaptic connections may contribute to the cooccurrence of AF and COPD. The identified hub genes and regulatory networks may act as potential biomarkers and therapeutic targets for these diseases.

Integrated Meta-Omics Analysis Unveils the Pathways Modulating Tumorigenesis and Proliferation in High-Grade Meningioma.

Meningioma, a primary brain tumor, is commonly encountered and accounts for 39% of overall CNS tumors. Despite significant progress in clinical research, conventional surgical and clinical interventions remain the primary treatment options for meningioma. Several proteomics and transcriptomics studies have identified potential markers and altered biological pathways; however, comprehensive exploration and data integration can help to achieve an in-depth understanding of the altered pathobiology. This study applied integrated meta-analysis strategies to proteomic and transcriptomic datasets comprising 48 tissue samples, identifying around 1832 common genes/proteins to explore the underlying mechanism in high-grade meningioma tumorigenesis. The in silico pathway analysis indicated the roles of extracellular matrix organization (EMO) and integrin binding cascades in regulating the apoptosis, angiogenesis, and proliferation responsible for the pathobiology. Subsequently, the expression of pathway components was validated in an independent cohort of 32 fresh frozen tissue samples using multiple reaction monitoring (MRM), confirming their expression in high-grade meningioma. Furthermore, proteome-level changes in EMO and integrin cell surface interactions were investigated in a high-grade meningioma (IOMM-Lee) cell line by inhibiting integrin-linked kinase (ILK). Inhibition of ILK by administrating Cpd22 demonstrated an anti-proliferative effect, inducing apoptosis and downregulating proteins associated with proliferation and metastasis, which provides mechanistic insight into the disease pathophysiology.

Pan-cancer analysis identifies RNF43 as a prognostic, therapeutic and immunological biomarker

BackgroundRING finger protein 43 (RNF43), an E3 ubiquitin ligase, is a homologous gene mutated in several cancers. However, the pan-cancer panoramic picture of RNF43 and its predictive value for tumor immune phenotypes and immunotherapeutic efficacy are still largely unclear. Our study aims to clarify the functions of RNF43 in predicting the prognosis, immune signature, and immunotherapeutic efficacy in pan-cancer.MethodsBy using RNA-seq, mutation, and clinical data from the TCGA database, the expression levels and prognostic significance of RNF43 in pan-cancer were analyzed. The genetic alteration characteristics of RNF43 were displayed by the cBioPortal database. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential biological functions and signaling pathways modulated by RNF43 in cancers. The relationship of RNF43 expression with immune cell infiltration, and immune modulators expression was interpreted by the ESTIMATE algorithm, CIBERSORT algorithm, and TISIDB database. The correlations between RNF43, microsatellite instability (MSI), and tumor mutation burden (TMB) were also investigated. Furthermore, the predictive value of RNF43 for immunotherapeutic efficacy and drug sensitivity was further illustrated. Besides, immunohistochemistry (IHC) was employed to validate the expression of the RNF43 in different cancer types by our clinical cohorts, including patients with lung cancer, sarcoma, breast cancer, and kidney renal clear cell carcinoma.ResultsThe results demonstrated that RNF43 was abnormally expressed in multiple cancers, and RNF43 is a critical prognosis-related factor in several cancers. RNF43 was frequently mutated in several cancers with a high frequency of 4%, and truncating mutation was the most frequent RNF43 mutation type. RNF43 expression was linked to the abundance of several immune cell types, including CD8+ T cells, B cells, and macrophages within the tumor immune microenvironment. Furthermore, RNF43 expression was significantly correlated with the efficacy of anti-PD-1/PD-L1 treatment, and it could predict the sensitivity of various anti-cancer drugs. Finally, IHC explored and validated the different expression levels of RNF43 in different cancers by our clinical samples.ConclusionOur results first present the expression pattern and the mutation signature of RNF43, highlighting that RNF43 is an important prognostic biomarker in pan-cancer. Furthermore, RNF43 seems to be a critical modulator in the tumor immune microenvironment and can function as a promising biomarker for predicting the immunotherapeutic efficacy of anti-PD-1/PD-L1 treatment, and drug sensitivity in cancer treatment.

A cross-disorder study to identify causal relationships, shared genetic variants, and genes across 21 digestive disorders

Digestive disorders are a significant contributor to the global burden of disease and seriously affect human quality of life. Research has already confirmed the presence of pleiotropic genetic loci among digestive disorders, and studies have explored shared genetic factors among pan-cancers, including various malignant digestive disorders. However, most cross-phenotype studies within the digestive tract system have been limited to a few traits, with no systematic coverage of common benign and malignant digestive disorders. Here, we analyzed data from the UK Biobank to investigate 21 digestive disorders, exploring the genetic correlations and causal relationships between diseases, as well as the common genetic factors and potential biological pathways driving these relationships. Our findings confirmed the extensive genetic correlation and causal relationship between digestive disorders, providing important insights into the genetic etiology, causality, disease prevention, and clinical treatment of diseases.

Personality and Cognition: The Mediating Role of Inflammatory Markers.

Five-Factor Model personality traits are associated consistently with cognition. Inflammation has been hypothesized as a biological pathway in this association, but this assumption has yet to be tested. The present study tested inflammatory markers as mediators between personality traits and cognition. Participants were from the Health and Retirement Study (HRS; N = 4,364; 60% women; mean age = 64.48 years, standard deviation = 8.79). Personality traits and demographic factors were assessed in 2010/2012. Data on inflammatory markers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], soluble tumor necrosis factor 1 (sTNFR1), interleukin-10 [IL-10], interleukin-1 receptor antagonist [IL-1Ra], and transforming growth factor [TGF]-β1) were obtained in 2016 from the HRS Venuous Blood Study. Cognition was assessed in 2020 using the modified Telephone Interview for Cognitive Status. Higher neuroticism was related to lower cognition at follow-up, whereas higher extraversion, openness, agreeableness, and conscientiousness were associated with better cognition. Higher extraversion and higher conscientiousness were related to lower hsCRP, IL-6, IL-10, IL-1Ra, and sTNFR1, and higher openness was associated with lower IL-10, IL-1Ra, and sTNFR1 and to higher soluble TGF-β1. Lower sTNFR1 partially mediated the associations between conscientiousness, extraversion, and openness and cognition at follow-up, explaining an estimated 4%-12% of these associations. The mediating role of sTNFR1 persisted when physical activity and depressive symptoms were included as additional mediators. The present study provides new evidence on personality and inflammatory markers. Consistent with the inflammation hypothesis, the sTNFR1 finding supports a potential biological pathway between personality and cognition.