Image7_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.JPEG

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

Image6_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.JPEG

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

Image4_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.JPEG

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

Image1_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.JPEG

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

Image3_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.JPEG

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

Image5_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.JPEG

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

DataSheet1_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.DOCX

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

Image2_Integrated analysis of WGCNA and machine learning identified diagnostic biomarkers in dilated cardiomyopathy with heart failure.JPEG

The etiologies and pathogenesis of dilated cardiomyopathy (DCM) with heart failure (HF) remain to be defined. Thus, exploring specific diagnosis biomarkers and mechanisms is urgently needed to improve this situation. In this study, three gene expression profiling datasets (GSE29819, GSE21610, GSE17800) and one single-cell RNA sequencing dataset (GSE95140) were obtained from the Gene Expression Omnibus (GEO) database. GSE29819 and GSE21610 were combined into the training group, while GSE17800 was the test group. We used the weighted gene co-expression network analysis (WGCNA) and identified fifteen driver genes highly associated with DCM with HF in the module. We performed the least absolute shrinkage and selection operator (LASSO) on the driver genes and then constructed five machine learning classifiers (random forest, gradient boosting machine, neural network, eXtreme gradient boosting, and support vector machine). Random forest was the best-performing classifier established on five Lasso-selected genes, which was utilized to select out NPPA, OMD, and PRELP for diagnosing DCM with HF. Moreover, we observed the up-regulation mRNA levels and robust diagnostic accuracies of NPPA, OMD, and PRELP in the training group and test group. Single-cell RNA-seq analysis further demonstrated their stable up-regulation expression patterns in various cardiomyocytes of DCM patients. Besides, through gene set enrichment analysis (GSEA), we found TGF-β signaling pathway, correlated with NPPA, OMD, and PRELP, was the underlying mechanism of DCM with HF. Overall, our study revealed NPPA, OMD, and PRELP serving as diagnostic biomarkers for DCM with HF, deepening the understanding of its pathogenesis.</p

Data for 25933206JEB-2012-00738.R1

Data for 25933206JEB-2012-00738.R

Design Principles of the Yeast G1/S Switch

<div><p>A hallmark of the G1/S transition in budding yeast cell cycle is the proteolytic degradation of the B-type cyclin-Cdk stoichiometric inhibitor Sic1. Deleting <i>SIC1</i> or altering Sic1 degradation dynamics increases genomic instability. Certain key facts about the parts of the G1/S circuitry are established: phosphorylation of Sic1 on multiple sites is necessary for its destruction, and both the upstream kinase Cln1/2-Cdk1 and the downstream kinase Clb5/6-Cdk1 can phosphorylate Sic1 <i>in vitro</i> with varied specificity, cooperativity, and processivity. However, how the system works as a whole is still controversial due to discrepancies between <i>in vitro</i>, <i>in vivo</i>, and theoretical studies. Here, by monitoring Sic1 destruction in real time in individual cells under various perturbations to the system, we provide a clear picture of how the circuitry functions as a switch <i>in vivo</i>. We show that Cln1/2-Cdk1 sets the proper timing of Sic1 destruction, but does not contribute to its destruction speed; thus, it acts only as a trigger. Sic1's inhibition target Clb5/6-Cdk1 controls the speed of Sic1 destruction through a double-negative feedback loop, ensuring a robust all-or-none transition for Clb5/6-Cdk1 activity. Furthermore, we demonstrate that the degradation of a single-phosphosite mutant of Sic1 is rapid and switch-like, just as the wild-type form. Our mathematical model confirms our understanding of the circuit and demonstrates that the substrate sharing between the two kinases is not a redundancy but a part of the design to overcome the trade-off between the timing and sharpness of Sic1 degradation. Our study provides direct mechanistic insight into the design features underlying the yeast G1/S switch.</p></div