Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

Background Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. Methods To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Results Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10− 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10− 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10− 12), as well as the TFAM knockout methylation (P = 4.41 × 10− 4) and expression (P = 4.30 × 10− 4) studies. Conclusions These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

Enhancement of Deep Learning in Image Classification Performance Using Xception with the Swish Activation Function for Colorectal Polyp Preliminary Screening

One of the leading forms of cancer is colorectal cancer (CRC), which is responsible for increasing mortality in young people. The aim of this paper is to provide an experimental modification of deep learning of Xception with Swish and assess the possibility of developing a preliminary colorectal polyp screening system by training the proposed model with a colorectal topogram dataset in two and three classes. The results indicate that the proposed model can enhance the original convolutional neural network model with evaluation classification performance by achieving accuracy of up to 98.99% for classifying into two classes and 91.48% for three classes. For testing of the model with another external image, the proposed method can also improve the prediction compared to the traditional method, with 99.63% accuracy for true prediction of two classes and 80.95% accuracy for true prediction of three classes.

Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs

ABSTRACTBackgroundMitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.MethodsTo investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2,507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings we assayed an additional 2,528 participants from the Cardiovascular Health Study (CHS) (N=533) and Framingham Heart Study (FHS) (N=1,995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.ResultsThirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P<5×10-8). Meta-analysis across all cohorts identified six mtDNA-CN associated CpGs at genome-wide significance (P<5×10-8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN directly drives changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the ‘neuroactive ligand receptor interaction’ KEGG pathway was found to be highly overrepresented in the ARIC cohort (P= 5.24×10-12), as well as the TFAM knockout methylation (P=4.41×10-4) and expression (P=4.30×10-4) studies.ConclusionsThese results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

A Question of Control? Examining the Role of Control Conditions in Experimental Psychopathology using the Example of Cognitive Bias Modification Research

While control conditions are vitally important in research, selecting the optimal control condition can be challenging. Problems are likely to arise when the choice of control condition is not tightly guided by the specific question that a given study aims to address. Such problems have become increasingly apparent in experimental psychopathology research investigating the experimental modification of cognitive biases, particularly as the focus of this research has shifted from theoretical questions concerning mechanistic aspects of the association between cognitive bias and emotional vulnerability, to questions that instead concern the clinical efficacy of ‘cognitive bias modification’ (CBM) procedures. We discuss the kinds of control conditions that have typically been employed in CBM research, illustrating how difficulties can arise when changes in the types of research questions asked are not accompanied by changes in the control conditions employed. Crucially, claims made on the basis of comparing active and control conditions within CBM studies should be restricted to those conclusions allowed by the specific control condition employed. CBM studies aiming to establish clinical utility are likely to require quite different control conditions from CBM studies aiming to illuminate mechanisms. Further, conclusions concerning the clinical utility of CBM interventions cannot necessarily be drawn from studies in which the control condition has been chosen to answer questions concerning mechanisms. Appreciating the need to appropriately alter control conditions in the transition from basic mechanisms-focussed investigations to applied clinical research could greatly facilitate the translational process.