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Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of dis- eases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high- resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue decon- volution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical util- ities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring. [ABSTRACT FROM AUTHOR]

Background·Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in FIF have not been fully elucidated. Methods and Results·To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (1CM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with 1CM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (P

Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21waf1/cip1) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration. [ABSTRACT FROM AUTHOR]