The role of DNA methylation in aging, rejuvenation, and age-related disease

DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-l-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation. © Copyright 2012, Mary Ann Liebert, Inc. 2012.

KM governance:the mechanisms for guiding and controlling KM program

Purpose: To establish and sustain their KM programs organizations need to establish mechanisms to ensure their governance. KM programs require business integration, senior management involvement and decision making authority. The present research investigates the KM governance mechanisms organizations use to guide and control their KM programs. The research seeks to contribute to a better understanding of the governance of KM and to support organizations in the development of their KM programs. Methodology: The study employs multiple case research methodology to analyze the KM governance arrangements of twelve international organizations and identify patterns in their governance configurations. Findings: The analysis identifies a range of structural, process and relational mechanisms that are critical for governing an organizational KM program. Different patterns among the KM governance mechanisms are identified which lead to the development of generic KM governance typologies. Research implications: The development of the KM governance framework allows future research to systematically investigate the KM governance phenomenon. As the present study is based on a configurational analysis future research should particularly target the performance implications of different KM governance configurations. Practical implications: The research provides insights into the diversity of KM governance mechanisms and their impact on a KM program. The KM governance framework can assist managers in reviewing their present and prospective KM programs and thereby support benchmarking or re-organization efforts. Originality: Building on prior research that has focused on individual KM governance aspects, the present study adopts a comprehensive perspective integrating structural, process and relational governance mechanisms.