Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway

The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents. © 2012 Elsevier Inc

Using the Steel Vessel Material-cost Index to Mitigate Shipbuilder Risk

Proceedings Paper (for Acquisition Research Program)This paper describes how the US Navy structures fixed-price and fixed-price, incentive-fee shipbuilding contracts and how labor- and material-cost indexes can mitigate shipbuilder risk in either type of contract. The Navy frequently uses the Steel Vessel material-cost index, a Bureau of Labor Statistics-derived cost index based on the mix of materials in a typical commercial cargo ship constructed in the 1950s. The Steel Vessel Index has excessive weighting on iron and steel, thereby providing shipbuilders with a mismatch between their actual and the Index-assumed material-cost structure. We recommend the Navy use a material-cost index with more up-to-date weightings.Naval Postgraduate School Acquisition Research ProgramApproved for public release; distribution is unlimited

Dollar Value and Risk Levels

Symposium Presentation (for Acquisition Research Program)Symposium PresentationNaval Postgraduate School Acquisition Research ProgramApproved for public release; distribution is unlimited

Using the Steel Vessel Material-cost Index to Mitigate Shipbuilder Risk

Symposium Presentation (for Acquisition Research Program)Symposium PresentationNaval Postgraduate School Acquisition Research ProgramApproved for public release; distribution is unlimited

Initial Fuelling Raj Raman

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