81 research outputs found

    Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

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    The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

    Applying modern portfolio theory and the capital asset pricing model to DoD's information technology investments

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    Program Managers (PMs) throughout the Department of Defense (DoD) were directed by the DoD Chief Information Officer to manage information technology (IT) investments as portfolios (to include Mission Areas, Subportfolios, and Components) within the DoD Enterprise. Managing portfolios of capabilities aligns IT with the overall needs of the warfighter, as well as the intelligence and business activities which support the warfighter. This thesis provides the detailed steps that PMs and Program Executive Officers (PEOs) should follow to closely manage their IT portfolios using the concepts described within Harry Markowitz' Modern Portfolio Theory. The first section will provide a demonstration of allocating revenue generated by a fictitious large corporation to the various sub-corporate levels and then applying Knowledge Value Added (KVA) in order to calculate a Return on Investment (ROI). The foundation of KVA analysis is that each subprocess output must be represented in common units of change; a price per unit of output is generated to allocate both cost and revenue at the subprocess level. The final section will apply a similar KVA analysis to the Naval Cryptologic Carry On Program (CCOP) systems to provide a public sector example.http://archive.org/details/applyingmodernpo109454795US Navy (USN) author.Approved for public release; distribution is unlimited

    The role of huntingtin interacting protein 1 (HIP1) in tumorigenesis.

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    Huntingtin Interacting Protein 1 (HIP1) is a clathrin, actin and inositol lipid binding protein that has been shown to modulate endocytic pathways. HIP1 was originally associated with cancer by the discovery of the oncogenic HIP1/PDGF(3R fusion protein that resulted from a t(5;7) chromosomal translocation in a patient with leukemia. HIP1 has since been implicated in a variety of additional cancers, as we show here that it is frequently over expressed in breast cancer, glial brain tumors, and lymphoma. We have found previously that HIP1 over-expression predicts a bad outcome in human prostate cancer, transforms fibroblasts in culture and is necessary for prostate cancer progression in mice. Genetic deletion of HIP1 together with its only known mammalian relative, HIP1r, has profound physiologic effects on the mouse that include spinal defects, weight loss and premature death between one and eight months of age. Remarkably, we have found that transgenic expression of the human HIP1 protein in the double HIP1/HIP1r mutant mice rescues all of these phenotypes. These genetic data confirm that HIP1 is necessary for the maintenance of multiple normal adult cell types and that the human HIP1 protein is functionally similar to the mouse HIP1 and HIP1r proteins. Finally, we show here that sera from individuals with prostate cancer, glioblastoma, oligodendroglioma, and lymphoma specifically contain anti-HIP1 antibodies. These discoveries provide strong support for the idea that HIP1 expression is required for the proliferation or survival of certain types of both normal and cancerous cells. Better understanding of when and how HIP1 is altered in newly diagnosed or recurrent cancers will lead to the development of more in depth investigations into the use of screens for HIP1 abnormalities in both the clinical and basic areas of cancer research.Ph.D.Health and Environmental SciencesOncologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127145/2/3406228.pd

    Elementary Organic Chemestry A Brief Course

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    Characterizing Arginyl-tRNA from Prevotella intermedia for Drug Design

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    Antibiotic resistance is becoming more prevalent; thus, the need to find other inhibition pathways. A possibility is the aminoacyl-tRNA synthetases which catalyze the attachment of the amino acid to its respective tRNA. These enzymes are an excellent target for drug development. Prevotella intermedia (Pi) is an orphan organism which causes Noma, an oral cavity flesh-eating disease. We selected the Pi arginyl-tRNA synthetase (ArgRS) because of its unusual features and dissimilarity to human homologs. More so, we are characterizing the ArgRS’s ability to bind tRNA and arginine as a prelude to drug design. Gel shift assays and aminoacylation assays will be used to characterize the interaction of the enzyme with tRNA and arginine. Once the enzymatic characterization is complete, we will pursue potential drugs, which include modified arginines. This work will lead to a better understanding of the interaction of the tRNA and arginine with the synthetase and will help computational work to determine a suitable inhibitor. By designing drugs against the tRNA synthetases, we can expand a powerful new class of antibiotics

    Prevalence and natural course of late-life depression in China primary care: A population based study from an urban community

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    Primary care is the most promising venue for the management of late-life depression in China. The current study was designed to establish the prevalence of major depressive disorder among older adults in primary care, and to examine the correlates, and the natural course of late-life depression over a year. A sample of 1275 adults aged over 60years was recruited from a primary care clinic in urban China for screening with PHQ-9, and 262 participants stratified by PHQ-9 score were interviewed to collect the presence of major depressive disorder (MDD), the availability of social support, and physical health and functional status. Participants were followed up for 12months at 3-month intervals. The estimated prevalence of MDD was 11.3% with the SCID interview. Increasing age, female gender, and lower educational level, living alone, low support from family, high medical illness burden, and impairment of daily function were significantly associated with MDD in later life. Less than 1% of these patients received treatments. More than 60% of patients with MDD at baseline remained depressed throughout the 12month follow-up period; and only 3 patients had been treated during the 12-month follow-up. The correlates of late-life depression observed here may not necessarily serve as risk factors guiding the development of future prevention strategies. In an urban Chinese primary care setting, late-life depression was found to be a common condition. Few patients with MDD received treatment for their condition, and the majority remained depressed over the following year
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