Case Western Reserve University

About: Case Western Reserve University is a education organization based out in Cleveland, Ohio, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 54617 authors who have published 106568 publications receiving 5071613 citations. The organization is also known as: Case & Case Western.

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Abstract: Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid β on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that ≈40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with β-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or Aβ-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid β production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.

Writing narrative literature reviews.

Abstract: Narrative literature reviews serve a vital scientific function, but few resources help people learn to write them. As compared with empirical reports, literature reviews can tackle broader and more abstract questions, can engage in more post hoc theorizing without the danger of capitalizing on chance, can make a stronger case for a null-hypothesis conclusion, and can appreciate and use methodological diversity better. Also, literature reviews can draw any of 4 conclusions: The hypothesis is correct, it has not been conclusively established but is the currently best guess, it is false, or the evidence permits no conclusion. Common mistakes of authors of literature review manuscripts are described. Narrative literature reviews form a vital part of most empirical articles, theses, and grant proposals, and of course many articles and book chapters are devoted specifically to reviewing the literature on a particular topic. Literature reviews serve a scientific field by providing a much-needed bridge between the vast and scattered assortment of articles on a topic and the reader who does not have time or resources to track them down. Reviews also present conclusions of a scope and theoretical level that individual empirical reports cannot normally address. For individual researchers, writing a major literature review article is a very infrequent but often a very important career contribution. Yet, despite the importance of narrative literature reviews, no easy and available way to learn to write them is known. Research methods textbooks do not usually explain how to do them, even though reviewing literature is an important research method. Most graduate seminars in research methods likewise devote little or no time to them. Apprenticeship with an accomplished literature reviewer seems to be one possible strategy to learn this technique, but such specialists are rare, and moreover it is generally considered more important for stu

HIV-1 Antiretroviral Drug Therapy

Abstract: The most significant advance in the medical management of HIV-1 infection has been the treatment of patients with antiviral drugs, which can suppress HIV-1 replication to undetectable levels. The discovery of HIV-1 as the causative agent of AIDS together with an ever-increasing understanding of the virus replication cycle have been instrumental in this effort by providing researchers with the knowledge and tools required to prosecute drug discovery efforts focused on targeted inhibition with specific pharmacological agents. To date, an arsenal of 24 Food and Drug Administration (FDA)-approved drugs are available for treatment of HIV-1 infections. These drugs are distributed into six distinct classes based on their molecular mechanism and resistance profiles: (1) nucleoside-analog reverse transcriptase inhibitors (NNRTIs), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs), (3) integrase inhibitors, (4) protease inhibitors (PIs), (5) fusion inhibitors, and (6) coreceptor antagonists. In this article, we will review the basic principles of antiretroviral drug therapy, the mode of drug action, and the factors leading to treatment failure (i.e., drug resistance).