Browsing by Subject "Regulation"

Now showing 1 - 10 of 15
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    Activation of Gcn2 by Pharmacological Agents Designed to be Inhibitors
    (2023-01) Carlson, Kenneth Reed; Wek, Ronald C.; Georgiadis, Millie M.; Liu, Yunlong; Staschke, Kirk A.; Turchi, John J.
    The integrated stress response (ISR) is an important mechanism by which cells confer protection against environmental stresses. Central to the ISR is a collection of related protein kinases that monitor stress conditions, such as Gcn2 (EIF2AK4) that recognizes nutrient limitations, inducing phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Gcn2 phosphorylation of eIF2 lowers bulk protein synthesis, conserving energy and nutrients, coincident with preferential translation of stressadaptive gene transcripts, such as that encoding the Atf4 transcriptional regulator. While Gcn2 is central for cell protection to nutrient stress and its depletion in humans leads to pulmonary disorders, Gcn2 can also contribute to the progression of cancers and facilitate neurological disorders during chronic stress. Consequently, specific ATP-competitive inhibitors of Gcn2 protein kinase have been developed. This thesis reports that one such Gcn2 inhibitor, Gcn2iB, can activate Gcn2, probes the mechanism by which this activation occurs, and compares the mechanism of Gcn2 activation by Gcn2iB to that of uncharged tRNA. In this study, Gcn2 activation was measured in cultured human cells by immunoblot and luciferase reporter assays making use of a genetic complementation assay to assess the contribution of various Gcn2 residues to its activation. Low concentrations of Gcn2iB increase Gcn2 phosphorylation of eIF2 and enhance Atf4 expression and activity. Of importance, Gcn2iB can activate Gcn2 mutants devoid of functional regulatory domains or with certain kinase domain substitutions derived fromGcn2-deficient human patients. Other ATP-competitive inhibitors can also activate Gcn2, although there are differences in their mechanisms of activation. These results provide a cautionary note about the pharmacodynamics of eIF2 kinase inhibitors in therapeutic applications. However, compounds designed to be kinase inhibitors that instead directly activate Gcn2, even loss of function variants, may provide tools to alleviate deficiencies in Gcn2 and other regulators of the ISR.
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    Advocacy 101 for Interventional Cardiologists: A Society for Cardiovascular Angiography & Interventions Policy Statement
    (Elsevier, 2023-07-27) Goldsweig, Andrew M.; Box, Lyndon C.; Hoyer, Mark; Klein, Andrew J.; Lata, Kusum; Rooney, Curtis; Snyder, Richard W.; Tariq, Afnan; Toggart, Edward; Tukaye, Deepali; Cigarroa, Joaquin E.; Pediatrics, School of Medicine
    Advocacy is a core mission of the Society for Cardiovascular Angiography & Interventions (SCAI). SCAI advocates on behalf of interventional cardiologists and our patients. This document provides foundational information and a toolkit for grassroots advocacy by interventional cardiologists. The first half of the document summarizes how health care laws are made, how medical devices are approved, and how procedure reimbursement is determined. The second half of the document is a playbook of advocacy strategies: legislative advocacy, judicial advocacy, advocacy with regulators and payors, advocacy in the media, and participation in SCAI advocacy initiatives, such as the Government Relations Committee and SCAI Political Action Committee. Equipped with this toolbox, interventional cardiologists must increase our advocacy activities with government, payors, and industry.
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    Building the Agenda for Institutional Research in Water Resource Management
    (JAWRA Journal of the American Water Resources Association, 2004) Blomquist, William; Heikkila, Tanya; Schlager, Edella
    This paper pursues more specifically the recommendations of a recent National Research Council report recommending greater attention to research on institutions in the field of water resource management. The important challenge for the future in institutional research lies in going beyond the observation that institutions are important and in explaining instead how institutions actually affect management options and outcomes. It is possible to illuminate the relationships between institutional features and water management through comparative institutional research. This paper offers recommendations for studying water institutions in a comparative context, including methodological recommendations concerning approaches to comparative institutional research, and topics for comparative institutional research that appear especially fruitful at this time. The example of conjunctive management is used to illustrate the importance of institutional factors in water management, drawing to some extent on the authors’ recent experience with a comparative study of conjunctive management institutions.
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    Deficits in Our Understanding of Natural Killer Cell Development in Mouse and Human
    (Wolters Kluwer, 2023) Schorr, Christopher; Krishnan, Maya Shraddha; Capitano, Maegan; Microbiology and Immunology, School of Medicine
    Purpose of review: Natural killer (NK) cells are a type of immune cell that play a crucial role in the defense against cancer and viral infections. The development and maturation of NK cells is a complex process, involving the coordination of various signaling pathways, transcription factors, and epigenetic modifications. In recent years, there has been a growing interest in studying the development of NK cells. In this review, we discuss the field's current understanding of the journey a hematopoietic stem cell takes to become a fully mature NK cell and detail the sequential steps and regulation of conventional NK leukopoiesis in both mice and humans. Recent findings: Recent studies have highlighted the significance of defining NK development stages. Several groups report differing schema to identify NK cell development and new findings demonstrate novel ways to classify NK cells. Further investigation of NK cell biology and development is needed, as multiomic analysis reveals a large diversity in NK cell development pathways. Summary: We provide an overview of current knowledge on the development of NK cells, including the various stages of differentiation, the regulation of development, and the maturation of NK cells in both mice and humans. A deeper understanding of NK cell development has the potential to provide insights into new therapeutic strategies for the treatment of diseases such as cancer and viral infections.
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    Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness
    (MDPI, 2016-11-26) Olivos III, David J.; Mayo, Lindsey D.; Department of Microbiology & Immunology, IU School of Medicine
    Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53's functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53's effects on stemness could lead to novel therapeutic strategies in cancer research.
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    EPA’s ‘secret science’ rule will make it harder for the agency to protect public health
    (The Conversation US, Inc., 2020-01-07) Filippelli, Gabriel; Earth and Environmental Sciences, School of Science
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    Open Access Legislation and Regulation in the United States: Implications for Higher Education
    (2020-11-30) Chaudhary, Anjam; Irwin, Kathy; Nguyen, David Hoa Khoa; School of Education
    Accessing quality research when not part of an academic institution can be challenging. Dating back to the 1980s, open access (OA) was a response to journal publishers who restricted access to publications by requiring a subscription and limited access to knowledge. Although the OA movement seeks to remove costly barriers to accessing research, especially when funded by state and federal governments, it remains the subject of continuous debates. After providing a brief overview of OA, this article summarizes OA statutory and regulatory developments at the federal and state levels regarding free and open access to research. It compares similarities and differences among enacted and proposed legislation and describes the advantages and disadvantages of these laws. It analyzes the effects of these laws in higher education, especially on university faculty regarding tenure and promotion decisions as well as intellectual property rights to provide recommendations and best practices regarding the future of legislation and regulation in the United States.
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    Predictions on and Analysis of Viral Proteins Encoded by Overlapping Genes
    (2011-08-19) Khosravi, Mahvash; Dunker, A. Keith
    Overlapping genes are adjacent genes that share a portion of their coding sequence. Such genes are often observed in the compact genomes of viruses, prokaryotes,and mitochondria. Overlapping genes are also seen in human and other mammalian genomes. Gene overlapping is a phenomenon to minimize genomic size and maximize encoding capacity. Overlapping genes produce different proteins. A major task in the post genomic era is the large-scale study of the structures and functions of proteins. Proteins play crucial roles in virtually all biological processes. In general it is assumed that 3-D structure determines the function of proteins, but many proteins or region of proteins may function in the absence of 3-D structure. The term disordered is used to describe these proteins. A large number of studies has shown that biological functions depend on both ordered and disordered proteins. Natively disordered regions are common and play essential roles in many proteins, especially, with regard to activities involved in signaling and regulation. The goal of this research was the analysis of the ordered and disordered tendencies of viral proteins encoded by overlapping genes. Our hypothesis is that, in a pair of proteins or protein regions encoded by overlapping genes, at least one of the pair is disordered (or unstructured). Our hypothesis is based on the observation that structural proteins require highly specific amino acid sequences, while unstructured (disordered) sequences are essentially unconstrained. Thus, given a structural protein and its associated mRNA sequence, any sequence derived from an overlapping reading frame seems highly unlikely to have a sequence pattern commensurate with a structural protein; on the other hand, a sequence pattern consistent with a disordered protein seems much more likely. We performed studies on the protein products of overlapping gene sequences, tested the hypothesis and addressed the following two questions: First do the proteins encoded by overlapping genes have opposite order-disorder content, that is, does the ordered part of one of the overlapping proteins correspond to a disordered part in the other overlapping protein? Second, does the encoded protein in the overlapping regions have more disordered amino acids than the non-overlapping regions? Using our database of overlapping viral genes and the protein predictor PONDR VL3, we predicted the order-disorder of amino acids in the sequence of 97 viral protein samples. An analysis of the results supported our hypothesis and indicated that the ordered amino acids are mostly associated with non-overlapping regions while disordered amino acids are more prevalent in overlapping regions. In the overlapping regions for 52 protein pairs, we showed that most of the amino acid pairs facing each other on the protein sequences had at least one disorder for most cases. Out of 52 pairs, there were 3 protein pairs where there were no disordered amino acids and 22 protein pairs where there were no ordered amino acids on either sequence. The fraction of ordered pairs in the pool of overlapping regions of 52 protein pairs was 0.28. The non-overlapping region of 97 proteins had predominantly ordered proteins. The fraction of ordered amino acids in the pool of non-overlapping regions was determined to be 0.77.
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    Renal Hemodynamics in AKI: In Search of New Treatment Targets
    (American Society of Nephrology, 2016-01) Matejovic, Martin; Ince, Can; Chawla, Lakhmir S.; Blantz, Roland; Molitoris, Bruce A.; Rosner, Mitchell H.; Okusa, Mark D.; Kellum, John A.; Ronco, Claudio; Department of Medicine, IU School of Medicine
    Novel therapeutic interventions are required to prevent or treat AKI. To expedite progress in this regard, a consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 to develop recommendations for research priorities and future directions. Here, we highlight the concepts related to renal hemodynamics in AKI that are likely to reveal new treatment targets on investigation. Overall, we must better understand the interactions between systemic, total renal, and glomerular hemodynamics, including the role of tubuloglomerular feedback. Furthermore, the net consequences of therapeutic maneuvers aimed at restoring glomerular filtration need to be examined in relation to the nature, magnitude, and duration of the insult. Additionally, microvascular blood flow heterogeneity in AKI is now recognized as a common occurrence; timely interventions to preserve the renal microcirculatory flow may interrupt the downward spiral of injury toward progressive kidney failure and should, therefore, be investigated. Finally, development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies.
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    Should the giving styles of the rich and famous alarm us all?
    (The Conversation US, Inc., 2017-04-26) Lenkowsky, Leslie; Lilly Family School of Philanthropy