1,720,961 research outputs found
Mitochondrial ROS formation catalyzed by monoamine oxidase is causally related to inflammation, fibrosis and diastolic dysfunction in type 1 diabetic hearts
Get PDFCardiovascular disease is the leading cause of death among diabetic patients. Amongst various mechanisms proposed to contribute to the development of diabetic cardiomyopathy, oxidative stress has received significant experimental and clinical evaluation. However, large scale clinical trials using antioxidant therapies for the treatment of these pathological disorders have been ineffective. Collectively, these studies point towards a serious need to develop therapeutic strategies aimed at inhibiting specific sources of reactive oxygen species (ROS). In the present thesis, we investigated the role of monoamine oxidases (MAOs), outer mitochondrial enzymes that generate HβOβ, in oxidative stress and mitochondrial dysfunction in cardiomyocytes exposed to diabetic milieu and cardiac damage in type 1 diabetes (T1D) mice in vivo.
Initially, we assessed ROS formation and mitochondrial function in primary cardiomyocytes treated with high glucose (HG) and/or interleukin-1β (IL-1β), a proinflammatory cytokine found to be elevated in diabetic patients. Cells exposed to these stimuli displayed an increase in ROS formation which was accompanied by mitochondrial dysfunction as documented by decreased mitochondrial membrane potential. MAO inhibitor pargyline completely prevented these alterations, suggesting that HG and IL-1β induce ROS
formation and mitochondrial dysfunction in a MAO-dependent manner. Moreover, to study whether MAO activity is also involved in endoplasmic reticulum (ER)-mitochondria crosstalk and activation of unfolded protein response (UPR), we assessed markers of ER stress in this model. Interestingly, in adult cardiomyocytes, protein expression of activating transcription factor 4 (ATF4), growth arrest and DNA damage-inducible protein (GADDγ4), 78 kDa glucose-regulated protein (GRP78) and phosphorylation levels of IRE1α (inositolrequiring enzyme 1α) were significantly upregulated, marking the clear occurrence of ER stress. Pargyline administration abrogated these changes, suggesting that MAO is involved in HG and IL-1β induced UPR. Moreover, this suggests that, at least in this setting, MAOdependent ROS formation is upstream of ER stress, and play an important role in the crosstalk between mitochondria, inflammation and ER stress occurring in cardiomyocytes exposed to diabetic milieu.
Given the involvement of MAO in HG and IL-1β induced cell damage, we investigated its role in cardiac dysfunction in streptozotocin (STZ)-induced T1D. We found that diastolic stiffness, an index of diastolic dysfunction, was significantly increased in STZ mice, whereas ejection fraction, an index of systolic function, remained unchanged. Moreover, markers of oxidative stress (4-hydroxynonenal) and UPR (ATF4 and GADDγ4) were significantly increased in STZ hearts as compared to controls. Importantly, STZ mice treated with MAO inhibitor pargyline displayed preserved diastolic function and absence of ER and oxidative stress. In agreement with previous reports showing that fibrosis is one of the major features of diabetic cardiomyopathy, we found that hearts from STZ-treated mice displayed increased collagen deposition. Interestingly, pargyline administration prevented this alteration, suggesting that MAO activity plays a crucial role in the progression of fibrosis in these animals. To understand whether MAO-mediated fibrosis was due to release of proinflammatory and pro-fibrotic factors from cardiac mast cells, we assessed mast cell degranulation. Indeed, mast cell degranulation increased by almost β-fold in STZ hearts as compared to control mice. MAO inhibition completely blocked the activation of mast cells in diabetic mice. These data indicate the novel role of these flavoenzymes in activating cardiac mast cell thereby leading to the remodeling of the extracellular matrix, fibrosis and ultimately, left ventricle (LV) dysfunction in T1D.
Collectively, these results demonstrate that MAOs not only contribute to HG and inflammation induced mitochondrial ROS formation and dysfunction, but they also perturb ER function leading to the activation of UPR. Moreover, we showed that these flavoenzymes
play a major role in the formation of a vicious cycle between oxidative stress and inflammation, which is likely the underlying cause of cardiac fibrosis and LV diastolic dysfunction in T1D mice. MAO inhibitors are clinically available and are being used for the treatment of several neurological and neurodegenerative diseases. Results from our study suggest that MAO inhibition could be a promising therapeutic strategy also for the treatment of cardiovascular complications in diabetes
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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