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Interactions between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases
Full text linkIn this special issue of Journal of Lipids, we acknowledge the contributions by several experts offering timely perspectives on the complex interactions between bile acids and nuclear receptors (NRs) on lipid metabolism and liver diseases at different levels and contexts in the body.
NRs are found within the interior of cells and are defined as ligand-activated transcriptional regulators of several key aspects of body physiology and pathophysiology. NRs regulate gene transcription through interaction with cellular coactivators and corepressors. In the liver, NRs play a key role in a large variety of metabolic processes such as cholesterol, bile acid, fatty acid, and glucose homeostasis, as well as drug disposition. Also, additional critical processes involving the pathophysiology of liver diseases—inflammation and fibrosis, regeneration, cell differentiation, and tumor formation—are modulated by NRs. Of note, NRs are or might soon become drug targets. Despite the huge accumulation of knowledge in the field, the true comprehension of interactions between bile acids and NRs on lipid metabolism and hepatobiliary diseases has remained elusive. Thus continuous efforts are being made to understand the molecular functions of NRs, the significance of bile acid-controlled signaling pathways, and interactions of NRs on a number of metabolic and hepatic diseases.
The paper of T. Li and Y. L. Chiang is focused on the role of bile acid signaling in the regulation of glucose and lipid metabolism. Besides their detergent properties and key physiological functions, bile acids are also acting as potent metabolic regulators of glucose and lipid homeostasis. The identification of bile acid-activated nuclear receptor farnesoid X receptor (FXR) and cell surface G-protein-coupled receptor TGR5 has significantly advanced our understanding on how bile acid signaling regulates cellular metabolism in health and disease. Thus, novel therapeutic strategies can be envisioned which target bile acid metabolism for the treatment of metabolic disorders such as obesity, insulin resistance, and the metabolic syndrome.
NRs comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. The paper by G. Garruti et al. deals with the myriad roles of small heterodimer partner (SHP), a unique orphan nuclear receptor lacking a DNA-binding domain, but containing a putative ligand-binding domain. About half of mammalian NRs and several transcriptional coregulators can interact with SHP. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. In humans, studies are emerging on the association of SHP genetic variation with birth weight, high body mass index, obesity, insulin resistance, and diabetes. Future research must be focused on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities.
One important issue in lipidology is the understanding of the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine and are transported to the liver. The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma total and LDL cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. The paper by O. de Bari et al. emphasizes the novel concept that, ezetimibe treatment also induces a complete resistance to two frequent metabolic abnormalities, namely, cholesterol gallstones and nonalcoholic fatty liver disease (NAFLD). Furthermore, it prevented hypercholesterolemia in mice on a Western diet. This model has high translational value and points to a key role for chylomicrons, the natural lipid carriers used by enterocytes to transport cholesterol and fatty acids into the body. The hypothesis that ezetimibe could prevent two prevalent hepatobiliary diseases (i.e., cholesterol cholelithiasis and liver steatosis) possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver is discussed here.
Because several proteins are implicated in determining biliary lipid secretion in the liver and are regulated by several transcription factors, including nuclear receptors liver X receptor (LXR) and FXR, the paper by M. C. Vázquez et al. is focused on molecular mechanisms underlying the link between nuclear receptor function and the formation of cholesterol gallstones. A potent role for estrogen receptors in the pathogenesis of cholesterol gallstone disease, involving both genomic and nongenomic activation of signaling pathways, is discussed. Evidence in this respect is heavily supported by human and murine genetic, physiological, pathophysiological, and pharmacological studies. Indeed, expanding the knowledge about the role of NRs in gallstone formation will certainly lead to the discovery of novel and more effective therapeutic strategies in a typical example of a metabolic “mass disease,” that is, cholesterol cholelithiasis.
In the wide field of lipopathy, NAFLD is currently evolving as the most common liver disease worldwide, with potential costly and severe sequelae, including liver cirrhosis and hepatocellular carcinoma. In his paper, M. Fuchs underscored the concept that NAFLD not only represents an insulin resistance state characterized by a cluster of dysmetabolic cardiovascular risk factors, but also represents an independent risk factor for cardiovascular diseases. Of note, the bile acid-activated nuclear receptor FXR has been shown to play a role not only in bile acid but also in lipid (cholesterol and triglyceride) metabolism and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. Activation of FXR may result in not only beneficial actions but also potential undesirable side effects. One example is the (still unpredictable) balance between pro- and anti-atherogenic effects of FXR activation.
J. A. López-Velázquez et al. described the important role of several NRs in the liver as regulators of several critical metabolic steps involved in the pathogenesis of NAFLD. Such crucial steps include fat storage, export, uptake, oxidation, and lipolysis. A whole family of NRs is targeted by many ligands controlling lipid metabolism including fatty acids, oxysterols, and lipophilic molecules. Understanding the molecular mechanisms underlying the involvement of NRs in the pathogenesis of NAFLD may, therefore, offer targets for the development of new treatments of one of the most frequent chronic liver diseases worldwide.
In their paper, R. Müllenbach et al. provided an update on genetic variants of NRs involved in regulating important aspects of liver metabolism. One such aspect is the application of NRs in genetic diagnosis of monogenic (Mendelian) liver diseases and their uses in clinical diagnosis. Moreover, a role of NR polymorphisms in common diseases can be anticipated, linking regulatory networks to complex and variable phenotypes. Technical advances contribute to the restless expansion of knowledge and include transgenic animal models, expression quantitative trait loci (eQTL) mapping, and genomewide association studies (GWASs). Thus, it is highly likely that personal genome information might eventually be able to predict a variety of risks associated with an individual\u27s lifestyle such as high fat diet and alcohol as well as susceptibility to infectious liver diseases such as hepatitis B or C.
Menopause is a consequence of the normal aging process in women and it is thought that menopause is associated with a higher risk for cardiovascular diseases. Indeed, the post-menopause lipid profile is often altered, which represents a risk factor for cardiovascular diseases. The paper by P. J. Oliveira et al. reports on the mechanisms linking alterations of mitochondrial bioenergetics in the heart, as a consequence from normal aging and/or from the menopausal process, to decreased fatty acid oxidation and accumulation of fatty acid intermediates in the cardiomyocyte cytosol. Such lipotoxic consequences might represent the important link to increased cardiovascular risk in the menopausal women.
In conclusion, the field of lipidology has become even more complex and exciting when considering that the discovery of NRs and their pleiotropic functions have opened the way to multidimensional, multidisciplinary and translational studies. Since NRs are involved in virtually all physiological functions, understanding how NRs work is therefore essential to explain the complex pathophysiological mechanisms underlying liver and extrahepatic diseases. A new era in which NRs will represent valid therapeutic targets for several disorders is hopefully approaching.
Lastly, we hope that this contribution will also help both young and experienced investigators in their daily difficult task to expand their research in the field of experimental and clinical lipidology in health and disease
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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