1,720,971 research outputs found
Evaluation of the Impact of Human Hepatocyte-Derived Exosomes on Immune Response in Idiosyncratic Drug-Induced Liver Injury
Full text linkIntroduction: Idiosyncratic drug-induced liver injury (IDILI) is a rare, but serious adverse drug reaction that occurs rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Previous work from our group suggests that hepatocyte-derived exosomes (HDEs) may play a role in activating the innate immune system, which is likely a critical step in the pathogenesis of idiosyncratic drug-induced liver injury. Several non-parenchymal liver cell types including liver sinusoidal endothelial cells (LSECs) participate in this innate immune response. In this study, we tested the hypothesis that HDEs released from IDILI drug-treated hepatocytes modulate the immune response of LSECs.
Methods: First, we determined the peak bosentan media concentrations that did not cause overt toxicity to modify cultures of the human hepatocyte cell line, HuH-7. The HuH-7 cells were treated with vehicle (DMSO) or bosentan at three different concentrations. Exosomes were then isolated from these cultures and applied to a human LSEC cell line, TMNK-1, for 24 hours. All treatments were done in the presence and absence of lipopolysaccharide (LPS). TMNK-1 cell media from each treatment group was then collected and analyzed for pro-inflammatory cytokine release (IL-1β, IL-6, and TNF-α).
Results: LPS stimulation induced a significant increase in pro-inflammatory cytokine release in TMNK-1 cells in the absence of HDE treatment (mock control) as expected. There was no significant difference in pro-inflammatory cytokine release from TMNK-1 cells exposed to control HDEs in comparison to mock control, with or without LPS stimulation. In addition, we did not observe a significant difference in cytokine release in TMNK-1 cells exposed to HDE’s from bosentan-treated HuH-7 cells in comparison to exposure to HDEs from untreated HuH-7 cells. Interestingly, we did observe a significant increase in ATP levels in TMNK-1 cells in response to HDEs in comparison to mock control, regardless of bosentan treatment or exposure to LPS.
Conclusions: We established a robust model to study immune stimulation of TMNK-1 cells by HDEs. Our data with bosentan do not support our hypothesis that HDEs released from untreated or IDILI drug-treated hepatocytes modulate the immune responsiveness of LSECs. However, our methods may be applied to study the effects of other IDILI inducing drugs. Our finding that HDEs caused increased ATP production in TMNK-1 cells is unexpected and should be further investigated.Doctor of Pharmac
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The role of neurexins in Insulin exocytosis from pancreatic beta cells
Full text linkNeurexins are a family of synaptic adhesion molecules that in neurons bind to constituents of the secretory machinery, play a key role in the organization and stabilization of the presynaptic active zone, and help mediate docking of synaptic vesicles. Neurexins, like many protein constituents of the neurotransmitter exocytotic machinery, are also expressed in pancreatic beta cells. I hypothesized that neurexins in beta cells help to mediate insulin granule docking and thereby inhibit secretion. The results from this project demonstrate that human, rat, and mouse islets express neurexin protein, but a more restricted pattern of neurexin transcripts than neurons. Neurexin-1alpha in INS-1E beta cells is expressed on the beta-cell membrane and interacts with several components of the secretory granule docking machinery, including the secretory granule-associated protein granuphilin. EM and secretion studies showed that siRNA knockdown of neurexin- 1alpha reduces granule docking at the beta-cell membrane and improves insulin secretion. These results were confirmed in primary islets isolated from neurexin-1alpha KO mice, and perifusion of the isolated islets demonstrated that loss of neurexin-1alpha resulted in a significant increase in second-phase insulin secretion with a trend towards an increase in first-phase secretion. Upon glucose stimulation, neurexin-1alpha protein levels decrease. This glucose-induced neurexin down-regulation may enhance stimulated insulin secretion. My hypothesis that changes in neurexin expression contribute to beta- cell dysfunction in type 2 diabetes has thus far tested negative. I demonstrated that neurexin-1alpha is a component of the beta-cell secretory machinery that contributes to secretory granule docking, most likely through interactions with granuphilin. My work supports the notion that docking is inhibitory to insulin secretion and is the first to identify a transmembrane component of the insulin granule docking machinery. These findings provide new insights into the mechanisms of insulin granule docking and exocytosis. Building on these findings, additional work may enable the development of drugs that improve insulin secretion (type 2 diabetes) or the development and function of islets for transplantation (type 1 diabetes). Because neurexins are beta-cell specific and cell-surface proteins, they are also promising targets for noninvasive beta-cell in vivo imaging. This technology could be used to monitor beta- cell mass in both disease and therapy conditions and therefore enhance the development of new therapies to prevent beta-cell loss or recover beta-cell mas
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
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