1,720,986 research outputs found
GLP1 receptor agonism ameliorates Parkinson's disease through modulation of neuronal insulin signalling and glial suppression
No full text<p><span><span>Neuronal i</span><span>nsulin resistance </span><span>is linked to the pathogenesis</span> <span>of</span><span> Parkinson’s </span><span>disease </span><span>through unclear, but potentially targetable, mechanisms. We delineated neuronal and glial mechanisms of insulin resistance and glucagon-like 1 peptide (GLP-1) receptor agonism in </span><span>human </span><span>iPSC models of </span><span>synucleinopathy</span><span>, and corroborated our findings in patient samples from a Phase 2 trial of a GLP-1R agonist in Parkinson’s (NCT01971242)</span><span>. </span><span>Human iPSC models of </span><span>synucleinopathy</span><span> exhibit neuronal insulin resistance and dysfunctional insulin signalling, which is associated with inhibition of the neuroprotective Akt pathways, and increased expression of the MAPK-associated p38 and JNK stress pathways. </span><span>Ultimately, this</span><span> imbalance is associated with cellular stress, impaired </span><span>proteostasis</span><span>, accumulation of α-synuclein, and neuronal loss. The GLP1-R agonist exenatide led to restoration of insulin signalling, associated with restoration of Akt signalling and suppression of the MAPK pathways in neurons. GLP-1R agonism reverses the neuronal toxicity associated with the </span><span>synucleinopathy</span><span>, through reduction of oxidative stress, improved mitochondrial and lysosomal function, reduced aggregation of α-synuclein, and enhanced neuronal viability. GLP1-R agonism further suppresses synuclein induced inflammatory states in glia, leading to neuroprotection through non cell autonomous effects. In the exenatide-PD2 clinical trial, exenatide treatment was associated with clinical improvement in individuals with higher baseline MAPK expression (and thus insulin resistance). Exenatide treatment led to a reduction of α-synuclein aggregates, and a reduction in inflammatory cytokine IL-6. Taken together, our patient platform defines the mechanisms of GLP-1R action in neurons and astrocytes, </span><span>identifies</span><span> the population likely to </span><span>benefit</span><span> from GLP-1R agonism, and highlights the utility of GLP-1R agonism as a disease </span><span>modifying</span><span> strategy in </span><span>synucleinopathies</span><span>.</span></span><span> </span></p>
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
Exenatide and the treatment of Parkinson's disease
No full textParkinson’s disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of people over the age of 65. Despite the best available medical and surgical therapies, there are no known treatments that can slow or alter clinical disease progression or continued neurodegeneration, thus any novel intervention that could delay or slow progression of PD would provide much needed health and socio-economic benefits. The mechanisms underlying PD pathogenesis remain unclear but there is accumulating evidence to suggesting that Type 2 diabetes and PD, both age-related diseases, share similar dysfunctional pathways. Alterations in metabolism, inflammation and mitochondrial function occur in both diseases and growing evidence suggests these pathways may impact on various tissues’ ability to respond to insulin, leading to “insulin resistance” in peripheral tissues and neurones, promoting cell death pathways and leading ultimately to diabetes and neurodegeneration respectively. The common pathways between these two conditions has led some to speculate that “insulin sensitizing” treatments for patients with Type 2 diabetes may be useful as novel treatments in neurodegenerative diseases such as PD. Exenatide is a Glucagon-like peptide-1 (GLP-1) agonist, currently licensed for the treatment for Type 2 diabetes and acts on insulin signalling pathways. It has demonstrated neuroprotective effects across a variety of animal toxin models of PD and also in a proof of concept, open label trial of mid-stage PD patients, conferring persistent motor and cognitive benefits sustained past the period of drug exposure. In this thesis I will present the first data from a fully randomised, placebo-controlled trial of exenatide in PD patients and explore the effects of exenatide on disease progression in PD and its influence on motor and non-motor symptoms. Furthermore, I will explore the pharmacokinetics of exenatide in this population and, utilising data from serum extracellular vesicles (exosomes) enriched for neuronal origin from the Exenatide-PD trial participants, demonstrate that peripherally administered exenatide can engage with neuronal insulin signalling pathways, providing some mechanistic context for the trial results. Taken together, data presented here will provide compelling evidence supporting the links between insulin signalling and PD and that the role of exenatide and other GLP-1 agonists as a novel treatment for PD should be explored further
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
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