1,720,977 research outputs found
Mesenchymal stem cell-derived exosomes and exosome-shuttled miRNAs ameliorate the reactive and neurotoxic phenotype of mouse SOD1G93A astrocytes and human-derived SOD1A4V astrocytes
No full textAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting primarily motor neurons (MNs) but involving also non-neuronal cells. Nowadays, it is well recognised that astrocytes, microglia and oligodendrocytes play a central role in disease onset and progression. In particular, astrocytes acquire a toxic phenotype characterized by an abnormal proliferation and by the release of neurotoxic factors, including pro-inflammatory cytokines (Lee et al., 2016). We have previously shown that the intravenous administration of mesenchymal stem cells (MSCs) in SOD1G93A mice prolonged survival, ameliorated motor skills and reduced gliosis and inflammation in spinal cord. These beneficial effects were not associated with MSC differentiation, being possibly mediated through paracrine mechanisms. We hypothesized that MSC-derived exosomes and exosome-shuttled miRNAs could mediate these positive effects. To verify our hypothesis we tested here the effects of exosomes derived from INF-activated MSCs on cultured astrocytes prepared from the spinal cord of 120 day-old late-symptomatic SOD1G93A mice. The phenotype of SOD1G93A astrocytes and the efficacy of the exosome treatment were characterized by Western blotting, confocal microscopy and ELISA immunoassay. Vimentin, GFAP and S100β, astrogliosis markers, were increased in astrocytes from 120 days-old SOD1G93A mice vs. age-matched WT astrocytes and their expression was reduced after exposure to exosomes. Nrf2, a booster of the response to oxidative stress, was decreased in SOD1G93A astrocytes vs. age-matched WT astrocytes. Exosome treatment normalized Nrf2 down-regulation both in the cytoplasm and nucleus. The quantification of TNF-α,IL-1β, IL-6 and CCL2 expression and release showed that these four pro-inflammatory factors were more expressed in and more efficiently released from SOD1G93A astrocytes and that the exposure to exosomes resulted in a significant decrease of their over-expression and release. Conversely, the anti-inflammatory cytokine IL-10 was decreased in SOD1G93A astrocytes and its expression was normalized after exposure to exosomes. Also NLRP3 expression, a marker of the multiprotein oligomer inflammasome, was increased in SOD1G93A astrocytes and the increase was reversed by exosomes. The amelioration of SOD1G93A astrocyte phenotype had a positive impact on MN viability in astrocyte-MN co-cultures. We observed a constant decrease of MN survival during time, both in control and exosome-treated co-cultures; however, the viability of MNs seeded on exosome-treated SOD1G93A astrocytes was always significantly higher when compared to co-cultures with untreated astrocytes. Exosome cargo was analysed for miRNAs and potential mediators of exosome activity were identified. The selected miRNAs showed a significant efficacy to reduce GFAP, IL-1β and TNF-α expression. Computational analysis highlighted their possible involvement in the modulation of NFκB and MAPK pathway activation, affecting numerous kinases and transcription factors involved in the regulation of these inflammatory signalling pathways. qPCR analysis confirmed the ability of these four miRNAs to reduce MAPK11 expression, regulating TNF-α synthesis. Unfortunately, the other selected targets were not affect by mimic transfection. Finally, we translated this study to human astrocytes derived from healthy donors and ALS patients carrying A4V-SOD1 mutation. Human ALS astrocytes were treated with exosomes derived from human MSCs, activated with INF. We observed only a slight amelioration of ALS astrocyte phenotype after the exosome treatment. Remarkably, analysis of MN viability showed an increased MN number in co-cultures with exosome-treated astrocytes compared to those co-cultured with untreated astrocytes. These results indicate that exosomes and exosome-shuttled miRNAs can reduce astrocyte reactivity and that this effect has a positive impact on MN viability. The in-vitro exosome activity, both in mouse and human models, paves the way to translational preclinical in-vivo treatments in SOD1G93A mice
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
The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity
No full textIn the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the “astrocytic signature” in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as “producers” and “targets” of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation
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
Astrocyte contribution to the excessive glutamate release in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis
No full textGlutamate (Glu) excitotoxicity plays a major role in amyotrophic lateral sclerosis (ALS) and elevated extracellular Glu levels were found in patients and animal models of the disease. Reduced astrocyte uptake was suggested as the main cause for increased Glu availability. On the basis of our experiments, we postulated that abnormal neurotransmitter release represents another source for elevated Glu. Indeed, we found that neuronal Glu release from spinal cord synaptosomes is abnormally high in the spinal cord of pre-symptomatic and symptomatic SOD1G93A mice, a widely used experimental model of ALS, under resting conditions and upon exposure to different stimuli able to induce Glu exocytosis, including KCl depolarization, ionomycin, hypertonic sucrose or activation of Group I metabotropic Glu receptors. Also GABA and glycine induced Glu release in mouse spinal cord synaptosomes by activation of the respective transportes expressed at Glu-releasing terminals (heterotransporters) and also this effect was more elevated in SOD1G93A mice than in controls.
We report here the effect of GABA on Glu release from gliosomes, an astrocytic preparation obtained by tissue homogenization and Percoll® gradient purification, that represent viable particles originating from the astrocytes sorrounding the synapses. Interestingly, GABA induced Glu release by a heterotransporter-mediated mechanism also from gliosomes purified from the spinal cord of SOD1G93A mice and the effect of GABA was up regulated, leading to over release of Glu. The excessive release of Glu evoked by GABA was already present in the pre-symptomatic stage of the disease.
Our results indicate that abnormal Glu release from astrocytes is present in pre-symptomatic and symptomatic SOD1G93A mice. Thus, astrocytes may contribute to the increased concentration of Glu at glutamatergic synapses, to the activation of presynaptic and post-synaptic Glu receptors, and to excitotoxicity
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
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