1,720,984 research outputs found
Characterization of Mouse and Human Astrocytes in Amyotrophic Lateral Sclerosis: Effects of Oxidative Stress and Blockade of the Metabotropic Glutamate Receptor 5
No full textAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to upper and lower motor neuron (MNs) death. Recognized as a non-cell-autonomous disease, ALS is also characterized by damage and degeneration of glial cells, such as astrocytes, microglia, and oligodendrocytes. Astrocytes acquire a reactive and toxic phenotype defined by an abnormal proliferation and by the release of neurotoxic factors.
Recent studies reported that the uptake of [18F]-fluorodeoxyglucose (FDG) is increased in the spinal cord (SC) and decreased in the motor cortex (MC) of patients with ALS, suggesting that the disease might differently affect the two nervous districts with different time sequence or with different mechanisms. Here we show that MC and SC astrocytes harvested from newborn B6SJL-Tg (SOD1G93A) 1Gur (SOD1G93A) mice could play different roles in the pathogenesis of the disease. Spectrophotometric and cytofluorimetric analyses showed an increase in redox stress, a decrease in antioxidant capacity, and a relative mitochondria respiratory uncoupling in MC SOD1G93A astrocytes. By contrast, SC mutated cells showed a higher endurance against oxidative damage, through the increase in antioxidant defense and a preserved respiratory function. Thus, SOD1G93A mutation differently impaired MC and SC astrocyte biology in a very early stage of life.
One major cause for MN degeneration in ALS is represented by glutamate-mediated excitotoxicity, due to the alteration of glutamate transmission mechanisms, including glutamate receptor function. In this context, the Group I metabotropic glutamate receptor 5 (mGluR5) has been proposed to play an important role in ALS, since it is largely overexpressed during disease progression and is involved in the altered neuronal and glial cellular processes. My research group previously demonstrated that mGluR5 produces abnormal glutamate release in the spinal cord of the SOD1G93A mouse model of ALS and that halving its expression has a positive impact on in-vivo disease progression, including motor neuron survival, astrogliosis, and microgliosis. They also investigated the consequences of reducing the mGluR5 expression in SOD1G93A mice on the reactive phenotype of spinal cord astrocytes cultured from late symptomatic (120 days old) SOD1G93A mice. Also in this model, reducing the mGluR5 expression ameliorated the astrocyte phenotype.
UNIVERSITY OF GENOVA 8
Here, I translated this study to human astrocytes derived from healthy donors and ALS patients. We investigated the in-vitro pharmacological treatment effect of chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), a negative allosteric modulator of mGluR5 on i-astrocytes differentiated from the inducible neural progenitor cells (iNPCs) obtained from the skin fibroblast (i-astrocytes) of two ALS patients and two healthy donors. The overexpression of anti-glial fibrillary acid protein (GFAP), S100 calcium-binding protein β (S100β), and Complement component 3 (C3), three markers of astrogliosis, was reduced in CTEP-treated i-astrocytes. The same positive effect was obtained in the case of NLR family pyrin domain containing 3 (NLRP3) and nuclear factor erythroid 2-related factor 2 (NRF2), markers strictly related to inflammation and oxidative stress respectively, which are upregulated in ALS astrocytes. In-vitro pharmacological treatment with CTEP also reduced the expression of mGluR5 in mutated i-astrocytes. In addition, the CTEP treatment caused a decrement in antioxidant enzymatic activity such as malondialdehyde (MDA), glucose-6-phosphate dehydrogenase (G6PD), Glutathione reductase (GR), Glutathione peroxidase (GP), and catalase compared to the untreated samples, suggesting that the drug could cause a reduction of oxidative stress.
Altogether, these results indicate that reduction of mGluR5 activation has a positive impact on i-astrocytes in ALS patients supporting the idea that the in-vivo amelioration of the disease progression, registered after mGluR5 genetical or pharmacological silencing, involve an astrocyte phenotype improvement also in humans. As a whole, mGluR5 may represent a potential therapeutic target to preserve MNs from death, also by modulating the reactive astroglial phenotype in ALS
The negative allosteric modulator CTEP ameliorates the reactive phenotype of iastrocytes from patients affected by Amyotrophic Lateral Sclerosis
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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
MicroRNA Alteration, Application as Biomarkers, and Therapeutic Approaches in Neurodegenerative Diseases
No full textMicroRNAs (miRNAs) are essential post-transcriptional gene regulators involved in various neuronal and non-neuronal cell functions and play a key role in pathological conditions. Numerous studies have demonstrated that miRNAs are dysregulated in major neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington’s disease. Hence, in the present work, we constructed a comprehensive overview of individual microRNA alterations in various models of the above neurodegenerative diseases. We also provided evidence of miRNAs as promising biomarkers for prognostic and diagnostic approaches. In addition, we summarized data from the literature about miRNA-based therapeutic applications via inhibiting or promoting miRNA expression. We finally identified the overlapping miRNA signature across the diseases, including miR-128, miR-140-5p, miR-206, miR-326, and miR-155, associated with multiple etiological cellular mechanisms. However, it remains to be established whether and to what extent miRNA-based therapies could be safely exploited in the future as effective symptomatic or disease-modifying approaches in the different human neurodegenerative disorders
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
The negative allosteric modulator CTEP ameliorates the reactive phenotype of iastrocytes from patients affected by Amyotrophic Lateral Sclerosis
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