1,721,111 research outputs found
Alteration of the protein quality control system in motor neuron and muscle expressing mutant proteins causing ALS and SBMA
No full textMotor neuronal system and muscle tissue are two districts differentially affected at onset and during the progression of diseases like amyotrophic lateral sclerosis (ALS) or spinal and bulbar muscular atrophy (SBMA).
The bases of these diseases are linked to mutated proteins: fALS is commonly caused by mutations in the SOD1 or the TDP43 genes and SBMA is caused by a of CAG repeat in the AR gene. A fraction of these proteins can not reach a mature conformation and misfolds. The Protein Quality Control (PQC) system is responsible for the correct protein homeostasis: the chaperones maintain proteins in their correct conformations. If they fail, mutated proteins are directed to the proteasome or the macroautophagy. When misfolded proteins are not correctly removed, they aggregate in nucleus and cytoplasm. To understand cellular behavior in presence of misfolded toxic proteins we investigate the different activation of the PQC system in the two mayor tissues involved.
Initially we investigated the differences in PQC activation between NSC34 motor neuronal and C2C12 muscular cell models. Using RTq PCR, western blot and immunocytochemical analysis for p62 and LC3 expression, localization, and turnover we demonstrated that C2C12 cells have a more active autophagic system than NSC34 cells.
Then, we compared the two models in presence of misfolded protein inhibiting degradative systems. With Filter Retardation Assay, we observed that these proteins tend to aggregate when PQC system is impaired. Then, we potentiated the PQC response to reduce the insoluble species. By overexpressing the small heat shock protein B8 in both systems we demonstrated that AR polyQ and SODG93A insoluble species were reduced.
Also autophagy activation by trehalose caused a reduction in protein aggregation in both cell models.
In conclusion misfolded protein aggregates can be reduced by modulating macroautophagy and this could represent a new therapeutical strategy for fatal disease like SBMA and ALS
The protein quality control in spinal and bulbar muscular atrophy
No full textThe protein misfolding and aggregation, typical of several neurodegenerative disease, are the results of an impairment of Protein Quality Control system (PQC). The PQC is composed by molecular chaperones, the Ubiquitin Proteasome System (UPS) and the autophagic pathway. Understanding the link between neurodegenerative diseases and the PQC might help to identify potential target for these diseases. To this purpose, we have studied the contribution of PQC in a motoneuron disease, the spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a polyglutamine-expanded tract (polyQ) in the androgen receptor protein (AR). The binding of the ligand testosterone to the ARpolyQ induces protein misfolding and aggregation. The expanded polyQ tract confers a toxic gain-of-function to mutant AR that alters a cascade of several downstream pathways, including the PQC.
Using SBMA motoneuronal cell line, we have already demonstrated that both the UPS and the autophagic pathway are altered or impaired.
Thus, we studied the ability of different compounds of promoting ARpolyQ clearance through the potentiation of the PQC activity. We found that a combination of an autophagic inducer, trehalose, with an anti-androgen Bicalutamide, have synergic activity in the autophagic clearance of ARpolyQ., Also Berberine, a natural compound, was able to induce the ARpolyQ clearance possibly through the UPS.
Moreover, using a SBMA knock-in mice model, we observed that in the spinal cord and in the skeletal muscle, the primary sites of pathogenesis, the UPS and the autophagic pathway seem to respond with a different degradative power to the ARpolyQ toxicity.
These data suggest that the up-regulation of PQC may be beneficial for the treatment of SBMA, and these compounds might represent therapeutic candidates in SBMA and in other misfolding-related diseases.
GRANTS: Fondazione AriSLA; Fondazione Cariplo; AFM Telethon France; Regione Lombardia; UNIMI; Telethon Italy
Modello computerizzato per la Valutazione Integrata del Rischio Cardiovascolare (VIRC): fattori di rischio noti ed emergenti
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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
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
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