1,720,994 research outputs found
COMPOSTI AD AZIONE ANTI-AGGREGANTE ESERCITANO UN EFFETTO BENEFICO SU MODELLI CELLULARI DI ATROFIA MUSCOLARE SPINALE BULBARE
No full textSpinobulbar Muscular Atrophy (SBMA) is a rare inherited X-linked neurodegenerative disease caused by an abnormal expansion of the CAG repeat, encoding for the poly-glutamine tract (polyGln), in the N-terminal region of the Androgen Receptor (AR) gene. This mutation leads the protein to form intranuclear aggregates in the spinal cord and brainstem and cause the death of those specific cell populations.
AR belongs to the nuclear hormone receptors superfamily and it works as a transcriptional factor after binding its specific ligand (testosterone or dihidrotestosterone) in the carboxyl-terminal ligand-binding domain (LBD). The interaction with the ligand has a central role in the aggregation process and converts the AR to an active conformation in which the transactivation domains are exposed and the AR can interact with transcriptional cofactors, bind the DNA on specific genes’ promoter and start the transcription. One of the fundamental events that occur during the AR activation is the close association between two transcriptional regions in a single protein, the AF2 domain (within the LBD) and the AF1 (a FXXLF motif in the N-terminal domain, NTD) in a N/C interaction. Previous studies suggest this interaction is one of the initial component of both the ligand-regulated AR function and the aggregation process of the mutant SBMA protein. In this study we tested in a PC12 cell model of SBMA (112 polyGln repeats AR expressed through an inducible system) six compounds, AR antagonist or partial agonists analogs, defined as SARMs (Selective AR Modulator), known to prevent the N/C interaction but to permit the nuclear receptor transcriptional activity. The treatment of our cells with this molecules indeed prevents the aggregation of the mutant AR [coupled to a slight reduction of protein levels] in absence of DHT and reduce the aggregation in presence of DHT, confirming that the N/C interaction is a central event in the aggregation process in SBMA, and making the SARMs possible candidates in the SBMA therapy.
Moreover, other experiments performed in our lab on different SBMA cell models (NSC34 transiently expressing ARQ46)showed that the cell quality control system was impaired, causing proteasome saturation and ineffective protein clearance. In addition. it has already been demonstrated that the over expression of several Heat shock proteins (Hsps) prevents aggregation of mutant proteins addressing them to a rapid degradation. We, therefore, tested the effect of the artificial chaperone cyclodextrin (CD) on ARpolyQ. CD is a water soluble, non-toxic, cyclic oligosaccharide used as vehicle for drug delivery. CD is also validated as artificial chaperone for protein refolding in vitro, preventing interactions between aberrantly exposed amino acids and avoiding the formation of incorrect secondary structures. In our models, we found that CD decreased the mutant proteins levels (western blot experiments) and aggregation rate (filter retardation assays, immunocytochemistry analyses). Moreover, using a proteasome activity reporter (YFPu), we also observed that CD was effective in desaturating the proteasome, even in presence of the proteasome inhibitor MG132. CD may, therefore, behave like a natural chaperone and enhance the clearance of mutant proteins. Eventually, CD may desaturate the proteasome machinery or enhance alternative degradation pathways (i.e. autophagy). This non-toxic compound might, thus, represent a potential therapeutic for diseases characterized by insoluble protein aggregation
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
17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17 AAG) A PHARMACOLOGICAL APPROACH TO INDUCE DEGRADATION OF MISFOLDED PROTEINS
No full textSelective Androgen Receptor Modulators reduce protein aggregation in a cellular model of SBMA
No full textInvolvement of the ubiquitin-proteasome pathway and autophagy in the clearence of mutant androgen receptor in the spinal and bulbar muscular atrophy
No full textTHE INVOLVEMENT OF SMALL HEAT SHOCK PROTEIN B8 IN THE DEGRADATION OF MUTANT PROTEINS IN MOTOR NEURONAL DISEASE
No full textVariations 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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