1,721,075 research outputs found
DIFFERENT APPROACHES TO UNDERSTAND AND COUNTERACT SPINAL AND BULBAR MUSCOLAR ATROPHY (SBMA).
No full textSpinal and Bulbar Muscular Atrophy (SBMA), or Kennedy’s disease, is a hereditary neuromuscular disorder that affect only men and is characterized by slowly progressive weakness and atrophy of bulbar, facial, and limb muscles, which are attributable to degeneration of lower motor neurons in the spinal cord and brainstem. The disease is associated with an abnormally expanded CAG repeat in the androgen receptor (AR) gene which results in a longer polyglutamine tract (polyQ) at the N-terminus of the protein. PolyQ tract triggers AR protein misfolding and aggregation and leads to nuclear toxicity and cell death. Many efforts have been done to examine in depth disease pathogenesis and to find strategies to counteract polyQ AR toxicity but many aspects remain incompletely understood. Here we propose three different approaches aimed to contrast the disease.
In the first chapter, the anti-androgen Bicalutamide is used in combination with the autophagy activator trehalose, in order to slowdown polyQ AR nuclear translocation and promote its clearance through the cytoplasmic autophagic machinery. The combined treatment strongly reduces polyQ AR protein levels more than the single treatment, thus suggesting an autophagy-mediated clearance as a potential therapeutic strategy.
The second chapter focuses on polyQ AR degradation via the ubiquitin-proteasome system (UPS), another major degradation process within the cell. We stabilized Hsp70 in its more active ADP-bound state with the small molecule JG98 and promoted a selective CHIP-mediated ubiquitination and proteasomal degradation of polyQ AR. This confirms the involvement of UPS in SBMA pathogenesis and proposes UPS-mediated degradation of polyQ AR as a possible approach for the treatment of the disease.
The last chapter proposes exercise as a non-pharmacological intervention for the treatment of SBMA. Wild type (wt) and AR113Q knock-in mice followed a mild exercise regimen for six weeks, then mice were run to exhaustion and sacrificed. Muscle tissues analysis revealed a significant decrease in type I and II fiber size in the exercised cohort of AR113Q mice compared to control rest mice. These data suggested the existence of muscle abnormalities, possibly exacerbated by exercise, in AR113Q 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
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
Second harmonic generation from radiation to guided modes for the characterization of reverse-proton-exchanged waveguides
No full textmultiphoton absorption of solutions of polydiacetylene poly DCHD-HS measured using ps Z-scan at 1064 nm and 1500 nm
No full textThe role of small heat shock protein B8 (HspB8) in the removal of mutant androgen receptor in spinal and bulbar muscular atrophy
No full textSpinal and bulbar muscular atrophy (SBMA) is a motorneuronal disease, caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR) protein. SBMA is characterized by conformational changes in ARpolyQ that result in misfolding and protein aggregation. Using SBMA in vitro models expressing mutant AR (AR.Q46), we observed that the inactive and soluble AR.Q46 impairs the UPS activity, while Testosterone-activated AR.Q46 induced cytoplasmic aggregation leading to UPS desaturation and removing AR.Q46 from the soluble compartment into the aggregates waiting for an alternative clearance, as autophagy. It is known that chaperones facilitate the removal of misfolded proteins. We thus tested the potential of a small Heat Shock Protein (HSPB8) to facilitate mutant protein turnover and its effect on the degradative systems. HSPB8 overexpression decreased the AR.Q46 levels without affecting the proteasome and the inhibition of the proteasomal function did not block the HspB8. HspB8 might facilitate the AR.Q46 clearance acting through the macroautophagy. In fact, HspB8 stimulated the formation of LC3-II increasing the number of autophagosomes and the LC3 silencing correlated with the loss of HspB8 prodegradative effects on AR.Q46. Finally, we tested the effects of HspB8 overexpression on a longer polyQ tract (AR.Q112) because AR with Q46 and Q112 showed different biochemical properties and AR.Q112 has a higher tendency to aggregate than AR.Q46. Using transient and stable transfections with AR.Q112, which recapitulates the nuclear accumulation and aggregation observed in SBMA patients, we found that HspB8 was unable to induce AR.Q112 clearance and to counteract aggregation.
All these data suggest that assisting protein folding with HspB8 we might reduce protein aggregation, stimulating the misfolded protein autophagic removal. Notably, HspB8 fail to suppress AR.Q112 aggregation suggesting that AR.Q46 and AR.Q112 might involve different mechanisms of neurotoxicity
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