1,720,987 research outputs found
Transthyretin Val122Ile, accumulated Aβ, and inclusion-body myositis aspects in cultured muscle
No full textCultured muscle fibers (CMF) from a patient with inclusion-body myositis (IBM) and cardiac amyloidosis associated with the transthyretin (TTR) Val122Ile mutation contained aspects of the IBM phenotype: vacuolation, congophilic inclusions, and clusters of immunocolocalizing amyloid β-peptide (Aβ) and TTR accumulations. These abnormalities are never present in normal human CMF. These perturbations were greatly increased after Aβ precursor protein gene transfer. The TTR mutation may be a genetic predisposition factor for the patient's IBM
Cystatin C colocalizes with amyloid-beta and coimmunoprecipitates with amyloid-beta precursor protein in sporadic inclusion-body myositis muscles
No full textCystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid-β (Aβ) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo-morphologic muscle phenotype of sporadic inclusion-body myositis (s-IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of Aβ deposits, we studied expression and localization of CC in muscle biopsies of 10 s-IBM, and 16 disease- and five normal-control muscle biopsies. Physical interaction of CC with amyloid-β precursor protein (AβPP) was studied by a combined immunoprecipitation/immunoblotting technique in the s-IBM muscle biopsies and in AβPP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, CC-immunoreactivity either colocalized with, or was adjacent to, the Aβ-immunoreactive inclusions in 80-90% of the vacuolated muscle fibers, mostly in non-vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity-colocalized with Aβ on 6-10 nm amyloid-like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with AβPP, both in s-IBM muscle and in AβPP-overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with AβPP, and (ii) suggest that CC may play a novel role in the s-IBM pathogenesis, possibly by influencing AβPP processing and Aβ deposition
Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle.
No full textProteins in the endoplasmic reticulum (ER) require an efficient system of molecular chaperones whose role is to assure their proper folding and to prevent accumulation of unfolded proteins. The response of cells to accumulation of unfolded proteins in the ER is termed "unfolded protein response" (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress, resulting from the accumulation of the unfolded/misfolded proteins. Because intracellular inclusions, containing either amyloid-beta (Abeta) or phosphorylated tau, are the characteristic feature of sporadic inclusion body myositis (s-IBM) muscle biopsies, we studied expression and immunolocalization of five ER chaperones, calnexin, calreticulin, GRP94, BiP/GRP78, and ERp72, in s-IBM and control muscle biopsies. Physical interaction of the ER chaperones with amyloid-beta precursor protein (AbetaPP) was studied by a combined immunoprecipitation/immunoblotting technique in s-IBM and control muscle biopsies, and in AbetaPP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, all five of the ER chaperones were immunodetected in the form of inclusions that co-localized with amyloid-beta. By immunoblotting, expression of ER chaperones was greatly increased as compared to the controls. By immunoprecipitation/immunoblotting experiments, ER chaperones co-immunoprecipitated with AbetaPP. Our studies provide evidence of the UPR in s-IBM muscle and demonstrate for the first time that the ER chaperones calnexin, calreticulin, GRP94, BiP/GRP78, and ERp72 physically associate with AbetaPP in s-IBM muscle, suggesting their playing a role in AbetaPP folding and processing
Amyloid-beta42 is preferentially accumulated in muscle fibers of patients with sporadic inclusion-body myositis.
No full textSporadic inclusion-body myositis (s-IBM) is the only muscle disease in which accumulation of amyloid-beta (Abeta) in abnormal muscle fibers appears to play a key pathogenic role. Increased amyloid-beta precursor protein (AbetaPP) and Abeta accumulation have been reported to be upstream steps in the development of the s-IBM pathologic phenotype, based on cellular and animal models. Abeta is released from AbetaPP as a 40 or 42 aminoacid peptide. Abeta42 is considered more cytotoxic than Abeta40, and it has a higher propensity to aggregate and form amyloid fibrils. Using highly specific antibodies, we evaluated in s-IBM muscle biopsies intra-muscle fiber accumulation of Abeta40 and Abeta42-immunoreactive aggregates by light- and electron-microscopic immunocytochemistry, and quantified their amounts by ELISA. In s-IBM, 80-90\% of the vacuolated muscle fibers and 5-20\% of the non-vacuolated muscle fibers contained plaque-like Abeta42-immunoreactive inclusions, while only 69\% of those fibers also contained Abeta40 deposits. By immuno-electronmicroscopy, Abeta42 was associated with 6-10 nm amyloid-like fibrils, small electron-dense floccular clumps and larger masses of amorphous material. Abeta40 was present only on small patches of floccular clumps and amorphous material; it was not associated with 6-10 nm amyloid fibrils. By ELISA, in s-IBM muscle biopsies Abeta42 was present in values 8.53-44.7 pg/ml, while Abeta40 was not detectable; normal age-matched control biopsies did not have any detectable Abeta42 or Abeta40. Thus, in s-IBM muscle fibers, Abeta42 is accumulated more than Abeta40. We suggest that Abeta42 oligomers and their cytotoxicity may play an important role in the s-IBM pathogenesis
BACE1 and BACE2 in pathologic and normal human muscle
No full textBACE1 and BACE2 are recently discovered enzymes participating in processing of amyloid P precursor protein (APPP). Their discovery is contributing importantly to understanding the mechanism of amyloid-beta generation, and hence the pathogenesis of Alzheimer's disease (AD). Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle diseases in which overproduction of APPP and accumulation of its presumably toxic proteolytic product amyloid-beta (Abeta) in abnormal muscle fibers appear to play an important upstream role in the pathogenic cascade. In normal human muscle APPP was also shown to be present and presumably playing a role (a) at neuromuscular junctions and (b) during muscle development. To investigate whether BACE I and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was studied in normal cultured human muscle. Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle: (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers-, and (c) are immunoreactive in necrotizing muscle fibers. Accordingly, BACE1 and BACE2 participate in normal and abnormal processes of human muscle, suggesting that their functions are broader than previously thought. (C) 2003 Elsevier Science (USA). All rights reserved
Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis
No full textSporadic inclusion-body myositis (IBM) is the most common, progressive muscle disease of older individuals. We investigated the presence of BACE1 and BACE2 - two β secretases that cleave amyloid-β-precursor protein - in muscle-biopsy samples from patients with IBM and from controls. On immunofluorescence, BACE1 and BACE2 co-localised with amyloid β in IBM vacuolated muscle fibres, but were not found in controls. Immunoblotting showed increased BACE2 but not BACE1 in patients with IBM compared with controls. Our study suggests that both of these proteases might participate in processing of amyloid-β-precursor protein in IBM muscle fibres
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
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