1,720,998 research outputs found
Caloric restriction prevents the age-associated activation of amyloidβ-peptide generation induced by the p75NTR-ceramide signaling pathway
No full textLate-onset Alzheimer’s disease (AD) represents 95 to 97% of all cases of AD. The age-associated increase in the prevalence of late-onset AD does not reach a plateau. Our group has recently shown that the second messenger ceramide regulates the rate of amyloid β-peptide (Aβ) generation by affecting the molecular stability of BACE1 (J. Biol. Chem. 2003). Here we explored the role of ceramide during aging by analyzing sphingomyelin/ceramide metabolism, amyloid precursor protein (APP) processing, and Aβ generation in the brain of normally aged mice. We found that aging of the brain is accompanied by a progressive activation of neutral sphingomyelinase (nSMase) that leads to increased production of ceramide. The activation of nSMase is induced by “re-expression” of the neurotrophin receptor p75NTR. We also found that aging is accompanied by increased levels of the β-secretase BACE1 and by increased β-cleavage of APP. To further confirm the role of aging on the above events, normally aged mice were restricted in their food intake, a condition that has been proved to extend the maximum-life-span and to delay many biological changes that are associated with aging. We found that caloric restriction down-regulates both the expression of p75NTR and the production of ceramide, blocking the increase of BACE1 steady-state levels and Aβ generation associated with aging. We conclude that p75NTR-ceramide is a molecular link between normal aging and late-onset AD, and that caloric restriction may represent a novel dietetic approach for the prevention of AD
Egr-1 and Hipk2 are required for the TrkA to p75(NTR) switch that occurs downstream of IGF1-R
No full textThe aging program mediated by IGF1-R is responsible for a naturally occurring TrkA to p75(NTR) switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid beta-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75(NTR), or ceramide are able to block the above events. Here, we show that the transcription factors Egr-1 and Hipk2 are required elements for the TrkA to p75(NTR) switch downstream of IGF1-R signaling. Specifically, Egr-1 is required for the upregulation of p75(NTR), whereas Hipk2 is required for the downregulation of TrkA. In fact, gene silencing of Egr-1 abolished the ability of IGF1 to upregulate p75(NTR), whereas similar approaches directed against Hipk2 blocked the downregulation of TrkA. In addition, IGF1 treatment favored binding of Egr-1 and Hipk2 to the promoter of p75(NTR) and TrkA, respectively. Finally, the expression levels of both Egr-1 and Hipk2 are upregulated in an age-dependent fashion. Such an event is opposed by caloric restriction, a model of delayed aging, and favored by the p44 transgene in p44(+/+) animals, a model of accelerated aging
A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging
No full textAging is the single most important risk factor for AD (Alzheimer's disease). However, the molecular events that connect normal aging to AD are mostly unknown. The abnormal accumulation of Abeta (amyloid beta-peptide) in the form of senile plaques is one of the main characteristics of AD. In the present study, we show that two members of the neurotrophin receptor superfamily, TrkA (tyrosine kinase receptor A) and p75NTR (p75 neurotrophin receptor), differentially regulate the processing of APP (amyloid precursor protein): TrkA reduces, whereas p75NTR activates, beta-cleavage of APP. The p75NTR-dependent effect requires NGF (nerve growth factor) binding and activation of the second messenger ceramide. We also show that normal aging activates Abeta generation in the brain by 'switching' from the TrkA to the p75NTR receptor system. Such an effect is abolished in p75NTR 'knockout' animals, and can be blocked by both caloric restriction and inhibitors of nSMase (neutral sphingomyelinase). In contrast with caloric restriction, which prevents the age-associated up-regulation of p75NTR expression, nSMase inhibitors block the activation of ceramide. When taken together, these results indicate that the p75NTR-ceramide signalling pathway activates the rate of Abeta generation in an age-dependent fashion, and provide a new target for both the understanding and the prevention of late-onset AD
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
- …
