1,721,212 research outputs found
Cellular functions of gamma-secretase-related proteins
Full text linkAmyloid-beta pepticle (A beta) is generated by gamma-secretase, a membrane protein complex with an unusual aspartyl protease activity consisting of the four components presenilin, nicastrin, APH-1 and PEN-2. Presenilin is considered the catalytic subunit of this complex since it represents the prototype of the new family of intramembrane-cleaving GxGD-type aspartyl proteases. Recently, five novel members of this family and a nicastrin-like protein were identified. Whereas one of the GxGD-type proteins was shown to be identical with signal pepticle peptidase (SPP), the function of the others, now called SPP-like proteins (SPPLs), is not known. We therefore analyzed SPPL2b and SPPL3 and demonstrated that they localize to different subcellular compartments suggesting nonredundant functions. This was supported by different phenotypes obtained in knockdown studies in zebrafish embryos. In addition, these phenotypes could be phenocopied by ectopic expression of putative active site mutants, providing strong evidence for a proteolytic function of SPPL2b and SPPL3. We also identified and characterized the nicastrin-like protein nicalin which, together with the 130-kDa protein NOMO (Nodal modulator), forms a membrane protein complex different from gamma-secretase. We found that during zebrafish embryogenesis this complex is involved in the patterning of the axial mesendoderm, a process controlled by the Nodal signaling pathway. Copyright (c) 2006 S. Karger AG, Basel
The Biochemical and Genetic Odyssey to the Function of a Nicastrin-Like Protein
Full text linkgamma-Secretase is a high-molecular-weight protein complex required for the proteolytic processing of various transmembrane proteins including the Alzheimer's disease-associated amyloid precursor protein and the signaling receptor Notch. One of the gamma-secretase complex components is the type I transmembrane protein nicastrin. Here we review the odyssey to a cyclopic fish, which at the end allowed the functional analysis of nicalin, a novel member of the nicastrin protein family. This 60-kDa protein is part of a previously unknown membrane protein complex unrelated to gamma-secretase and binds to Nomo (Nodal modulator, previously known as pM5), a novel 130-kDa transmembrane protein. Both proteins are highly conserved in metazoans and show almost identical tissue distribution in humans. Functional studies in zebrafish embryos and cultured human cells revealed that nicalin and Nomo collaborate to antagonize the Nodal/TGF beta signaling pathway. Thus, nicastrin and nicalin are both associated with protein complexes involved in cell fate decisions during early embryonic development. Copyright (C) 2004 S. Karger AG, Base
Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?
Full text linkSignal peptide peptidase (SPIP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the,gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPIP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/ SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2, and spp13 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNF(x intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article,we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others
Identification of the physiologically relevant α-secretase of the Alzheimer’s disease-related amyloid precursor protein and its relationship with β-secretase
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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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