1,721,016 research outputs found
Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model
Full text linkIt is well established that only a fraction of A beta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (A beta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified A beta starting at position 3 and ending with amino acid 42 [A beta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with A beta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of A beta at N-terminal glutamate can be catalyzed in vitro. Here, we show that A beta(3(pE)-42) induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of A beta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted A beta(3(pE)-42) in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal A beta(3(pE)-42) is neurotoxic in vivo
Isolation und Kultivierung von Mikrogliazellen aus murinen Hirngewebe und deren Stimulation zur Generierung eines ruhenden adulten Phänotyps
No full textKlonierung, Expression und Reinigung von Hüllproteinen Humaner Endogener Retroviren als Zielproteine in der Multiple Sklerose-Forschung
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Untersuchungen zur Rolle der Glutaminyl-Cyclase bei der pathologischen Bildung von Pyroglutamyl-Peptiden - [kumulative Dissertation]
Full text linkPosttranslationale Modifikationen spielen eine wichtige Rolle bei der Reifung von Proteinen und beeinflussen deren Funktion und Stabilität im Organismus. Die Bildung von Pyroglutamat (pGlu) ist für eine Reihe von Peptidhormonen, wie z.B. Thyreoliberin (TRH) und Gonadoliberin (GnRH) sowie sezernierten Proteinen beschrieben worden. Die pGlu-Modifikation entsteht durch intramolekulare Zyklisierung eines Glutaminylrestes. Die Reaktion wird in Tieren und Pflanzen durch Glutaminyl-Cyclasen (QC; EC 2.3.2.5) katalysiert. Im menschlichen Organismus geht offensichtlich eine Reihe von pathophysiologischen Veränderungen mit einer Bildung von Pyroglutamylpeptiden einher. Dies betrifft u.a. neurodegenerative Erkrankungen wie die Alzheimersche Krankheit oder entzündliche Prozesse. In der vorliegenden Arbeit wurde die QC-vermittelte Bildung von pGlu am N-Terminus der Peptide Aβ und CCL2 untersucht, welchen offenbar Schlüsselfunktionen in diesen Erkrankungen zukommen. Es konnte gezeigt werden, dass QC auch die Zyklisierung von Glutamat am N-Terminus von Aβ-Peptiden nach amyloidogener und Prohormonkonvertase-vermittelter Prozessierung in Säugerzellkultur katalysiert. Die Applikation eines spezifischen QC-Inhibitors verringerte sowohl die Glutaminyl- als auch die Glutamylzyklisierung. Die QC-katalysierte Bildung von pGlu-Aβ verläuft in den zellulären Modellsystemen vorwiegend intrazellulär. Der N-terminale pGlu-Rest von CCL2 beeinflusst die Stabilität und somit die chemotaktische Potenz dieses Chemokins. Durch eine Sezernierung von nicht vollständig gereiftem CCL2 kommt es zu einem Abbau durch Aminopeptidasen, wie z.B. DP4. Die Applikation eines QCInhibitors beeinflusste die arteriosklerotischen Veränderungen im Modell der „cuff“-induzierten Arteriosklerose. In einem weiteren Teil der Arbeit konnte ein Isoenzym der QC isoliert und charakterisiert werden. Humane QC und isoQC weisen eine Sequenzidentität von ca. 50% auf. Im Unterschied zur QC ist die isoQC ein Typ II-Transmembranprotein, welches im Golgi-Apparat zurückgehalten wird. Diesbezüglich ähnelt das Protein Glykosyltransferasen. Aufgrund der stabilisierenden Wirkung des pGlu-Restes für den N-Terminus verschiedener Proteine hat die Inhibierung von QC eine proteolysefördernde und dadurch aktivitätsmodulierende Wirkung. Dies könnte zur Behandlung verschiedener Krankheitssymptome dienen, welche durch das Auftreten von stabilen pGlu-Peptiden verursacht werden. Insofern sind die im Rahmen dieser Arbeit gewonnenen Erkenntnisse für die Entwicklung spezifischer QC-Inhibitoren zur Behandlung einer Reihe von pGlu-Proteinabhängigen Erkrankungen bedeutsam.von Holger Cyni
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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