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the role of the GxxxG-motif
No full textDer Oligomerisierung des Aß42 Peptids wird eine ursächliche Rolle bei der
Alzheimer Krankheit zugeschrieben. Bevor die Peptide zu Fibrillen aggregieren,
wirken besonders niedere Oligomere neurotoxisch und könnten für den Verlust
der kognitiven Fähigkeiten des Patienten verantwortlich sein. Da durch eine
sequenzielle Prozessierung des APP Aß mit variierender Länge entstehen, war
ein erster Schwerpunkt dieser Arbeit die Untersuchung der verschiedenen
Peptide. Dabei konnte gezeigt werden, je kürzer die Peptide sind, desto
weniger häufig werden höhere Oligomere ausbildet. Obwohl alle Peptide
vergleichbar hohe Mengen an Tetrameren gebildet hatten und diesen Formen in
der Literatur als potentiell toxisch beschrieben sind, konnte nur Aß42 ein
toxischer Effekt zugeschrieben werden. Für das GxxxG-Dimerisierungsmotiv
innerhalb der Aß Sequenz zeigte sich, dass dieses Motiv auch für die
Aggregation und das pathologische Verhalten des A42 Peptids kritisch ist. Im
Rahmen dieser Arbeit konnte erstmals der Einfluss eines Aminosäureaustausches
innerhalb des Aß GxxxG-Motivs auf Aggregation, Struktur und Toxizität
beschrieben werden. Strukturelle Untersuchungen zeigten, dass die Erhöhung der
Hydrophobizität an Position Gly33 den Faltungskern des Peptides stabilisiert
und die Oligomerisierung des Peptides forciert. Die Abschirmung der
hydrophoben Oberflächen, führt zur Krümmung der Aggregate und lässt somit
keine Fibrillenbildung mehr zu. Im Gegensatz dazu wird bei der Aß42 G29A
Variante die tetramere Untereinheit durch Anlagerung gegenüberliegender Gly29
durch erhöhte Hydrophobizität stabilisiert, was in einer verlängerten
Fibrillenbildung resultiert. Ein doppelter Austausch von Gly29 und Gly33 führt
zu einer intermediären Oligomerisierung, wobei auch hier keine reifen
Fibrillen gebildet wurden. Neben der Aggregation und Struktur wurde auch
erstmals detailliert die funktionelle Rolle des GxxxG-Motives mittels
Toxizitätstests und im Modellsystem für Lernen und Gedächtnis (LTP Messung)
untersucht. Dabei stellte sich heraus, dass eine Substitution an Position
Gly33 weder in vitro noch in vivo toxische Effekte hat, noch LTP inhibiert.
Für das Aß42 wt und Aß42 G29A Peptid hingegen konnte gezeigt werden, dass
weder Fibrillen, noch höhere Oligomere sondern ausschließlich niedere
Oligomere, vor allem Tetramere, toxisch wirken. Diese Effekte konnten in
reduzierter Form auch bei Aß42 G29/33A beobachtet werden, was das intermediäre
Verhalten der Variante weiter unterstreicht. Dennoch konnte sowohl bei Aß42 wt
als auch Aß42 G33I Peptid eine Reduktion der basalen synaptischen Transmission
und eine Aufnahme des Peptids in die Zelle und den Zellkern ermittelt werden.
Die Ergebnisse zeigen auf, dass das zentrale GxxxG-Motiv des Aß Peptids, und
Gly33 im Besonderen, eine essentielle Rolle nicht nur im Aggregationsverhalten
des Peptides spielt. In dieser Arbeit konnte erstmals gezeigt werden, dass vor
allem Tetramere toxische Oligomerformen sind, jedoch der Aggregationszustand
nicht grundsätzlich ausschlaggebend für die Toxizität ist. Besonders
interessant ist, dass die strukturelle Veränderung des Peptides durch
Austausch an Position Gly33 das pathologische Verhalten aufhebt. Diese
Erkenntnisse eröffnen die Möglichkeit, mit dem Werkzeug neuer Aß42 Varianten,
die genauen Mechanismen der toxischen Wirkungsweise von oligomeren Aß Formen
zu erforschen. Daraus wiederum könnten weiterführend neue Therapieansätze
entwickelt werden.The oligomerization of Aß42 peptides plays a critical role in Alzheimer’s
disease. Before aggregating to fibrils, low-n oligomers are known to be
neurotoxic and cause cognitive deficits. Based on the model of the sequential
cleavage of APP there exist a heterogenous mixture of different Aß species of
variying length. In the first part of this work, analysis of the
oligomerization and toxicity of those shorter peptides were performed. It
could be demonstrated that the shorter the peptide the fewer higher oligomers
were generated. Although all peptides formed high amounts of tetramers, which
were described in literature to be potentially toxic, only Aß42 cause toxic
effects. Earlier studies could already underline the importance of the GxxxG-
motivs within the Aß sequence in APP processing. Furthermore these motives
were postulated to play a role in aggregation and pathological behavior of
Aß42 peptides. In structural analyses it could be demonstrated that increased
hydrophobicity at position Gly33 stabilizes the folding nucleus of the peptide
and thereby accelerate the oligomerization. The shielding of the ß-sheets from
the polar milieu leads to a bending of the peptide and thus a suppression of
the fibril formation. In contrast, Aß42 G29A stabilizes the tetrameric subunit
resulting in an elongated fibril formation. Even though double substitutions
of Gly29 and Gly33 are resulting in an intermediate oligomerization but also
do not form fibrils. Despite the aggregation and structure, a detailed
functional role of the GxxxG-motifs was analyzed for the first time using
toxicity assays and a system for learning and memory (LTP measurements). It
was observed that Gly33 substitution neither in vitro nor in vivo had any
toxic effects, or inhibited LTP. For Aß42 wt and Aß42 G29A peptides it could
be demonstrated that neither fibrils nor higher oligomers influenced the cell
viability. Only low-n oligomers, mainly tetramers dramatically reduced the
number of cells. This effect could also be recorded in a reduced form for Aß42
G29/33A, underlining the intermediate behavior. Nevertheless, both Aß42 wt and
Aß42 G33I peptides reduced the basal synaptic transmission and were taken up
by the cells and transported into the nucleus. In conclusion these results
demonstrate that the central GxxxG-Motiv of Aß and especially Gly33 plays a
critical role in aggregational and toxic behavior of the peptide. Furthermore,
the data reveal that even though tetramers are most toxic oligomers, toxicity
does not depend on aggregation form, but the structural change. Interestingly,
the structural changes caused by amino acid exchange at position Gly33
completely abolish the pathological behavior. These findings enable, with the
new Aß42 variants as a powerful tool, the detailed analysis of the toxic
mechanism of Aß42 oligomers and opens new possibilities for developing new
therapeutic approaches
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
A Selective Oral GLYT1 Inhibitor, Improves Anemia and Red Cell Survival in a Mouse Model of Beta-Thalassemia
No full textThe unbalanced hemoglobin chain synthesis in beta-thalassemias leads to hemichrome-induced damage that contributes to ineffective erythropoiesis, hemolysis and reduced red cell survival. Iron overload related to ineffective erythropoiesis and abnormally low Hepcidin (Hamp), combined with the cytotoxic effects of free heme with free-alpha-chains play a key role in the increased generation of reactive oxygen species (ROS) in beta thalassemias. Here we used a specific and selective inhibitor of the plasma membrane expressed glycine transporter GlyT1 (Ro4917838). Use of Ro4917838 has been associated with a dose-dependent decrease in MCH, Hb, soluble transferrin receptor, and increase in absolute reticulocytes and RBC counts in several animal species, attributed to reduce glycine bioavailability in erythroblasts and decreased heme synthesis. In rats, Ro4917838 reduces heme synthesis, and down-regulates erythroid transferrin receptor, but does not interfere with hepcidin regulation and systemic iron homeostasis. We aimed to determine if reduced cellular availability of glycine in erythroblasts may reduce heme synthesis, and impact pathologic erythropoiesis in a mouse model for b-thalassemia. Wild-type control (WT) C57B6/2J, and beta-thalassemia Hbbth3/+ mice were treated with either vehicle or Ro4917838 at dosages of 3, 10, 30 mg/kg/d administered over 4 weeks once daily by gavage. RO4917838 administration was associated with significant improvements of central hallmarks of the b-thalassemia pathology. Reduced erythrocyte destruction was seen bydemonstrated a significant improvements in erythrocyte morphology and amelioration of hemoglobin reduction in reticulocytes. We also observed an impressively quick reduction of the circulating erythroblast count within 1 week of initiating treatment. This was also associated with decreased hemolysis biomarkers. Ro4917838 induced a significant reduction in extramedullary erythropoiesis and reduction in orthochromatic erythroblasts as well as insoluble alpha chain aggregates in circulating red cells. Red cell survival of b-thal mice treated with 30 mg/kg/day Ro4917838 significantly increased by more than 50%. CD71+ erythroid precursors significantly decreased in WT mice treated with Ro4917838 at 30 mg/kg and in b-thal mice at the dosage of 30 mg/kg/ d. These data suggest that Ro4917838 ameliorates anemia in a b-thalassemia mouse model and positively affects ineffective erythropoiesis and red cell survival in peripheral circulation. Ro4917838 may represent a novel therapeutic approach for the treatment of anemia in b-thalassemia patients
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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