1,720,981 research outputs found
Disruption of the Cellular Regulation of CDKL5 Might be Relevant for Rett Syndrome
No full textMutations in the human X-linked cyclin dependent kinase like 5 (CDKL5) gene have recently been identified in some Rett patients with the Hanefeld variant as well as in girls with mental retardation associated with early seizures. We have previously shown that CDKL5 works in a pathway common with that of MeCP2, the main cause of classic Rett Syndrome (RTT). In fact, the two proteins associate and the kinase is able to mediate the phosphorylation of MeCP2 in vitro. This suggests that mutations in CDKL5 cause RTT in part because important MeCP2 functions are impaired. Furthermore, CDKL5 might play a secondary role in RTT by acting as a modifier gene thereby influencing disease severity in patients with mutations in MECP2.
Even though our results do suggest a common molecular pathway belonging to CDKL5 and MeCP2, we still have to reveal in which brain areas and when the two factors are communicating. Furthermore, we have to get insight into the functional relevance of the identified interaction.
Our immunohistochemistry and western blot experiments show that in adult brain the two proteins have overlapping expression patterns. However, whereas MeCP2 levels appear rather uniform through late embryogenesis and postnatal stages as well as in the different brain areas, CDKL5 levels appear to be subject to a dynamic modulation. In particular, the CDKL5 protein is virtually absent in the mouse embryo brain and is strongly induced in early post-natal stages. Furthermore, whereas MeCP2 is confined to the nuclear compartment, CDKL5 is found in both the nuclear and cytoplasmic compartments indicating a possible role in transmitting signals between these two compartments. Interestingly, the subcellular distribution of CDKL5 varies in the different areas of the adult mouse brain as well as during development. Experiments in cell cultures have allowed us to show that CDKL5 shuttles between the nucleus and the cytoplasm and that an active nuclear export mechanism depending on the C-terminal tail of the protein is responsible for the cytoplasmic localization. The relevance of this regulation seems to be demonstrated by the fact that all the late RTT truncating mutations identified so far lead to an abnormal accumulation of the kinase into the nucleus
Molecular characterization of CDKL5, a novel kinase involved in Rett syndrome and infantile spasms
No full textRett Syndrome (RTT) is an X-linked neurological disorder affecting mainly females. In the classical form, patients have normal period of development of 6-18 months where after they display developmental arrest and a progressive regression leading to the loss of speech and purposeful movements with the appearance of a severe mental retardation. Atypical forms with differences in disease onset and severity exist. Mutations in the methyl-CpG binding protein (MECP2) gene, located on Xq28, cause the majority of RTT cases but have been found in less than half of atypical RTT patients. Recently, mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, on Xp22, have been found in some RTT patients with the Hanefeld variant, characterized by the onset of seizures in the very first months of life. Furthermore, mutations in CDKL5 have been found in girls with infantile spasms and mental retardation, suggesting an important role of this gene for neuronal function.
A main interest of our laboratory is to characterize the role of CDKL5 in the nervous system thereby clarifying the molecular mechanisms involved in disease onset. With this communication we will present our results showing that CDKL5 and MeCP2 function in a common pathway in accordance with the fact that mutations in the two genes cause a similar phenotype. In fact, besides sharing an overlapping expression pattern correlating with neuronal maturation and synaptogenesis, CDKL5 and MeCP2 associate and in vitro the kinase is able to mediate the phosphorylation of the methyl-binding protein. Furthermore, we will show our unpublished data indicating that CDKL5 catalytic activities are subject to different levels of regulation mediated by its long C-terminal tail. First of all, the C-terminus influences negatively the catalytic activity of the kinase and, moreover, an active nuclear export mediated by the tail is involved in regulating the subcellular localization of CDKL5. Finally, the turn over of the kinase seems to be regulated and disease causing mutations might affect it. It is important to keep in mind that besides missense mutations in the N-terminal catalytic domain a number of truncating mutations are found in the C-terminal tail; with the functional analysis of these mutated derivatives we try to provide a molecular explanation to their contribution to Rett Syndrome. We believe that this analysis will contribute in drawing a phenotype-genotype correlation
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
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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