1,720,993 research outputs found
Ciliary and non-ciliary functions of Bardet-Biedl syndrome proteins
Full text linkPrimary cilia are microtubule-based cell organelles that are required for the communication between cells in a tissue and the regulation of intracellular signalling pathways. They are important for tissue development and homeostasis, which is why defects in primary cilia are often associated with genetic disorders, collectively termed ciliopathies. Bardet-Biedl syndrome (BBS) as a flagship ciliopathy combines many clinical features such as retinopathies, kidney disease, obesity and polydactyly. Responsible for the occurrence of BBS are mutations in BBS genes, encoding proteins that are required for primary cilia development, maintenance and function. Although the ciliary function of BBS proteins has been largely discussed, recent research also suggests non-ciliary functions of BBS proteins, indicating more complex mechanisms being involved in the development of human ciliopathies. The knowledge of these complex processes is inevitable to understand ciliopathies in a broader context, enabling a better diagnosis and the potential for development of therapeutics that target these pathways. In the current thesis, the ciliary and non-ciliary functions of BBS proteins were investigated in more detail, demonstrating complex tissue-dependent mechanisms that shed light on the signalling networks of BBS proteins on a cellular level. Publication I suggested that the function of BBS proteins could possibly be tissue-dependent, indicating previously unidentified regulations in specific tissues that need to be examined in more detail. While analysing the ciliarelated function of BBS proteins more closely in Publication II, the BBS proteins BBS6 and BBS8 were found to cooperate with the Wnt signalling protein Inversin in regulating Wnt signalling and ciliary disassembly pathways. These data shed light on how BBS proteins regulate ciliogenesis in addition to their classical defined ciliary function and elucidate their role in Wnt signalling. Since Wnt signalling affects the downstream actin network, the implication on important actin-based structures such as filopodia was investigated in more detail in Manuscript I. These data showed that BBS6 affects filopodia via interaction with the actin regulator Fascin-1. Contrary, Fascin-1 localises to primary cilia and its loss provoked a ciliary phenotype, indicating a feedback regulation of Fascin-1 and actin in ciliogenesis. The ciliary phenotype further led to alterations of Wnt signalling, enlightening how actin proteins affect ciliogenesis and cilia-related signalling. In summary, this thesis demonstrates how ciliary BBS proteins affect ciliogenesis and cilia related Wnt signalling potentially in a tissue-dependent manner and provide a better understanding in how cilia, Wnt and actin regulators affect each other in complex feedback mechanisms. These data provide a basis for studying cilia-related and unrelated functions of BBS proteins in the context of different tissues. They further emphasise the tight connection between ciliogenesis and actin proteins that should be considered in future studies to understand the complex molecular background of human ciliopathies.Primärzilien sind Mikrotubuli-basierte Zellorganelle, die für die interzelluläre Kommunikation in Geweben und die Regulation von intrazellulären Signalwegen wichtig sind. Daher sind Primärzilien insbesondere für die Entwicklung und Homöostase von Organen bedeutsam, weshalb Defekte in ihrem Aufbau und ihrer Funktion oftmals mit genetischen Erkrankungen, den Ziliopathien, einhergehen. Das Bardet-Biedl-Syndrom (BBS) vereinigt viele der symptomalen Erscheinungen von Ziliopathien, wie beispielsweise Retinopathien, Nierenerkrankungen, Adipositas und Polydaktylie, weshalb die Forschung an BBS auch Rückschlüsse auf andere Ziliopathien zulässt. Verantwortlich für das Auftreten von BBS sind Mutationen in den BBS-Genen, welche Proteine kodieren, die für Aufbau, Instandhaltung und Funktion des Primärziliums verantwortlich sind. Die ziliären Funktionen von BBS-Proteinen sind seit langem Bestandteil der Forschung, jedoch weisen neuere Daten auch auf alternative Funktionen in der Zelle hin, die möglicherweise nicht mit dem Zilium in Verbindung stehen. Das genaue Verständnis der ziliären und nicht-ziliären Funktionen von BBS-Proteinen ist daher unabdingbar, um das Gesamtbild von Ziliopathien besser verstehen zu können, die Diagnose zu erleichtern und Behandlungsmöglichkeiten zu entwickeln. In der vorliegenden Arbeit wurden die ziliären und nicht-ziliären Funktionen von BBSProteinen genauer beleuchtet, wobei neue komplexe Mechanismen und Signalwege identifiziert wurden, in denen BBS-Proteine involviert sind. Publikation I konzentrierte sich dabei auf die Untersuchung von möglichen Gewebe-abhängigen Mechanismen, was auf potenzielle, bislang nicht identifizierte Regulationen von BBS-Proteinen in unterschiedlichen Organen hinweist. In Publikation II wurde die Zilien-abhängige Funktion der BBS-Proteine näher untersucht, wobei die Regulation der BBS-Proteine BBS6 und BBS8 im Wnt-Signalweg im Zusammenhang mit ihrer Interaktion mit dem Wnt-Regulator Inversin identifiziert wurde. Diese Daten erläutern, wie BBS-Proteine die Ziliogenese alternativ zu ihrer bisher bekannten ziliären Funktion regeln können und schlüsseln ihre Rolle im Wnt-Signalweg genauer auf. Da der Wnt-Signalweg nachgeschaltete Aktin-Netzwerke reguliert, wurde in Manuskript I die Auswirkung der BBSProteine auf Aktin-basierte Zellstrukturen wie Filopodien näher untersucht. Dabei wurde gezeigt, dass BBS6 Filopodien mittels Interaktion mit dem Aktin-Regulator Fascin-1 reguliert. Fascin-1 lokalisiert an Primärzilien und seine Abwesenheit bedingt einen ziliären Phänotypen, was ebenfalls den nachgeschalteten Wnt-Signalweg verändert. Diese Daten lassen auf Feedback-Mechanismen schließen, mit denen Fascin-1 und Aktin die Ziliogenese und ziliäre Signalwege steuern können. Zusammenfassend konnte im Rahmen der vorliegenden Thesis gezeigt werden, wie BBSProteine die Ziliogenese und den ziliären Wnt-Signalweg in Gewebe-abhängigen Mechanismen steuern. Diese Arbeit bedingt dabei ein besseres Verständnis der komplexen Mechanismen, in denen Primärzilien, der Wnt-Signalweg und Aktin-Regulatoren sich gegenseitig beeinflussen. Dabei schafft diese Arbeit die Basis für weitere Studien, die die genaue Funktion der BBSProteine insbesondere in unterschiedlichen Organen näher beleuchtet. Weiterhin wird die enge Beziehung zwischen Aktin-Regulatoren und dem Primärzilium herausgestellt, welche in zukünftigen Studien berücksichtigt werden sollte, um die komplexen Hintergründe in der Entstehung von Ziliopathien besser zu verstehen.VI, 79 Seiten, Illustrationen, Diagramm
Mutational and functional analyses of Bardet-Biedl syndrome
Full text linkThis thesis investigates some of the underlying causes of Bardet-Biedl syndrome, a leading example of emerging ciliopathies. Bardet-Biedl syndrome (BBS) is a heterogeneous disorder with primary features that include age-related retinal dystrophy, obesity, Polydactyly, renal dysplasia, reproductive tract anomalies and cognitive impairment. To date 12 loci have been found to be causative for the disease (BBS1-12) and evidence suggests that aspects of the BBS phenotype may result from defective ciliogenesis/basal body function. The aims of this project were to identify new genes involved with the disease, analyse the phenotype of the Bbs6"7" mouse and further elucidate the mechanism of the disease in a zebrafish model. Pathogenic sequence mutations identified in candidate genes aided the identifictaion of BBS3 and BBS5. Further candidate genes were identified through the mapping of translocation breakpoints in a BBS patient. A yeast two-hybrid screen, using Bbs6 as bait, revealed several potential protein interactions. Phenotypical analysis of the Bbs&A mouse showed features comparable to BBS patients and other Bbs null mice, confirming its value as a model for further study. Further investigations of BBS proteins in the cochlea suggested a role beyond that of cilia and basal body function, namely that BBS proteins play distinct roles in the processes of microtubule nucleation and growth. Observed disruption of cochlear stereociliary bundles, along with other phenotypes associated with planar cell polarity (PCP) mutants, implied cilia might be involved in PCP signalling. This observation was supported by further analysis in the zebrafish. Disruption of bbs8 resulted in similar phenotypes to other PCP mutants, and laterality defects, thought to arise from defective cilia function at the Kupffer's Vesicle, were enhanced on a PCP mutant background. The results presented in this thesis pave the way for further investigation with a view to broadening the knowledge of the developmental processes behind BBS and also the processes behind the development of other signaling pathways, tissues and organ systems
Mutational and Functional Analyses of Bardet-Biedi Syndrome
No full textEThOS - Electronic Theses Online ServiceGBUnited Kingdo
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
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