1,720,993 research outputs found
Large-scale data-driven analysis to understand the genetics of Congenital Heart Disease
Full text linkCongenital Heart Disease (CHD) delineates a large group of structural defects, which can occur due to perturbations at some stage in the cardiac embryogenesis process. With a global incidence ranging from 7 to 9 cases per 1000 live births, CHD accounts for a significant fraction of new-borns deaths worldwide. Different studies have identified genetics as an essential factor underlying CHD, along with environmental factors. The technological advances within the last years have helped improve CHD diagnosis and understand its genetic causes. Nevertheless, despite the advances in our understanding of the disease, many molecular mechanisms underlying CHD remain uncertain. Herein I present my efforts focused on discovering new genes and biological pathways altered in patients with CHD. The work is based on large CHD patient cohorts, collected and analysed as part of an international collaboration. The adopted integrative data-driven approach in this work can roughly be grouped into two principal aims: i) the development of statistical frameworks and bioinformatics tools to analyse high-dimensional data and ii) the meta-analysis of large-scale exome sequencing data to elucidate variants and genes conferring risk of CHD. By meta-analysing copy number variations and de novo variants in CHD probands, we implicated novel genes reaching genome-wide significant association with CHD and strengthened previously described associations. We also explored the differences between non-syndromic and syndromic CHD by analysing a large-scale exome cohort of patients. In summary, our integrative approach, supported by the data analysis of ~15,000 CHD patients, allowed us to gain new insights into the genetic origin of CHD. Consequently, we present here a valuable resource to continue investigating the causes of CHD and pave the way to promote new studies in this area
Subphenotype-based characterisation of signalling pathways in congenital heart defects (CHD)
Full text linkCongenital heart defects (CHDs) are the most common (1 - 2 %) birth defects amongst live newborns. Despite more than 200 genes having been associated with the development of CHD, the molecular basis remains partially unclear, and only a minority of patients can be assigned to an underlying genetic variant. The identification and characterisation of novel genetic variants increases diagnostic yields, improves risk stratification and, thus, the overall clinical management of CHD patients. By analysis of an exome-based case-control study comprising of 3907 CHD-cases and 5157 population matched controls, this thesis focussed on enhancing the understanding of the genetic contribution to CHD in general and on revealing sub-phenotype specific differences. Established CHD-genes were investigated with respect to deleterious variants that might account for the patient´s phenotype. Clustering based on phenotypic subtypes followed by GO-term enrichment revealed distinct genes and mechanisms underlying the different CHD subtypes. Secondly, a permutation-based analysis of signalling pathways revealed 26 of the tested combinations to be significantly enriched. Molecular dynamics was utilised to determine the molecular mechanisms of variants localised in PTPN11 and PIK3CA. The last part was focussed on NOTCH1, a gene that has been consistently determined to be one of the key contributors to CHD. Besides truncating variants, alterations in disulfide-bonds in NOTCH1 were significantly enriched. Functional analysis showed a complete impairment of the signalling capability for the tested nonsense variants and moderately reduced capabilities for missense variants. In summary, this thesis provides novel insights into the genetic background, including specific CHD subgroups, which might offer novel surveillance and treatment strategies for CHD patients in the future
Functional Analysis of Human Genetic Variants Using Zebrafish
Full text linkUtilizing zebrafish as a model organism, this study investigates the genetic factors con- tributing to congenital heart defects (CHD) and cardiomyopathy (CM). Zebrafish offer unique advantages in cardiovascular research, such as optical transparency and rapid development, making them well-suited for studying developmental processes and disease pathogenesis. Molecular cytogenetic techniques identified novel variants in the PRDM16 gene associated with ARVC. Additionally, ES (Exome sequencing) identified variants in the CAPZβ gene linked to patients with CHD. Functional analysis in zebrafish embryos revealed phenotypic similarities to human disease, implicating CAPZβ as a candidate gene for CHD and PRDM16 in ARVC. Specifically molecular cytogenetic techniques identified four novel variants in the PRDM16 gene in patients with ARVC and ES led to the identification of four novel variants in the CAPZβ gene among patients with CHD. Functional analysis in zebrafish embryos revealed that the CAPZβ-Ser192Asn variant led to impaired cardiac contractility and morphological defects resembling aspects of human CHD phenotypes
TET2-Mutationen in Patienten mit myeloischen Neoplasien: Eine molekulargenetische und molekularzytogenetische Analyse
Full text linkIn der vorliegenden Arbeit wurde ein Kollektiv von Patienten mit einer myeloischen Neoplasie in Hinblick auf TET2-Mutationen mittels molekularzytogenetischer und molekulargenetischer Methoden analysiert. Aufgrund der Seltenheit von molekularzytogenetischen Daten über den numerischen TET2-Status wurde das Patientenkollektiv mit Daten aus einer umfangreichen Literaturrecherche erweitert.
In der FISH-Diagnostik wurden mit einem Panel von 10 Sonden gearbeitet, mit Hilfe der Sanger-Sequenzierung erfolgte eine vollständige Sequenzierung der auffälligen Proben. Aus der Literatur wurden viele weitere Fälle mit detaillierten Daten zu Zytogenetik und vorhandener TET2-Mutation gefunden und eingeordnet. Anschließend erfolgte eine umfangreiche Analyse des gewonnenen Materials
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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