1,720,984 research outputs found
Decoding the genetic puzzle of inherited cardiac arrhythmias : insights from molecular autopsy, genetic profiling and iPSC-derived cardiomyocyte modelling
No full textAbstract: Inherited cardiac arrhythmias (ICA) encompass a group of cardiac diseases with common characteristics such as low prevalence, reduced penetrance and variable phenotypical expression including electrocardiogram abnormalities, syncopes, ventricular fibrillations and increased risk for sudden cardiac death (SCD). Approximately 70 genes contribute to ICAs, demonstrating substantial genetic overlap. Despite advancements in next-generation sequencing (NGS), many cases remain genetically unsolved due to complex inheritance patterns and variants of uncertain significance (VUS) in known genes. Functional analyses can provide the ultimate proof to reclassify a VUS but as this is labour intensive and expensive and not routinely done in a diagnostic setting. A case of SCD was investigated using NGS gene panels. We detected two VUS in the KCNQ1 and DSG2 genes. An in vitro functional analysis of the KCNQ1 variant did not show any effect on the potassium current. Segregation analysis revealed that the DSG2 variant was de novo, upscaling its classification to likely pathogenic. In only 30% of Brugada Syndrome (BrS) patients a genetic cause is identified. We analyzed 350 patients and found (likely) pathogenic variants in 9%. These patients showed more severe clinical features. Utilizing the Shanghai scoring system for definite BrS diagnosis increased yield to 18%. 31% of all the patients carried a VUS but such VUS do not contribute to more informative genetic counselling for the patient. Induced pluripotent stem cells (iPSCs) emerged as a valuable human cellular model. iPSCs, derived from Brugada syndrome patients with a specific SCN5A mutation, displayed pluripotency and validated through molecular assays. Despite sharing the same Belgian SCN5A founder mutation, patients exhibited diverse clinical phenotypes. Differentiated into cardiomyocytes, patient iPSC-CMs showed variations in SCN5A transcripts but similar total expression, sodium current, and action potential characteristics compared to controls. Notably, statistical analysis challenges arose from significant variability between iPSC clones and individuals. The use of a CRISPR-generated isogenic control underscores the promising utility as a strategy for studying mutations in Brugada syndrome. With enhanced molecular techniques for investigating the genetic landscape of ICAs, it has become clear that the effect of genetic variants is not always easy to interpret and functional analysis is needed. For this purpose, novel study models such as iPSC-CMs can play an important role as they represent the disease-relevant cell type with full cardiomyocyte-specific molecular machinery, can be patient-specific and isogenic lines can be generated. In this way, also more complex interactions can be studied in a relevant cell model
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Fish, founders and fluorescent indicators : progress of inherited cardiac arrhythmia genomics in the new sequencing era
No full textAbstract: Inherited Cardiac Arrhythmia (ICA) syndromes are a group of rare genetic disorders characterised by an increased risk for potentially lethal ventricular arrhythmias, which occur in structurally (seemingly) normal myocardium. While recent technological advances in DNA sequencing have improved in the diagnostic yield in ICA, they have also led to an increased identification of variants of uncertain significance (VUS). Functional characterisation plays a crucial role in variant annotation. Nevertheless, sufficiently high-throughput ICA disease models are still lacking. We set out to fill this gap by generating a zebrafish assay for cardiac arrhythmia, with co-expression of the Ace2N-mNeon genetically encoded voltage indicator and R-GECO genetically encoded calcium indicator in the heart. Our zebrafish cardiac arrhythmia assay was able to detect electrophysiological abnormalities induced by drugs and genetic models of ICA generated at our lab. These consisted of a long QT syndrome model, induced by a knock-in mutation in the cacna1c gene and a catecholaminergic polymorphic ventricular tachycardia (CPVT) model, due to a homozygous knockout of the casq2 gene. The use of light sheet imaging also enabled us to generate three-dimensional maps of the cardiac action potential characteristics of the entire heart in zebrafish embryos. Additionally, we optimized the process of the generation of zebrafish knock-in mutants through CRISPR-Cas9 gene editing. By combining minimally invasive early genotyping with the Zebrafish Embryo Genotyper device with next-generation sequencing, we were able to achieve an almost seventeen-fold improvement in editing efficiency. Lastly, we performed clinical and functional assessments of variants in known arrhythmia genes to clarify the remaining issues in ICA genetics. We explored a novel hypothesis of autosomal dominant CPVT for a heterozygous c.738-2A>G splice site variant in CASQ2. We assessed a cohort of (c.4813+3_4813+6dupGGGT) SCN5A founder mutation carriers for clinical signs of a complex genetic architecture in Brugada syndrome. Additionally, we demonstrated the role of the disease model in the functional assessment of the allelic effect of a recurrent KCNQ1 c.1124_1127delTTCA p.(Ile375Argfs*43) variant. With increased identification of VUS and the confounding contributions of poly- and oligogenic factors, as well as variable allelic effects of established pathogenic variants, the field of ICA genetics research remains complex and challenging. Future studies in promising disease models, such as zebrafish, as well as clinical and molecular investigations in cohorts of patients carrying the same pathogenic variant, will likely aid in clarifying some of the remaining questions
Variations on the Author
Get PDF“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
Get PDFWe 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
Fishing for genes : a disease transgressing approach to unravel the genetic basis of thoracic aortic aneurysm
No full textDispelling the Myths Behind First-author Citation Counts
Get PDFWe 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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