1,720,995 research outputs found
Clinical and Molecular Characterization of Classical-Like Ehlers-Danlos Syndrome Due to a Novel TNXB Variant
Get PDFThe Ehlers-Danlos syndromes (EDS) constitute a clinically and genetically heterogeneous group of connective tissue disorders. Tenascin X (TNX) deficiency is a rare type of EDS, defined as classical-like EDS (clEDS), since it phenotypically resembles the classical form of EDS, though lacking atrophic scarring. Although most patients display a well-defined phenotype, the diagnosis of TNX-deficiency is often delayed or overlooked. Here, we described an additional patient with clEDS due to a homozygous null-mutation in the TNXB gene. A review of the literature was performed, summarizing the most important and distinctive clinical signs of this disorder. Characterization of the cellular phenotype demonstrated a distinct organization of the extracellular matrix (ECM), whereby clEDS distinguishes itself from most other EDS subtypes by normal deposition of fibronectin in the ECM and a normal organization of the α5β1 integrin
Approaches to homozygosity mapping and exome sequencing for the identification of novel types of CDG
Get PDFIn the past decade, the identification of most genes involved in Congenital Disorders of Glycosylation (CDG) (type I) was achieved by a combination of biochemical, cell biological and glycobiological investigations. This has been truly successful for CDG-I, because the candidate genes could be selected on the basis of the homology of the synthetic pathway of the dolichol linked oligosaccharide in human and yeast. On the contrary, only a few CDG-II defects were elucidated, be it that some of the discoveries represent wonderful breakthroughs, like e.g, the identification of the COG defects. In general, many rare genetic defects have been identified by positional cloning. However, only a few types of CDG have effectively been elucidated by linkage analysis and so-called reverse genetics. The reason is that the families were relatively small and could—except for CDG-PMM2— not be pooled for analysis. Hence, a large number of CDG cases has long remained unsolved because the search for the culprit gene was very laborious, due to the heterogeneous phenotype and the myriad of candidate defects. This has changed when homozygosity mapping came of age, because it could be applied to small (consanguineous) families. Many novel CDG genes have been discovered in this way. But the best has yet to come: what we are currently witnessing, is an explosion of novel CDG defects, thanks to exome sequencing: seven novel types were published over a period of only two years. It is expected that exome sequencing will soon become a diagnostic tool, that will continuously uncover new facets of this fascinating group of diseases.Fil: Matthij, Gert. Katholikie Universiteit Leuven; BélgicaFil: Rymen, Daisy. Katholikie Universiteit Leuven; BélgicaFil: Bistue Millon, Maria Beatriz. Katholikie Universiteit Leuven; Bélgica. Universidad Nacional de Cordoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Souche, Erika. Katholikie Universiteit Leuven; BélgicaFil: Race, Valérie. Katholikie Universiteit Leuven; Bélgic
Congenitale Glycosylatiestoornissen: De Nieuwe generatie
No full textGlycosylation is one of the most abundant protein modifications found in nature. It results from a meticulously orchestrated process involving numerous proteins for the assembly and modification of oligosaccharide chains, and their attachment onto proteins and lipids. The importance of glycosylation is illustrated by a group of diseases called Congenital Disorders of Glycosylation (CDG). To date, almost 100 distinct disorders have been identified encompassing defects in N- and O-linked protein glycosylation, but also in the synthesis of GPI-anchors and glycolipids. Considering the possibility to screen for most deficiencies in protein N-glycosylation by means of isoelectric focusing of serum transferrin, the project focused on this group of disorders.
The genetic heterogeneity of CDG, but also the phenotypic overlap between the different disorders is remarkable. A clinical ‘hit and run’ diagnosis forms thus rather the exception than the rule. Therefore, patients with a biochemically proven glycosylation deficiency remain often without a molecular diagnosis. In this study, we aimed to circumvent the bottleneck of a gene by gene approach through the implementation of massive parallel sequencing techniques in as well CDG research as diagnostics (Chapter 3).
For the elucidation of novel CDG, whole exome sequencing was performed in 24 individuals with a presumed deficiency in the N-linked glycosylation pathway (Chapter 4 and 5). Once the genetic defect was identified, its pathogenic nature was confirmed using cell biological assays. In this way, a genetic diagnosis could be obtained in nine patients (i.e. 38%), while the most likely candidate gene is still under investigation in seven additional cases (i.e. 30%).
In parallel, a targeted assay for a panel of 79 genes was developed to improve CDG diagnostics (Chapter 6). Over a period of two years, the panel was used for molecular testing in a total number of 86 patients with a presumed deficiency in the N-linked glycosylation pathway. A final molecular diagnosis could be obtained in 38 of them (i.e. 44%). Based on these results, we proposed a tentative novel flowchart wherein a patient considered to have CDG first enters a diagnostic setting for gene panel testing. A close collaboration between the diagnostic and research department would then allow those patients, in whom the culprit gene could not be identified or in whom the pathogenicity of a variant needs to be verified, to subsequently enter a research setting for further biochemical testing.
During this study, mutations in MAN1B1 were identified to cause a novel CDG-II. The biochemical characteristics of the index case allowed for the rapid identification of 18 additional patients (Chapter 7). All cases displayed a similar phenotype characterized by intellectual disability, delayed motor and speech development, hypotonia, macrocephaly and truncal obesity.
During the time span of this PhD project, the intracellular localization of MAN1B1 became the subject of a still ongoing debate. Indeed, besides its role in N-glycan processing, the α(1,2)-mannosidase has been proposed to act as a key factor in ER quality control by targeting terminally misfolded proteins for proteasomal degradation. Since all mediators of ERAD are assumed to reside within the ER, it only seemed natural that MAN1B1 would execute its function within the same organelle. However, today opinions are changing. While some researchers still believe that MAN1B1 resides within the ER, others are convinced that the enzyme localizes to a presumed ERQC compartments or resides within the Golgi apparatus.
In Chapter 9, we could clearly demonstrate that the endogenous MAN1B1 in primary skin fibroblasts is localized within the Golgi apparatus, thereby confirming the initial –but still controversial– results of Sifers and coworkers. Our findings were further supported by the observation that MAN1B1 deficient fibroblasts display an aberrant Golgi morphology in the absence of an ER stress response (i.e. UPR or unfolded protein response) (Chapter 8 and 9).
While former studies mainly focused on the effect of MAN1B1 deficiency on the fate of misfolded cargo, we investigated –with respect to the phenotype– the effect on secretory proteins that attained their native folding state (Chapter 9). In this way, we could demonstrate that MAN1B1 deficiency does not only enable the intracellular accumulation and partial secretion of nonnative proteins, but in addition impairs the anterograde trafficking of the properly folded cargo.
In Chapter 10 of this manuscript, we assumed that the aforementioned accumulation of (mis-)folded proteins within the Golgi apparatus could overwhelm the capacity of the secretory pathway, thereby generating a primary Golgi stress response. Through several pilot experiments we could show that MAN1B1 deficiency generates a mild to moderate transcriptional response that was not only uniformly present among the different patients, but that also differed from the responses observed in other CDG-II cell lines. However, additional investigations are necessary to further address the extent of a possible Golgi stress response in MAN1B1-CDG and to understand how this transcriptional response might impact patient management.status: Publishe
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
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
Dispelling 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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