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Roles and physiopathological mechanisms of the gene mutations coding the surfactant protein C in the interstitial lung disease development
No full textLes mutations du gène codant pour la protéine C (SP-C) du surfactant pulmonaire (SFTPC) sont à l’origine de pathologies interstitielles chroniques du nourrisson, de l’enfant mais également de l’adulte. Une importante hétérogénéité phénotypique est cependant observée, y compris au sein d’une même famille. Par un épissage alternatif, le gène SFTPC permet la synthèse de deux isoformes du précurseur protéique de SP-C (proSP-C) pour aboutir à la protéine mature après plusieurs modifications post-traductionnelles. Les conséquences des mutations de SFTPC sur l'homéostasie du surfactant ne sont pas clairement élucidées, mais il semble que le mauvais repliement de la protéine soit une caractéristique commune. A l’issue de nos travaux antérieurs, nous avons mis en évidence un effet de certaines mutations et de polymorphismes sur l’épissage de SFTPC faisant ainsi varier significativement l’expression de chacune des deux isoformes protéiques, sans qu’à l’heure actuelle nous ne connaissions le rôle de chacune dans la synthèse de la protéine SP-C mature. Notre projet, s’inscrivant dans la continuité de mon master 2, a pour but de mieux comprendre les mécanismes physiopathologiques pré et post-transcriptionnels associés aux variations de SFTPC et leurs conséquences sur le développement des pneumopathies interstitielles. Le premier axe de notre projet repose sur l’étude in vitro (lignées cellulaires) et in vivo (modèle murin, ARN des patients) des variations de chacun des isoformes. Dans un second axe, nous souhaitons poursuivre l'étude de facteurs pouvant influencer le phénotype des patients porteurs de mutations du gène SFTPC, qu'ils soient d'origine externes (infections virales et bactériennes ou environnementaux comme le tabac) ou génétique. Collectivement, ces études nous permettrons de fournir une signature moléculaire pour cette maladie et d’identifier de nouvelles cibles thérapeutiques afin d’en améliorer le pronostic mais également la prise en charge et la qualité de vie des patients.Surfactant pathologies linked to mutations in the SFTPC gene, via autosomal dominant transmission, are most commonly associated with diffuse interstitial diseases in infants, children and adults, and may also be responsible for acute respiratory distress syndrome in newborns. They are most often accompanied by a high morbidity and mortality rate, thus rendering early diagnosis essential for ideal intervention and support. Mutations in the SFTPC gene lead to alveolar and intracellular accumulation of an abnormal form of the precursor protein SP-C (ProSP-C), which is responsible for the resulting tissue damage. However, the pathophysiological mechanisms are not yet completely deciphered. The gene encodes two isoforms of ProSP-C from three alternative transcripts. The expression level of each is currently unknown and the vast majority of studies evaluating the effect of mutations are performed on only one isoform. Incidentally, our preliminary results on the analysis of RNA extracted from bronchoalveolar washing, both from control subjects and patients harboring a mutation, show that the all three SFTPC transcripts are expressed and that the presence of a mutation is associated with a variation in the expression levels of the transcripts. The aim of my project is to study the expression level of SFTPC transcripts and ProSP-C isoforms from the heterologous expression of the SFTPC gene (exons and introns) in cell lines. I will beanalyzing the post-translational maturation profile of these pro-proteins and evaluating the effect of the mutations on their expression and maturation in both our cellular models and in vivo with two Knock-in mice models.A better understanding of the pathophysiology of genetic abnormalities associated with mutations in the SFTPC gene will not only greatly contribute to earlier management of patients, but also it will help in modifying the progression of lung injury and its prognosis
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
Functional study of NKX2-1 gene mutations associated with lung disease in children
No full textLes anomalies héréditaires du métabolisme du surfactant représentent 10% à 15% des causes de syndromes respiratoires associés à une atteinte pulmonaire alvéolo-interstitielle chez l’enfant. La synthèse de l’ensemble des protéines spécifiques du surfactant (SP-A, SP-B, SP-C et SP-D) et d’ABCA3 est contrôlée par le facteur de transcription NKX2-1 (NK2 homeobox 1). NKX2-1 est un membre de la famille des facteurs de transcription NK-2, identifié initialement comme une protéine nucléaire capable de fixer la thyroglobuline. Son expression est retrouvée au cours du développement du poumon, de la thyroïde et du système nerveux. Chez l’homme, une mutation du gène NKX2-1 a été retrouvée associée à un tableau regroupant de façon parfois incomplète des symptômes neurologiques, thyroïdiens et pulmonaires. Le tableau complet est appelé « Brain-Lung-Thyroid syndrome ». L’atteinte pulmonaire est caractérisée par une pathologie alvéolaire, responsable d’une détresse respiratoire néonatale et/ou d’une pathologie pulmonaire chronique plus ou moins sévère pouvant n’apparaître qu’à l’âge adulte. La triade « Cerveau-Poumon-Thyroïde » est rare et des associations cerveau-thyroïde sans manifestation respiratoire sévère sont le plus souvent décrites. Cette particularité pourrait être liée à un biais de recrutement, ces mutations ayant été recherchées initialement chez des enfants ayant une atteinte thyroïdienne ou neurologique. Nous avons donc initialement décrit l’atteinte pulmonaire, isolée ou non, associée à une mutation de NKX2-1. Cette cohorte a souligné entre autres l’atteinte pulmonaire variée allant de la détresse respiratoire néonatale à la fibrose pulmonaire se manifestant seulement à l’âge adulte, caractéristique des pathologies du surfactant.Notre objectif est donc :1/ d’étudier fonctionnellement les mutations identifiées chez des patients sur les lignées cellulaires pulmonaire et thyroïdienne2/ rechercher des cofacteurs pulmonaires qui pourraient exercer une activité synergique avec NKX2-1 sur les promoteurs des gènes cibles pulmonaires.Dans une première partie, j’ai comparé les mutations NKX2-1DUP et NKX2-1DEL, la première étant responsable de la triade symptomatique et la seconde d’une atteinte pulmonaire isolée. Ces deux mutations qui décalent le cadre de lecture produisent une protéine aberrante de 408 acides aminés avec une perte de l’homéodomaine. La localisation subcellulaire de ces protéines mutées est différente de la protéine sauvage. La protéine NKX2-1DEL est capable de transactiver le promoteur de la thyroglobuline avec le cofacteur PAX8, mais en revanche ne peut activer les promoteurs des gènes spécifiques du surfactant comme la protéine NKX2-1DUP.Dans une deuxième partie, l’analyse d’une famille porteuse de la mutation L191 de NKX2-1 sur trois générations mais dont seul l’enfant présente des symptômes respiratoires, a permis d’identifier par MedExome un variant sur un cofacteur pulmonaire de NKX2-1. L’enfant atteinte est porteuse de ce variant à l’état homozygote contrairement à ces parents et grands-parents. La coexistence de ces 2 variants modifie la localisation subcellulaire de la protéine NKX2-1. L’analyse fonctionnelle a permis de confirmer l’implication de ce deuxième gène dans la pathologie de cette enfant.Ces études contribuent à lever le voile sur l’hétérogénéité clinique des mutations de NKX2-1 et pointent l’importance des cofacteurs tissus spécifiques de la transactivation des gènes cibles pulmonaires et thyroïdiens. De plus, nous décrivons la première variation d’un cofacteur de NKX2-1 ayant un impact fonctionnel pulmonaire. Des mutations de cette protéine pourraient donc être impliquées dans les pathologies interstitielles diffuses isolées de l’enfant.Hereditary abnormalities of surfactant metabolism account for 10% to 15% of the causes of respiratory syndromes associated with interstitial lung disease involvement in children. The synthesis of all surfactant specific proteins (SP-A, SP-B, SP-C and SP-D) and ABCA3 is controlled by the transcription factor NKX2-1 (NK2 homeobox 1). NKX2-1 is a member of the NK-2 transcription factor family, initially identified as a nuclear protein capable of binding thyroglobulin. Its expression is found during the development of the lung, thyroid and nervous system. In humans, a mutation of the NKX2-1 gene has been found associated with neurological, thyroid and/or pulmonary symptoms. The complete picture is called "Brain-Lung-Thyroid Syndrome". The pulmonary involvement is characterized by an alveolar pathology, responsible for a neonatal respiratory distress and / or a more or less severe chronic pulmonary pathology that can only appear in adulthood. The "Brain-Lung-Thyroid" triad is rare and brain-thyroid associations without severe respiratory manifestations are most often described. This particularity could be related to a recruitment bias, these mutations having been sought initially in children having a thyroid or neurological disease. We therefore initially described the pulmonary involvement, isolated or not, associated with a mutation of NKX2-1. This cohort highlighted, among other things, the varied pulmonary involvement ranging from neonatal respiratory distress to pulmonary fibrosis occurring only in adulthood.Our goal is:1 / to functionally study mutations identified in patients on pulmonary and thyroid cell lines2 / to look for pulmonary cofactors that could exert a synergistic activity with NKX2-1 on the promoters of the pulmonary target genes.In a first part, I compared the NKX2-1DUP and NKX2-1DEL mutations, the first being responsible for the symptomatic triad and the second for isolated pulmonary involvement. These two mutations that shift the reading frame produce an aberrant 408 amino acid protein with loss of the homeodomain. The subcellular localization of these mutated proteins is different from the wild-type protein. The NKX2-1DEL protein is capable of transactivating the thyroglobulin promoter with the PAX8 cofactor, but on the other hand cannot activate promoters of the surfactant-specific genes such as the NKX2-1DUP protein.In a second part, the analysis of a family carrying the L191 mutation of NKX2-1 over three generations but of which only the child has respiratory symptoms, allowed to identify by MedExome a variant on a pulmonary cofactor of NKX2. -1. The affected child carries this variant in the homozygous state unlike these parents and grandparents. The coexistence of these 2 variants modifies the subcellular localization of the NKX2-1 protein. Functional analysis has confirmed the involvement of this second gene in the pathology of this child.These studies shed light on the clinical heterogeneity of NKX2-1 mutations and point to the importance of specific tissue cofactors in the transactivation of pulmonary and thyroid target genes. In addition, we describe the first variation of an NKX2-1 cofactor with pulmonary functional impact. Mutations of this protein could therefore be involved in diffuse interstitial pathologies isolated from the child
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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