1,721,224 research outputs found
Study of the neuroinflammatory component in FTD/ALS
No full textLes démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA) sont deux maladies neurodégénératives faisant partie d'un même spectre clinique, génétique et neuropathologique. Afin d’identifier une voie biologique commune aux DFTs et SLA, nous nous sommes intéressés aux mécanismes d’activation microgliale. Deux axes d’étude principaux ont composé cette thèse : 1/ La protéine TDP-43, qui forme les inclusions majoritaires des DFT-SLA, est-elle capable d’activer les cellules microgliales ? Par quels mécanismes ? 2/ La perte de fonction des protéines C9ORF72 et PGRN a-t-elle des conséquences sur la réactivité microgliale en présence de TDP-43? Par l’utilisation de modèles in vitro de cultures primaires microgliales nous montrons que la protéine TDP-43 active la voie non canonique microgliale de l'inflammasome NLRP3. Celle-ci se produit suite à l’interaction de TDP-43 avec les récepteurs TLR2/4, et à son internalisation dans les cellules microgliales. Les cellules microgliales murines déficientes C9orf72-/- et GrnR493X/R493X sont hyper-réactives vis-à-vis d’une stimulation par TDP-43. Cet effet est reproduit dans un modèle « MDMi » de cellules microgliales dérivées de monocytes de patients DFT porteurs de mutation GRN ou C9ORF72. Enfin, nous montrons que cet effet peut être lié aux fonctions des protéines PGRN et C9ORF72 nécessaires au bon fonctionnement de la boucle de rétrocontrôle de l’activité de l’inflammasome par la voie autophagique. Nos données mettent en évidence une voie commune de neuroinflammation dans les DFTs et la SLA, et ouvrent de nouvelles pistes sur les processus neurodégénératifs de ces maladies.Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two neurodegenerative diseases from the same clinical, genetic and neuropathological spectrum. In order to identify a common biological pathway for FTD and ALS, we examined the microglial activation mechanisms in FTD and mixed forms of FTD-ALS. Murine models mimicking GRN and C9ORF72 loss of expression, genes that are mutated in familial forms of FTD and FTD-ALS (C9ORF72 only), develop immune phenotypes. Thus, this thesis was composed by two main lines of study: 1/ Is the TDP-43 protein, which is the main component of inclusions in FTD-ALS, capable of activating microglial cells? By which mechanisms? 2/ Does C9ORF72 and PGRN loss of function have consequences on microglial reactivity to TDP-43? Using in vitro models of primary microglial cultures, we show that TDP-43 activates the non-canonical NLRP3 inflammasome microglial pathways. This activation occurs following the interaction of TDP-43 with TLR2/4, and its internalization in microglial cells. C9orf72-/- and GrnR493X/R493X deficient murine microglial cells are hyper-reactive to TDP-43 stimulation. This effect was also observed in an "MDMi" model consisting in microglia-like cells derived from FTD patients’ monocytes. These patients are GRN or C9ORF72 mutation carriers. Finally, we show that this effect may depend on the functions of PGRN and C9ORF72 which appear essential to the dynamics of the inflammasome-autophagy negative feedback loop regulating the activity of the inflammasome. Our data highlight a common pathway of neuroinflammation in FTD and ALS and open new insights into the neurodegenerative processes of these diseases
A cluster of progranulin C157KfsX97 mutations in Southern Italy: clinical characterization and genetic correlations
Get PDFFrontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases displaying high clinical, pathologic, and genetic heterogeneity. Several autosomal dominant progranulin (GRN) mutations have been reported, accounting for 5%-10% of FTLD cases worldwide. In this study, we described the clinical characteristics of 7 Italian patients, 5 with a diagnosis of frontotemporal dementia behavioral variant and 2 of corticobasal syndrome (CBS), carrying the GRN deletion g.101349_101355delCTGCTGT, resulting in the C157KfsX97 null mutation, and hypothesized the existence of a founder effect by means of haplotype sharing analysis. We performed plasma progranulin dosage, GRN gene sequencing, and haplotype sharing study, analyzing 10 short tandem repeat markers, spanning a region of 11.08Â Mb flanking GRN on chromosome 17q21. We observed shared alleles among 6 patients for 8 consecutive short tandem repeat markers spanning a 7.29Â Mb region. Therefore, also with this particular mutation, the elevated clinical variability described among GRN-mutated FTLD cases is confirmed. Moreover, this is the first study reporting the likely existence of a founder effect for C157KfsX97 mutation in Southern Italy
Etude des phases cliniques et précliniques des formes génétiques de dégénérescence lobaire fronto-temporale (DLFT) et recherche de biomarqueurs de la progression de maladie
No full textLes dégénérescences lobaires fronto-temporale (DLFT) sont des démences neurodégénératives rares. 30-50% des DLFT a une cause génétique, la plupart sont des mutations des gènes C9orf72 et progranuline (GRN). L'objectif de la thèse a été d'élargir le spectre mutationnel et phénotypique des mutations GRN. Nous avons identifié les premières délétions partielles du gène GRN chez des patients avec progranulinémie baisse (la progranulinémie est abaissée en cas de mutation), mais sans mutation détectée par séquençage. Nous avons contribué à élargir le spectre clinique de la maladie en décrivant un phénotype d'atrophie corticale postérieure et des lésions de la substance blanche cérébrale chez des patients GRN, caractéristique évocatrice de cette forme génétique. Enfin, nous avons étudié la phase présymptomatique de la maladie, alors que se développent les premiers essais thérapeutiques, par une approche longitudinale avec IRM et TEP-FDG. Le métabolisme cérébral est réduit dans le lobe temporal latéral gauche 20 ans avant l'apparition des symptômes et, après 20 mois, dans les régions frontales et l'épaisseur corticale dans les régions temporales gauche. Le lobe temporal latéral pourrait être donc l'"épicentre " de la maladie, et le processus lésionnel pourrait, secondairement, progresser vers les régions frontales. J'ai également contribué à définir les phénotypes associés aux mutations de gènes plus rares de DLFT/DLFT-SLA. TARDBP est associé à un large spectre phénotypique; TBK1 est caractérisé par une démence sémantique ou aphasie non fluent associés à l'atteinte de la corne antérieure. Cette étude importante souligne le rôle de ces mutations dans le spectre clinique des DLFT.Frontotemporal lobar degeneration (FTLD) are rare neurodegenerative dementias. 30-50% of FTLD has a genetic cause, most are mutations in C9orf72 and in progranulin gene (GRN). The aim of the thesis was to expand the mutational and phenotypic spectrum of GRN mutations. We identified the first partial deletions of GRN gene in patients with low plasmatic progranulin (the plasmatic progranulin is low in case of mutation), but without mutation detected by sequencing. We contributed to expand the clinical spectrum of the disease by describing a posterior cortical atrophy phenotype and lesions of the cerebral white matter in GRN patients, evocative feature of this genetic form. Finally, we studied the presymptomatic stage of the disease, while the first clinical trials develop, for a longitudinal approach with MRI and FDG-PET. The cerebral metabolism is reduced in the left temporal lobe 20 years before clinical onset and, after 20 months, the metabolism is reduced in the frontal regions and the cortical thickness in the left temporal regions. The lateral temporal lobe could thus be the "epicenter" of the disease, and the lesional process could secondarily progress towards the frontal regions. I also contributed to define the phenotypes associated with rare gene mutations in FTLD/FTLD-ALS. TARDBP is associated with a wide phenotypic spectrum; TBK1 is characterized by semantic dementia or not fluent aphasia associated with involvement of the anterior horn. This important study highlights the role of these mutations in the clinical spectrum of FTLD
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
- …
