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1
Boukhtouche, Fatiha. "Rôle du récepteur nucléaire RORα dans la survie et la différenciationneuronale." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2006. http://tel.archives-ouvertes.fr/tel-00080417.
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RORα (Retinoic acid receptor related Orphan Receptor α) est un récepteur nucléairedont la perte de fonction entraîne chez la souris staggerer - entre autres phénotypes - une
sévère ataxie cérébelleuse. RORα a longtemps été considéré comme un récepteur nucléaire
orphelin, cependant, le cholestérol (ou un de ses dérivés) semble être un ligand physiologique
de ce récepteur.
Le mutant staggerer, identifié dès 1962 par Sidman, Lane et Dickie, présente une
hypoplasie cérébelleuse liée à l'absence de la grande majorité des cellules de Purkinje, ainsi
que des grains du cervelet. L'expression de la mutation staggerer dans les cellules de Purkinje
conduit à leur mort massive pendant le développement, et les cellules de Purkinje survivantes
chez l'adulte présentent d'importantes anomalies de différenciation. Par ailleurs, à l'état
hétérozygote, le mutant staggerer présente une diminution de la survie des cellules de
Purkinje ainsi que des anomalies de différenciation au cours du vieillissement.
Le phénotype cérébelleux des mutants homozygote et hétérozygote staggerer
suggère que RORα est impliqué dans la survie et/ou la différenciation des cellules de Purkinje
au cours du développement et du vieillissement. Au cours de cette thèse, nous avons donc
tenté de déterminer le rôle de RORα dans la survie et la différenciation dans des neurones
corticaux et/ou dans des cellules de Purkinje, en étudiant l'effet de sa surexpression dans ces
processus.
Afin de surexprimer RORα, nous avons construit un vecteur lentiviral exprimant
l'isoforme humaine RORα1. Ce vecteur nous a permis de transduire avec une très grande
efficacité des neurones corticaux en culture primaire ainsi que les cellules de Purkinje en
culture organotypique.
Dans une première étude, nous avons cherché à déterminer si RORα pouvait exercer
un rôle dans la survie neuronale. Dans ce but, nous avons évalué la survie de neurones
corticaux surexprimant ou non RORα et soumis à un stress oxydatif entraînant l'apoptose des
neurones. RORα protège les neurones en diminuant le stress oxydatif causé par ces inducteurs
pro-apoptotiques. L'expression des deux enzymes Glutathion peroxydase 1 et Peroxiredoxine
6 est augmentée dans les neurones qui surexpriment hRORα1, et semble partiellement médier
l'effet neuroprotecteur de RORα. Nous avons par ailleurs évalué et comparé la survie des
cellules de Purkinje en culture organotypique qui expriment RORα de façon endogène, ou qui
surexpriment hRORα1, et nos résultats suggèrent que la surexpression de RORα a également
un effet neuroprotecteur dans ces cellules.
Dans une seconde étude, afin de déterminer le rôle de RORα dans la différenciation
des cellules de Purkinje, nous avons analysé en culture la progression de la différenciation
dendritique précoce de cellules de Purkinje en fonction de l'expression de RORα. RORα est
crucial pour l'étape de régression des neurites des cellules de Purkinje au stade bipolaire
embryonnaire. Alors que l'absence de RORα chez les mutants homozygotes staggerer
entraîne un arrêt de la différenciation des cellules de Purkinje à ce stade (les cellules de
Purkinje ne parviennent pas à entamer la régression des neurites), la surexpression de
hRORα1 accélère l'étape de régression. Cette étape de régression est totalement dépendantede l'expression de protéines RORα fonctionnelles et cet effet est vraisemblablementintrinsèque. Nous montrons enfin que l'hormone thyroïdienne accélère la différenciationdendritique précoce des cellules de Purkinje, et que RORα semble contribuer à ce processus.
L'ensemble de ces résultats montre que RORα intervient de façon cruciale à la foisdans la survie et dans la différenciation des cellules de Purkinje dans une étape très précoce de
leur développement post-natal.
2
Journiac, Nathalie. "Etude du rôle du facteur de transcription RORα dans la réaction gliale." Paris 6, 2007. http://www.theses.fr/2007PA066031.
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Notre objectif était de déterminer le rôle de RORalpha dans l’activation des astrocytes associée à une neurodégénérescence. Nous avons utilisé la souris staggerer exprimant une mutation perte de fonction dans le gène Rora à l’origine de la dégénérescence des neurones cérébelleux et réalisé des transfections stables de lignées astrocytaires. Nous avons montré que RORalpha, jusqu’alors considéré comme exclusivement neuronal, est exprimé dans les astrocytes et démontré qu’il module : -l’expression de la GFAP, un marqueur spécifique de l’activation astrocytaire. -la prolifération, avec un effet différent des isoformes RORalpha1 et 4. -la synthèse d’IL-6, un facteur clef de la réaction gliale, de façon ambivalente et en compétition avec Rev-erb, un autre facteur de transcription. L’étude de souris mutantes RORAsg/sg-p5’GFAP-LacZ confirme une anomalie de la fonction astroctaire. RORalpha est donc impliqué dans la modulation des mécanismes cellulaires et moléculaires de la réaction gliale.
3
Boukhtouche, Fatiha. "Rôle du récepteur nucléaire RORα dans la survie et la différentiation des neurones." Paris 6, 2006. http://www.theses.fr/2006PA066007.
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Sermikli, Benan Pelin. "Role of the nuclear receptor RORα expressed by myeloid cells in metabolic diseases." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S019.
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Retinoic acid receptor-related orphan receptor-alpha (RORa) is a transcription factor from the nuclearreceptor superfamily expressed by immune and non-immune cells involved in the regulation of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). Cholesterol, cholesterol-sulfate, 7-oxygenated sterols and oxysterols have been identified as potential endogenous RORa ligands. Tobetter understand the mechanisms of macrophage-expressed RORa regulation in obesity and IR, we generated a macrophage-specific RORa-deficient (MKO) mouse line by using a LysM-Cre and floxedRORa mouse line. We report that RORa deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an earlier report on the effect of HFD on NASHdevelopment upon HFD feeding nor in the more severe and obesity-independent choline-deficient, Lamino acid-defined diet model. We thus, suspected that LysM copy number may play a role in thisdiscrepancy, as the genotype at the LysM locus is a major difference between the two independent linesof work. The LysM-Cre mice carry an insertion of Cre recombinase into the Lyz2 gene, leading to Creexpression under the control of the Lyz2 promoter and enhancers, but abolishing endogenous Lyz2expression. While we intentionally maintained similar Cre and Lyz2 expression between WT and MKO by using only hemizygous animals for this locus (comparing Rora+/+Lyz2Cre/+ with Rorafl/flLyz2Cre/+),floxed mice (Rorafl/flLyz2+/+) were used as WT control and compared with MKO mice missing informationabout the Lyz2 locus (Rorafl/fLyz2Cre/?) in the earlier study. As, we hypothesized that the observed impact of RORa deletion in macrophages on NASH in the earlier study likely did not result from a specific effect of RORa deletion, but rather from a different Lyz2 copy number between WT and MKO mice, we decidedto verify this hypothesis experimentally. Surprisingly, our preliminary findings showed that the Lyz2-deficient mice exhibit slight protection, rather than a detrimental effect, in HFD-induced obesity and IR, as determined by lower body weight and adipose tissue masses, significantly improved glycemic control and decreased epiAT inflammation. Interestingly, whole body Lyz2 deficiency had no impact on hepaticsteatosis (NAFL) in HFD-fed mice. Nonetheless, our preliminary findings even suggest that Lyz2deficiency might protect against advanced and obesity-independent choline-deficient, L-amino aciddefined diet-induced NASH. Taken together, these preliminary findings indicate that different Lyz2 genecopy number in control mice is unlikely to account for the discrepancy between our work and the earlier study. Overall, our results show that RORa deletion in macrophages does not alter the development of obesity and IR and question its role in NASH. On the other hand, we believe that further investigations are of significant interest in the context of obesity, IR, and advanced NASH, as Lyz2 might possess atherapeutic valueRORa (Retinoic acid receptor-related orphan receptor-alpha) est un facteur de transcription de la superfamille des récepteurs nucléaires exprimé par des cellules immunitaires et non immunitaires impliqué dans le contrôle de l'obésité, de l'insulinorésistance (IR) et de la stéatohépatite non alcoolique(NASH). Le cholestérol, le cholestérol-sulfate, les stérols 7-oxygénés et les oxystérols ont été identifiés comme des ligands endogènes potentiels RORa. Pour mieux comprendre le rôle de RORa exprimé parles macrophages dans l'obésité et I’IR, nous avons généré une lignée de souris déficientes en RORa spécifiques aux macrophages (MKO) en utilisant des lignées de souris LysM-Cre et RORa foxée. Nous résultats montrent que l’inactivation de RORa dans les macrophages n'a pas d'impact sur l'obésité et l’insuline-résistance induites par une régime riche en graisses (HFD). Étonnamment, contrairement àdes travaux, notre étude ne montre pas d'effet sur le développement de la NASH ni suite à un régime HFD, ni dans le modelé d’alimentation défini par les acides aminés L, plus sévère et indépendant de l 'obésité et déficient en choline. Nous avons donc soupçonné que le nombre de copies de LysM pouvait jouer un rôle dans cette divergence, car le génotype des souris au l locus LysM est une différence majeure entre les deux études indépendantes. Les souris LysM-Cre portent une insertion de la recombinase Cre dans le gène Lyz2, ce qui conduit à l'expression de Cre sous le contrôle du promoteurLyz2 et ses activateurs, mais abolit l'expression endogène de Lyz2. Alors que nous avons intentionnellement maintenu une expression similaire de Cre et de Lyz2 entre WT et MKO en utilisant uniquement des animaux hémizygotes pour ce locus (en comparant Rora+/+Lyz2Cre/+ avec Rorafl/flLyz2Cre/+), des souris foxées (Rorafl/flLyz2+/+) ont été utilisées comme contrôle de WT et comparées avec des souris MKO pour lesquelles il manquait des informations sur le locus Lyz2(Rorafl/flLyz2Cre/ ?) dans l'étude antérieure. Aussi, nous avons émis l'hypothèse que l'impact observé de la délétion de RORa dans les macrophages sur la NASH dans l'étude précédente ne résultait probablement pas d'un effet spécifique de la délétion de RORa, mais plutôt d'un nombre de copies Lyz2différent entre les souris WT et MKO et avons décidé de vérifier cette hypothèse expérimentalement.De manière surprenante, nos résultats préliminaires ont montré que les souris déficientes en Lyz2présentent une légère protection, plutôt qu'un effet néfaste, dans l'obésité et l'IR induites par le HFD,comme le montre la diminution du poids corporel et des masses de tissu adipeux, l'amélioration significative du contrôle de la glycémie et la diminution de l'inflammation de l'épiAT. Il est intéressant de noter que la déficience totale en Lyz2 n'a eu aucun impact sur la stéatose hépatique (NAFL) chez les souris nourries au HFD. Néanmoins, nos résultats préliminaires suggèrent même que la carence enLyz2 pourrait protéger contre la NASH induite par le régime alimentaire, carence en choline. Dans leur ensemble, ces résultats préliminaires indiquent que le nombre différent de copies du gène Lyz2 chez les souris de contrôle n'explique probablement pas la différence entre notre travail et l'étude précédente.Globalement, nos résultats montrent que la délétion de RORa dans les macrophages ne modifie pas le développement de l'obésité et de l’IR et remettent en question son rôle dans la NASH. D'autre part,nous pensons que des recherches plus approfondies sur le rôle du lysozyme présentent un intérêt significatif dans le contexte de l'obésité, de l’IR et de la NASH avancée, car Lyz2 pourrait avoir un intérêt thérapeutique
5
Ermisch, Michael [Verfasser], Dieter [Akademischer Betreuer] Steinhilber, and Rolf [Akademischer Betreuer] Marschalek. "Regulation der nukleären Rezeptoren RORα und REVERBα / Michael Ermisch. Gutachter: Dieter Steinhilber ; Rolf Marschalek." Frankfurt am Main : Univ.-Bibliothek Frankfurt am Main, 2011. http://d-nb.info/1044274638/34.
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Gineste, Romain. "Régulation de l'activité transcriptionnelle des récepteurs nucléaires FXR, RORα et PPARγ par modifications post-traductionnelles." Lille 2, 2008. http://www.theses.fr/2008LIL2S041.
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Les facteurs de transcriptions FXR, RORα et PPARγ appartiennent à la superfamille des récepteurs nucléaires (RN). Ils ont pour fonction de moduler l'expression de nombreux gènes impliqués dans de nombreux processus physiologiques. Leurs rôles dans l'homéostasie glucidique, lipidique et énergétique font de ces récepteurs des cibles pharmacologiques d'intérêt pour le traitement de nombreuses maladies métaboliques comme les dyslipidémies, le diabète de type II, l'athérosclérose, l'obésité et les maladies neuro-dégénératives. Les RN activent leurs gènes cibles en se liant à l'ADN, sur une séquence spécifique nommée RE (Response Element) et en interagissant avec des partenaires protéiques appelés coactivateurs qui ont pour fonction principale de favoriser la transcription. L'activité transcriptionnelle des récepteurs nucléaires est aussi régulée par modification post-traductionnelle (PTM) telle que la phosphorylation, la SUMOylation et l'ubiquitination. L'objectif de cette thèse est d'étudier le rôle de ces modifications post-traductionnelles dans la régulation de l'activité des récepteurs FXR, RORα et PPARγ puis de replacer le rôle de ces PTMs dans un contexte pharmaco-thérapeutique. Jusqu'à aujourd'hui, l'implication d'événements post-traductionnelles dans le mécanisme d'action de FXR n'a pas été démontrée. En étudiant l'effet de différents inhibiteurs de kinases sur l'expression des gènes cibles de FXR, nous avons montré, dans les HepG2, que l'activité transcriptionnelle de FXR est modulée par les protéines kinases C (PKC), calcium-dépendantes. Le PMA, un activateur de PKC induit la phosphorylation de FXR endogène et la PKCα phosphoryle, in vitro, FXR dans son domaine de liaison à l'ADN sur les serines S135 et S154. La mutation de ces serines en alanines diminue la phosphorylation de FXR dans les cellules et le mutant FXR S135AS154A présente une diminution de son activité transcriptionnelle. Enfin, nous avons montré que la phosphorylation de FXR par la PKC induit le recrutement du coactivateur PGC1α. Durant cette thèse, l'étude de l'implication de la SUMOylation dans le mécanisme d'action des récepteurs nucléaires a aussi été abordée. Des études récentes démontrent que la SUMOylation de certains facteurs de transcription joue un rôle important dans plusieurs processus physiologiques comme l'inflammation, le stress oxydatif et le métabolisme lipidique. Nous avons montré, pour la première fois, que l'activité du récepteur orphelin RORα est régulée par SUMOylation et que la SUMO E2 ligase UBC9, diminue l'activité transcriptionnelle de RORα. De plus, le site de SUMOylation de RORα a été identifié dans la région charnière entre le DBD et le LBD. La mutation du site de SUMOylation de RORα augmente son activité transcriptionnelle et diminue sa dégradation. Nous avons trouvé que le site de SUMOylation de RORα est aussi un site d'ubiquitination. Nous avons conclue que la SUMOylation de RORα empêche son ubiquitination et par conséquent sa dégradation par le protéasome. Enfin, le dernier objectif de cette thèse était développer un outil de screening visant à identifier des nouveaux agonistes de PPARγ aux propriétés anti-inflammatoires. Une étude récente a montré un lien entre l'activité anti-inflammatoire de PPARγ et sa SUMOylation (Pascual e al 2005). A partir de cette étude, nous avons développé deux outils de screening. Le premier test basé sur le GST pull-down vise à étudier in vitro l'interaction de la SUMO E3 ligase PIAS1 avec PPARγ. Le second test a pour objectif de visualiser, dans la cellule, la SUMOylation de PPARγ par BRET (Bioluminescence Resonance Energy Transfer)
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Kadiri, Sarah. "Inflammation du tissu adipeux et dysfonctions de l'homéostasie lipidique : différences spécifiques de dépôts chez l'humain et la souris, et implication RORα." Paris 6, 2013. http://www.theses.fr/2013PA066518.
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Le tissu adipeux (TA) joue un rôle central dans l’homéostasie lipidique par ses capacités de stockage/déstockage des acides gras (AG). La voie de la glycéronéogenèse (GNG), qui permet la ré-estérification des acides gras en période de jeûne, participe à l’homéostasie lipidique en limitant la lipotoxicité des AG et leur localisation ectopique. Nous avons traité des explants de TA sous-cutané (TASC) et viscéral (TAV) issus de femmes minces par des inhibiteurs de la protéase du VIH (en cause dans les lipodystrophies) ou le lipopolysaccharide. Mes travaux ont mis en évidence une atteinte du TASC et non du TAV, se traduisant par une baisse des capacités de ré-estérification des AG via la GNG. Dans un modéle murin, j’ai observé également un effet dépôt-spécifique en réponse à un régime western diet pendant 12 semaines : le TA épididymaire (équivalent TAV) présente une inflammation associée à une insulino-résistance tandis que le TA inguinal (équivalent TASC) voit son statut inflammatoire diminuer et son insulino-sensibilité augmenter. Dans une seconde partie, je me suis intéressée au rôle d’un récepteur nucléaire Retinoic-related orphan receptor alpha (RORα) dans le TA. En utilisant la souris Staggerer déficiente pour RORα, j’ai montré une diminution du statut inflammatoire et une meilleure insulino-sensibilité locale, ce qui suggère un rôle anti-inflammatoire de RORα dans le TA. Parallèlement, j’ai identifié RORα comme un acteur positif de la GNG du fait d’une baisse de l’efficacité de la GNG chez les souris Staggerer. Ainsi, mes résultats permettent de montrer de nouvelles différences dépôt-spécifiques des TA et objectivent un rôle spécifique de RORα dans le métabolisme lipidique et l’inflammation du TAAdipose tissue (AT) is involved in the regulation of lipid metabolism by its capacity to store/release fatty acids (FA). Glyceroneogenesis (GNG), which controls FA storage by inducing their re-esterification during fasting in adipocytes, participates to lipid homeostasis by controlling the amount of FA released into circulation and, thereby, by limiting their lipotoxicity. We have treated explants of subcutaneous (SAT) and visceral AT (VAT) depots from lean women by HIV-protease inhibitors (involved in lipodystrophy) or lipopolysaccharide. My research demonstrates an alteration of this pathway in SAT, with a decreased capacity of FA re-esterification, but not VAT. In mice, also, we observed a depot-specific effect after a 12-week western diet. Epididymal AT (equivalent to VAT) presented an increased inflammatory status and decreased insulin sensitivity while inguinal AT (equivalent to SCAT) exhibited a decreased inflammatory status and improved insulin sensitivity. In a second part, I investigated the role of Retinoic-related orphan receptor alpha (RORα), a nuclear receptor, in AT. By using the Staggerer mice, a natural mutant RORα loss of function, we observed a decreased AT inflammatory status together with improved insulin sensitivity, suggesting that RORα acts as a pro-inflammatory agent in AT. Moreover, we observed a decreased GNG efficiency, suggesting that RORα acts as a positive regulator of GNG. Thus our results further reveal the depot-specific differences of AT depots and stress for a specific role of RORα in lipid metabolism and AT inflammation
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Kagwiria, Rosebeth [Verfasser], and Lars [Gutachter] Nitschke. "Evaluation of the nuclear receptor Retinoic Acid Receptor related Orphan Receptor α (RORα) as a regulator of osteoclastogenesis in rheumatoid arthritis and osteoporosis / Rosebeth Kagwiria ; Gutachter: Lars Nitschke." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2017. http://d-nb.info/1140228609/34.
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Boyault, Sandrine. "Modulation des effets et de la production de l'interleukine-1ß par des ligands des récepteurs nucléaires : PPAR, "peroxisome proliferator-activated receptor" et RORα "retinoic acid receptor-related orphan receptor alpha" dans les tissus de l'articulation." Nancy 1, 2003. http://docnum.univ-lorraine.fr/public/SCD_T_2003_0245_BOYAULT.pdf.
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La destruction progressive du cartilage, caractéristique commune des arthropathies inflammatoires et dégénératives, résulte d 'un déséquilibre entre les processus de synthèse et de dégradation matricielle. L'interleukine-l (IL-1) joue un rôle central dans la perte d 'homéostasie du cartilage lors de ces pathologies articulaires. Cette cytokine induit la production de médiateurs de l'inflammation, tels que le monoxyde d'azote (NO) et les prostaglandines ainsi que l'expression d'enzymes protéolytiques. La modulation des effets et/ou de la production d'IL-l par les chondrocytes et les synoviocytes est une stratégie essentielle pour prévenir la dégradation du cartilage. Les récepteurs nucléaires PPAR ("peroxisome proliferator-activated receptor")et RORα (" retinoic acid receptor-related orphan receptor alpha") sont des facteurs de transcription impliqués notamment dans la différenciation adipocytaire, le métabolisme lipidique et l'homéostasie du glucose. Des études récentes ont montré que ces récepteurs pouvaient être impliqués dans le contrôle de l'inflammation et plus particulièrement dans la modulation de l'action de cytokines pro-inflammatoires. Notre travail de thèse a consisté tout d'abord à mettre en évidence la présence de ces récepteurs dans les cellules articulaires traitées ou non par de l'IL-Iβ. Nous avons ensuite étudié la potentialité de ligands spécifiques à moduler les effets et/ou la production d'IL-Iβ ou les effets du lipopolysaccharide (LPS). Enfin, les mécanismes d'action de la I5d-PGJ2, ligand physiologique de PPARγ, et les cibles intracellulaires éventuelles dans les voies transcriptionnelles, NF-KB et AP-I, ont été explorés. Nos travaux menés in vitro sur des cultures de chondrocytes humains et de synoviocytes de type B de rat ont montré la présence de PPARα, PPARγet de RORα, au niveau de l'ARNm et de la protéine. Nous avons également observé que l'expression de ces 3 récepteurs était modulée différemment par l'IL-Iß dans les chondrocytes et par le LPS dans les synoviocytes. Ainsi, si l' expression de PPARα est inchangée après traitement, l'expression de PPARγ est diminuée et celle de RORα est augmentée. L'effet de ligands de PPAR et de RORα sur certains paramètres de l'inflammation induits par le LPS ou l'IL-1β a ensuite été étudié. Si dans nos deux modèles cellulaires, les ligands spécifiques de PPARα et RORα n' ont eu aucun effet, les ligands de PPARγ ont permis de s'opposer aux effets de l'IL-I~ ou du LPS. LaISd-PGh, ligand naturel de PPAR'Y, s'est néanmoins révélée bien plus efficace que les ligands synthétiques pour diminuer l'exp~sion de la NO synthase inductible, de la cyclooxygénase-2, de l'IL-Iβ et du tumor necrosis factor alpha (TNFα). De plus, la I5d-PGJ2 inhibe la production de NO induite par le LPS et l'IL-lβ ainsi que la baisse de synthèse des protéoglycanes induite par l'IL-lβ. Des analyses en Western-blot et en retard sur gel ont montré que la I5d-PGJ2 inhibe la translocation de p65 dans le noyau et la fixation de NF-KB et d' AP-1 sur l'ADN induite par le LPS ou l'IL-1β. Le peu d'effet observé avec la troglitazone suggère que l'action de la 15d-PGJ2 dans les chondrocytes et les synoviocytes est principalement indépendante de PPARγ. Cette hypothèse a été confirmée grâce à des expériences de transfection transitoire dans des chondrocytes de rat qui ont permis de surexprimer un récepteur fonctionnel ou muté (dominant-négatit). Enfin, nous avons pu mettre en évidence une action inhibitrice de la 15d-PGJ2 sur le complexe enz~atique IKB kinase ainsi qu'une inhibition de la dégradation de la protéine inhibitrice IKBα, et donc de la voie NF-KB. Ce mécanisme d'action anti-inflammatoire des cyclopentenones est tout à fait original et permet d'entrevoir de nouvelles voies thérapeutiques dans le domaine des arthropathies.
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Genoux, Annelise. "Régulation différentielle de la transcription des gènes murin et humain de l'apolipoprotéine A5 en réponse aux cytokines pro-inflammatoires par différents mécanismes impliquant respectivement NF-kB ou COUP-TFI : régulation transcriptionnelle du gène de l'APOA5 par RORα." Lille 2, 2006. http://www.theses.fr/2006LIL2S007.
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L'hypertriglycéridémie, considérée comme un facteur de risque indépendant de maladies cardiovasculaires, est souvent associée à des pathologies métaboliques et inflammatoires. L'apolipoprotéine A5 (APOA5), récemment découverte, exerce un rôle majeur dans l'homéostasie des triglycérides. De ce fait l'étude des facteurs régulant son expression est particulièrement intéressante. La première partie de nos travaux vise à déterminer le rôle de l'APOA5 dans l'inflammation en étudiant la régulation de son expression génique par les cytokines pro-inflammatoires et d'élucider le ou les mécanismes moléculaires impliqués. En utilisant des modèles cellulaires d'hépatomes humain et murin, nous avons initialement démontré que les cytokines pro-inflammatoire IL-1, TNFα et IL-6 régulent de manière opposée l'expression des gènes humain et murin de l'APOA5 in vitro selon différents mécanismes transcriptionnels faisant intervenir notamment les facteurs nucléaires NF-κB p50 et COUP-TFI. Ensuite, des expériences réalisées sur des souris sauvages et transgéniques surexprimant le gène humain de l'APOA5, ont montré que ces cytokines modulent également l'expression des gènes humain et murin de l'APOA5 in vivo. Enfin, la mesure des concentrations en triglycérides, TNFα et apoAV plasmatiques, réalisée chez 32 enfants présentant le syndrome néphrotique idiopathique (11 en rechute et 21 en rémission), a permis de mettre en évidence une corrélation inverse entre la concentration en apoAV et les concentrations en triglycérides et TNFα chez ces patients. Cette observation suggère qu'une inhibition de l'expression du gène de l'APOA5 par le TNFα synthétisé en grande quantité chez ces patients pourrait contribuer à l'hypertriglycéridémie observée. Cette première étude a mis en évidence un nouveau mécanisme impliquant pour lapremière fois COUP-TFI dans la réponse inflammatoire. La deuxième partie de nos travaux a porté sur l'étude de la régulation du gène de l'APOA5 par les facteurs nucléaires ROR. RORα joue un rôle dans le métabolisme des lipide et l'inflammation. Nous avons d'abord démontré que seuls les facteurs RORα1 et RORα4 stimulent fortement l'activité transcriptionnelle du promoteur de l'APOA5 humaine in vitro, en se fixant directement sur un élément de réponse spécifique. Ensuite, l'infection de cellules humaines d'hépatomes par des adénovirus exprimant hRORα1 et hRORα4 a conduit à une augmentation de l'expression des ARNm de l'APOA5. En outre, nous avons montré que le gène murin de l'apoa5 n'est pas régulé par ROR. Cette partie de l'étude identifie un nouveau gène cible de RORα renforçant son rôle dans l'homéostasie des triglycéridesHypertriglyceridemia, considered as an independent risk factor for coronary heart diseases, is often associated with metabolic and inflammatory disorders. The newly identified APOA5 is a crucial determinant of triglyceride levels and therefore the study of the factors regulating its gene expression is of significant importance. The first part of our studies aims at determining the rôle of APOA5 in inflammation by studying the regulation of its gene expression by pro-inflammatory cytokines and elucidate the molecular mechanisms involved. By using hepatic mouse and human cellular models, we initially demonstrated that the pro-inflammatory cytokines IL-1, TNFα and IL66 regulate in an opposite manner the expression of the mouse and human APOA5 genes in vitro, through different transcriptional mechanisms, involving in particular the nuclear factors NF-κB and COUP-TFI. Then, experiments carried out in wild type mice and mice overexpressing human APOA5 showed that cytokines modulate mouse and human APOA5 gene expressions in vivo. Finally, the measurement of plasma triglyceride, TNFα and apoAV in 32 children with an idiopatic nephrotic syndrome ( 11 in relapse and 21 in remission) allowed to establish a negative correlation between apoAV plasma concentration and triglyceride and TNFα concentrations. This observation suggests that the inhibition of the APOA5 gene expression by the high level of TNFα in these patients could contribute to hypertriglyceridemia. This first study identifies a new mechanism involving for the first time COUP6TFI in the inflammatory response. The second part of our studies is focused on the gene regulation study of APOA5 by nuclear factors, ROR. RORα plays a rôle in lipid metabolism and inflammation. We initially demonstrated that only RORα1 and RORα4 strongly stimulate the transcriptional activity of the human APOA5 promoter in vitro through a direct binding on a specific response element. Furthermore, the infection of human hepatic cells with adenovirus expressing hRORα1 and hRORα4 induce an increase of APOA5 mRNA expression. Moreover, we demonstrated that the mouse apoa5 gene is not regulated by ROR. This part of the study identifies a new target gene for RORα strengthening its rôle in triglyceride homeostasis
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Liang, Ruifang [Verfasser], Jörg [Akademischer Betreuer] Distler, and Michael [Gutachter] Stürzl. "Novel Insights into Hedgehog Signaling in Systemic Sclerosis at the level of GLI2 and HHAT and Characterization of the Role of the Orphan Nuclear Receptor RORα in Fibroblast Activation and Tissue Fibrosis / Ruifang Liang ; Gutachter: Michael Stürzl ; Betreuer: Jörg Distler." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/122642807X/34.
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Amundin, Eskil. "Modeling of fatigue in RORO ships." Thesis, KTH, Marina system, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-119767.
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The largest modern Pure Car and Truck Carriers (PCTC’s) are typically 230 meters long and have 13 cargo decks. In order to facilitate rapid loading and unloading these ships have been subject to a development of reducing any obstructing structures in the cargo hold, meaning that the transversal shear preventing structures, i.e. the racking bulkheads, has been taken to a minimum. Previous studies have concluded that some points on the racking bulkheads, as a result of the stripped down design, are subject to high stresses resulting from wave induced accelerations of the ship. In this M.Sc. Thesis the fatigue life of a corner of a transverse bulkhead opening in a 230 meter long PCTC with a capacity of 7200 cars is calculated with different methods. •Fatigue life is calculated from recorded ship motion data with the notch stress method in conjunction with rain flow counting and the cumulative damage principal. • Fatigue life is calculated according to (DNV CN. 30.7, 2010), based on a Lloyd’s Register FE model load case. • Actual findings on the ship are compared to the calculated results. Due to the lack of inspection data this comparison is not very extensive and only more briefly discussed. It is concluded that the fatigue life of the examined point, calculated from recorded motion data is 9.6 years and the fatigue life according to DNV is 8.0 years. It is also found that the fatigue damage is cumulated in almost discrete portions and thus the calculated fatigue life can be inaccurate when a short period of time is evaluated as is done in this thesis. A modification to the racking bulkhead with respect to fatigue life is also analyzed and it is concluded that the fatigue life in the examined point could be extended significantly by some simple modifications to the geometry.
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Chauvet, Caroline. "Etude du rôle du récepteur nucléaire RORa : analyse des effets de l'hypoxie sur l'expression du gène Rora et recherche de gènes cibles de RORa dans le foie." Paris 11, 2004. http://www.theses.fr/2004PA11T027.
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Pristrom, Sascha [Verfasser]. "Untersuchung zur Einschätzung von Schwimmlage und Stabilität an Bord von RoRo und RoRo-Passagierschiffen im Wassereinbruchfall / Sascha Pristrom." Wuppertal : Universitätsbibliothek Wuppertal, 2011. http://d-nb.info/1010773038/34.
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Paredes, Moscosso Solange Rosa. "ROR1 as a target for cancer immunotherapy." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10038730/.
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Receptor tyrosine-kinase like orphan receptor (ROR1) is a member of the tyrosine kinase family. Importantly, ROR1 is absent in healthy, critical tissue but overexpressed in various solid and haematological malignancies, including Chronic Lymphocytic Leukaemia (CLL). Moreover, recent studies suggest ROR1 is expressed on cancer stem cell-like cells (CSCs). The overriding aim of this study was therefore to combine the unique features of ROR1 with the exquisite specificity/therapeutic potential of monoclonal antibodies (MAbs) and/or their derivatives. To this end, our group generated a rat hybridoma library and screened >150 anti-ROR1+ clones. I then cloned 16 of our novel antibodies to human IgG1, kappa constant regions, of which 12 recognised ROR1 on different cell types. Based on functional/characterisation data, it was identified that clone SA1 exhibited significant CDC activity on primary CLL cells, whilst clone F was the only MAb able to bind the Frizzled domain of ROR1. Further investigation, however, revealed clone SA1 bound non-specifically to ROR1- cells. Therefore, my investigation focused instead on clone F, which was developed in parallel as a bispecific T-cell engager (BiTE) within our group. Having shown F BiTE elicited potent and specific cytotoxicity of ROR1+ cells on various solid cancer cell lines, including pancreatic cancer (PaCa), ROR1 BiTE was tested on PaCa cell line-derived CSCs using an in vitro tumoursphere model. Immunocytochemistry data confirmed specific elimination of cells expressing both CSC biomarkers and ROR1. As a whole, ROR1 MAb-based immunotherapy, particularly using BiTEs, seems to not only target ROR1+ cells present in the bulk of the tumour but, crucially, it also eliminates ROR1+ CSC subsets in PaCa. This approach represents a relevant and much needed addition to the current options for cancer treatment. Further preclinical and clinical studies will ultimately reveal the true therapeutic potential of ROR1 BiTEs alone and in combination.
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Tews, Rory [Verfasser]. "Social entrepreneurship in Germany: A Bourdieuan perspective / Rory Tews." Bielefeld : Universitätsbibliothek Bielefeld, 2015. http://d-nb.info/1080129863/34.
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Grieg, Thomas Willumsen, Ole Henrik F. Pedersen, and Jørgen Rønholt. "Simulation and Rescheduling of Operation for a RoRo-fleet." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for marin teknikk, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-22367.
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This master thesis is a part of the MARFLIX (MARitime FLeet size and mIX) project. The research project MARFLIX is a collaboration between NTNU, MARINTEK, DNV and WWL. The overall aim for the MARFLIX project is to develop and test methods for improved support for fleet size and mix decision-making through quantitative methods. Wallenius Wilhelmsen Logistics (WWL) is a global liner shipping company which delivers shipping and logistics solutions for manufacturers of car, trucks, heavy equipment and specialized cargo. In this master thesis a framework model that is able to test and verify deployment models was developed. This framework model contains a simulation part and an optimization part. The simulation model is constructed to simulate the day to day operations of a fleet. In the day to day operation disruptions will occur. These disruptions are simulated by the use of two different probability distributions and Monte Carlo Simulation. Disruptions occur regularly in a global liner shipping network. About 70-80 % of the vessels experience delays in at least one port during each roundtrip. When a disruption occurs in a liner shipping network, the impact on the network should be minimized.When a disruption occurs, the simulation model will first try to regain the delay by speeding up the delayed vessel. If speeding up is not sufficient, a rescheduling process is initiated. The simulation model will then call on the optimization model to perform a rescheduling. The optimization model considers omitting and changing the order of port calls, and space chartering cargo as possible recovery actions. It will then find the best way to recover from the delay. The new solution will then be implemented as new schedules for the vessels in the fleet.The optimization model is modeled as a set partition model, which can take use of the beneficial structure that appears in transportation problems. To solve a set partition model a column generation algorithm is needed. The column generation algorithm implemented in our model is a complete enumeration algorithm, which generates all possible routes that the vessels can sail. A benefit with the complete enumeration algorithm is that the same routes can be used for all reschedulings during a simulation.There are several incidents, e.g. machinery problems, extreme weather and collision, that can cause delays for a vessel and with that create a need for a rescheduling. Each of these incidents have different impacts on ships, e.g. reduced speed, delayed, changed resistance, port call canceled etc. The simulation and optimization model have been tested on several different problems with a different composition of ports, vessels and cargos. The time required to solve the different test instances varied between 30 and 240 seconds. The tests showed that the required computing time increased exponentially with an increase in the number of ports. The tests also showed that when the chartering cost increased, the number of chartered ships decreased and the rescheduling cost increased.The new routes generated and implemented by the optimization model show similarities with the original routes; in most scenarioes only one or two port calls are changed or left out. This is done contrary to what many shipping companies usually do when they experience delays; they often speed up until the delay is regained.The simulation and optimization models developed in this thesis are able to test and verify the MARFLIX deployment model. In case of a delay the models are able to find good schedules for the fleet within a reasonable amount of time. The different output values provided by the simulation model should be sufficient to verify the deployment model.
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Winkel, Andreas. "Die Signalvermittlung der Rezeptor-Tyrosinkinase Ror2 in mesenchymalen Bindegewebszellen." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976523868.
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Allen, John C. "FGF4 Induced Wnt5a Gradient in the Limb Bud Mediates Mesenchymal Cell Directed Migration and Division." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4309.
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The AER has a vital role in directing embryonic limb development. Several models have been developed that attempt to explain how the AER directs limb development, but none of them are fully supported by existing data. I provide evidence that FGFs secreted from the AER induce a gradient of Wnt5a. I also demonstrate that limb mesenchyme grows toward increasing concentrations of Wnt5a. We hypothesize that the changing shape of the AER is critical for patterning the limb along the proximal to distal axis. To better understand the pathway through which Wnt5a elicits its effects, we have performed various genetic studies. We demonstrate that Wnt5a does not signal via the Wnt/β-catenin pathway. However, we show that Wnt5a mutants share many common defects with Vangl2 mutants suggesting that Wnt5a signals through the Wnt/planar cell polarity (PCP) pathway.
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Wathne, Eivind. "Cargo Stowage Planning in RoRo Shipping : Optimisation Based Naval Architecture." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for marin teknikk, 2012. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-18597.
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Operations research has proven itself to be advantageous in several areas of the industry for many years, but is operations research a good approach to operational maritime planning? Expressions used to calculate the initial stability of a vessel are often non-linear. Optimisation models demand linearity, and approximated linearisations of the proven stability formulas needed to be developed. This was arguably found to be the biggest challenge when modelling the cargo stowage optimisation model. The characteristics of the RoRo shipping industry have been examined to gain a better understand of the segment. Further, some methods for calculating the initial stability of floating bodies have been presented for the readers that are not already familiar with this area of science.The thesis has used a published optimisation model as a foundation for further expansions. The model is a mathematical formulation of a cargo stowage problem in the RoRo shipping segment, where a predetermined vessel ships mandatory and optional cargoes from fixed loading ports to unloading ports. The reference model controls the vertical and transverse stability of the vessel by imposing constraints that are linear approximations of stability formulas. The model was expanded to ensure the longitudinal stability of the vessel as well. Additionally, the definitions of the existing vertical and transverse stability constraints were altered to provide more accurate co-ordinates for the expanded optimisation model.The computational study showed that the original model was able to find the optimal solution faster than the expanded model. The stowage flexibility was also better than for the expanded model, and the revenue generated was equal or higher in the original model for all scenarios. This was because the expanded model is of a greater size than the original, and is much more constrained in terms of stowage on the various decks. The expanded model divides the decks on the vessel not only into lanes, as the original model does, but also into slots. It can therefore ensure the longitudinal stability of the vessel as well. In addition to this, the lanes and slots in the expanded model are subject to lower and upper bounds for width and length, respectively. The original model allows the width of a lane to take values from zero up to the total width of the deck. In the original model, the size of the set of lanes therefore does not dictate the division of decks into lanes. This was found good for stowage flexibility, but is problematic to defend from a stability and safety perspective.
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Lloyd, Angela Jane. "Modal representation in the early madrigals of Cipriano de Rore." Thesis, Royal Holloway, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362748.
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Alqattan, Humoud. "An estimation model for private rate of return on education in high income petroleum based developing countries : the case of Kuwait." Thesis, Brunel University, 2013. http://bura.brunel.ac.uk/handle/2438/7650.
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The benefits of a good education are numerous; it not only offers knowledge and power to individuals, but also enables them to lead the life they wish to; and to benefit both their own family and country. Education has a positive impact on the development of a country. An educated society can eradicate poverty, illiteracy and unemployment, and help in the improvement of the health care standards, the political structures, and the national productivity. The contribution of education in this development process is evident and easily recognized. Many studies show that investments in education generate benefits for people (private benefits) and society (social benefits), similar to those of the physical capital investments. Due to the important role that education plays in the development of human capital, in order to conduct the process of development in developing countries, to achieve their growth aims, significant attention should be placed on studying human capital investment accumulation through the means of the rate of return on education (RORE). So far, numerous economists and researchers have attempted to estimate the RORE for the purpose of observing the efficiency of educational spending and resource allocation (see Psacharopoulos, 1973, 1980, 1985, 1994, 2002, and 2004), in order to be able to analyse the output of the educational process on the economy. The estimation of the rate of return on education (RORE) can help in describing different phenomena, such as the following: employees of the public sector benefiting greatly from higher earnings as compared to the employees of the private sector working in the same capacity; the observed difference in the attendance between males and females to complete their education; the large demand for 'easy-discipline', 'aversion‘ (sub) specialties and the high rate of dropouts from school by males. The research problem of this thesis is that there has been a lack of information regarding estimating the RORE in high income petroleum-based developing countries, such as Kuwait, as most of the existing research has not accurately differentiated between low and high income developing nations. The aim of this research is to clarify the influencing variables and factors affecting the investment on education and their relationships by identifying these factors. This study endeavours to develop a framework based on the RORE model and to verify it by estimating the rate of return in high-income petroleum based economies in developing countries, and in this context, data is acquired from Kuwait to verify it, as a case study. The results of the employed regression model show positive and economically significant parameters for return on education and a negative return for extra years of experience. The estimated rate of return for females is relatively higher than males. The average estimated rate of return to education is 5.2%; with the estimated return for females being 6.7%; and for males 5.5%. On the other hand, by expanding the model to include the 'level of education‘ terms, the results show the highest return for primary education and lowest for intermediate and diploma education. Results indicate also that the highest rates of return on education for females occur in high school, whereas for males in bachelor-level higher education.
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vadlamudi, jithin chand. "How a Discrete event simulation model can relieve congestion at a RORO terminal gate system : Case study: RORO port terminal in the Port of Karlshamn." Thesis, Blekinge Tekniska Högskola, Institutionen för datalogi och datorsystemteknik, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:bth-11720.
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Context. Due to increase in demand for RORO shipping services,the RORO terminal gate system need to handle more number of vehicles for every RORO vessel departure. Therefore, various congestion problems can occur; so, to address all possible congestion related problemsat RORO terminal, terminal gate systems are implemented with advanced technologies and updated to full or partial functioning automated gate systems. Objectives. In this research study considering the future increase in demand for wheeled cargo shipping, we attempt to propose a solution for reducing congestion and investigating optimal positions for each automated gate system service at RORO port terminal. Methods. In this Master thesis, as part of qualitative study we conduct a literature review and case study to know about the existing related work on this research problem and know about the real world system operation and behaviour of a RORO terminal gate system.Later, applying the adequate knowledge acquired from above mentioned qualitative studies, we perform a discrete event simulation experiment using Anylogic® professional 7.02 simulation software to address defined research objectives. Results. Considering the peak and low periods of present and future estimated demand volumes as different scenarios,various simulation experiment results are generated for different key performance indicators. The result values of these key performance indicators address various research objectives. Conclusions. This research study finally concludes that, the average queue length values at each automated gate system service implicates optimal position for each service and directly address the congestion problem. We also conclude that in every estimated increase in vehicles attending the RORO terminal, assigning optimal arrival time windows for respective vehicle types minimizes the congestion problem at automated gate system.
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Nylén, Christoffer. "Improving MCDC adequate test sets for safety critical software to be RORG adequate." Thesis, Linköpings universitet, Programvara och system, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-121729.
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A number of logical code coverage criteria have been used throughout the years in the testing of safety-critical software. Kaminski, et al. proposed Relational Operator Replacement Global (RORG), a method to bring benefits from ROR mutation to Modified Condition / Decision Coverage (MCDC), which is widely used in the avionics industry. However, there is a lack of studies in the industry to support this method. In this thesis, we report on the results of applying RORG to avionic code, augmenting an MCDC adequate test set to satisfy RORG, evaluating its ability to find real faults in industrial software. Conclusions drawn from this thesis are: (1) Faults in relational operators in avionic code are rare, no faults were found in this study. (2) 24% of the relational operators in our study would require additional software requirements to be verified for RORG coverage. (3) 37% of the relational operators in our study were infeasible to test due to program semantics. (4) 84% of the tests added covered enumeration comparisons.
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Alhomidan, Abdullah. "INVESTIGATION OF TRAFFIC CRASHES IN TWO-LANE RURAL HIGHWAYS IN OHIO." University of Akron / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=akron1165259225.
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Mangan, Daniel John. "A triangulated study of decision making in RoRo port/ferry choice." Thesis, Cardiff University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341586.
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Raschig, Barbara. "Bizarre Welten Ror Wolf von A bis Z /." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=964177846.
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Martinez, Sébastien. "Rôle de la protéine tyrosine kinase 7 dans le cancer colorectal et la polarité planaire cellulaire." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4019.
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La voie de signalisation WNT/PCP, couramment associée à la polarité planaire cellulaire, joue un rôle fondamental dans la morphogenèse chez les vertébrés. Parmi les différents composants protéiques de la voie WNT/PCP, on retrouve la protéine tyrosine kinase 7 (PTK7), dont les fonctions restent encore très peu décrites. Au cours de ma thèse, j’ai montré que PTK7 interagissait avec le récepteur tyrosine kinase ROR2. Ce complexe, après fixation du ligand WNT5A, induit la migration de fibroblastes embryonnaires murins via l’activation de JNK. Au cours du développement embryonnaire du xénope, Ptk7 interagit de manière fonctionnelle avec Ror2, et contrôle l’expression de la protocadhérine Papc ainsi que la morphogénèse. De plus, en utilisant une approche de Tissue MicroArray, réalisée sur des patients atteints de cancers colorectaux, j’ai pu montrer que PTK7 était retrouvé surexprimé chez 34% des patients, et que cette surexpression était un facteur de mauvais pronostic. Dans des lignées cellulaires issues de cancers colorectaux, la suppression de PTK7 par shRNA entraine une diminution de la migration des cellules tumorales, mais n’impacte pas leur prolifération et leur résistance aux drogues anticancéreuses. Dans un modèle de xénogreffe murin, la suppression de PTK7 induit une diminution du développement tumoral et l’expression de ce dernier, dans des cellules négative pour PTK7, entraine une augmentation de l’apparition de métastases chez les animaux injectés. Ce travail apporte de nouveaux éclaircissements sur le du récepteur PTK7 dans la voie de signalisation WNT/PCP, et le définit comme potentiel biomarqueur et cible thérapeutique dans le cancer colorectalThe non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. We show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells and physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, Ptk7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that Ptk7 is required for papc activation induced by Wnt5a and that Wnt5a stimulates the release of the Ptk7 intracellular domain, which can translocate into the nucleus and activate papc expression. Moreover, using a Tissue MicroArray produced from CRC patients we correlated PTK7 expression with pathological features and patient outcome. PTK7 was significantly up-regulated in CRC tissue, and its overexpression was found in 34% of patients. In CRC cell lines, shRNA PTK7 reduced migration, but did not affect cell proliferation and resistance to drugs. In a xenograft mouse model, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. This work reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements and define PTK7 expression as a potential prognostic biomarker and a novel therapeutic target in CRC
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Yahia, Hanane. "Regulation of RORC2 expression during human CD4+T cell differentiation." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC289.
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La différentiation des lymphocytes Th17 dépend fortement du facteur de transcription RORγt. RORγt a été identifié pour la première fois chez la souris comme un facteur spécifique des thymocytes, jouant un rôle important dans le développement du thymus. En effet, RORγt est exprimé sélectivement dans le stade double positif (DP) et il est ensuite réprimé dans le stade simple positif (SP) ainsi que dans les cellules CD4+ naïves périphériques. Les mécanismes moléculaires qui régulent l’expression transitoire de RORγt dans le thymus et en périphérie sont peu connus. Le but de ce projet est de définir les paramètres transcriptionnels et épigénétiques en corrélation avec l'expression de RORγt chez l’homme. Afin de caractériser les mécanismes moléculaires qui contrôlent l'expression de RORγt dans les thymocytes humains, nous avons effectué une analyse des modifications épigénétiques sur l’ensemble du locus RORC. Nos résultats montrent que le locus RORC subit un remodelage étendu, qui lui confère une conformation "permissive" lors de la transition du stade Double Négatif (DN) au stade DP (augmentation de H4ac et diminution de H3K27me3). Alors que, H3K4me3, qui est un marqueur de promoteurs actifs, est présente spécifiquement au niveau du promoteur RORC2, et uniquement dans les cellules qui expriment RORC2. Une analyse similaire des marqueurs épigénétiques pour les enhancers (H3K27ac) nous a permis d'identifier plusieurs régions avec une fonction potentiellement régulatrices de l'expression de RORC2. Nous avons démontré que certaines de ces régions avaient une fonction d'enhancer in vitro. Dans les cellules T humaines CD4+ naïves périphériques, nous avons observé que la stimulation du TCR en présence de TGFβ est suffisante pour induire RORγt et un remodelage du locus RORC. Nous avons également constaté que la cyclosporine A, un inhibiteur de la voie calcineurine/NFAT, inhibe fortement l'expression de RORC2. Cette inhibition est associée ˆ une diminution des marqueurs positifs de la chromatine. De plus, nous avons démontré que l’activation des cellules induit une activation de NFAT et sa liaison au promoteur RORC2 et aux enhancers. Cette liaison coïncide avec le recrutement de p300/CBP au promoteur qui est dépendant de la calcineurine, ce qui peut permettre le recrutement d'autres facteurs (tel que NFkB) importants pour la différenciation des Th17. Nous avons Également détecté la liaison de NFAT au locus RORC dans les thymocytes. Ces données démontrent un rôle central de NFAT dans la régulation Epigénétique et transcriptionnelle du locus RORCGeneration of inflammatory CD4+ Th17 cells is strongly dependent on the transcription factor retinoid-related orphan receptor, RORγt. RORγt was first identified in the mouse as a thymocyte-specific factor and was shown to play a critical role in the regulation of thymopoiesis. In the thymus RORγt is selectively expressed at the double positive stage (DP: CD4+ CD8+), and is down regulated in later stages of thymocyte development, as well as in naïve peripheral CD4+ T cells. The molecular mechanisms by which RORγt is transiently expressed during thymopoiesis and re-expressed in selected peripheral lymphocytes are poorly understood. The goal of this project is to define the transcriptional and epigenetic settings that correlate with RORγt expression. To start addressing the molecular mechanisms that control expression of human RORγt in thymocytes, we performed an analysis of epigenetic modifications at the RORC locus. Our findings show that the whole RORC locus undergoes extensive remodeling, assuming a more "permissive" conformation at the transition between the Double Negative and the DP stage (increase of H4ac and decrease of H3K27me3). However, H3K4me3, a mark of active promoters, is present specifically at the RORC2 promoter only at stages where RORC2 is expressed. A similar analysis of epigenetic marks for enhancers (H3K27ac) has allowed us to identify several regions with potential regulatory function on RORC2 expression, which displayed enhancer function in vitro. In human naïve peripheral CD4+ T cells we observed that TCR stimulation in the presence of TGFβ is sufficient to induce low levels of RORγt expression, and further remodeling of the RORC locus. We also found that cyclosporine A, an inhibitor of the calcineurin/NFAT pathway, strongly inhibited RORC2 expression, and was associated with a decrease in the positive chromatin marks at the RORC locus. Consistently, we demonstrated that cell stimulation induced NFAT activation, and binding to the RORC2 promoter and enhancers. This binding coincided with calcineurin-dependent p300/CBP recruitment and remodeling of the locus, which may allow binding of the transcriptional machinery and other factors (such as NFkB) important for Th17 differentiation. NFAT binding to the RORC locus could be also detected in thymocytes. These data demonstrate a central role for the NFAT pathway in the epigenetic priming the RORC locus for transcriptional competence
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Schick, Hartmut. "Musikalische Einheit im Madrigal von Rore bis Monteverdi : Phänomene, Formen und Entwicklungslinien /." Tutzing : H. Schneider, 1998. http://catalogue.bnf.fr/ark:/12148/cb369686802.
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Rice, Edward. "Rory lines : silver lining for seabirds in South Africa's demersal trawl fisheries." Master's thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/10902.
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Includes bibliographical references.Seabird bycatch in commercial fisheries is one of the major factors causing decreases in many seabird populations. In trawl fisheries, high mortalities have been recorded as a result of seabirds being struck by trawl warps (the cables used to tow the trawl net). Tori (bird-scaring) lines have been used to decrease seabird mortality in some trawl fisheries by up to 90%. However, tori lines are not effective at reducing the number of birds that drift towards the trawl warps while feeding on factory discards alongside the vessel. The Albatross Task Force (ATF) helped to develop and test a new device, the Rory Line (RL), to be used in conjunction with tori lines, and designed to reduce warp strikes by placing a physical barrier between the scupper (where factory discards are released) and the danger zone (where the trawl warps enter the water) at the stern of the vessel. This study tests the efficacy of the RL at reducing the number of birds drifting into the danger zone and the number of birds being struck by the trawl warps.
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Mani, Rajeswaran. "Preclinical development of a non-immunosuppressive FTY720 derivative OSU-2S forchronic lymphocytic leukemia and other B-cell malignancies." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1404067069.
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Kohlenberger, Judith, and Isabella Buber-Ennser. "Who are the refugees that came to Austria in fall 2015?" Austrian Academy of Sciences Institute for Social Anthropology, 2017. http://epub.wu.ac.at/5375/1/ROR%2DN_Blog_post_Kohlenberger_FINAL.pdf.
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Borcherding, Nicholas. "Noncanonical Wnt signaling in breast cancer initiation and progression." Thesis, University of Iowa, 2014. https://ir.uiowa.edu/etd/1294.
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Besnard, Sandrine. "Expression et fonctions de ROR alpha dans le système vasculaire." Paris 7, 2001. http://www.theses.fr/2001PA077169.
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Edey, Caitlin. "Retinoid-mediated Regulation of NR6A1, Prickle1 and Ror2 During Development of the Mouse Embryo." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23609.
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Vitamin A and its derivatives, collectively termed retinoids, are essential for proper growth and development as well as maintenance of homeostasis in the adult. Retinoic acid (RA), the major biologically active vitamin A metabolite, is well characterized for its crucial roles in gene activation during embryogenesis. Our lab had previously performed a microarray analysis to identify genes induced by exogenous RA in the tailbud of early mouse embryos. Three genes were chosen from the microarray results for further investigation; Germ Cell Nuclear Factor (GCNF/NR6A1), Prickle1 (Pk1) and Ror2, the latter of which are known members of the planar cell polarity (PCP) pathway. These genes were further examined for RA regulation by embryo culture and RT-PCR, which strongly supported a direct regulatory mechanism of NR6A1 by RA. Further analysis aiming to identify a functional response element in the promoter of the targets was attempted, including chromatin immunoprecipitation (ChIP), made possible by the generation and characterization of a highly specific antibody against RARγ. This antibody was used in a ChIP promoter walk, which identified regions on target gene promoters that are occupied by RARγ in vivo, and therefore likely harbor RA response elements.
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Susman, Michael Wen. "The Wnt5a-Ror Signaling Pathway in the Morphogenesis of the Embryo." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845401.
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Embryonic development is orchestrated by relatively few conserved core developmental signaling pathways that are used reiteratively to grow, specify and shape all tissues in the body into their final functional forms. The Wnt5a signaling pathway is necessary to shape and extend various tissues during morphogenesis, but how Wnt5a signals within cells has long remained unclear and controversial. Through loss-of-function experiments in mice, we demonstrate that the Ror family of receptors mediates Wnt5a-dependent processes in vivo at multiple stages of embryonic development. Of previously proposed mediators of Wnt5a-Ror signaling, we identify Dishevelled phosphorylation, but not the inhibition of β-catenin-dependent transcription or the activation of the JNK pathway, as a physiological target of Wnt5a-Ror signaling. To further understand the molecular mechanisms underlying Wnt5a-Ror function, we performed a proteomic mass spectrometry screen to identify additional mediators of the Wnt5a-Ror pathway. This screen led to the discovery that Kif26b, an atypical and largely uncharacterized member of the kinesin superfamily, is part of an evolutionarily conserved signaling cassette with Wnt5a and Ror proteins during embryonic development. Interestingly, we found that Kif26b protein exhibits a polarized subcellular localization at the trailing edge of cultured mesenchymal cells and functions to promote the migration of these cells. Wnt5a triggers the degradation of Kif26b by a proteasome-dependent mechanism and negatively regulates cell migration in a Kif26b- dependent manner. Together, these findings identify a new noncanonical Wnt5a-Ror-Kif26b signaling pathway that links extracellular signaling to cytoskeletal changes that influences the movement, polarity and shape of developing tissues, and pathological situations where this signaling may be dysregulated.Medical Sciences
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Lucas, Murilo Cesar. "Influência da precipitação e do uso solo sobre a taxa de recarga em zona de afloramento do Sistema Aquífero Guarani." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/18/18138/tde-31102012-092335/.
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As maiores taxas de recarga subterrânea do Sistema Aquífero Guarani (SAG) ocorrem nas áreas de afloramento das Formações Botucatu e Pirambóia. O principal objetivo deste trabalho foi avaliar as taxas de recarga subterrânea e suas relações com as variações da precipitação e do uso do solo na bacia hidrográfica do Ribeirão da Onça, situada em área de afloramento do SAG. A variação do nível freático foi medida em 11 poços de monitoramento, distribuídos em diferentes culturas agrícolas na bacia, durante o período de estudo (Outubro de 2004 até Setembro de 2011). Técnicas de tratamento de imagens multiespectrais foram usadas para mapear o uso do solo na bacia. A recarga direta em cada poço foi estimada por um método de escala local (Water Table Fluctuation, WTF) um método de escala de regional (Recession Curve Displacement Method, RCDM). Outro método de escala local foi avaliado (Chloride Mass Balance, CMB) em poços com cultura de pastagem. Foi estimado o armazenamento subterrâneo, o escoamento direto, o escoamento de base e a percolação profunda do aquífero em direção à Formação Botucatu. A espacialização da recarga direta para a bacia, usando os resultados do método WTF, foi feita de acordo com as áreas das culturas agrícolas. A recarga direta para a bacia foi estimada entre 80 mm e 359 mm, correspondente a 7% e 20% da precipitação anual de aproximadamente 1175 mm e de 1808 mm, respectivamente. A recarga direta, usando o método RCDM, variou entre 16% (229 mm) e 34% (~618 mm) da precipitação do ano 2009-2010 e 2010-2011, respectivamente. Foram observadas menores taxas de recarga nas áreas com cultura de eucaliptos em citros em relação às áreas com pastagem e cana-de-açúcar. Caso haja diminuição das precipitações e aumento das áreas de eucaliptos na bacia do Ribeirão da Onça, a recarga poderá sofrer diminuição, ocasionando menores escoamentos de base em direção ao Ribeirão da Onça. A avaliação contínua da recarga nas áreas de afloramento é essencial para a futura utilização das águas do SAG nas atividades agrícolas, industriais e de abastecimento público.The major groundwater recharge rates of the Guarani Aquifer System (GAS) occur in the outcrop areas of Botucatu and Pirambóia Formations. This work aimed at estimating recharge rates and its relation with precipitation and land use in Ribeirão da Onça watershed, located in outcrop area of the GAS, during a seven years term monitoring (October 2004 until September 2011). The water table fluctuations were measured at 11 piezometers, located in different crops areas. Processing techniques for multispectral images were used to map the land use. Recharge was estimated trough a local-scale method (Water Table fluctuation, WTF) and a basin-scale method (Recession Curve Displacement Method, RCDM). Another local-scale method was used (Chloride Mass Balance, CMB) to estimate recharge rate in grassland area. The upscaling of recharge estimates using the results of WTF method for the watershed was performed, according to crop areas. Groundwater storage, quickflow, baseflow and deep percolation toward from the shallow aquifer to Botucatu Formation were also estimated. The results demonstrated that recharge estimates for areas with eucalyptus and citrus was lower than areas with grassland, sugar cane and citrus. Annual recharge rates estimated by WTF ranged from 80 mm (7%) to 359 mm (20%) for annual rainfall of about 1175 mm and 1808 mm, respectively. Recharge rates by RCDM ranged between about 229 (2009-2010) mm to 618 mm (2010-2011) for the entire watershed. CMB method provides mean recharge rate about 590 mm (2010-2011). These results suggest that if eucalyptus areas continue rising in the watershed, the recharge rates and baseflow would considerably decrease. The continuing assessment of recharge in outcrop areas is essential for future use of the GAS.
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Mackenzie, Pierre. "Le langage musical dans les madrigaux tardifs (à partir de 1550) de Cyprien de Rore." Paris 4, 2000. http://www.theses.fr/1999PA040192.
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Cette thèse examine le langage musical des madrigaux tardifs (à partir de 1550), à quatre et à cinq voix de Cyprien de Rore, par une analyse méthodique utilisant les théories musicales de l'époque. La première partie résume l'ensemble de la théorie musicale ayant rapport au madrigal, en particulier les istitutioni harmoniche de Gioseffe Zarlino. Les quatre chapitres traitent respectivement de la mélodie, de l'harmonie, du mode et de la mise en musique des textes, format qui reflète l'organisation des traités théoriques de l'époque. La deuxième partie, divisée en cinq chapitres, consiste en un examen minutieux des madrigaux des cinq derniers recueils de Cyprien, en commençant par le premier livre à quatre voix de 1550, et en concluant avec les deux recueils posthumes. Les madrigaux sont analysés suivant le format de la première partie, à l'aide des points d'analyse qui y ont été relevés. L'analyse révèle les détails des techniques de composition qui caractérisent l'œuvre de Cyprien, et elle montre les développements plus généraux dans le langage musical d'un des plus grands compositeurs de l'époque, à une période centrale dans l'histoire du madrigal italien.
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Lo, Bernard Clement. "The role of ROR alpha and CD34 in mucosal inflammation and fibrosis." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62443.
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Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. Type 2 immunity has long been associated with fibrotic scarring because of its role in wound healing and parasite-initiated tissue remodeling. Our objective was to examine two components of this inflammatory pathway that could potentially be modulated to limit fibrosis, namely RORα, a nuclear receptor required for ILC2 development, and CD34, a sialomucin involved in trafficking of eosinophils and mast cells to peripheral tissues.
Using a model of infection-induced chronic gut inflammation, we demonstrate that Rora-deficient mice are protected from fibrosis; infected intestinal tissues displayed diminished pathology and attenuated collagen deposition. Although Rora is known for its role in ILC2s, we found that Salmonella-induced fibrosis was independent of eosinophils, STAT6 signaling and Th2 cytokines arguing that ILC2s are dispensable in this disease model. Instead, we observed reduced levels of ILC3- and T cell-derived IL-17A and IL-22 in infected tissues. Furthermore, using Rorasg/sg/Rag1-/- bone marrow chimeric mice, we found that restoring ILC function was sufficient to re-establish IL-17A and IL-22 production and a profibrotic phenotype. Our findings suggest that RORα-dependent ILC3 functions are pivotal in mediating gut fibrosis and they offer an avenue for therapeutic intervention in Crohn’s-like diseases.
CD34 has been shown to drive lung inflammation and colitis by coordinating immune cell recruitment. However CD34 is also expressed by multiple non-hematopoietic subsets including endothelial and mesenchymal cells. To assess CD34 function in pulmonary repair, we induced lung injury by bleomycin administration. We found that Cd34-/- mice displayed severe weight loss and early mortality compared to WT controls. CD34-deficient animals developed severe interstitial edema and endothelial delamination, indicating impaired endothelial function. Chimeric Cd34-/- mice reconstituted with WT hematopoietic cells exhibited early mortality compared to WT mice reconstituted with Cd34-/- cells thus confirming this to be a non-hematopoietic defect. Lastly, CD34-deficient mice were more sensitive to lung damage caused by influenza infection, displaying greater weight loss and more extensive pulmonary remodeling. These results suggest that CD34 plays a protective role in maintaining vascular integrity in response to lung damage.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
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Hinz, Laura Emily [Verfasser], Stefan [Akademischer Betreuer] Engelhardt, Bernhard [Gutachter] Küster, and Rory [Gutachter] Koenen. "Phosphorylation of the β1-adrenoceptor / Laura Emily Hinz ; Gutachter: Bernhard Küster, Rory Koenen ; Betreuer: Stefan Engelhardt." München : Universitätsbibliothek der TU München, 2017. http://d-nb.info/1139843885/34.
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Dahl, Tiffanie M. "Role of Wnt5a and Possible Pathway of Action Through Ror2 in Proximodistal Outgrowth of the Limb." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2600.
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Despite over 60 years of study, the molecular pathways and mechanisms governing limb outgrowth and patterning remain poorly understood. Fgfs expressed in the AER are known to be necessary and sufficient for proximodistal limb outgrowth and have been proposed to have a chemoattractive role. Wnt5a is a secreted factor which is expressed in a gradient in the distal limb with the highest concentration next to the AER. The presence of the AER is necessary to establish this gradient. Expression of Wnt5a in a concentration dependant manner can be induced in the limb through the implantation of a bead soaked in recombinant Fgf4 protein. This indicates that Fgfs from the AER may establish the gradient of Wnt5a in the limb mesenchyme. Wnt5a-/- mutants exhibit severe shortening of the face, limbs, and body axis, with limbs being progressively truncated proximally to distally. In normal limb proximodistal outgrowth, cells are seen to grow directionally toward the AER. Previous studies done in the Barrow lab, as well as those done by myself, have shown that if a portion of the AER is removed and the cells proximal to this area are labeled, those which are close enough to intact AER will redirect their growth toward this intact AER. When Wnt5a secreting cells are implanted in the limb mesenchyme of the chick this ectopic source of Wnt5a is sufficient to redirect the growth of the mesenchyme cells toward the Wnt5a source. This indicates that the AER may mediate directed growth of limb mesenchyme cells through the establishment of the Wnt5a gradient which provides positional information to the cells. This Wnt5a gradient results in the recruitment of the mesenchyme cells toward the AER. The Ror2 receptor has been found to be involved in several different pathways involving Wnt5a which are involved in changes in polarity and migration. This makes Ror2 a likely candidate for causing changes in cell polarity and migration during distal outgrowth in the limb. To test whether Ror2 is necessary for the polarizing response of limb mesenchyme cells to the Wnt5a gradient in vivo I co-transfected a dominant-negative Ror2 (Ror2ΔC) and a GFP expression vector in the embryonic chick limb using sonoporation. Limb mesenchyme cells transfected with dominant-negative Ror2 grew as radial clones in contrast to the directional outgrowth of the control limb mesenchyme cells along the proximodistal axis. This indicates that cells expressing the dominant-negative Ror2 could no longer respond to the Wnt5a gradient in the limb mesenchyme. This supports a role for Ror2 as a receptor or co-receptor for Wnt5a in mediating directional growth and movement during proximodistal outgrowth and patterning in the limb.
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Gohil, Satyen Harish. "Pre-clinical development of novel ROR1 chimeric antigen receptor T cells and bispecific T cell engagers." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10042372/.
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Receptor tyrosine kinase like orphan receptor 1 (ROR1) is an onco-embryonic antigen present on a range of solid and haematological malignancies, including chronic lymphocytic leukaemia. Additionally, limited, low level expression on normal tissues makes it an attractive therapeutic target. Chimeric antigen receptor T cells and Bispecific T Cell Engagers have emerged as exciting immunotherapeutic approaches, utilising the inherent cytotoxic potential of autologous T cells to yield demonstrable benefit for patients. We therefore aimed to generate novel ROR1 CAR T cells and BiTEs. Following a rat ROR1 immunisation programme, we screened over 150 single cell hybridoma clones to isolate 13 novel antibodies of which 10 bound in a single chain variable fragment format. Iterative optimisation led to two lead candidates that imparted superior cytotoxicity and cytokine secretion. To minimise immunogenicity we screened 50 humanised ROR1 scFv variants and selected a final humanised candidate, hF(1x1), which maintained effector function, specificity and demonstrated broad applicability against a panel of cell lines representing various tumour subtypes. Focusing specifically on haematological cell lines and CLL, our humanised CAR demonstrates superior cytotoxicity compared to previously reported ROR1 constructs. However, low ROR1 antigen density limits efficacy in B cell malignancies, compared to CD19 CAR T cells and strategies to overcome this are in development. Our ROR1 BiTE mediates cytotoxicity at low concentrations (ng/ml) and effector to target ratios against cell lines, but in untreated and relapsed CLL patients, inherent T cell dysfunction limits efficacy. This can be overcome with the BTK inhibitor Ibrutinib, with T cells isolated from patients on treatment, showing markedly improved cytotoxicity against autologous CLL cells. This work has laid the preclinical foundations for translation of these novel agents into clinical trials for a range of tumours including CLL and many of which have high unmet therapeutic need.
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Lima, Ariadne Ramalho de. "Pesquisa de mutações no gene ROR2 em pacientes com a forma recessiva da síndrome de robinow." reponame:Repositório Institucional da UnB, 2015. http://dx.doi.org/10.26512/2015.07.D.20074.
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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências Médicas, Programa de Pós-Graduação em Ciências Médicas, 2015.A Síndrome de Robinow se caracteriza por dismorfias faciais associadas a encurtamento mesomélico e genitália hipoplásica. Defeitos de segmentação costovertebral que incluem fusões de costelas também podem ser observados e permitem distinguir os pacientes com a forma autossômica recessiva da síndrome daqueles com a forma autossômica dominante. A forma recessiva é causada por mutações no gene ROR2 (related orphan receptor 2), sendo que apenas dezenove diferentes mutações foram descritas em pacientes com a síndrome. O objetivo desse trabalho foi identificar novas mutações no gene ROR2 em pacientes com a Síndrome de Robinow autossômica recessiva. Foram selecionados onze pacientes originários do Brasil, Estados Unidos, Índia e Turquia com características clínicas da forma recessiva da síndrome. O sequenciamento foi realizado a partir de amostras de sangue e saliva por sequenciamento Sanger, ou por sequenciamento de nova geração na plataforma Ion PGM. Em um paciente a mutação foi detectada por MLPA. Identificamos 13 diferentes mutações sendo que 10 ainda não haviam sido descritas na literatura. A comparação dos dados clínicos dos pacientes estudados com as frequências dos sinais clínicos proposta por Mazzeu e cols. (2007) revelou frequência semelhante para a maioria dos sinais clínicos com exceção da fusão de costelas, ausente no paciente 5, a língua bífida presente em todos os 11 pacientes, o lábio superior fino que teve uma frequência de 72% e anteriormente era de 26% e a má-oclusão dentária que teve uma frequência de 60% enquanto que a frequência descrita anteriormente era de 93%. Assim, a descrição clínica detalhada de pacientes com diagnóstico confirmado molecularmente contribuiu para a definição das frequências dos principais sinais clínicos nessa forma da síndrome. Observamos também uma maior gravidade das manifestações esqueléticas nos pacientes com mutações que alteram o quadro de leitura mostrando assim que pode haver correlação entre o tipo de mutação e o fenótipo dos afetados. O conjunto de novas mutações detectadas no trabalho colaboram para um melhor entendimento da fisiopatologia da síndrome.
Robinow syndrome is characterized by facial dysmorphisms, mesomelic limb shortening and hypoplastic genitalia. Costovertebral segmentation defects including rib fusions may be present and allow the distinction between the autosomal recessive and the autosomal dominant forms. Recessive form is caused by mutations in ROR2 gene (related orphan receptor 2) and only 19 different mutations have been described in the literature in patients with the syndrome. The main goal of this work was to identify new mutations in ROR2 in patients with RRS. Eleven patients with clinical signs of RRS from Brazil, United States, India and Turkey have been selected. Sequencing was performed from either blood or saliva samples by Sanger sequencing or Next generation sequencing using Ion PGM platform. In one patient the mutation was detected by MLPA. We identified 13 different mutations, 10 not previously described in the literature. Comparison of clinical data from our patients and the frequencies of clinical signs proposed by Mazzeu e cols., (2007) revealed similar frequencies for most clinical signs except for rib fusions, absent in patient 5; bifid tongue, present in all 11 patients; thin upper lip that had a frequency of 72% compared to 26% in the previous report and dental malocclusion that showed a frequency of 60% and the previous frequency was 93%. Therefore, a detailed clinical description of patients with a molecularly confirmed diagnosis contributed to the definition of frequencies of the main clinical signs of the syndrome. We also observed a more severe skeletal phenotype in patients with frameshift mutations showing that genotype and phenotype may correlate. The group of new mutations detected in the present work contribute to a better understanding of the physiopathology of the syndrome.
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Tročil, Jan. "Investigating Risk-On Risk-Off Patterns in Global Financial Markets." Master's thesis, Vysoká škola ekonomická v Praze, 2013. http://www.nusl.cz/ntk/nusl-192459.
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The aim of this thesis is to analyse the increased correlation within four major asset groups (Government Bonds, Equity Indices, Commodities and Currencies) from the beginning of Great Recession till July 2014. The effect of increased correlation is called Risk-On Risk-Off and is connected to problems, where investors struggle to create risk-oriented portfolios and instead minimalize loss. The methods analysing the correlations are Absolute Average Value Index (AAVI) and Heat-map analysis. The AAVI is transforming correlation matrix into a single number and investigating the intensity of correlations. The Heat-map is studying the relationship between any two assets. The results from this study were that the RORO effect was present during Great Recession with intensity never seen before and that in June 2014 the values are close to pre-recession levels.
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Schmidt, Christina [Verfasser]. "Funktionelle Analyse des Receptor tyrosine kinase-like orphan Receptor 1 (ROR1) bei der chronischen lymphatischen Leukämie / Christina Schmidt." Köln : Deutsche Zentralbibliothek für Medizin, 2013. http://d-nb.info/1042336253/34.
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Herrmann, Simon [Verfasser], and Henrik [Akademischer Betreuer] Schulze-Koops. "Histonmodifikationen in den Genloki RORC und IL17 bei Patienten mit rheumatoider Arthritis / Simon Herrmann ; Betreuer: Henrik Schulze-Koops." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1148940642/34.
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Takai, Akira. "Anterior neural development requires Del1, a matrix-associated protein that attenuates canonical Wnt signaling via the Ror2 pathway." Kyoto University, 2011. http://hdl.handle.net/2433/135377.
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Singh, Jaspal 1978. "Corepressor-specific control of ROR [alpha] transcriptional activity mediated by a calcium-dependent pathway." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=81440.
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Eukaryotic gene regulation by members of the nuclear receptor superfamily is crucial for a vast array of cellular and physiological processes including development, differentiation, proliferation and homeostasis. Regulation of the transcriptional activity of nuclear receptors occurs through the exchange of corepressor and coactivator complexes in a ligand-dependent manner. However, this may not be the case for orphan nuclear receptors, including RORalpha. Instead, RORalpha orphan nuclear receptor activity is modulated by Ca 2+/calmodulin-dependent protein kinase IV (CAMKIV), through a yet undetermined mechanism, and RORalpha itself regulates the expression of genes involved in the calcium signaling pathway. In this study, we report that RORalpha transcriptional activity is modulated by CaMKIV through direct phosphorylation of CIR, a novel nuclear receptor corepressor, thereby influencing its interactions with RORalpha. CIR exhibits ligand-oblivious and nuclear receptor AF-2 specific functional properties, similar to those of previously characterized RORalpha corepressor Hr. In contrast, the corepressors CIR and Hr display differential mechanisms of repression, comprising of HDAC-dependent and independent pathways, respectively. Furthermore, the calcium-dependent regulation of RORalpha transcriptional activity occuring through modulation of CIR does not extend to Hr, illustrating corepressor specificity. Thus, the molecular mechanisms governing active repression of RORalpha transcriptional activity involve distinct repression and signal transduction pathways, representing a dual mode of nuclear receptor regulation.
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Jadeland, Maria, and Jessica Harletun. "FAR ROR : MOR ÄR RAR.En studie om användningen av läromedel för läs- och skrivinlärning." Thesis, Kristianstad University College, School of Teacher Education, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:hkr:diva-4829.
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Uppsatsen inriktar sig på pedagogers arbete med läromedel för läs- och skrivinlärning med fokus på årskurs ett. I forskningsbakgrunden lyfts teorier och undersökningar inom läs- och skrivinlärning fram. Det finns två motpoler i läs- och skrivinlärningen: syntetisk metod, som utgår från delarna, och analytisk metod, som har sin utgångspunkt i helheten. Vidare tas styrdokumentens roll för läs- och skrivinlärningen upp och diskuteras i förhållande till undersökningens resultat. Syftet med uppsatsen är att se på vilka läromedel några pedagoger använder sig av, hur och varför. Undersökningen genomförs med fyra pedagoger på tre olika skolor med hjälp av intervju och observation och är då kvalitativ. De läromedel som framkom i undersökningen utgår från analytisk eller syntetisk grund. Pedagogerna använde sig av läromedel i olika utsträckningar och i varierad omfattning. Eleverna arbetade både enskilt och i grupp med eller utifrån läromedlen. Pedagogernas val av läromedel har i vissa fall skett genom diskussion i samspel med andra. Detta visar att behovet av diskussion inför valet av läromedel bör lyftas. Andra resultat som framkommit är att läromedlen inte till fullo tillgodoser de riktlinjer som anges i Lpo94 (Utbildningsdepartementet, 1994) vad gäller att utgå från elevens eget intresse och fantasi samt att på egen hand inhämta kunskaper. För att uppnå dessa mål använder lärarna i undersökningen andra metoder som komplement till läromedlen.