L’inhibition ou l’inactivation de la myostatine (mstn) entraine une hypertrophie musculaire qui permet d’envisager des thérapies efficaces dans la lutte contre la fonte musculaire dans de nombreuses pathologies (myopathies, maladies chroniques, sarcopénie). Cependant, le muscle déficient en mstn présente une fatigabilité musculaire accrue, associée à des altérations du métabolisme mitochondrial et lipidique. Or, les membranes musculaires et mitochondriales sont constituées principalement de lipides et phospholipides. Ces derniers participent au maintien de la structure et de la fonction métabolique de la fibre. Ils interviennent également dans la chaine respiratoire jouant un rôle clé dans la bioénergétique mitochondrial. Dans ce travail de thèse, nous avons émis l’hypothèse que la composition lipidique musculaire et mitochondriale est altérée dans le muscle KO mstn, expliquant en partie les altérations métaboliques et fonctionnelles de ce phénotype. Dans un second temps, nous avons recherché si l’entrainement en endurance normalise ces altérations phénotypiques musculaires. Nos résultats ont montré dans le muscle KO mstn une diminution de l’expression des différents transporteurs membranaires des lipides (FAT/CD36, FABP3, FATP1 et FATP4) associé à une réduction de l’activité des enzymes impliquées dans l’oxydation lipidique (Citrate synthase et βHAD) et une diminution de la lipogenèse (chute du contenu en triglycérides et en acides gras libres). D’une manière intéressante, nos résultats montrent une diminution de la proportion en cardiolipide au niveau de la membrane mitochondriale, en relation avec une réduction de l’expression des gènes PGPS et CRLS1, impliqués dans le processus de synthèse de cardiolipide. Nous avons également établi que 4 semaines d’entrainement en endurance sur tapis roulant améliorent en particulier la performance aérobie des souris KO mstn, qui retrouvent une capacité d’endurance comparable à celle des souris contrôles entrainées. L’expression des marqueurs de l’oxydation lipidique et du métabolisme oxydatif est également améliorée (Cpt1, Pparδ, Fas, contenu mitochondrial et citrate synthase). L’entraînement permet aussi d’augmenter l’activité des enzymes mitochondriales et la proportion membranaire en cardiolipide uniquement chez les souris KO mstn. En conclusion, ces résultats suggèrent que les qualités oxydatives du muscle hypertrophié KO mstn peuvent être remodelées sans impacter l’effet bénéfique hypertrophique. Enfin, ils présentent le métabolisme lié au cardiolipide et lipidique de manière générale comme de nouvelles pistes à explorer pour améliorer le métabolisme du muscle KO mstn et sa fonction mitochondriale. / Myostatin (mstn) inactivation or inhibition is considered as a promising treatment for various muscle-wasting disorders because it promotes muscle growth. However, mstn-deficient hypertrophic muscles show strong fatigability associated with abnormal mitochondria and lipid metabolism. Muscle membrane maintains the structure and the metabolic function of the fibre, and mitochondrial membrane including respiratory chain complexes, are composed mainly of lipids and phospholipids playing functional role in mitochondrial bioenergetics. In our study, we hypothesized first that changes in the muscle and mitochondrial lipid composition could exist in the KO mstn muscle, in relation with the metabolic and functional alterations, secondly that endurance training can normalize these phenotypic muscle alterations. We reported in KO mstn muscles a decrease of fat membrane transporter levels (FAT/CD36, FABP3, FATP1 and FATP4) associated with decreased lipid oxidative pathway (citrate synthase and βHAD activities) and decreased lipogenesis (decreased triglyceride and free fatty acids content). Interestingly, we demonstrated a decrease in mitochondrial cardiolipin content, in relation with a decrease in PGPS and CRLS1 gene expressions. Then, we showed in KO mstn mice that 4 weeks of daily running exercise session (65-70% of the maximal aerobic speed for 1 hour) improved significantly aerobic performance, particularly the endurance to levels comparable to those of trained wild type littermates.The expression of oxidative and lipid metabolism markers also was increased, as indicated by the upregulation of the Cpt1, Ppar, Fas genes, and increased citrate synthase level and mitochondrial protein content in KO mstn muscle. Interestingly, mitochondrial enzyme activity and the cardiolipin fraction in the mitochondrial membrane are increased by training only in KO mstn mice. In conclusion, these results suggest that the combination of mstn inhibition and endurance training could increase the muscle mass while preserving the physical performance. In addition, cardiolipin and lipid-related pathways could represent new targets to improve mstn-deficient muscle metabolism and restore mitochondrial function.

Disposal of the UK's legacy nuclear waste is the biggest challenge facing the industry at present. There is currently no long term storage facility in the UK and the inventory is continually growing. This project investigates the role that digital geoscientific data collection, analysis and modelling techniques play in the search for, and development of, a Geological Disposal Facility (GDF), critically analyses classical techniques and new, digital methodologies to assess what their impact would be on any site investigation. The Borrowdale Volcanic Group outcrop in Cumbria, NW England was chosen as it provides an analogue to a higher-strength crystalline basement setting for a GDF. Terrestrial lidar and photogrammetric surveys were conducted at four locations around the study area. These provided information on the fracture geostatistics which are the main fluid migration pathways in the subsurface in the BVG. The mechanics of deformation are identified by analysing the clustering of data points via digital stereonet analysis. The analysis shows the rocks sampled are highly fractured and their orientations and dips reflected the extensional tectonism experienced in the area. These are in the form of adjacent sets trending broadly NNE-SSW and NNW-SSE at very high angler dips (~70 degrees). A new workflow developed for this work demonstrates how a potential site's fracture statistics, and indeed the 3D geology, should be investigated as part of future GDF site investigations. Areas of complex geology such as the BVG present many difficulties in interpretation and analysis due to the poorly constrained polyphase nature of the deformation. These complexities make characterisation and modelling highly problematic, and as such, areas of simpler geology should be investigated first. Assessments which were based on early geological studies using traditional field data collection techniques underestimated the impact of heterogeneity on fluid flow migration modelling within the subsurface. This suggests that, should a GDF should be developed in such a geological setting, huge difficulties may be encountered. These will be associated with the development of performance assessments and safety cases which are typically based on geological models that should use such complex data. In addition to this, datasets collected using digital methods are a powerful visualisation tools for communication of complex geology, that can be utilised in stakeholder engagement activities that will form a key part of any GDF development process.

Submitted by Josimara Dias Brumatti (bcgdigital@ndc.uff.br) on 2017-03-13T14:53:22Z No. of bitstreams: 1 Dissertação versão CORRIGIDA E DEFINITIVA - 2015.pdf: 1146743 bytes, checksum: a3c99f8a98f5415b4bf71b2fac55b7fd (MD5) / Made available in DSpace on 2017-03-13T14:53:22Z (GMT). No. of bitstreams: 1 Dissertação versão CORRIGIDA E DEFINITIVA - 2015.pdf: 1146743 bytes, checksum: a3c99f8a98f5415b4bf71b2fac55b7fd (MD5) / Esta dissertação visa a analisar as funções pragmáticas tópico, foco e contraste presentes nos diálogos originais e na versão brasileira de sua legendagem eletrônica do filme argentino “El secreto de sus ojos”, de Juan José Campanella (2009), com o instrumental teórico da Gramática Discursivo-Funcional (GDF). De acordo com a GDF, as funções pragmáticas têm uma função primordial dentro dos padrões gramaticais e constituem primitivos gramaticais, de maneira que se considera que todo o enunciado é montado em sua ordenação lógica partindo-se das relações pragmáticas. Baseamo-nos, para a análise dos dados em português brasileiro (doravante PB), em Pezatti (2012a; 2012b; 2014) e Braga (2009. Por outro lado, para os dados em espanhol argentino (doravante EA), nos valemos de autores como Kovacci (1992) e Gutiérrez-Bravo (2008). O objetivo principal, explorado neste trabalho, é o de levantar as construções marcadas como funções pragmáticas no texto original em EA e observar que estrutura foi apresentada na sua legendagem em PB do filme citado. Para levantar estas ocorrências, utilizamos o programa YouAlign (Terminotix Inc.), de alinhamento de corpora paralelos. Foram analisados 48 casos de tópico – 37 em EA (77%) e 11 em PB (23%) –; 8 de foco – 5 em EA (67%) e 3 em PB (33%) – e 20 de contraste – 13 em EA (62%) e 7 em PB (38%). Os resultados indicaram um apagamento das funções dos diálogos originais em espanhol nas legendas brasileiras, o que pode dever-se à natureza do procedimento de legendagem, que tende à simplificação da sintaxe. / This dissertation analyzes pragmatic functions topic, focus and contrast in the original dialogues of the Argentinean movie The Secret in their eyes/ “El secreto de sus ojos”, directed by Juan José Campanella (2009), in Functional Discourse Grammar (FDG) framework (Hengeveld e Mackenzie 2008). According to FDG pragmatic functions have a paramount importance in the design of a grammar. Accordingly, every statement is built upon its pragmatic functions. For the analysis of Brazilian Portuguese (BP) data we based on Pezatti (2012a; 2012b; 2014) and Braga (2009). For Argentinean Spanish (AE) data we based on Kovacci (1992) and Gutiérrez-Bravo (2008). The main goal of this study is to point out constructions marked as focus, topic or contrast in the original dialogues and to investigate the corresponding structure assigned to them in BP subtitles. We used the software YouAlign for alignment of parallel corpora. We analyzed 48 cases of topic – 37 for AE (77%) and 11 for BP (23%) –, 8 cases of focus – 5 for AE (67%) and 3 for BP (33%), and 20 of contrast – 13 for AE (65%) and 7 for BP (35%). Results indicate an erasing process of topic constructions from the original Spanish dialogues in Brazilian Portuguese subtitles. This could be due to the syntactic simplification typical of the subtitling process.

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Cancers represent second the most common cause of death in the Czech Republic. The most common are breast and colorectal cancers. Identification of prognostic factors improving decision-making approaches for treatment optimization belongs to the key aims of clinical research in oncology. Carriers of mutation in cancer-susceptibility genes represent a small but clinically important group of high-risk patients. The implementation of NGS have accelerated predisposing genes analyses. The large extent of data about the presence of variants in predisposing genes is in striking contrast to only a very limited information available about clinico-pathological characteristics of mutation carriers. Determination of the risk of tumor development in carriers of rare mutations or variants of unclear significance in genes with incomplete penetrance represent substantial drawbacks of current NGS analyses. To address these issues, we have attempted i) to introduce a unified approach to NGS analysis in breast cancer patients, ii) to characterize importance of prognostic factors in BRCA1/BRCA2 mutation carriers, and iii) to identify the cancer risks in carriers of germline mutations in the CHEK2 gene. Colorectal cancer represents seemingly histologically homogeneous disease. However, at the molecular level it can be...

Myostatin (GDF-8) is the chief chalone in skeletal muscle and negatively controls adult skeletal muscle growth. The role of myostatin during overload-induced hypertrophy of adult muscle is unclear. We tested the hypothesis that overloaded adult rodent skeletal muscle would result in reduced myostatin protein levels. Overload-induced hypertrophy was accomplished by unilateral tenotomy of the gastrocnemius tendon in male adult Sprague-Dawley rats followed by a two-week period of compensatory overload of the plantaris and soleus muscles. Western blot analysis was performed to evaluate changes in active, latent and precursor myostatin protein levels. Significant hypertrophy was noted in the plantaris (494 ± 29 vs. 405 ± 15 mg, p < 0.05) and soleus (289 ± 12 vs. 179 ± 37 mg, p < 0.05) muscles following overload. Overloaded soleus muscle decreased the concentration of active myostatin protein by 32.7 ± 9.4% (p < 0.01) while the myostatin precursor protein was unchanged. Overloaded plantaris muscle decreased the concentration of active myostatin protein by 28.5 ± 8.5% (p < 0.01) while myostatin precursor levels were reduced by 17.5 ± 5.9% (p < 0.05). Myostatin latent complex concentration decreased in the overloaded soleus and plantaris muscle by 15.0 ± 5.9% and 70.0 ± 2.3% (p < 0.05), respectively. These data support the hypothesis that the myostatin signaling pathway in overloaded muscles is generally downregulated and contributes to muscle hypertrophy. Plasma concentrations of total and active myostatin proteins were similar in overloaded and control animals and averaged 8865 ± 526 pg/ml and 569 ± 28 pg/ml, respectively. Tissue levels of BMP-1, an extracellular proteinase that converts myostatin to its active form, also decreased in overloaded soleus and plantaris muscles by 40.4 ± 12.9% and 32.9 ± 6.9% (p < 0.01), respectively. These data support the hypothesis that local, rather than systemic, regulation of myostatin contributes to the growth of individual muscles, and that an association exists between the extracellular matrix proteinase BMP-1 and the amount of active myostatin in overloaded muscles.

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Introduction: Le principal objectif de cette étude est de mesurer l’effet du GDF-5 sur l’homéostasie du cartilage. Le GDF-5 est un gène de susceptibilité de l’OA faisant partie de la famille des BMPs et qui favorise la synthèse du cartilage. Le but de notre étude a été de déterminer l’effet du GDF-5 sur le métabolisme catabolique ainsi que sur l’équilibre global des chondrocytes, principalement au niveau de l’Aggrécan. Méthode : Des chondrocytes arthrosiques canins et humains OA ont été exposés au GDF-5. L’expression des ARNm et des protéines a été analysée afin d’évaluer la production de l’Aggrécan et le ratio Col-II/Col-I au niveau des facteurs anaboliques et du phénotype. Pour le catabolisme, l’expression et l’activité des aggrécanases ADAMTS-4 et ADAMTS-5 ont été mesurées. Les épitopes NITEGE et CTX-II ont aussi été quantifiés dans le liquide synovial canin après des injections intraarticulaires de GDF-5. Résultats : Le GDF-5 provoque une augmentation de l’activité cellulaire des chondrocytes canins et humains. Pour les ARNm et l’expression protéique, le GDF-5 augmente l’expression de l’Aggrécan alors que les facteurs cataboliques le diminuent. Le phénotype reste inchangé en présence du produit, sauf à haute dose où on augmente le ColI. L’activité des aggrécanases diminue puisque l’épitope NITEGE diminue alors que le CTX-II augmente dans l’articulation. Conclusion : En somme, les facteurs anaboliques du cartilage sont favorisés, alors que les facteurs cataboliques sont diminués par le GDF-5. Cette action double permet d’illustrer l’effet du GDF-5, le classant comme un potentiel médicament modifiant la maladie de l’OA qui mérite d’être étudiée. / Purpose: The objective of this study is to assess the effect of GDF-5 on cartilage homeostasis. GDF-5 is a susceptibility gene for OA and member of the BMP super family. Studies have shown that it can increase expression of anabolic factors in chondrocytes. Therefore, our study indentifies how GDF-5 influences this metabolism and the global homeostasis of chondrocytes, aiming mainly towards Aggrecan. Methods : Osteoarthritic (OA) chondrocytes from canine and human models were exposed to GDF-5. Protein expressions, along with mRNA expression were assessed in order to investigate Aggrecan production and the ratio of Col-II/Col-I, for the anabolic phenotype markers. The aggrecanases ADAMTS-4 and ADAMTS-5 and their global activity were assed for the catabolic factors. The NITEGE and CTX-II epitope were also measured in synovial fluid of Pond-Nuki dogs that received intraarticular GDF-5 injections. Results : GDF-5 increases chondrocyte cellular activity, in our canine and human models. Both mRNA and protein expression of the chondrocytes Aggrecan were increased and the aggrecanases expression and activity were decreased. Collagen ratio did not show a phenotype, except et high dosage where the Col-I production is induced. Aggrecanase activity was lowered while CTX-II was increased. Conclusion : In conclusion, the anabolic cellular activity of OA chondrocytes increases while the catabolic factors decrease in presence of GDF-5. This double action illustrates the global effect of GDF-5, identifying it as a potential disease modifying factor of OA that should be further investigated.

L'exploitation excessive des ressources énergétiques fossiles pose aujourd'hui des problèmes liés au changement climatique, à leur épuisement et en conséquence à l'augmentation de leur prix. Ces problèmes nécessitent des solutions innovantes, telles que le recours aux énergies renouvelables, afin d'en restreindre l'impact. Les travaux présentés dans ce manuscrit s'attachent à répondre à cette problématique par l'intermédiaire d'une méthodologie d'optimisation énergétique, appliquée au secteur du bâtiment et notamment au poste de chauffage, l'un des plus gros consommateurs d'énergie en France. Cette méthodologie est basée sur la modélisation du procédé de chauffage considéré et d'un moyen de stockage énergétique, ainsi que sur le développement d'outils de contrôle prédictif exploitant la connaissance de perturbations futures. Cette approche a été utilisée pour l'optimisation énergétique d'une chaufferie collective, gérée par la société Cofely GDF-SUEZ et qui alimente en eau chaude, via un réseau de chaleur, un quartier de La Rochelle. Un modèle modulaire de l'installation actuelle, dont le fonctionnement s'appuie sur un mix énergétique renouvelable et non renouvelable, a été développé à partir de mesures réalisées sur le site et de techniques de modélisation de types boite noire, boite grise ou boite blanche, en fonction de la connaissance disponible. La chaufferie ne disposant pas d'un système de stockage, nous avons proposé une modification hydraulique afin d'en intégrer un. Le modèle de ce système a complété le modèle de la chaufferie. Pour la gestion du stockage, deux contrôleurs différents, dont l'un basé sur la commande prédictive optimale et exploitant des prédictions pour anticiper le comportement de la chaufferie, ont été proposés. Ces prédictions sont fournies par un module intégrant une analyse multi-résolution par décomposition en ondelettes et utilisant les réseaux de neurones artificiels. Les résultats obtenus avec le contrôleur prédictif montrent que l'utilisation optimale d'un système de stockage permet d'améliorer de façon très significative le fonctionnement de la chaufferie. La consommation énergétique fossile, le coût de fonctionnement de l'installation, les émissions de CO2 et le taux de couverture de l'énergie fossile sont fortement réduits, tout en améliorant le respect des contraintes techniques de fonctionnement.