Characterisation of the Ovine Model of McArdle’s Disease: Development of Therapeutic Strategies. McArdle’s disease (OMIM 232600) is one of the most common glycogen storage diseases affecting skeletal muscle. It is inherited in an autosomal recessive manner and is caused by a defect in the muscle glycogen phosphorylase gene (PYGM) (Ch 11q13), a key metabolic enzyme. As a result, patients are unable to mobilise muscle glucose stores to provide the energy for muscle contraction; and suffer from exercise intolerance (myalgia, tachycardia, breathlessness and early fatigue) as well as cramps / contractures and occasionally rhabdomyolysis and myoglobinuria after bouts of strenuous exercise. Histopathologically, McArdle’s disease is characterised by an increase in subsarcolemmal storage of glycogen and reduced or absent glycogen phosphorylase activity. McArdle’s disease displays significant genetic heterogeneity, with 47 different disease-causing mutations in PYGM having been identified in human sufferers. In keeping with this genetic heterogeneity, significant molecular heterogeneity is observed in patients with regard to the effect of the disease-causing mutation on the PYGM mRNA transcript. In contrast, little biochemical heterogeneity is associated with the disease, with approximately 90% of human patients having no residual pygm protein and therefore no enzyme activity. A naturally occurring ovine model of McArdle’s disease was identified a number of years ago in a flock of merino sheep in Western Australia. The disease causing mutation responsible for ovine McArdle’s disease was identified and published in 1997 by Tan et al., (1997) [1]. The mutation occurs in the 3’ acceptor splice-site of intron 19 of the ovine PYGM gene, resulting in the activation of a cryptic splice-site site in exon 20 and the premature termination of the transcript. Hypothetically this mutant pygm protein should be 31 amino acids smaller than the wild-type. When I began my PhD, it was known that the ovine sufferers displayed exercise intolerance and histological examination of affected muscle revealed an excess subsarcolemmal storage of glycogen and absent phosphorylase, as occurs in their human counterparts. Due to their similarities in muscle mass to humans and the relative ease and low cost of maintenance, the ovine model of McArdle’s disease is an important and highly relevant test-bed for therapeutic strategies. This thesis can essentially be divided into two parts: 1) The characterisation of the ovine model of McArdle’s disease- In particular, determining the effect of the disease-causing mutation on both the PYGM mRNA and protein, characterising the sequences of the ovine glycogen phosphorylase isoforms and their developmental and tissue specific expression patterns, as well as determining the identity and the activity of the glycogen phosphorylase isoforms expressed in certain muscle groups (cardiac, extraocular and smooth muscles) which appear to be protected from the disease. Based upon this data and making use of the ovine model; 2) Development of therapeutic strategies- A number of potential therapeutic strategies were investigated including: • The upregulation of a functionally related gene, through the re-expression of non-muscle isoforms of glycogen phosphorylase via notexin induced muscle regeneration. • As well as the replacement of the PYGM gene using modified adenovirus 5 (AdV5) and adeno-associated virus 2 (AAV-2) vectors. Based upon the ability of the non-muscle isoforms of glycogen phosphorylase to function in-vivo in McArdle’s muscle in the absence of the muscle isoform, the ability of tributyrin (a butyrate prodrug and potent histone deacetylase inhibitor) to re-express brain glycogen phosphorylase in mature mouse muscle was also investigated.

No description available.

No description available.

Aux échelles multidécennales, le mode de variabilité principal de l'Atlantique Nord est connu sous le nom de AMO (Atlantic Multidecadal Oscillation). Il est révélé par les observations océaniques, mais les causes qui lui donnent naissance restent mal comprises. Certaines études décrivent l'AMO comme un mode océanique forcé par l'atmosphère, d'autres études décrivent l'AMO comme un mode intrinsèque à l'océan. Ce désaccord majeur est fortement lié aux approches utilisées par ces différentes études, i.e. analyses statistiques de données issues de modèles climatiques ou d'observations vs. expériences de sensibilité à l'aide de simulations idéalisées. Dans le cadre de cette thèse, nous nous intéressons aux mécanismes de variabilité basse fréquence de l'Atlantique Nord dans une série de simulations. Trois configurations couplées du MITgcm sont intégrées, avec une résolution horizontale de 4°, 2° et 1° (pour l'océan et l'atmosphère). La géométrie de l'océan est idéalisée. Le fond est plat, et l'Atlantique est représenté par un petit bassin, délimité par deux barrières méridiennes, orthogonales l'une à l'autre. Ces trois configurations reproduisent toutes une variabilité de la MOC (Meridional Overturning Circulation) dans l'Atlantique entre 30-40 ans, associée à la propagation d'ondes de Rossby de grande échelle à travers le petit bassin. Cette variabilité persiste dans des expériences d'océan seul. Dans nos simulations, la variabilité basse fréquence de l'Atlantique Nord est donc générée pas des processus internes à l'océan. Augmenter la résolution horizontale renforce par ailleurs le couplage océan-atmosphère, avec une NAO (North Atlantic Oscillation) qui devient significativement corrélée à la MOC deux ans plus tard à 1°. Ces corrélations sont mises en évidence dans la plupart des modèles climatiques, ainsi que dans les observations. Certaines études en déduisent alors que la variabilité océanique est forcée par l'atmosphère. Cependant, les expériences de sensibilité au couplage air-mer réalisées dans cette étude démontrent que de telles corrélations n'induisent pas de causalité. Elles illustrent la nécessité d'interpréter les résultats d'analyses statistiques avec précaution, lorsqu'il s'agit d'identifier l'origine de la variabilité basse fréquence de l'Atlantique Nord. L'origine interne de la variabilité océanique par instabilité barocline de grande échelle est ensuite approfondie à l'aide de deux méthodes : une approche diagnostique (bilan de variance) et une approche prognostique (analyse locale de stabilité linéaire). L'approche diagnostique permet de caractériser la variabilité qui se développe dans le modèle non-linéaire. L'approche prognostique consiste à calculer les modes propres de la circulation océanique moyenne, dans l'hypothèse quasigéostrophique. Nous montrons que la prise en compte de la viscosité turbulente dans l'analyse locale permet une meilleure cohérence avec les solutions du modèle non-linéaire. Nous interprétons finalement les ondes de Rossby, qui se propagent à travers le petit bassin, comme émanant d'une instabilité barocline de bord est. / At multidecadal time-scales, the principal mode of variability in the North Atlantic is referred to as the AMO (Atlantic Multidecadal Oscillation). It is revealed by oceanic observations, but its origin remains unclear. Some studies describe the AMO as an oceanic mode forced by the atmosphere, while other studies describe the AMO as an intrinsic oceanic mode. This significant disagreement mainly results from the methods that are used by these different studies, i.e statistical analysis of observations and climate models data vs. idealized simulations and sensitivity experiments.In this PhD thesis, we focus on mechanisms that drive the low frequency North Atlantic variability in a range of simulations. Three coupled configurations of the MITgcm are integrated, with horizontal resolution of 4°, 2° and 1° (in both the ocean and the atmosphere). The idealized oceanic geometry is a flat bottom, with two meridional boundaries that delimit a small basin, comparable to the Atlantic. All these three configurations reproduce a 30-40 year variability of the Atlantic MOC (Meridional Overturning Circulation), associated with large scale Rossby waves that travel across the small basin. This variability remains in ocean-only experiments. The North Atlantic oceanic variability in these simulations is then intrinsically driven.Furthermore, increasing the horizontal resolution strengthen the ocean-atmosphere coupling, with a NAO (NorthAtlantic Oscillation) that becomes significantly correlated to the MOC two years latter at 1°. Such correlations are usually found in most climate models and observations. Some studies then infer that the oceanic variability is forced by the atmosphere.Nevertheless, our sensitivity experiments to ocean-atmosphere coupling highlight that correlations do not necessarily imply causality. These experiments provide a relatively simple and illustrating example. They show that significant lag correlations can be misleading for the identification of driving processes in the context of North Atlantic low frequency variability.The intrinsic oceanic variability is investigated in terms of large scale baroclinic instabilities with two methods: a diagnostic approach (variance budget) and a prognostic approach (local stability analysis). The diagnostic approach aims to characterize the oceanic variability that develop in the non-linear model. The prognostic approach aims to identify the normal modes of the oceanic mean state, in the quasi-geostrophic framework. Taking into account the turbulent viscosity in the stability analysis increases the consistency with the non-linear model solutions. We finally interpret the origin of large scale Rossby waves that travel across the small basin, as a baroclinic instability of the eastern boundary.

Orientador: Lourenço Correr Sobrinho / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-13T08:17:31Z (GMT). No. of bitstreams: 1 Biscaro_SandroLuis_D.pdf: 1231684 bytes, checksum: 94a704d3aec635c1016ca3eb4b5ced3a (MD5) Previous issue date: 2009 / Resumo: O objetivo neste estudo foi avaliar a influência de diferentes doses de radiação X na resistência de união de restaurações adesivas à dentina, mediadas por sistemas que apresentam diferentes estratégias para união. Foram obtidas superfícies planas de dentina em molares humanos e amostras cilíndricas foram construídas com compósito (Z250, 3M ESPE), para o teste de resistência de união ao microcisalhamento, utilizando três sistemas de união: um adesivo de condicionamento total de dois passos (Single Bond 2 - SB2, 3M ESPE), um autocondicionante de dois passos (Clearfil SE Bond - CSE, Kuraray) e um autocondicionante de passo único (Adper Prompt - ADP, 3M ESPE). As amostras foram separadas em 4 grupos (n= 10), de acordo com a dose de radiação X: 0 (controle), 5, 35 ou 70 Gy. A radiação foi direcionada para a superfície dos cilindros de compósito. O teste de microcisalhamento foi realizado após 24 h, e os modos das falhas classificadas com aumento de 200x. Os dados foram submetidos à Análise de Variância dois fatores e teste de Holm-Sidak's (p < 0,05). Uma análise de regressão não-linear foi conduzida com "resistência de união" como variável dependente. Os resultados de resistência de união (MPa) foram dose e material dependentes. SB2: controle > 5 = 35 > 70; CSE: controle = 5 > 35 = 70; ADP: controle = 5 = 35 = 70. Generalizando, SB2 > CSE > ADP. A análise de regressão não-linear mostrou que, em geral, um aumento na dose de radiação promoveu diminuição na resistência de união (R2 < 0,905). Os modos de falhas foram dependentes do sistema de união, mas, em geral, não houve influência significativa da radiação. Concluindo, a radiação-X apresentou um efeito dosedependente significativamente negativo na adesão à dentina. / Abstract: This study investigated the influence of different x-ray radiation doses on the bond strength of adhesive restorations to dentin mediated by systems presenting distinct bonding strategies. Flat dentin surfaces in human molars were obtained and cylinder-shaped specimens for the microshear bond test were build-up with a composite (Z250, 3M ESPE), using three adhesive systems: a total-etch, two-step (Single Bond 2 - SB2, 3M ESPE), a self-etching, two-step (Clearfil SE Bond - CSE, Kuraray), or a self-etching, single step (Adper Prompt - ADP, 3M ESPE). The specimens were assigned to 4 groups (n = 10), according to the x-ray dose: 0 (control), 5, 35 or 70 Gy. Radiation was directed to the surface of the resin cylinders. Microshear testing was conducted after 24 h, and the failure modes classified under magnification (200x). Data were submitted to two-way ANOVA and Holm-Sidak's test (p<0.05). A non-linear regression analysis was carried out with 'bond strength' as dependent variable. Bond strength results were dose- and material-dependent. SB2: control > 5 = 35 > 70; CSE: control = 5 > 35 = 70; ADP: control = 5 = 35 = 70. Generally, SB2 > CSE > ADP. The non-linear regression plots showed that in general, an increase in radiation dose may predict a decrease in bond strength (R2 = 0.905). Failure modes were dependent on the bonding system, generally with no significant influence of radiation. X-ray radiation presented a significant, dose-dependent detrimental effect on the bond to dentin. / Doutorado / Radiologia Odontologica / Doutor em Radiologia Odontológica

The information about the Spanish composer Juan Arañés (*Zaragoza?, 1580c; ¿La Seu d'Urgell?, 1649c) has been transmitted by the historiography giving the idea of an author of particular relevance and significance in the Pan-Hispanic context. In fact, he is mentioned in many music treatises after the publication of his theoretical work (Libro segundo de tonos y villancicos a una, dos, tres y cuatro voces. Con la cifra de la guitarra española a la usanza romana), appeared in Rome, in the Giovanni Battista Robletti office, in 1624. Even, still today, some of his works continue being performed, and many of them are available in the international market. However, still there was not a critical and reliable biography available on him. It is true that the mere biographical data which have arrived till nowadays, have conveyed many mistakes, and, because of the mobility and darkness of his professional career, they remain quite a few gaps and questions. In the course of this research, I have been able to unlock some of the transmitted errors, cover certain gaps and find a really valuable information (particularly in archives of Zaragoza, La Seu d'Urgell and Tortosa), both about the composer and his musical output, which has been partially transcribed (including some handwritten parts which were scattered), noting the serious problems posed by the issue (of which, unfortunately only one copy has been preserved around the world, posing serious problems for its transcription), in particular, in its cipher (tabulatura / cifra) for the guitar. This thesis sets and establishes, for the first time, a critical biography of the composer and unveils the complete works (printed and handwritten) that is known today, prepared for public performance, timely computerized and presented on score and current musical notation. / El compositor Juan Arañés (*Zaragoza?, 1580c; ¿La Seu d'Urgell? 1649c) ha sido transmitido por la historiografía como un autor de especial relevancia y significación dentro del contexto panhispánico. De hecho, se le menciona en múltiples tratados teórico-musicales con posterioridad a la publicación de su obra (Libro segundo de tonos y villancicos a una, dos, tres y cuatro voces. Con la cifra de la guitarra española a la usanza romana), aparecida en Roma en las prensas de Giovanni Battista Robletti en 1624. Incluso todavía en la actualidad se interpretan algunas de sus obras, buena parte de las cuales se hallan disponibles en el mercado internacional. Y, sin embargo, todavía no existía una biografía crítica y contrastada sobre él mismo en la actualidad. Bien es cierto que los meros datos biográficos que han llegado hasta nosotros han transmitido no pocos errores, y que, habida cuenta de la movilidad y oscuridad de su trayectoria profesional, aún plantea no pocas lagunas e interrogantes. En el transcurso de esta investigación se han podido desvelar algunos de los errores transmitidos, cubrir ciertas lagunas y encontrar una información realmente valiosa (particularmente en archivos de Zaragoza, La Seu d'Urgell y Tortosa), tanto sobre el compositor como sobre la producción musical que se ha podido transcribir (incluidas algunas piezas manuscritas que se hallaban dispersas), constatando los serios problemas que plantea la edición (de la que, lamentablemente únicamente se ha conservado un ejemplar en todo el mundo, el cual plantea serios problemas para su transcripción), particularmente en su cifra para la guitarra. La presente tesis fija y establece por primera vez una biografía crítica del compositor y da a conocer la obra completa (impresa y manuscrita) de la que se tiene conocimiento a día de hoy, dispuesta para su ejecución pública, oportunamente informatizada y presentada en partitura y notación musical actual / El compositor Juan Arañés (*Zaragoza?, 1580c; ¿La seu d'Urgell? 1649c) ha estat transmès per la historiografia com un autor d'especial rellevància i significació en el context panhispànic. De fet, s'esmenta en diversos tractats teòric-musicals amb posterioritat a la publicació de la seua obra (Libro segundo de tonos y villancicos a una, dos, tres y cuatro voces. Con la cifra de la guitarra española a la usanza romana), apareguda a Roma en les premses de Giovanni Battista Robletti en 1624. Fins i tot, encara en la actualitat s'interpreten algunes de les seues obres, moltes de les quals es troben disponibles en el mercat internacional. I, no obstant això, encara no hi havia cap biografia crítica i contrastada sobre ell mateix en l'actualitat. Bé és cert que les dades biogràfiques que ens han aplegat fins ara han transmès no poques errades, i que, tenint en compte la mobilitat i la obscuritat de la seva trajectòria professional, encara planteja no pocs buits i qüestions. En el transcórrer d'aquesta recerca ha estat possible revelar algunes de les errades transmeses, cobrir determinades mancances i trobar una informació molt valuosa (específicament als arxius de Saragossa, La Seu d'Urgell i Tortosa), tant sobre el compositor, com sobre la seua producció musical que ha estat possible transcriure (incloent algunes peces manuscrites que estaven disperses), assenyalant els greus problemes que planteja l'edició (de la qual, malauradament s'ha conservat un únic exemplar arreu del món, el qual planteja seriosos problemes per a la seua transcripció), especialment en la seua xifra per a la guitarra. La present tesi fixa i estableix per primera vegada una biografia crítica del compositor i desvela l'obra completa (impresa i manuscrita) de la qual es té coneixement a dia de hui, disposada per a la seua execució pública, oportunament informatitzada i presentada en partitura i notació musical actual. / Cerveró Martínez, FJ. (2017). Juan Arañes y su "Libro segundo de tonos y villancicos... con la cifra de la guitarra española a la usanza romana" (Roma, Juan Bautista Robletti, 1624) [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/86138 / TESIS

Proefschrift--Groningen. / "Stellingen": [2] p. inserted. Includes bibliographical references.

Thesis (M.S.)--Middle East Technical University, 2003. / Keywords: X-ray scanning system, X-ray imaging, X-ray dedectors, transmission imaging, custom scanning.

v, 145 leaves : ill. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.1972) from the Dept. of Physics, University of Adelaide

vi, 177 leaves : graphs, ill. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.1972) from the Dept. of Physics, University of Adelaide