George MacDonald (1824-1905) is one of the most complex and significant Scottish writers of the nineteenth century, especially as a writer of children's fiction and literary fairy tales. His works, however, have seldom been studied as Scottish literature. This dissertation is the first full-length analysis of his writings for children in their Scottish context, focusing particularly on his use of Scottish folklore in his literary fairy tales. MacDonald wrote in the Scottish Romantic tradition of Robert Burns, Walter Scott, and James Hogg; by close reading his works alongside similar texts by his compatriots, such as Andrew Lang, MacDonald's own idiosyncratic contribution to that tradition becomes more apparent. His profound knowledge of and appreciation for Christian mysticism is in evidence throughout his work; his use of folklore was directly informed by his exploration of mystical ideas. Hogg is recast as a second Dante, and ‘bogey tales' become catalysts for spiritual awakening. MacDonald's fairy tales deal sensitively and profoundly with the theme of child death, a tragedy that held personal significance for him, and can thus be read as his attempt to come to terms with the reality of bereavement by using Scottish folklore to explain it in mystical terms. Traditional figures such as Thomas Rhymer, visionary poets, and doubles appear in his fairy tales as guides and pilgrims out of the material world toward mystical union with the Divine.

The master’s thesis deals with modelling of various architectures of hybrid powertrains for three vehicle sizes in GT-SUITE and compares them in daily commuting operating mode. On top of making of the hybrid vehicle simulation models, control algorithms had to be created to manage the energy split between the internal combustion engine and the electric motor for each of the architectures. Routes to work and back were logged using the GPS and postprocessed to obtain the speed and the road grade profiles. Resulting data was used as an input in simulations of daily commuting. To compare all hybrid powertrain architectures, fuel economy and electricity consumption were evaluated for WLTP and daily commuting operating modes. Finally, the environmental impact of each topology was assessed based on an estimation of corresponding well-to-wheel emissions.

Le Phosphatidylinositol(4,5)P2 (PtdIns(4,5)P2) est essentiel pour réguler divers processus cellulaires, y compris la signalisation cellulaire, le trafic intracellulaire et la cytocinèse. Le contrôle strict de son homéostasie est donc crucial et la dérégulation des kinases, des phosphatases et des phospholipases qui la contrôlent conduit à de multiples pathologies. Parmi elles, le syndrome de Lowe est une maladie rare et incurable causée par des mutations du gène OCRL qui code pour la PtdIns(4,5)P2 phosphatase OCRL1. La déplétion de dOCRL, l’orthologue d’OCRL1 chez la drosophile altère l’homéostasie du PtdIns(4,5)P2 avec (i) une accumulation anormale de PtdIns(4,5)P2 sur les endomembranes conduisant (ii) à des défauts de cytocinèse et à de la multinucléation. L’objectif de cette thèse était de comprendre comment le PtdIns(4,5)P2 est régulé sur les endomembranes. Dans les cellules de drosophile, nous avons découvert une fonction nouvelle et inattendue pour le suppresseur de tumeur PTEN, indépendante de son activité phosphatase. En effet, nous avons constaté que PTEN réduit les niveaux de PtdIns(4,5)P2 sur les endosomes grâce à l’action enzymatique de dPLCXD, une phospholipase C (PLC) atypique. Ainsi la voie de signalisation PTEN/dPLCXD peut compenser pour les défauts de cytocinèse dus à la perte de dOCRL. Enfin, nous avons identifié un activateur chimique des PLC qui restaure la perte fonctionnelle d’OCRL dans trois modèles de syndrome de Lowe distincts. Par la suite, nous avons étudié le rôle de la PTEN/PLCXD pendant l’autophagie, mécanisme d’autodigestion du matériel cellulaire. En effet, l’homéostasie du PtdIns(4,5)P2 lysosomale est essentielle pour l’étape autophagique de fusion des autophagosomes avec lysosomes. Nous avons observé que la déplétion de PLCXD et la surexpression d’un mutant catalytiquement inactif de PTEN altèrent l’autophagie chez les cellules de drosophile et de mammifère. Ces données suggèrent que la voie PTEN/PLCXD nouvellement identifiée régule le flux autophagique. Dans cette thèse, nous avons mis en lumière une nouvelle voie de signalisation PTEN/dPLCXD qui contrôle les niveaux de PtdIns(4,5)P2 sur les endolysosomes. Cette voie peut réguler l’autophagie et compenser la perte de dOCRL. Il s’agit d’une nouvelle fonction de PTEN indépendante de son activité phosphatase et c’est une première fonction biologique connue pour PLCXD. Cette découverte a conduit à l’identification d’une stratégie thérapeutique potentielle pour traiter les patients atteints du syndrome de Lowe. / Phosphatidylinositol(4,5)P2 (PtdIns(4,5)P2) is essential for various cellular processes, including cell signaling, intracellular traffic and cytokinesis. Therefore, strict control of its homeostasis is crucial. Indeed, the deregulation of the kinases, phosphatases and phospholipases which controls PtdIns(4,5)P2 leads to multiple pathologies. Among them, the Lowe syndrome is a rare and incurable disease caused by mutations in the OCRL gene which codes for PtdIns(4,5)P2 phosphatase OCRL1. Depletion of dOCRL, the orthologue of OCRL1 in drosophila, alters the homeostasis of PtdIns(4,5)P2 with (i) an abnormal accumulation of PtdIns(4,5)P2 on the endomembranes leading (ii) to cytokinesis defects and multinucleation. The objective of this thesis was to understand how PtdIns(4,5)P2 is regulated on endomembranes. In drosophila cells, we have discovered a new and unexpected function for the tumor suppressor PTEN independent of its phosphatase activity. Indeed, we have found that PTEN reduces the levels of PtdIns(4,5)P2 on endolysosomes thanks to the enzymatic action of dPLCXD, an atypical phospholipase C (PLC). Thus, the PTEN/dPLCXD signaling pathway can compensate for cytokinesis defects due to the loss of dOCRL. Finally, we identified a chemical activator of PLC that restores the functional loss of OCRL in three distinct Lowe syndrome models. Next, we studied the role of this newly identified PTEN/PLCXD pathway during autophagy, a self-digestion mechanism. Indeed, the homeostasis of lysosomal PtdIns(4,5)P2 is essential for the fusion of autophagosomes with lysosomes during autophagy. We have observed that depletion of PLCXD and overexpression of a catalytically inactive mutant of PTEN both alter autophagy in Drosophila and mammalian cells. These data suggest that this newly identified PTEN/PLCXD pathway regulates the autophagic flux. In this thesis, we have highlighted a new PTEN/dPLCXD signaling pathway which controls the levels of PtdIns(4,5)P2 on endolysosomes. This new PTEN function is independent of its phosphatase activity and the first biological function for PLCXD can regulate autophagy and compensate for the loss of dOCRL. This discovery led to the identification of a potential therapeutic strategy for treating patients with Lowe’s syndrome.

Myotubularins are lipid phosphatases that dephosphorylate phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate the position three of the inositol ring. This allows them to regulate the structure of the lipid layer of the membrane compartment. The first member of the family was described in association with a severe hereditary myopathy. From that point on, another thirteen members have been added to the family. The catalytically inactive MTMR9 carrying the conserved mutation in the phosphatase domain regulates the localization of the marker of the early secretory pathway, RAB1A, the cis-Golgi structure and the secretion. MTMR9 interacts with the catalytically active MTMR6 and MTMR8 that specifically localizes and increases their phophatase activity. The aim of this diploma thesis was to find out whether the phenotype observed in cells with altered MTMR9 levels is dependent on the catalytically active phosphatases MTMR6 and MTMR8. We proved the influence of MTMR6 and MTMR8 on the distribution of tranfected RAB1A between the intermediate compartment and the Golgi apparatus. MTMR6 and MTMR8 also take part in regulating the cis-Golgi structure. By the use of two different approaches we did not manage to clarify the influence of MTMR6 and MTMR8 on secretion. Changes in the catalytic...

Indiana University-Purdue University Indianapolis (IUPUI) / The first part of the study describes the development of a microCT based engineering model to study orthodontic responses. The second part investigated the relationship between orthodontic stimulus, root resorption and bone modeling. It was hypothesized that stress magnitudes are insufficient to portray the mechanical environment and explain the clinical response; directions also play a role. An idealized tooth model was constructed for finite element analysis. The principal stress magnitudes and directions were calculated in tipping and translation. It was concluded that within the same region of root, PDL and bone, there can be compression in one structure, tension in another. At a given point in a structure, compression and tension can coexist in different directions. Magnitudes of compression or tension are typically different in different directions. Previously published data presenting only stress magnitude plots can be confusing, perhaps impossible to understand and/or correlate with biological responses. To avoid ambiguities, a reference to a principal stress should include its predominant direction. Combined stress magnitude/direction results suggest that the PDL is the initiator of mechanotransduction. The third part of this project tested the role of the P2X7 receptor in the dentoalveolar morphology of C57B/6 mice. P2X7R KO (knockout) mice were compared to C57B/6 WT to identify differences in a maxillary molar and bone. Tooth dimensions were measured and 3D bone morphometry was conducted. No statistically significant differences were found between the two mouse types. P2X7R does not have a major effect on alveolar bone or tooth morphology. The final part examines the role of the P2X7 receptor in a controlled biomechanical model. Orthodontic mechanotransduction was compared in wild-type (WT) and P2X7R knock-out (KO) mice. Using Finite Element Analysis, mouse mechanics were scaled to produce typical human stress levels. Relationships between the biological responses and the calculated stresses were statistically tested and compared. There were direct relationships between certain stress magnitudes and root resorption and bone formation. Hyalinization and root and bone resorption were different in WT and KO. Orthodontic responses are related to the principal stress patterns in the PDL and the P2X7 receptor plays a significant role in their mechanotransduction.

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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal. / Les anomalies de l'activité des transporteurs d'ions et de l'expression des protéines de choc thermique (HSPs) ont été décrites dans les reins d'animaux hypertendus. Nous nous sommes particulièrement intéressés aux co-transporteurs Na, K+, Cl- et Na, Pi. Les isoformes NKCC 1 et NKCC2 du co-transporteur Na, K+, Cl- sont inhibées par des diurétiques tels que le furosémide et le bumétanide et sont impliquées dans la sécrétion et la réabsorption transépithéliale du sodium et de l'eau. L'implication de l'isoforme NKCC 1 a aussi été démontrée dans la régulation du volume cellulaire, ainsi que dans la progression du cycle cellulaire et dans la prolifération. Le co-transporteur Na, Pi de type II joue un rôle majeur dans la réabsorption du phosphate par le tubule proximal, ainsi que dans la régulation des concentrations plasmatiques du phosphate inorganique et du Ca2+. La régulation de ces transporteurs est spécifique à chaque tissu et à chaque segment des tubules rénaux. Puisqu'il est connu que les HSPs sont impliquées dans la protection de certaines fonctions du transport transépithélial dans les tubules rénaux de poisson, notre hypothèse était que les HSPs modulent la régulation des transporteurs rénaux d'ions connus pour leur activité anormale dans l'hypertension artérielle. Toutefois, aucune étude n'avait évalué l'implication des HSPs dans la régulation des transporteurs d'ions dans des cellules d'épithélium rénal de mammifère. De plus, les HSPs peuvent jouer un rôle non seulement dans la modulation de l'activité basale des transporteurs d'ions, mais aussi dans leur régulation. Encore une fois, il n'existait aucune donnée sur ce sujet. Pour cette thèse de doctorat, nous avons donc choisi d'étudier un modèle physiologique d'épithélium rénal avant d'entreprendre des études sur un modèle pathologique tel que l'hypertension artérielle. Le but de nos travaux de recherche était d'examiner les voies de signalisation impliquées dans la régulation de différents transporteurs d'ions dans des cellules d'épithélium rénal de mammifère, ainsi que la modulation de ces transporteurs par le stress thermique et les HSPs. Nous avons choisi comme modèle d'épithélium rénal les cellules "Madin-Darby canine kidney" (MDCK) puisque cette lignée cellulaire a conservé, in vitro, plusieurs propriétés de l'épithélium rénal in vivo, dont le transport vectoriel et la régulation hormonale. De plus, des protéines de choc thermique HSPs peuvent être induites dans cette lignée. L'activité des transporteurs d'ions a été évaluée à l'aide d'isotopes radioactifs. L'effet des stress thermiques modéré et sévère, ainsi que du stress hyperosmotique, a été évalué. L'accumulation de l'ARN messager et l'expression des protéines HSP70 et HSP27 ont été étudiées par buvardages de type northern et western. Dans des études complémentaires, nous avons aussi mesuré les concentrations intracellulaires de Na, de K+, et de Cl- à l'aide d'isotopes radioactifs; les concentrations intracellulaires de Ca2+ à l'aide du fluo-3; la production d'inositol triphosphate par la mesure du composé marqué myo-[2-31P]-inositol et la phosphorylation de la protéine kinase activée par les mitogènes (MAPK) par immuno-buvardage de lysats cellulaires avec les anticorps anti-phospho ERK. Nous avons démontré que, dans les cellules MDCK, la régulation du co-transporteur Na, K+, Cl- s'effectue principalement via des voies de signalisation impliquant les isoformes de la protéine kinase C sensibles au 4β-phorbol 12-myristate 13-acetate (PMA) et via l'activation des purinocepteurs-P2X et/ou P2Y. Nous avons aussi démontré qu'aucun mécanisme connu de la signalisation induite par l'ATP n'est impliqué dans l'inhibition du co-transporteur Na, K+, Cl- par les purinocepteurs-P2X. Nos résultats suggèrent la présence d'une nouvelle voie de signalisation induite par les purinocepteurs-P2X. Le co-transporteur Na, Pi est aussi régulé par le PMA et par l'ATP. L'activation des purinocepteurs-P2 par l'ATP, ainsi que l'activation de la protéine kinase C par le PMA, diminuent de façon importante l'activité des co-transporteurs Na, K+, Cl- et Na, Pi. L'activité basale des co-transporteurs Na, K+, Cl- et Na, Pi est indépendante de la production des HSPs induites par le stress thermique. Nous avons observé que le stress thermique sévère augmente l'activité basale des co-transporteurs Na, K+, Cl- et Na, Pi et abolit complètement la régulation de ces transporteurs par le PMA, sans modifier significativement celle obtenue par l'activation des purinocepteurs-P2. La production de HSP70 induite par le stress thermique modéré n'empêche pas l'activation des co-transporteurs Na, K+, Cl- et Na, Pi à la suite d'un stress thermique sévère ni leur inhibition par les purinocepteurs-P2. En conclusion, dans les cellules MDCK, les purinocepteurs-P2 et les isoformes de la protéine kinase C sensibles au PMA sont impliqués dans la régulation de l'activité des co-transporteurs Na, K+, Cl- et Na, Pi par des mécanismes différents, l'un insensible et l'autre sensible au stress thermique, respectivement. Mais cette régulation est indépendante de l'induction des HSP70 et HSP27. De plus, la régulation du co-transporteur Na, K+, Cl- par les purinocepteurs-P2 ne se fait pas par les mécanismes connus de la signalisation induite par l'ATP. Compte tenu de l'importance relative des membranes apicale et basolatérale pour la fonction de plusieurs transporteurs rénaux d'ions, dont les co-transporteurs Na, K+, Cl- et Na, Pi, des travaux sur le rôle des HSPs dans la régulation de ces transporteurs dans des cellules d'épithélium rénal cultivées sur un support perméable méritent d'être entrepris.

Made available in DSpace on 2016-06-02T19:22:55Z (GMT). No. of bitstreams: 1 4102.pdf: 1499777 bytes, checksum: 83d49633865ad84ab741b0091f168280 (MD5) Previous issue date: 2011-12-14 / Universidade Federal de Minas Gerais / Locus coeruleus (LC) is considered as a chemosensitive region to CO2/pH in mammals and amphibians, mainly its noradrenergic neurons. The LC purinergic neuromodulation is of particular interest since adenosine 5′-triphosphate (ATP) acts as a neuromodulator in many brainstem areas involved in cardiovascular and respiratory regulation, which includes Locus coeruleus (LC). ATP acting on LC P2 receptors influences the release of noradrenaline (NE) and the LC noradrenergic neurons are involved in the CO2-drive to breathing. Thus, the goal of the present study was to investigate the role of purinergic neuromodulation in the LC in the ventilatory, thermal and cardiovascular responses during normocapnia and hypercapnia in Wistar male unanesthetized rats. We assessed the purinergic modulation of cardiorespiratory and thermal responses by microinjecting ATP P2X receptor agonist (α,β-MeATP, 0.5 nmoL/40 nL and 1 nmoL/40 nL) and P2 receptor non selective antagonists (PPADS 0.5 nmoL/40 nL and 1 nmoL/40 nL; suramin, 1 nmoL/40 nL) into the LC. Pulmonary ventilation (VE, plethysmography), mean arterial pressure (MAP), heart rate (HR) and body core temperature (Tb, dataloggers) were measured before and after unilateral microinjection (40 nL) of α,β-MeATP, PPADS, suramin or 0.9% saline (vehicle) into the LC during 60 min normocapnia or 30 min period of 7% CO2 exposure followed by 30 min of normocapnia. Under normocapnic conditions, α,β-MeATP did not affect any parameter, whereas PPADS decreased respiratory frequency (f), increased MAP and HR and suramin increased Tb, MAP and HR and did not change ventilation. Hypercapnia induced an increase in ventilation, a fall in HR and did not change Tb in all groups. During hypercapnia, α,β-MeATP produced a further increase in ventilation and did not cause changes in cardiovascular and thermal parameters, PPADS caused an increase in MAP, did not alter ventilation and Tb and suramin elicited increases in ventilation, MAP and bradycardia and did not change Tb. Thus, our data suggest that purinergic neuromodulation in the LC plays an important role in the cardiorespiratory control during hypercapnia and modulates cardiorrespiratory and thermal control during normocapnic conditions in unanesthetized animals. / O LC é considerado uma região quimiossensível a CO2/pH em mamíferos e anfíbios, especificamente os neurônios noradrenérgicos. A neuromodulação purinérgica no LC desperta um interesse particular uma vez que a adenosina 5 -trifosfato (ATP) atua como neuromodulador em várias áreas do tronco encefálico envolvidas na regulação cardiorrespiratória, incluindo o LC e sua atuação em receptores P2 influencia a liberação de noradrenalina (NE) dos neurônios do LC. Portanto, o objetivo do presente estudo foi investigar a participação da neuromodulação purinérgica no LC nas respostas ventilatória, térmica e cardiovascular durante normocapnia e hipercapnia em ratos Wistar não anestesiados. A possível modulação do ATP nessas respostas foi realizada por meio da microinjeção do agonista de receptor P2X (α,β-MeATP, 0.5 nmol/40 nL e 1 nmol/40 nL) e dos antagonistas não seletivos de receptor P2 (PPADS 0.5 nmol/40 nL e 1 nmol/40 nL; suramin, 1nmol/40nL) no LC. Foram feitas medidas de ventilação pulmonar ( VE, pletismografia), temperatura corporal (TC) pressão arterial média (PAM) e frequência cardíaca (FC) antes da microinjeção unilateral de α,β--MeATP, PPADS, suramin ou salina (veículo, 40nL) no LC em condições basais, e após microinjeção durante 60 min de normocapnia ou 30 min de exposição a 7% CO2, seguido de 30 min de normocapnia. Em condições normocápnicas, a microinjeção de α,β-MeATP não afetou nenhuma das variáveis analisadas, enquanto que o PPADS promoveu uma redução da freqüência respiratória (fR), aumento da PAM e FC, e o suramin aumentou a TC, PAM e FC sem causar alterações na ventilação. A hipercapnia promoveu aumento da ventilação, uma redução na FC e não alterou a TC em todos os grupos. Durante hipercapnia, α,β-MeATP promoveu aumento da hiperpnéia sem causar alterações nas variáveis cardiovasculares e na temperatura, PPADS promoveu aumento da PAM sem alterar as variáveis respiratórias e a temperatura corporal e o suramin promoveu aumento da hiperventilação, aumento na PAM e bradicardia sem alterar a temperatura corporal. Portanto, nossos dados sugerem que a neuromodulação purinérgica no LC participa do controle cardiorrespiratório durante normocapnia e hipercapnia e modula a termorregulação em condições normocápnicas em animais não anestesiados.

This research project seeks to explore aspects of the post-reporting phase of the public inquiry process. Central to the public inquiry process is the concept of legitimacy and the idea that a public inquiry provides and opportunity to re-legitimate the credibility of failed public institutions. The current literature asserts that public inquiries re-legitimise through the production of authoritative narratives. As such, most of this scholarship has focused on the production of inquiry reports and, more recently, the reports themselves. However, in an era of accountability, and in the aftermath of such a poignant attack upon society, the production of a report may represent an apogee, but by no means an end, of the re-legitimation process. Appropriately, this thesis examines the post-reporting phase of the 9/11 Commission’s public inquiry process. The 9/11 Commission provides a useful research vehicle due to the bounded, and relatively linear, implementation process of the Commission’s recommendations. In little more than four months a majority of the Commission’s recommendations were passed into law. Within this implementation phase the dominant discursive process took place in the United States Congress. It is the legislative reform debates in the House of Representatives and the Senate that is the focus of this research project. The central research question is: what rhetorical legitimation strategies were employed in the legislative reform debates of the post-reporting phase of the 9/11 Commission’s public inquiry process? This study uses a grounded theory approach to the analysis of the legislative transcripts of the Congressional reform debates. This analysis revealed that proponents employed rhetorical strategies to legitimise a legislative ‘Call to Action’ narrative. Also, they employed rhetorical legitimation strategies that emphasised themes of bipartisanship, hard work and expertise in order to strengthen the standing of the legislation. Opponents of the legislation focused rhetorical de-legitimation strategies on the theme of ‘flawed process’. Finally, nearly all legislators, regardless of their view of the legislation, sought to appropriate the authoritative legitimacy of the Commission, by employing rhetorical strategies that presented their interests and motives as in line with the actions and wishes of the Commission.

This thesis argues for a dualistic, epistemological, framework for the study of legitimacy which recognises the different ways it might be understood to exist, and as such be managed, within organisations. It is based on an ethnography of a Scottish professional theatre, Dundee Rep, undertaken over a 30 month period. The research adopts a social constructionist ontology and an epistemological framework based on the knowing that / knowing how framework of Gilbert Ryle to present three accounts of the legitimacy of the theatre – as belonging, becoming and integrated- and to challenge the notion implicit in the organisation studies literature that legitimacy is treated (and should be treated) as a belonging by organisations. The proposed integrated epistemological framing of legitimacy explains how notions of legitimacy as an emergent, negotiated perception and as a competitive resource possessed are both crucial to developing an integrated understanding of how legitimacy is produced at the organisational level.