Heart disease is the developed world's biggest killer, and the shortage of donor hearts has accelerated the development of mechanical alternatives. Scientists, engineers and clinicians have attempted to replicate the human heart with a mechanical device for over 50 years. Although a number of pulsating devices have been developed, and in some cases worked briefly, they have invariably failed to match the success of heart transplantation. In an attempt to produce a suitable alternative, current research is focused on devices that do not replace the heart; but rather work along side it to assist its function. Many of these devices help the failing left ventricle; however some patients require the additional implantation of a second device to assist a failing right ventricle. This increases implantation time and associated risk, and because of the size of the current devices, reduces the access of smaller patients to this vital technology. The overall thesis objective focuses on the progressive design, development and preliminary evaluation of two novel centrifugal type ventricular assist devices, a bi-left ventricular device (Bi-LVAD) and a single bi-ventricular assist device (Bi-VAD). The devices have the respective capability to assist either the left ventricle, or both ventricles of a failing heart. The current concept for each VAD employs both magnetic and hydrodynamic suspension techniques to float a rotating double impeller, a technique that aims to reduce blood damage and component wear, two of the major problems encountered with current generation devices. Each VAD design was developed by conducting experimentation and drawing conclusions from a variety of engineering research fields, such as flow visualization, rotary pump design and testing, fluid dynamics, hemodynamics and heart failure, and magnetic motor bearing design. In order to evaluate pump prototype designs, it was necessary to design and develop a novel pulsatile systemic and pulmonary mock circulation loop capable of reproducing the hemodynamics of heart failure in the systemic and pulmonary circuits. The investigation then specifically examined the static hydraulic forces on the impeller of a centrifugal blood pump during operation in this mock circulation loop. The recorded magnitude and direction of radial and axial thrust then influenced the selection of magnetic and hydrodynamic bearing configurations to minimise impeller touchdown in the intended hemodynamic environment. This research required the development of correctly designed impeller (semi-open/closed) and volute (single, double, circular) components for each ventricular assist application and a unique test facility to isolate impeller hydraulic forces in addition to the mock circulation loop. The proposed Bi-LVAD incorporates symmetrical blade designs on each side of the double sided impeller. The device assists the function of the left ventricle only with symmetrical axial pressure distribution and elimination of stagnant regions beneath the impeller. These features improve axial touchdown capacity and reduce thrombus formation respectively. The proposed Bi-VAD incorporates different blade designs on each side of the double impeller to augment the function of both the left and right cardiac chambers. The design has the additional potential to act as a total artificial heart (TAH). To date there is no Bi-VAD/TAH system available that incorporates an LVAD and RVAD in one rotary pump. Successful development of each innovative VAD will provide an alternative to heart transplantation, potentially saving lives of many terminal heart patients each year. No longer would heart transplant candidates need to wait for the untimely death of a donor to provide a suitable heart. Instead, this new generation device would be available immediately, and be almost universally compatible with all patients. It has the potential to dramatically increase a patient’s expected lifetime, and to deliver them a higher quality of life.

L’asymétrie Droite-Gauche (DG) est responsable de l’empaquetage et l’enroulement stéréotypé des organes internes au cours du développement. Chez la Drosophile, l’intestin postérieur adulte (AHG) se développe asymétriquement selon l’axe DG en formant une boucle dextrale. Comme pour tous les organes asymétriques DG de la Drosophile, la mise en place de l’axe DG nécessite l’expression de la myosine non conventionnelle de type I : MyoID. Cette myosine se lie à la DE-Cadherine au niveau des jonctions adhérentes (AJ) pour mettre en place l’axe DG, mais le mécanisme moléculaire qui transforme la chiralité de MyoID en une morphogenèse asymétrique DG est totalement inconnu. Le AHG est un long tube situé au milieu de l’abdomen, qui présente une boucle dextrale dans sa partie proximale. Il se développe à partir d’un groupe de progéniteurs formés de deux populations de cellules : H1 et H2. Dans cette étude, nous avons mis en évidence que MyoID contrôle la formation de la boucle dextrale du AHG grâce à son interaction avec la cadhérine atypique Dachsous dans les cellules H1. De plus, nous avons pu mettre en évidence que la signalisation Dachsous-Fat est activée à travers les cellules H2 entrainant leur polarisation du coté droit, et ainsi formant l’enroulement du AHG. Les cellules H1 sont transitoires, elles disparaissent lors des premières heures de la métamorphose. Cependant, l’information dextrale générée dans les cellules H1 perdure dans les cellules H2 grâce à l’action coordonnée des composants de la polarité planaire. Nous montrons que la polarité planaire contrôle l’établissement de l’asymétrie DG en aval de MyoID, en transmettant l’information DG dans le AHG. / Stereotyped left right (LR) asymmetry ensures proper looping of internal organs. In Drosophila, the adult hindgut (AHG) has a clear stereotypical dextral loop and, like all LR asymmetric organs, require MyoID for correct orientation. MyoID is an unconventional myosin type I that binds to DE-Cadherin, this association is required for proper LR establishment; however the mechanism that translates MyoID chirality into proper morphogenesis remains unknown. The AHG is a long tube coiled dextrally and located in the middle of the abdominal region. It develops from a cluster of progenitors containing two different populations of cells, H1 and H2. Here, we show that MyoID controls the AHG dextral loop by binding to the atypical cadherin Dachsous in H1 cells. Further, Ds-Fat signaling propagates towards the H2 cells which in turn become polarized towards the right and consequently loop. H1 is a transient population of cells that wear off in the first hours of metamorphosis; nevertheless the dextral information generated in H1 is maintained in H2 cells due to the cooperative action of PCP components. We demonstrate that the molecular basis of the LR establishment downstream of MyoID action lies in the PCP system, which has a double role transmitting and maintaining a dextral signal in the AHG. Thus, we provide for the first time a link in L/R morphogenesis between Drosophila and vertebrates in which PCP mutants result in L/R defects. Furthermore, in our attempts to better understand the evolution of L/R morphogenesis we found the recently co-Appearance of a myoID cis-Regulatory element and the AHG dextral loop, during Drosophila evolution, suggesting that changes in myoID express.

The purpose of this study is to investigate to what extent skeptical attitudes towards the European Union is driven by materialistic-, postmaterialist values and populism in different parts of Europe. To achieve this aim, the study is based on multivariate regression analysis with data utilized from the European Social survey 2014. The findings show that cultural questions associated with TAN values, such as a nationalistic resistance towards immigration, have the best ability to predict EU-skepticism over economic questions related with a subjective placement on the political left-right scale, or populism associated with a lack of trust in the state of political governance. These findings suggest that the subjective left-right scale do not structure attitudes toward the European Union to a great extent. Instead, the results of this study are in line with scholars that argue that the TAN-GAL scale as well as populism have grown in importance, as these axes of competition are both more linked with opinions on EU. These results hold for all regions in Europe that are examined in this study, although particular strong effects are found in Germany, where populism and TAN values shape attitudes towards EU to the greatest extent.

Les vertébrés font partie des animaux à symétrie bilatérale mais celle-ci n'est pas parfaite et de nombreuses asymétries sont visibles entre les côtés gauche et droit, notamment au niveau du système nerveux. L'épithalamus s'est imposé comme le modèle de référence pour l'étude des mécanismes de latéralisation du cerveau. Cette structure dérivée du diencéphale dorsal se compose de deux noyaux bilatéraux, les habénulæ et du complexe pinéal, qui regroupe les glandes pinéale et parapinéale. Les habénulæ présentent des asymétries plus ou moins marquées chez tous les grands groupes de vertébrés. La parapinéale est également asymétrique mais elle est absente dans de nombreux taxa. Chez le poisson zèbre, espèce modèle de référence pour l'étude des mécanismes de formation des asymétries épithalamiques, une migration latéralisée de la parapinéale est nécessaire à l'élaboration des asymétries habénulaires. Les mécanismes génétiques sous-jacents ont également été en partie décryptés. La première asymétrie visible dans le diencéphale dorsal correspond à une activité de la voie de signalisation Nodal à gauche. Si cette voie Nodal est essentielle pour induire une asymétrie neurogénétique précoce, elle ne l'est pas pour la formation des asymétries épithalamiques définitives. Son rôle se restreint à biaiser la directionnalité des asymétries en influençant la migration de la parapinéale. Les asymétries habénulaires sont induites par la position finale de la parapinéale. La conservation à l'échelle des vertébrés des mécanismes décrits chez le poisson-zèbre reste une question ouverte. Au cours de ce travail de thèse, j’ai cherché à comprendre l’évolution de ces mécanismes en étudiant un chondrichtyen, la roussette Scyliorhinus canicula et des cyclostomes, les lamproies Petromyzon marinus et Lampetra planeri. Leur position phylogénétique ainsi que les asymétries majeures en taille observées entre les habénulæ gauche et droite font de ces espèces de bons modèles pour comprendre leur origine chez les vertébrés. Mes travaux conduisent à trois conclusions principales :(1) on retrouve, comme chez le poisson zèbre, une expression asymétrique de la voie Nodal dans le diencéphale dorsal gauche de la lamproie et de la roussette; la directionnalité de cette asymétrie est conservée entre les trois espèces, ce qui permet d’exclure une inversion de latéralité précédemment proposée chez la lamproie sur la base d’arguments de taille relative des habénulæ(2) La voie Nodal est essentielle à la formation des asymétries habénulaires chez la roussette et la lamproie, ce qui suggère un rôle ancestral dans l’élaboration des asymétries épithalamiques.(3) une analyse détaillée des patrons de prolifération-différenciation des habénulæ au cours du développement de la roussette met en évidence des asymétries moléculaires et cellulaires multiples ; elle démontre en particulier l’existence d’une neurogenèse asymétrique qui débute plus précocement à gauche. Ces travaux donnent un éclairage nouveau sur l’origine et la diversification des mécanismes contrôlant la formation des asymétries cérébrales chez les vertébrés. L’étude de la roussette et la lamproie, deux organismes modèles non conventionnels, ouvrent de nouvelles perspectives pour leur compréhension. / Vertebrates are part of the bilaterally symmetric animals but this one is not perfect and numerous asymmetries can be seen between the left and right sides, especially in the nervous system. The epithalamus has proven itself to be the model system for brain lateralization mechanisms’ studies. This structure derived from the dorsal diencephalon contains by the bilaterally paired habenular nuclei and the pineal complex, which includes the pineal gland and parapineal organ. The habenulae exhibit more or less marked left-right asymmetries among most of the major vertebrate taxa. The parapineal is also asymmetrical but it is absent in many taxa. Zebrafish is the model system for the studies of the developmental mechanisms of epithalamic asymmetries. In this species, a lateralized parapineal migration is required for the establishment of habenular asymmetries. The underlying genetic mechanisms have also been partially decrypted. The first conspicuous asymmetry in the dorsal diencephalon corresponds to a left-sided expression of components of the Nodal signalling pathway. This asymmetric Nodal signalling activity is essential to induce an early neurogenetic asymmetry but not necessary the formation of epithalamic asymmetries per se. Its role is restricted to provide a bias to the parapineal organ’s lateralized migration, and thus influence the laterality of epithalamic asymmetries. Indeed, habenular asymmetries are induced by the final position of the parapineal organ. Conservation of these mechanisms described in zebrafish across vertebrates remains an open question. During this thesis, I tried to understand the evolution of these mechanisms by studying a Chondrichthyes, the catshark Scyliorhinus canicula and cyclostomes, the lampreys Petromyzon marinus and Lampetra planeri. Their phylogenetic position and the major asymmetries in size observed between their left and right habenulae make these species good model systems to understand the origin of these mechanisms in vertebrates. My work leads to three main conclusions:(1) As in zebrafish, we have found an asymmetric expression of the components of the Nodal signalling pathway in the left dorsal diencephalon of the catshark and the lamprey. The laterality of the asymmetry is conserved between these three species, which allows us to exclude a reversed laterality in lampreys like it was proposed on the basis of arguments related to the size of habenular nuclei.(2) The Nodal signalling pathway is requied for the establishment of habenular asymmetries in the catshark and lamprey thus suggesting an ancestral role in the development of epithalamic asymmetries.(3) A detailed analysis of proliferation-differentiation patterns in the catshark habenulae during their development highlighted multiple cellular and molecular asymmetries. In particular it showed the existence of an earlier left-sided asymmetric neurogenesis.These studies provide new insights about the origin and diversification of the mechanisms controlling the establishment of vertebrates’ brain asymmetries. The study of the lamprey and the dogfish, two unconventional model systems open new perspectives for their understanding.

RésuméLa thèse porte sur les représentations spatiales et en particulier sur les cadres de référence spatiale. Ils permettent la localisation d’objets par rapport à d’autres dans un espace proche, comme dans l’exemple : « le sel est à gauche du poivre ». Il existe différents types de références : centré sur soi, centré sur l’objet et centré sur l’environnement. Celles qui sont préférentiellement utilisées par un individu dépendent de sa langue et de sa culture.Dans un premier temps, le développement des cadres de référence est analysé chez des sujets de culture française de 3 à 21 ans, grâce aux tâches du paradigme de rotation à 180° (Levinson, 2003). Dans un second temps, les relations entre les confusions gauche/droite et l’utilisation de cadres de référence sont examinées chez des adultes français, en s’appuyant sur un questionnaire d’auto-évaluation et sur une tâche du paradigme de rotation. Les résultats permettent de dessiner un chemin développemental concernant les cadres de référence en France, selon le modèle de la Redescription Représentationnelle de Karmiloff-Smith (1992). Ils montrent également le lien entre les confusions gauche/droite et les types de références spatiales utilisées chez certains adultes. / The thesis is about spatial representations, especially spatial frames of reference, which are used to locate an object with respect to another in a small-scale space, for example: « the salt is to the left of the pepper ». Different references exist: self-centred, object-centred and environment-centred. The references preferentially employed by a subject depend on his language and culture.First of all, the development of frames of reference is analysed with French subjects from 3 to 21 years of age, thanks to 180° rotation paradigm tasks (Levinson, 2003). Secondly, the relations between left/right confusions and the use of frames of reference are examined with French adults, with a self-judgment questionnaire and a rotation paradigm task.Results show that the development of frames of reference in France follows the predictions of the Representational Redescription model of Karmiloff-Smith (1992). They also highlight a link between left/right confusions and spatial references used by some adults.

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Background: Left/right judgment (LRJ) measurement is a potential way to identify dysfunction in cortical body maps, and to measure improvement related to corresponding treatments. Few studies have explored the reliability of various methods for LRJ measurement. Objectives: To determine measurement reliability of LRJ utilizing two methods: card-based (CB) and tablet-based (TB). Establish minimal detectable difference (MDD) for accuracy and reaction time for both assessments. Methods: Testing was done over two different days. Session 1 consisted of testing LRJ utilizing CB assessment with photos of left and right hands over two trial periods. The TB format was also tested over two trial periods. Session 2 tested with the CB assessment for two trial periods. 40 images were used in the basic upright position for both CB and TB formats. Results: Fifty participants (N = 50; female = 35) with an average age of 24.3 (range 19–35) were studied. ICC (2,k) for reaction time for both methods were >0.84. The MDD for reaction time was between 0.19 and 0.49 s for various test points for both methods. Combined left and right accuracy ICC (2,k) for both methods were >0.51, with MDD between 5 and 14%. Conclusions: This study examined the reliability and MDD for the LRJ measurement for card and tablet-based assessments. Generally, LRJ reaction time had good reliability, while accuracy had moderate reliability and varied between testing methods.

A semi-systematic literature review of research carried out on the evolution of the concept of Euroscepticism since the term first was reportedly used in 1986 with special focus on articles published around the year before the 2019 European Parliament elections and to this date. The thesis was conducted with a particular interest in gathering more knowledge on using an evidence-based method in political science. The purpose was twofold, therefore: one to see how the concept itself has evolved in research, in terms of definition and salience as well as in terms of measuring and explanatory factors, and the other to see if the method used is appropriate to this purpose. From the data gathered, it can be said that the method is pertinent and relevant when assembling research from a widespread and multifaceted area in terms of geography and content, since it is meant to avoid the pitfalls of ‘picking and choosing’ data. The articles thus uncovered have shown that there is a red thread in research on Euroscepticism, that its context has changed and therefore its content, and that Euroscepticism 2020 is a salient issue.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18169号 / 医博第3889号 / 新制||医||1003(附属図書館) / 31027 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 大森 治紀, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

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