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Variabilité phénotypique et corrélations génotype – phénotype des dystrophinopathies : contribution des banques de données. / Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies : contribution of genetic and clinical databases.Humbertclaude, Véronique 14 December 2011 (has links)
L'objectif de ce travail est de développer la partie clinique de la banque de données du gène DMD, afin d'étudier l'histoire naturelle des dystrophinopathies et les corrélations génotype–phénotype, et de faciliter la sélection des patients pour les futurs essais thérapeutiques. La méthodologie créée pour le gène DMD peut être généralisée et utilisée pour d'autres banques de données dédiées à des maladies génétiques. La collecte de 70 000 données cliniques chez 600 patients avec un suivi longitudinal moyen de 12 ans permet de décrire l'histoire naturelle des dystrophies musculaires de Duchenne et de Becker et des formes symptomatiques chez les femmes. Nous avons pu préciser l'hétérogénéité phénotypique sur le plan moteur, orthopédique et respiratoire (forme sévère et forme intermédiaire de la dystrophie musculaire de Duchenne), sur le plan cardiaque (absence de corrélation entre les atteintes motrice et cardiaque, variabilité de l'atteinte cardiaque), et sur le plan cérébral (atteinte intellectuelle chez les patients avec dystrophie musculaire de Becker, troubles psychologiques des dystrophinopathies). L'utilisation de cet outil par les cliniciens et les généticiens devrait faciliter le travail de recherche clinique et la réalisation des futurs essais cliniques. Ceci nécessite maintenant de développer l'accessibilité de la banque de données et d'envisager sa pérennisation. / The objective of this work is to develop the clinical part of the French dystrophinopathy data-base, in order to study the natural history and the genotype-phenotype correlations, and to facilitate the selection of the patients for the future therapeutic trials. The methodology developed for the DMD gene can be generalized and used for the other databases dedicated to genetic diseases. The collection of 70 000 clinical data for 600 patients with an average lon-gitudinal follow-up of 12 years allows to clarify the natural history of the muscular dystrophies of Duchenne and Becker and in symptomatic females. We were able to specify the pheno-typic heterogeneity of the motor, orthopaedic and respiratory involvements (severe form and intermediary form of the Duchenne muscular dystrophy), of the cardiac disorder (absence of correlation between motor and cardiac involvements, variability of the cardiomyopathy), and of the brain function (mental deficiency in the patients with Becker muscular dystrophy, psychological disorders in dystrophinopathies). The use of this tool by the clinicians and the ge-neticists should facilitate their clinical research work and the realization of the future clinical trials. This requires now to develop the accessibility of the database and to ensure its continued existence.
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Koherencí řízený holografický mikroskop s digitální optikou / Coherence Controlled Holographic Microscope with the digital opticsVavřinová, Jana January 2018 (has links)
The Digital Micromirror Device (DMD) technology has been developed especially for Digital Light Processing projectors, which allow the image projection. After this succesful implementation, and thanks to the commercial availibility and low initial cost of the DMD chip, a wide range of other applications became possible. Besides, it may be used in microscopy as a spatial light modulator. For example in Coherence-Controlled Holographic Microscope (CCHM) that finds its use especially for imaging and measurement of live-cell dynamic processes. The DMD chip placed in the illumination part of CCHM allows for broadening the application possibilities. Namely it could be different illumination mode experiments or tomographic applications. The master's thesis deals with the optical design of CCHM with digital optics, i. e. DMD chip. The selection of optical elements for CCHM, the experimental verification of the imaging setup and the process of designing the illumination part are described in detail. In the end, the analysis of different designs for illumination setup with the digital optics in object arm is carried out and the results are compared.
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Drag reduction using plasma actuatorsFutrzynski, Romain January 2015 (has links)
This thesis is motivated by the application of active flow control on the cabin of trucks, thereby providing a new means of drag reduction. Particularly, the work presented strives to identify how plasma actuators can be used to reduce the drag caused by the detachment of the flow around the A-pillars. This is achieved by conducting numerical simulations, and is part of a larger project that also includes experimental. The effect of plasma actuators is modeled through a body force, which adds very little computational cost and is suitable for implementation in most CFD solvers. The spatial distribution of this force is described by coefficients which have been optimized against experimental data, and the model was shown to be able to accurately reproduce the wall jet created by a single plasma actuator in a no-flow condition. A half cylinder geometry - a simplified geometry for the A-pillar of a truck - was used in a preliminary Large Eddy Simulation (LES) study that showed that the actuator alone, operated continuously, was not sufficient to achieve a significant reduction of the drag. Nevertheless, a significant drag reduction was obtained by simply increasing the strength of the body force to a higher value, showing that this type of actuation remains relevant for the reduction of drag. In the course of finding ways to improve the efficiency of the actuator, dynamic mode decomposition was investigated as a post-processing tool to extract structures in the flow. Such structures are identified by their spatial location and frequency, and might help to understand how the actuator should be used to maximize drag reduction. Thus a parallel code for dynamic mode decomposition was developed in order to facilitate the treatment of the large amounts of data obtained by LES. This code and LES itself were thereafter evaluated in the case of a pulsating channel flow. By using the dynamic mode decomposition it was possible to accurately extract oscillating profiles at the forcing frequency, although harmonics with lower amplitude compared to the turbulence intensity could not be obtained. / Denna avhandling behandlar tillämpningen av aktiv strömningskontroll för lastbilshytter, vilket är en ny metod för minskning av luftmotståndet. Mer i detalj är det övergripande målet att visa på hur plasmaaktuatorer kan användas för att minska luftmotståndet orsakat av avlösningen runt A-stolparna. In denna avhandling studeras detta genom numeriska simuleringar. Arbetet är en del av ett projekt där även experimentella försök görs. Effekten av plasmaaktuatorer modelleras genom en masskraft, vilket inte ger nämnvärd ökning av beräkningstiden och är lämplig för implementering i de flesta CFD-lösare. Den rumsliga fördelningen av kraften bestäms av koefficienter vilka i detta arbete beräknades utifrån experimentella data. Modellen har visat sig kunna återskapa en stråle nära väggen med god noggrannhet av en enskild plasmaaktuator för en halvcylinder utan strömning. Samma geometri - en halvcylinder som här används som förenklad geometri av A-stolpen på en lastbil - användes i en preliminär LES studie som visade att enbart aktuatorn vid kontinuerlig drift inte var tillräckligt för att uppnå en signifikant minskning av luftmotståndet. En signifikant minskning av luftmotståndet erhölls genom att helt enkelt öka styrkan på kraften, vilket visats att denna typ av strömningskontroll är relevant för minskning av luftmotståndet. I syfte att förbättra effektiviteten hos aktuatorn, studerades dynamic mode decomposition, som ett verktyg för efterbehandling för att få fram flödesstrukturer. Dessa strukturer identifieras genom deras rumsupplösning och frekvens och kan hjälpa till att förstå hur aktuatorerna bör användas för att minska luftmotståndet. En parallelliserad kod för dynamic mode decomposition utvecklades för att underlätta efterbehandlingen av de stora datamängder som fås från LES-beräkningarna. Slutligen, utvärderades denna kod och LES-beräkningar på ett strömningsfall med pulserande kanalflöde. Metoden, dynamic mode decomposition, visade sig kunna extrahera de oscillerande flödesprofilerna med hög noggrannhet för den påtvingade frekvensen. Övertoner med lägre amplitud jämfört med turbulensintensiteten kunde dock inte erhållas. / <p>QC 20150312</p>
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Characterisation and strategic treatment of dystrophic muscleLaws, Nicola January 2005 (has links)
The mdx mouse is widely used as a model for Duchenne Muscular Dystrophy, a fatal X-linked disease caused by a deficiency of the sub-sarcolemmal protein, dystrophin. This dissertation reports characterisation of the features of dystrophy in the mdx mouse, including parameters such as electrophysiological and contractile properties of dystrophic cardiac tissue, quantitative evaluation of kyphosis throughout the mdx lifespan, and contractile properties of respiratory and paraspinal muscles. Following these characterisation studies, the efficacy of antisense oligonucleotides (AOs) to induce alternative mRNA splicing in mdx skeletal muscles (diaphragm and paraspinal muscles) was evaluated. The left atria of younger (<6 weeks) and older (>15 months) mdx mice showed consistently lower basal forces and responsiveness to increased calcium, while action potential duration was significantly shorter in young mice (3 weeks) and older mice (9 and 12 months) (P<0.05). Cardiac fibrosis increased with age in mdx atria and ventricles and was elevated in young (6-8 weeks) and old (15 months) mdx compared to control mice (P<0.01). This study provided insights into DMD cardiomyopathy, and suggested that very young or old mdx mice provide the most useful models. Mdx mice show thoracolumbar kyphosis like boys with Duchenne Muscular Dystrophy. A novel radiographic index, the Kyphotic Index (KI), was developed and showed that mdx mice are significantly more kyphotic from 9 months of age, an effect maintained until 17 months (P<0.05). At 17 months, the paraspinal and respiratory muscles (latissimus dorsi, diaphragm and intercostal muscles) are significantly weaker and more fibrotic (P<0.05). Administration of AOs at four sites within the diaphragm at 4 and 5 months of age significantly increased twitch and tetanic forces compared to sham treated mdx (P<0.05). However, no difference in collagen was evident and dystrophin was not detected, possibly due to the low concentration of AO utilised. This study suggested that AOs can provide functional improvement in treated skeletal muscles. Monthly injections with AOs into the paraspinal muscles from 2 months to 18 months of age alleviated kyphosis, without significantly altering twitch and tetanic forces of latissimus dorsi, diaphragm and intercostal muscles. There was evidence of less fibrosis in diaphragm and latissimus dorsi muscles (P<0.05) and reduced central nucleation of the latissimus dorsi and intercostal muscles (P<0.05). Again, dystrophin was not detected by immunoblot. These studies indicate that very young and old mdx mice display previously uncharacterised dystrophic features, and are useful models for testing new therapies such as AOs. Low doses of AOs were shown to be safe and efficacious for long-term use, however there remains a need for testing higher concentrations and improved delivery strategies.
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Active Control and Modal Structures in Transitional Shear FlowsSemeraro, Onofrio January 2013 (has links)
Flow control of transitional shear flows is investigated by means of numerical simulations. The attenuation of three-dimensional wavepackets of Tollmien-Schlichting (TS) and streaks in the boundary layer is obtained using active control in combination with localised sensors and actuators distributed near the rigid wall. Due to the dimensions of the discretized Navier-Stokes operator, reduced-order models are identified, preserving the dynamics between the inputs and the outputs of the system. Balanced realizations of the system are computed using balanced truncation and system identification. We demonstrate that the energy growth of the perturbations is substantially and efficiently mitigated, using relatively few sensors and actuators. The robustness of the controller is analysed by varying the number of actuators and sensors, the Reynolds number, the pressure gradient and by investigating the nonlinear, transitional case. We show that delay of the transition from laminar to turbulent flow can be achieved despite the fully linear approach. This configuration can be reproduced in experiments, due to the localisation of sensing and actuation devices. The closed-loop system has been investigated for the corresponding twodimensional case by using full-dimensional optimal controllers computed by solving an iterative optimisation based on the Lagrangian approach. This strategy allows to compare the results achieved using open-loop model reduction with model-free controllers. Finally, a parametric analysis of the actuators/ sensors placement is carried-out to deepen the understanding of the inherent dynamics of the closed-loop. The distinction among two different classes of controllers – feedforward and feedback controllers - is highlighted. A second shear flow, a confined turbulent jet, is investigated using particle image velocimetry (PIV) measurements. Proper orthogonal decomposition (POD) modes and Koopman modes via dynamic mode decomposition (DMD) are computed and analysed for understanding the main features of the flow. The frequencies related to the dominating mechanisms are identified; the most energetic structures show temporal periodicity. / <p>QC 20130207</p>
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Determining biological sources of variation in residual feed intake in Brahman heifers during confinement feeding and on pastureDittmar (III), Robert Otto 15 May 2009 (has links)
Objectives were to characterize residual feed intake (RFI) and determine the
phenotypic correlation between performance, feed efficiency, and other biological
measurements in Brahman heifers, as well as the relationship between RFI determined in
confinement and measurements of grazing activity on pasture. Three separate 70 d
feeding trials were performed, and RFI was determined as the residual between actual
and predicted dry matter intake (DMI) for a given level of production. Brahman heifers
(n = 103; 5-to-9 mo of age) were individually limit-fed a pelleted 12% CP complete
ration daily in Calan gates. Weekly body weight (BW) and DMI data were collected, and
predicted DMI was determined by linear regression of actual DMI on mid-test metabolic
BW. Ytterbium chloride was used to evaluate digestive kinetics, and fecal samples were
collected to determine fecal volatile fatty acids (VFA) concentration and determine
apparent dry matter digestibility (DMD) utilizing acid insoluble ash as an internal
marker. Measurements of temperament were evaluated on all heifers at weaning. High (n
= 6) and low (n = 6) RFI heifers (Exp. I) grazed fescue and ryegrass to determine
variation in grazing behavior, DMI, and apparent DMD. Data from all three experiments were pooled, and RFI was not correlated with
average daily gain (ADG), DMI, BW, partial efficiency of gain, feed conversion ration,
fecal VFA concentration, or any measures of temperament. There were no significant
differences in digestive kinetics between the RFI efficiency groups. Fecal samples taken
for acid detergent insoluble ash (ADIA) determination were not collected at frequent
enough intervals to account for weekly variation in fecal ADIA concentration. Pasture
measurements were not different between the efficiency groups for heifers evaluated for
grazing behavior, as well as estimated intake as a proportion of BW, or apparent DMD.
Results of this study suggest that Bos indicus cattle appear to have similar efficiency
traits as Bos taurus and Bos indicus influenced cattle, making this measure of efficiency
equally as valid for use in both types of cattle. This indicates that selection based on RFI
can be made to increase feed efficiency without affecting ADG or BW in Brahman
cattle.
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Determining biological sources of variation in residual feed intake in Brahman heifers during confinement feeding and on pastureDittmar (III), Robert Otto 10 October 2008 (has links)
Objectives were to characterize residual feed intake (RFI) and determine the
phenotypic correlation between performance, feed efficiency, and other biological
measurements in Brahman heifers, as well as the relationship between RFI determined in
confinement and measurements of grazing activity on pasture. Three separate 70 d
feeding trials were performed, and RFI was determined as the residual between actual
and predicted dry matter intake (DMI) for a given level of production. Brahman heifers
(n = 103; 5-to-9 mo of age) were individually limit-fed a pelleted 12% CP complete
ration daily in Calan gates. Weekly body weight (BW) and DMI data were collected, and
predicted DMI was determined by linear regression of actual DMI on mid-test metabolic
BW. Ytterbium chloride was used to evaluate digestive kinetics, and fecal samples were
collected to determine fecal volatile fatty acids (VFA) concentration and determine
apparent dry matter digestibility (DMD) utilizing acid insoluble ash as an internal
marker. Measurements of temperament were evaluated on all heifers at weaning. High (n
= 6) and low (n = 6) RFI heifers (Exp. I) grazed fescue and ryegrass to determine
variation in grazing behavior, DMI, and apparent DMD. Data from all three experiments were pooled, and RFI was not correlated with
average daily gain (ADG), DMI, BW, partial efficiency of gain, feed conversion ration,
fecal VFA concentration, or any measures of temperament. There were no significant
differences in digestive kinetics between the RFI efficiency groups. Fecal samples taken
for acid detergent insoluble ash (ADIA) determination were not collected at frequent
enough intervals to account for weekly variation in fecal ADIA concentration. Pasture
measurements were not different between the efficiency groups for heifers evaluated for
grazing behavior, as well as estimated intake as a proportion of BW, or apparent DMD.
Results of this study suggest that Bos indicus cattle appear to have similar efficiency
traits as Bos taurus and Bos indicus influenced cattle, making this measure of efficiency
equally as valid for use in both types of cattle. This indicates that selection based on RFI
can be made to increase feed efficiency without affecting ADG or BW in Brahman
cattle.
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Cardiac calcium handling in the mouse model of Duchenne Muscular DystrophyWoolf, Peter James January 2003 (has links)
The dystrophinopathies are a group of disorders characterised by cellular absence of the membrane stabilising protein, dystrophin. Duchenne muscular dystrophy is the most severe disorder clinically. The deficiency of dystrophin, in the muscular dystrophy X-linked (mdx) mouse causes an elevation in intracellular calcium in cardiac myocytes. Potential mechanisms contributing to increased calcium include enhanced influx, sarcoplasmic reticular calcium release and\or reduced sequestration or sarcolemmal efflux. This dissertation examined the potential mechanisms that may contribute to an intracellular calcium overload in a murine model of muscular dystrophy. The general cardiomyopathy of the mdx myocardium was evident, with the left atria from mdx consistently producing less force than control atria. This was associated with delayed relaxation. The role of the L-type calcium channels mediating influx was initially investigated. Dihydropyridines had a lower potency in contracting left atria corresponding to a redued dihydropyridine receptor affinity in radioligand binding studies of mdx ventricular homogenates (P<0.05). This was associated with increased ventricular dihydropyridine receptor protein and mRNA levels (P<0.05). The function of the sarcoplasmic reticulum in terms of release and also sequestration of calcium via the sarco-endoplasmic reticulum ATPase were investigated. A lower force of contraction was evident in mdx left atria in response to a range of stimulation frequencies (P<0.05) and concentrations of extracellular calcium (P<0.05). However, in the presence of 1 nM Ryanodine to block sarcoplasmic reticular calcium release, increased stimulation frequency caused similar forces to those obtained in control mice suggesting enhanced calcium influx via L-type calcium channels in mdx. Rapid cooling contractures showed a reduced contracture in mdx compared to control in response to cooling. This suggests some dysfunction in SR storage, which may be associated with the delayed relaxation time. Concentration-response curves to inhibitors of the sarco-endoplasmic reticulum showed no difference in function of the enzyme responsible for calcium uptake into the sarcoplasmic reticulum. Although sarco-endoplasmic reticulum ATPase mRNA was upregulated, no functional benefit was evident. This study indicates that a deficiency of dystrophin leads to upregulation of L-type calcium channels that contribute to increased calcium influx, with no functional change in sarcoplasmic reticular sequestration. Upregulation of the influx pathway is a potential mechanism for the calcium overload observed in mdx cardiac muscle.
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Etats de surface de pièces métalliques obtenues en Fabrication Directe par Projection Laser (FDPL) : compréhension physique et voies d’amélioration / Improvement of surface finish of metallic materials obtained by the direct metal deposition techniqueGharbi, Myriam 05 July 2013 (has links)
Le procédé de fabrication directe par projection laser (FDPL), est un procédé de fabrication additive qui permet de fabriquer des pièces de forme complexe directement à partir d'un fichier CAO, sans outil et sans moule. L'un de ses inconvénients majeurs est la mauvaise qualité des états de surface obtenus (Ra supérieur à 15 μm) qui nécessite systématiquement des étapes de ré-usinage. Dans ce contexte, et dans le cadre du projet ANR « ASPECT », cette thèse a pour double objectif une meilleure compréhension de l'origine des états de surface dégradés, et le développement de différentes solutions expérimentales innovantes permettant d'améliorer les états de surface.Dans un premier temps, en considérant des géométries simples (murs) en alliage de titane Ti-6Al-4V, nous avons étudié l'interaction faisceau laser / jet de poudre / bain liquide métallique par différents diagnostics (caméra rapide, caméra thermique, pyrométrie…) pour comprendre l'évolution de la géométrie, la thermique et l'hydrodynamique de la zone fondue (ZF). Ces analyses nous ont permis de corréler les évolutions des ZF à celles des états de surface, et de mettre en évidence, sur le Ti-6Al-4V la prépondérance des effets de tension superficielle sur les effets de gravité, dans l'équilibre des ZF, et l'effet bénéfique de zones fondues larges et profondes combinées à de faibles hauteurs par couche, dans la réduction des micro et macro-rugosités. La réduction du débit massique local Dm* en vis-à-vis des parois latérales et l'augmentation du rayon de courbure des ZF avec l'élargissement des ZF (donc avec des rapports El= P/V (J/m) élevés) sont à l'origine des effets bénéfiques obtenus. Différents modèles analytiques et numériques ont également été utilisés ou développés, en complément des résultats expérimentaux, pour décrire le procédé (modèle d'interaction laser-poudre, modèle numérique thermique 3D du procédé, modèle de calcul des ondulations périodiques).En utilisant un large spectre de conditions expérimentales, et une caractérisation rigoureuse des conditions de fabrication (analyses de faisceau, de jet de poudre …) nous avons également apporté des améliorations notables à la qualité des états de surface obtenus. Ainsi, l'utilisation d'un éclairement laser uniforme plutôt que quasi-Gaussien, ou l'utilisation d'un régime quasi-pulsé plutôt que continu ont permis, sur le Ti-6Al-4V de réduire significativement les gradients thermiques en ZF et les mouvements de convection de Marangoni associés, et d'obtenir des qualités d'états de surface fortement améliorées (Ra< 3 µm) par rapport aux études antérieures sur le sujet.Pour finir, une partie de l'étude s'est concentrée sur l'utilisation d'un autre matériau: l'acier inoxydable 316L, afin d'analyser l'influence de la nature chimique et des propriétés thermo-physiques de la poudre projetée sur la qualité des états de surface. Les résultats ont montré que, contrairement à l'alliage de titane, les meilleures rugosités étaient obtenues pour les énergies linéiques El (J/m) les plus faibles, en raison de la formation, à El élevé, de macro-agglomérats de poudre sur les parois des murs. Ce résultat confirme la difficulté d'une approche prédictive globale des états de surface à partir des paramètres thermo-physiques des matériaux projetés. / The process of direct manufacturing by projection laser ( FDPL), is a process of additive manufacturing which allows to make rooms(parts,plays) of complex shape directly from a file CAD, without tool and without mold(mussel). One of its major inconveniences is the bad quality of the states of surface obtained (Ra upper to 15 µm) which requires systematically stages of remanufacturing. In this context, and within the framework of the project ANR " aspect ", this thesis(theory) has for double objective a better understanding of the origin of the degraded states of surface, and the development of various innovative experimental solutions allowing to improve the states of surface. At first, by considering simple geometries (walls) in alloy of titanium Ti-6Al-4V, we studied the interaction
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Combustion Noise and Instabilities from Confined Non-premixed Swirl FlamesMohamed Jainulabdeen, Mohammed Abdul Kadher 21 October 2019 (has links)
No description available.
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