Proximale Spinale Muskel Atrophie (SMA) ist eine autosomal rezessive Krankheit, charakterisiert durch eine Degeneration des zweiten Motorneurons und einer progressiven Paralyse und Atrophie proximaler Muskeln. Nach Zystischer Fibrose, ist SMA die häufigste autosomal rezessive Erkrankung bei Menschen und der häufigste genetische Grund für Säuglingssterblichkeit. SMA, monogenetisch im Ursprung, ist verursacht durch eine Mutation in einem einzelnen Gen, dem Survival Motor Neuron 1 (SMN1) Gen, was zu einer reduzierten Menge an Survival Motor Neuron (SMN) protein führt. SMN ist ein ubiquitär expremiertes Protein mit house-keeping Funktion in snRNP Biogenese und pre-mRNA splicen. Dennoch, eine reduzierte Menge an SMN beeinträchtigt vor allem Motor Neurone und Muskeln aus bisher unverständlichen Gründen. Es wurde demonstriert, dass SMN mit ß-actin mRNA interagiert und an dessen Transport entlang des Axons beteiligt ist. Funktionelle Studien an der Neuromuskulären Synapse (NMJ) haben gezeigt, dass Evozierte Neurotransmitterfreisetzung um 55 % reduziert war in den meist betroffenen Muskelgruppen, dies indiziert, dass eine verringerte Menge an Vesikeln fusioniert, währenddessen asynchrone Transmitterfreisetzung um 300 % erhöht ist aufgrund von einer abnormalen Akkumulation von Calcium in der Nervenendigung in SMA Mäusen. Eine Mögliche Erklärung für diese Calcium Erhöhung ist eine herabgesetzte Calcium Aufnahme durch Mitochondrien während Serien von Aktions Potenzialen. Diese Studie präsentiert eine umfassende Analyse mit einem Fluoreszens Konfokal Mikroskop über die Organisation und Fülle Synaptischer Vesikel (SVs), Mitochonrien und Aktin in Nervenendigungen von SMA Mäusen ( Smn -/-; SMN2; SMNdelta7). Wir visualisierten Synaptische Vesikel mit einem Antikörper gegen den Acetylcholin ( VACht) und konnten zeigen, dass im Transversus Abdominis (TVA) Muskel SV Klusters während des Reifungsprozesse klein verbleiben mit einer Reduzierung von 50% der totalen Fläche die von SVs bedeckt ist. Diese schwere Reduktion von SVs wurde auch im der kaudalen Muskelstrang des Levator auris longus (LAL) Muskel gefunden, obwohl nur leichte Veränderungen in der Postsynapse dieses Muskels festzustellen sind. Diese Ergebniss von Präsynaptischer Pathologie, neben fast normalen postsynaptischen Status, verstärkt die Hypothese dass SMN-induzierte Veränderungen im Muskel nicht auschließlich eine reine Konsequenz von Motor Neuron Degeneration sein können. Als Nächstes, haben wir Mitochondria mit Mitotracker angefärbt und haben gefunden, dass die Fläche,die von Mitochondrien in Mutanten Mäusen bedeckt ist, etwa nur die Hälfte der Fläche im Wild typ beträgt. Überraschenderweise waren SVs und Mitochondrien stak kolokalisiert. In vielen Fällen war ein Kern von Mitochondrien deutlich umgeben von einem Ring aus SVs. Diese Verteilung war unbeeinträchtig in der Mutanten Maus und könnte eine mehr generelle Bedeutung in Nervenendigungen haben. Phalloidin gefärbtes Aktin zeigte das F-aktin ringförmige Strukturen um SV Klusters formt. Diese Strukturen und der Prozentuale Anteil der Nervenendigung der von Aktin bedeckt ist, war geringer in SMA Mutanten Mäusen. Aktin ist an multiblen Schritten des Vesikel Zyklus beteiligt. Kurz Strecken-Transport von Vesikeln und Organellen, wie Mitochondrien in Wachstunskegeln und Nervendigungen ist vor allem vom aktin-myosin-basierten Transport abhängig. Weitere Arbeit ist notwendig um zu klären ob die Charakteristiken des SMA Phänotyps wie abnormales SV Klustering, Reduktion von Mitochondrien, unabhängig auftreten oder eine gemeinsame Konsequenz von einer Dysfunktion des Aktin Zytoskeleton sind, was Aktin eine Schlüsselrolle in der SMA Pathogenese verleihen würde.

L'amyotrophie spinale infantile (SMA) est une maladie génétique autosomique récessive de l'enfant pour laquelle aucun traitement efficace n'existe. La SMA est caractérisée par la perte spécifique des motoneurones spinaux conduisant à une faiblesse musculaire sévère. Le décès des patients survient lorsque les muscles vitaux sont touchés. Cette maladie est causée par la mutation du gène Survival of Motor Neuron 1 (Smn1) conduisant à une diminution importante de l’expression de la protéine Survival of Motor Neuron (SMN). Tous les patients possèdent un ou plusieurs gènes copie de Smn1, le gène Smn2. Ces copies modulent la sévérité de la maladie en produisant une faible quantité de transcrits SMN complets, en particulier possédant l’exon 7, un exon alternatif qui code pour un domaine important pour que la protéine SMN soit fonctionnelle et stable. Des résultats récents, obtenus au laboratoire, indiquent que l'exercice physique retarde la mort des motoneurones, conduit à une augmentation du taux de maturation postnatale des unités motrices et déclenche l’expression du gène Smn2 chez des souris mimant la SMA de type II. Les premières données moléculaires suggèrent que les effets de l'exercice physique pourraient être relayés par la signalisation dépendante 1) des récepteurs au NMDA (Biondi et coll., J Neurosci, 2008) et/ou 2) du récepteur à IGF-1. Dans notre étude, nous avons d’abord testé les effets de l’activation directe des récepteurs au NMDA (NMDAR) dans un contexte de SMA. Nous montrons qu’une activation adéquate de ces récepteurs dans plusieurs modèles souris mimant les SMA sévères accélère la maturation postnatale des unités motrices, limite l'apoptose dans la moelle épinière et active l’expression du gène Smn2 favorisant l'expression de la protéine SMN. Ces effets bénéfiques sont dépendants du niveau d’activation des NMDARs et suggèrent que l'accélération de la maturation postnatale des unités motrices, induite par le NMDA, est indépendante du niveau d’expression de la protéine SMN. De manière importante, l’activation pharmacologique des NMDARs augmente fortement la durée de vie de deux modèles différents de souris mimant la SMA de type sévère. L'analyse des cascades de signalisation intracellulaire a révélé une altération inattendue des profils d’activation des voies de signalisation ERK et AKT/CREB, qui se rééquilibrent quand les NMDARs sont activés (Branchu et coll., J Neurosci, 2010).Comme la kinase ERK est constitutivement suractivée dans la moelle épinière des souris mimant la SMA, nous avons ensuite examiné son rôle potentiel dans la régulation de l'expression des gènes Smn2. Nous avons démontré que l'inhibition pharmacologique de la voie de signalisation MEK/ERK/Elk-1, notamment avec un médicament anti-cancéreux actuellement en essai clinique de phase 2, est bénéfique pour les souris mimant la SMA de type I. Nous avons identifié une relation croisée entre les voies de signalisation ERK et AKT impliquant la modulation, calcium-dépendante, de l'activité CaMKII. Ainsi, l'inhibition pharmacologique de ERK durant la phase symptomatique de la maladie chez ces souris, entraîne l'activation de la voie CaMKII/AKT/CREB et conduit à une augmentation significative de l’expression de la protéine SMN dans les motoneurones suite à une augmentation de la transcription du gène Smn2. Ces modifications sont corrélées avec une augmentation remarquable de la durée de vie et de la mobilité des souris et une neuroprotection des motoneurones spinaux. De plus, l’inhibition de ERK dans des cellules musculaires différenciées provenant de patients atteints de SMA de type II induit également une augmentation de l’activité de la voie AKT/CREB et de l’expression de SMN (Branchu et coll., J Neurosci, en révision positive). Enfin, nous avons montré que l'exercice physique est capable de diminuer l'expression du récepteur à l'IGF-1 (IGF-1R), qui est surexprimé dans la moelle épinière des souris mimant la SMA sévère... / Spinal muscular atrophy (SMA) is a severe autosomal recessive disease in childhood for which no efficient therapy is currently available. SMA is characterized by the specific loss of spinal motor neurons leading to a severe muscular weakness and death when vital muscles are affected. This disease is caused by mutation of the survival of motor neuron 1 (Smn1) gene leading to a deficiency of the Survival of Motor Neuron (SMN) protein expression. All patients retain one or more copies of the Smn2 gene, which modulates the disease severity by allowing a small amount of full-length SMN transcripts and stable SMN protein to be produced. Recent results in our laboratory indicate that physical exercise delays motor neuron death, leads to an increase in the motor-units postnatal maturation rate and trigger Smn2 gene expression in motor neurons. Furthermore, on the one hand, exercise is capable of specifically enhancing the expression of the gene encoding NR2A, the major activating subunit of the NMDA receptor in motor neurons. This subunit is known to be dramatically down-regulated in the spinal cord of severe SMA-like mice. Accordingly, inhibiting NMDA-receptor activity abolishes the exercise-induced effects on muscle development, motor neuron protection and life span gain (Biondi et al., J Neurosci, 2008). Thus, we tried to restore NMDA-receptor function as a therapeutic approach to SMA treatment. We demonstrated that an adequate NMDA receptor activation in severe SMA-like mouse model significantly accelerated motor-unit postnatal maturation, counteracted apoptosis in the spinal cord, and induced a marked increase in SMN expression resulting from a modification of Smn2 gene transcription pattern. These beneficial effects are dependent on the level of NMDA receptor activation since a treatment with high doses of NMDA led to an acceleration of the motor unit maturation but favored the apoptotic process and decreased SMN expression. Thus, these results suggest that the NMDA-induced acceleration of motor-unit postnatal maturation occurred independently of SMN. The NMDA receptor activating treatment strongly extended the life span in two different severe SMA-like mouse models. The analysis of the intracellular signaling cascades that lay downstream the activated NMDA receptor revealed an unexpected competition between the MEK/ERK/Elk-1 and the AKT/CREB signaling pathways for Smn2 gene regulation. Actually, the reactivation of the AKT/CREB pathway, thought calcium influx and the phosphorylation of CaMKII, opposed to MEK/ERK/Elk-1 inhibition, induces an enhanced SMN expression (Branchu et al., J Neurosci, 2010). On the other hand, exercise is capable of strongly decreasing the expression of IGF-1 receptor (IGF-1R); which is over-expressed in the spinal cord of severe SMA-like mice. We report that this reduction is also correlated with a reactivation of the AKT/CREB pathway and a MEK/ERK/Elk-1 inhibition. Therefore we generated an IGF-1R+/- SMA-like mouse model to investigate the functional link between IGF-1R expression level and the intracellular signaling pathway triggered in SMA spinal cord. We provided the first evidence that reducing the IGF-1R expression level is neuroprotective for SMA motor neurons, accelerates motor-unit postnatal maturation and leads to a remarkable increase in SMN expression and lifespan. The analysis of the intracellular signaling cascades revealed the same competition for Smn2 gene regulation. However, the activation of AKT/CREB is calcium-independent. In addition, we showed a drastic reduction of STAT3 phosphorylation and SOCS-1 and -3 expressions, which are over-expressed in SMA spinal cord and known to positively modulate ERK phosphorylation and negatively AKT (Data not published). Taken together all these data suggest new perspectives to therapeutic strategy, based on specific pharmacological correction, for SMA...

L'Atrophie Musculaire spinale (SMA) est une maladie neurodégénérative causée par des mutations du gène SMN1 et caractérisée par la dégénérescence sélective des motoneurones alpha de la moelle épinière. les mécanismes moléculaires de la SMA ne sont aps clairs. cependant, deux hypothèses ont été retenues:D'une part, que la déficience en SMN entraine une perturbation de la biogenèse des snRNPs spliceosomales individuelles et par conséquent des défauts d'épissage. pendant ma thèse, nous avons montré que la déficience en SMN provoquait une diminution des particules tri-snRNPs majeures amis surtout mineures et que cela avait des conséquences sur l'épissage d'un sous-groupe de pré-ARNm contenant des introns mineurs.D'autre part, que la déficience en SMN entraine des altérations de transport d'ARN dans les axones, essentiels pour la survie des motoneurones. A part l'ARNm de la beta-actine et l'ARNm de cpg15 récemment identifié, ceux qui pourraient être transportés par SMN n'ont pas été décrits. nous avons donc identifié les ARN interagissant avec les isoformes a-SMN et SMN-fl dans des cellules neuronales, et montré que certains de ces ARN cibles colocalisent avec SMN dans les axones, suggérant qu'elle est impliquée dans leur transport. / Spinal Muscular Atrophy is a neurodegenerative disease caused by mutations in SMN1 gene. SMA is characterized by the loss of alpha-motoneurons of the spinal cord. However, the precise molecular mechanisms underlying the disease are still unkown. two hypotheses have been retained to explain SMA pathigenesis:In one hand, the fact that SMN deficiency leads to a perturbation of individual snRNPs biogenesis and consequently splicing defects. During my PhD, we have shown that SMN deficiency alters the levels of major, but mostly, minor tri-snRNPs. And that leads to splicing defects of a subset of pre-mRNA containing minor introns.In the other hand, that SMN deficiency causes alteration of axonal transport of RNAs crucial to motoneurons survival. Except beta-actin mRNA and the recently identified cpg mRNA, the RNA targets of SMN have not been described. We succeed to identify RNA targets of both a-SMN and SMN-fl isoformes in a neuronal cell line and colocalisation data of some of these targets suggested that SMN could be implicated in the transport of these RNAs.

Shape memory alloys (SMAs) have gained much attention as a powerful source of actuation due to their improved performance, reduced size, and reduced complexity between components as well as having a high work output density. Their primary mechanism of actuation relies on a non-diffusional cyclic phase transformation from martensite to austenite, where the amount of thermal energy needed per cycle is directly associated with the hysteresis width between the austenite final and martensite final temperatures. Consequently, a narrower gap between those two temperature ranges requires a much lower energy demand to produce the actuation needed. Previous studies have indicated that the hysteresis width is linked to a strong coherence between the austenite/martensite interface. It has been shown that elemental additions to NiTi-based SMAs can further improve this coherency. Another huge challenge facing this unique technology is linked with its thermo-mechanical stability. Binary NiTi SMAs often exhibit significant transformation temperature shifts after each thermo-mechanical cycle, which can contribute to a shorter lifespan. The primary goal of this project is to identify and develop thermo-mechanically stable, low hysteresis shape memory alloys (LHSMAs) for actuator applications. To accomplish this goal, elemental additions of Cu, Co, Hf, and Pd were incorporated into NiTi-based SMAs and the results were compared in respect to their hysteresis width and thermo-mechanical stability through differential scanning calorimetry, scanning electron microscopy with energy dispersive spectroscopy, and compressive thermo-mechanical testing. Two quaternary SMAs containing small additions of Cu and Pd were shown to exhibit promising results with respect to hysteresis width and good thermo-mechanical stability.

Low levels of survival motor neuron (SMN) protein cause the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA), through mechanisms that are poorly defined. SMN protein is ubiquitously expressed, however the major pathological hallmarks of SMA are focused on the neuromuscular system, including a loss of lower motor neurons in the ventral horn of the spinal cord and atrophy of skeletal muscle. At present there is no cure for SMA. Most research to date has focused on examining how low levels of SMN lead to pathological changes in motor neurons, therefore the contribution of other tissues, for example muscle, remains unclear. In this thesis I have used proteomic techniques to identify intrinsic molecular changes in muscle of SMA mice that contribute to neuromuscular pathology in SMA. I demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomics data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. In addition robust up-regulation of VDAC2 and down-regulation of parvalbumin was confirmed in two mouse models of SMA as well as in patient muscle biopsies. Thus intrinsic pathology of skeletal muscle is an important event in SMA. I then used proteomics to identify individual proteins in skeletal muscle of SMA that report directly on disease status. Two proteins, GRP75 and calreticulin, showed increased expression levels over time in different muscles as well as in skin samples, a more accessible tissue for biopsies in patients. Preliminary results suggest that GRP75 and calreticulin can be detected and measured in SMA patient muscle biopsies. These results show that proteomics provides a powerful platform for biomarker identification in SMA, revealing GRP75 and calreticulin as peripherally accessible potential protein biomarkers capable of reporting on disease progression in muscle as well as in skin samples. Finally I identified a role for ubiquitin-dependent pathways in regulating neuromuscular pathology in SMA. Levels of ubiquitin-like modifier activating enzyme 1 (UBA1) were reduced in spinal cord and skeletal muscle tissue of SMA mice. Dysregulation of UBA1 and subsequently the ubiquitination pathways led to the accumulation of β-catenin. I show here that pharmacological inhibition of β-catenin robustly ameliorates neuromuscular pathology in animal models of SMA. Interestingly, downstream disruption of β-catenin was restricted to the neuromuscular system in SMA mice. Pharmacological inhibition of β-catenin failed to prevent systemic pathology in organs. Thus disruption of ubiquitin homeostasis, with downstream consequences for β-catenin signalling, contributes to the pathogenesis of SMA, thereby highlighting novel therapeutic targets for this disease.

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder characterised by lower motor neuron degeneration and paralysis. Although it is a leading genetic cause of childhood death no approved treatment options currently exist. As SMA is caused by low levels of the survival motor neuron (SMN) protein the majority of therapeutic strategies under development are therefore aimed at trying to elevate SMN levels. However, a number of limitations with these approaches exist demonstrating a need for the investigation of SMN-independent therapeutics. Of these non-classical pathways, the ubiquitin proteasome system (UPS) is an exciting new area of SMA research. The UPS is a system which degrades unwanted or damaged proteins and alterations in the UPS (including reduced levels of ubiquitin-like modifier activating enzyme 1 [Uba1] and increased levels of ubiquitin carboxyl-terminal esterase L1 [Uchl1] and β-catenin) have been recently identified in the neuromuscular system of SMA mice, providing promising new targets for therapy development. In this thesis I demonstrate that UPS perturbations are also present in other organ systems of severe ‘Taiwanese’ SMA mice and in other SMA models including intermediate Smn2B/− mice, zebrafish and patient derived iPSC motor neurons. Given the previously demonstrated improved neuromuscular phenotype in SMA mice treated with the β-catenin inhibitor quercetin I have been establishing whether other compounds with β-catenin inhibition offer similar or even better therapeutic options. Aspirin, indomethacin and iCRT-14 trials did not improve the SMA phenotype with likely off-target adverse effects meaning that quercetin remains the most tolerable β- catenin inhibitor in SMA mice to date. Another potential target of the UPS for SMA therapeutics is the deubiquitinating enzyme Uchl1, levels of which are increased in SMA. In this thesis I show that pharmacological inhibition of Uchl1 did not improve survival or motor performance in SMA mice and instead had a detrimental impact on the disease phenotype which could be explained by worsening SMA ubiquitin defects. Histological analysis revealed that there was no improvement in lower motor neuron count numbers, neuromuscular junction deficits or muscle fibre diameters. Mimicking the UPS phenotype in primary neuronal cells suggested that targeting UPS perturbations observed in SMA that are upstream of Uchl1, particularly the loss of Uba1, may therefore offer a more effective therapeutic option. Finally, I therefore examined whether increasing Uba1 levels in SMA mice using gene therapy technology was able to improve the SMA phenotype. My initial studies indicate that delivery of AAV9-UBA1 to SMA mice may be beneficial as intraperitoneal injection of AAV9-UBA1 was found to increase the weight and improve motor performance of SMA mice. Intravenous delivery of AAV9-UBA1 was found to further improve expression levels and biodistribution of AAV9-UBA1 in the central nervous system as well as systemically in all body organs and tissues. Western blot and proteomic analysis revealed that AAV9-UBA1 gene therapy is also able to correct downstream UPS perturbations found in SMA as well as increase SMN levels. Together, these results suggest that AAV9-UBA1 gene therapy is an exciting novel therapeutic approach for SMA.

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder characterized by insufficient SMN protein, resulting in motoneuron death. Initially, it was thought that motoneuronal death is followed by muscle atrophy; however, recent research is beginning to reveal possible muscle intrinsic defects, independent of motoneuron defects, in SMA. Previous studies have elucidated the cooperative involvement of CARM1, HuD and SMN in motoneurons, revealing HuD as a possible key player in the SMA phenotype. In this study, we focus on HuR, a ubiquitous family member of HuD, and the possibility that it plays a similar key role with CARM1 and SMN in skeletal muscle. Through the use of an shCARM1 stable line of C2C12s, we show that CARM1 is necessary for HuR functionality during differentiation. We further show that the methylation of HuR is necessary for its capability to translocate cytoplasmically during differentiation. We confirm an interaction between HuR and SMN, suggestive of a similar mechanism as was shown previously with HuD. In light of these findings, we next progressed to determine whether HuR is misregulated in an SMA mouse model. We report increased CARM1 levels in skeletal muscles of these mice. We further discovered that a deficiency in SMN protein impairs HuR upregulation and cytoplasmic translocation in response to HuR activation through sciatic nerve denervation. These findings were correlated with aberrant mRNA expression of HuR targets upon denervation. Taken together, these results show that HuR methylation is essential for proper myogenesis, and that the mechanism by which it acts likely requires sufficient SMN protein levels. In a deficiency of SMN, HuR shows signs of misregulation that may play a role in the inability to maintain or repair muscle in SMA.

This thesis details an investigation into the properties and applications of shape memory alloy (SMA) composites. SMA-composites are a new material which have the possibility of having a large impact on what the structures as we know today, are constructed with. SMA-composites are adaptive materials which can be used to control the shape and frequencies of vibration of a structure. In order to determine the effectiveness of such a material, research into the functional properties of SMAs and SMA-composites was conducted. As an initial step, the transformation behaviour of constrained SMAs was investigated in order to obtain a better understanding into the recovery stress generation of these wires when embedded into a composite material. It is known that the transformation is based on two types of martensite within the alloy; self accommodating and preferentially oriented martensite. The amounts of each type and how they vary with differing pre-strain were determined through DSC measurements and an explanation for why preferentially oriented martensite is not observed during DSC testing was made. The next step was to investigate the effectiveness of embedding SMA wires into composites and the thermomechanical properties of the SMA wires and the SMA-composites were determined. This was completed using a specially designed tensile testing machine which was capable of having the whole specimen immersed into an oil bath and heated and cooled repeatedly. The stress-strain, strain-temperature, stress-temperature, resistance-strain and cyclic properties of various wires were obtained, giving a better understanding of the behaviour of SMA wires under different test conditions. NiTiCu SMA wires were embedded into kevlar composite materials and the recovery stress generation (stress-temperature), stress-strain, and strain-temperature behaviour was determined. If SMA-composites are to be used as new materials for structural applications, verification that the embedment of pre-strained SMA wires into the material doesn't adversely affect the impact behaviour needs to be carried out. SMA-composite specimens with varying volume fractions of superelastic SMA wires, pre-strain and position through the thickness were made up for impact damage characterisation. These specimens were impacted at three different energy levels. The results showed that by embedding SMA wires into composite materials there is a reasonably low damage accumulation after impact. There is also no adverse impact effect on the structure compared with structures without wires as well as structures with other types of wires such as steel and martensitic SMA wires. The SMA-composites showed good damping and energy absorption capabilities. A novel application of SMA-composites is their use as a SMA patch in order to repair damage in existing cracked metallic structures. An analytical study and finite element modelling showing the closure stresses obtainable for use as patches was made.

Bien souvent utilisée comme outils d'intégration et d'échange entre les différentes parties de projets scientifiques interdisciplinaires, la simulation numérique est en plein essor dans les sciences sociales, et notamment la simulation multi-agents. En effet, la capacité de calcul de plus en plus puissante des ordinateurs et les méthodes de recherche individu-centrées en sciences sociales (micro-économie ou individualisme méthodologique, pour ne citée que celles-ci) ont suscité un intérêt croissant pour la représentation logicielle de processus interagissant les un avec les autres dans le cadre d'un phénomène qualifié de complexe. Notre thèse se positionne ainsi dans ce contexte, plus particulièrement au niveau des relations causales entre des comportements microscopiques en interaction et un phénomène macroscopique émergeant. Notre travail de recherche s'inscrit dans un projet mené en collaboration avec des sociologues qui vise à rendre compte de phénomènes organisationnels. Plutôt que de s'emparer de cas empiriques et de produire des modèles ad'hoc, nous proposons une démarche innovante consistant à formaliser une théorie sociologique : la Sociologie de l'Action Organisée (SAO) de M. Crozier et E. Friedberg. L'intérêt d'une telle modélisation est de disposer d'un méta-modèle sociologiquement fondé permettant de modéliser de façon formelle différentes organisations relevant de son champ d'expertise. Nous proposons de mettre en œuvre cette formalisation via un laboratoire virtuel, SocLab, permettant d'éditer le modèle d'une organisation puis de mener des expériences et tester nos hypothèses. Du méta-modèle de la SAO à l'outil d'expérimentation SocLab, notre thèse propose une démarche méthodologique pour l'analyse organisationnelle assistée par l'expérimentation virtuelle. Dans la perspective d'analyser la causalité émergente des processus organisationnels, nous avons défini une série d'indicateurs numériques qui servent de base aux interprétations indispensables à la vérification et la validation d'un modèle. Ces indicateurs permettent de caractériser acteurs, relations, et transactions dans les termes de la SAO et de comparer différents modèles, d'une même organisation ou d'organisations différentes. Nous présentons ensuite un modèle d'agent adaptatif à base de règles qui rend compte du comportement stratégique des acteurs dont la rationalité est orientée vers la coopération tel que le postule la SAO. Nous présentons par ailleurs une méthodologie de validation des modèles de rationalité. Enfin nous illustrons notre démarche avec un cas d'étude issu du corpus SAO, que nous modélisons, soumettons à diverses hypothèses, que nous interprétons et (in)validons par la simulation. Outre la démarche de formalisation de la SAO et le développement du laboratoire virtuel SocLab, la thèse présente de nombreuses originalités que ce soit au niveau des concepts développés autour de l'échange et de la coopération, au niveau du modèle d'agent stratégique-coopératif, ou au niveau des outils d'analyse produits ou mis en œuvre. L'intérêt principal réside dans le développement d'une démarche rigoureuse couvrant de nombreux aspects de l'utilisation de l'expérimentation virtuelle en sociologie qui devrait permettre au chercheur, à l'étudiant comme aux consultants en organisation de produire des raisonnements solides sur le /phénomène organisation/.

Shape Memory Alloys (SMA) are a group of metallic alloys that have the ability to return to some previously defined shape or size when subjected to an appropriate thermal cycling procedure. In recent years there has been a lot of research on the development of small, light and, yet, powerful actuators for use in areas like robotics, prosthetics, biomimetics, shape control and grippers. Many of the miniaturized conventional actuators do not have sufficient power output to be useful and SMAs can be used advantageously here. The widespread use of SMAs in actuators is limited by their low bandwidth. Use of SMAs in two-way actuators requires that they undergo thermal cycling (heating and cooling). While SMAs can be heated quickly by resistive heating, conventional convection cooling mechanisms are much slower as the exothermic austenitic to martensitic phase transformation is accompanied by the release of significant amount of latent heat. While a number of cooling mechanisms have been studied in SMA actuator literature, most of the cooling mechanisms involve unidirectional forced convection. This may not be the most effective method. Oscillating flow in a channel can sometimes enhance heat transfer over a unidirectional flow. One possible explanation for this heat transfer enhancement is that the oscillatory flow creates a very thin Stokes viscous boundary-layer and hence a large time-dependent transverse temperature gradient at the heated wall. Therefore heat transfer takes place at a large temperature difference, thereby enhancing the heat transfer. In this work, the heat transfer from an SMA actuator under an oscillating channel is investigated and is compared to steady, unidirectional flow heat transfer. Oscillating flow is simulated using a finite volume based method. The resulting velocity field is made use of in solving the heat transfer problem using a finite difference scheme. A parametric study is undertaken to identify the optimal flow conditions required to produce the maximum output for a given geometry of the SMA actuator. The latent heat of transformation of the SMA is accounted for by means of a temperature dependent specific heat.