Les travaux concernent l'étude de l’assemblage dissimilaire d’alliages d'aluminium (Al4043, Al5356) et de magnésium (RZ5, AZ31) par les procédés CMT et laser. La méthode des plans d'expériences statistiques a été mise en oeuvre afin d'analyser les effets des paramètres opératoires de soudage et la nature chimique des substrats et des fils d’apport. Les effets chimiques, thermomécaniques et énergétiques ont été étudiés dans l'objectif de contrôler et de diminuer l’épaisseur de la couche intermétallique formée entre la zone fondue et le métal de base et considérée comme critique pour la fissuration. La microstructure a été caractérisée par microscopie optique, MEB, EDS, rayons X, dureté et nano-indentation.La rupture dans la couche d’interface est liée à la formation de composés intermétalliques (Al3Mg2, Al12Mg17), d'une dureté jusqu’à 350 HV0,025, ainsi qu'à l'épaisseur de la couche et des éléments d'alliage. Le RZ5 a été assemblé avec succès avec le fil d’apport Al4043 par les deux procédés CMT et laser.Suite à l’analyse systématique des résultats, qui montre un meilleur comportement d’Al4043/RZ5 qui contient du zirconium, l'ajout de cet élément dans la zone fondue a permis de montrer une amélioration de la qualité des joints par effet sur la microstructure.Pour l’assemblage laser, une modification des conditions des vitesses de refroidissement par un pompage thermique plus rapide par l’utilisation d’un support de plaques de cuivre a induit une modification des couches d'interface et montre tout l'intérêt de maîtriser les conditions opératoires. Par ailleurs, une vibration ultrasonore des substrats a été testée pour modifier la formation des zones problématiques / This work concern a study of the dissimilar joining of aluminium (Al4043, Al5356) and magnesium (RZ5, AZ31) by CMT and laser welding process. The method of statistical design of experiments has been implemented in order to analyse the effects of the technological welding parameters and the chemical nature of the base and filler metal. The chemical, thermo-mechanical and energetic effect were studied with the aim to control and decrease the thickness of the intermetallic layer formed between the melted zone and the base metal and considered to be critical to cracking. The microstructure was studied by optical and SEM microscopy, EDS, X-ray, hardness and nanoindentation.The fracture produced in the interface layer has been related to the intermetallic compounds (Al3Mg2 and Al12Mg17), with a hardness up to 350 HV0.025, as well of the thickness of the interface layer and to the alloying composition. The RZ5 as base metal was successfully joined with the Al4043 welding wire, in both CMT and laser process.According to the systematically analyse, who shows a better welding ability of the couples Al4043/RZ5, which contains zirconium, by the adding of this element in the molten metal the welding ability improvement was showed.For the laser joining, a modification of the cooling condition by a accelerate thermal cycle, by using a copper support for the base metal was induce a modification of the interface layer, showing the interest of mastering the technical condition. Moreover, a ultrasonically vibration of the base metal was tested in attempting to modify the formation of the problematical zones

La maladie de Charcot-Marie-Tooth (CMT) est une maladie neurologique héréditaire du système nerveux périphérique. A ce jour, près de 80 gènes sont décrits comme étant à l’origine d’une forme de CMT dont tous les modes de transmission sont connus. AR-CMT2A est due à une mutation faux-sens homozygote, c.892C>T, dans l’exon 5 du gène LMNA et conduit à la substitution d’une Arginine par une Cystéine (p.Arg298Cys) au sein d’un motif conservé du domaine central coil des Lamines de type A. L’étude présentée ici fait suite à un certain nombre d’observations ayant démontré la diminution de l’expression du gène dans les cellules de patients, et la perte d’interaction entre les Lamines A/C mutées et le facteur de transcription c-Jun. Or celui-ci participe au complexe régulateur AP-1 pour lequel le promoteur du gène LMNA possède deux éléments de fixation. L’ensemble du travail exposé dans ce manuscrit s’est donc basé sur l’hypothèse selon laquelle les Lamines de type A auraient la capacité de réguler leur propre expression et seraient capables, dans le nerf périphérique, d’établir des interactions avec des partenaires spécifiques du nerf périphérique. / Charcot-Marie-Tooth (CMT) disorders constitute a complex and heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities and electrophysiological changes. Genetically, CMT is characterized by a great heterogeneity, with all modes of inheritance and more than 50 genes described to date. My PhD work focuses on AR-CMT2A, a rare autosomal recessive axonal form of CMT, due to a unique homozygous missense mutation c.892C>T in LMNA exon 5, which leads to the substitution of an arginine by a cysteine (p.Arg298Cys) within a conserved motif in the central rod domain of A-type Lamins. My work aimed at providing clues toward a better understanding of the physiopathological mechanisms underlying AR-CMT2A and is based on previous results for my research team, showing a decrease in the expression of LMNA in patients’ cells, and a loss of interaction between A-type Lamins and the transcription factor c-Jun in patients’ cells. c-Jun is a member of the AP-1 complex, a well-known dimeric transcription factor, and for which interestingly, the LMNA promoter has two binding sites. All the work outlined in this manuscript is based on the hypothesis that A-type Lamins, have the capacity to regulate their own expression and therefore, are also most probably involved in interactions with partners involved in gene regulation, in particular in the Peripheral Nerve System.

Cell-type specific dendritic morphologies emerge via complex growth mechanisms modulated by intrinsic and extrinsic signaling coupled with activity-dependent regulation. Combined, these processes converge on cytoskeletal effectors to direct dendritic arbor development, stabilize mature architecture, and facilitate structural plasticity. Transcription factors (TFs) function as essential cell intrinsic regulators of dendritogenesis involving both combinatorial and cell-type specific effects, however the molecular mechanisms via which these TFs govern arbor development and dynamics remain poorly understood. Studies in Drosophila dendritic arborization (da) sensory neurons have revealed combinatorial roles of the TFs Cut and Knot in modulating dendritic morphology, however putative convergent nodal points of Cut/Knot cytoskeletal regulation remain elusive. Here we use a combined neurogenomic, bioinformatic, and genetic approach to identify and molecularly characterize downstream effectors of these TFs. From these analyses, we identified Formin3 (Form3) as a convergent transcriptional target of both Cut and Knot. We demonstrate that Form3 functions cell-autonomously in class IV (CIV) da neurons to stabilize distal higher order branching along the proximal-distal axis of dendritic arbors. Furthermore, live confocal imaging of multi-fluor cytoskeletal reporters and IHC analyses reveal that form3 mutants exhibit a specific collapse of the dendritic microtubule (MT) cytoskeleton, the functional consequences of which include defective dendritic trafficking of mitochondria and satellite Golgi. Biochemical analyses reveal Form3 directly interacts with MTs via the FH1/FH2 domains. Form3 is predicted to interact with two alpha-tubulin N-acetyltransferases (ATAT1) suggesting it may promote MT stabilization via acetylation. Analyses of acetylated dendritic MTs supports this hypothesis as defects in form3 lead to reductions, whereas overexpression promotes increases in MT acetylation. Neurologically, mutations in Inverted Formin 2 (INF2; the human ortholog of form3) have been causally linked to dominant intermediate Charcot-Marie-Tooth (CMT) disease E. CMT sensory neuropathies lead to distal sensory loss resulting in a reduced ability to sense heat, cold, and pain. Intriguingly, disruption of form3 function in CIV nociceptive neurons results in a severe impairment in nocifensive behavior in response to noxious heat, which can be rescued by expression of INF2 revealing shared primordial functions in regulating nociception and providing novel mechanistic insights into the potential etiological bases of CMT sensory neuropathies.

Submitted by Prieslei E. D. Goulart Santos (prieslei@ift.unesp.br) on 2017-12-07T16:59:31Z No. of bitstreams: 1 Thesis.pdf: 1801229 bytes, checksum: 71a64454056164c79eed45a9201789ac (MD5) / Submitted by Prieslei E. D. Goulart Santos (prieslei@ift.unesp.br) on 2017-12-11T18:47:11Z No. of bitstreams: 1 Thesis.pdf: 1801229 bytes, checksum: 71a64454056164c79eed45a9201789ac (MD5) / Submitted by Prieslei E. D. Goulart Santos (prieslei@ift.unesp.br) on 2017-12-14T11:25:03Z No. of bitstreams: 1 Thesis.pdf: 1801229 bytes, checksum: 71a64454056164c79eed45a9201789ac (MD5) / Submitted by Prieslei E. D. Goulart Santos (prieslei@ift.unesp.br) on 2017-12-14T13:50:32Z No. of bitstreams: 1 Thesis.pdf: 1801229 bytes, checksum: 71a64454056164c79eed45a9201789ac (MD5) / Approved for entry into archive by Hellen Sayuri Sato null (hellen@ift.unesp.br) on 2017-12-15T16:09:41Z (GMT) No. of bitstreams: 1 goulartsantos_ped_dr_ift.pdf: 1801229 bytes, checksum: 71a64454056164c79eed45a9201789ac (MD5) / Made available in DSpace on 2017-12-15T16:09:41Z (GMT). No. of bitstreams: 1 goulartsantos_ped_dr_ift.pdf: 1801229 bytes, checksum: 71a64454056164c79eed45a9201789ac (MD5) Previous issue date: 2017-11-21 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / No contexto de teorias de Einstein-Maxwell-dilaton, estudamos buracos negros, buracos de minhoca e aplicações à correspondência anti-de Sitter/Teoria de Matéria Condensada. Apresentamos a solução de buracos negro dyonica para a teoria de Einstein-Maxwell-dilaton escrita completamente em termos de constantes de integração, e então investigamos como definir parâmetros físicos dependentes e independentes. Escolhendo condições de contorno apropriadas para o dilaton no infinito, construímos buracos negros sem massa e uma ponte de Einstein-Rosen que satisfaz a condição de energia nula. Construímos uma solução carregada analítica de buraco de minhoca atravessável para a teoria de Einstein-Maxwell-phantom-dilaton que é livre de singularidades e conecta dois espaços de Minkowski. Usando o teorema de Gauss-Bonnet calculamos o ângulo de deflexão de um raio de luz que passa próximo este buraco de minhoca. Apresentamos o formalismo da função entropia de Sen e o aplicamos para o cálculo analítico da entropia do buraco negro extremo de uma teoria de supergravidade com N=8 em quatro dimensões. No contexto de holografia, calculamos coeficientes de transporte na presença de campos magnéticos para teorias com um termo topológico na ação. Definimos quantidades radialmente independentes subtraindo as correntes de magnetização, e então estudamos perturbações lineares em torno do horizonte a fim de expressar as condutividades elétrica, termoelétrica e térmica em termos de somente propriedades do horizonte. Combinamos as fórmulas para as condutividades com os dados do horizonte calculados usando o formalismo de Sen, e expressamos analiticamente as condutividades à temperatura zero para várias teorias cujas soluções de buraco negro não são conhecidas analiticamente. / In the context of Einstein-Maxwell-dilaton theory, we study black holes, wormholes and applications to the anti-de Sitter/Condensed Matter Theory correspondence. We present the dyonic black hole solution to the Einstein-Maxwell-dilaton theory written fully in terms of integration constants, and then investigate how to define dependent and independent physical parameters. Choosing appropriate boundary conditions for the dilaton at infinity, we construct massless black holes and an Einstein-Rosen bridge that satisfies the null energy condition. We construct an analytical charged traversable wormhole solution to the Einstein-Maxwell-phantom-dilaton theory which is free of singularities and connects two Minkowski spacetimes. Using the Gauss-Bonnet theorem we compute the deflection angle of a light ray passing close to this wormhole. We present the Sen's entropy function method and apply it to compute analytically the entropy of the extremal black hole of a gauged N=8 supergravity theory in four dimensions. In the holographic context, we compute the transport coefficients in the presence of magnetic fields for theories with a topological term in the action. We define radially independent quantities by subtracting off the magnetization currents, and then study linear perturbations around the horizon in order to express the electric, thermoelectric and heat conductivities in terms of horizon properties only. We combine the formulae for the conductivities with the horizon data computed using Sen's entropy function method, and express analytically the conductivities at zero temperature for several theories whose the full black hole solutions are not known analytically. / 2103/00140-7

This diploma thesis is focused on overall research of the quality of joining steel and aluminum alloy using the CMT welding process. The theoretical part describes the principle and the technology of the welding system that allows joining dissimilar materials by an electric arc. Attention is also given to other modes such as CMT Advanced, CMT Pulse and CMT Advanced Pulse, which further improve the innovative process. These modifications include an efficient tandem method CMT Twin that uses two electric arcs in various combinations. The main aim of the experiment is assessment of the quality of created CMT joints. Individual tests are conducted to evaluate the corrosion resistance in an aggressive environment (salt fog). The testing subsequently evaluates mechanical properties by a destructive tensile test to determine the tensile strength. Part of the quality assessment is metallographic analysis including determining the elemental composition of the weld.

Thesis deals with individual technology of new welding processes "specifically FRONIUS TPSi". The greatest emphasis is on welding technology, especially on the differences between the individual methods. The experimental part of the thesis is focused on finding suitable parameters for welding filled welds.Everythingwith respect to required welds quality welded by robotic welding. The samples were evaluated in terms of penetration depth, amount of heat introduced and the number of defects.

The purpose of this paper is to analyze weld joints made with the use of the CMT method. Two separate kinds of weld joints were used: one joining two pieces of titanium and another joining titanium with stainless steel. The theoretical part of this paper summarizes the basics of the CMT welding method and its modifications, the corrosion of metals, the tests used to determine the properties of the materials, the preparation of the metallographic cut and more detailed information on the materials used. The experimental part of this paper follows, dealing with precise specifications of the welding process, the materials and the conditions under which the subsequent tests were taken. Half of the samples undertook test in a salt corrosion chamber in order to determine the damage caused to the weld by the corrosion and to compare the results with the samples not exposed to the increased corrosive environment. Following that comes the evaluation part, where the results obtained from the tests undertaken are analyzed with the focus on the resulting formed, the strength test and the hardness of the weld and its surroundings.

This thesis is focused on the evaluation of hetereogeneous weld joints made by CMT technology using acoustic emission. The thesis is divided into four parts. The first one is focused on the describe CMT technology. The second part describe the principle of acoustic emission. The following part includes the methodology of experimental part. The final section deals with on the relation between the tensile strength of the samples with the measured values of acoustic emissions from the welding and cooling of the material.

Bei den Charcot-Marie-Tooth (CMT) Neuropathien handelt es sich um erbliche Erkrankungen des peripheren Nervensystems, die progredient zu motorischen und sensorischen Defiziten führen und für die bislang keine kausalen Therapieoptionen existieren. In verschiedenen Studien konnte gezeigt werden, dass Entzündungsreaktionen, insbesondere durch Lymphozyten und Makrophagen vermittelt, eine bedeutende Rolle bei der Pathogenese dieser Erkrankung spielen. Neben neuronaler und axonaler Schädigung, sowie Demyelinisierung ist in untersuchten Myelin Mutanten auch eine erhöhte Anzahl an denervierten neuromuskulärer Endplatten zu erkennen. Eine genetische Blockade der Makrophagen-Aktivierung konnte in den Studien eine Verbesserung sämtlicher neuropathologischer Merkmale bei gleichzeitig reduzierter Makrophagenanzahl zeigen. Ob und welche Rolle Makrophagen bei der Denervation neuromuskulärer Endplatten spielen, blieb bislang ungeklärt. In dieser Studie konnte in allen untersuchten Myelin Mutanten im Vergleich zum Wildtyp eine Zunahme an neuromuskulären Synapsen beobachtet werden, die mit Makrophagen räumlich assoziiert waren. Daneben zeigten entsprechende Myelin Mutanten eine Zunahme denervierter und partiell denervierter Endplatten und zwar interessanterweise direkt proportional zur Anzahl an Synapsen in Assoziation mit Makrophagen. Das bedeutet, dass die Anzahl an Endplatten in Assoziation mit Makrophagen verhältnismäßig parallel zur Anzahl an denervierten Endplatten zunahm, während die Anzahl an Makrophagen im gesamten Muskel nahezu unverändert blieb. Dies deutet eine mögliche Rolle der räumlich mit Endplatten assoziierten Makrophagen an deren Denervation an. Dabei waren alle Synapsen in Assoziation mit Makrophagen innerviert und damit morphologisch intakt. Bei doppel-mutanten Mäusen mit genetischer Blockade der Makrophagen-Aktivierung waren die beschriebenen pathologischen Merkmale an der neuromuskulären Synapse deutlich reduziert bei gleichzeitig signifikanter Abnahme an Makrophagen in Assoziation mit Endplatten. Ähnliche pathologische Auffälligkeiten wie bei Myelin Mutanten fanden sich in geringerer Ausprägung auch im Wildtyp im Rahmen des Alterungsprozesses sowie auch bei Mäusen mit Defizienz des neurotrophen Faktors CNTF. Zusammenfassend deuten die Ergebnisse darauf hin, dass sowohl in der Pathogenese der CMT Neuropathie wie auch im Rahmen altersbedingter Neurodegeneration ein Makrophagen-vermittelter Schaden an der neuromuskulären Endplatte entsteht. Wesentliche Mediatoren scheinen hierbei das von Fibroblasten und vermutlich auch perisynaptischen Fibroblasten exprimierte CSF-1 zu sein, sowie MCP-1, das durch Schwann Zellen und möglicherweise auch von terminalen Schwann Zellen freigesetzt wird. Auch eine Defizienz des neurotrophen Faktors CNTF bewirkt zumindest in geringem Ausmaß eine Zunahme der pathologischen Merkmale Denervation und Makrophagen-Endplatten-Assoziation im Vergleich zum Wildtyp. Diese Ergebnisse erweitern insbesondere das Wissen um Pathomechanismen an der neuromuskulären Endplatte und eröffnen neue Möglichkeiten der Behandlung für CMT und weitere neuromuskuläre Erkrankungen. / Charcot-Marie-Tooth (CMT) neuropathies are a group of hereditary diseases of the peripheral nervous system that progressively lead to motor and sensory deficits and for which currently no causal therapeutic options exist. Various studies revealed that inflammatory reactions, especially mediated by lymphocytes and macrophages, play a significant role in the pathogenesis of this disease. In addition to demyelination, neuronal and axonal damage, an increased number of denervated neuromuscular junctions were detected in myelin mutant mice. In these studies, a genetic blockade of macrophage activation induced an improvement in all neuropathological features with a simultaneous reduction in the number of macrophages. Whether and which role macrophages play in the denervation of neuromuscular endplates remained unclear by now. In this presented study, an increase in neuromuscular synapses spatially associated with macrophages was observed in all investigated myelin mutant mice compared to wild type mice. In addition, corresponding myelin mutants showed an increase in denervated and partially denervated endplates directly proportional to the number of synapses associated with macrophages. This means that the number of endplates in association with macrophages increased relatively in parallel with the number of denervated endplates, while the number of macrophages remained nearly unchanged throughout the skeletal muscle. This suggests a possible pathogenetic role of spatially endplate-associated macrophages in their denervation. All synapses in association with macrophages were innervated and thus morphologically intact. In dual mutant mice with a genetic blockade of macrophage activation, the described pathological features at the neuromuscular junction were significantly reduced with concomitant significant decrease in macrophages associated with endplates. Similar pathological abnormalities as in myelin mutants were found to a lesser extent also in the wild type in the context of the aging process as well as in mice with deficiency of the neurotrophic factor CNTF. In summary, these results suggest that macrophage-related damage of neuromuscular junctions occurs in both the pathogenesis of CMT neuropathy and in the context of age-related neurodegeneration. Important mediators seem to be CSF-1 expressed by fibroblasts and probably also perisynaptic fibroblasts, as well as MCP-1, which is released by Schwann cells and possibly also by terminal Schwann cells. Furthermore, a deficiency of the neurotrophic factor CNTF causes, at least to a small extent, an increase in the pathological features of denervation and macrophage-endplate association compared to the wild-type. In particular, these findings expand knowledge of pathomechanisms at the neuromuscular endplate and open up new treatment options for CMT and other neuromuscular diseases.

Dynein is a motor protein complex that transports various types of intracellular cargos from the cell periphery towards the cell center. Dynein mutations are linked to several neurodegenerative diseases, including Charcot-Marie-Tooth disease (CMT). A mouse model of CMT was generated with a knock-in H304R dynein allele. This mutation at position 304 corresponds to the H306R mutation found in humans that can cause CMT. Here, a behavioral test was developed to study the onset and progression of CMT symptoms in these mice. In the tail suspension test, mice were suspended briefly by their tails and the posture of their hind limbs was scored. Wildtype mice spread their hind limbs outwards in a characteristic splayed posture, whereas heterozygous and homozygous mutants display abnormal phenotypes. In further investigation, the neuromuscular junctions of these mice were analyzed in order to understand the histological effects of the mutation and how the potential differences could result in the behavioral effects observed. The extent of neuromuscular junction innervation was examined along with the size and complexity of the neuromuscular junctions themselves through multiple criteria. This, when combined with the effects observed during the tail suspension behavioral test, seeks to establish the H304R mutant mouse as a successful model for CMT.