This document deals with the development of drilling tools by means of CAD and CAE technologies. At first, a brief overview of various design procedures of 3D drill models is presented, possibilities of measurement of force and moment loading during drilling are mentioned, a chip formation mechanism is briefly described and then a list of commonly used explicit (mesh) finite element methods used for cutting simulations is presented. A meshless SPH method have been selected for this work. Although it is able to handle the large deformations easily, it has been used for cutting simulations very rarely and only an orthogonal cutting simulations related information can be found in scientific databases. It has been demonstrated on the orthogonal cutting simulation of A2024-T351 alloy that was also the starting point for SPH simulation of drilling. The following is a decription of the design, simulation and prototyping of new drilling tools - drills with three and two cutting edges and an internal chip channel. This document is focused in detail on the variant with two cutting edges for which SPH drilling simulation has also been performed. Some drawbacks related to more precise chip simulation demands have been revealed, especially a rapid increase in number of SPH elements followed with prolongation of a computational time. Information related to the design of the drilling head with two cutting edges were then used to create the patent application.

This diploma thesis is focused on the concept of threaded connection of the turbine wheel and shaft. At the beginning are described current welding methods of the turbine wheel and shaft connections as well as methods of the compressor wheel and shaft connections. Four possible concepts were designed and evaluated, and the best concept was chosen. For this concept was calculated tightening torque and concept was evaluated in terms of turbocharger operating conditions.

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La douleur neuropathique est un syndrome secondaire à une maladie ou à une lésion affectant le système nerveux somatosensoriel. Environ 30% des patients souffrant de douleurs neuropathiques présentent des troubles de l’humeur. Les causes biologiques de ces comorbidités ne sont pas clairement établies. Grâce à l’utilisation d’un modèle murin de douleur neuropathique, nous avons cherché à comprendre l’apparition des conséquences émotionnelles de cette douleur. Pour cela, nous avons cherché à identifier des régions cérébrales impliquées dans les différentes composantes et conséquences de la douleur ainsi que les modifications moléculaires y prenant place. Nous avons mis en évidence une ségrégation corticale de la douleur avec l’intégration de la composante sensorielle par le cortex insulaire postérieur d’une part et l’intégration de la composante aversive et des conséquences émotionnelles par le cortex cingulaire antérieur d’autre part. Nous avons ensuite montré l’implication de la protéine MKP-1 dans l’expression des comportements de type anxiodépressif dans notre modèle. / Neuropathic pain is defined as a pain caused by a lesion or disease of the somatosensory nervous system. Around 30% of neuropathic pain patients develop mood disorders. The biologic bases of these comorbidities are not clearly established. Using a murine model of neuropathic pain, we tried to understand the emotional consequences of neuropathic pain. Thus, we identified cerebral regions involved in the different components of pain and molecular modifications taking place in these regions. We showed a cortical separation of the pain experience with on one hand the integration of the sensory component of pain in the posterior insular cortex and on the other hand the integration of the aversive component and the emotional consequences of pain in the anterior cingulate cortex (ACC). Looking at the molecular modifications in the ACC, we showed that MKP-1, a protein able to dephosphorylate the MAPK, is involved in the development of pain-related mood disorders in our model of neuropathic pain.

This thesis is focused on behavior of control arm opening with bushing pressed in. The tested component is a part of control arm of a car. The parts were tested in tensile and compressive strength. Real experiments were measured by optical system Aramis during the testing to determine deformations of the part. These tests are also modeled by a finite element method using an Abaqus software. In GOM Correlate software is created full-field comparison of deformation results from Aramis and FEA. Based on this comparison computational model is calibrated. Sensitivity analysis is performed at the end of the thesis.

Platelet-derived growth factor (PDGF) is a family of signaling molecules that stimulates cell growth, survival and migration. PDGF is recognized by specific transmembrane proteins, the PDGF receptors, which relay the signals to the cell activating the Mitogen-activated protein (MAP) kinases and other signaling pathways. Aberrant activation of these pathways is frequently detected in cancer. Hence, the study of these processes is essential for identifying potential drug targets or diagnostic markers. In paper I, we identified Receptor Subfamily 4 Group A Member 1 NR4A1 to be regulated by PDGF via MAP kinases, clarifying the role of Extracellular signal–regulated kinases (Erk) 1/2, Erk5 and Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in its regulation. NR4A1 was found to be important for the tumorigenic potential, measured as anchorage-independent growth, of glioblastoma cells. Since the cellular responses elicited by PDGF result from the balance between phosphorylation and dephosphorylation events, we investigated the role of the dual specificity phosphatases DUSP4/MKP-2 and DUSP6/MKP-3. In paper II, we describe the crucial role of Erk1/2 and p53 in the expression of DUSP4/MKP2. Moreover, we observed that DUSP4/MKP-2 downregulation decreases Erk5 activation and accelerates PDGFRβ internalization and downregulation resulting in a specific inhibition of Signal transducers and activators of transcription (Stat) 3, Src and protein kinase C (PKC), and partially of p38, Stat1/5 and Phoshoplipase Cγ (PLCγ). In paper III, we report that DUSP6/MKP-3 creates a negative cross-talk between Erk1/2 and Erk5 and an auto-inhibitory feedback loop on the PI3-kinase/Akt pathway. In paper IV, we identify a new regulative mechanism of the PDGF pathway. PDGF induces Erk5 expression and activation that modulates the PDGFRβ activity. After Erk5 downregulation, the receptor undergoes to a faster and stronger activation that results in a faster internalization and degradation. In conclusion, we present a mechanism through which the PDGF/MAP kinases support tumor growth, and elucidate different regulatory pathways involved in PDGF signaling.

In the first chapter of the thesis we present an introduction to the visco- plasticity and overview of the presented problems. The constitutive relation for Bingham fluid is derived and in the second chapter. Further there is demon- strated a procedure of proving existence and uniqueness with classical varia- tional method. This method is compared with the same process using modern implicit theory. The last chapter starts with summary of used problem formu- lations and used software. It is then followed by the main part with results of numerical simulations, both for the purpose of used formulations comparison and then verification of the preferred one in more complicated simulations. We expect a possible application of tested approaches on different materials. 1

Le TNF-α est une cytokine pro-inflammatoire du système immunitaire qui, lorsque sa production est déréglée, induit de nombreuses pathologies chez l’homme (cachexie, arthrite rhumatoïde, etc.) Outre une régulation transcriptionnelle de cette cytokine, il existe aussi une régulation post-transcriptionnelle permettant un contrôle affiné de sa production. Le laboratoire de Biologie du Gène étudie cette régulation post-transcriptionnelle faisant intervenir une séquence consensus dans l’ARNm appelée séquence AU-riche (ou ARE pour AU-rich element) et les protéines qui y sont impliquées. Généralement, les ARNm porteurs d’ARE codent pour des protéines dont l’expression est transitoire. Ces gènes requièrent un contrôle très précis de leur expression et c’est pourquoi, en plus d’être soumis à de nombreux contrôles transcriptionnels, la traduction et la stabilité de leurs ARNm sont très finement régulées. La réponse immune innée implique de nombreux ARNm de ce type. Jusqu’à présent, la fonction de la protéine TIAR dans la régulation de l’expression du TNF-α n’a pas été complètement élucidée. Outre le TNF-α, la participation à la réponse immune innée de nombreuses protéines encodées par des ARNm porteurs d’ARE pourrait conférer à la protéine TIAR un rôle de régulateur essentiel dans le contrôle de l’inflammation. Nous avons donc générés plusieurs lignées de macrophages RAW 264.7 surexprimant la protéine TIAR entière ou différents mutants de TIAR afin de déterminer, par une analyse globale par puces à ADN, les ARNm cibles de TIAR au cours de la réponse immune. Cette approche nous a permis de démontrer que la protéine TIAR exerce un contrôle sur le métabolisme de l’ARNm du TNF-α et de MKP-1 (MAP kinase phosphatase 1), une phosphatase majeure dans la voie de signalisation de la MAPK p38. Cette voie de signalisation joue un rôle essentiel dans la stabilisation et la traduction de nombreux ARNm porteurs d’ARE encodant des protéines de la réponse inflammatoire. D’autre part, nous avons voulu étudier in vivo la fonction de la protéine TIAR au cours de la réponse immune. Nous avons, dans ce but, généré des souris transgéniques surexprimant l’isoforme courte de la protéine TIAR. Si nous n’avons pas encore pu mesurer les effets d’une surexpression de TIAR sur la réponse inflammatoire chez ces souris, ces individus transgéniques ont révélé qu’une expression anormale de la protéine TIAR induit une létalité importante au cours du développement embryonnaire.

This thesis examines the issues associated with drumstick mechanical properties and possibilities of experimental methods and theoretical descriptions. Gradually, it focuses on the use of numerical methods to describe the behavior of musical instruments, especially percussion. The methodology explains the construction of a model drumstick and execution of modal analysis using a commercially available software ANSYS. The goal of the methodolgy is a comparison of natural frequencies and mode shapes for each alternative model. Design alternatives were also compared in terms of geometry, material composition and the impact on the natural frequencies and vibration shapes. The final step of this method was a creation of a modified drumstick model using composite materials.

This thesis deals with the issue of founding wooden structures above the ground level, i.e. with the existence of a crawl space between the ground and the floor structure. The thesis focuses on the utilisation of numerical methods for describing behaviour of the crawl space and its effects on temperature in adjacent structures. The methodology deals with the possibilities of determining thermal conductivity of air in the crawl space, which is a necessary input for a modal analysis in the ANSYS environment. Further, models with various levels of ventilation, crawl space shape, and material composition of the floor structure were constructed. These models served for monitoring temperature within the floor structure and for evaluating the level of influence of changed crawl space parameters.