La dystrophie musculaire est une maladie génétique monogénique récessive liée au chromosome X. Elle atteint 1 garçon sur 3500 naissances mâles. Le garçon atteint de la maladie présente des troubles de la locomotion à l’âge de 3-4 ans et la perd vers l’âge de 11 ans. La mort survient entre 18-30 ans suite à des complications cardio-pulmonaires. Il n’existe pas à ce jour un traitement curatif efficace contre cette grave maladie. Nous avons développé une approche de thérapie génique appelée CRISPR-induced deletion (CinDel) pour corriger le gène DMD muté. Elle utilise deux ARNg qui ciblent les exons précédant et suivant la délétion responsable du décalage du cadre de lecture. La reconnaissance des sites ciblés par les deux ARNg permet le recrutement de la nucléase Cas9 qui génère des coupures double-brin. Les séquences exoniques et introniques situées entre les deux coupures sont ensuite délétées. Les restes des exons sont joints par la recombinaison non homologue (NHEJ) pour produire un exon hybride, rétablir le cadre de lecture et permettre la synthèse d’un edystrophine tronquée ayant une structure correcte des répétitions de type spectrine (Spectrin-Like Repeat: SLR) et des heptades. Cette approche CinDel a été utilisée dans le cadre de ce projet d’abord pour corriger le gène DMD muté dans les myoblastes d’un patient avec une délétion des exons 51-53. Les exons 50 et 54 ont été ciblés avec deux ARNg et la Spcas9 pour produire des coupures double-brin et déléter les séquences situées entre ces deux sites et produire par NHEJ un exon hybride 50-54. L’approche a également permis de corriger in vivo le gène DMD muté dans le modèle animal, la souris transgénique avec un gène DMD humain ayant une délétion de l’exon 52 (del52hDMD) en utilisant un vecteur viralAAV9 contenant le gène SpCas9 et deux ARNgs. Pour vérifier la localisation par rapport au sarcolemme de la dystrophine tronquée avec ou sans une structure correcte des SLR et des heptades, nous avons électroporé les muscles Tibialis anteriorde souris mdx/mdx avec des plasmides codant pour les gènes normal et tronqué de la dystrophine fusionnée avec le gène de l’EGFP. Les résultats de cette expérience montrent que les dystrophines tronquées et normale se localisent correctement sous le sarcolemme. En vue de réprimer efficacement le gène de la SpCas9 et éviter son expression prolongée qui peut être à la base de coupures aléatoires et inattendues (off-target effects) dans le génome, nous avons mis au point une méthode de répression appelée Hara-Kiri moléculaire. Elle utilise la méthode CinDel et consiste à cibler deux régions du gène de SpCas9 avec deux ARNg. Le recrutement de la nucléase permet à celle-ci de couper son propre gène (Hara-Kiri). La séquence située entre les deux sites de coupures est délétée. Par NHEJ, les restes du gène de SpCas9 sont joints en générant un codon stop TAA au point de jonction. Cette approche a permis de réprimer efficacement le gène de SpCas9 in vitro et in vivo / Duchenne Muscular Dystrophy (DMD) is an X-linked genetically recessive genetic disorder. It affects 1 boy out of 3500 male births. The boy with the disorder presents walking disorders at the age of 3-4 years and loses it around the age of 11. Death occurs around 18-30 years of age from cardiopulmonary complications. To date, there is no effective cure for this serious disease. We have developed a gene therapy approach called CRISPR-induced deletion (CinDel) to correct the mutated DMD gene. It uses two gRNAs that target the exons preceding and following the deletion responsible for the frame shift. The recognition of the target sites by the two gRNAs allows the recruitment of the Cas9 nuclease, which generates double-strand breaks. The exonic and intronic sequences located between the two cuts are then deleted and the remains of the exons are fused by Non-Homologous End Joining (NHEJ) to produce a hybrid exon and restore the reading frame and to allow the synthesis of the truncated dystrophin with correct SLR structure and heptads. The CinDel approach was used in this project to correct the mutated DMD gene in the myoblasts of a patient with a 51-53 deletion. Exons 50 and 54 were targeted by SpCas9 and two gRNAs and to produce double strand breaks, delete the sequences between the two cleavage sites and produce a hybrid exon 50-54 by NHEJ. This restored the normal reading frame and allowed the expression of truncated dystrophin in the patient's myotubes. The approach also made it possible to correct in vivo the mutated DMD gene in the animal model, the transgenic mouse with a human DMD gene having a deletion of exon 52 (del52hDMD) using an AAV9 viral vector containing the SpCas9 gene and two ARNgs. To verify the location with respect to the sarcolemma of truncated dystrophin with or without a correct SLR structure and heptads, we electroporated the Tibialis anterior muscles of mdx/mdx mice with the plasmids encoding the normal or the truncated dystrophin gene fused with the eGFP gene. The results of this experiment show that truncated and normal dystrophins were well localized under sarcolemma. In order to effectively repress the SpCas9 gene and avoid its prolonged expression that may be the basis of random and unexpected (off-target effects) cuts in the genome, we have developed a method of repression called molecular Hara-Kiri. It uses the CinDel method and consists of targeting two regions of the SpCas9 gene with two gRNAs. Recruiting nuclease allows it to cut its own gene (Hara-Kiri). The sequence between the two cleavage sites is deleted. The residues of the SpCas9 gene are then joined by NHEJ generating a TAA stop codon at the junction point. This approach effectively repressed the SpCas9 gene in vitro and in vivo.

With the traditional fracture mechanics approaches, an initial crack and self-similar progression of cracks are assumed. In this treatise, theoretical and numerical tools are developed to mathematically describe non-self-similar progression of cracks without specifying an initial crack. A cohesive-decohesive zone model, similar to the cohesive zone model known in fracture mechanics as Dugdale-Barenblatt model, is adopted to represent the degradation of the material ahead of the crack tip. This model unifies strength-based crack initiation and fracture based crack progression. The cohesive-decohesive zone model is implemented with an interfacial surface material that consists of an upper and lower surface connected by a continuous distribution of normal and tangential nonlinear elastic springs that act to resist either Mode I opening, Mode II sliding, Mode III sliding, or mixed mode. The initiation of fracture is determined by the interfacial strength and the progression of fracture is determined by the critical energy release rate. The material between two adjacent laminae of a laminated composite structure or the material between the adherend and the adhesive is idealized with an interfacial surface material to predict interfacial fracture. The interfacial surface material is positioned within the bulk material to predict discrete cohesive cracks. The proper work-conjugacy relations between the stress and deformation measures are identified for the interfacial surface theory. In the principle of virtual work, the interfacial cohesive-decohesive tractions are conjugate to the displacement jumps across the upper and lower surfaces. A finite deformation kinematics theory is developed for the description of the upper and lower surface such that the deformation measures are invariant with respect to superposed rigid body translation and rotation. Various mechanical softening constitutive laws thermodynamically consistent with damage mechanics are postulated that relate the interfacial tractions to the displacement jump. An exponential function is used for the constitutive law such that it satisfies a multi-axial stress criterion for the onset of delamination, and satisfies a mixed mode fracture criterion for the progression of delamination. A damage parameter is included to prevent the restoration of the previous cohesive state between the interfacial surfaces. In addition, interfacial constitutive laws are developed to describe the contact-friction behavior. Interface elements applicable to two dimensional and three dimensional analyses are formulated for the analyses of contact, friction, and delamination problems. The consistent form of the interface element internal force vector and the tangent stiffness matrix are considered in the formulation. We investigate computational issues related to interfacial interpenetration, mesh sensitivity, the number of integrations points and the integration scheme, mathematical form of the softening constitutive law, and the convergence characteristics of the nonlinear solution procedure when cohesive-decohesive constitutive laws are used. To demonstrate the predictive capability of the interface finite element formulation, steadystate crack growth is simulated for quasi-static loading of various fracture test configurations loaded under Mode I, Mode II, Mode III, and mixed-mode loading. The finite element results are in agreement with the analytical results available in the literature and those developed in this work. A progressive failure methodology is developed and demonstrated to simulate the initiation and material degradation of a laminated panel due to intralaminar and interlaminar failures. Initiation of intralaminar failure can be by a matrix-cracking mode, a fiber-matrix shear mode, and a fiber failure mode. Subsequent material degradation is modeled using damage parameters for each mode to selectively reduce lamina material properties. The interlaminar failure mechanism such as delamination is simulated by positioning interface elements between adjacent sublaminates. The methodology is validated with respect to experimental data available in the literature on the response and failure of quasi-isotropic panels with centrally located circular cutouts. Very good agreement between the progressive failure analysis and the experiments is achieved if the failure analyses includes the interaction of intralaminar and interlaminar failures in the postbuckling response of the panels. In addition, ideas concerning the implementation of a fatigue model incorporated with a cohesive zone model are discussed. / Ph. D.

Although many selection techniques have been proposed and developed over the years, selection by pointing is perhaps the most popular approach for selection. In 3D interfaces, the laser-pointer metaphor is commonly used, since users only have to point to their target from a distance. However, the task of selecting objects that have a small visible area or that are in highly cluttered environments is hard when using pointing techniques. With both indirect and direct pointing techniques in 3D interfaces, smaller targets require higher levels of pointing precision from the user. In addition, issues such as target occlusion as well as hand and tracker jitter negatively affect user performance. Therefore, requiring the user to perform selection in a single precise step may result in users spending more time to select targets so that they can be more accurate (effect known as the speed-accuracy trade-off). We describe an approach to address this issue, called Progressive Refinement. Instead of performing a single precise selection, users gradually reduce the set of selectable objects to reduce the required precision of the task. This approach, however, has an inherent trade-off when compared to immediate selection techniques. Progressive refinement requires a gradual process of selection, often using multiple steps, although each step can be fast, accurate, and nearly effortless. Immediate techniques, on the other hand, involve a single-step selection that requires effort and may be slower and more error-prone. Therefore, the goal of this work was to explore this trade-off. The research includes the design and evaluation of progressive refinement techniques for 3D interfaces, using both pointing- and gesture-based interfaces for single-object selection and volume selection. Our technique designs and other existing selection techniques that can be classified as progressive refinement were used to create a design space. We designed eight progressive refinement techniques and compared them to the most commonly used techniques (for a baseline comparison) and to other state-of-the-art selection techniques in a total of four empirical studies. Based on the results of the studies, we developed a set of design guidelines that will help other researchers design and use progressive refinement techniques. / Ph. D.

As part of the Composite Technology for Exploration (CTE) project at NASA, woven fabric composites are being investigated for their use in Space Launch System (SLS) hardware. Composites are more difficult to analyze than isotropic materials and require more complex methods for predicting failure. NASA is seeking a method for predicting the damage initiation and propagation of woven fabric composites in order to utilize these materials effectively in SLS hardware. This work focuses on notched woven fabric composites under tensile loading. An analytical model consisting of a macro-level failure criterion and damage propagation was developed and implemented in explicit finite element analysis to simulate woven composite materials. Several failure criteria and propagation models were investigated and compared. A response surface was used to better understand the effects of damage parameters on the failure load of a specimen. The model chosen to have best represented the physical specimen used the Tsai-Wu failure criterion. Additional physical tests are needed to further validate the model. / Master of Science / A composite material consists of two or more different materials that are joined together to form a new material with improved properties. Woven fabric composites weave strips of fibers and a bonding material into a pattern to increase the material’s ability to withstand loads in various directions. NASA is seeking a method to predict the conditions under which woven fabric composites will break. A greater understanding of the capabilities of woven fabric composites will help NASA improve the structures involved in space exploration. This work attempts to build an analytical model that can predict the loads under which a woven fabric composite will break in tension. Several different analytical theories were used to model a woven fabric composite and the results were compared with lab tests. One of the theories, the Tsai-Wu failure criterion, was selected as the best representation of the physical specimen. Further additional physical tests are necessary to further validate the analytical model.

This study shows how the different ways of expressing the progressive in Jamaican Creole,using the three aspect markers a, de and gwain, differ from each other. It is a corpus study thatshows that these three particles that are used have different other functions and meanings. Itbriefly explains the history and grammar of the creole language along with what previousstudies state about the three aspect markers that are subject for this analysis.The aim of this study is to indicate that creole languages do not necessarily have tobe less complex, just because they are different from their original language. Each aspectmarker and its different functions are analyzed and compared to each other, as well ascontrasted with English, in order to see how and in what ways they differ.The results of the study show that there is a tendency towards a being morefrequently used as the progressive marker nowadays, but de used to be the most frequent one.Gwain has no other function apart from marking the progressive. These particles haveundergone a grammatical change through time. There does not seem to be any clear rules forin which contexts these markers should be used. The study concludes that Jamaican Creoledoes not seem to have a less complex way of expressing things, at least not the progressive,rather the opposite.

No description available.

Cette thèse traite de la modélisation et la diffusion de grandes scènes 3D naturelles. Nous visons à fournir des techniques pour permettre à des utilisateurs de naviguer à distance dans une scène 3D naturelle, tout en assurant la cohérence botanique et l'interactivité. Tout d'abord, nous fournissons une technique de compression multi-résolution, fondée sur la normalisation, l'instanciation, la décorrélation, et sur le codage entropique des informations géometriques pour des modèles de plantes. Ensuite, nous étudions la transmission efficace de ces objets 3D. L'algorithme de paquétisation proposé fonctionne pour la plupart des représentations multi-résolution d'objet 3D. Nous validons les techniques de paquétisation par des expériences sur un WAN (Wide Area Network), avec et sans contrôle de congestion (Datagram Congestion Control Protocol). Enfin, nous abordons les questions du streaming au niveau de la scène. Nous optimisons le traitement des requêtes du côté serveur en fournissant une structure de données adaptée et nous préparons le terrain pour nos travaux futurs sur l'évolutivité et le déploiement de systèmes distribués de streaming 3D. / This thesis deals with the modeling and the interactive streaming of large natural 3D scenes. We aim at providing techniques to allow the remote walkthrough of users in a natural 3D scene ensuring botanical coherency and interactivity.First, we provide a compact and progressive representation for botanically realistic plant models. The topological structure and the geometry of the plants are represented by generalized cylinders. We provide a multi-resolution compression scheme, based on standardization and instantiation, on difference-based decorrelation, and on entropy coding. Then, we study efficient transmission of these 3D objects. The proposed packetization scheme works for any multi-resolution 3D representation. We validate our packetization schemes with extensive experiments over a WAN (Wide Area Network), with and without congestion control (Datagram Congestion Control Protocol). Finally, we address issues on streaming at the scene-level. We optimize the viewpoint culling requests on server-side by providing an adapted datastructure and we prepare the ground for our further work on scalability and deployment of distributed 3D streaming systems.

Diploma thesis introduces the design of a functional part of a wine opener, focusing on simplicity and effectivity of the manufacturing process with the use of progressive stamping tool. The part will be made by technology of progressive cutting and bending. For the production of the specified part stainless steel coil marked as 17 241.4 will be used This material is suitable for the use in commercial gastronomy thanks to its qualities. Also in this thesis there are technical calculations, suggestios for of optimal tools, economic calculations, and technical-economic evaluation of the production of the specified part.

Intelligens handlar om förmågan att förstå, lösa problem, planera, tänka abstrakt, bearbeta information, tillgodogöra sig ny kunskap, samt förmågan att anpassa sig till sin miljö. Tidigare studier visar att kvällsmänniskor har högre IQ än morgonmänniskor. En orsak är att intelligenta personer är mer progressiva. Studier visar också att det inte finns könsskillnader i IQ. I denna studie undersöks om det finns ett samband mellan intelligens och dygnsrytm, samt mellan intelligens och faktiska sovtider. Ett annat syfte med denna undersökning var att undersöka om det finns skillnader i intelligens mellan män och kvinnor. Experimentet bistod av 250 deltagare, varav 151 kvinnor och 99 män i åldrarna 15-60. Ravens Standard Progressive Matrices användes för att mäta deltagarnas IQ. Morningness-Eveningness Questionnaire (MEQ) användes för att ta reda på deltagarnas dygnsrytm, och deltagarnas faktiska sovtider skrevs i timme och minut. Resultaten visade att kvällsmänniskor har i genomsnitt högre IQ än morgonmänniskor. Ett samband mellan deltagarnas faktiska sovtider och IQ fanns inte. Vidare visade resultaten att det inte finns någon skillnad i IQ mellan män och kvinnor.

Recent tragedies involving the collapse of several large and prominent buildings have brought international attention to the subject of progressive collapse, and the field of structural engineering is actively investigating ways to better protect structures from such catastrophic failures. One focus of these investigations is the behavior and performance of shear tab connections in steel structures during progressive collapse events. The shear tab, a simple connection, is typically modeled as a perfect pin in standard design, but in progressive collapse analysis, a much more accurate model of its true behavior and limits is required. This report documents the development of a simple yet accurate shear tab model and its use in understanding the behavior and limits of shear tab connections in column removal scenarios. Particular attention is paid to the connections’ axial force limit state, an aspect of behavior that is typically unimportant in standard design. / text