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The innate immune pathways that stimulate the expression of cytokines and proapoptotic factors in response to infection are triggered by the activation of the cytosolic receptors retinoic acid-inducible gene I (RIG-I) and melanoma differentiationassociated gene 5 (MDA5). Activation of both receptors occurs as a result of binding to RNA. MDA5 only recognizes double stranded forms of RNA, whereas RIG-I is capable of recognizing both single and double stranded RNA. In vivo, MDA5 is known to be stimulated by long (>1 kb) strands of RNA, forming filaments along the phosphate backbone. However, the manner in which MDA5 can recognize the terminal end of its RNA ligand is uncertain. I have examined the mechanism of binding of the MDA5 protein by comparing MDA5 binding to short (<18 bp) blunt RNA, 5’ triphosphate RNA, and RNA with a 3’ or 5’ overhang. It is shown that while the MDA5 protein regulatory domain (RD) is essential for RNA recognition, the MDA5 RD only weakly recognizes short double stranded RNA ligands with overhangs or a 5’ triphosphate group. The Cys951 residue was shown to disrupt stability of the MDA5 RD-RNA complex. Binding analyses were performed using a combination of SDS-PAGE, gel filtration analysis, and nondenaturing gel electrophoresis. In addition, structural data was gathered by crystallization of the MDA5 RD-RNA complex using X-ray crystallography. These results help to establish the manner in which MDA5 is regulated predominantly to the binding of long RNA ligands. Also included in this document is structural data on the dimer form of the PepQ protein from E. coli. PepQ is a highly conserved proline peptidase that has a secondary activity of hydrolyzing organophosphorus triesters, toxic compounds found in many pesticides. The PepQ protein was crystallized and analyzed by X-ray diffraction. The dimer interface was clearly defined within the structure and provides insight into how the active dimer forms from the PepQ monomer.

Automotive transmission rattle is the noise generated due to impacts between manual transmissions meshing gear teeth in the presence of backlash. It is considered to be a Noise, Vibration and Harshness (NVH) phenomenon and is originated due to combustion irregularities (engine order vibrations), especially in diesel vehicles. This thesis focuses in the case of creep rattle for the MMT6 Ford Getrag transmission (six speeds plus reverse) with a DW10b, 4-cylinder, 4-stroke, 2.0 litres diesel engine. This particular rattle condition is fundamentally similar to any other where an engaged gear is pertained (drive, over-run or float), with the 1st or 2nd gear engaged at a very low engine speed. The numerical models include an initial single degree of freedom (DoF) simulation. It comprises either of the engaged gear pair under Hertzian contact conditions or of a loose gear pair under hydrodynamic regime of lubrication. Once the validity of this model is established and correlated with the results obtained from a single gear pair test rig, simulations of increasing complexity can be envisaged. A 7 DoF numerical model is, therefore, developed. The Hertzian contact model still prevails for the engaged gear pair, whereas an analytical hydrodynamic solution is implemented for the remaining 6 loose gear wheels and Petrov s law is applied to the needle bearings retaining the gear wheels. With the aim of accommodating a fully lubricated model of all the tribological conjunctions, an analytical elastohydrodynamic (EHL) Grubin type algorithm is employed. Also, the energy equation is analytically solved for hydrodynamic and elastohydrodynamic conjunctions, based on the assumptions dictated by the Peclet number. Therefore, under hydrodynamic conditions, the energy equation is governed by viscous heating and convective cooling, whereas in the EHL conjunctions the governing terms are viscous and compressive heating, together with conductive cooling. The retaining needle bearings follow the same heat generation mechanism as journal bearings. The effective viscosity, as obtained from the Houpert s equation accounting for pressure and thermal effects, is fundamental for the study of the friction in the contact. The hydrodynamic contacts are only governed by viscous friction, whereas EHL conjunctions exhibit asperity iv interactions as well as viscous effects. The results obtained from this new 7 DoF model are then compared to the experimental measurements taken from the vehicle tests and various purpose-built drivetrain rigs. A metric named Impulsion Ratio is hereby introduced, aiming to shed some light into the predictions obtained by the various models presented. This metric is the ratio of driving over resistive forces acting on each individual gear wheel. Its use is tested to predict single or double-sided rattle scenarios and, therefore, ascertaining higher and lower rattle levels. The 13 DoF model from which these conclusions were obtained includes shafts planar translation and rocking moments. The rolling element bearings supporting the shafts are, therefore, modelled to capture the inherent frequencies arising from their motion. The final model introduces the effects of transient thermo-elastohydrodynamics. This 7 DoF dynamic model accounts for a numerical solution of Reynolds equation with Elrod s cavitation algorithm for simultaneous teeth in mesh. The results obtained validate the previously used Grubin assumption by comparing the predicted central film thickness along the full mesh of one tooth. Also, the effect of starved input conditions and thermal and isothermal solutions are studied.

Le système immunitaire inné constitue la première barrière de défense du corps humain contre les agents infectieux. Constitue d'une poignée de récepteurs seulement (approximativement 50), ce système est capable de détecter la plupart des agents pathogènes et d'activer le système immunitaire adaptatif. Dans le cas d'une infection virale, deux classes de récepteurs sont mobilisées : les RLRs (Retinoic acid Like Récepteurs) et les TLRs (Toll Like Receptors). La famille des RLRs comprend notamment trois protéines, RIG-I, MDA-5 et LGP2, qui reconnaissent la présence d'ARN viral dans le cytosol. Dans la première partie de cette thèse, nous discuterons de la voie d'activation de RIG-I : avec quels type d'ARN et de quelle manière RIG-I interagit-il ? L'etat d'oligomerisation de RIG-I change-t-il lors de l'interaction avec l'ARN ? De quelle manière RIG-I est-il influence par l'ubiquitine et sa ligase E3, TRIM25 ? Nous présenterons egalement la structure du domaine PRYSPRY de TRIM25, domaine minimum nécessaire à l'interaction avec RIG-I. Nous d'écrirons également les travaux préliminaires obtenus sur un complexe constitue de MDA5 et une molecule d'inhibition virale. L'ARN des virus de la grippe est un des activateurs du récepteur RIG-I. Les virus de la grippe appartiennent 'a la famille des Orthomyxoviridae qui touche les mammifères et les aves créant des épidémies saisonnières. Ces dernières peuvent causer jusqu'à plusieurs millions de morts lors de pandémies, soulignant le besoin de trouver de nouvelles solutions thérapeutiques. Dans la seconde partie de ma thèse, nous nous intéresserons à l'activité endonucléase de l'ARN polymérase du virus A/California/04/2009-H1N1 de la grippe porcine comme une cible pour de nouvelles molécules antivirales. Les structures de quatre inhibiteurs en complexe avec ce domaine seront présentés. Nous présenterons également la structure de PA-Nter avec les substrats rUMP et dTMP co-cristallisés dans le site actif. Toutes ces structures atomiques forment une base pour l'optimisation et la synthèse d'inhibiteurs.

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The increase of intelligent systems can be seen in every industry. Integrated sensors and processors are used with internal control systems to create better performance for mobile hydraulic applications. The report describes how an evaluation was made to see if the productivity of a drill rig could be increased. This was done by implementing a programmable hydraulic valve to control the hydraulic drilling functions. The productivity would be increased by reducing the downtime due to jamming in the drill hole. Jamming occur when the system does not compensate for changes in rock conditions. By conducting a series of tests in a controlled environment with simulated loads, the response time of the CMA system and original system could be determined and compared. The CMA system had a response time that was 60-64% faster than the original system. Two different implementations of a controller was tested. Ziegler-Nichols method was used to get the initial value of the PI parameters. The controller that was implemented onboard the valve’s CPU was considered more successfull to reduce jamming. A drill test was conducted to ensure that the programmable valve could handle a drilling procedure with the controller that was implemented onboard the valve’s CPU. The valve handled the drilling procedure well.

Nous présentons dans cette thèse en premier lieu la méthode de Bootstrap par permutation appliquée à la méthode des blocs maxima utilisée en théorie des valeurs extrêmes (TVE) univariée. La méthode est basée sur un échantillonnage particulier des données en utilisant les rangs des blocs maxima dont la distribution est présentée et introduite dans les simulations. Elle amène à une réduction de la variance des paramètres de la loi GEV et des quantiles estimés. En second lieu, on s’intéresse au cas où les observations sont indépendantes mais non identiquement distribuées en TVE. Cette variation dans la distribution est quantifiée en utilisant une fonction dite « skedasis function » notée c qui représente la fréquence des extrêmes. Ce modèle a été introduit par Einmahl et al. dans le papier « Statistics of heteroscedastic extremes ». On étudie plusieurs modèles paramétriques pour c (log-linéaire, linéaire, log-linéaire discret) ainsi que les résultats de consistance et de normalité asymptotique du paramètre θ représentant la tendance. Le test θ =0 contre θ ≠0 est interprété alors comme un test de détection de tendance dans les extrêmes. Nous illustrons nos résultats dans une étude par simulation qui montre en particulier que les tests paramétriques sont en général plus puissants que les tests non paramétriques pour la détection de la tendance, d’où l’utilité de notre travail. Nous discutons en plus le choix du seuil k en appliquant la méthode de Lepski. Enfin, nous appliquons la méthodologie sur les données de températures minimales et maximales dans la région de Fort Collins, Colorado durant le 20ème siècle afin de détecter la présence d’une tendance dans les extrêmes sur cette période. En troisième lieu, on dispose d’un jeu de données de précipitation journalière maximale sur 24 ans dans 40 stations. On réalise une prédiction spatio-temporelle des quantiles correspondants à un niveau de retour de 20 ans pour les précipitations mensuelles dans chaque station. Nous utilisons des modèles de GEV en introduisant des covariables dans les paramètres. Le meilleur modèle est choisi en termes d’AIC et par la méthode de validation croisée. Pour chacun des deux modèles choisis, nous estimons les quantiles extrêmes. Finalement, on applique la TVE unvariée et bivariée sur les vitesses du vent et la hauteur des vagues dans une région au Liban en vue de protéger la plateforme pétrolière qui y sera installée de ces risques environnementaux. On applique d’abord la théorie univariée sur la vitesse du vent et la hauteur des vagues séparément en utilisant la méthode des blocs maximas pour estimer les paramètres de la GEV et les niveaux de retour associés à des périodes de retour de 50, 100 et 500 années. Nous passons ensuite à l’application de la théorie bivariée afin d’estimer la dépendance entre les vents et les vagues extrêmes et d’estimer des probabilités jointes de dépassement des niveaux de retour univariés. Nous associons ces probabilités jointes de dépassement à des périodes de retour jointes et nous les comparons aux périodes de retour marginales. / We firstly present in this thesis the permutation Bootstrap method applied for the block maxima (BM) method in extreme value theory. The method is based on BM ranks whose distribution is presented and simulated. It performs well and leads to a variance reduction in the estimation of the GEV parameters and the extreme quantiles. Secondly, we build upon the heteroscedastic extremes framework by Einmahl et al. (2016) where the observations are assumed independent but not identically distributed and the variation in their tail distributions is modeled by the so-called skedasis function. While the original paper focuses on non-parametric estimation of the skedasis function, we consider here parametric models and prove the consistency and asymptotic normality of the parameter estimators. A parametric test for trend detection in the case where the skedasis function is monotone is introduced. A short simulation study shows that the parametric test can be more powerful than the non-parametric Kolmogorov-Smirnov type test, even for misspecified models. We also discuss the choice of threshold based on Lepski's method. The methodology is finally illustrated on a dataset of minimal/maximal daily temperatures in Fort Collins, Colorado, during the 20th century. Thirdly, we have a training sample data of daily maxima precipitation over 24 years in 40 stations. We make spatio-temporal prediction of quantile of level corresponding to extreme monthly precipitation over the next 20 years in every station. We use generalized extreme value models by incorporating covariates. After selecting the best model based on the Akaike information criterion and the k-fold cross validation method, we present the results of the estimated quantiles for the selected models. Finally, we study the wind speed and wave height risks in Beddawi region in the northern Lebanon during the winter season in order to protect the oil rig that will be installed. We estimate the return levels associated to return periods of 50, 100 and 500 years for each risk separately using the univariate extreme value theory. Then, by using the multivariate extreme value theory we estimate the dependence between extreme wind speed and wave height as well as joint exceedance probabilities and joint return levels to take into consideration the risk of these two environmental factors simultaneously.

The Gravity Control for Maya will be extraordinary beneficial to an animator trying to create realistic animation, by calculating the center of gravity and area of balance. This control will provide the animator with the ability to rotate around the center of gravity and keep the character in a balanced pose. With that ability, the animator can easily create accurate poses and animation, such as mid-air flips. The system also supports a vast number of characters with different shapes, sizes and number of limbs.

This project consists of a prototype of a stereo camera rig where you can mount two DSLR cameras, and a multithreaded software application, written in C++, that can move the cameras, change camera settings and take pictures. The resulting 3D-images can be viewed with a 2-view autostereoscopic display. Camera position is controlled by a step engine which is controlled by a PIC microcontroller. All communication with the PIC and the computer is made over USB. The camera shutters are synchronized so it is possible to take pictures of moving objects at a distance of 2.5 m or more. The results shows that there are several things to do before the prototype can be considered a product ready for the market, most of all the camera callback functionality. / Detta projekt består av en stereokamerarigg som kan bestyckas med två DSLR-kameror, samt en applikation indelad i flera trådar (multithreaded) , skriven i C++, som kan förflytta kamerorna på riggen, ändra fotoinställningar och ra bilder. Resultatet blir 3D-bilder som kan ses på en autostereoskopisk skärm. Kamerornas position kontrolleras med en stegmotor, som i sin tur styrs av en PIC-mikrokontroller. Kommunikationen mellan PIC-enheten och datorn sker via USB. Slutarna på kamerorna är synkroniserade så det är möjligt att ta bilder på objekt i rörelse på ett avstånd av 2,5 m eller mer. Resultaten visar att det är flera punkter som måste åtgärdas på prototypen innan den kan anses vara redo för marknaden. Den viktigaste punkten är att kunna få fungerande respons (callback) från kamerorna.

Road vehicle tyres, railway wheels and ball bearings all generate rolling contact forces which are transferred within a finite area of contact between the rolling element and the substrate. Either it is visible or not for the human eye, a certain degree of roughness is always present on the contacting surfaces and it influences the generation of both vertical and lateral contactforces. The purpose of this investigation is to enhance the understanding and modelling of the influence from small-scale surface roughness on the generation of rolling contact forces. To this end, a computationally efficient method to include roughness-induced contact nonlinearities in the dynamic modelling of rolling contacts is proposed. The method is implemented in a time domain model for vertical wheel–track interaction to model rolling-induced rail vibrations, showing good agreement with measurements. Furthermore, a test rig is developed and used for the investigation of tyre–road rolling contact forces. Detailed studies are performed on the influence of substrate roughness on the resulting contact forces for a tyre tread block which is rolling at different operating conditions. The choice of substrate as well as the rolling velocity and the slip ratio is observed to have significant influence on the resulting friction coefficient. For high slip ratios, stick–slip oscillations appear, exhibiting frequency content which is largely dependent on the choice of substrate. The outcomes of this study can potentially be used to improve future tyre–road contacts with respect to wear, traction and noise generation. / <p>QC 20161013</p> / Centre for Eco2 Vehicle Design