Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause loss function of the CFTR channel on the apical surface of epithelial cells. ΔF508-CFTR, the major mutation in patients, is misfolded, retained in the endoplasmic reticulum (ER) and degraded. Small molecule corrector compounds partially rescue the trafficking defect of ΔF508-CFTR by allowing escape from the ER and trafficking to the plasma membrane where it exhibits partial function. These compounds may bind directly to the mutant protein and rescue the biosynthetic defect by inducing improved protein conformation. We tested this hypothesis by evaluating the consequence of corrector compound on the conformation of each nucleotide-binding domain (NBD) in the context of the full-length mutant protein in limited proteolytic digest studies. We found that VRT-325 was capable in partially restoring compactness only in NBD1. In comparison, ablation of the arginine framed peptide sequence: R553XR555 (ΔF508-KXK-CFTR) modified the protease resistance of NBD1, NBD2 and the full-length protein. Singly, each intervention led to a partial correction of the processing defect. Together these interventions restored processing of ΔF508-CFTR to near wild-type levels. Importantly however, a defect in NBD1 conformation persisted, as did a defect in channel activation after the combined interventions. This defect in channel activation can be fully corrected by addition of the potentiator: VX-770. The experiments performed partly elucidated ii the molecular mechanism of action for drug therapy and suppressor mutation. It is important to understand these basic concepts in hopes to layout a blue print for future drug design.

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause loss function of the CFTR channel on the apical surface of epithelial cells. ΔF508-CFTR, the major mutation in patients, is misfolded, retained in the endoplasmic reticulum (ER) and degraded. Small molecule corrector compounds partially rescue the trafficking defect of ΔF508-CFTR by allowing escape from the ER and trafficking to the plasma membrane where it exhibits partial function. These compounds may bind directly to the mutant protein and rescue the biosynthetic defect by inducing improved protein conformation. We tested this hypothesis by evaluating the consequence of corrector compound on the conformation of each nucleotide-binding domain (NBD) in the context of the full-length mutant protein in limited proteolytic digest studies. We found that VRT-325 was capable in partially restoring compactness only in NBD1. In comparison, ablation of the arginine framed peptide sequence: R553XR555 (ΔF508-KXK-CFTR) modified the protease resistance of NBD1, NBD2 and the full-length protein. Singly, each intervention led to a partial correction of the processing defect. Together these interventions restored processing of ΔF508-CFTR to near wild-type levels. Importantly however, a defect in NBD1 conformation persisted, as did a defect in channel activation after the combined interventions. This defect in channel activation can be fully corrected by addition of the potentiator: VX-770. The experiments performed partly elucidated ii the molecular mechanism of action for drug therapy and suppressor mutation. It is important to understand these basic concepts in hopes to layout a blue print for future drug design.

The Hobby-Eberly Telescope (HET)(+), located in West Texas at the McDonald Observatory, operates with a fixed segmented primary (M1) and has a tracker, which moves the prime-focus corrector and instrument package to track the sidereal and non-sidereal motions of objects. We have completed a major multi-year upgrade of the HET that has substantially increased the pupil size to 10 meters and the field of view to 22 arcminutes by deploying the new Wide Field Corrector (WFC), new tracker system, and new Prime Focus Instrument Package (PFIP). The focus of this paper is on the delivery, installation, and on-sky verification of the WFC. We summarize the technical challenges encountered and resolutions to overcome such challenges during the construction of the system. We then detail the transportation from Tucson to the HET, on-site ground verification test results, post-installation static alignment among the WFC, PFIP, and M1, and on-sky verification of alignment and image quality via deploying multiple wavefront sensors across 22 arcminutes field of view. The new wide field HET will feed the revolutionary new integral field spectrograph called VIRUS, in support of the Hobby-Eberly Telescope Dark Energy Experiment (HETDEX), a new low resolution spectrograph (LRS2), an upgraded high resolution spectrograph (HRS2), and later the Habitable Zone Planet Finder (HPF).

One challenge for Autonomous Underwater Vehicle (AUV) multibeam surveying is the limited ability to assess internal vertical agreement rapidly and reliably. Applying an external ellipsoid reference to AUV multibeam data would allow for field comparisons. A method is established to merge ellipsoid height (EH) data collected by a surface vessel in close proximity to the AUV. The method is demonstrated over multiple collection missions in two separate areas. Virtual tide corrector values are derived using EH data collected by a boat and a measured ellipsoid to chart datum separation distance. Those values are compared to measurements by a traditional tide gauge installed nearby. Results from the method had a mean difference of 6 centimeters with respect to conventional data and had a mean total propagated uncertainty of 15 centimeters at the 95% confidence interval. Methodologies are examined to characterize their accuracies and uncertainty contribution to overall vertical correction.

Dans ce mémoire, nous abordons le problème de la correction d'erreurs systématiques et de la recherche des composés prometteurs (i.e. «hits») dans les procédures de criblage à haut débit (HTS). Nous introduisons une nouvelle approche pour la correction des erreurs systématiques dans les procédures HTS et la comparons à quelques méthodes couramment utilisées. La nouvelle méthode, appelée «well correction» ou correction par puits, procède par une analyse des erreurs systématiques localisées au niveau des puits, à travers toute la procédure de criblage. Cette méthode permet une amélioration des résultats obtenus lors de la sélection des «hits», par des méthodes utilisant un seuil prédéfini. La correction par puits à montré des résultats supérieurs aux méthodes suggérées dans la littérature telles que: correction par soustraction de l'arrière-plan («background correction» : Kevorkov et Makarenkov, 2005a, 2005b); «median-polish» et «B score» (Brideau et al., 2003; Malo et al., 2006). Nous avons également comparé trois méthodes de recherche des «hits» utilisant des approches de groupement (i.e. «clustering»): k-mean; somme des distances inter-cluster moyennes (SASD) et distance moyenne entre clusters (AICD). Ces méthodes proposent des algorithmes différents pour mesurer la distance entre les données provenant du criblage. Les méthodes de groupement utilisant k-means et SASD ont montré des résultats intéressants, mais aucune des méthodes étudiées n'a montré des performances pouvant justifier son utilisation dans tous les cas de figure. Un logiciel, «HTS Corrector», a été développé dans le cadre de ce travail. Il intègre toutes les méthodes étudiées dans ce mémoire. D'autres fonctionnalités auxiliaires, pouvant aider le praticien dans l'analyse des résultats provenant d'une procédure HTS, ont aussi été intégrées. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Criblage à haut débit, High-throughput Screening, Erreurs systématiques, Correction de données, Méthodes de groupement, Recherche de hits, Normalisation de données.

To fulfill the requirements of the operation in a wide power range, a parallel configuration with modular power factor correctors (PFCs) is proposed. Each PFC module is composed of a bridge-rectifier, a fly-back converter and associated passive filters. The fly-back converter is independently operated at a fixed frequency with a discontinuous inductor current. This allows the modules to achieve a high power factor and to regulate the output power with simple control. With the same duty-ratio and frequency, the total current will be distributed equally to each operating module without complex current sharing control. The operating modules are equally phase-shifted to take the advantages of the continuous current mode when operated at a higher power. Experiments were conducted to achieve a power rating of 1 kVA by operating 10 PFC modules in parallel. The duty-ratio of the operating modules is controlled by a micro-controller to regulate the output power in accordance with the load requirement. A complex programmable logic device (CPLD) is used for phase-shifting. All modules are operated in turn to share the operating cycles in a more equal manner. Experimental results demonstrate the parallel configuration can achieve the expected performances.

Jednou z možností korekce sférické vady v elektronové mikroskopii je hexapólový korektor. Ačkoliv samotný princip korekce je poměrně dobře v literatuře popsán, jen relativně málo je věnováno samotnému seřízení hexapólového korektoru, jež je stěžejní pro správnou funkčnost. Práce je věnována analytickému rozboru vad seřízení a jejich vlivu na rozlišení obrazu za použití metody eikonálu a aberačních integrálů. Je ukázáno, že nejdůležitější roli v parazitických aberací hrají výchylky a náklon hexapólů. V závěru je pak popsáno, jakým způsobem je třeba hexapólový korektor seřídit pro odstranění parazitických vad.

A pitch-control predictor-corrector ascent guidance algorithm has been developed and evaluated for a rocket-based upper stage of a two-stage-to-orbit launch vehicle. Detailed descriptions of the predictor-corrector algorithm and a neural network loop modification are given. The mission requirement is insertion into a stable 50 x 100 nmi orbit at 375,000 ft altitude, coasting toward apogee at a positive inertial flight path angle. Three degree-of-freedom trajectory analysis is performed using the Program to Optimize Simulated Trajectories (POST2). Results of Monte Carlo simulations including uncertainties in atmosphere, thrust, aerodynamics and initial state are presented and compared to trajectories optimized for maximum injected weight. / Master of Science

Background: Lower incisor proclination has been shown to increase during Class II correction with appliances such as the Forsus. This lower incisor flaring shows great variability among patients. The purpose of this study was to evaluate the effects of Class II severity, mandibular growth, and occlusal plane rotation on lower incisor flaring in patients treated with the Forsus appliance. Materials and Methods: 121 records of Class II patients treated with the Forsus appliance were analyzed retrospectively. Cephalograms were traced at three time points. ANOVA was used to compare changes in cephalometric measurements over time. Pearson’s correlation was used to test for relationships between variables. Multiple regression tested for correlation between multiple variables. Results/Conclusions: Lower incisor flaring during Class II correction with the Forsus appliance was only weakly associated with sex, molar relationship change, and occlusal plane steepening. There was no correlation between the change in lower incisor proclination and mandibular growth.

Les systèmes électroniques embarqués à bord des aéronefs rassemblent des informations sur l’environnement qui les entourent au moyen de différents types de capteurs. À l’heure actuelle, l’acquisition des signaux générés par ces capteurs se fait au moyen de circuits électroniques d’interfaçage dédiés à un type de capteur en particulier, ce qui limite les possibilités d’évolution des calculateurs de bord.Nos travaux visent à remplacer ces circuits d’interfaçage par une interface dite versatile, capable de faire l’acquisition de signaux issus de différents types de capteurs. L’environnement dans lequel les systèmes avioniques sont amenés à fonctionner est particulièrement difficile, notamment par la présence de modes communs parasites importants, supérieures à plusieurs dizaines de volts. Après une exploration détaillée de cet environnement, nous proposons une architecture d’interface versatile, basée sur un ASIC mixte et un FPGA. L’ASIC est chargé du conditionnement analogique des signaux et de leur conversion dans le domaine numérique, et peut-être configuré à plusieurs niveaux (gains, offsets, impédances...). Le FPGA comprend les différents traitements numériques nécessaires à l’extraction de l’information contenue dans les signaux. Nous proposons de plus une méthode mixte permettant de corriger les imprécisions analogiques, telles que les défauts d’appairage, souvent critiques dans l’acquisition de signaux différentiels. Un circuit de test a été réalisé dans une technologie CMOS High Voltage 0.35µm afin de valider les différents principes proposés dans nos travaux. / Avionic embedded systems sense their environment through the use of various sensors. Currently, the electrical signals generated by these sensors are acquired by dedicated interface circuits, which limits the functionalities that can be implemented in the computer and slows down their evolution.Our work aims at replacing these interfacing circuits by a more flexible interface, called versatile interface, which has the ability to acquire different kind of signals. Avionic embedded systems usually operate in a pretty harsh environment, in which important common mode voltages of more than thirty volts can superimpose to useful signals. After a thorough exploration of this environment and its specifities, we propose an architecture of the versatile interface, based on a mixed signal ASIC and a FPGA. The ASIC includes a programmable analog signal conditioning stage which is able to withstand the high voltages present in the harsh avionic environment. The FPGA processes the different signals and extract the useful information from them. We also propose method which allows to correct the analog imprecisions due to mismatch or temperature drifts. This method uses analog and digital processing, and allow our versatile interface to be immune to process or temperature variations. A test circuit has been realized in a high voltage 0.35µm CMOS technology, in order to validate the different principles that we propose in this work.