Transglutaminases are a family of enzymes expressed in various tissues of our body. Some are expressed ubiquitously while others are specific to a tissue. Their primary catalytic activity is to crosslink substrates via an isopeptidic bond. The work described in this thesis focuses on two of these transglutaminases; human tissue transglutaminase (hTG2) and human factor XIIIa (FXIIIa). Divided into two projects for each enzyme, the main objective of this thesis was directed towards the discovery of potent and selective covalent inhibitors for each isozyme, namely hTG2 and hFXIIIa. The first project was concentrated on the inhibition of hTG2 activity. Ubiquitously expressed in tissues, hTG2 is a multifunctional enzyme. Its primary activity is the formation of isopeptide bonds between glutamine and lysine residues found on the surface of proteins or substrates. In addition to its catalytic activity, hTG2 is also a G-protein, distinguishing it from other members of the transglutaminase family. Much evidence illustrates that hTG2’s multifunctional abilities are conformationally regulated between its “open” and “closed” forms. Overexpression and unregulated hTG2 activity has been associated with numerous human diseases; however, most evidence has been collected for its association with fibrosis and celiac sprue. More recently, elevated hTG2 expression has been linked to cancer stem cell survival and metastatic phenotype in certain cancer cells. These findings call for the development of suitable and potent inhibitors that selectivity inactivate human hTG2 as a potential therapeutic target. Starting with previously designed acrylamide based peptidomimetic irreversible inhibitors, a structure-activity relationship (SAR) study was conducted. In this work, >20 novel irreversible inhibitors were prepared and kinetically evaluated. Our lead inhibitors allosterically inhibited GTP binding by locking the enzyme in its open conformation, as demonstrated both in vitro and in cells. Furthermore, our most potent and efficient irreversible inhibitors revealed selectivity for hTG2 over other relevant members of the transglutaminase family (hTG1, hTG3, hTG6 and hFXIIIa), providing higher confidence towards our goal of developing an ideal drug candidate. The second project was concentrated on the inhibition of hFXIIIa activity. In the blood, coagulation factor XIII (FXIII) is a tetrameric protein consisting of two catalytic A subunits (FXIII-A2) and two carrier/inhibitory B (FXIII-B2) subunits. It is a zymogen, which is converted into active transglutaminase (FXIIIa) in the final phase of coagulation cascade by thrombin proteolytic activity and Ca2+ binding. hFXIII is essential for hemostasis and thus its deficiency results in severe bleeding conditions. Further, hFXIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. Due to the enzyme’s involvement in the stability of blood clots, inhibition of hFXIIIa activity has been linked to thrombotic diseases. Furthermore, inhibitors of the enzyme have the therapeutic potential to be used as anticoagulant agents. The current number of selective and potent inhibitors of hFXIIIa are few, mainly due to the similarity between its catalytic pockets and hTG2. Inspired by a poorly reactive hTG2 inhibitor discovered in this work’s hTG2 SAR study, we synthesized a small library of covalent inhibitors for hFXIIIa. Our kinetic results from this pioneering SAR study will pave the way for future hFXIIIa inhibitor SAR studies.

The goal of this Master’s thesis is to develop a more realistic simulation of Synthetic Aperture Radar (SAR) that has the ability to image detailed targets, and that can be used for Automatic Target Recognition (ATR). This thesis project is part of ongoing SAR ATR research at California Polytechnic State University (Cal Poly) sponsored by Raytheon Space & Airborne Systems and supervised by Dr. John Saghri. SAR is a form of radar that takes advantage of the forward motion of an antenna mounted on a moving platform (such as an airplane or spacecraft) to synthetically produce the effect of a longer antenna. Since most SAR images used for military ATR are classified and not available to the general public, all academic research to date on ATR has been limited to a small data set of Moving and Stationary Target Acquisition and Recognition Radar (MSTAR) images. Due to the unavailability of radar equipment or a greater range of SAR data, it has been necessary to create a SAR image generation scheme in which the parameters of the radar platform can be directly modified and controlled to be used for ATR applications. This thesis project focuses on making several improvements to Matthew Schlutz’s ‘Synthetic Aperture Radar Imaging Simulated in Matlab’ thesis. First, the simulation is optimized by porting the antenna pattern and echo generator from Matlab to C++, and the efficiency of the code is improved to reduced processing time. A three-dimensional (3-D) graphics application called Blender is used to create and position the target models in the scene imaged by the radar platform and to give altitude, target range (range of closest approach from the platform to the center area of the target) and elevation angle information to the radar platform. Blender allows the user to take pictures of the target as seen from the radar platform, and outputs range information from the radar platform plane to each point in the image. One of the major advantages of using Blender is that it also outputs range and reflectivity information about each pixel in the image. This is a significant characteristic that was hardcoded in the previous theses, making those simulations less realistic. For this thesis project, once the target scene is created in Blender, an image is rendered and saved as an OpenEXR file. The image is rendered in orthographic mode, which is a form of projection whereby the target plane is parallel with the projection plane. This parameter means that the simulation cannot image point targets that appear and disappear during the platform motion. The echo generation program then uses the range and reflectivity obtained from the OpenEXR file, the optimized antenna pattern, and several other user defined parameters to create the echo (received signal). Once the echo is created in the echo generation program, it is then read into Matlab in order for it to go through the Range Doppler Algorithm (RDA) and then output the final SAR image.

N-Methylthio beta-lactams represent a promising new family of antibacterial agents whose in vitro activity is confined largely to Staphylococcus species, including multidrug-resistant forms of S. aureus. Originally developed in the 1980's for use as synthetic intermediates, N-methylthio beta-lactams have recently been shown in these laboratories to possess intriguing biological properties which are addressed in Chapters I-IV. In terms of the antibacterial activities, the structural features and species specificities exhibited by these compounds are unlike those of any existing family of beta-lactam drugs. The lactams seem to exert their effects intracellularly, requiring passage of the bioactive species through the cellular membrane, rather than acting extracellularly on cell wall components in the manner of penicillin and related antibiotics. The lipophilic nature of these molecules, which lack the polar side chain functionality of all other microbially-active Beta-lactams, suggests the compounds do not target the penicillin binding proteins within bacterial membranes. The most active members of this Beta-lactam class appear to be those bearing an aryl (Ar) substituent at C4 of the ring. The synthesis and structure-activity relationship of these analogues is discussed in Chapter III. Moreover, microscopy and 3H pulse-labeling studies, which are described in Chapter IV, demonstrate that N-methylthio beta-lactams appear to be inhibitors of protein biosynthesis.

Un développement récent de la polarimétrie en imagerie radar consiste à l'associer à l'interférométrie. L'analyse polarimétrique permet de comprendre les mécanismes électromagnétiques qui ont lieu au sein d'une cellule de résolution, tandis que l'interférométrie permet de calculer la hauteur du "centre de phase" de cette même cellule. L'utilisation conjointe de ces deux techniques permet d'envisager des bénéfices aussi divers que l'amélioration de la qualité des cartes d'élévations pour une zone urbaine, ou l'estimation des paramètres descriptifs d'une forêt à partir de modèles de diffusion. Les principaux outils théoriques proposés sont validés par des résultats de mesures en chambre anéchoïque et des images SAR du système aéroporté RAMSES de l'ONERA en bandes X, P et L.

Depuis quelques années, l'interférométrie radar a largement démontré son aptitude à recréer des Modèles Numériques de Terrain (MNT). Cependant, son usage reste délicat aux hautes résolutions, notamment en milieu urbain. En effet, les caractéristiques géométriques d'acquisition et les propriétés de l'onde radar créent des ambiguïtés dans le signal interférométrique. Dans un premier temps, une approche par simulation a donc été retenue, afin d'étudier l'impact des phénomènes mis en jeu, et de tester les techniques susceptibles de lever les ambiguïtés. Ainsi, les travaux sur la haute résolution radar ont mis en évidence des cas de corrélation spatiale de la phase sur des données réelles et simulées. Une proposition de modélisation du phénomène a été effectuée, et nous en avons montré les implications dans le cadre des traitements interférométriques. Nous avons ensuite étudié la possibilité d'un traitement optimal des zones de repliement pour la reconstruction du 3D sur des données simulées, grâce à des techniques de filtrage fréquentiel. Enfin, nous avons souligné l'intérêt d'une reconstruction adaptée à l'objet traité, grâce à une classification floue obtenue à partir de l'ensemble des informations extraites de l'image.

Les villes regroupent la moitié de la population mondiale. Le suivi de leur croissance est devenu un enjeu majeur en aménagement du territoire, en écologie ou pour la défense. Ce suivi nécessite une connaissance fine de l'occupation du sol et de la géométrie tridimensionnelle du bâti. L'interférométrie par radar à synthèse d'ouverture (RSO) a fait ses preuves pour mesurer l'élévation du milieu naturel à basse résolution, mais il n'est pas certain que les progrès récents en imagerie RSO à haute résolution offrent des capacités suffisantes pour rendre compte de la complexité du milieu urbain. L'objectif de cette thèse était de répondre à cette question. En raison des réflexions multiples, des discontinuités et de la grande diversité des matériaux du milieu urbain, les images RSO et, a fortiori les interférogrammes, sont difficiles à interpréter. Une inversion classique de l'interférogramme ne fournit pas un Modèle Numérique de Surface exploitable. Nous avons donc proposé un ensemble de traitements de plus haut niveau qui prend en compte toute l'information disponible, aussi bien dans les images que dans leur interférogramme. Notre travail comporte une étape d'analyse du signal RSO et une chaîne de reconstruction 3D. L'analyse est faite à trois échelles: au niveau de la cellule de résolution par simulation électromagnétique, au niveau de l'objet par un découpage en sous-bandes et au niveau de la texture par modélisation statistique. Elle aboutit à l'identification de plusieurs caractéristiques de la scène et au calcul joint de l'élévation en chaque pixel et d'une classification.

Cette thèse présente une méthode de reconstruction 3D de bâtiments à empreinte à angles droits et à toit plat par morceaux, à partir d'images interférométriques RSO (RADAR à synthèse d'ouverture) haute résolution en bande X provenant du capteur RAMSES (ONERA). De part l'acquisition en visée latérale et la nature électromagnétique de l'onde RADAR, les images RSO sont très différentes des images optiques et difficilement interprétables. C'est pourquoi, une analyse géométrique et phénoménologique des images RSO est tout d'abord effectuée. Cette analyse permet de comprendre l'origine des primitives utilisées lors de la reconstruction. Pour réduire le chatoiement, les images RSO sont tout d'abord filtrées. Le filtre non paramétrique mean shift est introduit en imagerie RSO et étendu à l'image de cohérence. L'extraction des primitives est ensuite effectuée grâce à des algorithmes basés sur la transformée de Hough. La méthode de reconstruction utilise la gestion d'hypothèses car l'ensemble des primitives extraites ne suffit généralement pas à décrire le bâtiment complètement. Pour cela le bâtiment est décomposé de façon hiérarchique par un ensemble d'éléments (façade, toit etc.). La gestion d'hypothèses permet de générer l'ensemble des hypothèses de bâtiments à partir des primitives extraites. Ensuite, les hypothèses générées sont validées ou rejetées par la détection des incompatibilités géométriques et interférométriques. Enfin, un classement des hypothèses validées est effectué. En perspective, les contributions apportées dans cette thèse sont mises en avant en montrant leur adaptabilité à d'autres données (polarimétrie, meilleure résolution).

Natural hydrocarbon seeps harbor distinctive geological, chemical, and biological features in the marine environment. This thesis verified remote sensing signatures of seeps using in-situ observation and repeated collections of satellite imagery. Bubble streams in the Gulf of Mexico water column from four natural seep sites on the upper continental slope were imaged by a side-scan sonar, which was operated from a submarine near the seafloor, and by acoustic profilers, which were operated from surface ships. These data were correlated with sea surface slicks imaged by Synthetic Aperture Radar (SAR) on the RADARSAT satellite. Comparing non-oily bubble streams from rapidly venting mud volcanoes with oily bubble streams from shallow deposits of gas hydrate showed that they produced notably different signatures. Non-oily bubbles produced high backscatter on the side-scan sonar records, but were difficult to detect with the acoustic profilers. Oily bubbles from hydrate deposits produced acoustic shadows on the side-scan sonar records. The oily bubbles generated clear signatures extending from the seafloor to the near surface on the acoustic profile records. RADARSAT SAR images verified the presence of surface oil slicks over the hydrate deposits, but not over the mud volcanoes. This indicates that SAR imagery will not be able to capture every oil and gas seep in a region because non-oily bubble streams do not create surface oil slicks. A total of 113 natural oily seep sources were identified based on surface slicks in eleven SAR images collected over the northern continental slope. A persistence analysis verified that SAR is a dependable tool for capturing oil slicks because 93.5% of the slick sources identified in the 2001 images were corroborated with slicks in the 2002 images. The sources ranged in depth from 100 to 2000 m and 79% of the sources were in 900 meters or greater of water. Seventy-six percent of the seep sources were associated with salt less than 1500 m below the seafloor and none of the sources were located in the bottom of salt withdrawal basins. Geographical Information Systems (GIS) proved to be a useful tool in these analyses.

The Greenland Ice Sheet is the largest ice sheet in the northern hemisphere. Ongoing melting of the ice sheet, resulting in increased mass loss relative to the longer term trend, has raised concerns about the stability of the ice sheet. Melt water generated at the surface is temporarily stored in supra-glacial lakes on the ice sheet. Connections between melt water generation, storage and ice sheet dynamics highlight the importance of the surface hydrological system. In this thesis different methods are used that improve our ability to observe the supra-glacial lake system on the west Greenland Ice Sheet. This region of the Greenland Ice Sheet has the most extensive supra-glacial hydrological system with a dense network of streams connecting lakes that can exceed several square kilometres in area. Synthetic Aperture Radar (SAR) and visible-near infrared (VNIR) images are used to explore the potential of different sensor systems for regular observations of the supra-glacial lakes. SAR imagery is found to be a useful complement to VNIR data. VNIR data from moderate resolution sensors are preferred as these provide high temporal resolution data, ameliorating problems with cloud cover. The dynamic nature of the lakes makes automated classification difficult and manual mapping has been widely used. Here a new method is proposed that improves on existing methods by automating the identification and classification of lakes, and by introducing a flexible system that can capture the full range of lake forms. Applying our new method we are better able to analyse the evolution of lakes over a number of melt seasons. We find that lakes initiate after approximately 40 positive degree days. Most lakes exist for less than 20 days before draining, or later in the season, and less often, freezing over. Using the automated method developed in this thesis lakes have been mapped in imagery from 2001–2010 at approximately five day intervals. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.</p>

Das Radar mit synthetischer Apertur (Synthetic Aperture Radar - SAR) liefert eine quasi-fotographische Abbildung der beleuchteten Bodenoberfläche mit zusätzlichen Informationen, die von der gesendeten und empfangenen Polarisation der Wellen abhängig sind. Eine nützliche Anwendung der polarimetrischen SAR-Daten liegt bei der Klassifizierung der Bodenstruktur anhand der polarimetrischen Streuungseigenschaften. In diesem Zusammenhang beschäftigt sich die vorliegende Arbeit mit der Entwicklung und Untersuchung neuer polarimetrischen Fokussierungsfunktion für die SAR-Datenverarbeitung mit Hilfe der polarimetrischen Rückstreuungseigenschaft, die zu einer alternativen quantitativen Auswertung der polarimerischen SAR-Daten führen kann. Die physikalische Optik Approximation wird für die numerische Berechnung der rückgestreuten elektrischen Felder der kanonischen Ziele unter SAR-Geometrie unter Berücksichtigung der Polarisationslage verwendet. Aus den rückgestreuten elektrischen Felder werden die polarimetrischen Radarrückstreuquerschnitte berechnet. Ein SAR-Simulator wird zur Datenverarbeitung der E-SAR des DLR entwickelt. Der Ansatz des polarimetrischen Radarrückstreuquerschnittes ermöglicht die approximierte numerische Berechnung der Rückstreuungseigenschaften der kanonischen Ziele sowohl im kopolaren als auch im kreuzpolaren Polarisationsbetrieb. Bei der SAR-Datenverarbeitung werden die Rohdatensätze durch die Referenzfunktion eines Punktzieles in der Entfernungsrichtung verarbeitet. Bei der Azimutkompression werden die vier Referenzfunktionen, das heißt die Referenzfunktion eines Punktzieles, die polarimetrische Fokussierungsfunktion einer flachen Platte, die polarimetrische Fokussierungsfunktion eines Zweifach-Reflektors und die polarimetrische Fokussierungsfunktion eines Dreifach-Reflektors, eingesetzt. Die qunatitativen Auswertung der SAR-Daten werden anhand des Pauli-Zerlegungstheorems, der differentiellen Reflektivität und des linearen Depolarisationsverhältnises durchgeführt.