Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Nutrition and Metabolism, Agricultural, Food and Nutritional Science. Title from pdf file main screen (viewed on September 25, 2009). Includes bibliographical references.

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed June 30, 2007). Includes bibliographical references (p. 30-36).

Les parasites apicomplexes sont ubiquitaires et ont une forte incidence en médecine humaine et vétérinaire. Certains de ces parasites, comme Plasmodium falciparum, l’agent du paludisme, ou Toxoplasma gondii, l’agent de la toxoplasmose, posent des problèmes de santé publique. Les thérapies existantes montrent parfois une efficacité limitée, une forte toxicité et entraînent des résistances, d’où la nécessité de nouvelles approches plus spécifiques. Dans ce contexte, nous avons développé deux approches d’inhibition des apicomplexes : -la synthèse de biphénylimidazoazines à large spectre efficaces au micromolaire sur cinq parasites apicomplexes différents in vitro. -la synthèse d’imidazo[1,2-b]pyridazines ciblant spécifiquement une protéine kinase (CDPK1) de T. gondii et efficaces au submicromolaire sur le parasite in vitro. Une diminution de plus de 90 % de la charge parasitaire chez la souris et une innocuité à court terme font de ces imidazo[1,2-b]pyridazines de bons candidats thérapeutiques. / Apicomplexan parasites are ubiquitous and have a strong incidence in veterinary and human medicine. Some of them, like Plasmodium falciparum, causing malaria, or Toxoplasma gondii, causing toxoplasmosis, are matter of public health concern. The existing therapies may have limited efficiency, high toxicity, and may lead to resistance, highlighting the necessity of new more specific approaches. In this context, we have developed two approaches to inhibit Apicomplexa: -the synthesis of biphenylimidazoazines with broad-spectrum and efficient at the micromolar range on five different apicomplexan parasites in vitro. -the synthesis of imidazo[1,2-b]pyridazines specifically targeting a kinase protein (CDPK1) of T. gondii and efficient at the submicromolar range on the parasite in vitro. More than 90% diminution of parasite burden in mice and short term safety make these imidazo[1,2-b]pyridazines good therapeutic candidates.

Abstract  Purpose – The purpose of the study is to investigate how distribution centers can prevent delays to achieve higher on-time delivery.  To fulfill the purpose of the study three study questions have been conducted:  • What factors causes delays in distribution centers?  • Why do delays occur in distribution centers?  • How can distribution centers prevent delays to achieve higher on-time delivery?  Method – A qualitative approach has been used throughout the study to enable fulfilment of the study´s purpose. The study has implemented a case study at a distribution center to investigate what factors causes delays. A theoretical framework that attends the research areas of on-time delivery, distribution centers function, operational problems and classification of factors was used to conduct suggestions addressing how businesses can prevent delays.  Findings – The study emphasizes that all delays that effect on-time delivery could be classified as individual- or system dependent. The study suggests that businesses should focus on preventing delays classified as system dependent, since they may also prevent individual dependent delays. By improving education and prioritize development of education and standards businesses should be able to improve their on-time delivery.  Implications – The study maps factors that causes delays in distribution centers. Categorization and classification could be used to identify where factors occur and explain their dependencies. This study focuses on how on-time delivery is affected by distribution centers performance. The study indicates the possibility to applicate already presented theories in this context but also that categorization and classification of factors is possible. Furthermore, the study has identified problems due to non-used standards, even though they are available for the user.  Limitations – The delimitations of the study mark the study’s focus to stocked goods in distribution centers and do not attend economic aspects of on-time delivery.  Key words: On-time delivery, distribution centers, delays, individual dependent, system dependent / Sammanfattning  Syfte – Syftet med studien är att undersöka hur distributionscentraler kan förhindra förseningar för att uppnå högre leveransprecision.  För att uppfylla syftet har tre frågeställningar utformats:  • Vilka faktorer orsakar förseningar i distributionscentraler?  • Varför uppstår förseningar i distributionscentraler?  • Hur kan distributionscentraler förhindra förseningar för att uppnå högre leverans-precision?  Metod – För att uppnå syftet har studien använt en kvalitativ ansats där en fallstudie har genomförts på en distributionscentral i syfte att undersöka vilka faktorer som kan orsaka förseningar. Ett teoretiskt ramverk som behandlar leveransprecision, distributionscentralers funktion, verksamhetsproblem och klassificering av faktorer har använts för att ta fram förslag på hur distributionscentraler kan förhindra faktorer som orsakar förseningar.  Resultat – Studien indikerar att alla identifierade faktorer som orsakar förseningar och därmed påverkar leveransprecision kan vara antingen individ- eller systemberoende. Studien föreslår att verksamheter bör fokusera på att förhindra systemberoende faktorer som orsakar förseningar eftersom de även kan förhindra individberoende förseningar. Studien föreslår; genom att förbättra utbildning samt prioritera utveckling av utbildning och standarder skulle verksamheters leveransprecision kunna öka.  Implikationer – Det har kartlagts faktorer som kan orsaka förseningar i distributions-centraler. Kategoriseringen tillsammans med klassificering kan användas för att identifiera var faktorer uppstår och vad de beror på. Kategoriseringen tillsammans med klassificering kan användas för att identifiera var faktorer uppstår och vad de beror på. Vidare identifierar studien problem på grund av att standarder inte används, trots att de finns tillgängliga för användare.  Begränsningar – Studien är avgränsad till att endast studera produkter som lagerförs i distributionscentraler och tar inte hänsyn till ekonomiska aspekter kopplat till leverans-precision.  Nyckelord: Leveransprecision, distributionscentraler, förseningar, individberoende, systemberoende.

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Diese Arbeit liefert einen Beitrag zur Auslegung geklebter Karosserie-Mischbaustrukturen. Die derzeit verwendeten Strukturklebstoffe genügen komplexen mechanischen und schon im Fertigungsprozess hohen thermischen Beanspruchungen. Die Beschreibung der physikalischen, thermischen und mechanischen Eigenschaften des Klebstoffs über den gesamten Prozess hinweg ist für die Auslegung der Klebverbindung vor allem in Mischbaustrukturen entscheidend. Temperaturen von bis zu 200 °C im KTL-Lacktrocknungsprozess führen zum einen zur Vernetzung der Klebstoffe, zum anderen aber auch zur thermischen Ausdehnung der artfremden Werkstoffpaarungen. Die so auftretenden Relativverschiebungen in großflächigen, geklebten Mischbaustrukturen können aufgrund der in dieser Arbeit vorgestellten Vorgehensweise schon in der Konzeptphase numerisch berechnet und die damit verbundenen bleibenden Deformationen sowie festigkeitsrelevanten Bereiche in der Klebschicht prognostiziert werden. Für die Dimensionierung der Klebverbindungen ist hiermit ein Nachweis der temperatur- und vernetzungsgradabhängigen Klebstofffestigkeit unter mehrachsiger Beanspruchung erbracht worden.

Nous avons étudié par des méthodes numériques et en théorie k.p avancée les propriétés tunnel d’électrons et de trous dans des systèmes modèles et hétérostructures composés de semi-conducteurs impliquant des interactions spin-orbite de volume. Nous démontrons que le couplage entre les interactions spin-orbite et d’échange à l’interface de jonctions tunnel résulte en un fort contraste de transmission de porteurs selon le signe de la composante de leur vecteur d’onde dans le plan de la jonction. Cet effet conduit à un effet tunnel anormal d’interface que nous appelons « Effet Hall Tunnel Anormal » (ATHE). De façon similaire, des processus tunnel non-conventionnels se manifestant sur des isolants topologiques ont été prédits par d’autres auteurs. Alors que l’ensemble de ces effets Hall anormaux sont liés aux interactions spin-orbite, les effets tunnel anormaux diffèrent des effets Hall tunnel, des effets Hall et des effets Hall de spin par la forte amplitude prédite ainsi que par des phénomènes de chiralité. Ces propriétés possèdent un lien nontrivial avec la symétrie du système. L’ensemble de ces résultats démontre l’existence d’une nouvelle classe d’effets tunnel qui devaient être étudiés expérimentalement dans un futur proche. En ce qui concerne la bande de valence, nous démontrons, en utilisant un Hamiltonien 14x14 prolongeant un modèle 2x2, que le calcul décrivant l’ATHE repose sur un traitement subtil des états dits « spurious » (états non-physiques) et nous donnons quelques éléments d’amélioration et de compréhension. Dans ce mémoire de thèse, nous développons deux méthodes numériques pour résoudre le problème des états spurious en développant en parallèle des méthodes k.p respectivement à 14 bandes et 30 bandes afin de décrire des matériaux semiconducteurs à gap indirect. Les calculs menés dans la bande de valence d’hétérostructures semiconductrice incluant interfaces et barrières tunnel (approches 6x6 et 14x14) sans centre de symétrie d’inversion mettent en évidence des propriétés d’asymétrie équivalente à celles obtenues dans la bande de conduction. De tels effets sont interprétés, dans le cadre de calculs de perturbation en transport basés sur des techniques de fonctions de Green, par des effets chiraux orbitaux lors du branchement tunnel des fonctions évanescentes dans la barrière. / We report on theoretical, analytical and computational investigations and k.p calculations of electron and hole tunneling, in model systems and heterostructures composed of exchange-split III-V semiconductors involving spin-orbit interaction (SOI). We show that the interplay of SOI and exchange interactions at interfaces and tunnel junctions results in a large difference of transmission for carriers, depending on the sign of their incident in-plane wave vector (k//): this leads to interfacial skew-tunneling effects that we refer to as Anomalous Tunnel Hall Effect (ATHE). In a 2x2 exchange-split band model, the transmission asymmetry (A) between incidence angles related to +k// and -k// wave vector components, is shown to be maximal at peculiar points of the Brillouin zone corresponding to a totally quenched transmission (A = 100%). More generally, we demonstrate the universal character of the transmission asymmetry A vs. in-plane wavevector component, for given reduced kinetic energy and exchange parameter, A being universally scaled by a unique function, independent of the spin-orbit strength and of the material parameters. Similarly, striking tunneling phenomena arising in topological insulators have just been predicted. While they all are related to the spin-orbit directional anisotropy, ATHE differs from the tunneling Hall effect, spontaneous anomalous, and spin Hall effects, or spin-galvanic effect, previously reported for electron transport, by its giant forward asymmetry and chiral nature. These features have non-trivial connection with the symmetry properties of the system. All these results show that a new class of tunneling phenomena can now be investigated and experimentally probed.When valence bands are involved, we show (using 14x14 Hamiltonian and within a 2x2 toy model) that ATHE accurate calculations rely on a subtle treatment of the spurious (unphysical) states and we give an insight into the topology of the complex band structure. We introduce two numerical methods to remove spurious states and successfully, include them in 30-band codes able to describe indirect bandgap group-IV semiconductors. Calculations performed in the valence bands of model heterostructures including tunnel barriers, in both 6x6 and 14x14 k.p Hamiltonians without inversion asymmetry, more astonishingly highlight the same trends in the transmission asymmetry which appears to be related to the difference of orbital chirality and to the related branching (overlap) of the corresponding evanescent wave functions responsible for the tunneling current. Besides, we built an analytical model and developed scattering perturbative techniques based on Green’s function method to analytically deal with electrons and holes and to compare these results with numerical calculations. The agreement between the different approaches is very good. In the case of holes, the asymmetry appears to be robust and persists even when a single electrode is magnetic.

abstract: The problem of multiple object tracking seeks to jointly estimate the time-varying cardinality and trajectory of each object. There are numerous challenges that are encountered in tracking multiple objects including a time-varying number of measurements, under varying constraints, and environmental conditions. In this thesis, the proposed statistical methods integrate the use of physical-based models with Bayesian nonparametric methods to address the main challenges in a tracking problem. In particular, Bayesian nonparametric methods are exploited to efficiently and robustly infer object identity and learn time-dependent cardinality; together with Bayesian inference methods, they are also used to associate measurements to objects and estimate the trajectory of objects. These methods differ from the current methods to the core as the existing methods are mainly based on random finite set theory. The first contribution proposes dependent nonparametric models such as the dependent Dirichlet process and the dependent Pitman-Yor process to capture the inherent time-dependency in the problem at hand. These processes are used as priors for object state distributions to learn dependent information between previous and current time steps. Markov chain Monte Carlo sampling methods exploit the learned information to sample from posterior distributions and update the estimated object parameters. The second contribution proposes a novel, robust, and fast nonparametric approach based on a diffusion process over infinite random trees to infer information on object cardinality and trajectory. This method follows the hierarchy induced by objects entering and leaving a scene and the time-dependency between unknown object parameters. Markov chain Monte Carlo sampling methods integrate the prior distributions over the infinite random trees with time-dependent diffusion processes to update object states. The third contribution develops the use of hierarchical models to form a prior for statistically dependent measurements in a single object tracking setup. Dependency among the sensor measurements provides extra information which is incorporated to achieve the optimal tracking performance. The hierarchical Dirichlet process as a prior provides the required flexibility to do inference. Bayesian tracker is integrated with the hierarchical Dirichlet process prior to accurately estimate the object trajectory. The fourth contribution proposes an approach to model both the multiple dependent objects and multiple dependent measurements. This approach integrates the dependent Dirichlet process modeling over the dependent object with the hierarchical Dirichlet process modeling of the measurements to fully capture the dependency among both object and measurements. Bayesian nonparametric models can successfully associate each measurement to the corresponding object and exploit dependency among them to more accurately infer the trajectory of objects. Markov chain Monte Carlo methods amalgamate the dependent Dirichlet process with the hierarchical Dirichlet process to infer the object identity and object cardinality. Simulations are exploited to demonstrate the improvement in multiple object tracking performance when compared to approaches that are developed based on random finite set theory. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2019

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Simple Summary Glioblastoma is the most common primary brain cancer in adults. One reason for the development and malignancy of this tumor is the misregulation of certain cellular proteins. The oncoprotein STAT3 that is frequently overactive in glioblastoma cells is associated with more aggressive disease and decreased patient survival. Autophagy is a form of cellular self digestion that normally maintains cell integrity and provides nutrients and basic building blocks required for growth. While glioblastoma is known to be particularly resistant to conventional therapies, recent research has suggested that these tumors are more sensitive to excessive overactivation of autophagy, leading to autophagy-dependent tumor cell death. Here, we show a hitherto unknown role of STAT3 in sensitizing glioblastoma cells to excessive autophagy induced with the repurposed drug pimozide. These findings provide the basis for future research aimed at determining whether STAT3 can serve as a predictor for autophagy-proficient tumors and further support the notion of overactivating autophagy for cancer therapy. Abstract Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.