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La thrombine, une protéase à sérine connue pour être l'acteur clé de la cascade de coagulation, a été décrite pour réguler les processus apoptotiques au niveau du côlon via l'activation de récepteurs activés par des protéases ou PARs (Protease-Activated Receptors). Cependant, les effets de la thrombine sur la cellule épithéliale colique n'ont été étudiés qu'en utilisant des lignées cellulaires. Les conséquences d'une exposition à différentes doses de thrombine sur un épithélium complexe, composés de différents types cellulaires plus ou moins différenciés sont inconnues à ce jour. Un nouveau modèle cellulaire, nommé organoïde, permet de reconstituer un épithélium colique fonctionnel en 3-dimensions (3D) à partir de résections ou de biopsies humaines, et ce, grâce aux capacités d'auto-renouvellement et de différenciation des cellules souches issues des cryptes coliques. Le 1er objectif de ma thèse a été d'évaluer les effets de la thrombine sur la survie, la prolifération, l'apoptose et la différenciation de l'épithélium colique humain, en utilisant le modèle organoïde. Puis, de déterminer l'implication des récepteurs PAR1 et PAR4 activés par la thrombine dans ces effets. Ainsi, l'ajout de thrombine (à faible dose : 10mU/mL et à forte dose : 50mU/mL) sur une culture d'organoïdes établis à partir de tissus colorectaux normaux entraîne une diminution de moitié de l'activité métabolique et de la prolifération cellulaire. Ces effets sont bloqués en présence d'un antagoniste de PAR1. Le processus apoptotique est, cependant, augmenté d'un facteur 8 en réponse à la thrombine (aux deux doses). Ce processus est inhibé en présence d'antagoniste de PAR1 ou de PAR4. Concernant la différenciation épithéliale, la thrombine diminue le nombre de colonosphères (structures immatures), au profit d'une augmentation du nombre de structures apoptotiques et de colonoïdes (structures plus matures présentant des néo-cryptes). Cet effet est dû à l'activation à la fois de de PAR1 et de PAR4 dans les cellules épithéliales coliques. Mes résultats démontrent que la thrombine exogène agit sur les processus d'apoptose, de prolifération et de différenciation sur un épithélium complexe, issu de la culture de tissus humains. L'utilisation de ce modèle ex vivo permet de comparer les organoïdes pathologiques et normaux, voire de tester les effets d'approches pharmacologiques et de nouveaux médicaments sur ces cultures. Ainsi, la 2nde partie de ce travail de thèse a été d'aborder la mise en place des conditions de culture et d'imagerie nécessaires pour réaliser un screening à haut débit robuste et reproductible, HCS (High-Content Screening), appliquée aux organoïdes. Les conditions de culture d'organoïdes en plaques 96-puits ont été mises au point de même que les conditions permettant d'acquérir des images répondant aux critères nécessaires pour une analyse via un système HCS. Le système Operetta HCS couplé au logiciel d'analyse Harmony (PerkinElmer) a été utilisé pour mettre en place une procédure d'analyse permettant de reconnaître les organoïdes, de les dénombrer, de les classer selon leur état de différenciation et de suivre leur croissance tout au long de la culture. Pour conclure, ces travaux de thèse ont permis de mettre en évidence les effets de la thrombine sur l'état métabolique, l'apoptose et la différenciation de l'épithélium colique humain, grâce au modèle 3D ex vivo d'organoïdes colorectaux. L'utilisation de ce modèle complète les approches jusque-là effectuées dans des modèles de lignées de cellules épithéliales, proposant une vision intégrée du comportement d'un épithélium complexe humain. L'approche HCS initiée lors de ces travaux de thèse pourrait permettre d'analyser de façon robuste et automatisée dans ce modèle, les effets d'autres composés et avoir ainsi un impact majeur sur notre compréhension des pathologies épithéliales et sur les tests de nouvelles approches thérapeutiques. / Thrombin, a serine protease known for its role in the coagulation cascade, was described for its effects on the induction of apoptosis in colonic epithelial cell lines, through the activation of Protease Activated Receptors (PARs). However, the effects of thrombin on complex epithelial structures such as the human intestinal epithelium composed of different cell types and cells at different stages of differentiation, has never been investigated. A new cellular model, named organoid, enables to reconstitute a functional epithelium in 3-dimensions (3D), from human resections or biopsies, thanks to the self-renewal and differentiation properties of stem cells isolated from colonic crypts. The first objective of this thesis was to evaluate thrombin's effects on survival, proliferation, apoptosis and differentiation in human colonic epithelium, using the organoid model. Then, we aimed to determining the implication of PAR1 and PAR4 in the thrombin's effects. Thus, thrombin added (at low dose: 10mU/mL and higher dose: 50mU/mL) to organoid cultures from control patients, led to a decrease by half of metabolic activity and cell proliferation. These effects were blocked by the addition of a PAR1 antagonist. Apoptotic process was 8-fold higher in organoid cultures exposed to thrombin (both doses) and this effect was inhibited by the addition of a PAR1 or a PAR4 antagonist. As per epithelial differentiation, thrombin decreased the number of colonospheres (immature structures) favoring the increase of apoptotic structures and colonoids (budding structures considered as more mature). This effect was due to PAR1 and PAR4 activation as again, it was blocked both by PAR1 and PAR4 antagonist. Taken together, these results reveal that exogenous thrombin acts on apoptosis, proliferation and differentiation processes in complex human colonic epithelium. The use of this ex vivo model will allow to compare pathological versus normal organoid cultures, but also to test the effects of pharmacological approaches and new treatment options directly in cultured human tissues. Thus, the 2nd part of this thesis was to setup the best culture conditions and the best imaging conditions to perform a robust and reproducible screening approach, HCS (High-Content Screening), using organoid cultures. Culture conditions in 96-well plates were set up and allowed to acquire images with the HCS system. Operetta HCS coupled to an analysis software (Harmony, PerkinElmer) was used to develop a specific program enabling the recognition of organoids, their counting, their classification according to their differentiation status and enabling to follow organoid growth in cultures. To sum up, the work performed allowed to highlight the effects of thrombin on metabolic status, apoptosis and differentiation of human colon epithelium, using an ex vivo 3D organoid model. The use this model nicely completed epithelial cell line approaches, offering an integrated view of the complex behavior of human epithelium. The HCS approach initiated within this thesis should allow the automated analysis of a number of drugs and treatments. It should help our understanding of epithelial pathologies and the testing of new therapeutic approaches.

IEEE 802.11n Wireless Local Area Networks (WLANs) employ Multiple-Input-Multiple-Output (MIMO), which significantly boosts the raw data rate at the Physical layer (PHY). But the potential of enhancing Medium Access Control (MAC) layer efficiencies by MIMO is still in its early stage and is the aim of the research in this thesis. Many existing works in this field mainly employ distributed MIMO spatial multiplexing/Multi-User Detection (MUD) technique and stream sharing to enable multiple simultaneous transmissions. Most works require synchronization among multiple transmissions, split the channel, and aim for single-hop networks. In this thesis, a novel Hybrid Carrier Sense (HCS) framework is proposed, mainly at the MAC layer to exploit the power of MIMO. HCS senses the channel availability jointly by the virtual carrier sense and physical carrier sense. HCS does not require synchronization among nodes; each node independently and locally determines when to start its transmission. HCS not only shares the channel, but also exploits the bi-directional handshakes of the wireless transmissions and increases the number of simultaneous stream transmissions. For a network with M antennas in each node, HCS can accommodate 2x(M-1) streams instead of M streams achieved by all other existing works. Moreover, HCS is aimed for multi-hop wireless ad hoc networks, in which the hidden terminal, exposed terminal, and deafness problems greatly degrade network performance. The HCS framework incorporates solutions to these problems. HCS is implemented in an NS2 network simulator and the performance evaluation shows that HCS significantly outperforms MIMO-enabled IEEE 802.11 (in which MIMO is only used for enhancing the raw data rate in the physical layer), resulting in higher aggregate throughput, packet delivery ratio and fairness in multi-hop wireless ad hoc networks. The HCS framework will be in wide use in the future generation of wireless networks and opens up more research possibilities. Some ideas in the HCS framework can be applied not only for MIMO, but also for many other techniques surveyed in this thesis; or we may combine them with HCS to further boost the network performance. / Thesis (Ph.D, Electrical & Computer Engineering) -- Queen's University, 2013-10-15 21:46:15.983

L’augmentation de la moyenne de vie a modifié le spectre des maladies cardiaques vers l'insuffisance cardiaque, un désordre progressif incurable, marqué par une perte massive de cardiomyocytes. En raison de la rareté des donneurs, la transplantation cardiaque, devient de plus en plus difficile. En 2003, la découverte des cellules souches cardiaques humaines (hCSC) pouvant supporter la réparation du myocarde après un infarctus a soulevé l’espoir d’approches thérapeutiques plus prometteuses. La transplantation des cellules autologues (issues du patient) a montré une efficacité limitée en raison de la mauvaise qualité des cellules après infarctus. De ce fait, l’utilisation des CPC allogéniques provenant de donneurs sains semble aujourd’hui le choix le plus réaliste et représente un potentiel produit thérapeutique abordable et disponible pour tous. Cependant les cellules allogéniques soulèvent des problèmes immunologiques importants qu’il faut résoudre avant leur utilisation clinique. Concernant la réponse immune innée, nos résultats indiquent que les hCPC allogéniques ont une susceptibilité modeste à la lyse NK et pourraient même être protégées contre cette lyse en contexte inflammatoire. Contrairement à la réponse immunitaire innée favorable contre les hCPC allogéniques, la présence des alloanticorps anti-HLA peut être néfaste. Nos résultats ont montré que les DSA-HLA I spécifiques de l’haplotype des hCPC peuvent induire leur lyse par CDC et ADCC et cette lyse est fortement augmentée par les conditions inflammatoires. L’ensemble de ces résultats indique que les hCPC allogéniques sont des cellules à faible risque immunologique en ce qui concerne la réponse immune innée, par contre une élimination rapide par CDC ou tardive par ADCC des hCPC pourrait se produire chez les patients ayant des DSA-HLA I spécifiques de l’allèle(s) exprimé(s) par les hCPC incitant ainsi le dépistage des DSA-HLA avant l’infusion thérapeutique des hCPC. / The increase in average life changed the spectrum of heart disease to heart failure, a progressive incurable disorder, characterized by a massive loss of cardiomyocytes. Due to the scarcity of donors, cardiac transplantation, only effective treatment known to date is becoming increasingly difficult. In 2003, the discovery of human cardiac stem cells (HCS/PC) can support the repair of the myocardium after myocardial raised hopes of promising therapeutic approaches. Transplantation of autologous (from the patient) showed limited efficiency because of the poor quality of the cells after infarction. Therefore, the use of stem / progenitor heart (CPC) from allogeneic healthy donors seems today the most realistic choiceand represents a potential therapeutic product available to all. However allogeneic cells raise significant immunological problems that must be resolved before clinical use. Regarding the innate immune response, our results indicate that allogeneic HCPC have a modest susceptibility to NK lysis and could even be protected against this lysis in the inflammatory context. In addition, allogeneic HCPC seem able to inhibit the activity of NK cells. Unlike the favorable innate immune response against the allogeneic HCPC, the presence of anti-HLA alloantibodies can be harmful. Our results showed that the DSA-specific HLA class I haplotype of the HCPC can induce their lysis by CDC and ADCC and this lysis is greatly increased by inflammatory conditions. However, the DSA-specific HLA II do not induce HCPC lysis. All these results indicate that allogeneic HCPC are cells with low immunological risk regarding the innate immune response. On the contrary, rapid elimination by CDC or ADCC of HCPC may occurs in patients with DSA- HLA class I specific allele (s) expressed by the HCPC thus prompting the screening of HLA-DSA prior to therapeutic infusion of HCPC.

The topic of this thesis is knowledge discovery and artificial intelligence based knowledge discovery algorithms. The knowledge discovery process and associated problems are discussed, followed by an overview of three classes of artificial intelligence based knowledge discovery algorithms. Typical representatives of each of these classes are presented and discussed in greater detail. Then a new knowledge discovery algorithm, called Hybrid Classifier System (HCS), is presented. The guiding concept behind the new algorithm was simplicity. The new knowledge discovery algorithm is loosely based on schemata theory. It is evaluated against one of the discussed algorithms from each class, namely: CN2; C4.5, BRAINNE and BGP. Results are discussed and compared. A comparison was done using a benchmark of classification problems. These results show that the new knowledge discovery algorithm performs satisfactory, yielding accurate, crisp rule sets. Probably the main strength of the HCS algorithm is its simplicity, so it can be the foundation for many possible future extensions. Some of the possible extensions of the new proposed algorithm are suggested in the final part of this thesis. / Dissertation (MSc)--University of Pretoria, 2007. / Computer Science / unrestricted

The natural resources offer a unique opportunity for the discovery of active compounds, due to the complexity and biodiversity of their chemical structures. Natural resources have been used as medicines throughout human history. Saudi Arabia’s natural resources, for instance its terrestrial medicinal plants and the Red Sea sponges, have not been extensively investigated with regard to their biological activities. To better identify the diversity of compounds with bioactive potential, new techniques are also necessary in order to improve the drug discovery path. This study comprises three sections. The first section examines Juniperus phoenicea (Arar), Anastatica hierochuntica (Kaff Maryam) and Citrullus colocynthis (Hanzal); these herbal plants were screened for potential bioactivity using a newly developed pipeline based on a high-content screening technique. We report a new cell-based high-throughput phenotypic screening for the bio-prospecting of unknown natural products from Saudi Arabian plants, in order to reveal their biological activities. The second section investigates Avicennia marina plants, screened for reverse transcriptase anti-HIV bioactivity using biochemical assay. Image-based high-content screening with a set of cellular stains was used to investigate the phenotypic results of toxicity and cell cycle arrest. The third section considers the isolation of Actinomycetes from Red Sea Sponges. Actinomycetes bacterial isolates were tested for bioactivity against West Nile Virus NS3 Protease. Analytical chemical techniques such as liquid chromatography–mass spectrometry (LC-MS), gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) were used to gain more understanding of the possible chemical compounds responsible for this bioactivity. Overall, the aim of this work is to investigate the potential bioactive effect of several Saudi Arabian plants and Red Sea sponges against cancer cells and viral infections. Our study demonstrates the efficiency of the newly developed pipeline using cell-based phenotypic screening. Anti-cancer potential activity was detected in Juniperus phoenicea. Bioactive potential against the reverse transcriptase enzyme of HIV virus was confirmed in Avicennia marina leaves. The organic extracts of Actinomycetes bacterial isolates were found active against West Nile Virus NS3 Protease. Here, promising starting point for the potential of drug discovery of plants and marine organism of Saudi Arabia.

Data were analyzed from the 1998-2004 Uniform Data System (UDS) to identify trends and predictors of financial performance (costs, productivity, and overall financial health) for health centers (HCs). Several differences were noted regarding revenues, self-sufficiency, service offerings, and urban/rural setting. Urban centers with larger numbers of clients, centers that treated high numbers of patients with chronic diseases, and centers with large numbers of prenatal care users were the most fiscally sound. Positive financial performance can be targeted through strategies that generate positive revenue, strive to decrease costs, and target services that are in demand.

According to science, food allergy is a growing health problem. In home- and consumer studies (HCS), food and meals are central parts. According to the Education Act, teachers must be given professional development to create a safe environment for students.   The purpose of this study was to examine how teachers in home economics and consumer studies experienced the conditions for teaching students with food allergies. The focus was on the classroom, routines, allocated budget, and professional development.   Qualitative method was used. Nine qualified home economics teachers were interviewed based on a semi-structured question guide. The interviews were transcribed and analyzed with a qualitative content analysis.   The results showed that the classroom and the economic conditions limited the teaching. The teachers felt confident in their current knowledge but were positive about continuing education. Routine improvements regarding information management and action plan are desired.     The study showed that the classroom was important for the teaching and that the few students with food allergies did not affect the budget in general. Routines around these students should be reconsidered. Basic education needs to be strengthened and teachers need to be given the opportunity for further training.

Yes / In this work, the effect of the nanosized CZA2 (cerium-zirconium-aluminium) on the performance and emissions in a two- cylinder indirect injection (IDI) diesel engine, was studied. CZA2 was dispersed in diesel (D100) and waste cooking oil and tallow origin biodiesel-diesel blends (B10, B20, B30) and tested at different engine loads and constant speed. The nanocatalyst (CZA2) increased the brake specific fuel consumption (BSFC) and decreased the brake thermal efficiency (BTE, %) of all tested fuels, at all loads, except B20 at the lowest load. CZA2 reduced nitrogen oxides (NOx) from D100 at low and high engine loads, as well as carbon monoxide (CO) and unburned hydrocarbons (HC) at medium and high tested loads. The dispersion of CZA2 promoted the combustion of the biodiesel blends by almost eliminating HC while reducing NOx and CO emissions at various loads. Thermogravimetric analysis (TGA) coupled with Attenuated Total Reflectance- Fourier Transform Infrared (ATR-FTIR) spectroscopy revealed that the addition of CZA2 in diesel and biodiesel under pyrolysis and oxidation conditions resulted in the presence of saturated species like ketones and final oxidation products such as CO2, supporting their improved combustion and emissions’ reduction in the engine tests.

Over the last few years, public transportation has become more desirable as capacity of existing roadways failed to keep up with rapidly increasing traffic demand. Buses are one of the most common modes of public transportation with low impact on network capacity, especially in small and congested urban areas. However, the use of regularly scheduled buses as the main public transport mode can become useless with the presence of traffic congestion and dense construction areas. In cases like these, innovative solutions, such as bus rapid transit (BRT), can provide an increased level of service without having to resort to other, more expensive modes, such as light rail transit (LRT) and metro systems (subways). Transit signal priority (TSP), which provides priority to approaching buses at signalized intersections by extending the green or truncating the red, can also increase the performance of the bus service. Understanding the combined impact of TSP and BRT on network traffic operations can be complex. Although TSP has been implemented worldwide, none of the previous studies have examined in depth the effects of using conditional and unconditional TSP strategies with a BRT system. The objective of this research is to evaluate the effectiveness of BRT without TSP, then with conditional or unconditional TSP strategies. The micro-simulation software VISSIM was used to compare different TSP and BRT scenarios. These simulation scenarios include the base scenario (before implementation of the TSP and BRT systems), Unconditional TSP (TSP activates for all buses), Conditional TSP 3 minutes behind (TSP only activates for buses that are 3 minutes or more behind schedule), Conditional TSP 5 minutes behind (only activates for buses 5 minutes or more behind schedule), BRT with no TSP, BRT with Unconditional TSP, BRT with Conditional TSP 3 minutes behind, and BRT with Conditional TSP 5 minutes behind. The VISSIM simulation model was developed, calibrated and validated using a variety of data that was collected in the field. These data included geometric data, (number of lanes, intersection geometries, etc.); traffic data (average daily traffic volumes at major intersections, turning movement percentages at intersections, heavy vehicle percentages, bus passenger data, etc.); and traffic control data (signal types, timings and phasings, split history, etc.). Using this field data ensured the simulation model was sufficient for modeling the test corridor. From this model, the main performance parameters (for all vehicles and for buses only) for through movements in both directions (eastbound and westbound) along the corridor were analyzed for the various BRT/TSP scenarios. These parameters included average travel times, average speed profiles, average delays, and average number of stops. As part of a holistic approach, the effects of BRT and TSP on crossing street delay were also evaluated. Simulation results showed that TSP and BRT scenarios were effective in reducing travel times (up to 26 %) and delays (up to 64%), as well as increasing the speed (up to 47%), compared to the base scenario. The most effective scenarios were achieved by combining BRT and TSP. Results also showed that BRT with Conditional TSP 3 minutes behind significantly improved travel times (17 – 26%), average speed (30 – 39%), and average total delay per vehicle (11 – 32%) for the main corridor through movements compared with the base scenario, with only minor effects on crossing street delays. BRT with Unconditional TSP resulted in significant crossing street delays, especially at major intersections with high traffic demand, which indicates that this scenario is impractical for implementation in the corridor. Additionally, BRT with Conditional TSP 3 minutes behind had better travel time savings than BRT with Conditional TSP 5 minutes behind for both travel directions, making this the most beneficial scenario. This research provided an innovative approach by using nested sets (hierarchical design) of TSP and BRT combination scenarios. Coupled with microscopic simulation, nested sets in the hierarchical design are used to evaluate the effectiveness of BRT without TSP, then with conditional or unconditional TSP strategies. The robust methodology developed in this research can be applied to any corridor to understand the combined TSP and BRT effects on traffic performance. Presenting the results in an organized fashion like this can be helpful in decision making. This research investigated the effects of BRT along I-Drive corridor (before and after conditions) at the intersection level. Intersection analysis demonstrated based on real life data for the before and after the construction of BRT using the Highway Capacity SoftwareTM (HCS2010) that was built based on the Highway Capacity Manual (HCM 2010) procedures for urban streets and signalized intersections. The performance measure used in this analysis is the level of service (LOS) criteria which depends on the control delay (seconds per vehicle) for each approach and for the entire intersection. The results show that implementing BRT did not change the LOS. However, the control delay has improved at most of the intersections' approaches. The majority of intersections operated with an overall LOS "C" or better except for Kirkman Road intersection (T2) with LOS "E" because it has the highest traffic volumes before and after BRT construction. This research also used regression analysis to observe the effect of the tested scenarios analyzed in VISSIM software compared to the No TSP – No BRT base model for all vehicles and for buses only. The developed regression model can predict the effect of each scenario on each studied Measures of Performance (MOE). Minitab statistical software was used to conduct this multiple regression analysis. The developed models with real life data input are able to predict how proposed enhancements change the studied MOEs. The BRT models presented in this research can be used for further sensitivity analysis on a larger regional network in the upcoming regional expansion of the transit system in Central Florida. Since this research demonstrated the operational functionality and effectiveness of BRT and TSP systems in this critical corridor in Central Florida, these systems' accomplishments can be expanded throughout the state of Florida to provide greater benefits to transit passengers. Furthermore, to demonstrate the methodology developed in this research, it is applied to a test corridor along International Drive (I-Drive) in Orlando, Florida. This corridor is key for regional economic prosperity of Central Florida and the novel approach developed in this dissertation can be expanded to other transit systems.