T lymphocytes play a critical role in adaptive immunity by eliciting and regulating specific immune responses against viral and bacterial pathogens. The development of T cells occurs within the highly specialized thymus and follows a defined set of stage-specific differentiation steps. However, the molecular and cellular events occurring at early stages of human T-cell development remain to be fully elucidated. This was in part due to the inability to obtain substantial numbers of T-lineage cells from hybrid/human fetal thymic organ culture (FTOC) and the inability to recapitulate human T-lymphopoiesis using other systems. To address the molecular and cellular events occurring during early human T-lymphopoiesis, human umbilical cord-blood (UCB) hematopoietic stem cells (HSCs) were induced to differentiate to the T-lineage utilizing OP9-DL1 stromal cells. A developmental program involving a sequential and temporally discrete expression of key differentiation markers was revealed. In addition, this Thesis demonstrates that in vitro-generated CD34+CD7++ progenitors effectively engrafted the thymus of immunodeficient mice. In addition, two distinct progenitor subsets, CD34+CD45RA+CD7++CD5-CD1a- (proT1) and CD34+CD45RA+CD7++CD5+CD1a- (proT2), were identified with proT2 cells showing a 3-fold enhanced engrafting capacity than the proT1 subset. As proT2 cells exhibit superior engrafting capacity, these cells were tested for their ability to enhance T cell generation following hematopoietic stem cell transplant (HSCT). We observe that when HSCs are coinjected with proT2 cells, a dramatic improvement in HSC-derived T-lymphopoiesis is observed. This Thesis demonstrates that in vitro-derived proT2 cells reorganize the thymus stromal compartment of the host NOD/SCID/γcnull mouse compared to the highly disorganized cortical and medullary compartments in mice not receiving proT cells. This alteration in thymic architecture likely favours the recruitment of BM derived progenitors. Lastly, we address whether functional CD8 T cells can be generated in vitro using hematopoietic stem cells (HSCs) in coculture with OP9-DL1 cells and indeed these cells were capable of proliferating, and secreting effector molecules typical of cytotoxic T cells. Taken together, the ability to generate proT cells and mature T cells from Notch-ligand cultures offers a new tool to study human T cell development.

T lymphocytes play a critical role in adaptive immunity by eliciting and regulating specific immune responses against viral and bacterial pathogens. The development of T cells occurs within the highly specialized thymus and follows a defined set of stage-specific differentiation steps. However, the molecular and cellular events occurring at early stages of human T-cell development remain to be fully elucidated. This was in part due to the inability to obtain substantial numbers of T-lineage cells from hybrid/human fetal thymic organ culture (FTOC) and the inability to recapitulate human T-lymphopoiesis using other systems. To address the molecular and cellular events occurring during early human T-lymphopoiesis, human umbilical cord-blood (UCB) hematopoietic stem cells (HSCs) were induced to differentiate to the T-lineage utilizing OP9-DL1 stromal cells. A developmental program involving a sequential and temporally discrete expression of key differentiation markers was revealed. In addition, this Thesis demonstrates that in vitro-generated CD34+CD7++ progenitors effectively engrafted the thymus of immunodeficient mice. In addition, two distinct progenitor subsets, CD34+CD45RA+CD7++CD5-CD1a- (proT1) and CD34+CD45RA+CD7++CD5+CD1a- (proT2), were identified with proT2 cells showing a 3-fold enhanced engrafting capacity than the proT1 subset. As proT2 cells exhibit superior engrafting capacity, these cells were tested for their ability to enhance T cell generation following hematopoietic stem cell transplant (HSCT). We observe that when HSCs are coinjected with proT2 cells, a dramatic improvement in HSC-derived T-lymphopoiesis is observed. This Thesis demonstrates that in vitro-derived proT2 cells reorganize the thymus stromal compartment of the host NOD/SCID/γcnull mouse compared to the highly disorganized cortical and medullary compartments in mice not receiving proT cells. This alteration in thymic architecture likely favours the recruitment of BM derived progenitors. Lastly, we address whether functional CD8 T cells can be generated in vitro using hematopoietic stem cells (HSCs) in coculture with OP9-DL1 cells and indeed these cells were capable of proliferating, and secreting effector molecules typical of cytotoxic T cells. Taken together, the ability to generate proT cells and mature T cells from Notch-ligand cultures offers a new tool to study human T cell development.

CRMP5 appartient à la famille des Collapsin Response Mediator Protein. Ces protéines sont très exprimées dans le cerveau en développement et les zones de neurogénèse chez l'adulte. Dans un contexte tumoral, l'expression des messagers de CRMP5 émergent dans un cluster de gènes associés à la plus faible survie des 20 patients suivis, et à la prolifération (Liang et al., 2005). Nous avons confirmé ces résultats dans une série rétrospective de 183 GBM où la forte expression protéique de CRMP5 est corrélée à une plus faible survie des patients (7.14 mois vs 10 mois) ; de plus les tumeurs exprimant fortement CRMP5 présentent un index mitotique 2 fois plus important (p = 0.0009) que les tumeurs exprimant faiblement CRMP5. Dans des cultures primaires ou lignées cellulaires de GBM nous montrons que la prolifération des glioblastomes est dépendante de l'expression de CRMP5 et de la voie de signalisation Notch. Des analyses en western blot démontrent que CRMP5 protège les récepteurs Notch de la dégradation lysosomale. Nous avons approfondi ce mécanisme et montré une nouvelle voie de régulation de Notch par CRMP5 qui par une interaction protéique avec Numb, l'inhibiteur de Notch empêche la dégradation du récepteur. Parallèlement, l'analyse en immunohistochimie sur les biopsies de GBM montrent une forte expression Notch et sa cible Hes1 dans les tumeurs exprimant fortement CRMP5. Ces résultats montrent la corrélation entre l'expression de CRMP5 dans les GBM, l'activation de la voie Notch et la faible survie des patients. Le ciblage de l'interaction CRMP5-Numb est une stratégie potentielle pour un traitement ciblé des glioblastomes

Le facteur de transcription Ikaros est un régulateur essentiel de la lymphopoïèse. Ikaros est nécessaire à la différenciation des lymphocytes B et joue aussi un rôle important dans la suppression des LAL-T. Contrairement aux souris mutantes nulles pour Ikaros, les souris mutantes hypomorphes IkL/L développent des lymphocytes B matures après la naissance. Avec l'âge, toutes les souris IkL/L développent des leucémies T Notch dépendantes avec des mutations similaires à celles trouvées chez les patients atteints de LAL-T. La souris IkL/L est donc un excellent modèle pour étudier l'activation des cellules B matures et la pathogenèsedes LAL-T. Nous avons montré que la délétion spécifique du promoteur et de l'exon 1 de Notch1 dans les cellules T conduit à l'activation de promoteurs cryptiques dans la région 3' du gène, qui génèrent des transcrits codant pour des protéines Notch1 constitutivement actives qui accélèrent la leucémogenèse dans la souris IkL/L. De plus, nous mettrons en évidence l'existence de cellules initiatrices de leucémie dans les tumeurs IkL/L puisque nous avons trouvé que des cellules ayant la capacité de s'auto-renouveler représentent 1 sur 500. Enfin, nous avons montré que les cellules B IkL/L ont une activation excessive d'ERK et dep38 après la stimulation du BCR, ce qui résulte en une hyper-prolifération et une production d'autoanticorps liés au lupus systémique érythémateux. Nos résultats suggèrent qu'Ikaros est un régulateur négatif de l'activation des lymphocytes B.

This Master of Applied Science thesis presents an inverter control system design and implementation with active damping of LCL filter resonance for a single phase grid-connected Distributed Power Generation (DPGS). The focus of the thesis is to actively damp the LCL filter resonance while keeping inverter control variables well regulated. The mathematical model of the LCL filter is analyzed and the filter is designed. Then, a PLL, and a PI compensator in the synchronous reference frame, and a PR compensator in stationary reference frame along a notch filter in cascade are designed and implemented. System level simulation and implementation are conducted. The idea of systematic applying the low loss power conversion topology, effective grid condition detection, grid synchronization, and advanced signal processing theory provides some advantages for single phase grid-connected inverter control design to meet the standard specifications of the interaction between the DPGS and utility grid. / Thesis (Master, Electrical & Computer Engineering) -- Queen's University, 2014-06-26 17:06:03.693

No description available.

Superconducting microelectronics (SME) technology has the potential of realizing very high speed digital receivers capable of performing direct digitization of radio frequency signals with very low power consumption. The SME receiver is implemented on a single chip using Niobium based low temperature superconductive (LTS) Josephson Junction (JJ) technology by HYPRES. Analogue RF filters are still required at the receiver front end and are key components of the overall superconductor digital receiver. SME receivers usually require two types of RF filters; a wideband bandpass filter and a bandstop filter (a notch filter). The notch filter is required to eliminate interference and unwanted signals in the passband. In this thesis, design of highly miniaturized lumped element wideband and bandstop filters is investigated and some challenges are addressed. The filters are fabricated by the HYPRES process and therefore can be integrated with the SME receiver on the same chip. In a wideband filter, the coupling between the adjacent resonators is high. Achieving such a strong coupling is one of the challenges of designing wideband filters. The wideband filters realized with distributed elements usually suffer from very low spurious frequency. As the bandwidth of the filter becomes wider, the spurious peak of the second harmonic gets closer to the passband of the filter. In the first part of this work, the possibility of realizing lumped element superconducting bandpass filters (BPF) with a relative bandwidth of 80% is investigated. In the second part of the thesis, design and realization of lumped element superconducting bandstop filters (BSF) is discussed. The challenge for designing a bandstop filter is providing a good match over a wide frequency range. So narrowband inverters cannot be used. Instead, usually λ/4 matched transmission lines provide 90° phase shift between the resonators of a notch filter. The possibility of replacing the long transmission line with other means or eliminating the inverters and using both shunt and series resonators are investigated. Having both series and shunt resonators introduces some new challenges that are addressed in the thesis and discussed thoroughly. A tunable notch resonator is presented. The tunability is provided by a superconducting MEMS varactor that is realized in our group by doing some post processing on the device fabricated by HYPRES. The tunability range of the device at cryogenic temperatures is investigated. A 3-pole tunable BSF is also designed that uses the same tunable resonators. The tunability of the filter is investigated through simulation.

No description available.

Colorectal tumors with mutations on Wnt family members show an overexpression of several Notch target genes, suggesting a link between Wnt and Notch signaling pathways. In this work, we have demonstrated that there is a direct relation between Wnt and Notch pathways that it is responsible for the maintenance of the intestinal proliferative compartment and crucial for intestinal tumorigenesis. We have identified two different mechanisms through β-catenin interacts with Notch to activate transcription: 1) β-catenin activates Notch through the transcriptional activation of Notch ligand Jagged1. Jagged1 expression leads the binding to the Notch receptor, promoting its cleavage and activation. This mechanism occurs in human colorectal tumors, with nuclear β-catenin, overexpressed Jagged1 and activated Notch. 2) β-catenin and Notch bind simultaneously to a specific group of gene promoters. We observed that this group of genes is overexpressed in tumours with mutations in Wnt signaling. Moreover, β-catenin and Notch physically interact in the nucleus of colorectal tumour cell lines. We have characterized a group of genes that are double target genes for β-catenin and Notch; in other words, these genes require the activation of both Wnt and Notch signaling pathways. These genes are expressed in the intestinal undifferentiated compartment. The loss of any of these signalling pathways reduced stem cell marker expression, reinforcing the importance of the interaction between both signalling pathways. The study of conditional knockouts mice for Jagged1 indicated that Jagged1 is not required for maintaining the intestinal homeostasis. However, Jagged1 is crucial during the tumorigenic process. Our data opens a new possibility for colorectal treatment, using inhibitors of Notch ligand Jagged1, avoiding side effects in the intestinal normal tissue.

Bridges form a vital link in the physical infrastructure and must be maintained in a "safe working order" at all times. It is estimated that there are currently 20,000 timber road bridges in service throughout Australia. Increasing demands on these bridges due to heavier and faster moving loads, together with deterioration are placing these aging structures at a higher risk of collapse. Unfortunately, many local governments and government departments have neglected the benefits of preventative maintenance and have opted for "just in time" repairs. This is especially true for timber bridges. This past neglect has placed bridge stock in a poor state that is only now being recognised as a significant problem. A key component of this research is to develop improvements to this current situation. This research thesis generates detailed knowledge on the load carrying capacities of timber bridges and new non destructive testing techniques that can be substituted for conventional testing procedures. For the first time guidelines have been developed for undertaking capacity assessment on timber bridges by specifying intervention levels for notched timber and limiting maximum allowable strains in timber members. This newly acquired knowledge will enable Asset Managers to more accurately determine the capacity of sniped timber bridge girders to enable appropriate retrofitting and maintenance while also allowing the safe movement of heavy vehicles. The knowledge generated through destructive testing of timber girders and the analysis of the vast amount of experimental data has enabled the first instance of developing specifications for replacement girders. These specifications detail both functional and performance related targets for three different types of replacement girders. Testing of these replacement girders also demonstrates that through some minor modifications that the specification targets can be met. The outcomes of this thesis provide an innovative approach to accessing the condition and capacity of timber girders and to increasing the safety and life of timber bridges in Queensland. By using new techniques such as Non-destructive testing, species identification and limiting maximum allowable strains, as described in this thesis, the road transport network can be safety used by heavy and permit vehicles. It is only through the effective management of timber bridge maintenance and rehabilitation that Australia can have an efficiently running road transportation network.