The genetic mechanisms underlying the specification of thymic epithelial (TE) lineage cells are poorly understood. Foxn1 is an early specific marker of thymic epithelial cells (TECs) in the third pharyngeal pouch (3PP) and is required for development of all mature TE lineage cells but does not specify the TE lineage. The upstream regulators of Foxn1 are currently unknown, however evidence points to a potential role for Pax1 and Pax9. While the thymus phenotypes of the Pax1-/- and Pax9-/- mutant mice have been investigated in detail and TECs in these mice are known to express Foxn1, the possibility of functional redundancy exists and the compound mutants of these genes have not been studied. Therefore, the aim of this thesis was to test the hypothesis that Pax1 and Pax9 are required for TE lineage specification and regulation of Foxn1 expression. This hypothesis was addressed by analysis of thymus development and TEC function in Pax1/Pax9 compound mutant mice. The data presented in this thesis indicates that prenatally, Pax1 and Pax9 cooperatively regulate thymus organogenesis, such that the size, structure and location of the thymus is affected in a Pax1/Pax9 gene dosage-dependent manner, and the Pax1unex/unexPax9lacZ/lacZ embryo is functionally athymic. Furthermore, they establish that the thymic rudiment of Pax1unex/unexPax9lacZ/lacZ embryos does not express Foxn1, establishing that Pax1 and Pax9 are required together for the initiation of Foxn1 and suggesting they are required to specify the TEC lineage. Postnatally, enlarged blood vessels observed in the Pax1unex/unex thymus suggested a role for Pax1 in vascularisation of the thymus. In addition, the effect of loss of one or more Pax1/Pax9 alleles on the expression of Foxn1 and other genes known to regulate TEC development or function was assessed. These data demonstrate that Pax1 and Pax9 co-operate to regulate Foxn1 in a dosage-dependent manner. Furthermore, Pax1 and Pax9 appear to negatively regulate both Hoxa3 and Vegfa, providing a possible explanation for the enlarged blood vessels in the postnatal Pax1unex/unex thymus. Finally, an inducible and reversible recombinase-mediated cassette exchange system that will allow the knockdown of Pax1 and Pax9 at defined time points during development has been established, that has the potential to test the function of these genes during thymus organogenesis and in the postnatal thymus.

Thymic epithelial cells (TECs) are indispensable for the development of T cells in the thymus. Two subtypes of TECs exist in the thymus, medullary mTECs and cortical cTECs. Both mTECs and cTECs originate from endodermal thymic epithelial progenitor cells (TEPCs) in the embryo, but how the differentiation of TEPCs is regulated is not well understood. The aims of this thesis were to establish the role of Notch signalling in TEPC differentiation, and how it interacts with known regulators such as FOXN1 and the NFκB pathway. Gene expression data showed that Notch is active in TEPCs and exhibits a correlation with the mTEC lineage. Loss of Notch function led to a significant reduction in the number of mTECs in the thymus, and this can be attributed to aberrant mTEC specification. Furthermore, the duration of Notch activity in determining mTEC number appears limited to the early phase of organogenesis, and precedes RANK/NFκB mediated mTEC proliferation. Gain of Notch function resulted in a considerable shift to a primitive, TEPC-like phenotype, and subsequently a latent increase in mTEC frequency. Finally, transcriptomic and functional analyses pointed to a cross-repressive mechanism between Notch and FOXN1 in TEPCs. Taken together, these results identified Notch as a novel regulator of mTEC specification, likely through maintaining the potency of fetal TEPCs, a prerequisite for mTEC lineage commitment.

There are two traditional aircraft categories: fixed-wing which have a long endurance and a high cruise airspeed and rotorcraft which can take-off and land vertically. The tailsitter is a type of aircraft that has the strengths of both platforms, with no additional mechanical complexity, because it takes off and lands vertically on its tail and can transition the entire aircraft horizontally into high-speed flight. In this dissertation, we develop the entire control system for a tailsitter with a ducted fan. The standard method to compute the quaternion-based attitude error does not generate ideal trajectories for a hovering tailsitter for some situations. In addition, the only approach in the literature to mitigate this breaks down for large attitude errors. We develop an alternative quaternion-based error method which generates better trajectories than the standard approach and can handle large errors. We also derive a hybrid backstepping controller with almost global asymptotic stability based on this error method. Many common altitude and airspeed control schemes for a fixed-wing airplane assume that the altitude and airspeed dynamics are decoupled which leads to errors. The Total Energy Control System (TECS) is an approach that controls the altitude and airspeed by manipulating the total energy rate and energy distribution rate, of the aircraft, in a manner which accounts for the dynamic coupling. In this dissertation, a nonlinear controller, which can handle inaccurate thrust and drag models, based on the TECS principles is derived. Simulation results show that the nonlinear controller has better performance than the standard PI TECS control schemes. Most constant altitude transitions are accomplished by generating an optimal trajectory, and potentially actuator inputs, based on a high fidelity model of the aircraft. While there are several approaches to mitigate the effects of modeling errors, these do not fully remove the accurate model requirement. In this dissertation, we develop two different approaches that can achieve near constant altitude transitions for some types of aircraft. The first method, based on multiple LQR controllers, requires a high fidelity model of the aircraft. However, the second method, based on the energy along the body axes, requires almost no aerodynamic information.

This thesis examines how the right of free movement of persons is governed through surveillance databases represented as security measures by applying the governmentality perspective. In order to do that, the study focuses on the relationship between freedom of movement, security and surveillance databases in the European Union such as Schengen Information System (SIS), European Dactylographic System (EURODAC) and the Europol Computer System (TECS). The main argument of the thesis is to analyze the role of surveillance databases in controlling the free movements of certain kinds of people that are seen as a &quot / threat&quot / to the European internal security.

No description available.