We sought to evaluate the individual contributions of Notch1 and PKC-ζ to disease progression in a mouse model of immune-mediated bone marrow failure and to define a mechanism for their potential cellular cooperation. We transferred parental bulk splenocytes into F1-hybrid recipients to induce a robust immune-mediated bone marrow failure (BMF) that we could partially rescue by administering a pharmacological inhibitor of Notch activation. Transferring splenocytes from PKC--ζ-/- animals did not induce disease, and treating animals with a pharmacological inhibitor of PKC-ζ also provided full protection from disease. We found that inhibiting Notch1 resulted in PKC-ζ down-regulation, and blocking PKC-ζ reduced Notch1 activation, possibly within a positive feedback loop. Our data suggest that both Notch1 and PKC-ζ contribute to disease progression in our mouse model of immune-mediated bone marrow failure. Furthermore, additional findings from the lab demonstrated physical interactions between Notch1, members of the T cell signalosome and PKC-ζ that are essential to mediating full activation of T cells following signaling through the TCR and CD28. Notch1 and/or PKC-ζ may represent novel therapeutic targets in the treatment of bone marrow failure.

<p> An improvement on the synthesis of a distributed RC notch filter, by computer-aided design techniques, is appraised. A brief presentation of the synthesis of thin-film RC tapered networks is made, along with applied uses of computer-aided design to RC distributed networks, particularly in the realizability of certain RC transfer functions.</p> <p> The preparation of the problem, accompanied by different methods of approach, is explained. Included are criticisms made, leading to the reasons for abandoning the more tasking ones.</p> <p> The Adjoint Network method of determining, gradients, with respect to circuit adjustable parameters, is evaluated fully, and the important use which it lends to the optimization problem is demonstrated. The outcome of the design approaches are given in tables, with theoretical responses compared in graphs. Actual circuit responses are indicated in photographs, and comparisons with theoretical responses are shown in graphs.</p> / Thesis / Master of Engineering (MEngr)

<p> Small scale tests were utilized in order to obtain characteristic fracture mechanics parameters such as the crack opening displacement (C.O.D.) and the J-integral. Two main types of steels were used (H.S.L.A. and AISI 4340) in obtaining data over a wide range of yield strengths and ductilities. Tests were done to see the effect of both notch geometry and sample geometry·in one of the H.S.L.A. steels, and it is verified that the minimum value of C.O.D., at crack initiation in plane strain, is independent of the geometry and plastic zone size. Further the development of a simple single specimen J-integral test method is done during this work. In terms of the data obtained both the minimum C.O.D.i values and the Jlc values increase with increasing ductility of the materials tested. In the attempt to relate the magnitude of the fracture toughness with microstructural parameters and the limiting processes occuring at the crack tip prior to fracture, the concept of the process zone is discussed. For this study a simple plain carbon steel spheroidized with different carbon contents was examined in addition to the H.S.L.A. and 4340 steels. From the data obtained the minimum C.O.D.i at crack initiation was found to be approximately equal to the product of the materials plain strain ductility and a characteristic distance scaling with the spacing between large non metallic inclusions or the spacing between the bands of the sulphides. </p> / Thesis / Master of Engineering (MEngr)

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