Thesis (M.Eng.)--Memorial University of Newfoundland, 1999. / Bibliography: leaves 86-88.

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The healthy immune system is a delicate and precisely orchestrated balance between activation and suppression. It is well established that regulatory T cells (Tregs) have substantial immunosuppressive properties and play a pivotal role in maintaining this balance. Many autoimmune states have been characterized by disproportionately high numbers of T effector cells, and comparatively low numbers of regulatory T cells (Hori et al., 2003; Sakaguchi et al., 1995; Choileain et al., 2006). Furthermore, mouse models in which regulatory T cells are removed or rendered ineffective show rapid development of autoimmunity. It is therefore hypothesized that regulatory T cells are essential to the acquisition and maintenance of self-tolerance. Type 1 diabetes is an increasingly common autoimmune condition, with 30,000 new diagnoses each year (JDRF Fact Sheet). Pancreatic islet transplantation holds great promise as a potential cure for this difficult disease; however human trials have had limited success. Attempts to promote self-tolerance or maintain a physical barrier to the transplanted islets have largely failed (Groot et al., 2004). Because of this, insulin dependence normally resumes fiver years post-operation. The deleterious effects of long-term immunosuppression to promote extended islet survival are considered too great to justify this treatment. Because of their important role in promoting self-tolerance, many immunologists believe regulatory T cells are the key to developing tolerance of islet allograft tissue. Rapamycin and anti-CD154 are immunoregulatory treatments that specifically inhibit the activation of T effector cells and promote the growth of regulatory T cell populations. As regulatory T cell numbers increase, self-tolerance is established and the need for immunosuppressant drugs is eliminated. Unfortunately, treatments such as anti-CD154 and rapamycin have had limited success due to the ability of toll-like receptor (TLR) pathways to bypass such activation blockades. TLR stimulation results in a potent and direct activation that acts to bolster the immune response. This TLR activation results in the release of inflammatory cytokines, which render regulatory T cells unstable. Regulatory T cells have been shown to adopt effector phenotypes in such environments and may have pathogenic potential. This study aims to elucidate aspects of Treg plasticity that result from TLR activation. In vitro models were used to demonstrate how TLR agonists change Treg phenotypic expression. Our findings indicate that the presence of lipopolysaccharides (LPS) has a relatively significant effect on regulatory T cell phenotypes. Specifically, our findings indicate that LPS causes increased GATA3 expression in Tregs, promoting differentiation to a TH2 phenotype (p= 0.0543). Regulatory T cells were also examined for the expression of RORγt and Tbet transcription factors. Neither transcription factor was significantly expressed, indicating the absence of TH17 and TH1 phenotypes, respectively. It is also worth noting that stability of the foxp3 transcript appeared to be greater in cells treated with LPS, than in those without (p= 0.0009). In addition, this study utilized an in vivo model for tracking regulatory T cell changes after pancreatic islet transplantation. Diabetic reporter mice received pancreatic islet transplants, as well as TLR agonist to induce allograft rejection. Mice were treated with rapamycin, anti-CD154 and TLR agonist. After 12 days, regulatory and ex-regulatory T cells were harvested from the transplanted area and analyzed. This experiment is still in progress and results have yet to be determined. This study establishes proof of concept of an effective system for the study of regulatory T cell plasticity. Additional investigation must be done in order to more thoroughly understand these important cells. This study is not complete, but our progress thus far is a strong foundation for further experimentation.

The ability of neurons to regulate their activity (homeostatic plasticity) is thought to be responsible for changes in neural responsiveness/gain induced by sensory deprivation, or augmented stimulation. For example, following auditory deprivation, excitatory and inhibitory synaptic transmission is strengthened and weakened, respectively. Abnormally high neural gain results in an 'over amplification' of spontaneous and stimulus-evoked firing rates, and may result in aberrant auditory perceptions including tinnitus and/or hyperacusis, respectively. The first manuscript in the thesis 'Pump up the Volume' (Chapter Three) provides a summary of the neural gain mechanism in the adult auditory system. Aspects of neural gain, including temporal characteristics and frequency specificity, had not been systematically investigated. Therefore, the aim of this thesis was to investigate characteristics of the neural gain mechanism. The thesis comprises three related studies involving normal hearing adult listeners: two studies involved short term sensory deprivation and one study involved short term augmented stimulation. The main outcome measures were the acoustic reflex threshold (ART), auditory brainstem response (ABR) and loudness. In Study One, the time course, frequency specificity and anatomical location of changes in the ART, following 6 days of unilateral earplug use (ca 30 dB attenuation at 2-4 kHz), were investigated. The reduction in ART in the treatment ear was greatest at day 4 and at frequencies most attenuated by the earplug. Ipsilateral and contralateral ARTs were similar when stimuli were presented to the treatment ear. ARTs were not statistically significant from baseline when measured 4 and 24 hours after earplug removal. In Study Two, the ART and ABR were measured at baseline and after 7 days of unilateral and bilateral hearing aid use (13-17 dB real ear insertion gain), to compare the effect of symmetrical and asymmetrical inputs. There was no change in ART and ABR after treatment, suggesting that the augmented stimulation was insufficient to modify neural gain. In Study Three, ARTs, ABRs and loudness were investigated after 4 days of unilateral earplug use (30 dB attenuation at 2-4 kHz). There was a significant reduction in ART (ca 6 dB) in the treatment ear, which returned to baseline within 1-2 hours of earplug removal. There was an unexpected but significant 35 nV decrease in the ABR wave V peak-to-trough amplitude in the treatment ear, and a 12 nV increase in the control ear. The change in ABR was opposite in direction to the change in ART. There was no change in loudness. The thesis has provided information on the threshold of deprivation/stimulation required to elicit a change in neural gain, along with the frequency specificity and temporal characteristics of the gain control mechanism. The anatomical location for changes in neural gain is around the level of the cochlear nucleus. The change in ABR was in the opposite direction to those predicted, but could be due a difference in the compensatory changes of contralateral and ipsilateral inputs at the level of the inferior colliculus.

Dans le cadre de l’étude du couplage entre la plasticité et les interactions de l’hydrogène avec les matériaux métalliques, l’objectif de ce travail de thèse est l’implémentation dans le code de calcul par éléments finis Abaqus© de la loi de diffusion de l’hydrogène couplée aux champs mécaniques, tenant compte notamment du piégeage dû à la déformation plastique. La stratégie d’implémentation retenue permet de résoudre simultanément les problèmes de diffusion et de mécanique ; elle s’est appuyée sur les travaux de la littérature, et a nécessité le développement de procédures en fortran 77, et en particulier, de procédures utilisateur UMAT et UMATHT permettant de définir respectivement le comportement mécanique, et un flux de matière. Ces procédures ont été confrontées avec succès à plusieurs cas de la littérature. Les outils développés ont été appliqués à l’étude numérique d’un essai de pliage en U, utilisé pour la caractérisation de la rupture différée par fragilisation par l’hydrogène de tôles minces prédéformées plastiquement. Une étude paramétrique portant sur les conditions de l’essai, les conditions limites en hydrogène et la relation entre plasticité, hydrogène piégé et hydrogène diffusif a été menée. Enfin, une transposition à l’échelle du polycristal 3D a été effectuée, en utilisant une procédure UMAT de comportement polycristallin modifiée. Une étude sur les paramètres constitutifs d’un Volume Elémentaire Représentatif a été réalisée, puis, une étude de l’essai en U à l’échelle du polycristal effectuée grâce à un transfert de conditions limites entre un calcul global et le VER, afin de simuler l’effet de l’anisotropie cristalline sur les champs de concentration d’hydrogène. / In the framework of the coupling between plasticity and hydrogen interactions with the metallic material, the aim of this thesis is to implement in the finite element code Abaqus © the hydrogen diffusion law coupled with the mechanical fields, accounting particularly for the trapping caused by the plastic strain. The chosen implementation strategy allows to simultaneously solve the diffusion and mechanical problems. It is based on works from the literature and needs the development of procedures in fortran 77, in particular the user procedures UMAT and UMATHT allowing the definition of the mechanical behavior and the material flux respectively. These procedures were confronted with several cases in literature. The developed procedures were applied to the numerical study of the U-bend test, used for characterizing the delayed cracking caused by hydrogen embrittlement. A parametric study on test conditions, boundary conditions on hydrogen and relationship between plasticity, trapped hydrogen, diffusive hydrogen was carried out. Finally, a transposition to the scale of a 3D polycristal was performed using a modified UMAT procedure with crystalline elastoviscoplasticity. A numerical study on the relevant parameters for defining a Representative Volume Element was carried out. Then, the simulation of a virtual u-bend test at the polycristal scale was performed thanks to a boundary condition transfer between global calculation and the RVE, in order to simulate the effect of crystal anisotropy on hydrogen concentration field.

Phenotypic plasticity is the ability of the single genotype to pruduce multiple phenotypes in response to evironmental conditions. There are many factors affecting phenotypic plasticity. The aim of this thesis is to summarize the current knowledge of phenotypic plasticity of aquatic insects with emphasis on the role of temperature and food availability. The review is complemented by a laboratory experiments designed to investigate the effect of temperature and food availability on growth and development rate of diving beetle Acilius canaliculatus (Coleoptera: Dytiscidae). The results are discussed in the light of the ecological concepts of temperature-size rule and developmental isomorphy.

Amputation induces substantial reorganization of the body part somatotopy in primary sensory cortex (S1), and these effects of deafferentation increase with time. Determining whether these changes are reversible is critical for understanding the potential to recover from deafferenting injuries. Here, we report evidence that the representation of a transplanted hand and digits can actually recapture the pre-amputation S1 hand territory in two transplant patients. With limited sensation 4 months post operation, one of the patient's (D.S.) palmar tactile stimulation evoked contralateral S1 responses that were indistinguishable in location and amplitude from those detected in healthy matched controls. The other patient (M.S.) demonstrated not only much improved sensation but also recovered ability to localize tactile stimuli 120+ months after the operation. The results described suggest that even decades after complete deafferentation, restoring afferent input to S1 leads to re-establishment of the gross hand and digits representations within their original territory. Stimulation of the deafferented cortical maps may play an important role in maintaining their viability until the afferent input is restored. Motor imagery and creation of virtual visual feedback of the absent hand with a mirror have been proposed as stimuli. We used fMRI to record neural activity while 11 unilateral hand amputees and matched controls performed aurally-paced thumb-finger sequencing movements with their intact hand (matching hand in case of controls) under visual guidance during four conditions: 1) intact hand (ME), 2) ME with motor imagery of the amputated hand, 3) ME with virtual visual feedback of the amputated hand, and 4) ME with motor imagery and the virtual visual feedback of the amputated hand. In contrast to controls, amputees showed increases in activity during all four conditions within the former functionally-defined sensorimotor hand territory. Movements of the intact hand likely increase activity in the former hand territory as a result of decreased interhemispheric inhibition. This stimulation may maintain deafferented hand representations that can recover soon after the afferent input is restored by hand transplantation.

Phenotypic plasticity is the ability of the single genotype to pruduce multiple phenotypes in response to evironmental conditions. There are many factors affecting phenotypic plasticity. The aim of this thesis is to summarize the current knowledge of phenotypic plasticity of aquatic insects with emphasis on the role of temperature and food availability. The review is complemented by a laboratory experiments designed to investigate the effect of temperature and food availability on growth and development rate of diving beetle Acilius canaliculatus (Coleoptera: Dytiscidae). The results are discussed in the light of the ecological concepts of temperature-size rule and developmental isomorphy.

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