Alcoholism is a devastating chronic relapsing disorder with significant costs to individuals and society. The mesolimbic dopamine (DA) system plays an important role in regulating reward and addiction. GABA neurons located in the ventral tegmental area (VTA) regulate VTA DA neuron activity, and are a relevant target for alcohol in the brain. VTA GABA neurons exhibit marked hyperexcitability during withdrawal from ethanol. Past research has demonstrated that the motivational effects of opiates cause a change in VTA GABA(A) receptors in opiate-dependent animals, which switch from a GABA-induced hyperpolarization of GABA neurons to a GABA-induced depolarization. The focus of this study was to characterize excitatory and inhibitory synaptic activity in VTA GABA neurons during withdrawal from acute and chronic alcohol, and to evaluate the function of the GABA(A) receptor in the pathway to dependence. Animals were either given injections of ethanol or saline, or were kept in ethanol vapor or air chambers for three weeks. We used standard whole-cell, perforated patch, and cell-attached mode electrophysiological techniques and pharmacology to obtain recordings of cellular activity. Results for excitatory and inhibitory synaptic events were somewhat mixed and inconclusive. There is evidence for a shift in function of the GABA(A) receptor after exposure to ethanol. We found that after a single injection of ethanol (4.0 g/kg) or a chronic intermittent ethanol vapor exposure, VTA GABA neuron firing rate is less sensitive to muscimol's inhibitory effects. The neural substrates of addiction studied here are important steps in the road to alcohol dependence, and a better understanding of them may lead to novel therapies.

Equal channel angular pressing ECAP is a process whereby simple shear is applied to a billet during multiple passages through an angled channel of constant cross section. The process is capable of generating very large plastic strains that significantly refines the microstructure without altering the external dimensions of the billet. A number of properties are influenced by grain refinement with the generation of a submicron grain structure SMG by ECAP resulting in improved strength and hardness and enhanced superplasticity. In this thesis, both an AA7075 alloy and AA7075 Al-base metal matrix composite MMC reinforced with 5 wt. percent of 50 nm diameter SiC particles was produced by a powder metallurgy route followed by hot extrusion. The materials were subsequently deformed by ECAP at 350 C to a true effective strain of 4.6 in an attempt to refine the microstructure and further distribute the SiC reinforcement phase in the composite. The high temperature microstructural stability of both the as-deformed alloy and composite was investigated to elucidate the effect of the reinforcement phase on continuous and discontinuous grain coarsening. It was found that ECAP generated a fine equiaxed grain size of ~ 2.3 !m and ~1.8 !m in the alloy and composite, respectively. The composite was more refined after ECAP since the SiC particles allow the matrix to undergo more grain refinement during deformation. ECAP was found to be a reasonable method for further distributing SiC clusters in this composite which is important for optimizing the reinforcement phase in terms of ambient temperature strengthening and enhanced grain stability at elevated temperature. Both the alloy and composite were annealed at times up to 5h at 500 C to assess grain stability. During annealing, the grain structure of both materials evolved in a continuous manner unlike the discontinuous process of recrystallization. Such a process is similar to continuous recrystallization observed in a range of heavily deformed Al alloys. Substantial grain boundary interactions with MgZn2 precipitates and oxide particles were found in the alloy, with precipitate, oxide and SiC particles found in the composite. The strong pinning force exerted by these particles minimised grain growth in both materials with the composite exhibiting a finer less than 2.5 !m grain size than the alloy less than 3.5 !m after extended annealing. This enhanced grain stability was attributed to the high volume fraction SiC particles which resulted in a large value of the dispersion parameter f/d which results in significant boundary pinning during annealing. Grain stability was also analysed in terms of a recently-proposed mean field model of annealing where it was predicted that the composite should not undergo discontinuous coarsening, as observed experimentally.

Evolutionary processes in any population depend upon patterns of phenotypic variation available to selection and their underlying heritability. In this thesis, I used the filamentous red seaweed Asparagopsis armata, with particular focus on its modularity, to test several key questions underlying its growth-form evolution in heterogeneous environments. I established that experimental manipulations of light quantity and quality mimicking variation in underwater light due to shading or depth induce growthform plasticity in A. armata that may be evolutionarily significant given its variability among clones. Current patterns of plasticity displayed by A. armata appear adaptive, moreover, given that a reciprocal transplant of phenotypes between light environments found densely-branched (phalanx-like) phenotypes to have higher relative growth rates than sparsely-branched (guerrilla-like) phenotypes in well-lit patches, but lower relative growth rates than the latter in shaded patches. Using the capacity for rapid growth as a proxy for fitness, multivariate selection analyses identified environment-dependent patterns of directional selection on single traits coupled with linear and nonlinear selection on multi-trait combinations that shape growth-form variation within patches of differing light intensity, thereby reinforcing plasticity across light environments. Quantitative genetic analyses, however, suggest that the modular iteration of genes in morphogenesis may limit further growth-form evolution in A. armata populations exposed to spatial heterogeneity in light by constraining thallus responses to environment-dependent selection. Last, heritable responses to artificial selection on growth-form variation among clonal cell-lineages revealed the surprising capacity for A.armata to circumvent genetic constraints inherent to its development by adapting to environmental change in the absence of sexually-generated variance among clones.

The phenomenological approaches to embodiment presented by Levinas and Merleau-Ponty cannot provide an adequate account of bodily identity because their methodological commitments forbid them from admitting the central role that sensation plays in the constitution of experience. This neglect is symptomatic of their tradition's suspicion toward sensation as an explanatory concept, a suspicion stemming from Kant's critique of empiricist metaphysics and Husserl's critique of psychologism and objectivism. By contrast, I suggest that only with a robust theory of sensation can the integrity of the body and its relations be fully captured. I therefore develop--contra Kant and Husserl's idealism--a realist conception of sensation that is at once materialist and phenomenological. / McAnulty College and Graduate School of Liberal Arts; / Philosophy / PhD; / Dissertation;

This paper summarizes a recently developed continuum theory for the elastic-viscoplastic deformation of amorphous solids such as polymeric and metallic glasses. Introducing an internal-state variable that represents the local free-volume associated with certain metastable states, we are able to capture the highly non-linear stress-strain behavior that precedes the yield-peak and gives rise to post-yield strain-softening. Our theory explicitly accounts for the dependence of the Helmholtz free energy on the plastic deformation in a thermodynamically consistent manner. This dependence leads directly to a backstress in the underlying flow rule, and allows us to model the rapid strain-hardening response after the initial yield-drop in monotonic deformations, as well as the Bauschinger-type reverse-yielding phenomena typically observed in amorphous polymeric solids upon unloading after large plastic deformations. We have implemented a special set of constitutive equations resulting from the general theory in a finite-element computer program. Using this finite-element program, we apply the specialized equations to model the large-deformation response of the amorphous polymeric solid polycarbonate, at ambient temperature and pressure. We show numerical results to some representative problems, and compare them against corresponding results from physical experiments. / Singapore-MIT Alliance (SMA)

EphrinB ligands and their Eph receptor tyrosine kinases are known to regulate excitatory synaptic functions in the hippocampus. In the CA3-CA1 synapse, ephrinB ligands are localized to the post-synaptic membrane, while their cognate Eph receptors can be expressed in both pre-and post-synaptic membranes. Previous studies show that interaction of ephrinB molecules with Eph receptors leads to changes in long-term potentiation (LTP), suggesting that reverse signaling through postsynaptic ephrinBs may be required for learning and memory. Our collaborative studies demonstrate that the cytoplasmic domain of ephrinB3, and hence reverse signaling, is not required for ephrinB-dependent learning and memory tasks or for LTP of these synapses. We demonstrate that ephrinB3 null mutants show changes in several synaptic proteins including reduced levels of NMDA receptor subunits. These abnormalities are not observed in ephrinB3lacZ reverse signaling mutants, supporting an Eph receptor forward signaling role for ephrinB3 in these processes. NMDA receptors are important in regulating synaptic functions and plasticity in the adult hippocampus, and Eph receptors have been shown to cluster NMDA receptors to the cell membrane. These studies show that ephrinB3 interacts with EphA4 to regulate plasma membrane levels of NR1 in Cos-1 cells and primary hippocampal neurons. In the absence of ephrinB3, NR1 levels are decreased in synaptosomal membranes, increased in microsomal tissues, but not changed in total extracts. This suggests that ephrinB3 regulates NR1 levels through protein trafficking and not gene transcription. Analysis of protein trafficking confirmed that ephrinB3 specifically interacts with EphA4 receptor to regulate NR1 exocytosis but not endocytosis in both transfected Cos-1 cells and primary hippocampal neurons. We postulate that ephrin-Eph receptor interactions are important mediators of synaptic formation and function, in part, through their regulation of NMDA receptors in the hippocampal synapse. In addition, we find that both ephrinB3KO and ephrinB3lacZ mice show an increased number of excitatory synapses, demonstrating a cytoplasmic-dependent reverse signaling role of ephrinB3 in regulating synapse number. Together, these data suggest that ephrinB3 may act like a receptor to transduce reverse signals to regulate the number of synapses formed in the hippocampus, and that it likely acts to stimulate forward signaling through Eph receptors to modulate NMDA receptor trafficking, LTP and learning.

Thesis (M.S.)--Brigham Young University. Dept. of Mechanical Engineering, 2005. / Includes bibliographical references (p. 115-118).

This study presents a method for predicting the undrained behavior of plate anchors, including out-of-plane loading of simple plates and performance of suction embedded plate anchors (SEPLA). Three dimensional finite element models are used to investigate the behavior of square and rectangular plate anchors under normal loading with eccentricity in any direction. Upper bound analyses are performed for parallel loading and torsion loading. A simple model is then fit to the FE and upper bound solutions to determine required fitting parameters for both square and rectangular plates. The simple models can, in turn, be used both to predict anchor capacity and as yield surfaces for conducting plastic limit analyses, a method capable of predicting post yield anchor trajectory. The model predictions are shown in reasonable good agreement with the experimental results. For SEPLA, a theoretical model of plastic limit analysis is developed to predict the trajectory during the “keying” process and the ultimate capacity after the “keying” is complete. The predicted results are consistent with relevant known solutions.

This thesis includes four studies designed to improve the ability to predict and assess language representation in healthy children and/or individuals with neurological disorders arising in childhood. In the first study, the role of pathology type on interhemispheric plasticity of language was determined by comparing lateralization in children with developmental, acquired, and tumour pathologies. Findings from 105 consecutive intracarotid sodium amobarbital procedures were retrospectively analyzed, revealing no lateralization differences between pathology groups. In the second study, a novel verb generation paradigm and magnetoencephalography (MEG) were used to determine the spatial-temporal characteristics of language expression in healthy subjects (n = 12) and children with neurological disorders (n = 4). Time-frequency and differential beamformer analyses revealed low-beta event-related desynchronization (ERD) in the left inferior frontal lobe for verb generation. The paradigm was well-tolerated by all subjects. The third study involved assessment of expressive language lateralization in 25 healthy subjects, aged 5-18 years, using two novel MEG paradigms: covert picture naming and verb generation. Novel analyses permitted objective quantification of ERD lateralization on an individual basis. For both tasks, left lateralization of frontal lobe ERD tended to increase with advancing age. Findings suggest that adult-typical left lateralization emerges from an early bilateral language network in normal development. In the fourth study, frontal lobe ERD lateralization for naming and verb generation was characterized in 14 children and adolescents with neurological disorders. Novel analyses permitted objective assessment of individual scans at multiple contrast time windows. In several cases, rapid hemispheric shifts in predominant frontal lobe ERD were observed through the response period. On an individual basis, the assessment protocol showed promise for future use in a presurgical context. These studies serve to advance the understanding of normal paediatric language representation, and improve the ability to predict and assess language lateralization in individuals who have experienced early neurological insults.

This thesis includes four studies designed to improve the ability to predict and assess language representation in healthy children and/or individuals with neurological disorders arising in childhood. In the first study, the role of pathology type on interhemispheric plasticity of language was determined by comparing lateralization in children with developmental, acquired, and tumour pathologies. Findings from 105 consecutive intracarotid sodium amobarbital procedures were retrospectively analyzed, revealing no lateralization differences between pathology groups. In the second study, a novel verb generation paradigm and magnetoencephalography (MEG) were used to determine the spatial-temporal characteristics of language expression in healthy subjects (n = 12) and children with neurological disorders (n = 4). Time-frequency and differential beamformer analyses revealed low-beta event-related desynchronization (ERD) in the left inferior frontal lobe for verb generation. The paradigm was well-tolerated by all subjects. The third study involved assessment of expressive language lateralization in 25 healthy subjects, aged 5-18 years, using two novel MEG paradigms: covert picture naming and verb generation. Novel analyses permitted objective quantification of ERD lateralization on an individual basis. For both tasks, left lateralization of frontal lobe ERD tended to increase with advancing age. Findings suggest that adult-typical left lateralization emerges from an early bilateral language network in normal development. In the fourth study, frontal lobe ERD lateralization for naming and verb generation was characterized in 14 children and adolescents with neurological disorders. Novel analyses permitted objective assessment of individual scans at multiple contrast time windows. In several cases, rapid hemispheric shifts in predominant frontal lobe ERD were observed through the response period. On an individual basis, the assessment protocol showed promise for future use in a presurgical context. These studies serve to advance the understanding of normal paediatric language representation, and improve the ability to predict and assess language lateralization in individuals who have experienced early neurological insults.