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The discovery of large, room temperature magnetoresistance (MR) in magnetic tunnel junctions in 1995 sparked great interest in these devices. Their potential applications include hard disk read head sensors and magnetic random access memory (MRAM). However, the fabrication of repeatable, high quality magnetic tunnel junctions is still problematic. This thesis investigates methods to improve and quantify the quality of tunnel junction fabrication. Superconductor-insulator-superconductor (SIS) and superconductor-insulator ferromagnet(SIF) tunnel junctions were used to develop the fabrication route, due to the ease of identifying their faults. The effect on SIF device quality of interchanging the top and bottom electrodes was monitored. The relationship between the superconducting and normal state characteristics of SIS junctions was investigated. Criteria were formulated to identify devices in which tunneling is not the principal conduction mechanism innormal metal-insulator-normal metal junctions. Magnetic tunnel junctions (MTJs) were produced on the basis of the fabrication route developed with SIS and SIF devices. MTJs in which tunneling is the principal conduction mechanism do not necessarily demonstrate high MR, due to effects such as magnetic coupling between the electrodes and spin scattering. Transmission electron microscope images were used to study magnetic tunnel junction structure, revealing an amorphous barrier and crystalline electrodes. The decoration of pinholes and weak-links by copper electrodeposition was investigated. A new technique is presented to identify the number of copper deposits present in a thin insulating film. The effect of roughness, aluminium thickness and voltage on the number of pinholes and weak-links per unit area was studied. High frequency testing of read heads at wafer level was performed with a network analyser. Design implications for read head geometry were investigated, independent of magnetic performance. This technique has great potential to aid the rapid development of read and write heads whilst improving understanding of the system.

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Gap Junctions als wichtigste Elemente der Zelle zur Ermöglichung einer interzellulären Kommunikation erlauben eine koordinierte Antwort auf externe und interne Stimuli und somit ein Zusammenspiel von Zellgruppen und Organen im Gesamtorganismus. In der vorliegenden Arbeit wurde der Einfluss einer mittelfristigen und chronischen Stimulation neonataler Rattenkardiomyozyten durch Insulin und den Wachstumsfaktoren Insulin-like Growth Factor-1 (IGF-1), Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor-β (TGF-β) und Fibroblast Growth Factor-2 (FGF-2) auf die Expression der Connexine 40, 43 und 45 untersucht. Dabei zeigte sich unter der Insulin-Stimulation eine konzentrationsabhängige Regulation der Connexin 43 (Cx43) Expression. Die Exposition gegenüber IGF-1 hatte einen signifikanten Anstieg der Cx43 Proteinmenge zur Folge. Unter 24stündiger VEGF- oder FGF-2-Stimulation fand sich dagegen diesbezüglich kein relevanter Unterschied. Die Analysen nach langfristiger Exposition gegebenüber TGF-β zeigten eine signifikante Abnahme der Cx43 Proteinmenge bei unveränderter Cx43 mRNA. Zur Erfassung mittelfristiger Veränderungen wurden die Kardiomyozyten jeweils 3 Stunden mit den Wachstumsfaktoren VEGF und TGF-β inkubiert. Dabei zeigte sich jeweils eine signifikante Zunahme der Cx43 Proteinmenge und –mRNA. Die Connexine 40 und 45 waren in den ventrikulären Kardiomyozyten nur spärlich nachweisbar und durch keinen der untersuchten Faktoren signifikant induzierbar.

by Hu Xiao Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 103-111). / Abstracts in English and Chinese. / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Basic Physiology of the Nervous System --- p.1 / Chapter 1.1.1 --- Membrane Potential and Its Propagation --- p.2 / Chapter 1.1.2 --- Cellular Communication --- p.3 / Chapter 1.2 --- Background of Neural Modeling --- p.5 / Chapter 1.2.1 --- Models for Membrane --- p.5 / Chapter 1.2.2 --- The Models for Gap Junctions --- p.9 / Chapter 1.2.3 --- A Study on the Pulse Train --- p.11 / Chapter 1.3 --- Main Purposes of the Study --- p.14 / Chapter 1.4 --- Organization of Thesis --- p.15 / Chapter 2 --- Electrical Synaptic Model --- p.17 / Chapter 2.1 --- Introduction --- p.17 / Chapter 2.2 --- Model Description --- p.19 / Chapter 2.2.1 --- An Introduction of the Active Membrane Model --- p.19 / Chapter 2.2.2 --- The Electrical Synaptic Model --- p.25 / Chapter 2.3 --- Numerical Calculation --- p.32 / Chapter 2.4 --- Simulation Results --- p.37 / Chapter 2.5 --- Discussion --- p.44 / Chapter 3 --- Analysis of the Synaptic Model --- p.46 / Chapter 3.1 --- Introduction --- p.46 / Chapter 3.2 --- Time Constant Analysis --- p.48 / Chapter 3.2.1 --- Junctional Time Constant in Bennette's Model --- p.48 / Chapter 3.2.2 --- The Junctional Time Constant in Our Model --- p.52 / Chapter 3.3 --- Model Reconstruction --- p.57 / Chapter 3.4 --- Discussion --- p.62 / Chapter 4 --- Action Potential Train Transmission Analysis --- p.69 / Chapter 4.1 --- Theoretical Analysis on the Refractory Period at the Post-membrane --- p.70 / Chapter 4.1.1 --- Introduction of Membrane Threshold and Refractory Period --- p.71 / Chapter 4.1.2 --- Stochastic Models of Neuron Firing --- p.73 / Chapter 4.1.3 --- Effect of Refractory Period on the p.d.f. of Poisson Process --- p.78 / Chapter 4.2 --- Simulation of the Action Potential Train Transmission --- p.85 / Chapter 4.2.1 --- Effects of the Model Parameter on the Action Potential Train Transmission --- p.90 / Chapter 4.2.2 --- Effects of the Refractory Period of the Post-membrane on the Action Potential Train Transmission --- p.94 / Chapter 4.3 --- Results --- p.96 / Chapter 4.3.1 --- Section Summary --- p.98 / Chapter 5 --- Conclusions and Future Studies --- p.99 / Chapter 5.1 --- Conclusions of Major Contributions --- p.99 / Chapter 5.2 --- Topics for Future Studies --- p.101

Cell-cell junctions are essential for tissue homeostasis. Prominent among these junctions are adherens junctions and tight junctions. Adherens junctions mediate adhesion between adjacent cells while tight junctions are responsible for establishing apical-basolateral polarity and limiting paracellular permeability. Loss or disruption of either adherens junctions or tight junctions leads to a myriad of disease states, thus these junctions need to be tightly regulated to prevent dysfunction. A unique property of tight junctions is their dependence on adherens junctions for proper assembly and maintenance. Loss or disruption of adherens junction leads to abnormal tight junctions. Understanding the mechanisms that mediate tight junction coupling to adherens junctions is important for treating diseases that arise from disrupted cell-cell junctions. Currently, two controversial models exist for how tight junctions are coupled to adherens junctions. In the first model, the adherens junction protein α-catenin is critical for tight junction assembly. The second model suggests that a second adherens junction protein, nectin is critical for tight junction assembly through binding the tight junction protein ZO-1, and disruption of tight junction assembly is independent of E-cadherin. α-catenin also binds ZO-1, but the consequences of this interaction are unknown. I hypothesized that α-catenin binding to ZO-1 plays a critical role in coupling tight junctions to adherens junctions. To test this, I mapped the ZO-1 binding site on α-catenin and engineered a point mutant of α-catenin that failed to bind ZO-1. Expression of this point mutant in epithelial cells showed that ZO-1 binding to α-catenin is essential for tight junction assembly and maintenance, while adherens junctions were unaffected. These findings established a role for ZO-1 binding to α-catenin in coupling tight junctions to adherens junctions during junction assembly, as well as at steady-state conditions. After discovering the importance of ZO-1 binding to α-catenin in coupling tight junctions to adherens junctions, I wanted to study whether this interaction is critical in a physiological setting. Tight junctions and adherens junctions are both strengthened in response to mechanical force; however the mechanisms responsible for tight junction strengthening were unknown. Using the system I previously developed, I show that ZO-1 binding to α-catenin is essential for increased tight junction integrity in response to mechanical force, coupling changes in tight junctions to increased stability of adherens junctions. Together, these findings identify a novel interaction that is critical for coupling tight junctions to adherens junctions under several conditions, and provide mechanistic insight into the cellular response to mechanical force.

Adherens junctions are a main cell-cell adhesion structure found in epithelial cells. The stability of adherens junctions is attributed to various protein-signaling cascades and importantly the interaction between the transmembrane protein E-cadherin and cytoplasmic p120 catenin. This interaction is critical for cell adhesion and prevention of uncontrolled growth in normal cells. The interaction interface between these two binding partners was previously determined to comprise p120's Armadillo repeat domain (p120Arm) and Ecadherin's cytoplasmic juxtamembrane domain (Ecadc). Based on this information, peptide aptamers were derived from p120Arm and their interaction with Ecadc was tested in vitro. We reasoned that those could be expressed in vivo to stabilize adherens junctions at the cell-cell junction. In this study, we established protein-protein interaction assays to demonstrate p120Arm's ability to bind Ecadc and then used these assays to determine if p120Arm-derived peptides may competitively bind Ecadc. We demonstrated the interaction between p120Arm and Ecadc using assays that were not previously used such as: co-precipitation, analytical gel filtration and the bacterial-2-hybrid assay. However, the p120Arm-derived peptides did not bind to Ecadc or compete its interaction with p120Arm. This may be due to the nature of the assays that may not reflect competitive binding or the aptamers may not adopt the native conformation preventing binding to Ecadc. / Thesis / Master of Science (MSc)

published_or_final_version / Physics / Doctoral / Doctor of Philosophy

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Biological Sciences / Doctoral / Doctor of Philosophy