Thesis (Ph. D.)--University of Hawaii at Manoa, 2000. / Includes bibliographical references (leaves 77-89). Also available in microform.

Thesis (Ph. D.)--University of Hawaii at Manoa, 1991. / Includes bibliographical references (leaves 177-207) / Microfiche. / xiii, 207 leaves, bound ill. 29 cm

Thesis (M.S.)--Missouri State University, 2008. / "May 2008." Includes bibliographical references (leaves 45-50). Also available online.

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

Gap junctions are a class of membrane proteins that facilitate cell-to-cell communication by forming channels that directly couple the cytoplasm of neighboring cells. The channels are composed of monomers called connexins. Humans express 21 connexin isoforms in a cell-type specific fashion, and each isoform has distinct mechanisms of permeation and regulation. Co-assembly of multiple isoforms into a single intercellular channel can change channel properties, such as conductance and selectivity to substrates (e.g., ions, metabolites and signaling molecules). However, the mechanistic basis for this functional diversity has remained poorly understood. This lack of mechanistic insight has been due in large part to the lack of high-resolution (atomic-level) structural knowledge on this class of proteins. Prior to this work, the only high-resolution information available on gap junction structure came from a single connexin isoform, connexin-26 (cx26). CryoEM has recently transformed from a low-resolution technique into one capable of rivaling the atomic-level resolutions achieved by x-ray crystallography -- but without the necessity for crystal formation, which has hindered progress towards understanding many classes of proteins (ie, membrane proteins, intrinsically disordered cell signaling complexes and other structurally dynamic systems). For my thesis research, I applied novel methods in single particle electron cryo-microscopy (CryoEM) to study a class of membrane proteins called gap junctions isolated from native lens tissue, as well as two signaling complexes not amenable to other structural techniques. I determined the structure of the lens gap junction, which contains connexin-46 (cx46) and connexin-50 (cx50), to a resolution of 3.4 Å and generated atomic models for both connexin isoforms. Structural analysis paired with molecular dynamics gave insight into energetic features of these channels that determine their isoform-specific conductance and selectivity to electrically charged ions. The cx46/50 gating domain was found to be stabilized by hydrophobic anchors, and also seems to adopt a more stable open state than found in cx26. Genetic mutations associated with congenital cataract formation were found to map to hot-spots of conserved structural and functional importance, rationalizing their disease-causing effects. As part of collaborative efforts, I used methods in single particle EM to characterize two separate signaling complexes that had proven difficult to study with x-ray crystallography and NMR spectroscopy. One system, Ca2+/Calmodulin Kinase II (CaMKII), is a signaling complex in the brain involved in memory formation. Characterization of the CaMKII complex by single particle EM revealed an extended state, which was also shown to be prevalent in cells -- giving more depth to our understanding of how this signaling molecule functions. The second collaboration characterized the multimeric binding sites of the hub protein LC8, which interacts with the disordered region of a transcription factor (ASCIZ). This provided support for a novel model of transcription regulation, wherein LC8 fine-tunes its own transcription levels through multi-valent binding to the disordered region of its own regulatory transcription factor.

published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy

published_or_final_version / Surgery / Master / Master of Philosophy

Thesis (Ph. D.)--University of Hawaii at Manoa, 1995. / Includes bibliographical references (leaves 76-93). / Microfiche. / vii, 93 leaves, bound ill. (some col.) 29 cm

Thesis (M.S.)--Missouri State University, 2008. / "August 2008." Includes bibliographical references (leaves 45-51). Also available online.

Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 120-134).