Thesis (M.S.)--Oregon State University, 2008. / Printout. Includes bibliographical references. Also available on the World Wide Web.

Thesis (M.S.)--Rochester Institute of Technology, 1982. / Typescript. Includes bibliographical references (leaves 40-55).

Amyloidosis is a group of clinical disorders caused by the aggregation of specific proteins into abnormal extracellular deposits. Today, 31 different proteins have been linked to amyloid diseases including transthyretin-related amyloidosis (ATTR). ATTR occurs through the aggregation of either wild-type plasma protein transthyretin (TTR) or a mutated form. TTR is a homotetramer that under normal circumstances functions as a carrier of thyroxine and retinol binding protein. The aggregation cascade requires dissociation of the tetramer into monomers, and preventing this dissociation represents a potential mode of intervention. Interestingly, small molecules, referred as kinetic stabilizers, can bind to TTR’s thyroxine-binding site (TBS) and such molecules are currently being used as a therapeutic approach to impair tetramer dissociation. The efficacy of TTR stabilization is directly correlated to the binding affinity of the ligand to TBS. However, the binding of the ligand to TTR in vivo can be affected by other plasma components resulting in poor efficacy. Thus, the selectivity of ligands is an important parameter. We have designed an assay where the ability to stabilize TTR can be directly evaluated in plasma and we have investigated the stabilizing effect of nine potential TTR binders (Paper I). The results, surprisingly, revealed that the binding affinity of molecules has a poor correlation to its selectivity. However, the nature of protein-ligand complex formation can also be described by enthalpic (∆H) and entropic (∆S) energy contributions. ∆H represents the change in chemical bonds and frequently requires a higher order of orientation compared to the ∆S component, which mainly represents the hydrophobic effect via the exclusion of water. We hypothesized that ligands possessing high ΔH in binding to their co-partner would also be more specific in a complex environment such as plasma. By applying a thermodynamic analysis using isothermal titration calorimetry, we found that the selectivity in plasma correlates well with the ∆H contribution and might, therefore, be a better predictor for selectivity. Luteolin was found to be a highly selective stabilizer of TTR and was investigated further (Paper II). The ligand displayed a significant rescuing effect in both cell culture and animal models. However, luteolin undergoes rapid enzymatic degradation in the liver and this impairs its use as a potential therapeutic drug. To attempt to circumvent this issue, we modified the most exposed hydroxyl group thus rendering the molecule inert towards glucuronidation (Paper III). The substitutions resulted in higher stability in the face of hepatic degradation molecules, but they also affected the selectivity in a negative manner. The screening for new TTR stabilizers resulted in the discovery of tetrabromobisphenol A, which displayed a very high selectivity (Paper IV). This study also included a comparison with the drug Vyndaqel™ which currently is in clinically use, and showed how the dosage could be altered to acquire a better level of saturation and possibly also a better clinical effect. Taken together we present new molecules with the ability to stabilize TTR, and these can serve as scaffolds for the design of new drugs. We present a method to measure the efficacy of a TTR-stabilizing drugs in a complex matrix and as well as a way to adjust the dosage of existing drugs. We also show that the selectivity of a drug is affected by the relative proportion of ∆H and ∆S, and this is of interest for drug design in general.

Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2016. / The subject of this current study concerns highly concentrated emulsions of the explosive grade. A distinguishing characteristic of these systems is a high internal to external phase volume ratio. The volume fraction of the aqueous phase of such an emulsion generally far exceeds the close packing limit. Continuous phase of the system is a supersaturated aqueous solution of ammonium nitrate inorganic salt. In combination with high internal phase concentration, this inevitably leads to the destabilisation of the system. The thermodynamic instability of such systems is attributed to two major factors: 1) crystallisation of dispersed phase and 2) coalescence of the individual droplets within the bulk. This poses a significant problem since destabilisation of the bulk emulsion in turn leads to partial or complete loss of sensitivity to detonation of the final product of which highly concentrated emulsion is the base. Since the invention of such types of bulk explosives, a considerable and on-going effort has targeted the improvement of the stability of these systems, with a scope primarily focused on the use of various surfactant agents with different properties as well as stabilising mixtures containing numerous surfactants. In recent years, a new approach has been explored: the stabilisation of highly concentrated emulsions with the use of solid fumed silica nanoparticles. This is a promising new field of study, already being implemented by manufacturers and actively developing. The focus of this present study is to investigate and lay the ground work for further research in the principally new approach towards the stabilisation of highly concentrated emulsions with the use of the polyhedral oligomeric silsesquiozane nanomolecules. These are unique compounds possessing hybrid inorganic-organic structures and properties, and carrying a range of advantages over currently implemented surfactants. As opposed to silica nanoparticles, these compounds are not solid particles but can be regarded as molecular silica. This investigation will focus on the general possibility of implementation of such compounds as stabiliser agents for emulsions in general, and highly concentrated emulsions of the explosive grade in particular, and the resultant effects on the stability. Effects on stability will be investigated both when used solely and in combination with common surfactants. In addition, stability both on shelf and under stress will be investigated within the framework of the study.

Thesis (Ph. D.)--University of Florida, 2000. / Title from first page of PDF file. Document formatted into pages; contains xvii, 174 p.; also contains graphics. Vita. Includes bibliographical references (p. 165-173).

Thesis (M.S.)--University of Texas at El Paso, 2008. / Title from title screen. Vita. CD-ROM. Includes bibliographical references. Also available online.

Thesis (M.A. Sc.)--Centre for Building Studies, Concordia University, 1993. / Includes bibliographical references (leaves 88-93). Available also on the Internet.

This thesis focuses on implementation of the swing-up, switching and stabilizing controllers for the rotary inverted pendulum. An energy based method to swing-up the pendulum and a state feedback controller to keep the pendulum in the upright position are employed. The mixed H2/H∞; state feedback controller is used to stabilize the pendulum with reduced oscillations. The results have been compared with the standard full state feedback and LQR. The Quanser rotary inverted pendulum is used as the testbed. All controllers are implemented in real-time using dSPACE 1104 rapid prototyping system. Microstick II with dsPIC33FJ128MC802 and Simulink embedded target for Microchip® is used as a standalone way to implement the controllers.

The membrane-spanning phospholipids of the domain Archaea are postulated to provide membrane stability; this thesis reports the design and synthesis of a synthetic membrane-spanning macrocyclic lipid to test this hypothesis. Protected glutaric anhydride reacted with 10-undecyn-1-ol to produce a glutarate monoester. Copper-mediated azide-alkyne coupling (CuAAC) using 1,5-diazido-3-oxapentane(bis-azide) afforded a dicarboxylicacid with a hydrophobic chain of sufficient length to span a 35 Å bilayer membrane. The carboxylic acids were each esterified with an equivalent of 10-undecyn-1-ol. After optimization an 87% yield was obtained in the closure of the 72-membered macrocycle with the bis-azide using CuAAC. Deprotection and coupling with p-nitrophenyl phosphorodichloridate completed the synthesis. Two other phospholipids, a linear bolaamphiphile derived from the precursor to the second click reaction, and a linear amphiphile created from a glutarate bis-dodecyl ester, were also synthesized to provide controls for probing the orientation of the macrocyclic phospholipid in the bilayer membrane of vesicles. The amphiphile, linear bolaamphiphile, and macrocyclic bolaamphiphile were synthesized in 4, 5, and 6 steps with yields of 19, 4, and 5% respectively. The hydrophilic head group of the macrocyclic phospholipid was designed to release p-nitrophenolate in basic conditions from the p-nitrophenylphosphate head group to produce an absorbance at 400 nm. This assay was expected to elucidate the membrane-spanning orientation of the phospholipid in the bilayer membrane of vesicles. The final target compound failed to release p-nitrophenolate under basic conditions and underwent phosphate elimination to produce an α, β-unsaturated ester instead. Although the macrocyclic lipid produced associates with membranes and may be membrane-spanning, this lipid design was unable to reveal its membrane orientation. / Graduate

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