Physical Sciences and Mathematics Commons^™

Studies On Silicon Nmr Characterization And Kinetic Modeling Of The Structural Evolution Of Siloxane-Based Materials And Their Applications In Drug Delivery And Adsorption, Jyotrhirmai Ambati

University of Kentucky Doctoral Dissertations

This dissertation presents studies of the synthetic processes and applications of siloxane-based materials. Kinetic investigations of bridged organoalkoxysilanes that are precursors to organic-inorganic hybrid polysilsesquioxanes are a primary focus. Quick gelation despite extensive cyclization is found during the polymerization of bridged silane precursors except for silanes with certain short bridges. This work is an attempt to characterize and understand some of the distinct features of bridged silanes using experimental characterization, kinetic modeling and simulation. In addition to this, the dissertation shows how the properties of siloxane- materials can be engineered for drug delivery and adsorption.

The phase behavior of polymerizing …

Novel Solution Processable Acceptors For Organic Photovoltaic Applications, Ying Shu

University of Kentucky Doctoral Dissertations

The field of organic electronics has become an increasingly important field of research in recent years. Organic based semiconductors have the potential for creating inexpensive, solution processed devices on flexible substrates. Some of the applications of organic semiconductors include organic field effect transistors, organic light emitting diodes and organic photovoltaics.

Functionalized pentacenes have been proven to be viable donor materials for use in organic photovoltaic devices. The goal of this research is to synthesize and test the viability of novel electron deficient pentacenes and pentacene based materials as acceptors to be used as drop-in replacements for PCBM in bulk-heterojunction organic …

Interactions And Effects Of Biomolecules On Au Nanomaterial Surfaces, Manish Sethi

University of Kentucky Doctoral Dissertations

Au nanoparticles are increasingly being used in biological applications. Their use is of interest based upon their unique properties that are achieved at the nanoscale, which includes strong optical absorbances that are size and aggregation state dependent. Such absorbances can be used in sensitive chemical/biological detection schemes where bioligands can be directly attached to the nanoparticle surface using facile methods. Unfortunately, a number of complications persist that prevent their wide-scale use. These limitations include minimal nanoparticle stability in biological-based media of high ionic strength, unknown surface functionalization effects using simple biomolecules, and determining the binding motifs of the ligands to …

Partially Halogenated Acenes And Heteroacenes For Organic Electronics, Balaji Purushothaman

University of Kentucky Doctoral Dissertations

Inorganic materials have dominated electronic applications such as photovoltaic cells, thin film transistors (TFTs) and light emitting diodes (LEDs). However developments in the field of organic electronics over the past three decades have enabled the use of organic materials in these devices. While significant improvements have been made to improve their electronic properties there are several road blocks towards commercial application. One of the significant obstacles is the poor charge carrier mobility associated with organic semiconductors processed by well established printing methods. The goal of my research project is to improve the charge carrier mobility of solution cast films of …

Evaluation Of The Physicochemical Properties And Stability Of Solid Lipid Nanoparticles Designed For The Delivery Of Dexamethasone To Tumors, Melissa Howard

University of Kentucky Doctoral Dissertations

Pre-clinical and clinical trials suggest that pre-treatment with dexamethasone (Dex) may facilitate enhanced uptake of subsequently administered chemotherapeutic agents. To reduce the side effects associated with systemic administration of Dex, solid lipid nanoparticles (SLNs) containing dexamethasone palmitate (Dex-P) were prepared as a means of achieving tumor-targeted drug delivery. These studies were aimed at evaluating the physicochemical properties and both the physiological and storage stability of the SLNs.

SLNs were prepared using nanotemplate engineering technology. Stearyl alcohol (SA) was used as the lipid phase with Brij^® 78 and Polysorbate 60 as surfactants and PEG6000 monostearate as a long-chain PEGylating agent. …

Fabrication And Characterization Of Mesoscale Protein Patterns Using Atomic Force Microscopy (Afm), Pei Gao

University of Kentucky Doctoral Dissertations

A versatile AFM local oxidation lithography was developed for fabricating clean protein patterns ranging from nanometer to sub-millimeter scale on octadecyltrichlorosilane (OTS) layer of Si (100) wafer. This protein patterning method can generate bio-active protein pattern with a clean background without the need of the anti-fouling the surface or repetitive rinsing.

As a model system, lysozyme protein patterns were investigated through their binding reactions with antibodies and aptamers by AFM. Polyclonal anti-lysozyme antibodies and anti-lysozyme aptamer are found to preferentially bind to the lysozyme molecules on the edge of a protein pattern before their binding to the interior ones. It …

Periodic Trends In Structure Function Relationship Of Organic Heteroacenes, Marsha Loth Grimminger

University of Kentucky Doctoral Dissertations

Our group has previously shown that small changes to molecular structure result in large changes to device properties and stability in organic electronic applications. By functionalizing aromatic heteroacenes with group 14 and group 16 elements, it is possible to control morphology and improve stability for a variety of applications such as thin film transistors and solar cells. Functionalization within the heteroacene core led to changes in electronic structure as observed by electrochemistry and light absorption. By substituting down the periodic table, the carbon heteroatom bond length increased, leading to subtle changes in crystal packing. Absorption maxima were red-­‐shifted and stability …

Biochemical Characterization Of Human Mismatch Recognition Proteins Mutsα And Mutsβ, Lei Tian

University of Kentucky Doctoral Dissertations

The integrity of an organism's genome depends on the fidelity of DNA replication and the efficiency of DNA repair. The DNA mismatch repair (MMR) system, which is highly conserved from prokaryotes to eukaryotes, plays an important role in maintaining genome stability by correcting base-base mismatches and insertion/deletion (ID) mispairs generated during DNA replication and other DNA transactions. Mismatch recognition is a critical step in MMR. Two mismatch recognition proteins, MutSα (MSH2-MSH6 heterodimer) and MutSβ (MSH2-MSH3 heterodimer), have been identified in eukaryotic cells. MutSα and MutSβ have partially overlapping functions, with MutSα recognizing primarily base-base mismatches and 1-2 nt ID mispairs …

Explorations In Homeoviscous Adaptation And Mass Spectral Analysis Of Membrane Lipids, Michael Douglas Timmons

University of Kentucky Doctoral Dissertations

The focus of this dissertation is centered on the mass spectral analysis of lipids and changes occurring in keeping with the concept of homeoviscous adaptation [1]. Homeoviscous adaptation is the process of modification of membrane lipids in response to environmental stimuli [1]. Dissertation investigations applied this concept to prokaryotic and eukaryotic organisms, and expanded the perception of environmental factors from exogenous organic solvents to intracellular environment.

The field of lipidomics deals with the analysis of phospholipid and fatty acid components of membranes the changes that occur due to environmental stimuli and their biological significance [2-6]. The high sensitivity of mass …

Development Of Novel Ahr Antagonists, Hyosung Lee

University of Kentucky Doctoral Dissertations

Aryl hydrocarbon receptor (AHR) is a sensor protein, activated by aromatic chemical species for transcriptionally regulating xenobiotic metabolizing enzymes. AHR is also known to be involved in a variety of pathogenesis such as cancer, diabetes mellitus, cirrhosis, asthma, etc. The AHR signaling induced by xenobiotics has been intensively studied whereas its physiological role in the absence of xenobiotics is poorly understood. Despite a number of ligands of AHR have been reported thus far, further applications are still hampered by the lack of specificity and/or the partially agonistic activity. Thus, a pure AHR antagonist is needed for deciphering the AHR cryptic …

Immobilization Of Mercury And Arsenic Through Covalent Thiolate Bonding For The Purpose Of Environmental Remediation, Lisa Y. Blue

University of Kentucky Doctoral Dissertations

Mercury and arsenic are widespread contaminants in aqueous environments throughout the world. The elements arise from multiple sources including mercury from coal-fired power plants and wells placed in natural geological deposits of arseniccontaining minerals. Both elements have significant negative health impacts on humans as they are cumulative toxins that bind to the sulfhydryl groups in proteins, disrupting many biological functions. There are currently no effective, economical techniques for removing either mercury or arsenic from aqueous sources. This thesis will demonstrate a superior removal method for both elements by formation of covalent bonds with the sulfur atoms in N,N’-Bis(2-mercaptoethyl)isophthalamide (commonly called …

Studies Toward The Total Synthesis Of (±)-Α-Yohimbine By Double Annulation, Raghu Ram Chamala

University of Kentucky Doctoral Dissertations

The indole alkaloids, a class of natural products, have received much synthetic attention for years due to their diverse structures and interesting biological properties. We are particularly interested in synthesizing some of the yohimbine alkaloids extracted from the bark of a tall evergreen African tree (Corynanthe yohimbe, commonly known as fringe tree). Yohimbine and its stereoisomers have been tempting targets for synthetic organic chemists for more than fifty years. These compounds feature a pentacyclic ring system with two heteroatoms and five stereogenic centers.

Broadly, the fifteen different synthetic approaches that led to the successful completion of yohimbine alkaloids …

Progress Towards The Synthesis Of Type B Polycyclic Polyprenylated Acylphloroglucinol 7-Epi-Clusianone, Pushpa Suresh Jayasekara Mudiyanselage

University of Kentucky Doctoral Dissertations

Plants of the family Guttiferae produce polycyclic polyprenylated acylphloroglucinols (PPAPs), which have interesting biological activities including anticancer and antibacterial properties. The main structural features of PPAPs comprise of bicyclo[3.3.1]nonane-2,4,9-triketone with one acyl group together with prenyl, geranyl, or other C₁₀H₁₇ groups. 7-epi-Clusianone, a type B PPAP with C-7 endo stereochemistry, is being approached by establishing the cis relationship with C(4) allyl group and C(2) methyl ester in the early stage of the synthesis. Then C(2) methyl ester is converted to alkyne aldehyde and syn reduction followed by intramolecular aldol reaction to give bicyclo[3.3.1]nonane structure with …

15N Solid-State Nmr Detection Of Flavin Perturbation By H-Bonding In Models And Enzyme Active Sites, Dongtao Cui

University of Kentucky Doctoral Dissertations

Massey and Hemmerich proposed that the different reactivities displayed by different flavoenzymes could be achieved as a result of dominance of different flavin ring resonance structures in different binding sites. Thus, the FMN cofactor would engage in different reactions when it had different electronic structures. To test this proposal and understand how different protein sites could produce different flavin electronic structures, we are developing solid-state NMR as a means of characterizing the electronic state of the flavin ring, via the ¹⁵N chemical shift tensors of the ring N atoms. These provide information on the frontier orbitals. We propose that …

In Vivo Oxidative Stress In Alzheimer Disease Brain And A Mouse Model Thereof: Effects Of Lipid Asymmetry And The Single Methionine Residue Of Amyloid-Β Peptide, Miranda Lu Bader Lange

University of Kentucky Doctoral Dissertations

Studies presented in this dissertation were conducted to gain more insight into the role of phospholipid asymmetry and amyloid-β (Aβ)-induced oxidative stress in brain of subjects with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). AD is a largely sporadic, age-associated neurodegenerative disorder clinically characterized by the vast, progressive loss of memory and cognition commonly in populations over the age of ~65 years, with the exception of those with familial AD, which develop AD symptoms as early as ~30 years-old. Neuropathologically, both AD and FAD can be characterized by synapse and neuronal cell loss in conjunction with accumulation of …

Opioid-Cannabinoid Codrugs With Enhanced Analgesic And Pharmacokinetic Profile, Harpreet Kaur Dhooper

University of Kentucky Doctoral Dissertations

The central hypothesis of the dissertation is that “the design and synthesis of a codrug of an opiate and a cannabinoid can be achieved which is stable in the gastrointestinal tract and shows a superior pharmacological and pharmacokinetic profile when compared to a physical mixture of the two parent drugs.” To prove the hypothesis, a series of novel codrugs were prepared by conjugation of the opiate drug codeine with Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol, abn-cannabidiol and an opiate prodrug 3-O-acetylmorphine with Δ⁹-THC. Codeine-cannabinoid codrugs were evaluated for analgesic activity in the rat after oral administration. The …

Bootstrap Enhanced N-Dimensional Deformation Of Space With Acoustic Resonance Spectroscopy, David John Link

University of Kentucky Doctoral Dissertations

Acoustic methods can often be used with limited or no sample preparations making them ideal for rapid process analytical technologies (PATs). This dissertation focuses on the possible use of acoustic resonance spectroscopy as a PAT in the pharmaceutical industry. Current good manufacturing processes (cGMP) need new technologies that have the ability to perform quality assurance testing on all products. ARS is a rapid and non destructive method that has been used to perform qualitative studies but has a major drawback when it comes to quantitative studies. Acoustic methods create highly non linear correlations which usually results in high level computations …

Pattern Recognition Integrated Sensing Methodologies (Prisms) In Pharmaceutical Process Validation, Remote Sensing And Astrobiology, Thaddaeus S. Hannel

University of Kentucky Doctoral Dissertations

Modern analytical instrumentation is capable of creating enormous and complex volumes of data. Analysis of large data volumes are complicated by lengthy analysis time and high computational demand. Incorporating real-time analysis methods that are computationally efficient are desirable for modern analytical methods to be fully utilized. The use of modern instrumentation in on-line pharmaceutical process validation, remote sensing, and astrobiology applications requires real-time analysis methods that are computationally efficient.

Integrated sensing and processing (ISP) is a method for minimizing the data burden and sensing time of a system. ISP is accomplished through implementation of chemometric calculations in the physics of …

Imide-Functionalized Conjugated Polymers: Synthesis, Structure-Property And Device Studies, Xugang Guo

University of Kentucky Doctoral Dissertations

Organic semiconductors are widely studied as potential active components for consumer electronics due largely to their easily tuned properties and the promise of lower-cost solution-based processing technology. Imide-functionalized organic small molecule compounds have been one of the more important and studied organic semiconductors. However, very few imide-functionalized conjugated polymers have been reported in the literature. The body of this dissertation focuses on the synthesis, structure-property and device studies of imide-functionalized conjugated polymers. Reasons for choosing arylene imides as polymer building blocks include: a) they impart low-lying LUMOs to polymers, allowing band-gap engineering through choice of comonomers with variable electron-donating ability; …

Investigations Of S-Glutathionylation Of Brain Proteins In The Progression Of Alzheimer's Disease And Of A Potential Glutatione Mimetic As A Treatment Of Alzheimer's Disease, Shelley Faye Newman

University of Kentucky Doctoral Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neurofibrillary tangles, senile plaques and loss of synapses. Many studies support the notion that oxidative stress plays an important role in AD pathogenesis. Previous studies from our laboratory employed redox proteomics to identify oxidatively modified proteins in the AD inferior parietal lobule (IPL). The proteins were consistent with AD pathology and have been central to further investigations of the disease. The present study was focused on the identification of specific targets of protein S-glutathionylation in AD, early AD (EAD), and mild cognative impairment (MCI) using a redox proteomics approach. In AD …

Alterations Of Zinc Transporters In Alzheimer's Disease, Ganna Lyubartseva

University of Kentucky Doctoral Dissertations

Alzheimer’s disease (AD), one of the major causes of disability and mortality in Western societies, is a progressive age-related neurodegenerative disorder. Increasing evidence suggests the etiology of AD may involve disruptions of zinc (Zn) homeostasis. We hypothesize that disruption of Zn homeostasis leads to alterations of Zn transporter (ZnT) proteins, resulting in increased production of neurotoxic amyloid beta (Aβ) peptide in AD brain. To address this hypothesis we carried out the following studies.

1. We characterized alterations of ZnT-1, ZnT-4 and ZnT-6 in the brain of preclinical AD (PCAD) subjects, who show no overt clinical manifestations of AD but demonstrate …

Metabolite Analysis Of Clostridium Thermocellum Using Capillary Electrophoresis Based Techniques, Anup P. Thakur

University of Kentucky Doctoral Dissertations

Clostridium thermocellum is a thermophilic bacterium that converts biomass to ethanol directly; however, high sensitivity of this bacterium toward ethanol limits its commercial utility. To elucidate the effect of ethanol on the growth of this bacterium a metabolite analysis of C. thermocellum was performed. The hypothesis of the project was that exogenous ethanol alters the metabolite profile of C. thermocellum. For metabolite analysis, capillary electrophoresis-electrospray ionization-mass spectrometry method (CE-ESI-MS) was developed due to highly polar and charged nature of metabolites. To increase the sensitivity of CE-ESI-MS, several parameters at the ESI interface were optimized. The application of 50% isopropanol …

Methods Development In Qualitative And Quantitative Proteomics, Ting Liu

University of Kentucky Doctoral Dissertations

Proteomics based on liquid chromatography coupled to mass spectrometry has developed rapidly in the last decade and become a powerful tool for protein mixtures analysis. LC-MS based proteomics involves four steps, sample preparation, liquid chromatography, mass spectrometry and bioinformatics. Improvements in each step have extended its applications to new biological research areas. This dissertation mainly focuses on method developments in both qualitative and quantitative proteomics.

The first part of this dissertation focuses on qualitative analysis of T. gondii Parasitophorous Vacuole Membrane (PVM) proteins, which is very important for T. gondii’s survival. The hypothesis of this study is that proteomic …

Mechanistic Investigations Of The Trans Excision-Splicing And Trans Insertion-Splicing Reaction, Perry Patrick Dotson Ii

University of Kentucky Doctoral Dissertations

Group I intron-derived ribozymes are catalytic RNAs that have been engineered to catalyze a variety of different reactions, in addition to the native self-splicing reaction. One such ribozyme, derived from a group I intron of Pneumocystis carinii, can modify RNA transcripts through either the excision or insertion of RNA sequences. These reactions are mediated through the trans excision-splicing (TES) or trans insertionsplicing (TIS) reaction pathways. To increase our current understanding of these reactions, as well as their general applicability, a mechanistic and kinetic framework for the TES reaction was established. Furthermore, additional ribozymes were investigated for their ability to …

Benzene-1,3-Diamidoethanethiol (Bdeth2) And Its Metal Compounds, Kamruz Md Zaman

University of Kentucky Doctoral Dissertations

There is a global need to find a permanent and readily implemented solution to the problem of heavy metal pollution in aqueous environments. A dithiol compound, benzene-1,3-diamidoethanethiol (BDETH₂), also known as N,N'-bis(2-mercaptoethyl) isophthalamide or N,N'-bis(2-mercaptoethyl)-1,3-benzenedicarboxamide, capable of binding divalent metal ions, has been synthesized and characterized. A broad range of BDET-metal compounds, spanning the periodic chart, has been prepared and characterized by IR, MS, EA, Raman, XAFS and TGA. The characteristics of the BDET-M compounds were determined through secondary reactions. In an effort to derivatize BDET-M compounds through alkylalumination a new cyclic compound, 1,3- bis(4,5-dihydrothiazolo)benzene, has …

Regulation Of L-Type Voltage-Dependnet Calcium Channels By The Rem Gtpase, Chunyan Pang

University of Kentucky Doctoral Dissertations

The Rem, Rem2, Rad, and Gem/Kir GTPases, comprise a novel subfamily of the small Ras-related GTP-binding proteins known as the RGK GTPases, and have been shown to function as potent negative regulators of high voltage-activated (HVA) Ca²⁺ channels upon overexpression. HVA Ca²⁺ channels modulate Ca²⁺ influx in response to membrane depolarization to regulate a wide variety of cellular functions and they minimally consist of a pore-forming α1 subunit, an intracellular β subunit, and a transmembrane complex α₂/δ subunit. While the mechanisms underlying RGK-mediated Ca²⁺ channel regulation remain poorly defined, it appears that both membrane …

Carbon Nanotube Supported Metal Catalysts For NoX Reduction Using Hydrocarbon Reductants, Eduardo Santillan-Jimenez

University of Kentucky Doctoral Dissertations

Nitrogen oxides (NO_x) are atmospheric pollutants that pose a serious threat to both the environment and human health. Although catalytic deNO_x technologies for engines working under stoichiometric air-to-fuel ratios (i.e., most gasoline engines) are already available, their performance is unsatisfactory under excess air conditions like those under which diesel engines operate.

The selective catalytic reduction of NO_x with hydrocarbon reductants (HC-SCR) is a potential deNO_xsolution for diesel engines, whose operating temperatures are 150-500 ºC. Given that is unlikely for a single catalyst to show acceptable activity throughout this entire temperature span, the use of …

Nitroreductase: Evidence For A Fluxional Low-Temperature State And Its Possible Role In Enzyme Activity, Peng Zhang

University of Kentucky Doctoral Dissertations

The enzyme nitroreductase (NR) catalyzes two-electron reduction of high explosives such as trinitrotoluene (TNT), a wide variety of other toxic nitroaromatic compounds, as well as riboflavin derivatives, using a tightly-bound flavin mononucleotide (FMN) cofactor. It has important environmental and clinical implications. Previous studies have focused on elucidating NRs catalytic mechanism and solving its crystal structure.

In this dissertation work, we first develop and implement new strategies for labeling NR with stable isotopes, and report a completely re-designed protocol for NRs purification. Then we report the successful assignment of over half of NRs backbone resonances using 3d-NMR methods. The most significant …

Polymorphism Of Four Enantiotropic Crystalline Systems Containing Ni(Ii), H2O, 15-Crown-5 And No3-, Maxime Andre Siegler

University of Kentucky Doctoral Dissertations

The series of compounds [M(H₂O)₂(15-crown-5)](NO₃)₂, M = Mg, Mn, Co, Cu and Zn, has been extended to include two new phases for M = Fe and two new phases for M = Ni. The system [M(H₂O)₂(15-crown-5)](NO₃)₂ is remarkable for having many high-Z’ phases (Z’ > 1) with similar packing and for having solid-solid phase transitions through which there is no significant loss of crystallinity. The synthesis of the analogous Ni complex was carried out. Single-crystal X-ray diffraction showed …

Solution And Solid State Interactions Between Ionic Π-Systems, Jing Chen

University of Kentucky Doctoral Dissertations

Although attractive interactions between π systems (π-π interaction) have been known for many years, understanding of its origin is still incomplete. Quantitative measuring of π-stacking is challenging due to the weak nature of the π-π interaction. This dissertation aims at elucidating a quantitative conformational analysis by NMR ring current anisotropy of an organic compound capable of intramolecular π-stacking in solution and studying charge effects on the stacking of π-systems. This dissertation offers four contributions to the area. (1) A general approach to four-state, conformational analysis based on the magnetic anisotropy of molecules undergoing fast dynamic exchange is described. (2) Study …