Physical Sciences and Mathematics Commons^™

Toward The Combinatorial Development Of Hydrophobic-Tagged Antifolate-Directed Degradation Of Human Thymidylate Synthase, Daniel J. Menasco

Theses and Dissertations

Direct post-translational control over a protein of interest (POI) can be exploited by manipulating the cells protein quality-control systems responsible for either intracellular turnover through ubiquitination (POI half-life) or repairing and degrading misfolded proteins.1 In an effort to target and degrade a high value POI we selected the enzyme human thymidylate synthase (TS) for post-translational degradation through ligand-directed ubiquitination and hydrophobic tagging. Thymidylate synthase catalyzes the reductive methylation of 2’-deoxyuridine monophosphate (dUMP) to 2’-deoxythymidine monophosphate (dTMP). As the de novo source of dTMP the regulation of intracellular TS is strictly controlled by ubiquitinindependent proteasomal degradation mediated by an internal TS-degron …

Cationic Metallocene-Containing Polymers: From Synthesis To Applications, Jiuyang Zhang

Theses and Dissertations

Metallopolymers, with the combination of metals and polymeric framworks, have attracted a lot of attention during the past decades. The development of metallopolymers has been largely driven by the desire to combine the synthetic efficiency and versatility of an organic polymer framework with the unique redox, responsive and catalytic properties of inorganic metals. Among different kinds of metallopolymers, metallocene-containing polymers， have been widely utilized for applications ranging from electrochemical sensors to templates for advanced inorganic catalysts to battery materials, due to their unique physicochemical properties. In the first part of my thesis, we showed controlled/living polymerization strategies to prepare well-defined …

Universal Two-Electron Correlation Operator On Excited States, Bryan Thomas Nichols

Theses and Dissertations

Excited states of chemical systems are extremely important in understanding spectra, chemical phenomena, as well as how a particular compound behaves in reactions. Computationally, excited states are normally very expensive to calculate. The difficulty in calculating these states with wavefunction based methods can be mainly attributed to the calculation of large multi-determinant wavefunctions. One reason to use a complicated multi-determinant wavefunction is to include some of the effects of correlation energy. The quantity of correlation energy can most simply be defined as the reduction in energy caused by any two or more electrons trying to avoid each other. The most …

Surface Functionalization Of Inorganic Substrates With Polymeric Ligands Using Raft Polymerization, Anand Viswanath

Theses and Dissertations

This work focused on using polymers to modify the surface of various inorganic substrates, ranging from TiO2, ITO, CDSe and CdS nanostructures to micron sized silica particles. The synthesis of the polymers using the RAFT technique and the characterization of the functionalized substrates were analyzed in detail to provide insights into their use for various applications. In the first part of this work, novel phosphate based RAFT agents and phosphate containing polymers, including poly(methyl methacrylate) (PMMA), poly(glycidyl methacrylate) (PGMA) and poly(dimethyl siloxane) (PDMS) were synthesized. Alkyne functionalized PGMA was used to click to ITO surfaces in a grafting-to method, and …

Design And Implementation Of A Near-Field Scanning Optical Module For Inverted Microscopes, Taher Ababneh

Theses and Dissertations

This dissertation describes the design and implementation of a home-built near-field scanning optical microscope (NSOM) module for inverted microscopes. In this design, the NSOM module is built atop an inverted fluorescence microscope. This is particularly well suited for applications in which the normal imaging modes of the inverted microscope are still required to locate and study the sample before performing NSOM experiments. This module is used as a near-field instrument for nanostructure investigation of various samples including plane-ruled reflection gratings, AFM calibration standards, nanospheres and gold nanoparticles. In addition, we will demonstrate the ability to achieve nanometer-scale surface modification of …

Modification Of Pyrimidine And Purine Nucleotides By "Click" Chemistry: Design, Synthesis And Properties Study, Mohammad Mojibul Haque

Theses and Dissertations

This dissertation consists of three main parts, totaling five chapters, and focuses on developing novel nucleosides via "click" chemistry and studying their potential biological

properties. Chapter three describes the synthesis and properties of coumarin-modified fluorescent DNAs. Coumarin-modified 2'-deoxythymidine was synthesizedvia "click" chemistry and incorporated into oligodeoxynucleotides (ODNs) which induce photoreversible interstrand cross-link (ICL) upon 350/254 nm photoirradiation. The irradiation at 350 nminduces DNA cross-linking with ODNs containing coumarin. The cross-linked DNA products formed from coumarin are not fluorescent. Further investigation showed that coumarin moiety undergoes the (2π+2π) photocycloaddition with 2'-deoxythymidine (dT), 2'-deoxycytidine (dC), and to a much lower extent, 2'-deoxyadenine …

Cellular Zinc Trafficking: The Zinc Proteome And Its Reactions With Cadmium, Mohammad Ali Namdarghanbari

Theses and Dissertations

Metals play a crucial role in living systems. Iron, zinc, copper, molybdenum, and manganese are involved in many essential biological activities. Among transition metals, zinc after iron is the most abundant transition metal in the human body and the most abundant in the brain. It exists in more than 3000 proteins, which comprise about 10% of the human proteome. Zn2+ dyshomeostasis is associated with chronic diseases such as metabolic syndrome, diabetes and related complications, bone loss, growth retardation in young children, and neurological and behavioral problems. Despite a good knowledge obtained for metabolism of some metal ions such as copper, …

Part I: Synthesis And Biological Evaluations Of Potent Class L Selective Histone Deacetylase Inhibitors Part Ii: Aqueous Complexes For Efficient Sizebased Separation Of Americium From Curium Part Iii: Designing Strong Chiral Bronsted Acids And Their Application For Oxaxinanones Derivatization And The Aza-Henry Reaction, Joseph Steve Ulicki

Theses and Dissertations

PART I: SYNTHESIS AND BIOLOGICAL EVALUATIONS OF POTENT CLASS l SELECTIVE HISTONE DEACETYLASE INHIBITORS

Histone deacetylase inhibitors (HDACi) have found a wide variety of medicinal uses and are most noted for their specific apoptotic action towards cancer cells1. Several hydroxamates and tetrapeptides HDACi have since been moved on to phase 1 and 2 clinical trials, with FK228 & SAHA having already been approved for treatment of advanced cutaneous T-cell lymphoma (CTCL). FK228 & SAHA are pan-HDACi which d compounds describes the unselective inhibition for any of the 11 Zn2+-dependent HDAC isoforms. Research in the past five years, has shifted towards …

Chaperone-Mediated Folding And Assembly Of Β-Propeller Proteins Into Cellular Signaling Complexes, Rebecca L. Plimpton

Theses and Dissertations

G protein signaling depends on the ability of the individual subunits of the G protein heterotrimer to assemble into a functional complex. Formation of the G protein βγ (Gβγ) dimer is particularly challenging because it is an obligate dimer in which the individual subunits are unstable on their own. Recent studies have revealed an intricate chaperone system that brings the Gβ and Gγ subunits together. This system includes the cytosolic chaperonin containing TCP-1 (CCT) and a co-chaperone phosducin-like protein 1 (PhLP1). Two key intermediates in the Gβγ assembly process, the Gβ-CCT and the PhLP1-Gβ-CCT complexes, were isolated and their structures …

Microchip Thermal Gradient Gas Chromatography, Anzi Wang

Theses and Dissertations

Although the airbath oven is a reliable heating method for gas chromatography (GC), resistive heating is needed for higher analytical throughput and on-site chemical analysis because of size, heating rate and power requirements. In the last thirty years, a variety of resistive heating methods were developed and implemented for both benchtop and portable GC systems. Although fast heating rates and low power consumption have been achieved, losses in column efficiency and resolution, complex construction processes and difficulties experienced in recovering damaged columns have also become problematic for routine use of resistively heated columns. To solve these problems, a new resistively …

Fabrication, Characterization, Optimization And Application Development Of Novel Thin-Layer Chromatography Plates, Supriya Singh Kanyal

Theses and Dissertations

This dissertation describes advances in the microfabrication of thin layer chromatography (TLC) plates. These plates are prepared by the patterning of carbon nanotube (CNT) forests on substrates, followed by their infiltration with an inorganic material. This document is divided into ten sections or chapters. Chapter 1 reviews the basics of conventional TLC technology. This technology has not changed substantially in decades. This chapter also mentions some of the downsides of the conventional approach, which include unwanted interactions of the binder in the plates with the analytes, relatively slow development times, and only moderately high efficiencies. Chapter 2 focuses primarily on …

Synthesis And Characterization Of Complex Molecular Assemblies On Surfaces, Nitesh Madaan

Theses and Dissertations

The research presented in this dissertation is focused on the construction of complex molecular structures on planar gold and silicon dioxide surfaces using a variety of surface modification techniques, along with thorough surface characterization at each modification step. The dissertation is structured into six separate chapters. In Chapter 1, an introduction to the importance and implications of molecular level surface modification, commonly employed surface modification methods, and available surface characterization techniques is presented. Chapter 2 shows applications of novel methodologies for the functionalization of gold surfaces using alkane dithiol self-assembled monolayers and thiol-ene click chemistry. The resulting functionalized gold substrates …

Ion Structure And Energetics In The Gas Phase Characterized Using Fourier Transfom Ion Cyclotron Resonance Mass Spectrometry, Chad A. Jones

Theses and Dissertations

In this dissertation, I use Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) to study the structure and energetics of gas phase ions. Infrared multiphoton dissociation spectroscopy (IRMPD) is a technique for measuring the IR spectrum of gas phase ions in a Penning trap. I use this technique to investigate the conformation of cucurbituril complexes, terminal diamines, and protonated amino acids. Cross sectional areas by Fourier transform ion cyclotron resonance mass spectrometry (CRAFTI) is a technique developed by the Dearden lab to measure the cross section of gas phase ions. In this work, I further develop a fundamental understanding of …

Simple, Label-Free And Non-Instrumented Analyte Quantitation By Flow Distance Measurement In Microfluidic Devices, Debolina Chatterjee

Theses and Dissertations

Rapid determination of the concentrations of molecules related to diseases can provide timely information for treatment options. However, most biomarker quantitation methods require costly and complex equipment. On the other hand, point-of-care systems have less complex instrumentation needs than laboratory-based equipment, but often provide less information; for example, biomarker presence or absence instead of concentration. A complete analysis setup addressing key limitations of both laboratory-based and portable systems is highly desirable. I developed microfluidic devices with visual inspection readout of a target’s concentration from microliter volumes of solution flowed into a microchannel. Microchannels are formed within polydimethylsiloxane (PDMS), and the …

Design, Synthesis, Characterization, And Evaluation Of Surface Modified Boronate Ester Covalent Organic Frameworks, Matthew W. Di Carmine

Theses and Dissertations

Covalent Organic Frameworks (COFs) were first reported in 2005 and are analogous to Metal Organic Frameworks (MOFs), with proposed applications in separation, storage and sequestration. Since COFs are comprised of lighter elements they are considered more advantageous for weight-sensitive applications. However, COFs are susceptible to degradation by weak nucleophiles such as water (i.e. hydrolysis). The Lavigne group has focused on developing structure-property relationships for COFs. It was previously demonstrated that the porosity of the COFs could be tailored by incorporating small alkyl chains on one monomer. Inclusion of these alkylated monomers into COF materials effectively increased the COF hydrophobicity resulting …

Carboxylate Selective Lanthanide Imprinted Polymer Sensors For Sensor Array, Yang Xu

Theses and Dissertations

A europium-based molecularly imprinted polymer (MIP) was developed and characterized, which combined the highly luminescent properties of europium and the recognition properties of molecularly imprinted polymers. The europium-based MIPs were used as selective sensors for different types of carboxylates. The ultimate goal of this work was to develop a europium-based sensor array to differentiate carboxylates anions. The polymer was synthesized by using a europium–salen complex as the monomer and ethylene glycol dimethacrylate (EGDMA) as the crosslinker. First, a europium containing non-imprinted polymer (NIP) and a series of europium containing MIPs imprinted with acetate, benzoate and phenylacetate were synthesized by free …

Insights Into The Evolutional Adaptations And Functional Switching Mechanism In Dual Function Hemoglobin/Dehaloperoxidase (Dhp) And Modeling Of Cytochrome P450 Active Site With H93g Myoglobin Cavity Mutant, Shengfang Sun

Theses and Dissertations

The coelomic hemoglobin, dehaloperoxidase (DHP), from the sea worm Amphitrite ornata, is a dual function oxygen-binding heme protein that also possesses a significant peroxidase activity. As evolved from an ancient oxygen carrier globin, several structural adaptations have enabled DHP to evolutionally gain significantly enhanced peroxidase capability for self-protection while only minimally compromising its primary function as an O2 carrier. To elucidate these adaptations, the peroxidase activities and O2 affinities of several DHP and sperm whale myoglobin (Mb) mutants have been prepared. Several heme environmental structural factors that regulate the dual functions of DHP have been found, providing insight into how …

Synthesis And Characterization Of Polymer Nanomaterials Using Controlled Radical Polymerization, Lei Wang

Theses and Dissertations

This research focuses on creating and investigating polymer/organic bound interfaces on nanoparticles with advanced architectures to tailor the properties of polymer nanocomposites for various applications. Reversible addition-fragmentation chain transfer (RAFT) polymerization and a toolbox of surface functionalization from the simple to the advanced were developed to prepare the polymer nanomaterials.

In the first part (Chapter 2), a variety of RAFT agents (xanthate, dithiocarbamate and trithiocarbonate) were used to mediate the polymerizations of several classes of free radical polymerizable monomers. These monomers consist of styrene, methyl acrylate, methyl methacrylate, vinyl acetate and isoprene, which have different activities and require different classes …

Biopolymeric Hydrogels Functionalized With Tobacco Mosaic Virus For In Vitro Three Dimensional Culture And Differentiation Of Stem Cells And In Vivo Tissue Regeneration, Jittima Amie Luckanagul

Theses and Dissertations

Plant viruses have been highlighted among material research due to their well-defined structures in nanoscale, mono-dispersity, stability, and chemical functionalities. Each of the thousands coated protein subunits on a viral nanoparticle can be homogenously modified, chemically, and genetically with a functional ligand leading to a high-density and spatial distribution of ligands on each particle (multivalency). Many reports from our group have clearly shown that virus coated substrates induced the acceleration of bone marrow stromal cells differentiation into bone cells. We hypothesized that this phenomenon could rely on the multivalency that the viral nanoparticle has to offer. Moving to a more …

Mechanistic Investigation Of A Silylation-Based Kinetic Resolution Using Linear Free Energy Relationships And Its Application To Substrate Expansion And Polymer Supported Kinetic Resolutions, Ravish K. Akhani

Theses and Dissertations

This dissertation represents our preliminary mechanistic investigations on the silylation-based kinetic resolution of secondary alcohols, and how we use that knowledge for further expansion of this methodology. Chapter 2 describes how we came up with a preliminary mechanism of our silylation-based methodology using a linear free energy relationship and a rate study. In this chapter, several para substituted triphenylsilyl chlorides were prepared that varied electronically and sterically in order to understand the substituent effects on the rate and the selectivity of the reaction. Selectivity factors and initial rates were experimentally determined for the kinetic resolution reactions with the newly designed …

Investigation Into The Synthesis And Characterization Of Poly(Dioxaborolane)S, Shakena Daniel

Theses and Dissertations

Boronate esters have evolved from being primarily used as sensors to being the integral linkage in complex materials such as macrocycles, covalent organic frameworks, and linear polymers. Poly(boronate)s, linear polymers that are linked via a boronate ester, have not been extensively researched. In 2005, the Lavigne group published the first manuscript on poly(dioxaborolane)s, i.e., six-membered, nonconjugated polyboronates. The behavior of the materials in solution was studied extensively, but little is known about the solid state properties of the material other than they form brittle films.

Poly(dioxaborolane)s are generated in high yield through a facile step-growth polymerization, but the reaction parameters, …

Synthesis, Characterization And Optical Properties Of Conjugated Boronate-Linked Materials And Their Applications In Optical Sensing Of Lewis Bases, Min Cai

Theses and Dissertations

Organoboron compounds, with Lewis acidic boron centers, have been emerged as an important class of materials, especially in the area of chemical sensors. Herein, boranes and boronate esters in the sensing perspective were overviewed in Chapter 1. Examples of synthesis and sensing applications of boron-containing conjugated polymers were highlighted.

Boronate ester formation provides the advantages of facile synthesis, tunable optical properties, enhanced stability and planar geometry. Thus, boronate esters, especially dioxaboroles, were proposed to use as alternatives of boranes to design better sensors for Lewis bases. Based on the previous investigation of fluorenyl bis- and poly- dioxaboroles by our group, …

Novel Monomers And Solution Polymerization Methods For Polybenzimidazole Polymers, Jason Hoffman

Theses and Dissertations

The goal of this work was to identify and study various monomers and polymerization methods for polybenzimidazole polymers. Beginning with the solution polymerization of polybenzimidazole via a bisulfite adduct monomer, Chapter 2 describes the efforts to optimize and scale up this process. Chapter 3 then covers an alternative method to prepare polybenzimidazole in solution by using an orthoester monomer. Finally, in Chapter 4, the research to incorporate an adamantane moiety into the backbone of polybenzimidazole is described.

Development Of Novel Methods For Characterization Of Complex Organic Mixtures By Liquid Chromatography And Raman Spectroscopy, Veronica Maria Marco Alvarez

Theses and Dissertations

ABSTRACT

DEVELOPMENT OF NOVEL METHODS FOR CHARACTERIZATION OF COMPLEX ORGANIC MIXTURES BY LIQUID CHROMATOGRAPHY AND

RAMAN SPECTROSCOPY

by

Veronica Marco Alvarez

The University of Wisconsin-Milwaukee, 2014

Under the Supervision of Professor Joseph H. Aldstadt III

The development of methods for the study of Humic Acids (HAs) and related substances is described. In the first part, a reversed-phase liquid chromatography (RP-LC) instrument was designed, fabricated, and a method for the separation of HAs was optimized for application as the second dimension in a two-dimensional LC (LCxLC) system. The optimized method for the RP-LC was used in the study of amino acid …

The Implications Of Content Analysis For The Interpretation Of Unguentaria In Museum Collections, Jenna L. Mortensen

Theses and Dissertations

Scent has traditionally been an ephemeral component of rituals in ancient societies, including burial and other practices associated with the anointing of the body (Classen et al. 1994: 43; Houston and Taube 2000: 271). This thesis investigates the possible signifiers and social impact such scents might have had for individuals participating in such rituals by using the little explored approach of sensory archaeology. A discussion of the correlation between olfaction and the triggering of both the experiential and emotional aspects of memory contributes to a broader view of these rituals in the anthropological literature (Classen et al. 1994), while Houston …

Microfluidic Device Integration Of Electrostatic Corral Trapping Systems, Alaknanda Amin

Theses and Dissertations

This thesis describes the development, characterization, and application of the microfluidics device integration of electrostatic corral trapping systems. Optical traps or "laser tweezers", which are capable of trapping microscopic dielectric particles through the production of steep electromagnetic field gradients, have been significant in the development of the field of biophysics and the manipulation of microscopic objects. This method of trapping unfortunately has a fundamental size limitation, making it incapable of trapping molecular-scale objects. We have developed a new tool for the trapping and manipulation of nanoscale objects including single molecules, the corral trap, which has distinct characteristics that set it …

The Development Of Vdr-Coactivator Inhibitors And Their Evaluation Using Biochemical And Cell-Based Assays, Belaynesh Feleke

Theses and Dissertations

The vitamin D receptor (VDR) belongs to the family of nuclear receptors and plays a crucial role in many biological processes such as cell differentiation, cell proliferation and calcium homeostasis. VDR is a good pharmaceutical target for many diseases including cancer, metabolic disorders, skin diseases and cardiovascular diseases. Upon binding with its endogenous ligand calcitriol in the body, VDR undergoes a conformational change that disrupts the interaction with corepressor proteins and instead enables the interaction with coactivator proteins that mediated transcription. The goal of the research is the development of new small molecules that will selectively inhibit the interaction between …

The Synthesis Of Alpha 5 Subtype Selective Gaba(A) /Benzodiazepine Receptors Ligands, Poonam Biawat

Theses and Dissertations

GABAA complexes are a class of receptors that respond to the neurotransmitter GABA, the chief inhibitory neurotransmitter in the vertebrate CNS. A widely accepted pharmacological target for enhancing cognition is the benzodiazepine-binding site on the gamma-aminobutyric acid type A (GABAA) receptor complex. Inverse agonists acting at 5 subunits containing GABAA receptors are thought to act as cognitive enhancers while eliminating unwanted side effects associated with non-selective compounds. From the recent work of Rowlett, Cook et al. it was demonstrated that the novel 5 selective inverse agonist PWZ-029 (20) was active as a cognitive enhancer in rhesus monkeys in the CANTAB …

Synthesis Of 4'-Ester Resveratrol Analogues, Chromium Trioxide Oxidation Of Terpenes, And Synthesis Of Mimics Of (-)-Englerin A, Mark Jeffrey Acerson

Theses and Dissertations

4’ -ester analogues of resveratrol were synthesized using reaction conditions developed to produce mono-ester products in the presence of two other unprotected phenols. Basic conditions were employed to deprotonate the most acidic 4’ phenol followed by addition of anhydrides or acid chlorides to give the ester product. The reaction favored 4’-ester formation in polar aprotic solvents with DMSO being the optimal solvent.

(—)-Englerin A is a guaiane-type sesquiterpene containing two ester side chains. Mimics of (—)-englerin A were proposed that retained the ester side chains while replacing the non-polar core with less complicated structures. These proposed mimic cores would maintain …

Extension And Applications Of The Gvvpt2 Method To The Study Of Transition Metals, Patrick K. Tamukong

Theses and Dissertations

The ground and low-lying excited electronic states of molecules of the first ( 2 Sc , 2 Cr , 2 Mn , and 2 Ni ) and second ( 2 Y , 2 Mo , and 2 Tc ) row of transition elements have been investigated for the first time with the generalized Van Vleck second order multireference perturbation theory (GVVPT2) method, a variant of MRPT. All potential energy curves (PECs) obtained in these studies were smooth and continuous; that is, they are free from wiggles or inflexion points. In order to account for relativistic effects, which become important in …