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School of Chemistry and Biochemistry

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College of Sciences

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Surface Modification of Hard PVC by Molecules with Antibacterial Activity

(Georgia Institute of Technology, 2019-12-09) Pigliautile, Lucrezia

In this work, we present an analysis of different PVC surface modifications, attempted with the intention of attaching antibacterial small molecules, polymers, and oligomers on the plastic. These modifications allowed us to obtain intrinsically antibacterial PVC, which can be potentially applied in healthcare and medical devices. The modification was performed with two procedures, copper-catalyzed azide-alkyne cycloaddition, and nucleophilic substitution. In the first case, the surface of PVC was initially treated with sodium azide to obtain partially azidated PVC, followed by treatment with alkyne-bearing small molecules and polymers. In the second method, the surface was treated with amine-bearing small molecules and polymers, directly substituting the chlorine atoms on PVC. We concluded that the hydrophilicity, the size of the molecule, and the reaction conditions, are the main factors that influence the success of these modifications. Bacteria viability tests were performed on differently-substituted PVC samples, showing good antibacterial activities for PVC surfaces treated with quaternary ammonium salts and acceptable activities for samples modified with polyethyleneimine and oligoethylene glycol.
Crosslinked Polytriazoles toward Chemically Stable Separations Membranes

(Georgia Institute of Technology, 2019-11-08) Hamlett, Breanne Leigh

Membranes have emerged as energy efficient molecular separation platforms relative to traditional energy-intensive processes in the fields of hydrocarbon separations and water desalination. However, membranes are seldom used in large scale industrial separations because they suffer from (1) high cost and (2) difficulty in tunability between different separation processes. Ultra-thin membranes can decrease operation costs and as well as decrease polymer cost by using less material. However, current ultra-thin polyamide membranes are not capable of withstanding the harsh cleaning and pretreatment conditions used in water desalination. To achieve the goal of chemical resistant membranes, the copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction was used to create highly stable and chemical resistant triazole linkages throughout the polymer membrane. Additionally, triazoles were used to crosslink polymers of intrinsic microporosity (PIMs), to add to PIMs already exceptional gas properties and address PIMs deficiencies in liquid separations. Furthermore, interfacial polymerization was used to create ultra-thin polytriazole membranes. Lastly, CuO hollow fiber membranes were used as a macroporous support to simultaneously add mechanical stability to the polytriazole membranes and catalyze the CuAAC reaction on the surface, creating a polytriazole composite hollow fiber membrane.
Photophysical investigation of xanthenes for use in background suppression

(Georgia Institute of Technology, 2019-11-07) Demissie, Aida

Fluorescence imaging is an important tool in biological imaging applications. Even with the many advances in this field endogenous background remains a challenge. Herein we present a way of circumventing background fluorescence by using dark-state photophysics of dyes. Amplitude modulation, as presented in Synchronously amplified fluorescence/photoacoustic image recovery (SAFIRe/SAPhIRe), is a technique employed to generate background free signals. This work focuses on understanding the properties of optically the modulatable dyes in the xanthene family, rose bengal, erythrosin B and Eosin Y, with the goal of designing better contrast agents for biomedical imaging. Results show previously undescribed methods for optical modulation of xanthenes that give long lived fluorescence as a result of direct repopulation of the singlet excited state from the triplet state. This technique described as optically activated delayed fluorescence (OADF) allows for fluorescence signals to persist much after (~μs) the decay of prompt fluorescence (~ns) allowing for background free detection of signal. The mechanism of modulation was investigated using both experimental and theoretical methods and modulation depth and in turn OADF generation was shown to increase with higher triplet quantum yields and at higher excitation rates. Dual laser modulation schemes have been used for photophysical characterization of dyes giving triplet lifetimes of 240μs, 420μs and 2.3ms for rose bengal, erythrosin B and eosin Y respectively. Finally, optical modulation in photoacoustic imaging was investigated and because both fluorescence and photoacoustic signal generations depend on the population of ground state molecules, similar approaches to dynamically shift population from the long-lived dark-states back to ground state will allow for background free photoacoustic imaging, (SAPhIRe). SAPhIRe was used to distinguish rose bengal loaded silica nanoparticles from blood background as well as buried ~10mm in rat muscle.
Understanding the Effects of Structure on the Charge Transport Properties and Doping of Dioxythiophene Polymers

(Georgia Institute of Technology, 2019-11-06) Pittelli, Sandra

Redox-active conjugated polymers have been investigated for a multitude of applications including electrochromic displays, transistors, and transparent conducting electrodes. As with all fields of polymer science, the material properties observed for these conjugated polymers are determined by their structure. While the groundwork for probing their fundamental structure-property relationships has been established, there is still much to be explored in order to have a holistic understanding of these systems. This dissertation aims to investigate how the structure of dioxythiophene polymers can affect the processes of chemical and electrochemical oxidation, their charge transport properties, and their use in electrochemical and solid-state applications. Chapter 1 provides an introduction to the fundamental properties and concepts of conjugated polymers, and their use in potential applications. Characterization methods used in this work, including electrochemical experimentation and dry-film characterizations are highlighted in Chapter 2. Chapter 3 describes the work exploring how the use of chemical oxidants and phosphonic acids can be used as pre-treatment steps in the construction of electrochemical devices. A family of polymers including two dixoythiophenes (DOTs) and one dioxypyrrole (DOP) were exposed to a series of chemical oxidant salts with the oxidizing agent either being Ag+ or Fe3+. The structure and redox properties of the conjugated polymers were shown to affect the overall extent of oxidation. Specifically, the DOT polymer that had the highest onset of oxidation in the family was oxidized to a lesser extent when using Ag+ as the chemical oxidant rather than Fe3+. In contrast, the DOT polymer with the lowest onset of oxidation in the family was oxidized to the same extent using both dopants. Using Fe3+ was shown to disrupt the interface between films of each polymer in the family and the conducting substrate, however this was rectified through modification of the surface energy of the substrate using phosphonic acids. Ultimately, it was shown that devices constructed after chemical pre-oxidation had comparable electrochromic contrasts to those using an electrochemical pre-oxidation step. Chapter 4 explores the effects of side chain alteration on the charge transport properties of a family of either 3,4-propylenedioxythiophene (ProDOT) or acyclic dioxythiophene (AcDOT) homopolymers. It was shown that the incorporation of linear side chains rather than branched side chains for both the ProDOT and AcDOT polymers allowed for a decrease in the onset of electrochemical oxidation by 300 mV and a 2 order of magnitude increase in the solid-state in-plane conductivity (10-3 vs 10-1 S/cm) after chemical oxidation. This study ultimately showed that there is a delicate balance in the degree of ordering of the polymer film and effective charge transport. Chapter 5 further supported this concept of balance by probing a family of soluble dioxythienothiophene (DOTT) polymers for their structure-property relationships. These polymers also showed that too much intermolecular ordering inhibits the processes of oxidation and charge transport. Specifically, the DOTT homo polymer showed higher degrees of intermolecular ordering according to GIWAXS measurements, and had an electrochemical onset of oxidation that was almost 700 mV higher (0.05 vs -0.62 V) than the less ordered DOTT co-polymerized with two EDOT units (DOTT-BiEDOT). The introduction of two EDOT units also raised the solid-state in-plane conductivity by 4 orders of magnitude (10-3 vs 101 S/cm).
Prebiotic chemistry on mineral surfaces: Proto-oligopeptide formation on silica and other substrates within depsipeptide forming systems

(Georgia Institute of Technology, 2019-11-06) McKee, Aaron D.

The chemical origins of life on Earth and perhaps elsewhere in the universe is not utterly unknowable, though the subject is incredibly complex. To endeavor to understand what events brought about life on early-Earth nearly 4 billion years ago, life itself must be broken down into its major processes, which themselves are constructed from increasingly simple and ordinary sub-units, and eventually, examined to describe the building blocks of life and how they might assemble. The presence of amino acids on extra-terrestrial bodies and in prebiotic simulation experiments suggests the plausibility of their existence on early Earth. In contrast to extant biological protein production, abiotic polypeptide formation presents several challenges, such as the thermodynamically disfavored condensation of non-activated amino acids in aqueous solution. Recent work has introduced α-hydroxy acids, a class of molecules found alongside amino acids in prebiotic contexts, into peptide forming systems. This has been shown as a robust route towards proto-polypeptides, producing long mixed-acid oligomers, referred to as depsipeptides. In pursuit of realistic model prebiotic environments, mineral-molecule interactions must be considered, and may facilitate new chemical pathways at interfacial regions. Presented in this thesis is a demonstration that the inclusion of silica and other minerals in hydroxy-acid/amino-acid and related reactions effects the composition of oligomers, resulting in amino acid enrichment relative to a substrate-absent controls. Evidence of surface ester formation suggests that the same ester aminolysis mechanism that proceeds in a homogeneous condition is also able to proceed on the substrate surface as silyl-ester aminolysis, indicating that silica is directly involved in the oligomer growth process and departs from previous studies of mineral catalyzed peptide formation on metal oxides. If depsipeptides are model proto-polypeptides, then surface functionalization of minerals with simple HAs might provide catalytic pathways useful for unraveling plausible routes to the production of complex molecules under early-Earth conditions or on extraterrestrial bodies.
Probing Heme Trafficking Using Genetically Encoded Fluorescent Heme Sensors

(Georgia Institute of Technology, 2019-11-05) Martinez-Guzman, Osiris

In this thesis, we describe genetic screens in Baker’s yeast to identify factors that regulate a. steady-state heme availability, b. the dynamics of heme mobilization to different subcellular compartments as it is being synthesized, and c. heme uptake. Regarding steady-state heme availability, the Saccharomyces cerevisiae haploid gene deletion library was transformed with cytosolic heme sensors and mutants with altered heme availability were discovered in order to identify possible heme transporters, trafficking factors, and buffering proteins. The screen identified 114 strains with high cytosolic heme and 323 strains with low cytosolic heme. Amongst the deletion mutants with high heme, we found that the glycolytic enzyme glyceraldehyde phosphate dehydrogenase (GAPDH) is responsible for buffering intracellular heme and regulating the activity of the nuclear heme-dependent transcription factor heme activator protein (Hap1p). Amongst the deletion mutants with low heme, we found that Golgi-to-vacuolar vesicular trafficking is a key requirement to for ensuring heme is accessible to the cytosol. We propose a model in which heme is transported from endosomes into the cytosol. Altogether, for the first time, we identified genome-wide determinants of heme bioavailability. In order to probe heme distribution dynamics as heme is being synthesized, we developed a live-cell assay in yeast to monitor inter-compartmental heme trafficking kinetics to different subcellular compartments, including the mitochondrial matrix, cytosol, or nucleus. Surprisingly, we found that heme trafficking rates from the matrix side of the IM, where heme is made, to the mitochondrial matrix and cytosol are similar, while trafficking to the nucleus is ~25% faster. Moreover, we discovered that the heme biosynthetic enzyme, aminolevulinic acid synthase (ALAS) negatively regulates mitochondrial-nuclear heme trafficking, highlighting the close coordination of heme synthesis and trafficking. In addition, we identified GTPases that directly (Gem1) and indirectly (Dnm1 and Mgm1) regulate ERMES as being modulators of nuclear heme transport. Based on our results, we propose a model in which heme is trafficked via ER- mitochondrial membrane contact sites to other organelles such as the nucleus. Most eukaryotes have the capacity to both make and import heme. We used fluorescent heme sensors in Saccharomyces cerevisiae to determine if heme availability and utilization differs whether heme is derived from exogenous or endogenous sources. Our results demonstrate that S. cerevisiae is capable of acquiring and utilizing exogenous heme under high concentrations but not in an efficient way. Biosynthesized heme is more available than exogenous heme and is more efficient at activating heme dependent processes such as catalase activity and Hap1 activity, a heme dependent transcription factor. We observed conditions such as iron starvation promoted heme availability from exogenous sources in a heme oxygenase (HO) dependent manner. In addition, we screened the yeast deletion collection for factors that altered heme uptake and utilization and identified 33 deletion mutants that displayed an improvement in heme uptake, including mfm1∆ cells, which lacks a magnesium transporter and has a defect in mitochondrial membrane potential. Overall, our work probing heme homeostasis with genetically encoded heme sensors have identified a host of new factors that regulate heme trafficking dynamics and availability from both endogenous and exogenous heme sources. The tools and approaches described herein to identify new heme trafficking factors in Baker’s yeast are now being applied to probe heme homeostasis in human cell lines, where defects in heme metabolism cause a number of diseases, and in bacterial and fungal pathogens, which require heme for virulence.
Enrichment and Isolation of Iron-Oxidizing Bacteria from an Ancient Earth Analogue

(Georgia Institute of Technology, 2019-08) Ghazi, Layla

Fe2+ was an abundant component of ancient anoxic oceans and could have acted as a respiratory electron donor. The overall goals of this study were to test whether anaerobic microbial growth could occur with Fe2+ as the electron donor in Fe2+-rich sediments from an ancient ocean analogue (Lake Matano, Indonesia) and to determine the taxonomic identity of the bacteria. Sediments were incubated with Fe2+ sulfide as the electron donor in a nitrogen:carbon dioxide (90/10%) atmosphere. Manganese (III), nitrate, nitrite, and oxygen were provided as electron acceptors. With Mn3+ as the electron acceptor, cultures showed some evidence of growth near the middle of the gradient tube. However, orange Fe3+ oxides were absent, suggesting that anaerobic Fe2+ oxidation had not occurred. Ferric oxides were also absent in tubes containing nitrate and nitrite. A white precipitate was present in cultures with Mn3+, which indicated that the microbes reduced Mn3+ to Mn2+. The precipitate was not present in uninoculated controls. With oxygen as the electron donor, a layer of orange Fe3+ oxide minerals formed near the water-air interface, indicative of growth of microaerophilic Fe2+-oxidizing bacteria. This layer did not form in uninoculated controls. Our preliminary results suggest that anaerobic Lake Matano enrichments are capable of Fe2+ oxidation using oxygen but not alternative electron acceptors. After subsequent transfers of the enrichments that showed growth of microaerophilic Fe2+-oxidizing bacteria, the bacteria were isolated and their 16S rRNA gene was sequenced. Sequences were most similar to the Betaproteobacteria genus Comamonas and the Alphaproteobacteria genus Skermanella. Some species of Comamonas are known to oxidize Fe2+, while the exact mechanism of the metabolism of Skermanella are not well known. The presence of microaerophilic Fe2+ oxidizing bacteria from Lake Matano, Indonesia serves as a link between understanding the transition from an anoxic to an oxic world.
Physical organic principles governing the spontaneous prebiotic emergence of proto-nucleic acids

(Georgia Institute of Technology, 2019-07-30) Fialho, David M.

The origin of life on Earth is a poorly understood phenomenon. The influential RNA world hypothesis states that, at some early stage in the evolution of life, RNA was the sole (or primary) biopolymer, performing both informational and catalytic functions. In some interpretations of the RNA world hypothesis, RNA is the first polymer to arise from prebiotic chemical processes. However, the prebiotic synthesis of RNA is problematic: forming the various components of RNA selectively and covalently linking them is prebiotically difficult. For these reasons, it has been hypothesized that RNA is the product of evolution. In this view of the origin of nucleic acids, RNA is the penultimate member in an evolutionary series of nucleic acids, starting with the first informational polymer to arise on the early Earth: the proto-nucleic acid. The chemical components of the proto-nucleic acid, and of pre-RNAs, are not necessarily the same as those in RNA, but their functions were similar. In this dissertation, candidate proto-nucleic acid components, such as noncanonical nucleobases and noncanonical backbone motifs, are described, and criteria to judge their candidacy, such as chemical reactivity and propensity for oligomerization and self-assembly in water, are discussed. Although the chemical space of informational polymers is vast, the principles arrived at greatly reduce the size of this space by ruling out inviable chemical motifs. This work culminates with the introduction of a new class of informational polymer that is considered a strong candidate for proto-RNA. Important general principles for the evolution of proto-nucleic acids and pre-RNAs are also discussed.
Development of biocompatible dextran-oxanorbornadiene hydrogels

(Georgia Institute of Technology, 2019-07-23) Lloyd, Jessica

Hydrogels have garnered much attention over the past few decades for their ability to deliver therapeutics with spatial and temporal control. However, many of these systems can exhibit burst release and are not easily adjusted to realize different release kinetics. The research reported in this thesis aims to develop tunable degradable hydrogels from oxanorbornadiene linkers, which have been shown to have programmable fragmentation rates that can be tuned over an exceptionally wide range of time. OND hydrogels of different crosslinking compositions were all able to form robust gels in as little as seconds and release of entrained cargo was found to be tunable over 0.5 to 25 days by changing the OND substitution or crosslinking system. Oxanorbornadiene hydrogels were then applied to in vivo models seeking to improve healing in chronic wounds where it was found that OND hydrogels were able to deliver therapeutic cargo at the expected preprogrammed rates to improve wound healing. Degradable hydrogels comprised of OND cleavable linkages continue to show great promise as simple drug delivery systems that can be widely useful to applications requiring controlled release over hours or months.
Furthering the reactivity of low-nuclearity N-heterocyclic carbene supported copper(I) complexes

(Georgia Institute of Technology, 2019-07-17) Jordan, Abraham John

This thesis focuses on the synthesis of N-heterocyclic carbene (NHC) supported copper(I) complexes and their bond-breaking and bond-forming reactivity. The body of this work discusses new (NHC)copper(I) hydride dimers, the electrophilic fluorination of (NHC)copper(I) vinyls, and the nitrosylation of (NHC)copper(I) sulfide complexes. First, the expanded-ring N-heterocyclic carbenes 6Dipp and 7Dipp (6Dipp = 1,3-bis(2,6-diisopropylphenyl)-3,4,5,6-tetra-hydropyrimidin-2-ylidene and 7Dipp = 1,3-bis(2,6-diisopropyl-phenyl)-4,5,6,7-tetrahydro-1,3-diazepin-2-ylidene) are shown to support isolable neutral copper hydride dimers. [(6Dipp)CuH]2 reacts with 1-hexene to give (6Dipp)copper(I) hexyl by 1,2-insertion, and with benzyl isonitrile to afford an η1-formimidoyl by 1,1-insertion. Next, we show that the electrophilic fluorination of (NHC)copper(I) vinyls results in fluoroalkene formation. Alkynes can be converted to cis-(β-fluorovinyl)boronates by reaction with an (NHC)copper(I) boryl generated in situ, followed by N-fluorobenzenesulfonimide (NFSI). This sequence gives rise to anti-Markovnikov fluorination products from terminal alkynes. Oxidation of a cis-(β-fluorovinyl)trifluoroboronate yields an α-fluoroketone, whereas a palladium-catalyzed Suzuki-Miyuara coupling yields a tetrasubstituted monofluoroalkene. Lastly, the reactivity of a series of copper(I) sulfide complexes stabilized by the expanded-ring N-heterocyclic carbene 7Dipp, towards nitrosonium (NO+) is shown. 7Dipp is shown to support neutral sulfide- and disulfide-bridged dicopper(I) complexes, in addition to a mononuclear copper(I) hydrosulfide. Addition of NO+ to each of these results in the formation of NHC-supported copper(I) cations and elemental sulfur. Concomitant decomposition of copper(I) to Cu0 upon reaction of NO+ with the dicopper(I) sulfide or disulfide is observed, whereas ammonium ion formation is observed upon reaction of the copper(I) hydrosulfide with NO+. Ammonium ion formation is likewise observed upon reaction of NO+ with (7Dipp)copper(I) hydride.