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School of Chemistry and Biochemistry

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College of Sciences

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Now showing 1 - 10 of 1916

A New Luminescence-Based Assay for Monitoring Mutant Myocilin Cellular Localization

(Georgia Institute of Technology, 2024-07-30) Harris, Ethan Foley

Glaucoma is a heterogenous eye disease that is the leading cause of irreversible blindness worldwide, caused by a blockage in the outflow of aqueous humor from the eye, leading to an increase in intraocular pressure. The most common glaucoma subtype is primary open angle glaucoma, affecting ~60 million people worldwide. 2-4% of primary open angle glaucoma (POAG) and 10% of juvenile open angle glaucoma (JOAG) cases are attributed to mutations in the gene encoding for the protein myocilin. One of the key characteristics of a pathogenic variant is its inability to be secreted from trabecular meshwork cells. Instead of secretion, pathogenic myocilin variants accumulate in the endoplasmic reticulum and causes cell death. Mutant myocilins are studied in the lab using cellular secretion assays. In the past, different cellular fractions were detected using immunoblot, which has sensitivity limitations. In this thesis, we implement a new method that utilizes HiBiT, a luciferase-based assay, which we hypothesized would be more sensitive than immunoblot. The myocilin mutants tested using HiBiT (T377K, T377R, D384G, D395ins, C433Y, T455K, and L486F) to detect myocilin cellular localization exhibited negligible secretion when compared to WT. In addition, all the mutants except for L486F accumulated intracellularly. Unexpectedly, L486F was not detected intracellularly to the same degree as the other mutants, as evidenced by low band intensity in both the western and HiBiT blots for all three fractions. HiBiT blotting provides more sensitive detection than traditional immunoblotting, as evidenced by increased band intensity in the HiBiT blots for the same sample and lower quantities of cells needed for robust detection. Further studies on L486F will be required to determine whether it is poorly expressed or being degraded intracellularly. Overall, HiBiT detection of mutant myocilin enables new insights to be made into the mechanism of myocilin-associated POAG.
Noble-metal nanocrystals with metastable phases and their applications

(Georgia Institute of Technology, 2024-07-26) Nguyen, Quynh Nhu

Noble-metal nanocrystals serve as an innovative platform for the rational development of next-generation catalysts, owing to their tunable physical attributes, including size, shape, composition, and defects. The ability to modify atomic configurations as materials transition to nanoscale dimensions has pivoted the focus of recent research towards manipulating the atomic packing within the internal structure, particularly the crystal structure or phase, to enhance existing properties and uncover new phenomena. Such a precise control over the polymorphism of nanocrystals opens a new avenue to boost their catalytic performance by modifying the interactions between surface atoms and reaction intermediates. This dissertation presents a series of systematic studies that delve into the thermodynamic and kinetic factors responsible for the seed-mediated growth of noble-metal nanocrystals with unconventional, metastable crystal phases, together with an evaluation of their potential applications in catalysis. With an initial focus on Ru, I first elucidated the roles of shape and size of the preformed seeds in controlling the crystal phase taken by the deposited Ru overlayers, using fcc-Pd cubic and octahedral nanocrystals with different edge lengths as seeds. The Ru shell consistently adopted a metastable face-centered cubic (fcc) phase regardless of the size of the cubic seeds, while it retained the fcc phase on small octahedral seeds before reverting to the native hexagonal close-packed (hcp) phase on larger ones. This phenomenon could be attributed to the differences in surface atomic arrangement of the {100} facets displayed on a cubic seed and the facets of hcp-Ru, forcing the deposited Ru to take the fcc phase. In contrast, the {111} facets on an octahedral seed could be symmetrically aligned with the {0001} facets of hcp-Ru, allowing the deposited Ru to take either an hcp or fcc phase. The crystal phase of the Ru shell was then determined by the interplay between the surface and bulk energies as the area proportions of edges and faces on the octahedral seed changed with size. When tested as catalysts towards ethylene glycol oxidation, the fcc-Ru outperforms hcp-Ru, while the cubic shape is advantageous over the octahedral counterpart. Further exploration into other experimental parameters affecting the outcome of a phase-selective epitaxial growth demonstrated that the reduction kinetics played a more dominant role than the templating effect from the preformed seed in dictating the crystal phase of the deposited overlayers. Specifically, the use of ethylene glycol and triethylene glycol led to the formation of Ru shell in its natural hcp and metastable fcc phases, respectively, regardless of the size and phase of the seed. Quantitative measurements and theoretical calculations suggested that this trend was a manifestation of the different reduction kinetics associated with the precursor and the chosen polyol, which in turn, affected the reduction pathway (solution versus surface) and packing sequence of the deposited Ru atoms. Building on these insights, I extended the seed-mediated growth to obtain hcp-Rh deposition on hcp-Ru seeds. Under careful control of the reaction kinetics via dropwise injection of the precursor, Rh could be deposited on hcp-Ru seeds in either a novel, metastable hcp phase, or its native fcc phase, depending on the growth mode employed to achieve a balance between the bulk and surface energies. The metastable hcp-Rh phase within the Ru@Rh core-shell nanocrystals exhibited stability up to 400 °C and enhanced catalytic activity for ethanol oxidation reaction, highlighting the potential of phase-controlled synthesis for developing efficient catalysts.
Integrating Machine Learning Solutions into Untargeted Metabolomics and Xenobiotics Workflows

(Georgia Institute of Technology, 2024-05-01) Rainey, Markace Alan

Untargeted metabolomics explores the entirety of small molecules within biological samples, providing insights into metabolic alterations associated with various conditions. Standard methodologies like NMR and LC-MS are pivotal in identifying molecular markers but often fall short in fully deciphering the metabolic landscape due to limitations in accurately annotating a vast number of metabolites. This gap in annotation hampers the diagnostic application and biological interpretation of metabolomic data. Ion mobility spectrometry (IMS) offers a solution by providing semi-orthogonal data that enhances metabolite annotation. IMS separates ions based on their collision cross-section (CCS), a property influenced by an ion's mass, shape, charge, and external factors like temperature and pressure. When integrated with mass spectrometry (MS), IMS aids in resolving ions’ of similar or identical mass-to-charge ratio (m/z), offering a refined approach to metabolite characterization. This thesis focuses on employing computational strategies within LC-IM-MS workflows to facilitate rapid metabolite characterization. Chapter 1 outlines the challenges in metabolomics, specifically the limitations of current LC-MS workflows and the concept of the "dark metabolome." This introductory chapter provides the theoretical framework to better understand ion mobility and the use of quantitative-structural activity relationships to predict molecular properties. The chapter also discusses xenobiotics—external compounds impacting health—and their characterization challenges. Chapter 2 introduces Collision Cross Section Predictor 2.0 (CCSP 2.0), a machine learning-based tool for predicting ion mobility-derived CCS values. CCSP 2.0, developed to improve the accuracy and ease of CCS prediction, is evaluated for its efficacy in enhancing annotation accuracy in LC-MS workflows. It utilizes a support-vector regression model and incorporates a comprehensive library of molecular descriptors, demonstrating superior prediction accuracy and utility in reducing false positive annotations. Chapter 3 presents a workflow for automated detection of polyhalogenated xenobiotics in biological samples using LC-IM-MS. This approach combines CCS to m/z ratios, Kendrick mass defect analysis, and CCS prediction to filter isomeric candidates. A case study on the detection of per- and polyfluorinated alkyl substances in human serum exemplifies the workflow's effectiveness. Chapter 4 describes an analytical chemistry experiment for undergraduate students, focusing on laser-induced breakdown spectroscopy (LIBS) and its application in data science education. This chapter emphasizes enhancing students' programming literacy and analytical skills through hands-on experiments and analysis using Jupyter Notebooks. The experiment, adaptable to various curricula, showcases real-world applications of LIBS, including its use in space exploration. Chapter 5 summarizes key findings from the research, discussing the implications of integrating computational methods in metabolomics and the potential advancements in ion-mobility mass spectrometry. Future research directions are proposed to further explore and refine these methodologies. Appendix A explores an on-going project aimed at predicting analyte concentrations without standard calibration curves using machine learning. This approach predicts relative ionization efficiencies of lipids from their structural properties, demonstrating the potential of machine learning in streamlining quantitative analyses in metabolomics. In conclusion, this thesis underscores the importance of computational approaches in enhancing metabolite annotation and characterizing xenobiotics, contributing valuable tools and methodologies to the field of metabolomics.
Evolution Before Origin: A Conceptual and Experimental Framework

(Georgia Institute of Technology, 2024-04-27) Matange, Kavita

The search for chemical processes preceding the emergence of life presents a significant challenge in scientific inquiry. The development of biochemistry on early Earth presents some of the most creative chemistry in the known universe. In this work, we present a novel approach to advance our understanding of chemistry on early Earth based on wet-dry cycling. We outline a conceptual and experimental model of chemical evolution. As context, we outline currently accepted models of the origins of life and emphasize the utility of chemical evolution. With water at the center of the model, we demonstrate or infer that chemical systems are capable of selection, coupling, and creativity. We outline the framework of our wet-dry cycling-based model of chemical evolution and hold that during early chemical evolution, molecules were selected based on solubility in water, condensation-dehydration chemistry and resistance to hydrolysis upon assembly assemblies. Our model maps evolutionary concepts onto chemical processes. (a) a generation is a single wet-dry cycle; (b) heredity is information passed from one generation to the next; (c) information is associated with non-random chemical composition; (d) selection results in inheritance of certain molecular species over generations; (e) fitness confers persistence (i.e., survival) of molecules and specific molecular assemblies; (f) variation is spatiotemporal differences in information; and (g) water is an “energy currency” that links reactions and, upon changing activity, alters reaction free energies. In this work, we have employed wet-dry cycling and observed unexpected experimental outcomes like combinatorial compression, synchronicity, and continuous chemical change. We have suggested that biologically relevant concepts like adaptation and exaptation are universal, synergistic, and recursive, and along with biopolymers, apply to small molecules such as metabolites, cofactors, and building blocks of extant polymers. Altogether, this research establishes a platform for the analysis of complex mixtures at the Origin of Life and offers new horizons for the mapping of evolutionary phenomena onto prebiotic systems.
Exciton and Charge Carrier Nonlinear Dynamics in Hybrid Organic-Inorganic Metal Halides

(Georgia Institute of Technology, 2024-04-27) Rojas Gatjens, Jorge Esteban

Hybrid-organic inorganic metal-halide semiconductors pose an interesting photophysical scenario. Due to the ionic and dynamic nature of the structure, their excited-state properties are highly correlated with the structure's vibrations, distortions, and solvation dynamics. This thesis studies the interactions between excited states (nonlinear dynamics), their manifestation in physical observables, and their relation to the material's structure and fabrication. We explore the exciton and charge carrier nonlinear dynamics, via incoherent and coherent spectroscopy, in hybrid organic-inorganic mixed-halide lead perovskites, Ruddlesden-Popper metal halides, and perovskite nanocrystals. The many-body interactions manifest in incoherent spectroscopy as nonlinearities in the photoluminescence and/or photocurrent and, in two-dimensional coherent spectroscopy lineshapes, in the spectral linewidth, phase, and many-particle state feature (e.g. biexcitons, trions). For bulk hybrid organic-inorganic mixed-halide lead perovskites, we resolve incoherent nonlinear dynamics with sub-picosecond resolution in the photoluminescence and photocurrent. We were able to characterize the competition between defect-assisted recombination, Auger recombination, and amplified spontaneous emission. For the Ruddlesden-Popper metal halide perovskites and perovskite nanocrystals, we used two-dimensional coherent spectroscopy to explore ultrafast exciton scattering events and exciton-carrier coupling dictating the exciton-quantum dynamics. The work of this thesis sheds light on the many-body interactions in hybrid-organic inorganic metal-halide semiconductors and provides the tools to transition from the description to the control of nonlinear dynamics.
Probing nonlinear phenomena with multidimensional and entangled photon spectroscopies

(Georgia Institute of Technology, 2024-04-25) Malatesta, Ravyn Alysha

This dissertation is concerned with understanding what is learned from novel spectroscopic techniques using entangled photon pairs and how they compare to coherent multidimensional spectroscopy. With both theory and experiment, it considers what is learned by treating the light in light-matter interactions semi-classically (as a periodic perturbation of a quantum system) versus treating light fully quantum-mechanically, taking advantage of quantum characteristics of light such as polarization or time-frequency entanglement.
Ionic Liquids: Understanding Behavior at Electrochemical Interfaces

(Georgia Institute of Technology, 2024-02-08) Parmar, Shehan ; McDaniel, Jesse

Ionic liquids (ILs) are room-temperature molten salts composed of cation/anion pairs. Over the past several decades, the discovery of new ILs has led to exciting battery electrolyte alternatives that improve energy storage capacity and safety. Understanding compatible ILs for battery applications requires a fundamental understanding of the electrochemical interface—the layer of ILs that accumulate and uniquely order near the charged electrode surface. In this work, we examine how a novel, quaternary ammonium-based IL, methyltrioctylammonium bis(trifluoromethylsulfonyl)imide or [N1888][TFSI], rearranges near a gold electrode surface. We showcase the power of statistical mechanics and advanced computational chemistry methods in interpreting macroscopic implications at the application level via microscopic studies. We compare our simulations with experimental results to improve our current understanding of electrical double layers (EDL) for [N1888][TFSI].
Optically Modulated Fluorescence-Informed Photoacoustic Imaging

(Georgia Institute of Technology, 2023-12-10) Islam, Md Shariful

Advanced imaging technology is crucial for detecting early anomalies in deep tissue. While current medical imaging techniques show great potential, there is still a persistent need for improvements in sensitivity, resolution, penetration depth, and cost-effectiveness. Photoacoustic imaging combines optical excitation with acoustic detection to enhance tissue penetration depth and functional imaging capabilities. However, despite these advantages, photoacoustic imaging still suffers from poor signal-to-noise ratio and interference from endogenous chromophores in the background. Dual-laser background suppression techniques have the potential to enhance imaging sensitivity, especially in high-background noise situations. Synchronously amplified fluorescence image recovery (SAFIRe) reduces background interference in fluorescence imaging by manipulating ground-state and intermediate-state populations of contrast agents through pump and probe excitations. The main focus of this thesis is to combine the benefits of SAFIRe with photoacoustic imaging using the same pump-probe technique. Photoacoustic imaging provides signals from deep tissue, and SAFIRe removes the background from that signal. To achieve this objective, optically modulatable contrast agents and their nanoparticles, such as Rose Bengal (RB) and Eosin Y (EY), were used to produce synchronously amplified photoacoustic image recovery (SAPhIRe) signals from tissue-mimicking phantoms and dead rat muscles. This thesis explores the possible uses of SAPhIRe in temporal unmixing, a technique that allows for the separate detection of multiple contrast agents with the same absorption window simultaneously by using their unique triplet-state lifetimes. The study demonstrated the unmixing of RB and EY signals using both fluorescence and photoacoustic techniques. This was achieved by adjusting the pump-probe delay to distinguish their distinct triplet-state lifetimes. The fitting coefficients of triplet-state lifetimes were used to reconstruct images within tissue-mimicking phantoms. Prior to photoacoustic imaging, fluorescence was used for modulation screening. In addition, this work investigates the photophysical properties of three near-infrared (NIR) thiacarbocyanine dyes. Various optical modulation techniques, such as single and dual laser modulation, were conducted to explore their modulation depth, optical properties, and dark-state lifetimes. The results revealed that 3,3'-Diethylthiatricarbocyanine iodide (DTTCI) and 3,3'-Diethylthiacarbocyanine (DTCI) iodide have long dark states and are optically modulatable. Among the two, DTTCI appears to be an ideal candidate for SAPhIRe as it absorbs around 760 nm.
Synthesis and analysis of low-valent NHC supported nickel complexes

(Georgia Institute of Technology, 2023-12-10) Dodd, Neil Alexander

This thesis focuses on the synthesis of N-heterocyclice carbene (NHC) supported nickel complexes and their reactivity in bond-breaking and bond forming reactions. The body of this work discusses isolation of (NHC)Nickel(I) alkoxides and their subsequent chemical transformations into different (NHC)Nickel complexes. First, we demonstrate that (IDipp)Ni(I) hexamethyldisilazide (IDipp = 1,3-bis(2,6- diisopropylphenyl)-imidazole-2-ylidene) cleanly deprotonates neopentyl and methyl alcohols to form the corresponding (IDipp)Ni(I) alkoxides. Both alkoxides form dimeric solid-state structures. Abstraction of one alkoxide fragment forms the corresponding alkoxy-bridged dinickel cation species with an inner sphere bridging triflate. Abstraction of both neopentoxide fragments result in formation of (IDipp)Ni(OTf)(Et2O), a synthetic equivalent of (IDipp)Ni(I)+. Next, we show that the reaction of [(IDipp)Ni)]2(μ-ONp)(μ-OTf) with pentamethyldisiloxane results in isolation of {[(IDipp)Ni]2(μ-H)}[OTf]. Deprotonation of this hydride complex results in formation of [(IDipp)Ni]2, further supporting the interpretation of {[(IDipp)Ni]2(μ-H)}+ as proton bridging two (IDipp)Ni(0) fragments. The reactivity of {[(IDipp)Ni]2(μ-H)}[OTf] with alkyl nitriles was further studied by 1H NMR. [(IDipp)Ni(CN)2]4, a product of the reaction between {[(IDipp)Ni]2(μ-H)}+ with alkyl nitriles, can be synthesized by the reaction of [(IDipp)Ni(Cl)]2(μ-Cl)2 with trimethylsilyl cyanide. Subsequently, we show that the mixed valent complex, {[(IDipp)Ni]2}+ [OTf]− can be synthesized by combining synthetic equivalents of (IDipp)Ni(0) and (IDipp)Ni(I)+. Computational studies of this complex classify it as Robin-Day Class II. Cyclic voltammetry shows that the [Ni2]2+/+ and [Ni2]+/0 couples are reversible. The reactions of {[(IDipp)Ni]2}+ [OTf]− with CO and NO form mononuclear products and the reaction of {[(IDipp)Ni]2}+ [OTf]− with aryl bromide leads to predominant C-arylation of IDipp. Lastly, we show our pursuit of the first reported (NHC)Ni(I) fluoride. The reaction of [(IDipp)Ni)]2(μ-ONp)(μ-OTf) with benzoyl fluoride resulted in isolation of crystals of {[(IDipp)Ni]2(μ-F)(μ-C7H8)}[OTf] suitable for study by X-ray diffraction. Despite varying synthetic attempts, bulk isolation of {[(IDipp)Ni]2(μ-F)(μ-C7H8)}[OTf] was ultimately unsuccessful. Next, we show that {[(IDipp)Ni]2(μ-PPh2)}[OTf] can be isolated from the reaction of [(IDipp)Ni)]2(μ-OMe)(μ-OTf) with (trimethylsilyl)diphenylphosphine. We also show that (IDipp)Ni(C6H6) reacts with acyl fluorides to form the corresponding [(IDipp)Ni(R)(μ-F)]2 complexes. Lastly, we show that sodium naphthalenide can reduce [(IDipp)Ni(μ-Cl)]2 to form a synthetic equivalent of (IDipp)Ni(0).
Seed-Mediate Synthesis of Gold Nanocrystals: The Effects of Lattice Mismatch on Growth Patterns

(Georgia Institute of Technology, 2023-12-08) Pawlik, Veronica Dana

Nanomaterials have long fascinated both the casual observer and scientific mind alike. The utility of Au nanocrystals in particular has inspired applications ranging from plasmonics to catalysis. Over time, the ability to finely tune both shape and size has greatly improved their merits for these applications. To further expand and enhance the properties of Au nanocrystals, bimetallic compositions were introduced. Of the various atomic arrangements possible for bimetallic nanocrystals, the core-shell structure is most commonly utilized. This morphology is typically synthesized through a seed-mediated process. Growing one metal on another can introduce challenges. In this dissertation, I explore the effects that increasing lattice mismatch has on the seed-mediated growth of noble-metal nanocrystals. First, the case of no lattice mismatch was investigated during the growth of Au on Au spherical seeds to generate AuRD fully enclosed by {110} facets. The lack of lattice mismatch led to layer-by-layer growth. The kinetics of the synthesis could easily be tuned to favor either deposition or diffusion to achieve concave RD, trisoctahedra, or octahedra. These AuRD were then utilized in another seed-mediated growth to improve the thermal stability of the AuRD. Specifically, 1 ML of Pt was added and this ultrathin layer of Pt was able to improve the thermal stability of the high energy {110} facets from degrading at 100 °C to persisting at 450 °C. Computational studies revealed that the thermal stability of the Au-supported Pt skin was even greater than that expected for pure Pt. This effect was attributed to the strain induced by the formation of a 3.8% lattice-mismatched Pt overlayer on Au. Finally, single-crystal Rh@Au truncated octahedra were synthesized at a lattice mismatch of 7.2%. The large mismatch led to an island growth mode, which, could be tuned through the use of gentle kinetic knobs. The addition of NaOH indirectly increased the reduction rate to help modulate the number of Au islands formed on the Rh seeds. Conversely, the addition of KBr slowed down the reduction, allowing the Au adatoms to diffuse across the Rh seed. This work provides insight into the effects of lattice mismatch on the growth mode of nanocrystals, moving one step closer to the rational synthesis of novel nanomaterials with desired characteristics.