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- Genre: Academic theses
- Language: English
Description
Nucleosomes are the basic repetitive unit of eukaryotic chromatin and are responsible for packing DNA inside the nucleus of the cell. They consist of a complex of eight histone proteins (two copies of four proteins H2A, H2B, H3 and H4) around which 147 base pairs of DNA are wrapped in ~1.67 superhelical turns. Although the nucleosomes are stable protein-DNA complexes, they undergo spontaneous conformational changes that occur in an asynchronous fashion. This conformational dynamics, defined by the "site-exposure" model, involves the DNA unwrapping from the protein core and exposing itself transiently before wrapping back. Physiologically, this allows regulatory proteins to bind to their target DNA sites during cellular processes like replication, DNA repair and transcription. Traditional biochemical assays have stablished the equilibrium constants for the accessibility to various sites along the length of the nucleosomal DNA, from its end to the middle of the dyad axis. Using fluorescence correlation spectroscopy (FCS), we have established the position dependent rewrapping rates for nucleosomes. We have also used Monte Carlo simulation methods to analyze the applicability of FRET fluctuation spectroscopy towards conformational dynamics, specifically motivated by nucleosome dynamics. Another important conformational change that is involved in cellular processes is the disassembly of nucleosome into its constituent particles. The exact pathway adopted by nucleosomes is still not clear. We used dual color fluorescence correlation spectroscopy to study the intermediates during nucleosome disassembly induced by changing ionic strength. Studying the nature of nucleosome conformational change and the kinetics is very important in understanding gene expression. The results from this thesis give a quantitative description to the basic unit of the chromatin.
ContributorsGurunathan, Kaushik (Author) / Levitus, Marcia (Thesis advisor) / Lindsay, Stuart (Committee member) / Woodbury, Neal (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2011
Description
In this thesis I introduce a new direction to computing using nonlinear chaotic dynamics. The main idea is rich dynamics of a chaotic system enables us to (1) build better computers that have a flexible instruction set, and (2) carry out computation that conventional computers are not good at it. Here I start from the theory, explaining how one can build a computing logic block using a chaotic system, and then I introduce a new theoretical analysis for chaos computing. Specifically, I demonstrate how unstable periodic orbits and a model based on them explains and predicts how and how well a chaotic system can do computation. Furthermore, since unstable periodic orbits and their stability measures in terms of eigenvalues are extractable from experimental times series, I develop a time series technique for modeling and predicting chaos computing from a given time series of a chaotic system. After building a theoretical framework for chaos computing I proceed to architecture of these chaos-computing blocks to build a sophisticated computing system out of them. I describe how one can arrange and organize these chaos-based blocks to build a computer. I propose a brand new computer architecture using chaos computing, which shifts the limits of conventional computers by introducing flexible instruction set. Our new chaos based computer has a flexible instruction set, meaning that the user can load its desired instruction set to the computer to reconfigure the computer to be an implementation for the desired instruction set. Apart from direct application of chaos theory in generic computation, the application of chaos theory to speech processing is explained and a novel application for chaos theory in speech coding and synthesizing is introduced. More specifically it is demonstrated how a chaotic system can model the natural turbulent flow of the air in the human speech production system and how chaotic orbits can be used to excite a vocal tract model. Also as another approach to build computing system based on nonlinear system, the idea of Logical Stochastic Resonance is studied and adapted to an autoregulatory gene network in the bacteriophage λ.
ContributorsKia, Behnam (Author) / Ditto, William (Thesis advisor) / Huang, Liang (Committee member) / Lai, Ying-Cheng (Committee member) / Helms Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2011
Description
Healthy mitochondria are essential for cell survival. Described herein is the synthesis of a family of novel aminoquinone antioxidants designed to alleviate oxidative stress and prevent the impairment of cellular function. In addition, a library of bleomycin disaccharide analogues has also been synthesized to better probe the tumor targeting properties of bleomycin. The first study involves the synthesis of a benzoquinone natural product and analogues that closely resemble the redox core of the natural product geldanamycin. The synthesized 5-amino-3-tridecyl-1,4-benzoquinone antioxidants were tested for their ability to protect Friedreich's ataxia (FRDA) lymphocytes from induced oxidative stress. Some of the analogues synthesized conferred cytoprotection in a dose-dependent manner in FRDA lymphocytes at micromolar concentrations. The biological assays suggest that the modification of the 2-hydroxyl and N-(3-carboxypropyl) groups in the natural product can improve its antioxidant activity and significantly enhance its ability to protect mitochondrial function under conditions of oxidative stress. The second project focused on the synthesis of a library of bleomycin disaccharide-dye conjugates and monitored their cellular uptake by fluorescence microscopy. The studies reveal that the position of the carbamoyl group plays an important role in modulating the cellular uptake of the disaccharide. It also led to the discovery of novel disaccharides with improved tumor selectivity.
ContributorsMathilakathu Madathil, Manikandadas (Author) / Hecht, Sidney M. (Thesis advisor) / Rose, Seth (Committee member) / Woodbury, Neal (Committee member) / Arizona State University (Publisher)
Created2013
Description
Complex dynamical systems consisting interacting dynamical units are ubiquitous in nature and society. Predicting and reconstructing nonlinear dynamics of units and the complex interacting networks among them serves the base for the understanding of a variety of collective dynamical phenomena. I present a general method to address the two outstanding problems as a whole based solely on time-series measurements. The method is implemented by incorporating compressive sensing approach that enables an accurate reconstruction of complex dynamical systems in terms of both nodal equations that determines the self-dynamics of units and detailed coupling patterns among units. The representative advantages of the approach are (i) the sparse data requirement which allows for a successful reconstruction from limited measurements, and (ii) general applicability to identical and nonidentical nodal dynamics, and to networks with arbitrary interacting structure, strength and sizes. Another two challenging problem of significant interest in nonlinear dynamics: (i) predicting catastrophes in nonlinear dynamical systems in advance of their occurrences and (ii) predicting the future state for time-varying nonlinear dynamical systems, can be formulated and solved in the framework of compressive sensing using only limited measurements. Once the network structure can be inferred, the dynamics behavior on them can be investigated, for example optimize information spreading dynamics, suppress cascading dynamics and traffic congestion, enhance synchronization, game dynamics, etc. The results can yield insights to control strategies design in the real-world social and natural systems. Since 2004, there has been a tremendous amount of interest in graphene. The most amazing feature of graphene is that there exists linear energy-momentum relationship when energy is low. The quasi-particles inside the system can be treated as chiral, massless Dirac fermions obeying relativistic quantum mechanics. Therefore, the graphene provides one perfect test bed to investigate relativistic quantum phenomena, such as relativistic quantum chaotic scattering and abnormal electron paths induced by klein tunneling. This phenomenon has profound implications to the development of graphene based devices that require stable electronic properties.
ContributorsYang, Rui (Author) / Lai, Ying-Cheng (Thesis advisor) / Duman, Tolga M. (Committee member) / Akis, Richard (Committee member) / Huang, Liang (Committee member) / Arizona State University (Publisher)
Created2012
Description
It has been well established that mitochondria play a critical role in the pathology of Friedreich's Ataxia. This disease is believed to be caused by a deficiency of frataxin, which research suggests is responsible for iron sulfur cluster assembly. This incomplete assembly of iron sulfur clusters is believed to be linked with dysfunctional complexes in the mitochondrial respiratory chain, increased oxidative stress, and potential cell death. Increased understanding of the pathophysiology of this disease has enabled the development of various therapeutic strategies aimed at restoring mitochondrial respiration. This thesis contains an analysis of the biological activity of several classes of antioxidants against oxidative stress induced by diethyl maleate in Friedreich's Ataxia lymphocytes and CEM leukemia cells. Analogues of vitamin E α-tocopherol have been shown to protect cells under oxidative stress. However, these same analogues show various levels of inhibition towards the electron transport chain complex I. Bicyclic pyridinols containing a ten carbon substituent provided favorable cytoprotection. N-hydroxy-4-pyridone compounds were observed to provide little protection. Similarly, analogues of CoQ10 in the form of pyridinol and pyrimidinol compounds also preserved cell viability at low concentrations.
ContributorsJaruvangsanti, Jennifer (Author) / Hecht, Sidney (Thesis advisor) / Woodbury, Neal (Committee member) / Skibo, Edward (Committee member) / Arizona State University (Publisher)
Created2012
Description
What can classical chaos do to quantum systems is a fundamental issue highly relevant to a number of branches in physics. The field of quantum chaos has been active for three decades, where the focus was on non-relativistic quantumsystems described by the Schr¨odinger equation. By developing an efficient method to solve the Dirac equation in the setting where relativistic particles can tunnel between two symmetric cavities through a potential barrier, chaotic cavities are found to suppress the spread in the tunneling rate. Tunneling rate for any given energy assumes a wide range that increases with the energy for integrable classical dynamics. However, for chaotic underlying dynamics, the spread is greatly reduced. A remarkable feature, which is a consequence of Klein tunneling, arise only in relativistc quantum systems that substantial tunneling exists even for particle energy approaching zero. Similar results are found in graphene tunneling devices, implying high relevance of relativistic quantum chaos to the development of such devices. Wave propagation through random media occurs in many physical systems, where interesting phenomena such as branched, fracal-like wave patterns can arise. The generic origin of these wave structures is currently a matter of active debate. It is of fundamental interest to develop a minimal, paradigmaticmodel that can generate robust branched wave structures. In so doing, a general observation in all situations where branched structures emerge is non-Gaussian statistics of wave intensity with an algebraic tail in the probability density function. Thus, a universal algebraic wave-intensity distribution becomes the criterion for the validity of any minimal model of branched wave patterns. Coexistence of competing species in spatially extended ecosystems is key to biodiversity in nature. Understanding the dynamical mechanisms of coexistence is a fundamental problem of continuous interest not only in evolutionary biology but also in nonlinear science. A continuous model is proposed for cyclically competing species and the effect of the interplay between the interaction range and mobility on coexistence is investigated. A transition from coexistence to extinction is uncovered with a non-monotonic behavior in the coexistence probability and switches between spiral and plane-wave patterns arise. Strong mobility can either promote or hamper coexistence, while absent in lattice-based models, can be explained in terms of nonlinear partial differential equations.
ContributorsNi, Xuan (Author) / Lai, Ying-Cheng (Thesis advisor) / Huang, Liang (Committee member) / Yu, Hongbin (Committee member) / Akis, Richard (Committee member) / Arizona State University (Publisher)
Created2012
Description
ABSTRACT Peptide microarrays may prove to be a powerful tool for proteomics research and clinical diagnosis applications. Fodor et al. and Maurer et al. have shown proof-of-concept methods of light- and electrochemically-directed peptide microarray fabrication on glass and semiconductor microchips respectively. In this work, peptide microarray fabrication based on the abovementioned techniques were optimized. In addition, MALDI mass spectrometry based peptide synthesis characterization on semiconductor microchips was developed and novel applications of a CombiMatrix (CBMX) platform for electrochemically controlled synthesis were explored. We have investigated performance of 2-(2-nitrophenyl)propoxycarbonyl (NPPOC) derivatives as photo-labile protecting group. Specifically, influence of substituents on 4 and 5 positions of phenyl ring of NPPOC group on the rate of photolysis and the yield of the amine was investigated. The results indicated that substituents capable of forming a π-network with the nitro group enhanced the rate of photolysis and yield. Once such properly substituted NPPOC groups were used, the rate of photolysis/yield depended on the nature of protected amino group indicating that a different chemical step during the photo-cleavage process became the rate limiting step. We also focused on electrochemically-directed parallel synthesis of high-density peptide microarrays using the CBMX technology referred to above which uses electrochemically generated acids to perform patterned chemistry. Several issues related to peptide synthesis on the CBMX platform were studied and optimized, with emphasis placed on the reactions of electro-generated acids during the deprotection step of peptide synthesis. We have developed a MALDI mass spectrometry based method to determine the chemical composition of microarray synthesis, directly on the feature. This method utilizes non-diffusional chemical cleavage from the surface, thereby making the chemical characterization of high-density microarray features simple, accurate, and amenable to high-throughput. CBMX Corp. has developed a microarray reader which is based on electro-chemical detection of redox chemical species. Several parameters of the instrument were studied and optimized and novel redox applications of peptide microarrays on CBMX platform were also investigated using the instrument. These include (i) a search of metal binding catalytic peptides to reduce overpotential associated with water oxidation reaction and (ii) an immobilization of peptide microarrays using electro-polymerized polypyrrole.
ContributorsKumar, Pallav (Author) / Woodbury, Neal (Thesis advisor) / Allen, James (Committee member) / Johnston, Stephen (Committee member) / Arizona State University (Publisher)
Created2013
Description
Computational models have long been used to describe and predict the outcome of complex immunological processes. The dissertation work described here centers on the construction of multiscale computational immunology models that derives biological insights at the population, systems, and atomistic levels. First, SARS-CoV-2 mortality is investigated through the lens of the predicted robustness of CD8+ T cell responses in 23 different populations. The robustness of CD8+ T cell responses in a given population was modeled by predicting the efficiency of endemic MHC-I protein variants to present peptides derived from SARS-CoV-2 proteins to circulating T cells. To accomplish this task, an algorithm, called EnsembleMHC, was developed to predict viral peptides with a high probability of being recognized by CD T cells. It was discovered that there was significant variation in the efficiency of different MHC-I protein variants to present SARS-CoV-2 derived peptides, and countries enriched with variants with high presentation efficiency had significantly lower mortality rates. Second, a biophysics-based MHC-I peptide prediction algorithm was developed. The MHC-I protein is the most polymorphic protein in the human genome with polymorphisms in the peptide binding causing striking changes in the amino acid compositions, or binding motifs, of peptide species capable of stable binding. A deep learning model, coined HLA-Inception, was trained to predict peptide binding using only biophysical properties, namely electrostatic potential. HLA-Inception was shown to be extremely accurate and efficient at predicting peptide binding motifs and was used to determine the peptide binding motifs of 5,821 MHC-I protein variants. Finally, the impact of stalk glycosylations on NL63 protein dynamics was investigated. Previous data has shown that coronavirus crown glycans play an important role in immune evasion and receptor binding, however, little is known about the role of the stalk glycans. Through the integration of computational biology, experimental data, and physics-based simulations, the stalk glycans were shown to heavily influence the bending angle of spike protein, with a particular emphasis on the glycan at position 1242. Further investigation revealed that removal of the N1242 glycan significantly reduced infectivity, highlighting a new potential therapeutic target. Overall, these investigations and associated innovations in integrative modeling.
ContributorsWilson, Eric Andrew (Author) / Anderson, Karen (Thesis advisor) / Singharoy, Abhishek (Thesis advisor) / Woodbury, Neal (Committee member) / Sulc, Petr (Committee member) / Arizona State University (Publisher)
Created2022
Description
This work focuses on a novel approach to combine electrical current with cyanobacterial technology, called microbial electrophotosynthesis (MEPS). It involves using genetically modified PSII-less Synechocystis PCC 6803 cells to avoid photoinhibition, a problem that hinders green energy. In the work, a cathodic electron delivery system is employed for growth and synthesis. Photoinhibition leads to the dissipation energy and lower yield, and is a major obstacle to preventing green energy from competing with fossil fuels. However, the urgent need for alternative energy sources is driven by soaring energy consumption and rising atmospheric carbon dioxide levels. When developed, MEPS can contribute to a carbon capture technology while helping with energy demands. It is thought that if PSII electron flux can be replaced with an alternative source photosynthesis could be enhanced for more effective production. MEPS has the potential to address these challenges by serving as a carbon capture technology while meeting energy demands. The idea is to replace PSII electron flux with an alternative source, which can be enhanced for higher yields in light intensities not tolerated with PSII. This research specifically focuses on creating the initiation of electron flux between the cathode and the MEPS cells while controlling and measuring the system in real time.
The successful proof-of-concept work shows that MEPS can indeed generate high-light-dependent current at intensities up to 2050 µmol photons m^‒2 s^‒1, delivering 113 µmol electrons h^‒1 mg-chl^‒1. The results were further developed to characterize redox tuning for electron delivery of flux to the photosynthetic electron transport chain and redox-based kinetic analysis to model the limitations of the MEPS system.
ContributorsLewis, Christine Michelle (Author) / Torres, César I (Thesis advisor) / Fromme, Petra (Thesis advisor) / Woodbury, Neal (Committee member) / Hayes, Mark (Committee member) / Arizona State University (Publisher)
Created2023
Description
The fundamental photophysics of fluorescent probes must be understood when the probes are used in biological applications. The photophysics of BODIPY dyes inside polymeric micelles and rhodamine dyes covalently linked to proteins were studied. Hydrophobic boron-dipyrromethene (BODIPY) dyes were noncovalently encapsulated inside polymeric micelles. Absorbance and fluorescence measurements were employed to study the photophysics of these BODIPY dyes in the micellar environments. Amphiphilic polymers with a hydrophobic character and low Critical Micelle Concentration (CMC) protected BODIPYS from the aqueous environment. Moderate dye loading conditions did not result in ground-state dimerization, and only fluorescence lifetimes and brightnesses were affected. However, amphiphilic polymers with a hydrophilic character and high CMC did not protect the BODIPYS from the aqueous environment with concomitant ground-state dimerization and quenching of the fluorescence intensity, lifetime, and brightnesses even at low dye loading conditions. At the doubly-labeled interfaces of Escherichia coli (E. coli) DNA processivity β clamps, the interchromophric interactions of four rhodamine dyes were studied: tetramethylrhodamine (TMR), TMR C6, Alexa Fluor 488, and Alexa Fluor 546. Absorbance and fluorescence measurements were performed on doubly-labeled β clamps with singly-labeled β clamps and free dyes as controls. The absorbance measurements revealed that both TMR and TMR C6 readily formed H-dimers (static quenching) at the doubly-labeled interfaces of the β clamps. However, the TMR with a longer linker (TMR C6) also displayed a degree of dynamic quenching. For Alexa Fluor 546 and Alexa Fluor 488, there were no clear signs of dimerization in the absorbance scans. However, the fluorescence properties (fluorescence intensity, lifetime, and anisotropy) of the Alexa Fluor dyes significantly changed when three methodologies were employed to disrupt the doubly-labeled interfaces: 1) the addition of sodium dodecyl sulfate (SDS) detergent to denature the proteins, 2) the addition of clamp loader (γ complex) to open one of the two interfaces, and 3) the use of subunit exchange to decrease the number of dyes per interface. These fluorescence measurements indicated that for the Alexa Fluor dyes, other interchromophoric interactions were present such as dynamic quenching and homo-Förster Resonance Energy Transfer (homo-FRET).
ContributorsDonaphon, Bryan Matthew (Author) / Levitus, Marcia (Thesis advisor) / Van Horn, Wade (Committee member) / Woodbury, Neal (Committee member) / Arizona State University (Publisher)
Created2018