Matching Items (196)
Description
Diseases have been part of human life for generations and evolve within the population, sometimes dying out while other times becoming endemic or the cause of recurrent outbreaks. The long term influence of a disease stems from different dynamics within or between pathogen-host, that have been analyzed and studied by many researchers using mathematical models. Co-infection with different pathogens is common, yet little is known about how infection with one pathogen affects the host's immunological response to another. Moreover, no work has been found in the literature that considers the variability of the host immune health or that examines a disease at the population level and its corresponding interconnectedness with the host immune system. Knowing that the spread of the disease in the population starts at the individual level, this thesis explores how variability in immune system response within an endemic environment affects an individual's vulnerability, and how prone it is to co-infections. Immunology-based models of Malaria and Tuberculosis (TB) are constructed by extending and modifying existing mathematical models in the literature. The two are then combined to give a single nine-variable model of co-infection with Malaria and TB. Because these models are difficult to gain any insight analytically due to the large number of parameters, a phenomenological model of co-infection is proposed with subsystems corresponding to the individual immunology-based model of a single infection. Within this phenomenological model, the variability of the host immune health is also incorporated through three different pathogen response curves using nonlinear bounded Michaelis-Menten functions that describe the level or state of immune system (healthy, moderate and severely compromised). The immunology-based models of Malaria and TB give numerical results that agree with the biological observations. The Malaria--TB co-infection model gives reasonable results and these suggest that the order in which the two diseases are introduced have an impact on the behavior of both. The subsystems of the phenomenological models that correspond to a single infection (either of Malaria or TB) mimic much of the observed behavior of the immunology-based counterpart and can demonstrate different behavior depending on the chosen pathogen response curve. In addition, varying some of the parameters and initial conditions in the phenomenological model yields a range of topologically different mathematical behaviors, which suggests that this behavior may be able to be observed in the immunology-based models as well. The phenomenological models clearly replicate the qualitative behavior of primary and secondary infection as well as co-infection. The mathematical solutions of the models correspond to the fundamental states described by immunologists: virgin state, immune state and tolerance state. The phenomenological model of co-infection also demonstrates a range of parameter values and initial conditions in which the introduction of a second disease causes both diseases to grow without bound even though those same parameters and initial conditions did not yield unbounded growth in the corresponding subsystems. This results applies to all three states of the host immune system. In terms of the immunology-based system, this would suggest the following: there may be parameter values and initial conditions in which a person can clear Malaria or TB (separately) from their system but in which the presence of both can result in the person dying of one of the diseases. Finally, this thesis studies links between epidemiology (population level) and immunology in an effort to assess the impact of pathogen's spread within the population on the immune response of individuals. Models of Malaria and TB are proposed that incorporate the immune system of the host into a mathematical model of an epidemic at the population level.
ContributorsSoho, Edmé L (Author) / Wirkus, Stephen (Thesis advisor) / Castillo-Chavez, Carlos (Thesis advisor) / Chowell-Puente, Gerardo (Committee member) / Arizona State University (Publisher)
Created2011
Description
Fluoroquinolone antibiotics have been known to cause severe, multisystem adverse side effects, termed fluoroquinolone toxicity (FQT). This toxicity syndrome can present with adverse effects that vary from individual to individual, including effects on the musculoskeletal and nervous systems, among others. The mechanism behind FQT in mammals is not known, although various possibilities have been investigated. Among the hypothesized FQT mechanisms, those that could potentially explain multisystem toxicity include off-target mammalian topoisomerase interactions, increased production of reactive oxygen species, oxidative stress, and oxidative damage, as well as metal chelating properties of FQs. This review presents relevant information on fluoroquinolone antibiotics and FQT and explores the mechanisms that have been proposed. A fluoroquinolone-induced increase in reactive oxygen species and subsequent oxidative stress and damage presents the strongest evidence to explain this multisystem toxicity syndrome. Understanding the mechanism of FQT in mammals is important to aid in the prevention and treatment of this condition.
ContributorsHall, Brooke Ashlyn (Author) / Redding, Kevin (Thesis director) / Wideman, Jeremy (Committee member) / Borges, Chad (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
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
Solution methods for certain linear and nonlinear evolution equations are presented in this dissertation. Emphasis is placed mainly on the analytical treatment of nonautonomous differential equations, which are challenging to solve despite the existent numerical and symbolic computational software programs available. Ideas from the transformation theory are adopted allowing one to solve the problems under consideration from a non-traditional perspective. First, the Cauchy initial value problem is considered for a class of nonautonomous and inhomogeneous linear diffusion-type equation on the entire real line. Explicit transformations are used to reduce the equations under study to their corresponding standard forms emphasizing on natural relations with certain Riccati(and/or Ermakov)-type systems. These relations give solvability results for the Cauchy problem of the parabolic equation considered. The superposition principle allows to solve formally this problem from an unconventional point of view. An eigenfunction expansion approach is also considered for this general evolution equation. Examples considered to corroborate the efficacy of the proposed solution methods include the Fokker-Planck equation, the Black-Scholes model and the one-factor Gaussian Hull-White model. The results obtained in the first part are used to solve the Cauchy initial value problem for certain inhomogeneous Burgers-type equation. The connection between linear (the Diffusion-type) and nonlinear (Burgers-type) parabolic equations is stress in order to establish a strong commutative relation. Traveling wave solutions of a nonautonomous Burgers equation are also investigated. Finally, it is constructed explicitly the minimum-uncertainty squeezed states for quantum harmonic oscillators. They are derived by the action of corresponding maximal kinematical invariance group on the standard ground state solution. It is shown that the product of the variances attains the required minimum value only at the instances that one variance is a minimum and the other is a maximum, when the squeezing of one of the variances occurs. Such explicit construction is possible due to the relation between the diffusion-type equation studied in the first part and the time-dependent Schrodinger equation. A modication of the radiation field operators for squeezed photons in a perfect cavity is also suggested with the help of a nonstandard solution of Heisenberg's equation of motion.
ContributorsVega-Guzmán, José Manuel, 1982- (Author) / Sulov, Sergei K (Thesis advisor) / Castillo-Chavez, Carlos (Thesis advisor) / Platte, Rodrigo (Committee member) / Chowell-Puente, Gerardo (Committee member) / Arizona State University (Publisher)
Created2013
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
Cancer claims hundreds of thousands of lives every year in US alone. Finding ways for early detection of cancer onset is crucial for better management and treatment of cancer. Thus, biomarkers especially protein biomarkers, being the functional units which reflect dynamic physiological changes, need to be discovered. Though important, there are only a few approved protein cancer biomarkers till date. To accelerate this process, fast, comprehensive and affordable assays are required which can be applied to large population studies. For this, these assays should be able to comprehensively characterize and explore the molecular diversity of nominally "single" proteins across populations. This information is usually unavailable with commonly used immunoassays such as ELISA (enzyme linked immunosorbent assay) which either ignore protein microheterogeneity, or are confounded by it. To this end, mass spectrometric immuno assays (MSIA) for three different human plasma proteins have been developed. These proteins viz. IGF-1, hemopexin and tetranectin have been found in reported literature to show correlations with many diseases along with several carcinomas. Developed assays were used to extract entire proteins from plasma samples and subsequently analyzed on mass spectrometric platforms. Matrix assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) mass spectrometric techniques where used due to their availability and suitability for the analysis. This resulted in visibility of different structural forms of these proteins showing their structural micro-heterogeneity which is invisible to commonly used immunoassays. These assays are fast, comprehensive and can be applied in large sample studies to analyze proteins for biomarker discovery.
ContributorsRai, Samita (Author) / Nelson, Randall (Thesis advisor) / Hayes, Mark (Thesis advisor) / Borges, Chad (Committee member) / Ros, Alexandra (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
The field of biomedical research relies on the knowledge of binding interactions between various proteins of interest to create novel molecular targets for therapeutic purposes. While many of these interactions remain a mystery, knowledge of these properties and interactions could have significant medical applications in terms of understanding cell signaling and immunological defenses. Furthermore, there is evidence that machine learning and peptide microarrays can be used to make reliable predictions of where proteins could interact with each other without the definitive knowledge of the interactions. In this case, a neural network was used to predict the unknown binding interactions of TNFR2 onto LT-ɑ and TRAF2, and PD-L1 onto CD80, based off of the binding data from a sampling of protein-peptide interactions on a microarray. The accuracy and reliability of these predictions would rely on future research to confirm the interactions of these proteins, but the knowledge from these methods and predictions could have a future impact with regards to rational and structure-based drug design.
ContributorsPoweleit, Andrew Michael (Author) / Woodbury, Neal (Thesis director) / Diehnelt, Chris (Committee member) / Chiu, Po-Lin (Committee member) / School of Molecular Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Lung cancer is the leading cause of cancer-related deaths in the US. Low-dose computed tomography (LDCT) scans are speculated to reduce lung cancer mortality. However LDCT scans impose multiple risks including false-negative results, false- positive results, overdiagnosis, and cancer due to repeated exposure to radiation. Immunosignaturing is a new method proposed to screen and detect lung cancer, eliminating the risks associated with LDCT scans. Known and blinded primary blood sera from participants with lung cancer and no cancer were run on peptide microarrays and analyzed. Immunosignatures for each known sample collectively indicated 120 peptides unique to lung cancer and non-cancer participants. These 120 peptides were used to determine the status of the blinded samples. Verification of the results from Vanderbilt is pending.
ContributorsNguyen, Geneva Trieu (Author) / Woodbury, Neal (Thesis director) / Zhao, Zhan-Gong (Committee member) / Stafford, Phillip (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Department of Psychology (Contributor)
Created2015-05
Description
I travelled and worked in international fisheries policy for 7 months in preparation for this thesis. During this time I completed one internship in Rome, Italy with the Food and Agriculture Organization of the United Nations (UNFAO) and another internship on the island of Pohnpei with the Secretariat of the Western and Central Pacific Fisheries Commission (WCPFC). From these experiences, I selected the subject of this thesis. My thesis analyzes the management system for South Pacific albacore tuna, the source stock for brands like "Chicken of the Sea" and "Starkist". South Pacific albacore tuna pass through international waters and the waters of several Pacific Island countries and territories, necessitating States to cooperate and coordinate to sustain the future viability of the stock. A case study for transboundary natural resource management, I discuss the institutional complexity that arises from managing such a resource. I use common-pool resource (CPR) theory to describe this complexity, which frames natural resource management as a collective-action problem among resource users. I first conceptualize the management system as having multiple institutional scales and multiple levels of organization. Then, employing Ostrom's 8 design principles for successful CPR management, I conduct a multi-institution analysis of the international, regional, and subregional institutions that participate in the management system. Finally, I also conduct a cross-institution analysis by examining the interactions between these institutions. I find that significant space for theoretical development exists in CPR theory for understanding complex management systems for transboundary natural resources. Furthermore, I find that interactions between institutions create linkages that could be retooled to improve the performance of the South Pacific albacore tuna management system.
ContributorsAbolhassani, Angela Maryam (Author) / Abbott, Kenneth (Thesis director) / Schoon, Michael (Committee member) / Barrett, The Honors College (Contributor) / School of Politics and Global Studies (Contributor) / School of Life Sciences (Contributor) / Department of English (Contributor)
Created2015-05