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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
The overall goal of this dissertation is to advance understanding of biofilm reduction of oxidized contaminants in water and wastewater. Chapter 1 introduces the fundamentals of biological reduction of three oxidized contaminants (nitrate, perchlorate, and trichloriethene (TCE)) using two biofilm processes (hydrogen-based membrane biofilm reactors (MBfR) and packed-bed heterotrophic reactors (PBHR)), and it identifies the research objectives. Chapters 2 through 6 focus on nitrate removal using the MBfR and PBHR, while chapters 7 through 10 investigate simultaneous reduction of nitrate and another oxidized compound (perchlorate, sulfate, or TCE) in the MBfR. Chapter 11 summarizes the major findings of this research. Chapters 2 and 3 demonstrate nitrate removal in a groundwater and identify the maximum nitrate loadings using a pilot-scale MBfR and a pilot-scale PBHR, respectively. Chapter 4 compares the MBfR and the PBHR for denitrification of the same nitrate-contaminated groundwater. The comparison includes the maximum nitrate loading, the effluent water quality of the denitrification reactors, and the impact of post-treatment on water quality. Chapter 5 theoretically and experimentally demonstrates that the nitrate biomass-carrier surface loading, rather than the traditionally used empty bed contact time or nitrate volumetric loading, is the primary design parameter for heterotrophic denitrification. Chapter 6 constructs a pH-control model to predict pH, alkalinity, and precipitation potential in heterotrophic or hydrogen-based autotrophic denitrification reactors. Chapter 7 develops and uses steady-state permeation tests and a mathematical model to determine the hydrogen-permeation coefficients of three fibers commonly used in the MBfR. The coefficients are then used as inputs for the three models in Chapters 8-10. Chapter 8 develops a multispecies biofilm model for simultaneous reduction of nitrate and perchlorate in the MBfR. The model quantitatively and systematically explains how operating conditions affect nitrate and perchlorate reduction and biomass distribution via four mechanisms. Chapter 9 modifies the nitrate and perchlorate model into a nitrate and sulfate model and uses it to identify operating conditions corresponding to onset of sulfate reduction. Chapter 10 modifies the nitrate and perchlorate model into a nitrate and TCE model and uses it to investigate how operating conditions affect TCE reduction and accumulation of TCE reduction intermediates.
ContributorsTang, Youneng (Author) / Rittmann, Bruce E. (Thesis advisor) / Westerhoff, Paul (Committee member) / Krajmalnik-Brown, Rosa (Committee member) / Halden, Rolf (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
With a quantum efficiency of nearly 100%, the electron transfer process that occurs within the reaction center protein of the photosynthetic bacteria Rhodobacter (Rh.) sphaeroides is a paragon for understanding the complexities, intricacies, and overall systemization of energy conversion and storage in natural systems. To better understand the way in which photons of light are captured, converted into chemically useful forms, and stored for biological use, an investigation into the reaction center protein, specifically into its cascade of cofactors, was undertaken. The purpose of this experimentation was to advance our knowledge and understanding of how differing protein environments and variant cofactors affect the spectroscopic aspects of and electron transfer kinetics within the reaction of Rh. sphaeroides. The native quinone, ubiquinone, was extracted from its pocket within the reaction center protein and replaced by non-native quinones having different reduction/oxidation potentials. It was determined that, of the two non-native quinones tested—1,2-naphthaquinone and 9,10- anthraquinone—the substitution of the anthraquinone (lower redox potential) resulted in an increased rate of recombination from the P+QA- charge-separated state, while the substitution of the napthaquinone (higher redox potential) resulted in a decreased rate of recombination.
ContributorsSussman, Hallie Rebecca (Author) / Woodbury, Neal (Thesis director) / Redding, Kevin (Committee member) / Lin, Su (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2015-12
Description
Advances in peptide microarray technology have allowed for the creation of fast-paced and modular experiments within affinity ligand discovery. Previously, low density peptide arrays of 10,000 peptides were used to identify low affinity peptide ligands for a target protein; an approach that can be subsequently improved upon with a number of techniques. VDAP[a] offers more information about the relative affinity of protein-peptide interactions via signal intensity in contrast to high throughput screening (HTS) and display technologies which offer binary data. Now, high density peptide arrays with 130,000 to 330,000 peptides are available that allow screening across peptide libraries of greater diversity. With this increase in scale and diversity, faster analytical tools are needed to adequately characterize array data. Using the statistical power available in the R programming language, we have created a flexible analysis package that efficiently processes high density peptide array data from a variety of layouts, rank existing peptide hits, and utilize signal intensity data to generate new hits. This analysis provides a user-friendly method to efficiently analyze high density peptide array data, generate peptide leads for targeted therapeutic development, and further improve peptide array technologies.
ContributorsMoore, Cody Allen (Author) / Woodbury, Neal (Thesis director) / Diehnelt, Chris (Committee member) / Barrett, The Honors College (Contributor)
Created2015-12
Description
Photosynthesis is the process by which plants, algae, and bacteria use light energy to synthesize organic compounds to use as energy. Among these organisms are a kind of purple photosynthetic bacteria called Rhodobacter sphaeroides, a non-sulfur purple bacteria that grows aerobically in the dark by respiration. There have been many contributions throughout the history of this group of bacteria. Rhodobacter sphaeroides is metabolically very diverse as it has many different ways to obtain energy--aerobic respiration and anoxygenic photosynthesis being just a couple of the ways to do so. This project is part of a larger ongoing project to study different mutant strains of Rhodobacter and the different ways in which carries out electron transfer/photosynthesis. This thesis focused on the improvements made to protocol (standard procedure of site directed mutagenesis) through a more efficient technique known as infusion.
ContributorsNucuta, Diana Ileana (Author) / Woodbury, Neal (Thesis director) / Lin, Su (Committee member) / Loskutov, Andrey (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2014-05
Description
Through this creative project, I executed a Distracted Driving Awareness Campaign at Arizona State University to raise awareness about the dangers of distracted driving, specifically texting while driving. As an Undergraduate Student Government Senator, my priority is the safety and success of students, both in and out of the classroom. By partnering with State Farm and AT&T, we were able to raise awareness about the dangers of distracted driving and collected over 200 pledges from students to never text and drive.
ContributorsHibbs, Jordan Ashley (Author) / Miller, Clark (Thesis director) / Parmentier, Mary Jane (Committee member) / Barrett, The Honors College (Contributor) / College of Liberal Arts and Sciences (Contributor) / School of Politics and Global Studies (Contributor) / Department of Psychology (Contributor) / Graduate College (Contributor)
Created2014-05
Description
The influenza virus is the main cause of thousands of deaths each year in the United States, and far more hospitalizations. Immunization has helped in protecting people from this virus and there are a number of therapeutics which have proven effective in aiding people infected with the virus. However, these therapeutics are subject to various limitations including increased resistance, limited supply, and significant side effects. A new therapeutic is needed which addresses these problems and protects people from the influenza virus. Synbodies, synthetic antibodies, may provide a means to achieve this goal. Our group has produced a synbody, the 5-5 synbody, which has been shown to bind to and inhibit the influenza virus. The direct pull down and western blot techniques were utilized to investigate how the synbody bound to the influenza virus. Our research showed that the 5-5 synbody bound to the influenza nucleoprotein (NP) with a KD of 102.9 ± 74.48 nM. It also showed that the synbody bound strongly to influenza viral extract from two different strains of the virus, the Puerto Rico (H1N1) and Sydney (H3N2) strains. This research demonstrated that the 5-5 synbody binds with high affinity to NP, which is important because influenza NP is highly conserved between various strains of the virus and plays an important role in the replication of the viral genome. It also demonstrated that this binding is conserved between various strains of the virus, indicating that the 5-5 synbody potentially could bind many different influenza strains. This synbody may have potential as a therapeutic in the future if it is able to demonstrate similar binding in vivo.
ContributorsKombe, Albert E. (Author) / Diehnelt, Chris (Thesis director) / Woodbury, Neal (Committee member) / Legutki, Bart (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of International Letters and Cultures (Contributor)
Created2014-05