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Coupling Chemical And Genomic Data Of Marine Sediment-Associated Bacteria For Metabolite Profiling, Stephanie P. Suarez

USF Tampa Graduate Theses and Dissertations

Marine sediment-associated bacteria house many new and exciting novel secondary metabolites. These metabolites can be tested for bioactivity against various types of cancer and fungal, bacterial, and viral infections. In this thesis, we investigated the combination of biosynthetic gene cluster information with mass spectra to perform a chemical profiling of sediment- associated bacteria. Furthermore, we utilized a scoring technique to provide an identification and confidence score to each annotated compound. The sediment was collected from east Arthur Harbor, Palmer Station, Antarctica, at depths of 20 ft and 60 ft. After plating on agar, 52 unique bacterial strains were isolated, with …

Coupling Chemical And Genomic Data Of Marine Sediment-Associated Bacteria For Metabolite Profiling, Stephanie P. Suarez

USF Tampa Graduate Theses and Dissertations

Marine sediment-associated bacteria house many new and exciting novel secondary metabolites. These metabolites can be tested for bioactivity against various types of cancer and fungal, bacterial, and viral infections. In this thesis, we investigated the combination of biosynthetic gene cluster information with mass spectra to perform a chemical profiling of sediment- associated bacteria. Furthermore, we utilized a scoring technique to provide an identification and confidence score to each annotated compound. The sediment was collected from east Arthur Harbor, Palmer Station, Antarctica, at depths of 20 ft and 60 ft. After plating on agar, 52 unique bacterial strains were isolated, with …

Host-Pathogen Coevolution Between Tasmanian Devils (Sarcophilus Harrisii) And Devil Facial Tumor Disease, Dylan Garret Gallinson

USF Tampa Graduate Theses and Dissertations

Coevolution is a driving force of rapid evolution, yet the complexity of coevolutionary interactions has made it difficult to characterize the genomic basis of traits mediating such relationships. Coevolutionary dynamics are especially important in host-pathogen systems where the host and pathogen must constantly adapt to one another. The Tasmanian devil and its species-specific transmissible cancer, devil facial tumor disease (DFTD), provide the rare opportunity to study host-pathogen coevolution in a complex natural system. Extensive spatiotemporal devil sampling, high linkage disequilibrium in devils, and a large selective pressure imposed by DFTD facilitate a system tractable for study. Here, we characterized devil …

Cell-Free Dna Methylation Signatures In Cancer Detection And Classification, Jinyong Huang

USF Tampa Graduate Theses and Dissertations

Early detection of cancer is believed as one of the best solutions to improve the therapeutic outcomes and overall survival of cancer patients. Analysis of circulating nucleic acids in bodily fluids, referred to as “liquid biopsies”, is rapidly gaining prominence for this purpose. Cell-free DNA (cfDNA) methylation has emerged as a promising biomarker for early cancer detection, tumor type classification, and treatment response monitoring. Currently, most cfDNA methylation profiling technologies are based on bisulfite conversion, while enrichment-based methods such as cfMeDIP-seq are beginning to show potential. To expand the use of enrichment-based methods in cfDNA methylation profiling, here, we report …

Using Artificial Intelligence To Decipher Epigenetic Code Of Drug Resistance In The Deadliest Human Malaria Parasite, Samira Jahangiri

USF Tampa Graduate Theses and Dissertations

Malaria remains one of the immense global public health challenges, with an estimated ~200 million cases worldwide in 2019 despite the remarkable gains in reducing this deadly disease over the past decade. The recent emergence and spread of artemisinin resistance (ART-R) in Plasmodium falciparum will increasingly impede global efforts to control and eliminate malaria. Previous studies have observed broad transcriptional changes and identified several noncoding genetic variants strongly associated with ART-R. The broad transcriptional variations suggest that the malaria parasite uses sophisticated epigenetic regulation to survive under drug pressure. Therefore, evaluating the regulatory effects of noncoding-variants in malaria parasites is …

Discrete Models And Algorithms For Analyzing Dna Rearrangements, Jasper Braun

USF Tampa Graduate Theses and Dissertations

In this work, language and tools are introduced, which model many-to-many mappings that comprise DNA rearrangements in nature. Existing theoretical models and data processing methods depend on the premise that DNA segments in the rearrangement precursor are in a clear one-to-one correspondence with their destinations in the recombined product. However, ambiguities in the rearrangement maps obtained from the ciliate species Oxytricha trifallax violate this assumption demonstrating a necessity for the adaptation of theory and practice.

In order to take into account the ambiguities in the rearrangement maps, generalizations of existing recombination models are proposed. Edges in an ordered graph model …

Feature Selection Via Random Subsets Of Uncorrelated Features, Long Kim Dang

USF Tampa Graduate Theses and Dissertations

The role of feature selection is crucial in many applications. A few of these include computational biology, image classification and risk management. In biology, gene expression micro array data sets have been used extensively in many areas of research. These data sets typically suffer from an important problem: the ratio between the number of features over the number of examples is very high. This problem mainly affects prediction accuracy because it is best to collect more labeled examples than features. A correlation based random subspace ensemble feature selector (CCC_RSM) was proposed to handle this problem [5]. In this approach, first …

Novel Long Non-Coding Rna Cdlinc Promotes Nsclc Progression, Christina J. Moss

USF Tampa Graduate Theses and Dissertations

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide with a low 5-year survival rate of only around 21%. This low 5-year survival rate is due to two main reasons. First, NSCLC is often diagnosed at the later stages when it has already metastasized. Second, NSCLC is an incredibly diverse, heterogenous disease making it very hard to target the true molecular oncogenic drivers. New targets for personalized therapeutics are needed based on the expression status of each individual lung cancer tumor.

One way of looking for these new therapeutics is to begin by identifying the oncogenotype …

Mass Spectrometry Discovery-Based Proteomics To Examine Anti-Aging Effects Of The Nutraceutical Nt-020 In Rat Serum, Samantha M. Portis

USF Tampa Graduate Theses and Dissertations

Aging is a complex physiological process that leads to the deterioration of all cells and tissues throughout the body. Aging is a major risk factor for the onset of many degenerative diseases in both the central nervous system (CNS) and the periphery, but even nonpathological aging (“normal” aging) is associated with chronic inflammation, oxidative stress, and decreased stem cell proliferation and regenerative capacity. This decreased regenerative capacity in stem cell niches is thought to be a key component underlying the aging process and many disease states associated with aging.

While the exact biological mechanisms underlying impaired stem cell proliferation and …

Novel Strategies On Characterizing Biologically Specific Protein-Protein Interaction Networks, Bi Zhao

USF Tampa Graduate Theses and Dissertations

The function, behavior, and environmental response of biological systems are essentially determined by the complex interaction and regulation of biomolecules inside the systems. Therefore, it is critical to characterize the inter-molecular interaction and regulation of biomolecules inside these systems. In this direction, many experimental techniques have been developed and these techniques have been used in many different model systems under various conditions. Consequently, a massive amount of data has been generated. These data cover multiple aspects of molecular interaction and regulation, such as protein-protein interaction, microRNA-RNA interaction, gene expression profiles, etc. While carrying rich information, these data may also contain …

Evolutionary Dynamics Of Influenza Type B In The Presence Of Vaccination: An Ecological Study, Lindsey J. Fiedler

USF Tampa Graduate Theses and Dissertations

Understanding the evolutionary dynamics of influenza type B in human hosts is a public health concern as we strive to minimize the disease burden in seasonal epidemics. Vaccination is considered the best defense against contracting influenza, and everyone over the age of 6 months is advised to get vaccinated before each season. The effect that vaccine-acquired immunity has on the evolution of influenza B remains unclear. In the U.S., vaccine-uptake is irregular across the states, and the differing coverages present an opportunity to study how vaccination influences viral evolution. This thesis analyzes the evolutionary patterns of influenza B in the …

Contribution Of Retrotransposons To Breast Cancer Malignancy, Isaac D. Raplee

USF Tampa Graduate Theses and Dissertations

The components contributing to cancer progression, especially the transition from early to invasive are unknown. Consequently, the biological reasons are unclear as to why some patients diagnosed with atypia and ductal carcinoma in situ (DCIS) never progress into invasive breast cancer. The “one gene at a time” approach does not sufficiently predict progression. To elucidate the early stage progression to invasive ductal cancer, expression signature of transcripts and transposable elements in micropunched samples of formalin-fixed, paraffin embedded (FFPE) tissue was conducted. A bioinformatics pipeline to analyze poor quality, short reads (>36 nts) from RNA-Seq data was created to compare …

Genomics And Transcriptomics Approaches To Understanding Drug Resistance Mechanisms In The Malaria Parasite Plasmodium Falciparum, Justin Allan Gibbons

USF Tampa Graduate Theses and Dissertations

The malaria parasite Plasmodium falciparum is responsible for about 500,000 deaths a year and is evolving resistance to the front-line treatment of artemisinin-based combination therapy. Resistance is currently confined to South East Asia, however millions of lives will be at risk if resistance spreads to Africa. Understanding the mechanism of resistance to artemisinins would aid containment strategies to prevent the spread of artemisinin resistance. There is also an urgent need to accelerate drug discovery since drug resistance has already been documented to all existing antimalarials. Here, I report on our efforts to understand the function of the gene k13, the …

Integrated Molecular Characterization Of Lung Adenocarcinoma With Implications For Immunotherapy, Nicholas T. Gimbrone

USF Tampa Graduate Theses and Dissertations

This dissertation covers a variety of the genetic and molecular abnormalities of lung adenocarcinoma with an emphasis on STK11 loss and its implications on immunotherapy response. Given that lung cancer is the leading cancer killer, novel therapies are in great demand. In particular, immunotherapy has shown some of the most promise in the last decade but remains limited due to nearly 80% of patients not significantly responding. This dissertation aims to molecularly characterize lung adenocarcinoma while attempting to explain the reason why patients with STK11 loss do not respond to immunotherapy.

In the first chapter we discuss the relationship between …

Off-Target Based Drug Repurposing Using Systems Pharmacology, Brent M. Kuenzi

USF Tampa Graduate Theses and Dissertations

The goal of this study was to identify novel drug repurposing opportunities in cancer by utilizing the off-target profiles of clinically relevant kinase inhibitors. This was based on the observation that the global target profiles of compounds are largely ignored and that many compounds have activity that cannot be explained by their cognate target alone. Additionally, by utilizing clinically relevant compounds, any results would hold a high potential for eventual clinical implementation. We utilized a systems pharmacology approach utilizing cell viability-based drug screening to identify compounds with beneficial off-target activity and then using chemical and phosphoproteomics in order to elucidate …

Signal Detection Of Adverse Drug Reaction Using The Adverse Event Reporting System: Literature Review And Novel Methods, Minh H. Pham

USF Tampa Graduate Theses and Dissertations

One of the objectives of the U.S. Food and Drug Administration is to protect the public health through post-marketing drug safety surveillance, also known as Pharmacovigilance. An inexpensive and efficient method to inspect post-marketing drug safety is to use data mining algorithms on electronic health records to discover associations between drugs and adverse events.

The purpose of this study is two-fold. First, we review the methods and algorithms proposed in the literature for identifying association drug interactions to an adverse event and discuss their advantages and drawbacks. Second, we attempt to adapt some novel methods that have been used in …

Modeling Of Dynamic Allostery In Proteins Enabled By Machine Learning, Mohsen Botlani-Esfahani

USF Tampa Graduate Theses and Dissertations

Regulation of protein activity is essential for normal cell functionality. Many proteins are regulated allosterically, that is, with spatial gaps between stimulation and active sites. Biological stimuli that regulate proteins allosterically include, for example, ions and small molecules, post-translational modifications, and intensive state-variables like temperature and pH. These effectors can not only switch activities on-and-off, but also fine-tune activities. Understanding the underpinnings of allostery, that is, how signals are propagated between distant sites, and how transmitted signals manifest themselves into regulation of protein activity, has been one of the central foci of biology for over 50 years. Today, the importance …

Mitochondrial Heteroplasmy Contributes To The Dynamic Atovaquone Resistance Response In Plasmodium Falciparum, Sasha Victoria Siegel

USF Tampa Graduate Theses and Dissertations

Of the considerable challenges researchers face in the control and elimination of malaria, the development of antimalarial drug resistance in parasite populations remains a significant hurdle to progress worldwide. Atovaquone is used in combination with proguanil (Malarone) as an antimalarial treatment in uncomplicated malaria, but is rendered ineffective by the rapid development of atovaquone resistance during treatment. Previous studies have established that de novo mutant parasites confer resistance to atovaquone with a substitution in amino acid 268 in the cytochrome b gene encoded by the parasite mitochondrial genome, yet much is still unknown about how this resistance develops, and whether …

Regulation Of Palmitoylation Enzymes And Substrates By Intrinsically Disordered Regions, Krishna D. Reddy

USF Tampa Graduate Theses and Dissertations

Protein palmitoylation refers to the process of adding a 16-carbon saturated fatty acid to the cysteine of a substrate protein, and this can in turn affect the substrate’s localization, stability, folding, and several other processes. This process is catalyzed by a family of 23 mammalian protein acyltransferases (PATs), a family of transmembrane enzymes that modify an estimated 10% of the proteome. At this point in time, no structure of a protein in this family has been solved, and therefore there is poor understanding about the regulation of the enzymes and their substrates. Most proteins, including palmitoylation enzymes and substrates, have …

Intrinsic Disorder Where You Least Expect It: The Incidence And Functional Relevance Of Intrinsic Disorder In Enzymes And The Protein Data Bank, Shelly Deforte

USF Tampa Graduate Theses and Dissertations

Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) exist as interconverting conformational ensembles, without a single fixed three-dimensional structure in vivo. The focus in the literature up to this point has been primarily on IDPs that are mostly or entirely disordered. Therefore, we have an incomplete understanding of the incidence and functional relevance of IDPRs in proteins that have regions of both order and disorder. This work explores these populations, by examining IDPRs in the Protein Data Bank (PDB) and in enzymes. By applying disorder prediction methods combined with an analysis of missing regions in crystal structure data, …

Computational Methods For Biomarker Identification In Complex Disease, Amin Ahmadi Adl

USF Tampa Graduate Theses and Dissertations

In a modern systematic view of biology, cell functions arise from the interaction between molecular components. One of the challenging problems in systems biology with high-throughput measurements is discovering the important components involved in the development and progression of complex diseases, which may serve as biomarkers for accurate predictive modeling and as targets for therapeutic purposes. Due to the non-linearity and heterogeneity of these complex diseases, traditional biomarker identification approaches have had limited success at finding clinically useful biomarkers. In this dissertation we propose novel methods for biomarker identification that explicitly take into account the non-linearity and heterogeneity of complex …

Estimating Likelihood Of Having A Brca Gene Mutation Based On Family History Of Cancers And Recommending Optimized Cancer Preventive Actions, Mehrnaz Abdollahian

USF Tampa Graduate Theses and Dissertations

BRCA1 and BRCA2 are gene mutations that drastically increase chances of developing breast and ovarian cancers, up to 20-fold, for women. A genetic blood test is used to detect BRCA mutations. Though these mutations occur in one of every 400 in the general population (excluding Ashkenazi Jewish ethnicity), they are present in most cases of hereditary breast and ovarian cancer patients. Hence, it is common practice for the physicians to require genetic testing for those that fit the rules as recommended by the National Cancer Comprehensive Network. However, data from the Myriad Laboratory, the only provider of the test until …

Design Of Novel Inhibitors For Infectious Diseases Using Structure-Based Drug Design: Virtual Screening, Homology Modeling And Molecular Dynamics, Divya Ramamoorthy

USF Tampa Graduate Theses and Dissertations

The main aim of the study in this thesis was to use structure-based protocols to design new drugs for enzymes, DXS and DXR in the non mevalonate pathway. Another aim of this study was to identify the dimer interface in E.coli FabH as an allosteric binding site for designing new class of anti-infective drugs. We have attempted to identify potential inhibitors for DXS by docking the NCI Diversity set compounds, compound libraries available from GSK-MMV and St. Jude's Children's research center. FabH dimer interface has been identified as a potential target using SiteMap, Alanine mutagenesis and docking studies.

The first …