Life Sciences Commons^™

Data-Driven Modeling Of The Causes And Effects Of Interneuronal Dysfunction In Alzheimer’S Disease And Dravet Syndrome, Carlos Perez

USF Tampa Graduate Theses and Dissertations

One of the defining features of Alzheimer’s disease (AD) is the increased cleavage of the amyloid precursor protein (APP), causing abnormally high levels of the aggregation form of amyloid beta (Aβ ). Many studies have shown that both AD patients and AD mice models exhibit abnormal network activity, including hypersynchronous excitatory neuron behavior, altered brain rhythms, and in some instances epileptic seizures when exposed to high levels of Aβ In particular, strong experimental evidence suggests that it is the small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) rather than the more stable, late stage rigid fibrils (RFs) that cause …

Posttranslational Modification And Protein Disorder Regulate Protein-Protein Interactions And Dna Binding Specificity Of P53, Robin Levy

USF Tampa Graduate Theses and Dissertations

p53 is an intrinsically disordered transcription factor that suppresses tumor development by arresting the cell cycle and promoting DNA repair. p53 deletions or mutations can lead to cancer due to the inability of cells to respond to stress. The protein levels and post-translational modification state of p53 changes in response to cellular stress like DNA damage. Previous studies have shown that p53 can undergo coupled folding and binding with the E3 ubiquitin ligase, Mdm2, and the histone deacetylase, p300. In normal cells, p53 is kept at a low level by Mdm2, which marks it with ubiquitin, targeting p53 for proteasome …

New Mechanisms That Control Fact Histone Chaperone And Transcription-Mediated Genome Stability, Angelo Vincenzo De Vivo Diaz

USF Tampa Graduate Theses and Dissertations

The Role of deubiquitinating enzymes (DUBs) in transcription, replication and genome integrity is not one that has been extensively researched. OTU DUBs are a particular class of enzyme with very little known about them.OTUD5 is a cysteine protease in the OTU family responsible to processing lysine 48 and lysine 63 ubiquitin chains. Recently, it has been implicated in to play a role in transcription through its binding partner UBR5. OTUD5 has also been shown to interact with proteins such as PDCD5 and p53, potentially have great importance in cell fate. In this study, I describe new discovered functions for OTUD5 …

Origins Of Amyloid Oligomers And Novel Approaches For Their Detection, Jeremy Barton

USF Tampa Graduate Theses and Dissertations

Alzheimer’s disease, type II diabetes, and other amyloid diseases are known to be associated with the formation of amyloid aggregates. It has been thoroughly researched whether amyloid fibrils or oligomers are the main culprit for these diseases, and recent evidence has connected oligomers as the most disease relevant aggregate species. However, many difficulties have arose in confirming this hypothesis. Techniques for oligomer detection are often limited in their sensitivity, and in many cases are unable to distinguish oligomers from rigid fibrils. Additionally, the role oligomer splay in fibril assembly is still unclear, and has led to the belief that different …

New Mechanisms That Regulate Dna Double-Strand Break-Induced Gene Silencing And Genome Integrity, Dante Francis Deascanis

USF Tampa Graduate Theses and Dissertations

Proliferating cells are constantly threatened by genotoxic stressors that can potentially lead to genomic instability. Breaks in the DNA, namely double-strand breaks, are detrimental sources of damage that must be repaired to maintain genomic integrity and prevent potential tumorigenesis. Here we discuss a gene silencing mechanism flanking damaged chromatin. Gene silencing and transcriptional repression at damaged DNA are necessary to prevent potential genomic aberrations from occurring through conflicts with the DNA repair machinery. BMI1, a core polycomb protein in the polycomb repressive complex 1 (PRC1) has been known to play a role in gene silencing at damaged chromatin. However, the …

The Impacts Of Membrane Modulators On Membrane Material Properties At Microscopic And Nanoscopic Levels, Chinta Mani Aryal

USF Tampa Graduate Theses and Dissertations

Peptide-membrane interactions depict the cell’s response to an external molecule. This is a critical event to evaluate the peptide’s function and effect as well as the response of target molecule. The understanding of the mechanism of action of peptide in a molecular level is important, for example, this may be useful in developing the therapeutic strategy. Peptides are the functional macromolecules which are actively researched among bio-related fields. Model membrane systems that mimic the real cell have been useful platform to test the perturbation upon peptide addition. In this thesis, we investigate the membrane modulation behavior of three peptides (modulators) …

Role Of Ceramide-1 Phosphate In Regulation Of Sphingolipid And Eicosanoid Metabolism In Lung Epithelial Cells, Brittany A. Dudley

USF Tampa Graduate Theses and Dissertations

Ceramide 1-Phosphate (C1P) is a sphingolipid metabolite which plays a large role in inflammation, cell survival and proliferation¹. C1P is known to have both pro- and anti-apoptotic roles in lung cancer cells, governed by ceramide kinase (CERK), upstream of precursor ceramide (Cer)². Previous work reveals C1P serves as the liaison between sphingolipid and eicosanoid synthesis, by decreasing the dissociation rate of group IVA cytosolic PLA₂ (cPLA_2α) from the Golgi membrane, C1P directly activates this phospholipase for downstream eicosanoid synthesis and subsequent inflammatory response³. CERK has been discovered to modulate eicosanoid synthesis, …

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 …

A Health Evaluation Of Gulf Of Mexico Golden Tilefish (Lopholatilus Chamaeleonticeps) And Red Snapper (Lutjanus Campechanus) Following The Deepwater Horizon Oil Spill, Kristina Leigh Deak

USF Tampa Graduate Theses and Dissertations

A lack of baseline heath indices for offshore Gulf of Mexico (GoM) teleosts complicated impact assessments of the Deepwater Horizon (DWH) oil spill. While measurement of contaminant levels in fish after a pollution event can document exposure, such data fail to provide meaningful information about how this contact affects an animal's physiology. Controlled exposure studies have highlighted the utility of biomarkers that may indicate deleterious, long-lasting effects of pollutant exposure on various life stages of fish, however, their extrapolation to wild-caught, non-model species is challenging. In an increasingly chemically-saturated environment, it can also be difficult to separate the influence of …

Genome Maintenance Roles Of Polycomb Transcriptional Repressors Bmi1 And Rnf2, Anthony Richard Sanchez Iv

USF Tampa Graduate Theses and Dissertations

The coordination of transcription, replication, and DNA damage response (DDR) is vital for maintaining normal cellular homeostasis. All of these processes take place on the chromatin and thus, the temporal and spatial separation of the factors responsible are necessary for each to be correctly completed. Here we detail several novel processes contributing to this network.

BMI1 is a component of the Polycomb Repressive Complex 1 (PRC1) which plays a key role in maintaining epigenetic silencing programs during development. Recently, BMI1 and other members of PRC1 like RNF2 have been implicated gene silencing during the DDR; however, the mechanism through which …

Mechanistic And Translational Studies On Skeletal Malignancies, Jeremy Mcguire

USF Tampa Graduate Theses and Dissertations

New treatment strategies are desperately needed for treating skeletal malignancy. Skeletal malignancies can be either primary cancer that originated in the bone, such as osteosarcoma, or metastatic cancer that spread from another organ to the skeleton, as in the case of breast or prostate cancer. In this thesis, I will detail two projects that focus on the discovery of new treatment strategies for both primary skeletal malignancy and metastatic skeletal malignancy.

The first project focuses on the primary skeletal malignancy, osteosarcoma, a rare cancer that is commonly diagnosed in children and young adults and metastasizes to the lungs. The survival …

Discovery And Characterization Of Small Molecule Inhibitors Of Bromodomains, Md Rezaul Karim

USF Tampa Graduate Theses and Dissertations

The epigenetic “reader” modules bromodomains (BRDs) exert their diverse cellular functions through the recognition of acetylated lysines on histones and other proteins. Small molecule inhibitors of bromodomains have emerged as a promising therapeutic strategy to treat atherosclerotic cardiovascular diseases and cancers. Therefore, a large number of small molecule bromodomain inhibitors have been developed in the last decade, some of which are currently being assessed in the clinic. However, the success of bromodomain inhibitors is currently limited to the bromodomain and extra-terminal domain (BET) subfamily.

To address these, bromodomains outside the BET subfamily (non-BETs) such as TAF1, BRD7/9, TRIM28, and BRD8 …

Study Of The Therapeutic Effects Of Synchronization-Modulation Of The Na/K Pump On Muscle Fatigue, Jason E. Mast

USF Tampa Graduate Theses and Dissertations

It has been shown that by applying a specially designed oscillating external electric field to a cell membrane that the membrane's sodium/potassium pumps can be synchronized to all work at the same rate. Then by slowly increasing the electric field's frequency the pumps' turnover rate can also be increased. By increasing the pumps' turnover rate, the sodium and potassium concentration gradients can be increased, this type of stimulation is called synchronization-modulation. There are three generations of the synchronization-modulation waveform each with different utilities. In particular, the third generation of synchronization-modulation has the ability to use the energy of the external …

Allosteric Control Of Proteins: New Methods And Mechanisms, Nalvi Duro

USF Tampa Graduate Theses and Dissertations

Allostery describes the phenomenon where perturbations in one region of a protein affect protein behavior in another non-overlapping region. Considerable efforts made over decades to understand the molecular basis of allostery, yet an overarching theory that can predict signaling pathways and contributions from chemical components is still lacking. In fact, molecular details in even the most well-studied of model systems, PDZ domains and GPCRs, remain unclear. In this dissertation I use molecular simulation methods to understand the role of allostery in the regulated entry of paramyxovirus into host cells, and also develop a new method to determine time-dependent signaling pathways …

A Novel Intramolecular Interaction In P53, Fan He

USF Tampa Graduate Theses and Dissertations

The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription to regulate cell survival and proliferation. The activation process involves post-translational modifications that suppress p53 degradation by MDM2 and increase p53 DNA binding affinity. p53 is mutated in ~50% of human tumors, with higher frequency in specific tumor types and after relapse. Mutated p53 loses transcriptional activity and gains new functions that drive tumor progression. Both N-terminus (NT) and C-terminus (CT) of p53 contain intrinsically disordered regions. The p53 CT has well-documented effects in regulating DNA binding. CT truncated p53 mutants showed defective DNA binding and …

To Mid-Cell And Beyond: Characterizing The Roles Of Gpsb And Ypsa In Cell Division Regulation In Gram-Positive Bacteria, Robert S. Brzozowski

USF Tampa Graduate Theses and Dissertations

The bacterial cell division protein FtsZ is a tubulin homolog that forms a ring-like structure at the site of cell division in most bacterial species. There it acts as a scaffold, aiding in the recruitment of other divisome proteins to the site of cell division. Furthermore, studies focusing on the role of FtsZ treadmilling and septal peptidoglycan synthesis implicates that FtsZ plays a direct role in the ultimate closure of the division septum. Thus, many studies in the field of bacterial cell division have focused on FtsZ in terms of its spatial and temporal regulation as well as its ability …

The Role Of Apkcs And Apkc Inhibitors In Cell Proliferation And Invasion In Breast And Ovarian Cancer, Tracess B. Smalley

USF Tampa Graduate Theses and Dissertations

Research has demonstrated that the atypical protein kinase C-zeta (PKC-ζ) is a component of many dysregulated pathways in breast and ovarian cancer, including cellular proliferation, survival, and cell cycle upregulation. Breast and ovarian cancers affect women every day and are second and fifth leading cause of cancer death. Women who seek treatments are commonly met with invasive surgeries or chemotherapy. Protein kinase C (PKC) is a family of serine and threonine phosphorylating kinases that have been shown to modulate and transduce signaling cascades that play roles in the development and survival of cancers. Atypical PKC (aPKC), have been heavily suggested …

Structure Based Inhibitor Discovery Targeting Multiple Β-Lactamases Involved In Antibiotic Resistance, Afroza Akhtar

USF Tampa Graduate Theses and Dissertations

Emergence of antibiotic resistance severely threatens the existing medication and prevention facilities against an over increasing range of infections caused by a wide range of microbes. Specifically, treatment of Gram-negative bacterial infection is getting more problematic due to their resilience against β-lactam antibiotics: the most commonly prescribed antibiotics in clinical settings. Production of β-lactamases is the most prevalent mechanism utilized by various Gram-negative pathogens to become resistant to the β-lactam antibiotics e.g, penicillins, cephalosporins, carbapenems and monobactams. These enzymes mediate their function through hydrolyzing the core β-lactam ring present in all β-lactam antibiotics which causes opening of the ring and …

Development And Application Of Computational Models For Biochemical Systems, Fiona L. Kearns

USF Tampa Graduate Theses and Dissertations

Chemistry is the study of matter and its transformations. Computational chemistry uses computer models to study chemistry in all its intricate complexity. In this thesis I hope to accessibly introduce fundamental concepts central for computational chemistry including quantum mechanics, molecular mechanics, and multiscale modeling. I then present several works which I have conducted throughout my graduate career employing many different computational methods. The investigations described here can be summarized as follows. Chapter 2.1 modeling proteins involved in crustacean molting, and identifying possible inhibitors to this molting. Chapter 2.2 modeling d-fructose bound to synthetic saccharide receptors with hopes of improving saccharide …

Evaluation Of Optimal Technique For Left Breast Irradiation, Amitpal Singh Saini

USF Tampa Graduate Theses and Dissertations

Numerous studies have indicated that radiation therapy reduces the risk of the local recurrence of breast cancer in several cases and that it has increased the overall survival rate. Although radiation therapy is beneficial for the treatment of breast cancer, it is known to increase the risk of both radiation toxicity and secondary breast cancer. In left-sided breast cancer, radiation therapy treatment often leads to the heart and its components—such as the left ventricle and left anterior descending artery—being exposed to high doses of radiation because of the proximity of the heart to the left breast, resulting in cardiac complications …