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Synthesis And Evaluation Of Anibamine And Its Analogs As Novel Anti-Prostate Cancer Agents, Kendra Haney
Synthesis And Evaluation Of Anibamine And Its Analogs As Novel Anti-Prostate Cancer Agents, Kendra Haney
Theses and Dissertations
The chemokine receptor CCR5 has been implicated in the pathogenesis of prostate cancer. A novel natural product, anibamine, was isolated and found to be a micromolar inhibitor of the receptor. Anibamine was used as a new anti-prostate cancer lead compound. To discover the pharmacophore, analogs of anibamine were designed using the “deconstruction-reconstruction-elaboration” approach and synthesized. The establishment of a stereoselective route to only one isomer was explored, to increase yield and eliminate elaborate purification procedures. Analogs were found to have anti-prostate cancer activity at levels higher than the parent compound. The molecular modeling studies of the deconstructed analogs indicate that …
Examination Of Platelet Adhesion By Streptococcus Sanguinis, Brian Mahoney
Examination Of Platelet Adhesion By Streptococcus Sanguinis, Brian Mahoney
Theses and Dissertations
Streptococcus sanguinis is a leading cause of infective endocarditis. Bacterial adhesion to platelets is likely important in the pathogenesis of infective endocarditis. Bacterial cell wall-anchored (Cwa) proteins may mediate this adhesion. To begin to test this hypothesis, S. sanguinis adhesion to platelets was examined in vitro. The requirement of 12 Cwa proteins for S. sanguinis-platelet adhesion was individually assessed, measuring adhesion of purified platelets to polystyrene wells coated with S. sanguinis strain SK36 or 12 isogenic Cwa protein mutants. Significantly fewer platelets adhered to wells coated with one mutant strain, VT1614. However, results of a whole-cell enzyme-linked immunosorbent assay (ELISA) …
Mechanical Structures Resisting Anterior Instability In A Computational Glenohumeral Joint Model, Kevin Elmore
Mechanical Structures Resisting Anterior Instability In A Computational Glenohumeral Joint Model, Kevin Elmore
Theses and Dissertations
The glenohumeral joint is the most dislocated joint in the body due to the lack of bony constraints and dependence on soft tissue, primarily muscles and ligaments, to stabilize the joint. The goal of this study was to develop a computational model of the glenohumeral joint whereby joint behavior was dictated by articular contact, ligamentous constraints, muscle loading, and external perturbations. Validation of this computational model was achieved by comparing predicted results from the model to the results of a cadaveric experiment in which the relative contribution of muscles and ligaments to anterior joint stability was examined. The results showed …
Preparation And Characterization Of Stable Macroporous Titania Nano-Wells, Hema Santhi Aluri
Preparation And Characterization Of Stable Macroporous Titania Nano-Wells, Hema Santhi Aluri
Theses and Dissertations
Silica based sol-gel thin films have been extensively studied because of their advantages that include optical transparency, high biodegradability and low intrinsic fluorescence. However, one concern with silica based sol-gel derived materials is their long term stability in aqueous solutions. Another concern is their limited porosity. These two concerns limit the application of these materials in catalysis and separations. The main objective of this study is to prepare porous, thin films using titanium alkoxides as precursors and evaluate their long term stability in aqueous solutions. Colloidal crystal templating will be used to introduce macrosized pores into the titania network. The …
Assessment Of Perceived Positive And Negative Outcomes In Risky Adolescent Dating And Peer Situations: A Descriptive Analysis Of Risk And Benefit Perception, Sarah Helms
Theses and Dissertations
Peer and dating violence perpetration and victimization are common experiences placing adolescents at-risk for maladaptive outcomes, yet little research has focused on specific problematic situations associated with these types of violence and other related risk-taking behaviors. Further, prevention programs have typically focused on changing beliefs, attitudes, and skill-deficits, with little attention to adolescents’ motivations or perceptions of costs and benefits associated with risky situations, despite support for this type of research in other health-related fields (e.g., substance abuse, behavioral medicine). The current study assessed adolescents’ perceptions of potential positive and negative outcomes associated with risky dating and peer situations, many …
Analysis Of The Regulation Of The Transferrin Iron Acquisition System In Neisseria Gonorrhoeae, Acevedo Rosuany Vélez
Analysis Of The Regulation Of The Transferrin Iron Acquisition System In Neisseria Gonorrhoeae, Acevedo Rosuany Vélez
Theses and Dissertations
The neisserial transferrin binding proteins (Tbps) comprise a bipartite system for iron acquisition from human transferrin. TbpA is a TonB-dependent outer membrane protein that forms the pore for iron internalization. TbpB is a surface-exposed lipoprotein that makes the iron-uptake process more efficient. Previous studies have shown that the genes encoding these proteins are arranged in a bicistronic operon, with the tbpB gene located upstream of tbpA. The operon is under the control of the ferric uptake regulator (Fur) protein. However, promoter elements necessary for the regulation of the operon have not been experimentally defined. In this study, putative regulatory motifs …
Ethnic Effects On Biological, Psychosocial And Disease Care Factors In African-American Youth With Type 1 Diabetes, Priscilla Powell
Ethnic Effects On Biological, Psychosocial And Disease Care Factors In African-American Youth With Type 1 Diabetes, Priscilla Powell
Theses and Dissertations
Person-oriented and variable-oriented analyses were conducted to investigate sociodemographic differences in biological, psychosocial and disease care factors in youth with type 1 diabetes. Additionally, diabetes knowledge was evaluated as a potential mediator of SES effects on HbA1c and disease care. The sample included 349 youth, age 9-17 years (79.9% Caucasian, 71.3% lived with two biological parents, M SES = 46.24). Person-oriented t-tests confirmed commonly reported ethnic differences in HbA1c and disease care behaviors. However, variable-oriented analyses controlling for confounding sociodemographic influences showed most disease care effects attributed to ethnicity were better explained by SES. While diabetes knowledge was not a …
Optimization Of Functional Mri Methods For Olfactory Interventional Studies At 3t, Vishwadeep Ahluwalia
Optimization Of Functional Mri Methods For Olfactory Interventional Studies At 3t, Vishwadeep Ahluwalia
Theses and Dissertations
Functional MRI technique is vital in investigating the effect of an intervention on cortical activation in normal and patient population. In many such investigations, block stimulation paradigms are still the preferred method of inducing brain activation during functional imaging sessions because of the high BOLD response, ease in implementation and subject compliance especially in patient population. However, effect of an intervention can be validly interpreted only after reproducibility of a detectable BOLD response evoked by the stimulation paradigm is first verified in the absence of the intervention. Detecting a large BOLD response that is also reproducible is a difficult task …
Quantitative Analysis Of Tobacco Specific Nitrosamine In Human Urine Using Molecularly Imprinted Polymers As A Potential Tool For Cancer Risk Assessment, Kumar Shah
Theses and Dissertations
Measuring urinary tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide conjugate may provide the best biomarker of tobacco smoke lung carcinogen metabolism. Existence of differences in the extent of NNAL metabolism rates may be potentially related to an individuals’ lung cancer susceptibility. Low concentrations of NNAL in smokers urine (<1 ng/mL) require sensitive and selective methods for analysis. Traditionally, this involves extensive, time-consuming sample preparation that limits throughput and adds to measurement variability. Molecularly imprinted polymers (MIPs) have been developed for the analysis of urinary NNAL by offline cartridge extraction combined with LC-MS/MS. This method when reproduced demonstrated problems with matrix effects. In the first part of this work, investigation of matrix effects and related problems with sensitivity for the published offline extraction method has been conducted. In order to address the need to improve throughput and other analytical figures of merit for the original method, the second part of this work deals with development of a high-throughput online microfluidic method using capillary-columns packed with MIP beads for the analysis of urinary NNAL. The method was validated as per the FDA guidance, and enabled low volume, rapid analysis of urinary NNAL by direct injection on a microfluidic column packed with NNAL specific MIP beads. The method was used for analysis of urinary NNAL and NNAL-Gluc in smokers. Chemometric methods were used with this data to develop a potential cancer-risk-assessment tool based on pattern recognition in the concentrations of these compounds in urine. In the last part, method comparison approaches for the online and the offline sample extraction techniques were investigated. A ‘fixed’ range acceptance criterion based on combined considerations of method precision and accuracy, and the FDA bioanalytical guidance limits on precision and accuracy was proposed. Data simulations studies to evaluate the probabilities of successful transfers using the proposed criteria were performed. Various experimental designs were evaluated and a design comprised of 3 runs with 3 replicates each with an acceptance range of ±20% was found appropriate. The off-line and the on-line sample extraction methods for NNAL analysis were found comparable using the proposed fixed range acceptance criteria.
Robust Protective Factors That Help Youths With A Parent Experiencing Depression Achieve Positive Adjustment, Hsing-Jung Chen
Robust Protective Factors That Help Youths With A Parent Experiencing Depression Achieve Positive Adjustment, Hsing-Jung Chen
Theses and Dissertations
Based on a resilience framework, the purpose of this study was to address knowledge gaps about minority youths who lived in rural and poor areas, had a primary caregiver with a diagnosis of depression, and faced multiple psychosocial stressors. Three research objectives included: 1) To explore the association between ecological protective factors and four developmental outcomes-emotional adjustment, behavioral adjustment, school performance, and educational aspiration; 2) To identify the robust protective factors; and 3) To explore the interactive relationships between risk and robust protective factors. Families (N=126) where the primary caregiver had a diagnosis of major depression and had a child …
Nonlinear Models In Multivariate Population Bioequivalence Testing, Bassam Dahman
Nonlinear Models In Multivariate Population Bioequivalence Testing, Bassam Dahman
Theses and Dissertations
In this dissertation a methodology is proposed for simultaneously evaluating the population bioequivalence (PBE) of a generic drug to a pre-licensed drug, or the bioequivalence of two formulations of a drug using multiple correlated pharmacokinetic metrics. The univariate criterion that is accepted by the food and drug administration (FDA) for testing population bioequivalence is generalized. Very few approaches for testing multivariate extensions of PBE have appeared in the literature. One method uses the trace of the covariance matrix as a measure of total variability, and another uses a pooled variance instead of the reference variance. The former ignores the correlation …
The Genetic Epidemiology Of Purging Disorder, Anorexia Nervosa, And Obsessive Compulsive Personality Disorder, Sara Trace
Theses and Dissertations
Although a variety of factors influence the development of eating disorders, genetic factors contribute notably to their etiology. Understanding genetic factors associated with eating disorders is important, as they can influence how these disorders are recognized, researched, and treated. This dissertation included two studies addressing important questions within the fields of eating disorders and genetics; specifically, Study 1 addressed the prevalence and heritability of purging and purging disorder in a population-based sample of female twins from the United States; and Study 2 investigated the nature of the co-morbidity between anorexia nervosa and obsessive compulsive personality disorder in a population-based sample …
Dilute Sulfuric Acid Pretreatment Of Switchgrass In Microwave Reactor For Biofuel Conversion: An Investigation Of Yields, Kinetics,, Oscar Martin
Theses and Dissertations
Lignocellulosic materials provide a raw material source for biofuel conversion and offer several advantages over fossil fuels- usage of a renewable resource, reduced greenhouse emissions, a decreased dependence on foreign oil, and stimulation of the agricultural sector. However, a primary technological challenge in converting lignocellulosic biomass into fuel is overcoming the recalcitrance of its matrix to enzymatic hydrolysis. To overcome these problems for chemical processing, naturally occurring cellulose biomass must be pretreated before it can be further processed using enzymatic hydrolysis or bioconversion. The goal of this work was to develop a model that predicts the glucose yield (pretreatment and …
Nonhomologous End-Joining: Tdp1-Mediated Processing, Atm-Mediated Signaling, Amy Hawkins
Nonhomologous End-Joining: Tdp1-Mediated Processing, Atm-Mediated Signaling, Amy Hawkins
Theses and Dissertations
This thesis investigates two separate features of nonhomologous end-joining (NHEJ) DNA repair: end processing, and DNA repair kinase signaling. DNA end processing was investigated in a mouse model of hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), a congenital neurodegenerative disease. SCAN1 is caused by a homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1). To address how the H493R mutation elicits the specific pathologies of SCAN1 and to further elucidate the role of TDP1 in processing DNA end modifications, we generated a Tdp1 knockout mouse and characterized their behavior and specific repair deficiencies in extracts of embryonic fibroblasts …
Joint Mixed-Effects Models For Longitudinal Data Analysis: An Application For The Metabolic Syndrome, John Thorp Iii
Joint Mixed-Effects Models For Longitudinal Data Analysis: An Application For The Metabolic Syndrome, John Thorp Iii
Theses and Dissertations
Mixed-effects models are commonly used to model longitudinal data as they can appropriately account for within and between subject sources of variability. Univariate mixed effect modeling strategies are well developed for a single outcome (response) variable that may be continuous (e.g. Gaussian) or categorical (e.g. binary, Poisson) in nature. Only recently have extensions been discussed for jointly modeling multiple outcome variables measures longitudinally. Many diseases processes are a function of several factors that are correlated. For example, the metabolic syndrome, a constellation of cardiovascular risk factors associated with an increased risk of cardiovascular disease and type 2 diabetes, is often …
Mechanical Behavior And Length Adaptation Of Rabbit Bladder Smooth Muscle, Atheer Almasri
Mechanical Behavior And Length Adaptation Of Rabbit Bladder Smooth Muscle, Atheer Almasri
Theses and Dissertations
Overactive bladder (OAB), involuntary contractions during bladder filling, is a common condition affecting 17% of the adult population worldwide, and in the U.S. ranks ahead of diabetes in a list of the 10 most common chronic disorders (Mullins 2009). Mechanical mechanisms contributing to OAB are not completely understood and because of the unique function and broad volume range of the bladder, there may be mechanical characteristics that distinguish detrusor smooth muscle (DSM) in bladder from other smooth muscles. Recent studies have shown that the length-passive tension curve in DSM exhibits adjustable passive stiffness (APS) characterized by a passive curve that …
Systematics And Biogeography Of The Didymopanax Group Of Schefflera (Araliaceae), Pedro Fiaschi
Systematics And Biogeography Of The Didymopanax Group Of Schefflera (Araliaceae), Pedro Fiaschi
Theses and Dissertations
Schefflera is the largest genus in the angiosperm family Araliaceae, with about 900 species, of which c. 300 belong to five subgeneric groups in the Neotropical region. Previous phylogenetic studies of Schefflera have been limited to a small number of species from this region, and very little is know about phylogenetic relationships in the Brazilian-centered Didymopanax group of this genus. Therefore, to gain a better understanding of the diversity and evolution of the Didymopanax group of Schefflera, I investigated the systematics of these plants in the broader context of the entire Neotropical clade. The main goals were (1) to investigate …
Sphingolipid-Induced Activation Of The Volume-Sensitive Cl− Current Is Mediated By Mitochondrial Reactive Oxygen Species, Frank Raucci
Sphingolipid-Induced Activation Of The Volume-Sensitive Cl− Current Is Mediated By Mitochondrial Reactive Oxygen Species, Frank Raucci
Theses and Dissertations
Swelling-activated Cl− current (ICl,swell) is an outwardly-rectifying current that plays an important role in cardiac electrical activity, cellular volume regulation, apoptosis, and acts as a potential effector of mechanoelectrical feedback. Persistent activation of ICl,swell has been observed in a number of models of cardiovascular disease. Previously we showed that angiotensin II (Ang II), endothelin-1 (ET-1), endothelial growth factor receptor (EGFR), and reactive oxygen species (ROS) produced by NADPH oxidase (NOX) and mitochondria are involved in the activation of ICl,swell by both osmotic swelling and Beta1 integrin stretch. Sphingolipid metabolism is modulated in several cardiopathologies and because sphingolipids are bioactive lipids …
The Regulation Of Alternative Splicing By Oncogenic Signaling Pathways., Jacqueline Shultz
The Regulation Of Alternative Splicing By Oncogenic Signaling Pathways., Jacqueline Shultz
Theses and Dissertations
In the presented study, we demonstrate that the alternative splicing of caspase 9 was dysregulated in a large percentage of NSCLC tumors and cell lines. These findings led to the hypothesis that survival pathways activated by oncogenic mutation regulated this mechanism. Indeed, the oncogenic PI3-Kinase/Akt pathway was demonstrated to regulate the alternative splicing of caspase 9. Further mechanistic studies demonstrate that multiple Akt isoforms can regulate the alternative splicing of caspase 9 in NSCLC. Akt was additionally shown to mediate the exclusion of the exon 3,4,5,6 cassette of caspase 9 via the phospho-state of the RNA trans-factor, SRp30a. Mutagenesis studies …
Inhibition Of The Calcium Plateau Following In Vitro Status Epilepticus Prevents The Development Of Spontaneous Recurrent Epileptiform Discharges, Nisha Nagarkatti
Inhibition Of The Calcium Plateau Following In Vitro Status Epilepticus Prevents The Development Of Spontaneous Recurrent Epileptiform Discharges, Nisha Nagarkatti
Theses and Dissertations
Status epilepticus (SE) is a major clinical emergency resulting in continuous seizure activity that can cause brain injury and many molecular and pathophysiologic changes leading to neuronal plasticity. The neuronal plasticity following SE-induced brain injury can initiate epileptogenesis and lead to the ultimate expression of acquired epilepsy (AE), characterized clinically by spontaneous, recurrent seizures. Epileptogenesis is the process wherein healthy brain tissue is transformed into hyperexcitable neuronal networks that produce AE. Understanding these alterations induced by brain injury is an important clinical challenge and can lend insight into possible new therapeutic targets to halt the development of AE. Currently there …
Genes And Symptoms Of Schizophrenia: Modifiers, Networks, And Interactions In Complex Disease, Sarah Bergen
Genes And Symptoms Of Schizophrenia: Modifiers, Networks, And Interactions In Complex Disease, Sarah Bergen
Theses and Dissertations
Understanding the genetic foundations of schizophrenia and the resultant symptom manifestations is an important step as we work toward development of new prevention and treatment strategies. This work has sought better understanding of this disease through use of three subject cohorts and two studies using simulated data exploring features of complex disease. First, we probed the symptoms of schizophrenia in subjects of African and European ancestry drawn from the Genetic Association Information Network (GAIN) schizophrenia study and found significant differences between groups, particularly in affective symptoms. The genetic basis of symptom variation was then explored in a selection of candidate …
Therapeutic Strategies Aimed To Facilitate Axonal Regeneration And Functional Recovery Following Traumatic Spinal Cord Injury, Woon Chow
Theses and Dissertations
Traumatic spinal cord injury (SCI) is a physically debilitating, emotionally devastating, financially costly, and life-changing condition that afflicts more than 1,000,000 people in the United States alone. Owing to the characteristic neuropathology and low regenerative capacity of the central nervous system, many victims of SCI are left permanently paralyzed. Though the tissue damage caused by the initial insult almost certainly cannot be reversed, intensive research in recent years to elucidate the cellular and molecular events that follows has provided new grounds for optimism. Accordingly, in this dissertation, we present a number of potential treatment strategies aimed to address some of …
Deriving Optimal Composite Scores: Relating Observational/Longitudinal Data With A Primary Endpoint, Rhonda Ellis
Deriving Optimal Composite Scores: Relating Observational/Longitudinal Data With A Primary Endpoint, Rhonda Ellis
Theses and Dissertations
In numerous clinical/experimental studies, multiple endpoints are measured on each subject. It is often not clear which of these endpoints should be designated as of primary importance. The desirability function approach is a way of combining multiple responses into a single unitless composite score. The response variables may include multiple types of data: binary, ordinal, count, interval data. Each response variable is transformed to a 0 to1 unitless scale with zero representing a completely undesirable response and one representing the ideal value. In desirability function methodology, weights on individual components can be incorporated to allow different levels of importance to …