Engineering Commons^™

Friend Or Foe? The Role Of Transforming Growth Factor-Β (Tgfβ) Signaling In Calcineurin Inhibitor-Induced Renal Damage, Adaku Uwe

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With its incorporation into clinical practice in the early 1980s, the class of pharmacological agents known as calcineurin inhibitors (CNIs) quickly became the cornerstone of immunosuppressive therapy post-organ transplantation. However, its use is limited by irreversible kidney damage in the form of renal fibrosis. The molecular mechanism by which CNIs induce renal fibrosis remains to be better understood, and to date, there are no specific therapeutic strategies to mitigate this damage. This dilemma presents a critical need to explain mechanisms by which CNIs cause renal damage. Kidneys of patients on chronic CNI therapy show increased expression of the proinflammatory cytokine …

Friend Or Foe? The Role Of Transforming Growth Factor-Β (Tgfβ) Signaling In Calcineurin Inhibitor-Induced Renal Damage, Adaku Ume

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With its incorporation into clinical practice in the early 1980s, the class of pharmacological agents known as calcineurin inhibitors (CNIs) quickly became the cornerstone of immunosuppressive therapy post-organ transplantation. However, its use is limited by irreversible kidney damage in the form of renal fibrosis. The molecular mechanism by which CNIs induce renal fibrosis remains to be better understood, and to date, there are no specific therapeutic strategies to mitigate this damage. This dilemma presents a critical need to explain mechanisms by which CNIs cause renal damage. Kidneys of patients on chronic CNI therapy show increased expression of the proinflammatory cytokine …

Erk3 And Dgkζ Interact To Modulate Cell Motility In Lung Cancer Cells, Amanda Myers

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Extracellular-regulated kinase 3 (ERK3) is overexpressed in a variety of cancers, including lung cancer. This atypical mitogen-activated protein kinase (MAPK) has a unique structure which includes a C34 domain and C-terminus and about which relatively little is known. ERK3 has been demonstrated to promote cell migration and metastasis in multiple cancer types. A yeast two-hybrid assay using ERK3 as bait indicated Diacylglycerol kinase ζ (DGKζ) is a binding partner. DGKζ is an isoform in the DGK family, all the members of which phosphorylate the lipid diacylglycerol (DAG) to generate phosphatidic acid (PA). DGKζ was shown to promote migration in mouse …

The Role Of Son In Chromatin-Mediated Gene Expression, Melissa Jordan Ward

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Gene expression in mammalian cells requires complex nuclear choreography, and there is increasing evidence that spatiotemporal organization of chromatin and nuclear compartments plays an important role in gene expression. In this dissertation, I examined the function of SON, a splicing factor with a known role in nuclear organization, in chromatin-mediated gene expression. SON association with a transcriptionally inactive U2OS 2-6-3 reporter gene array provided a useful model to study SON’s chromatin dynamics. I demonstrated that SON associates with the inactive but not the activated array, and that SON’s RNA binding domains are not necessary for that association. Second, I discovered …

Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda

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Huntington’s disease (HD) has classically been categorized as a neurodegenerative disorder. However, the expression of the disease-causing mutated huntingtin gene in skeletal muscle may contribute to the symptoms of HD, namely those that involve involuntary muscle contraction. In the R6/2 transgenic mouse model of HD, we previously observed ion channel defects that could contribute to involuntary muscle contraction. Here, in R6/2 muscle we investigated the consequence of these ion channel defects on action potentials (APs), the first step in excitation-contraction (EC) coupling. We found that the ion channel defects were associated with depolarizing the baseline membrane potential during AP trains. …

Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda

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Huntington’s disease (HD) has classically been categorized as a neurodegenerative disorder. However, the expression of the disease-causing mutated huntingtin gene in skeletal muscle may contribute to the symptoms of HD, namely those that involve involuntary muscle contraction. In the R6/2 transgenic mouse model of HD, we previously observed ion channel defects that could contribute to involuntary muscle contraction. Here, in R6/2 muscle we investigated the consequence of these ion channel defects on action potentials (APs), the first step in excitation-contraction (EC) coupling. We found that the ion channel defects were associated with depolarizing the baseline membrane potential during AP trains. …

Proteomic Analysis Of Fetal Rat Neural Stem Cells After Treatment With Hericium Erinaceus, Bright Adam Test

University of the Pacific Theses and Dissertations

The fungus, Hericium erinaceus, has outstanding chemical properties, displaying health benefits in digestive, hepatic, and nervous tissues. Its ease of accessibility and use makes it one of the most common substances used for treatment in Eastern medicine. More and more recent research is confirming the incredible health benefits of this fungus, especially the impact that is seen on nervous tissue growth and recovery post-treatment. Such neurite outgrowth and myelin sheath regeneration could illustrate the beginning of the cure to lifelong neurodegenerative diseases such as Multiple Sclerosis. In this first-of-its-kind study, we cultured and differentiated fetal rat neural stem cells while …

Global Identification Of Human Modifier Genes Of Alpha-Synuclein Toxicity, Ishita Haider

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Alpha-synuclein is a small lipid binding protein abundantly expressed in the brain. Lewy body or Lewy-like pathology, primarily composed of misfolded alpha-synuclein, is a pathological feature shared by several neurodegenerative disorders, including Parkinson's disease (PD). Both missense mutations and increased copy numbers of the SNCA gene, encoding the alpha-synuclein protein, have been genetically linked to autosome dominant PD. Other genetic variations affecting the expression of the SNCA gene have been associated with sporadic PD. Although the physiological function of alpha-synuclein is not well understood, its localization to plasma and vesicular membranes at the presynaptic terminals suggests a role in neurotransmission. …

Mitochondria-Dependent Cellular Toxicity Of Α-Synuclein Modeled In Yeast, Rajalakshmi Santhanakrishnan

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Parkinson’s disease is the second most common neurodegenerative disease. This disease is caused by the degeneration of dopaminergic neurons, leading to debilitating motor symptoms and early mortality. The protein α-synuclein (α-syn), encoded by SNCA, misfolds and forms inclusions in Parkinson’s disease brains. When α-syn is overexpressed in yeast, it causes cellular toxicity and an increased number of aggregates, recapitulating the toxic phenotypes observed in humans and animal models. Yeast models are a powerful tool to perform high-throughput overexpression screening to identify modifiers of α-syn toxicity. α-syn causes mitochondrial dysfunction by inhibiting complex I and inducing mitochondrial fragmentation. Prior screening of …

A Synthesis Platform For Temperature Responsive Star Polymers, Schmitt J. Richard Jr.

ETD Archive

Star polymers are a class of branched polymers comprised of several polymer chains extending from a central point. Star polymers have applications in biopharmaceuticals where they have been proposed to be suitable drug delivery vehicles. Star polymers have traditionally been synthesized through chemical synthesis with added functionality provided by grafting on the arms. This complex synthesis can be simplified by using a biosynthetic approach which enables precise control of molecular weight and composition. This approach is demonstrated using star polymers with arms composed of a temperature responsive protein-based polymer termed elastin-like polypeptide (ELP). Star polymers are characterized based on the …

Association Between Mechanics And Biology In Vascular Graft Remodeling, David Andrew Prim

Theses and Dissertations

Coronary artery bypass grafting (CABG) restores myocardial perfusion in patients with severe coronary artery disease by utilizing autografts – usually at least one of the internal thoracic artery (ITA), radial artery (RA), and great saphenous vein (GSV) – to bypass stenosed regions of coronary arteries. While decades of research and clinical improvements have made CABG an indispensable procedure, tens of thousands of grafts fail each year, which is due, at least in part, to an inability of the source vessels to adapt to the altered stimuli of the coronary circulation. In this dissertation, we first quantify and compare the mechanical …

A Novel System For Detection Of Dna Double Strand Breaks And Repair In Human Cells, Todd Warren Lewis

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Imperative to genomic stability is the ability of the cell to repair damaged DNA which can occur from numerous endogenous byproducts of metabolism or exogenous components from the environment. The Fanconi anemia pathway is a DNA repair mechanism used by human cells to resolve multiple forms of DNA damage including interstrand crosslinks (ICL). Fanconi anemia (FA) is an autosomal recessive inherited disorder characterized by genome instability, developmental abnormalities, cancer predisposition and bone marrow failure. FA is attributed to a mutations in at least 18 genes (FANCA-FANCT) that play a concerted role in DNA repair. FANCT is the latest discovery in …

Novel Therapeutic Approach For Regulating The Susceptibility Of Epitheliato Adenovirus Infection, Mahmoud Soliman Salem Alghamri

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Human Adenoviruses (AdVs) are etiologic agents for respiratory tract, digestive tract, heart, and eye infections. Although most AdV infections are self-resolving, some infections progress to acute respiratory disease with up to 50% mortality, particularly in immunosuppressed people. Except for vaccines for serotypes, 4 and 7, serotypes that are prevalent in the military, no vaccines or therapeutics that specifically prevent or treat AdV infection exist. On the other hand, AdV remains the most common vector system used in gene therapy clinical trials worldwide and several AdV vectors show promise in phase III clinical trials. The majority of AdVs use the coxsackievirus …

Evaluation Of The Signature Molecular Descriptor With Blosum62 And An All-Atom Description For Use In Sequence Alignment Of Proteins, Lindsay M. Aichinger

Williams Honors College, Honors Research Projects

This Honors Project focused on a few aspects of this topic. The second is comparing the molecular signature kernels to three of the BLOSUM matrices (30, 62, and 90) to test the accuracy of the mathematical model. The kernel matrix was manipulated in order to improve the relationship by focusing on side groups and also by changing how the structure was represented in the matrix by increasing the initial height distance from the central atom (Height 1 and Height 2 included).

There were multiple design constraints for this project. The first was the comparison with the BLOSUM matrices (30, 62, …

The Molecular Genetics Learning Progressions: Revisions And Refinements Based On Empirical Testing In Three 10th Grade Classrooms, Amber Nicole Todd

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In the past few decades, there has been a large push for increasing scientific literacy (AAAS, 1989; AAAS, 1993; Achieve, 2013; NRC, 1996; NRC, 2012), especially in areas that are rapidly advancing, like molecular genetics. Much research has been done on student understandings of molecular genetics and the consensus is that the concepts are difficult both to learn and teach (Fisher, 1992; Horwitz, 1996; Kindfield, 1992; Lewis & Kattmann, 2004; Marbach-Ad & Stavy, 2000; Stewart et al., 2005; Venville & Treagust, 1998; etc.). Two learning progressions in molecular genetics have been produced (Duncan et al., 2009; Roseman et al. 2006), …

Eeg During Pedaling: Brain Activity During A Locomotion-Like Task In Humans, Sanket G. Jain

Master's Theses (2009 -)

This study characterized the brain electrical activity during pedaling, a locomotor-like task, in humans. We postulated that phasic brain activity would be associated with active pedaling, consistent with a cortical role in locomotor tasks. 64 channels of electroencephalogram (EEG) and 10 channels of electromyogram (EMG) data were recorded from 10 neurologically-intact volunteers while they performed active and passive (no effort) pedaling on a custom-designed stationary bicycle. Ensemble average waveforms, two dimensional topographic maps and amplitude of the beta (13-35 Hz) frequency band were analyzed and compared between active and passive trials. The absolute amplitude (peak positive-peak negative) of the EEG …

Numerical Modeling Of Hemodynamics In The Thoracic Aorta And Alterations By Dacron Patch Treatment Of Aortic Coarctation, Ronak Jashwant Dholakia

Master's Theses (2009 -)

Coarctation of the aorta (CoA) is a major congenital heart disease, characterized by a severe stenosis of the proximal descending thoracic aorta. Traditionally, surgery has been the treatment of choice for CoA. Dacron patch aortoplasty gained increased popularity after its introduction in the mid-twentieth century due to its advantages over other surgical treatment methods available at the time. A major complication with Dacron patch aortoplasty has been the formation of late aneurysm with as much as 51% incidence reported in follow up studies. The change in aortic morphology and formation of aneurysms after Dacron patch surgery could lead to local …