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Role Of Oxidative Stress And T Cell Homing In The Development Of Murine Syngeneic Graft-Versus-Host Disease, Jacqueline Perez-Rodriguez

University of Kentucky Doctoral Dissertations

Syngeneic graft-versus-host disease (SGVHD) is induced by reconstituting lethally irradiated mice with syngeneic BM cells followed by a 21 day treatment with the immunosuppressive agent cyclosporine A (CsA). Clinical symptoms of the disease appear 2-3 weeks following cessation of CsA therapy and disease-associated inflammation occurs primarily in the colon and liver.

The development of SGVHD is a complex process resulting from the cooperative interaction of multiple effector cell populations including NK cells, T cells and macrophages. T_H1 cytokines (IL-12, TNF-α, IFN- γ), produced by these effector cells, serve as inflammatory mediators contributing to the pathogenesis of SGVHD. The …

Regulation Of Survivin Gene Expression In The Human Endometrium And Endometrial Cancer, Nancy H. Nabilsi

Dissertations and Theses (Open Access)

In the United States, endometrial cancer is the leading cancer of the female reproductive tract. There are 40,100 new cases and 7,470 deaths from endometrial cancer estimated for 2008 (47). The average five year survival rate for endometrial cancer is 84% however, this figure is substantially lower in patients diagnosed with late stage, advanced disease and much higher for patients diagnosed in early stage disease (47). Endometrial cancer (EC) has been associated with several risk factors including obesity, diabetes, hypertension, previously documented occurrence of hereditary non-polyposis colorectal cancer (HNPCC), and heightened exposure to estrogen (25). As of yet, there has …

Beliefs And Practices Of Expert Respiratory Care Faculty On Critical-Thinking Learning: A Case Study, James Leland Hulse

Dissertations

Problem. The development of critical-thinking skills during the professional training of respiratory therapists is imperative for good practice. Research evidence suggests that interactive instructional strategies are far more effective than traditional lectures. Missing from the literature are thick descriptions of how faculty organize the delivery of respiratory therapy curriculum to develop critical thinking. This case study describes the beliefs and practices of faculty members in an academically strong program in view of developing critical thinking.

Method. A qualitative, single case-study design was used to identify critical-thinking strategies and beliefs incorporated by the faculty. The program was nominated by expert members …

Autistic Disorder Associated With A Paternally Derived Unbalanced Translocation Leading To Duplication Of Chromosome 15pter-Q13.2: A Case Report., David J Wu, Nicholas J Wang, Jennette Driscoll, Naghmeh Dorrani, Dahai Liu, Marian Sigman, N Carolyn Schanen

Department of Pediatrics Faculty Papers

Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15. Here we describe a boy with a chromosome 15 duplication arising from a 3:1 segregation error of a paternally derived translocation between chromosome 15q13.2 and chromosome 9q34.12, which led to trisomy of chromosome 15pter-q13.2 and 9q34.12-qter. Using array comparative genome hybridization, we localized the breakpoints on both chromosomes and sequence homology suggests that the translocation arose from non-allelic homologous recombination involving the low copy repeats on chromosome 15. The child manifests many characteristics of the maternally-derived duplication …

Micrornas: Key Modulators Of Posttranscriptional Gene Expression., Steven P. O'Hara, Justin L. Mott, Patrick L. Splinter, Gregory J. Gores, Nicholas F. Larusso

Journal Articles: Biochemistry & Molecular Biology

No abstract provided.

Glutamate Regulation In The Hippocampal Trisynaptic Pathway In Aging And Status Epilepticus, Michelle Lee Stephens

University of Kentucky Doctoral Dissertations

A positive correlation exists between increasing age and the incidence of hippocampal-associated dysfunction and disease. Normal L-glutamate neurotransmission is absolutely critical for hippocampal function, while abnormal glutamate neurotransmission has been implicated in many neurodegenerative diseases. Previous studies, overwhelmingly utilizing ex vivo methods, have filled the literature with contradicting reports about hippocampal glutamate regulation during aging. For our studies, enzyme-based ceramic microelectrode arrays (MEA) were used for rapid (2 Hz) measurements of extracellular glutamate in the hippocampal trisynaptic pathway of young (3-6 months), late-middle aged (18 mo.) and aged (24 mo.) urethane-anesthetized Fischer 344 rats. Compared to young animals, glutamate terminals …

Pyramidobacter Piscolens Gen. Nov., Sp. Nov., A Member Of The Phylum ‘Synergistetes’ Isolated From The Human Oral Cavity, Julia Downes, Sonia R. Vartoukian, Floyd E. Dewhirst, Jacques Izard, Tsute Chen, Wen-Han Yu, Iain C. Sutcliffe, William G. Wade

Department of Food Science and Technology: Faculty Publications

Four strains of anaerobic, gram-negative bacilli isolated from the human oral cavity were subjected to a comprehensive range of phenotypic and genotypic tests and were found to comprise a homogeneous group distinct from any species with validly published names. 16S rRNA and 23S rRNA gene sequence analyses and DNA–DNA reassociation data revealed that the strains constituted a novel group within the phylum ‘Synergistetes’ and were most closely related to Jonquetella anthropi. Two libraries of randomly cloned DNA were prepared from strain W5455T and were sequenced to provide a genome survey as a resource for metagenomic studies. A new genus …

Human Ubc9 Contributes To Production Of Fully Infectious Human Immunodeficiency Virus Type 1 Virions, Tareq Jaber, Christopher R. Bohl, Gentry L. Lewis, Charles Wood, John T. West Jr., Robert A. Weldon Jr.

Nebraska Center for Virology: Faculty Publications

Ubc9 was identified as a cellular protein that interacts with the Gag protein of Mason-Pfizer monkey virus. We show here that Ubc9 also interacts with the human immunodeficiency virus type 1 (HIV-1) Gag protein and that their interaction is important for virus replication. Gag was found to colocalize with Ubc9 predominantly at perinuclear puncta. While cells in which Ubc9 expression was suppressed with RNA interference produced normal numbers of virions, these particles were 8- to 10-fold less infectious than those produced in the presence of Ubc9. The nature of this defect was assayed for dependence on Ubc9 during viral assembly, …

A Comparative Study Of Hiv-1 Clade C Env Evolution In A Zambian Infant With An Infected Rhesus Macaque During Disease Progression, For Yue Tso, Federico G. Hoffmann, Damien C. Tully, Philippe Lemey, Robert A. Rasmussen, Hong Zhang, Ruth M. Ruprecht, Charles Wood

Nebraska Center for Virology: Faculty Publications

Objective—To evaluate whether HIV-1 clade C (HIV-C) envelope variations that arise during disease progression in rhesus macaque model reflect changes that occur naturally in human infection.

Design—An infant macaque was infected with SHIV-1157i, an R5 tropic clade C SHIV (SHIV-C) which expresses a primary HIV-C envelope derived from an infected human infant, and monitored over a five-year period. Genetic variation of the V1-V5 envelope region, which is the main target for humoral immune responses, derived from the infected macaque and infant was examined.

Methods—V1-V5 envelope region were cloned and sequenced from longitudinal PBMC samples collected from the infected macaque and …

Regulation Of Innate Immune Responses By Bovine Herpesvirus 1 And Infected Cell Protein 0 (Bicp0), Clinton Jones

School of Veterinary and Biomedical Sciences: Faculty Publications

Bovine herpesvirus 1 (BoHV-1) infected cell protein 0 (bICP0) is an important transcriptional regulatory protein that stimulates productive infection. In transient transfection assays, bICP0 also inhibits interferon dependent transcription. bICP0 can induce degradation of interferon stimulatory factor 3 (IRF3), a cellular transcription factor that is crucial for activating beta interferon (IFN-β) promoter activity. Recent studies also concluded that interactions between bICP0 and IRF7 inhibit trans-activation of IFN-β promoter activity. The C3HC4 zinc RING (really important new gene) finger located near the amino terminus of bICP0 is important for all known functions of bICP0. A recombinant virus that contains a single …

Ectopic Intra-Abdominal Fascioliasis, Ali̇ Ulvi̇ Öngören, Ayşegül Taylan Özkan, Ari̇f Hakan Demi̇rel, Hüseyi̇n Üstün, Mustafa Dönmez

Turkish Journal of Medical Sciences

Human fascioliasis, caused by Fasciola hepatica, is emerging as an important chronic zoonotic disease in many areas of the world, including Turkey. It primarily involves the liver and may also cause severe damage in the tissue. Herein we report on a patient with ectopic intra-abdominal fascioliasis that presented to our clinic with abdominal pain and distention. Physical and radiological examination as well as an exploratory laparotomy revealed a 10 × 10-cm mass in the splenic flexura of the colon and multiple cystic formations in the liver, spleen, and omentum, which mimicked peritoneal carcinoma. Histopathological examination revealed a granulomatous reaction due …

A Comparison Of Different Doses Of Remifentanil And Tracheal Lidocaine On Attenuation Of Cardiovascular Responses To Laryngoscopy And Tracheal Intubation, Mohammadreza Safavi, Azim Honarmand

Turkish Journal of Medical Sciences

Background: The efficacy of remifentanil infusion versus tracheal lidocaine for attenuation of the cardiovascular responses to tracheal intubation has been previously reported. This study compared hemodynamic stability during anesthesia induction and intubation using tracheal lidocaine and remifentanil. Materials and Methods: The study included 90 patients that were scheduled for elective surgery under general anesthesia and randomly allocated to 3 treatment groups: remifentanil 1 µg kg-1 min-1 bolus over 30 s, followed by an infusion of 0.5 µg kg-1 min-1 (R1); remifentanil 0.5 µg kg-1 min-1 over 30 s and an infusion of 0.25 µg kg-1 min-1 (R2); tracheal lidocaine (TL) …

Evaluation Of The Performance Of A Carotid Subclavian By-Pass As A Source For Internal Thoracic Artery, İbrahi̇m Duvan, Alper Gürbüz, Meti̇n Demi̇rci̇n

Turkish Journal of Medical Sciences

The concomitance of atherosclerotic subclavian occlusive lesion with coronary artery disease has an extraordinary importance in coronary artery bypass surgery. The development of a lesion in the subclavian artery proximal to the internal thoracic artery (ITA) before or after coronary artery bypass graft (CABG) by ITA can result with the coronary-subclavian steal syndrome and myocardial ischemia may occur. It is pretty vital to be aware of the presence of the subclavian occlusive lesion in patients undergoing CABG. We present in this paper an atherosclerotic case that had a concomitant brachiocephalic and coronary artery disease. He had both carotid and subclavian …

Analysis Of Cystic Kidney Disease-Related Genes In Caenorhabditis Elegans, Corey L. Williams

All ETDs from UAB

Cilia are evolutionarily conserved, membrane-bound, microtubule-based organelles found on a diverse array of cell types in eukaryotic organisms. Inherited diseases of cilia protein dysfunction include Nephronophthisis (NPHP), Joubert Syndrome (JBTS), Meckel-Gruber Syndrome (MKS), and Bardet-Biedl Syndrome (BBS). Important insight in the basic cell biological functions of BBS and NPHP proteins has been gained from analysis in the nematode Caenorhabditis elegans. My goal in this dissertation was to model MKS protein function in cilia biology utilizing the powerful genetic malleability of C. elegans. mks-1 and mks-3, the C. elegans homologs of two MKS-associated proteins in humans, were selected for this analysis. …

Structural Studies Of Yeast Mitochondrial Peripheral Membrane Protein Tim44, Ratnakar Josyula

All ETDs from UAB

Tim44 is a peripheral membrane protein and a component of the TIM23 translocon on the matrix side. It is well established that Tim44 tethers the presequence associated motor (PAM) complex to the Inner Mitochondrial Membrane (IMM), through its C-Terminal Domain (CTD). This study focuses on understanding the high resolution structure of Tim44 CTD and the molecular basis for its membrane anchoring mechanism. The crystal structure of Tim44 CTD revealed that it exists as a single domain. The N-terminal amphipathic helices A1 and A2 protrude away from the main body of Tim44 CTD. These two flexible helices have been tested for …

Mouse Model Of Cooley's Anemia, Yongliang Huo

All ETDs from UAB

β thalassemia major or Cooley’s anemia (CA) is a heterogeneous group of inherited disorders characterized by deficient β globin chain production. Newborns with CA are healthy because of the high fetal hemoglobin (HbF) levels present in their red blood cells (RBCs). As HbF levels decline during the first year of life, patients develop severe anemia that necessitates regular blood transfusion to maintain life. CA has been difficult to model in the mouse due to the lack of a fetal hemoglobin equivalent in the mouse. By utilizing a human fetal to adult delayed hemoglobin switching cassette, I hypothesize that a CA …

Polycistronic Lentiviral Vector For Hit And Run Reprogramming Of Mouse And Human Somatic Cells To Induced Pluripotent Stem Cell, Chia-Wei Chang

All ETDs from UAB

Embryonic stem (ES) cells are pluripotent and, therefore, can differentiate into most if not all somatic cell types. Because of this characteristic, ES cells have great potential for medical therapies. Since the first cloned mammal, Dolly the sheep, was published in 1996 (1), several groups have successfully cloned other animals by the same nuclear transfer method (2). Isogenic ES cell lines can also be established from donor cells by the same technique (3). However, to date there has been no report of successful derivation of human ES cells by nuclear transfer. Based on the cell fusion (4) and nuclear transfer …

The Effect Of Zinc On Cytokine Release And Signal Transduction In Airway Epithelial Cells, Nai-Lin Cheng

All ETDs from UAB

Zinc is an essential cation for life that is involved in numerous physiology and pathophysiology processes. Despite its wide use as a cytoprotective agent in medications, its cellular and molecular mechanisms of action have not been well established. In order to define the potential therapeutic benefit of zinc, I used several Cystic Fibrosis (CF) and non-CF human airway epithelial cell lines as models in my studies. Extracellular zinc caused release calcium from the endoplasmic reticulum though zinc-sensitive Gq-coupled receptor(s) that may subsequently modulate ion channels. In addition, zinc also exhibited anti-inflammatory effects. Zinc inhibited pro-inflammatory molecular TNFα-induced cytokine and chemokine …

Calreticulin And Its Role In Collagen Regulation, Lauren Van Duyn

All ETDs from UAB

Calreticulin (CRT), classically known for its chaperone functions in the endoplasmic reticulum and as a calcium regulator, also is found on the cell surface and in the extracellular matrix. It is involved in many cellular processes including signaling, adhesion, migration, apoptotic cell clearance, gene regulation, and production of a fibronectin matrix. CRT has been suggested to play a role in wound healing and fibrosis. Therefore, these studies investigated the role of CRT in collagen production, an important extracellular matrix molecule in wounding and fibrosis. We demonstrated that CRT regulates collagen through transcription, secretion, and processing. We also investigated the role …

Characterizing The Role Of Primary Cilia In The Hair Follicle And Skin, Jonathan Merle Lehman

All ETDs from UAB

Primary cilia have been established as a nearly ubiquitous microtubule based signaling organelle, yet their function in many organs, including the hair and skin, is unknown. We hypothesized that the primary cilium would play vital roles in the hair follicle and skin based on the cilium's well characterized interactions with the Shh and Wnt developmental signaling pathways. This dissertation describes our efforts to determine the localization of the primary cilia in the murine hair follicle and assess the function of this organelle in the hair and skin. We used confocal immunofluorescence microscopy to virtually section the entire hair follicle and …

Mitochondrial Bioenergetics And Cellular Stress, Brian Dranka

All ETDs from UAB

Mitochondria are responsible for most of the energy produced in human tissues, and this is dependent on the reduction of oxygen (O2) to water by the mitochondrial respiratory chain. Defects in mitochondrial energy production are now recognized to be involved in diabetes, cancer, cardiovascular disease, and other pathologies. To date, studies of these defects have employed quantification of O2 consumption in isolated, purified mitochondria. By using this strategy however, the cellular context, role of glycolysis, and normal regulation of mitochondrial function by metabolite availability are lost. Thus, an understanding of how mitochondria function and respond to stimuli in an intact …

Structural And Functional Studies On Heat Shock Protein Hsp40-Hdj1 And Golgi Er Trafficking Protein Get3, Junbin Hu

All ETDs from UAB

Molecular chaperones are a large group of proteins that bind and stabilize nascent polypeptides and facilitate protein folding. One major function of chaperones is to bind hydrophobic segments of nascent polypeptides to prevent them from aggregating. How chaperone Hsp40 recognizes and interacts with polypeptides and cooperates with chaperone Hsp70 is a fundamental question. The crystal structure of the putative peptide-binding fragment of Hdj1, a human member of the type II Hsp40 family was determined, suggesting the domain I of Hsp40 may possess significant flexibility which is important for Hsp40 to regulate the size of the cleft. The flexibility may be …

The Protective Role Of Transglutaminase 2 In Ischemic Stroke, Anthony J. Filiano

All ETDs from UAB

Stroke is a leading cause of long term disabilities in the US. Currently, administration of thrombolytics is the only approved therapy. Due to the variability, small management time window, and lack of options for effective treatment, there is a clear need for new compounds to alleviate cell death post-stroke. Transglutaminase 2 (TG2) can decrease apoptotic signaling during stroke and lead to increased neuronal survival making it a potential target for therapeutic intervention. TG2, a multifunction enzyme that has both transamidase (TG) and GTPase activities, amongst others, has recently been shown to be upregulated in numerous neurodegenerative conditions, including stroke. In …

Erythrocyte Invasion By Plasmodium Falciparum, Matthew L. Jones

All ETDs from UAB

Malaria poses a severe threat to global public health, with the majority of the world’s population living in malaria-endemic settings. Plasmodium falciparum is a major cause of malaria, and is the predominant cause of fatal malaria. This parasite, like other Plasmodium spp., has a complex life cycle, but causes disease only as a result of a lytic life cycle phase that occurs within the erythrocyte. As development within the erythrocyte is fully responsible for disease pathology, it follows that a detailed molecular understanding of the process of erythrocyte invasion by P. falciparum parasites would allow the development of new and …

Epigenetic Control Mechanisms In Somatic Cells Mediated By Dna Methyltransferase 1, Bongyong Lee

Electronic Theses and Dissertations

DNA methylation regulates gene expression through a complex network of protein/protein and protein/DNA interactions in chromatin. The maintenance methylase, DNA methyltransferase 1 (DNMT1), is a prominent enzyme in the process that is linked to DNA replication and drives the heritable nature of epigenetic modifications in somatic cells. The mechanistic details that explain how DNMT1 catalytic action is directed in a chromatin setting are not well understood. We hypothesize that post translational modifications and a variety of protein-protein interactions processes are key regulatory elements that set the methylation of CpG elements essential for normal growth behavior in somatic cells. These fundamental …

Mouse Modeling Of Pancreatic Ductal Adenocarcinoma (Pdac); Search For Early Diagnostic Markers And Therapeutic Targets, Kyoko Kojima

All ETDs from UAB

PDAC is a highly malignant neoplasm that carries a very poor prognosis. PDAC development is a multistage transformation process that involves multiple genetic alterations that include activation of EGFR/HER2 and KRAS, and loss-of-function mutations in INK4A/ARF, p53 and SMAD4. In recent years, several genetically engineered mouse models that accurately recapitulate human pancreatic neoplasia have been developed. Histological characterizations of those models have revealed possible roles for the mutated RAS, INK4a/ARF and p53 in pancreatic tumorigenesis. However, the role of SMAD4 mutation, which is associated with late stages of tumor progression, has yet to be explored. Additionally, those models that would …

Genome Copy Number Profiles Of African-American And European-American Early-Onset Breast Cancer, Tyesha Latrece Farmer

All ETDs from UAB

Breast cancer is the second leading cause of cancer related death among women in the United States, surpassed only by lung cancer. It is estimated that over 200,000 women developed breast cancer and more than 40,000 died of the disease in 2008 alone. Although the overall incidence of breast cancer is lower in African-American women, the incidence of early-onset breast cancer is higher than that observed in European-American women. African-American women also have higher mortality rates due to this disease than those observed in their European-American counterparts. Breast cancer exhibits heterogeneity at the molecular, cellular, and clinical levels, and the …

Insulin Signaling And Function In Osteoblasts, Keertik S. Fulzele

All ETDs from UAB

Insulin and insulin-like growth factor-1 (IGF-1) are evolutionarily conserved hormonal signaling pathways with structurally similar ligands and receptors. Recent stu-dies suggest that that insulin and IGF-1 exert distinct as well as overlapping functions to regulate different aspects of skeletal development. A major problem in distinguishing the actions of insulin and IGF-1 is the fact that the receptors are co-expressed in many cell types and each ligand is able to cross-activate the other ligands' receptor. To distinguish direct skeletal actions of insulin from that of IGF-1, we have conditionally disrupted each receptor in vitro and in vivo specifically in osteoblasts. Studies …

A Functional Analysis Of The Human Immunodeficiency Virus, Sushma Jyotika Bhakta

All ETDs from UAB

The retroviral life cycle is separated into two distinct phases of infection. In the first phase, viral enzymes and proteins allow the virus to establish infection. The virus usurps host machinery in the second stage to produce infectious virus. In both phases of the replication cycle, the envelope (Env) glycoprotein (gp) is a key component of infectivity. Env plays a pivotal role in viral entry, by mediating attachment and facilitating fusion of the viral and cellular membranes, and during assembly, where Env must be incorporated into budding virions in order to produce infectious virions. The Env cytoplasmic domain (CD) interacts …

Genetic Complexity And Population Diversity Of Plasmodium Falciparum In The Peruvian Amazon, Patrick Lee Sutton

All ETDs from UAB

GENETIC COMPLEXITY AND POPULATION DIVERSITY OF PLASMODIUM FALCIPARUM IN THE PERUVIAN AMAZON PATRICK LEE SUTTON MICROBIOLOGY GRADUATE PROGRAM ABSTRACT Characterizing the genetic complexity of immunologically relevant proteins, expressed during the life cycle of P. falciparum, is essential for identifying and advancing potential vaccine candidates. The current malaria immunity paradigm is rooted in high transmission studies which have investigated the impact of high genetic diversity on the development of humoral responses. Given the dynamic nature of malaria parasites, especially their ability to acclimate to change, it is likely that regions of low transmission do not share the same malaria immunity paradigm …