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Generation And Analysis Of The Oncolytic Efficacy Of A Conditionally Replicating Adenovirus Bearing Rgd Modifications On Pix And Fiber Capsid Proteins, Lena Jeanelle Gamble Jan 2010

Generation And Analysis Of The Oncolytic Efficacy Of A Conditionally Replicating Adenovirus Bearing Rgd Modifications On Pix And Fiber Capsid Proteins, Lena Jeanelle Gamble

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Ovarian cancer is the leading cause of gynecological disease death in women. For the past two decades, scientists have attempted to perfect the use of adenovirus as an anti-cancer therapeutic agent. One major impediment to ovarian tumor infection with adenovirus has been dearth of adenovirus native receptor, Coxsackie and Adenovirus receptor, (CAR), on the surface of tumor cells. To address this problem, scientists have engineered CAR-independent adenoviruses which target the AlphavBeta3 and AlphavBeta5 by adding an arginine-glycine-aspartate (RGD) motif to the fiber knob of a conditionally replicating adenovirus (CRAd) Delta24FiberRGD CRAd. We hypothesize that incorporation of RGD into the pIX …

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Optical Mapping Of The Interactions Between Cardiac Geometry And Electrical Activity, Elliot B. Bourgeois Jan 2010

Optical Mapping Of The Interactions Between Cardiac Geometry And Electrical Activity, Elliot B. Bourgeois

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In healthy hearts, the synchronized spread of electrical activation drives contraction. To investigate the role of cardiac geometry in modulating normal and abnormal electrical rhythms, we stained cardiac tissues with a fluorescent, voltage sensitive dye and imaged activation patterns with fast video cameras (optical mapping). This work is presented in three projects. Computer modeling has shown that conduction velocity increases when fibers are bowed toward the oncoming wavefront and decreases when fibers are bowed in the opposite direction. In the first project, cultured monolayers of cardiac myocytes were optically mapped to experimentally verify the theoretical effect of fiber curvature on …

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Maternal Gestational Glucose Concentration And Offspring Body Composition, Insulin Sensitivity, And Ss-Cell Function, Nikki C. Bush Jan 2010

Maternal Gestational Glucose Concentration And Offspring Body Composition, Insulin Sensitivity, And Ss-Cell Function, Nikki C. Bush

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Background: Evidence suggests that intrauterine exposure to elevated glucose concentrations may be a mediating factor in prenatal programming of offspring disease risk. However, studies examining the effects of maternal glucose concentration on measures of body composition, insulin sensitivity, and ß-cell response in prepubertal children are limited. Therefore, the objective of this study was to determine the associations of maternal glucose concentration with children's fat mass, insulin sensitivity, and ß-cell response using robust and physiologic measures. Methods: Participants were 40 children aged 5-10 years. Children's insulin sensitivity index (SI) and measures of basal, static, dynamic, and total ß-cell response were determined …

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The Role Of Usp14 In Regulating Synaptic Development And Function Of The Neuromuscular Junctions, Ping-Chung Chen Jan 2010

The Role Of Usp14 In Regulating Synaptic Development And Function Of The Neuromuscular Junctions, Ping-Chung Chen

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The ubiquitin proteasome system (UPS) plays critical roles in regulating multiple cellular functions, including protein abundance, trafficking, and cell signaling. In the nervous system, the UPS has been implicated in controlling a wide diversity of cellular process such as synaptic transmission, axon outgrowth, axon targeting, and synapse development. Although impairment of the UPS is observed in both neurodegenerative and developmental diseases, the mechanisms underlying how UPS dysregulation contributes to disease pathogenesis are not known. The proteasome, an approximate 2.5 megadaltons protein complex composed of 19S and 20S assemblies, is the site of ubiquitin-dependent protein degradation. Recent studies have demonstrated dysfunction …

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Cathelin-Related Antimicrobial Peptide (Cramp) Regulates B Cell Igg1 Production, Yao Chen Jan 2010

Cathelin-Related Antimicrobial Peptide (Cramp) Regulates B Cell Igg1 Production, Yao Chen

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Mammalian antimicrobial peptides, including cathelicidins and defensins, play an important role in host defense via direct antimicrobial activity as well as immune regula-tion. The cathelin-related antimicrobial peptide (mCRAMP) is the only identified mouse cathelicidin and the orthologue of human LL-37. We show that all mouse B cell subsets, including follicular, marginal zone, B1a, and B1b cells, as well as CD4+ and CD8+ T cells produce mCRAMP directly ex vivo. In addition, mCRAMP-deficient B cells produced less IgG1 antibody in vitro in response to CD40L or LPS plus IL-4 when compared to WT B cells. The addition of recombinant mCRAMP at …

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The Effects Of Weight Reduction On Obesity-Related Cancer Biomarkers And In Vitro Cancer Cell Growth, Maria Azrad Jan 2010

The Effects Of Weight Reduction On Obesity-Related Cancer Biomarkers And In Vitro Cancer Cell Growth, Maria Azrad

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Obesity increases the risk for breast and endometrial cancers while weight loss reduces the risk for these cancers. One aim of this dissertation was to determine the effects of weight loss from an overweight state [body mass index (BMI) 27-30] to a normal weight state on several obesity-related cancer biomarkers in African-American (AA) and European-American (EA) premenopausal women. We also sought to determine whether the method of weight loss, caloric restriction alone (CR) or combined with exercise resulted in similar changes in cancer biomarkers. The biomarkers of interest were urinary estrogen metabolites, and serum adiponectin, leptin, insulin-like growth factor (IGF)-1, …

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Study Of The Role Of The Amygdala In The Effects Of Stress On Sensory Processing Of The Urinary Bladder, Jennifer Deberry Jan 2010

Study Of The Role Of The Amygdala In The Effects Of Stress On Sensory Processing Of The Urinary Bladder, Jennifer Deberry

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Interstitial cystitis (IC) is a chronic visceral condition of the urinary bladder characterized by pelvic/suprapubic pain, and urinary frequency and urgency. There is no documented cause for IC, but a prominent role for stress in its pathophysiology and presentation are well-documented. In the clinical setting, IC pain-related symptomatology is exacerbated during periods of stress. Numerous laboratory studies of humans and animals have similarly demonstrated stress-induced visceral hypersensitivity. The amygdala is highly connected with physiological stress response systems and pain modulatory pathways, and its connectivity with these systems places it in a unique anatomical position for mediating the reciprocal relationship between …

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The Role Of Post-Translational Modifications And Valosin-Containing Protein In The Turnover And Stability Of The Microtubule-Associated Protein Tau, Philip James Dolan Jan 2010

The Role Of Post-Translational Modifications And Valosin-Containing Protein In The Turnover And Stability Of The Microtubule-Associated Protein Tau, Philip James Dolan

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Alzheimer Disease (AD) is pathologically characterized by the appearance of senile plaques composed of ß-amyloid and neurofibrillary tangles composed of the microtubule-associated protein tau. During the development of AD pathology, tau is hyperphosphorylated and aberrantly cleaved, both of which potentially contribute to its pathogenic and fibrillogenic nature. The accumulative nature of these post-translational products, and their contribution to tau pathology, has led to a great deal of study regarding mechanisms for both the maintenance of tau stability and degradation. The first part of this study reviews the developments regarding the contribution of phosphorylated tau to different physiological and pathological processes. …

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Characterization Of The Oligosaccharides Of B. Anthracis Exosporium, Shengli Dong Jan 2010

Characterization Of The Oligosaccharides Of B. Anthracis Exosporium, Shengli Dong

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Fatal systemic anthrax is caused by exposure to spores of Bacillus anthracis. The outermost layer of the B. anthracis spore is called the exosporium. It consists of a paracrystalline basal layer and an external hair-like nap. The filaments of the hair-like nap are primarily composed of the glycoprotein BclA. Our previous studies showed that a 715-Da tetrasaccharide and a 324-Da disaccharide are attached to BclA through GalNAc. We named the novel nonreducing terminal sugar of the 715-Da tetrasaccharide anthrose. We subsequently proposed a plausible anthrose biosynthetic pathway and identified a gene cluster of four continuous genes that appeared to encode …

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Lens Cataract: Biochemical Analysis Of The Alpha Crystallins, David Ray Stella Jan 2010

Lens Cataract: Biochemical Analysis Of The Alpha Crystallins, David Ray Stella

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The cataract is a common ailment affecting the aged population. It appears over time and affects the quality of one’s life by the eventual loss of vision. Currently, there is no effective strategy to prevent or treatment to reverse the development of a cataract. As well, there is no consensus on one particular mechanism or sequence of events that contributes to its formation. In order to better understand the possible etiology of the cataract, it is necessary to define the biochemical changes that occur to lens proteins as one ages, as these are the key players in the prevention of …

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Exosomal Curcumin: Its Bioavailability And Potential Anti-Inflammation Activity, Dongmei Sun Jan 2010

Exosomal Curcumin: Its Bioavailability And Potential Anti-Inflammation Activity, Dongmei Sun

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Curcumin, a pleiotropic polyphenol derived from turmeric plants Curcuma Longa with rhizome, exhibits strong evidence as an anti-inflammation, anti-oxidant and anti-cancer reagent both in vitro and in vivo. Due to its low stability and systemic bioavailability, a large amount of curcumin has to be administrated to achieve therapeutic effects both in animal and in human. The major effort to overcome this barrier is making by encapsulation of curcumin into nanoparticles such as polymers and liposomes; some promising data have demonstrated the effectiveness of such method. Exosomes are vesicle-like nanoparticles secreted by living cells. Exosomes contain both cell surface molecules and …

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Structural And Functional Study Of P58(Ipk), Jiahui Tao Jan 2010

Structural And Functional Study Of P58(Ipk), Jiahui Tao

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P58(IPK) is an endoplasmic reticulum (ER)-resident protein which is upregulated during unfolded protein response (UPR). In stressed cells, P58(IPK) functions to restore protein folding equilibrium in ER by suppressing protein aggregation and promoting protein folding. P58(IPK) associates with the unfolded protein via its N-terminal TPR domain and presents it to BiP (binding immunoglobulin protein) for subsequent folding. P58(IPK) belongs to the Hsp40 family. Collectively, P58(IPK) is a stress-inducible ER-resident molecular chaperone. In this dissertation, we report the crystal structure of P58(IPK) TPR domain to 2.5 Å resolution. In the crystal structure, the 43-kDa TPR domain consists of nine tandemly linked …

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Roles Of Adiponectin And Its Receptors In Foam Cell Transformation, Ling Tian Jan 2010

Roles Of Adiponectin And Its Receptors In Foam Cell Transformation, Ling Tian

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Macrophages play a critical role in the initiation and progression of atherosclerosis by producing pro-inflammatory mediators and transforming into lipid-laden foam cells. The prevention of lipid accumulation and inflammation in macrophage foam cells, therefore, represents a promising target for effective therapy for atherosclerosis. Adiponectin is a circulating cytokine primarily expressed and secreted by adipocytes, and is downregulated in obesity-linked diseases including type 2 diabetes, coronary artery disease and hypertension. In oxidized low-density lipoprotein (oxLDL)-induced human THP-1 macrophage foam cells, adiponectin suppresses lipid accumulation through decreasing lipid uptake and increasing high-density lipoprotein (HDL)-mediated lipid efflux. The potential mechanisms that adiponectin utilizes …

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One Of Us Is Gay, Timothy Alan Tipton Jan 2010

One Of Us Is Gay, Timothy Alan Tipton

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This is an original work of creative nonfiction centered on the challenges of living a gay lifestyle during the early years of the AIDS crisis. This work is primarily a memoir, engaging real life events and people, crafted into a chronicle of everyday life in the deep South of the mid 1980s and early 1990s. Aspects of gay life are exposed through the lense of the author's relationship with his first partner. One of Us is Gay provides a graphic exposé of the journey that a young man takes through the vulnerable and innocent awareness of his homosexuality, to the …

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Red Blood Cell And Hemoglobin Dependent Modulation Of Reactive Species Metabolism: Implications For Vascular Homeostasis, Dario A. Vitturi Jan 2010

Red Blood Cell And Hemoglobin Dependent Modulation Of Reactive Species Metabolism: Implications For Vascular Homeostasis, Dario A. Vitturi

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The recent discovery that red blood cells might mediate hypoxic blood flow together with accumulating evidence that suggests a role for the modulation of vascular inflammation has reshaped the way we think about the function of these cells. In this thesis we investigate the mechanisms that regulate these newly appreciated functions and focus on i) the ability of red cells to couple oxygen sensing with nitrite reduction and nitric oxide formation and ii) the role of the beta93cys, a conserved residue amongst mammalian hemoglobins and whose function remains unclear. Data will be presented that demonstrate that nitrite reduction to nitric …

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Pre-Disaster Planning For Transportation Infrastructure Recovery, Stephanie Victoria Watson Jan 2010

Pre-Disaster Planning For Transportation Infrastructure Recovery, Stephanie Victoria Watson

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The US is dependent upon a functioning transportation network for many aspects of daily life, and those aspects that become largely important during times of disaster. For example, emergency medical response is a crucial activity that relies upon a functioning transportation network during regular daily operations as well as during times of emergency. The US has experienced several natural and manmade devastating events within the past decade including the September 11, 2001 terrorist attacks, Hurricanes Ivan, Katrina and Rita, and record flooding in Tennessee. When disasters occur, the potential of disrupting various infrastructures either individually or simultaneously exists. During a …

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Role Of The Human Cytomegalovirus Tegument Protein Pp150 In The Trafficking And Assembly Of Infectious Virions, Sabarish Vellatheri Indran Jan 2010

Role Of The Human Cytomegalovirus Tegument Protein Pp150 In The Trafficking And Assembly Of Infectious Virions, Sabarish Vellatheri Indran

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Human cytomegalovirus, a ubiquitous human pathogen, establishes a persistent infection in the infected host. HCMV assembly takes place in the nucleus and cytoplasm of infected cells by a complex and incompletely defined process. The viral DNA is enclosed by the capsid, which is surrounded by a proteinaceous tegument, which is covered by a cell-derived envelope studded with viral glycoproteins. The assembly pathway and protein interactions required for formation of the tegument layer and the function of most of the proteins in the tegument remain poorly understood. In this study, we investigated the functions of an essential abundant tegument protein, pp150, …

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Molecular Mechanisms Of Hepatic Insulin Resistance Following Injury, Shaoning Jiang Jan 2010

Molecular Mechanisms Of Hepatic Insulin Resistance Following Injury, Shaoning Jiang

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Insulin resistance commonly occurs following injuries or critical illness independent of previous diabetic status. The development of insulin resistance and hyperglycemia is associated with increased mortality and morbidity in critically ill patients. However, the molecular mechanisms underlying the acute insulin resistance following injuries remain poorly understood. With an animal model of trauma and hemorrhage, we have previously demonstrated the rapid development of insulin resistance in liver, and a critical role of TNFα in hemorrhage-induced defects in insulin signaling following resuscitation. However, hepat-ic insulin signaling is impaired prior to a significant increase in plasma TNFα, suggesting the initial development of hemorrhage-induced …

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In Vitro Elucidation Of The Role And Mechanism Of Rankl In Tnf-And Il-1-Mediated Osteoclast Formation And Function, Joel Jules Jan 2010

In Vitro Elucidation Of The Role And Mechanism Of Rankl In Tnf-And Il-1-Mediated Osteoclast Formation And Function, Joel Jules

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The receptor activator of NF-қB (RANK) ligand (RANKL) and its receptor RANK play a critical role in osteoclast biology. RANK has three tumor necrosis factor receptor associated factor (TRAF)-binding motifs [PFQEP369-373 (Motif 1), PVQEET559-564 (Motif 2), and PVQEQG604-609 (Motif 3)] that regulate osteoclast formation and function. RANK also contains a TRAF-independent motif (IVVY535-538) that commits bone marrow macrophages (BMMs), which are osteoclast precursors, to the osteoclast lineage for osteoclastogenesis. Notably, tumor necrosis factor-α (TNF) and interlukin-1 (IL-1) utilize TRAFs to initiate most of the signaling pathways known to be activated by RANKL but fail to form osteoclasts unless attended by …

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The Role Of The Intracellular Signaling Pathway In Ehrlichia Canis Infection In Vitro, Chang-Hyun Kim Jan 2010

The Role Of The Intracellular Signaling Pathway In Ehrlichia Canis Infection In Vitro, Chang-Hyun Kim

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Ehrlichia canis is a pleomorphic obligatory intracellular gram-negative bacterium that causes tick-borne canine ehrlichiosis. A systematic investigation on the pathogenesis of the disease has been hindered largely by lack of a reliable quantitative assay. Using quantitative real time PCR (qPCR), a quantitative assay for E. canis was developed and validated. Using the qPCR, the intracellular proliferation kinetics of E. canis in the canine 030F cell-line was studied for the first time. Many intracellular bacterial pathogens have been shown to use Ca2+ signaling in the host cells to induce their own internalization and proliferation. However, it is not clear how Ca2+ …

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Identification And Characterization Of Downstream Target Genes Of The Bmp Signaling Pathway, Nam Chul Kim Jan 2010

Identification And Characterization Of Downstream Target Genes Of The Bmp Signaling Pathway, Nam Chul Kim

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During nervous system development, neurons proliferate, differentiate, project their axons to their targets and make synapses with them. At the neuromuscular junction of Drosophila, these functional synapses enlarge as the body grows to maintain physiologically effective synaptic transmission with the muscles. Drosophila Bone Morphogenetic Protein (BMP) type II receptor, Wishful thinking (Wit), is important in this proper synaptic growth and function. To identify transcriptional targets of Wit signaling, we performed microarray experiments comparing normal controls to wit mutants. Through this study, we found that some of the verified target genes showed isoform-specific regulation in wit mutants, and that several neuropeptide …

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Development Of A Multiscale Material Model For Brain Tissue And Its Application To The Impact Response Of The Human Head, Sandeep Kulathu Jan 2010

Development Of A Multiscale Material Model For Brain Tissue And Its Application To The Impact Response Of The Human Head, Sandeep Kulathu

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The development of a finite element model capable of predicting brain injury sustained as a result of an impact load to the head is of considerable importance not only for the development of adequate protection systems but also in deciding an appropriate mode of treatment for an individual. With advancements in imaging technologies, it is now possible to visualize the neuron fiber structures in the brain. In the first half of this project, an analytical micro-mechanical model was developed from the individual isotropic behaviors of the Cerebro-Spinal Fluid (CSF) and brain tissue present in the brain, such that the resultant …

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Identification And Characterization Of Virulence Factors Of Mycoplasmas, Wenyi Luo Jan 2010

Identification And Characterization Of Virulence Factors Of Mycoplasmas, Wenyi Luo

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Mycoplasmas cause a group of diseases that are characterized by their chronicity and resistance to treatment. Diseases caused by the murine pathogens Mycoplasma pulmonis and Mycoplasma arthritidis are often studied as models of human diseases caused by a variety of chronic pathogens that induce a similar pathology. Among several candidate pathogenic factors, superantigens and degradative enzymes such as glycosidases are potentially important but not well characterized. The M. arthritidis mitogen (MAM) is a superantigen secreted by M. arthritidis. Its role with respect to arthritogenicity and toxicity is unclear. To improve the efficiency of transformation and hence enhance efforts to generate …

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Lim Kinase 1 And Twinstar In Synaptic Plasticity Of Drosophila Motoneurons, James Brian Machamer Jan 2010

Lim Kinase 1 And Twinstar In Synaptic Plasticity Of Drosophila Motoneurons, James Brian Machamer

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Modification of the actin cytoskeleton is essential for synaptic plasticity, which is believed to underlie the brain's capacity for learning and memory. Regulation of the actin cytoskeleton by LIM Kinases (LIMK1 and LIMK2) and their downstream targets Actin Depolymerization Factor/Cofilin (ADF/Cofilin) in the mouse forebrain modulates dendritic spine morphology, synaptic function, long-term potentiation (LTP), and learning and memory, but appear dispensable for the regulation of most forms of presynaptic plasticity. However, these analyses were performed in mice mutant for single members of these gene families, and thus the interpretation of these results is confounded by potential compensatory activity of homologous …

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A Comparative Study Of Radiological Threat Environments And Radiation Control, Lisa C. Mccormick Jan 2010

A Comparative Study Of Radiological Threat Environments And Radiation Control, Lisa C. Mccormick

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Radiation Control Programs (RCPs) differ from state to state as does their integration with public health agencies. The purpose of this study was threefold: to describe and compare across states the environmental radiological attributes of RCPs, to describe how these programs are organized structurally within state government, and to identify if RCPs differ structurally in environments of differing radiological attributes. Publicly available information from the Nuclear Regulatory Commission and state agency websites was used to determine both the environmental attributes and the different approaches states use to organize RCPs. States were grouped based on environmental attributes by employing a principle …

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Specialization And Integration Of Brain Responses To Object Recognition And Location Detection, Mark Ryan Pennick Jan 2010

Specialization And Integration Of Brain Responses To Object Recognition And Location Detection, Mark Ryan Pennick

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Visual information in the brain is processed by two distinct pathways, the dorsal and the ventral visual streams, which operate in a parallel and distributed manner. While the dorsal stream, associated with locating objects in space, extends from the occipital towards the parietal lobe, the ventral stream, associated with recognizing objects, projects from occipital to the temporal lobes (Ungerleider & Mishkin, 1982). This division of labor evidenced from lesion studies in monkeys may be rather reductionistic in the context of humans where the experience-driven knowledge base is rich and may prompt neural integration (Mesalum, 2008). The present fMRI study investigated …

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Regulation Of Glycogen Synthase Kinase 3 In The Pathophysiology And Treatment Of Mood Disorders, Abigail Marie Polter Jan 2010

Regulation Of Glycogen Synthase Kinase 3 In The Pathophysiology And Treatment Of Mood Disorders, Abigail Marie Polter

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Mood disorders are devastating psychiatric illnesses that will affect as many as one in every five persons worldwide over the course of their lifetime. Significant gaps still remain in our understanding of these illnesses and outcomes for many patients are far from optimal. Glycogen Synthase Kinase 3 (GSK3) is a protein kinase that is increasingly recognized as playing an important role in a number of neuronal functions, as well as in pathological states such as mood disorders. GSK3 is inhibited in the brain by phosphorylation on an N-terminal serine. Several treatments for mood disorders, including lithium, antidepressants, and atypical antipsychotics …

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Response Dynamics Of Retinal Ganglion And Early Visual Cortical Cells To Simulated Optical Blur, Michael Lance Risner Jan 2010

Response Dynamics Of Retinal Ganglion And Early Visual Cortical Cells To Simulated Optical Blur, Michael Lance Risner

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Visual neurons are highly sensitive to changes in luminance around the mean level of light. The effects of changes in luminance contrast on the responses of retinal ganglion cells (RGCs) and V1 neurons have been extensively studied. Sharp transitions in luminance signify edges, which are key features in the visual environment. However, edges are rarely sharp and may be blurred. Edges are generally blurred because eyes have a restricted depth of field, sources of light are rarely point sources, edges are typically smooth, and rapid motion induces blur. The purpose of this research was to understand how RGCs and V1 …

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Heparanase Drives The Aggressive Myeloma Phenotype: Preclinical Development Of A Heparanase Inhibitor For The Treatment Of Multiple Myeloma, Joe Ritchie Jan 2010

Heparanase Drives The Aggressive Myeloma Phenotype: Preclinical Development Of A Heparanase Inhibitor For The Treatment Of Multiple Myeloma, Joe Ritchie

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Heparanase, an endoglycosidase which cleaves heparan sulfate chains at specific sites, is rarely expressed in normal tissues but becomes evident in many human cancers. We have previously shown that heparanase promotes myeloma growth and angiogenesis through modulation of the tumor microenvironment. Recognition that heparanase drives the aggressive myeloma phenotype has led to new strategies designed to therapeutically target this enzyme. SST0001, a non-anticoagulant heparin that is 100% N-acetylated and 25% glycol split, was previously described as a potent inhibitor of heparanase activity in vitro, and, in limited in vivo experiments, SST0001 was identified to have efficacy as an anti-tumor agent …

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Therapeutic Interventions For Chlorine Gas Induced Lung Injury, Amit Kumar Yadav Jan 2010

Therapeutic Interventions For Chlorine Gas Induced Lung Injury, Amit Kumar Yadav

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Rationale: Nitrite (NO2-) has been shown to limit injury to the heart, liver and kidneys in various models of ischemia-reperfusion injury. Currently, potential protective effects of systemic NO2- in limiting lung injury or enhancing repair have not been documented. Objectives: To assess the efficacy and mechanisms by which post-exposure intra-peritoneal injections of NO2- mitigate Cl2 induced lung injury in rats. Methods: Rats were exposed to Cl2 (400 ppm) for 30 minutes and returned to room air. Nitrite (1mg/Kg) or saline were administered intraperitoneally at 10 min, 2, 4 and 6 hrs post exposure. Rats were sacrificed at 6 hrs or …

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