Medical Sciences Commons^™

Plasma Insulin-Degrading Enzyme: Characterisation And Evaluation As A Potential Biomarker For Alzheimer's Disease, Michelle Tegg

Theses: Doctorates and Masters

Alzheimer’s disease (AD) is increasing in prevalence due to increasing lifespan and altered lifestyle. It is the fourth major cause of death in Western countries, resulting in significant economic and social impact (Von Strauss, et al., 1999; Goate, 1997). There are no blood biomarkers currently accepted for the diagnosis of AD, and the identification of suitable biomarkers would eventually reduce the necessity for invasive, expensive and slow diagnostic procedures, as well as facilitate prognostic studies. An AD blood test would decrease the need for delaying diagnosis due to ambivalent presentation, and allow therapeutic intervention to commence at an earlier …

Three‐Dimensional Brain Mri For Dbs Patients Within Ultra‐Low Radiofrequency Power Limits, Subhendra N. Sarkar, Efstathios Papavassiliou, David Hackney, David Alsop, Ananth Madhuranthakam, Ludy Shih, Reed Busse, Susan Laruche, Rafeeque Bhadelia

Publications and Research

Background: For patients with deep brain stimulators (DBS), local absorbed radiofrequency (RF) power is unknown and is much higher than what the system estimates. We developed a comprehensive, highquality brain magnetic resonance imaging (MRI) protocol for DBS patients utilizing three-dimensional (3D) magnetic resonance sequences at very low RF power. Methods: Six patients with DBS were imaged (10 sessions) using a transmit/receive head coil at 1.5 Tesla with modified 3D sequences within ultra-low specific absorption rate (SAR) limits (0.1 W/kg) using T2, fast fluid-attenuated inversion recovery (FLAIR) and T1- weighted image contrast. Tissue signal and tissue contrast from the low-SAR images …

Hypothesis Testing In Normal Admixture Models To Detect Heterogeneous Genetic Signals, Qian Fan, Richard Charnigo, Zohreh Talebizadeh, Hongying Dai

Manuscripts, Articles, Book Chapters and Other Papers

In this work we consider a three-component normal mixture model in which one component is known to have mean zero and the other two contaminating components have a nonnegative and a nonpositive mean respectively, while all three components share a common unknown variance parameter. One potential application of this model may be in prioritizing statistical scores obtained in biological experiments, including genetics data. Such a mixture model may be useful in describing the distribution of numerous Z test statistics corresponding to different genes or SNPs, such that a “significant” Z test statistic for a particular gene suggests its connection to …

Fluid Flow Shear Stress Over Podocytes Is Increased In The Solitary Kidney., Tarak Srivastava, Gianni E. Celsi, Mukut Sharma, Hongying Dai, Ellen T. Mccarthy, Melanie Ruiz, Patricia A. Cudmore, Uri S. Alon, Ram Sharma, Virginia A. Savin

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Glomerular hyperfiltration is emerging as the key risk factor for progression of chronic kidney disease (CKD). Podocytes are exposed to fluid flow shear stress (FFSS) caused by the flow of ultrafiltrate within Bowman's space. The mechanism of hyperfiltration-induced podocyte injury is not clear. We postulated that glomerular hyperfiltration in solitary kidney increases FFSS over podocytes.

METHODS: Infant Sprague-Dawley rats at 5 days of age and C57BL/6J 14-week-old adult mice underwent unilateral nephrectomy. Micropuncture and morphological studies were then performed on 20- and 60-day-old rats. FFSS over podocytes in uninephrectomized rats and mice was calculated using the recently published equation …

American And Brazilian Children With Primary Urolithiasis: Similarities And Disparities., Maria Goretti Moreira Guimarães Penido, Marcelo De Sousa Tavares, Milena Maria Moreira Guimarães, Tarak Srivastava, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

Objectives. Considering the differences in location, socioeconomic background, and cultural background, the aim of this study was to try to identify possible factors associated with the increased incidence of urolithiasis by comparing American and Brazilian children with stones.
Methods. Data of 222 American and 190 Brazilian children with urolithiasis were reviewed including age, gender, body mass index, imaging technique used (ultrasound and computed tomography), and 24-hour urine volume and chemistries.
Results. There were no differences between age and gender at diagnosis. Brazilian children were leaner but in no population did obesity rate exceed that of the general population. Ultrasound was …

Extending The Indications Of Flow Diversion To Small, Unruptured, Saccular Aneurysms Of The Anterior Circulation., Nohra Chalouhi, Md, Robert M Starke, Steven Yang, Cory D Bovenzi, Stavropoula Tjoumakaris, David Hasan, L. Fernando Gonzalez, Robert H. Rosenwasswer Md, Pascal Jabbour Md

Department of Neurosurgery Faculty Papers

BACKGROUND AND PURPOSE: Flow diverters are currently indicated for treatment of large and complex intracranial aneurysms. The purpose of this study was to determine whether the indications of flow diversion can be safely extended to unruptured, small, saccular aneurysms (<10 >mm) of the anterior circulation.

METHODS: Forty patients treated with the pipeline embolization device (PED) were matched in a 1:4 fashion with 160 patients treated with stent-assisted coiling based on patient age, sex, aneurysm location, and aneurysm size. Procedural complications, angiographic results, and clinical outcomes were analyzed and compared.

RESULTS: The rate of periprocedural complications was 5% in the PED …

The Quetiapine Active Metabolite N-Desalkylquetiapine And The Neurotensin Nts1 Receptor Agonist Pd149163 Exhibit Antidepressant-Like Effects On Operant Responding In Male Rats, Todd M. Hillhouse, Zachary Shankland, Katelin S. Matazel, Ashley Keiser, Adam J. Prus

Journal Articles

Major depressive disorder (MDD) is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that are apparent following one week of quetiapine treatment, and it is possible that the active metabolite N-Desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS₁ receptor agonist PD149163 are suggestive of antidepressant efficacy, but the effects of a NTS …

Neurobiological Mechanisms That Contribute To Stress-Related Cocaine Use, John R. Mantsch, Oliver Vranjkovic, Robert C. Twining, Paul J. Gasser, Jayme R. Mcreynolds, Jordan M. Blacktop

Biomedical Sciences Faculty Research and Publications

The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the …

Osteoblast And Odontoblast Specific Regulatory Actions Of Runx2 For The Development Of Mineralized Tissues, Mitra Darice Adhami

All ETDs from UAB

The Runx2 transcription factor is necessary for commitment and differentiation of mesenchymal cells into the chondroblasts, osteoblasts and odontoblasts. Runx2 induces the expression of several key genes involved in mineralization of both the bone and dentin matrices. Global Runx2-null mice are completely void of mineralized tissue and do not express osteoblast markers, indicating that Runx2 is required for commitment to the osteoblast lineage. Tooth development in Runx2-null mice is arrested in the bell stage, prior to the differentiation of odontoblasts. Thus, Runx2 is essential for development of osteoblast and odontoblast lineages. However, the functional requirements of Runx2 after commitment to …

Modulating The Cxcl12/Cxcr4 Axis In The Pulmonary Vasculature By Adenoviral Vector-Mediated Delivery Of Soluble Cxcr4 (Scxcr4): A Prophylactic Approach To The Prevention Of Cancer Metastasis To The Lung, Anand Chandrasekaran Annan

All ETDs from UAB

The results also indicate that in situ nests were cooler than egg corral nests but still

Assessing The Active Kinome Of Influenza Virus Infected A549 Cells, Colm Atkins

All ETDs from UAB

Influenza A Virus is a respiratory pathogen of the family Orthomyxoviridae and causes significant worldwide morbidity and mortality during seasonal epidemics and periodic pandemics. As with all viruses, influenza's limited coding capacity requires the use of host proteins and processes in its replication and release cycle. Phosphorylation, mediated by cellular kinases and phosphatases, represents a significant mechanism of post-translational modification of cellular products, and is responsible for regulating the activi-ty, lifespan and localization of many lipids and proteins in host-cells. Several cellular kinases have been associated with various steps of the Influenza lifecycle, including PKC-ßII (viral entry), PKR (host defense), …

Mitochondrial Genetics Modify Body Composition, Metabolic Efficiency And Myocardial Metabolism, Kimberly Joanne Dunham-Snary

All ETDs from UAB

Obesity and cardiometabolic pathologies have reached epidemic levels worldwide over the last 30 years. Currently, the majority of research investigating possible genetic causes of obesity is focused on nuclear DNA (nDNA). While this has lead to the development of numerous animal models, it is apparent the etiology of obesity is more complex than single gene mutations. Recently it has also been suggested that mitochondrial DNA (mtDNA) mutations sustained during evolution as a consequence of our prehistoric environment may influence individual propensity and risk of disease. Contemporary human populations are no longer faced with the challenges of our ancestors such as …

Francisella Tularensis Lvs Invasion Of Primary Murine Macrophages And Mtor Signaling, Michael Warren Edwards

All ETDs from UAB

Francisella tularensis is an intracellular pathogen and the etiologic agent of tularemia. Because virulent strains cause morbidity and lethality in human, the attenuated live vaccine strain (LVS) has been used to study F. tularensis pathogenesis in murine models, since the disease in mice resembles human tularemia. Despite growing knowledge about host responses to Francisella infection, there is scarce information on the cell signaling events involved in Francisella host cell entry and in early immune re-sponses. Therefore, the purpose of this dissertation was to assess the involvement of the mammalian target of rapamycin (mTOR) in these processes. First, we evaluated the …

Characterization Of Glycosylation-Associated Protein, Gap2, Required For The Biogenesis Of Streptococcus Parasanguinis Fimbriae-Associated Protein, Fap1, Haley Echlin

All ETDs from UAB

Streptococcal species possess a multitude of adhesins that facilitate adherence to a wide range of substrates; this is the first step necessary for the development of disease. Streptococcus parasanguinis is a primary colonizer of the oral cavity and adheres to the tooth surface using long fimbriae, which are composed of Fap1, a serine-rich repeat glycoprotein (SRRP). SRRPs are conserved in many Gram-positive bacteria and play a role in bacterial adhesion, fimbrial formation, biofilm formation, and bacterial pathogenesis. Although SRRPs play such an important role, the exact mechanism of their biogenesis remains a mystery. For Fap1, an eleven gene cluster is …

The Role Of Wnt5a In Tumor Suppression And Differentiation, Stephanie Easter

All ETDs from UAB

TGF-beta and the Wnt signaling pathways play key roles in regulating ductal growth and branching morphogenesis in the mammary gland. Disruption to this signaling can cause deregulation of the normal mammary stem cell population and foster an environment favorable for tumorigenesis and recurrence. Recent studies show that TGF-beta up-regulates expression of the non-canonical Wnt, Wnt5a, in the mammary gland and that Wnt5a antagonizes canonical Wnt/beta-catenin signaling in mammary epithelial cells. Canonical Wnt/beta-catenin signaling has been strongly implicated in expanding the mammary stem/progenitor cell pool. Here, we test the hypothesis that Wnt5a suppresses the expansion of the mammary stem and progenitor …

The Expression And Function Of Icam-2 In Neuroblastoma, Joseph Feduska

All ETDs from UAB

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for 15% of all childhood cancer deaths. At the time of initial diagnosis, the majority of patients present with NB that has already metastasized. While initial remission is often achieved following treatment, roughly 50% of these patients will relapse and die from the development of intractable metastatic progression. Intercellular adhesion molecule-2 (ICAM-2) is a transmembrane glycoprotein, normally expressed only in endothelial cells and subsets of leukocytes. ICAM-2 expression in cancer cells had not been previously investigated, until our lab recently reported the novel finding of endogenous ICAM-2 expression …

Mitochondrial Genetics And Cellular Metabolism Regulate Tumorigenicity And Metastatic Potential, Kyle Paul Feeley

All ETDs from UAB

Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors combine to influence an individual's predilection for breast cancer and related metastatic tumor formation. The genetic component, in particular, has become the focus of many emergent studies. A renewed focus on cancer metabolism and the Warburg effect has similarly cast a spotlight on the role, if any, of the mitochondrion in directing disease progression. Analysis of the direct contribution of mitochondrial DNA on tumorigenicity is made possible through the use of mitochondrial-nuclear exchange (MNX) mice in which nuclei from normal FVB mice (the background strain of the tg: …

Elucidating The Role Of Gsk3 In Synaptic And Cognitive Deficits In Fragile X Syndrome, Aimee Vinson Franklin

All ETDs from UAB

Fragile X Syndrome (FX) is the most common inherited form of mental retarda-tion. Prominent characteristics of FX are mimicked in a mouse model with deleted fmr1 including hyperactivity, anxiety, developmental delay and social deficits. Additionally, FX mice display deficits in n-methyl-d-aspartate receptor (NMDAR) dependent long-term potentiation (LTP) at medial perforant path synapses onto dentate granule cells (MPP-DGC synapses). Because LTP is a cellular correlate of learning and memory, defi-cits in LTP at this synapse are thought to underlie impairments in pattern separation, a form of learning and memory dependent on proper DG function. Identifying the patho-logical mechanisms that cause impaired …

Tumorgraft Models As A Platform For Molecular Characterization And Drug Evaluation In Pancreaticobiliary Malignancies, Patrick Lee Garcia

All ETDs from UAB

arribada nesting behavior. The first chapter addresses the potential effects of a nest’s

Using Mce4 Sirna Molecular Beacons For Detection And Eradication Of Mycobacterial Infection In Macrophages, Remo George

All ETDs from UAB

temperatures. The third chapter represents the most comprehensive evaluation to date of

Innate Immune Defense Against The Fungal Pathogen Aspergillus Fumigatus, Melissa Ann Gessner

All ETDs from UAB

The opportunistic fungal pathogen Aspergillus fumigatus is a ubiquitous mold that causes severe, invasive life-threatening infections in patients that are severely immunocompromised. Major risk factors include neutropenia, neutrophil dysfunction and immunosuppressive therapies. Recently, however, rising incidences of colonizing A. fumigatus have been reported in patients without classical risk factors. We sought out to elucidate non-classical pre-disposing conditions that may render a lung environment susceptible to fungal colonization as well as mechanisms involved in immune defense against the invading fungal pathogen. Further defining a role for Dectin-1 in an Aspergillus fumigatus infection, we demonstrated a critical role for Dectin-1 dependent interleukin-22 …

Mitochondrial Dysfunction In Response To Neurotoxins And The Role Of Mitophagy, Samantha Giordano

All ETDs from UAB

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Two major factors in both familial and sporadic PD are mitochondrial dysfunction and insufficient autophagy. My thesis research focuses on the interplay between these activities in PD. To investigate the common and differential effects of PD-inducing neurotoxins on mitochondrial bioenergetics and their relationships to cell survival, we used an in vitro culture system, differentiated dopaminergic SH-SY5Y neuroblastoma cells. We found that the neurotoxins rotenone, 1-methyl-4- phenylyridinium (MPP+) and 6-hydroxydopamine (6-OHDA), decreased mitochondrial respiration and induced cell death in these cells. The extent and characteristics of mitochondrial dysfunction in response to …

Regulation Of Skeletal Muscle Plasticity Using Engineered Configurations Of The Transcription Factors Myod And E12, Vladimir Grubisic

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Skeletal muscle fibers, although terminally differentiated, can change their features, such as contraction speed and endurance, and throughout adult life in response to variety of stimuli, like exercise. This process is called plasticity and is mainly regulated by the type of nerve activity. Over the past several decades, research has shown that the properties of myofibers are also determined during muscle development. Ultimately, the change in phenotype requires a change in gene expression which is, in turn, regulated by transcription factors (TFs). Basic helix-loop-helix (bHLH) TFs regulate myogenesis and the central role belongs to the myogenic differentiation 1 (MyoD), often …

Determining The Role Of Neuregulin-1 And Its Erbb Receptors In The Pathogenesis Of Malignant Peripheral Nerve Sheath Tumors, Stephanie Brosius

All ETDs from UAB

Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in patients with neurofibromatosis type-1. These aggressive, Schwann cell-derived tumors have no treatment beyond surgical resection. Developing targeted chemotherapeutics remains crucial to improving patient survival. The Schwann cell mitogen neuregulin-1 (NRG1) was shown to mediate the migration, proliferation and survival of MPNSTs. Furthermore, overexpression of NRG1 in Schwann cells (P0-GGF beta 3 mice) on an outbred C57BL/6J x SJL/J background induced the formation of neurofibromas and MPNSTs similar to human disease, yet these mice have intact neurofibromin. To determine if NRG1 acts within the same signaling cascade …

Cd5-Dependent Ck2 Activation Is Critical For The Maintenance Of B-1a B Cells, Kevin S. Cashman

All ETDs from UAB

CD5 has classically been shown to act as a negative regulator of antigen receptor signaling, however recent evidence has discerned that the CD5 molecule contains a previously undefined cytoplasmic domain which constitutively binds inactive CK2 and facilitates its activation through CD5 ligation. With the development of a mouse model which contains a micro-deletion knock-in form of CD5 which lacks the amino acids necessary to facilitate this CD5-CK2 interaction, it is now understood that CD5 plays a more significant role in cellular physiology than previously appreciated. T cells from this mouse model show increased AICD and dysregulation in T helper subset …

Synaptic And Circuit Mechanisms Of Glutamate Spillover Signaling, Luke Teichert Coddington

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Glutamate is the most prominent fast excitatory neurotransmitter released at mammalian central synapses, where point-to-point activation of receptors in postsynaptic densities is accepted to be the primary pathway for information flow through neural circuits. More controversial are the activities of synaptically-released glutamate outside the synaptic cleft of origin, as "spillover" glutamate may signal through neighboring synapses or through extrasynaptic receptors. The role of such extrasynaptic signaling in physiological neuronal communication is unproven and its inappropriate occurrence has been proposed to underlie a range of neurodegenerative conditions. Elucidation of spillover signaling mechanisms thus benefits our understanding of the brain in both …

Il-8 Is Necessary And Sufficient For X-Ray Radiation Enhanced Endothelial Adhesion., Stephen Kyle Babitz

All ETDs from UAB

Ionizing radiation (IR) is a potent inflammatory stimulus to the human body. In the vasculature, inflammation is a major contributing factor for atherosclerosis. In addition, radiation from several sources has been linked with increased risk for multiple cardiovascular complications. A key compnent of radiation associated inflammation is an increase in the adhesiveness of the endothelium which leads to a pathogenic accumulation of leukocytes in the vascular wall. This is one of the initial steps in vascular inflammation and leads to a number of adverse complications such as heart disease and stroke. The molecular mechanisms behind radiaton enhanced endothelial adhesion have …

Targeted Delivery Of Osteoinductive Peptides To Bone Graft Utilizing A Calcium Binding Domain To Enhance The Regenerative Potential, Jennifer Leigh Bain

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Bone grafting procedures are common practice. Autogenous bone is considered optimal, however, complications associated with bone harvesting often lead clinicians to use off-the-shelf materials that have limited osteoinductivity. Alternatively, bioactive factors passively adsorbed onto various carriers are available. These materials, while effective, are expensive to produce, require supraphysiological doses, and have adverse side effects due to dissemination from the graft site. This dissertation aims to reintroduce osteoinductive factors to bone grafts to enhance regenerative capacity. Specifically, we utilized negatively-charged calcium-binding domains (polyglutamate) to anchor two osteoinductive peptides bone graft materials including an allograft, xenograft, alloplast, and bone cement. The peptides …

Recognition Of Hiv-1 Cryptic Epitopes During Infection And Following Vaccination, Anne Bet

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Cryptic epitopes (CE) are a unique set of human leukocyte antigen class I (HLA-I)-restricted peptides that are encoded by alternative reading frames (ARFs) of genes. During human immunodeficiency virus-1 (HIV-1) infection, CE translated from either sense or antisense transcripts elicit epitope-specific CD8 T cell responses. Previous studies using simian immunodeficiency virus (SIV)-vaccinated animals have shown that an increased breadth of CD8 T cell responses is correlated with controlling viral replication, therefore stressing the potential clinical benefit of vaccine-induced T cell responses to a diverse set of viral epitopes. Yet, the genetic profiles and immunological significance of CE remain poorly understood. …

The Modulation Of High Density Lipoprotein Metabolism In Systemic Lupus Erythematosus, Leland Latham Black

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Apolipoprotein A-I (ApoA-I), the major lipid-binding protein of high-density lipoprotein (HDL), can suppress inflammation and autoimmunity in hypercholesterolemic mice by modulating cellular cholesterol homeostasis and lipid oxidation. However, the cellular and molecular mechanisms involved are poorly understood, and whether ApoA-I or ApoA-I mimetic peptides can similarly exert immunosuppressive effects or improve inflammatory organ disease in SLE under normolipidemic conditions remains unresolved. We therefore first took a genetic approach in which bone marrow from SLE-prone Sle123 mice was transferred into wild-type, ApoA-I knockout (ApoA-I-/-) and ApoA-I transgenic (ApoA-Itg) mice. Transgenic expression of ApoA-I suppressed CD4+ T and B lymphocyte activation, reduced …