Medicine and Health Sciences Commons^™

Role Of The Lpa2 Receptor In Protecting Against Apoptosis, Shuyu E

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) is a naturally occurring lipid mediator. It exists abundantly in biological fluids such as serum, saliva, follicular fluid, seminal fluid and malignant effusions and induces a vast array of biological responses affecting cell growth, survival, differentiation, migration and morphology. We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. Based on computational modeling octadecenyl thiophosphate (OTP) was synthesized: a novel rationally designed, metabolically stabilized LPA mimic. OTP was more efficacious than LPA in reducing g-irradiation-, camptothecin-, or TNF-a/cycloheximide-induced apoptosis and caspase 3, 8 and 9 activity in the IEC-6 cell line. The …

Abcb6 Is A Porphyrin Transporter With A Novel Trafficking Signal That Is Conserved In Other Abc Transporters, Yu Fukuda

Theses and Dissertations (ETD)

The ATP-binding cassette (ABC) transporters play an important role as a barrier to protect cells from the accumulation of toxic xenobiotics and metabolites due to their ability to translocate a wide array of compounds across lipid bilayers. However, many ABC transporters, especially the ones localized in the intracellular organelles, are involved in critical biological processes such as antigen presentation. The core unit of ABC transporters contains two functional domains: the membrane spanning domain (MSD) and the nucleotide binding domain. The full transporters contain two of these units in tandem in a single polypeptide, whereas the half transporters only contain one …

Factors Affecting Long-Term Outcomes Following Intensive In-Home Services, Sarah Hurley

Theses and Dissertations (ETD)

Intensive in-home services (IIHS) work with families toward building skills and resources to better manage their children with behavioral difficulties. Factors that impact long-term outcomes following IIHS are not well understood. This study examined the relative importance of youth demographic and clinical characteristics, family history variables, characteristics of program participation, and organizational-level factors in explaining placement stability, educational progress, and contact with legal authorities one year following discharge from IIHS.

The sample included all youth who received IIHS, were discharged between January 1, 2001 and December 31, 2006, and completed a follow up at one-year post-discharge (n = 2,649) from …

Studies To Characterize The Requirements For The Binding And Release Of Erdj3, A Mammalian Er Dnaj Homolog, From Substrates, Yi Jin

Theses and Dissertations (ETD)

Heat shock protein 70s (Hsp70s) and their DnaJ co-factors exist in all organisms and in all eukaryotic organelles. These highly conserved chaperone pairs facilitate a large number of cellular processes. ERdj3 was identified as a soluble, lumenal DnaJ family member that binds to unassembled immunoglobulin heavy chains (HC) along with the BiP chaperone complex in the endoplasmic reticulum of mammalian cells. Here we demonstrate that ERdj3 binds directly to two unfolded substrates: immunoglobulin γHC and denatured firefly luciferase. Using mutagenesis studies on ERdj3 in both in vivo and in vitro binding assays, we defined ERdj3’s critical amino acids in domain …

The Tetraspanin Cd9 Localizes To Platelet-Platelet Contacts And Regulates Thrombus Stability, Sarah Kathleen Hill

Theses and Dissertations (ETD)

CD9, a member of the tetraspanin family, is highly expressed on platelets (50,000-80,000 copies per platelet). Tetraspanins have been implicated in modulation of integrin function, and it is hypothesized that CD9 will modulate GPIIb-IIIa, the major platelet integrin.

The association between CD9 and GPIIb-IIIa was analyzed using immunoprecipitations and confocal microscopy. These two proteins were found to associate with each other, particularly at areas of platelet-platelet contact and at the periphery. Confocal analysis revealed CD9 localization was most intense at platelet-platelet contact, as well as in platelet filopodia and lamellipodia, but there is a lack of CD9 at areas of …

Studies Of Entry, Reverse Transcription, And Regulation Of Splicing In Retroviruses, Timothy A. Sullivan

Theses and Dissertations (ETD)

The study of retroviruses and their lifecycle has contributed immensely to our knowledge of the world of biology and medicine. The central dogma of the basic flow of genetic information was shattered when the discovery that retroviruses copy their RNA genome into DNA was made. The same enzyme that performs this step, reverse transcriptase (RT), also revolutionized molecular biology when it was used as a tool to generate full length cDNA clones of expressed genes. The impact of retroviruses on the medical field has been extremely exciting as the ideas of using retroviral vectors to deliver genes providing long term …

Predictors Of Depressive Symptoms And Obesity In African American Women Transitioning From Welfare To Work, Mayola Rowser

Theses and Dissertations (ETD)

Depression and obesity are significant public health problems that adversely affect the health and quality of life of women in the United States, particularly female African American welfare recipients transitioning to work. African American women are twice as likely to experience depressive symptoms as women of other races. Fifty percent of African American women are obese. The prevalence of depression and depressive symptoms and obesity is higher among African American women who receive welfare benefits. These health conditions jeopardize their health status, ability to work, and chances to become self-sufficient. To ensure the successful transition of recipients to work, health …

Use Of Compliant Interbody Force Sensing Grafts To Compare Load Sharing Properties Of Unidirectional And Bidirectional Multilevel Dynamic Translational Anterior Cervical Plates, Jason Roscoe Roberson

Theses and Dissertations (ETD)

INTRODUCTION: Pseudoarthrosis is a relatively rare complication following anterior cervical arthrodesis, and is felt to be related to stress shielding. To address this, dynamic anterior cervical plates have emerged to maintain load sharing as an arthodesis matures. Dynamic plates can translate bidirectionally (allow translation in compressive and tensile loads), or unidirectionally (allow translation in compression, but maintain its position under tensile loads). The objective of this study was to compare the graft load mechanics between three plated conditions during settling using compliant interbody load cells: A static (fixed, non-moving) plate, a unidirectional multi-level translational plate design, and a bidirectional two-level …

Interaction Of Bacteriophage Mu Middle Transcription Activator Protein Mor With Promoter Dna, Kartik Iyer

Theses and Dissertations (ETD)

Gene expression during lytic development of bacteriophage Mu is regulated by a

transcriptional cascade in three phases: early, middle and late. Transcription from the middle promoter Pm requires the 129-amino acid transcriptional activator Mor, a product of early transcription, and the Escherichia coli RNA polymerase. The Pm promoter has a recognizable -10 hexamer but lacks a -35 hexamer. Mor binds as a dimer to an imperfect dyad-symmetrical element containing two 6-bp inverted repeats and centered at -43.5 in Pm. The goals of this study were:

1. To test the prediction from the crystal structure of Mor that residues Y70 and …

Investigation Of The Vesicular Stomatitis Virus Matrix Protein: Uncoating And Assembly, Chad E. Mire

Theses and Dissertations (ETD)

Vesicular Stomatitis Virus (VSV) is a simple, enveloped, nonsegmented negative-strand RNA virus and is the prototype rhabdovirus to study viral entry, transcription, replication, and assembly. The matrix protein (M) of VSV is a central component of the viral replication cycle. While being the smallest of the viral proteins it is multifunctional and is involved in uncoating, cytopathic effects (CPE), and assembly of the virus. M protein interactions involved in the uncoating and assembly of VSV have been examined in this dissertation.

Uncoating of VSV involves dissociation of M from the ribonucleoprotein core (RNPs) of the virus. Current models of VSV …

Manipulation Of The Moloney Murine Leukemia Virus Envelope Protein In An Effort To Develop Directly And Indirectly Targeted Retroviral Vectors For Use In Human Gene Therapy, Geneva M. Vasser

Theses and Dissertations (ETD)

Highly effective, targeted therapies against cancer would revolutionize the way people recover from this devastating illness. Gone would be the lingering side effects of the current non-specific treatments and in their place would be faster recovery times, better quality of life both during and after treatment, and less ambiguity about whether or not treatment was effective. This concept will elude modern medicine until treatments can be tailored to the patient's individual and unique disease. This concept of a transient, targeted, and tailored vehicle aimed at cancer cells lends itself to the use of replication deficient retroviral gene therapy vectors with …

C-Reactive Protein Polymorphism And Serum Levels As An Independent Risk Factor In Sickle Cell Disease, Elizabeth A. Chismark

Theses and Dissertations (ETD)

This study explored the relationship of a dinucleotide repeat polymorphism in the intron of the CRP gene and serum CRP levels as independent risk factors for end-organ dysfunction (mild vs. severe) in adults with sickle cell disease. The pathogenesis of secondary complications of sickle cell disease is complex and poorly understood. Predicting the severity of these complications could assist in therapeutic decision-making.

The study measured serum CRP levels and the number of CA intron repeats located on the CRP gene in 29 adults (31.74 ± 11.54 years) with sickle cell disease The hemoglobin genotypes were distributed as Hgb SS 48.6% …

Structure-Activity Relationship And Mechanistic Studies On The Chemopreventive Activity Of Dipyridamole And Its Analogues, Ja’Wanda Shavon Grant

Theses and Dissertations (ETD)

There is an escalating demand in the area of cancer prevention and control for the development of novel agents and molecular targets that have potential to reduce the incidence of cancer. In this study, the JB6 mouse epidermal cell-culture based transformation model was used in efforts to identify novel chemopreventive agents and targets. The nucleoside transport inhibitor dipyridamole (DPM) showed potent chemopreventive activity against JB6 P⁺cells (tumor promotion sensitive). To probe the effects of DPM structural features on its antitumor promotion activity, the soft-agar colony forming efficiency assay was used to screen an in-house library of …

The Relationships Among Adaptive Behaviors Of Children With Autism Spectrum Disorder, Their Family Support Networks, Parental Stress, And Parental Coping, Heather Roberts Hall

Theses and Dissertations (ETD)

Purpose: The purpose of this study was to examine the adaptive behaviors of children with Autism Spectrum Disorder (ASD), their family support networks, parental stress, and parental coping and the relationships among these variables.

Background: Autism is the fastest growing diagnosed developmental disorder. When parents receive a diagnosis of autism for their child, mothers and fathers are affected differently. The costs to families of children with autism are personal, social, and affect family finances and day to day living. Parents of a child with autism are at high risk for increased stress levels. The child’s socially unacceptable behaviors and communication …

Kinematic Demands Of Nucleus Arthroplasty Technology, Elizabeth J. Sander

Theses and Dissertations (ETD)

Recent advancements in biomaterial technologies have fostered growth in alternative surgical procedures to fusion surgery for treatment of early stages of degenerative disc disease. One application of immediate interest is that of nucleus arthroplasty (NA). Novel materials are being developed to better match the nonlinear biomechanical properties of the native tissue. The effects of changing the motion segment unit (MSU) properties via surgery (nucleotomy) or placement of a nucleus arthroplasty material, changes the effort or work required to move the altered spine condition through a prescribed kinematic path relative to the intact spine condition. The closer the loading mechanics of …

Regulation Of The Human Parainfluenza Virus (Hpiv3) Fusion Protein, Amanda Ruth Chapman

Theses and Dissertations (ETD)

Paramyxoviruses include a number of important human pathogens, including measles virus, mumps virus, and the human parainfluenza viruses (hPIV) 1-4, as well as several animal pathogens, such as Sendai virus, Nipah virus and Hendra virus. The creation of effective drugs and vaccines against this family of viruses would play an important role in decreasing the prevalence of these viruses and contributing to the health of both humans and animals worldwide. The purpose of this work was to determine how the fusion (F) protein is regulated with a focus on the heptad repeat B (HRB) region of the F protein located …

The Role Of Fgf Signaling In Retinal Development, Abbie A. Hartge

Theses and Dissertations (ETD)

The development of the retina is a precise balance between intrinsic competence and extrinsic factors. This interplay is known to regulate the generation of cell types in the developing retina and similar mechanisms have been found in other regions of the CNS. In the developing retina, FGFs are a large family of secreted polypeptide growth factors. Fgf15 is the major Fgf expressed during retinal development in mice. Fgf15 is an example of an FGF that has been shown to control proliferation, cell fate specification, differentiation and migration during development. In this thesis I used analysis of specific genes throughout retinal …

Structure- And Ligand-Based Design Of Novel Antimicrobial Agents, Kirk Edward Hevener

Theses and Dissertations (ETD)

The use of computer based techniques in the design of novel therapeutic agents is a rapidly emerging field. Although the drug-design techniques utilized by Computational Medicinal Chemists vary greatly, they can roughly be classified into structure-based and ligand-based approaches. Structure-based methods utilize a solved structure of the design target, protein or DNA, usually obtained by X-ray or NMR methods to design or improve compounds with activity against the target. Ligand-based methods use active compounds with known affinity for a target that may yet be unresolved. These methods include Pharmacophore-based searching for novel active compounds or Quantitative Structure-Activity Relationship (QSAR) studies. …

A Kinematics-Based Testing Protocol To Study The Mechanics Of The Human Lumbar Spine, Nephi A. Zufelt

Theses and Dissertations (ETD)

The objective of this work was to develop a new kinematics-based testing protocol to quantify the axial and shear force components and rotational moment properties of the human cadaveric lumbar motion segment unit (MSU) in response to specific kinematic inputs. Modern, non-fusion spinal devices claim to treat degenerative disc disease better than traditional fusion surgery. Though there have been many biomechanical studies completed on these devices, there is still a debate over their efficacy. Conventional testing methods provide insight into the rotational properties of the MSU but lack the sensitivity or capacity to quantify lumbar MSU’s mechanical properties including shear …

Synthesis And Evaluation Of Tetramic Acids As Antimicrobial Agents, Jason B. Wilson

Theses and Dissertations (ETD)

As bacterial infectious diseases are a major cause of morbity and mortality throughout the world, and many causative organisms are resistant to currently available antibiotics, the motivation for the development of new drugs is readily apparent. A number of natural products exhibiting antimicrobial activity possess a tetramic acid (2,4-pyrrolidinedione) functional group. As their antibacterial mechanism of action is different from that of many of the currently available antibiotics, these compounds have potential to serve as a basis for a pharmacophore in synthetic compounds. However, toxicity to eukaryotic cells is frequently a problem with currently known tetramic acids. The purpose of …

Torsina And The Pathophysiology Of Dyt1 Dystonia, Yu Zhao

Theses and Dissertations (ETD)

The goal of my dissertation work was to examine the systems biology of torsinA, a DYT1 dystonia-associated protein, by using rodent model systems. TorsinA is a putative ATPase associated with a variety of cellular activities (AAA+). Deletion of glutamic acid residue 302/303 in TOR1A is causally associated with many cases of early-onset primary dystonia.

In our work, transient forebrain ischemia and sciatic nerve transection were used as central and peripheral neural perturbations, respectively, to gain insight into the in vivo role(s) of torsinA. Moreover, transgenic mouse models that overexpress either human mutant torsinA (hMT) or wild-type torsinA (hWT) were used …

Controlled Release Of Insulin And Modified Insulin From A Novel Injectable Biodegradable Gel, Om Anand

Theses and Dissertations (ETD)

The objective of the study was to develop a controlled release dosage form of
insulin, which can provide basal concentrations of insulin in diabetic rats for 1 to 2 weeks after a single subcutaneous injection.
A biodegradable injectable drug delivery gel was prepared by dissolving a
biodegradable polymer, polylactic-co-glycolic acid (PLGA), in biocompatible
plasticizer(s), triethyl citrate (TEC) and/or acetyl triethyl citrate (ATEC). Insulin was
then loaded into the blank gel to form an insulin suspension in the polymer solution.
After the insulin-loaded gel was injected subcutaneously, the plasticizer(s) dissolved in the aqueous media and were gradually taken away from the …

The N-Terminal Domain Of The Y-Box Binding Protein Yb-1 Plays A Major Role In Cell Proliferation And Apoptosis, Payal Khandelwal

Theses and Dissertations (ETD)

Y-box binding protein, YB-1, is a member of the cold shock domain superfamily of proteins. It is involved in a plethora of cellular functions, including cell proliferation. The molecular mechanisms governing the involvement of YB-1 in cell proliferation are still unclear. Earlier studies done in chicken pre-B lymphocyte DT-40 cells in our laboratory have shown that a targeted disruption in one allele of chicken YB-1

(Chk-Yb-1b) gene at its N-terminal domain resulted in multiple abnormalities in the heterozygous mutants, including slower growth rate, abnormal cell morphology, increased cell size, increased genomic DNA content and significant changes in levels of cell …

Influence Of Tooth Crown Size On Malocclusion, Michael Kelly Agenter

Theses and Dissertations (ETD)

Malocclusion is an increasingly common, multifactorial problem in industrialized countries. Although the causes of dental malocclusion are obscure in most instances, one contributing factor may be tooth size. While several researchers have studied whether tooth size contributes to malocclusion, there still is no consensus. Some have found that the mesiodistal widths of the mandibular incisor teeth are significantly larger in subjects with anterior crowding, while others have been unable to support this conclusion. Study designs often have been confounded by combining the sexes, which confuses sexual dimorphism with the supposed effect of tooth size on crowding. The present study tested …

The Unfolded Protein Response Increases Production Of Pro-Angiogenic Factors By Tumor Cell Lines, Nan Liao

Theses and Dissertations (ETD)

The rapid growth and proliferation of tumor cells will be limited at a stage when they encounter inadequate levels of oxygen and nutrient supply within the poorly vascularized tumor mass. These severe conditions negatively affect the proper folding of nascent proteins in the endoplasmic reticulum (ER) and lead to accumulation of unfolded protein within ER which is referred to as ER stress. Consequently, it will trigger the unfolded protein response (UPR) signal pathway through ER membrane stress sensor proteins including activating transcription factor 6 (ATF6), inositol-requiring 1 (IRE1) and PKR-like ER localized kinase (PERK). The UPR is largely a cytoprotective …

An Analysis Of The Differences In Preemptive Kidney Transplantation Between Blacks And Whites, Kennard D. Brown

Theses and Dissertations (ETD)

Background. This cohort study investigates whether there are inequities in the allocation of cadaver kidneys for preemptive kidney transplants (PKT) between blacks and whites.

Methods. This analysis uses descriptive statistics and univariate and multivariate analyses to identify factors associated with the determination of whether a patient receives a PKT or a conventional, post dialysis kidney transplant. The sample includes patients identified by the Centers for Medicare and Medicaid Services (CMS) as having end stage renal disease (ESRD), >19 years of age, either black or white, and receiving either a PKT (0-<6 months dialysis) or conventional transplant between January 1, 2000 and December 31, 2003 (n = 10,067) from any of the 11 organ procurement regions in the United States.

Results. Whites were more likely to receive a PKT …

A Mechanical And Histological Study Of Functionally Graded Hydroxyapatite Implant Coatings, Suzanne Kemp Coco

Theses and Dissertations (ETD)

Ever since Dr. Brånemark discovered that titanium was biocompatible with bone, extensive research has been done to improve the osseointegration of dental implants. As advances in medicine continue, the average life span of the population is ever increasing. Today, people of all ages are investing more money and time into dental treatment than ever before. Patients are becoming more educated on dental treatment options and expect the best treatment possible. As a result, the replacement of missing teeth with implants is becoming more and more commonplace in dental practices.

The purpose of the present study is to evaluate bone-implant interaction …

Esthetic Evaluation Of Edgewise Orthodontic Treatment In Matched Class Ii, Division 1 Subjects, With And Without A Mara, Kelly-Gwynne Mason Fergus

Theses and Dissertations (ETD)

Orthodontics’ concern about facial esthetics has motivated the investigation of treatment options, and their effects, in hopes of discerning the optimal treatment for patients, both esthetically and functionally. In our efforts to determine the optimal treatment option for patients with Class II, division 1 malocclusions, we examined two current treatment methods’ effects on facial esthetics, namely (1) orthopedic functional therapy using a MARA in combination with Edgewise appliances and (2) Edgewise mechanics alone. This study was a retrospective esthetic evaluation of profile silhouettes (prior to and following orthodontic treatment) of 30 consecutively treated American white adolescents with Class II, division …

Maxillary Incisor Crown Form And Crowding In Adolescent Orthodontic Patients, Kortne King Frederick

Theses and Dissertations (ETD)

Dental crowding occurs when the mesiodistal tooth crown widths exceed the space available in the dental arch for proper alignment. Previous research dealing with this common orthodontic problem has measured mesiodistal (MD) tooth widths or clinical tooth height-to-width ratios from dental casts. The present study used full mouth periapical series of dental radiographs, which provided an opportunity to study anatomical crown form of the maxillary incisors, as measured from the cementoenamel junction (CEJ), in relation to crowding. The aim of this study was to evaluate the statistical association between maxillary incisor crown form and the extent of crowding in adolescent …

Design, Synthesis, And Evaluation Of Small Molecules In The Discovery Of Novel Antimicrobial Agents, Kimberly D. Grimes

Theses and Dissertations (ETD)

The increasing prevalence of antibiotic-resistant bacteria, including Mycobacterium tuberculosis, Streptococcus pneumoniae, Staphylococcus aureus, and Enterococcus faecalis, pushes us to discover new antibacterial agents to maintain adequate patient coverage. This body of work highlights the use of medicinal chemistry methodologies that encompass cross-disciplinary fields of study. Chapter 1 gives an introduction to the antibacterial drug targets, resistance, and how scientists are working to overcome obstacles encountered with drug-resistant bacteria. It also details modern medicinal chemistry applications in antimicrobial drug discovery. Chapter 2 details the use of a structure-guided library approach to drug design, in which large virtual libraries against the target …