In 2007, Child Protective Services received 3.2 million child abuse and neglect referrals that involved 5.8 million children. According to Health and Human Services, these reports resulted in nearly 796,000 cases of confirmed maltreatment, requiring 271,000 children to enter foster care. Research indicates children in care have a higher prevalence of medical, emotional, behavioral, and developmental disorders or concerns. Despite this increased prevalence, foster care children have a heightened risk for their mental health needs going unmet. By review of CPS records, this paper intends to examine the mental health assessments, service utilization, provider characteristics, and placement decisions for a sample of maltreated children. This history is then compared to findings and recommendations resulting from a multidisciplinary mental health evaluation. Results indicate that 50% of children were diagnosed with AD/HD prior to the interdisciplinary evaluation and those evaluations performed by medical practitioners resulted in AD/HD in 70% of cases. Inventory and assessment methods were unknown or not given in the records from every MD evaluation and the resultant recommendation always included medication. Psychologists and Masters-level professionals used 4.5 diagnostic inventories on average to determine clinical impairments and offered therapy, skills training, and academic considerations as recommendations. They diagnosed fewer cases of AD/HD and more mood disorders and developmental delays. In contrast, the interdisciplinary evaluation used 9 inventories on average, recommended a form of therapy for every child, and more often included recommendations specific to the home, school, and social environments of each child. Diagnoses included fewer behavioral disorders and highlighted more emotional and developmental concerns. The decline in AD/HD diagnoses from previous evaluations is a significant finding due to the use of stimulant medication as the primary means for mediating symptoms. In addition, discrepant diagnostic findings, especially in regards to learning disorders and developmental delays, may have kept some children from receiving educational interventions permitted to them by law. Given the vulnerability of maltreated children, it is paramount that evaluations incorporate valid means of identifying familial, social, emotional, and behavioral concerns in order to guide effective service decisions, which can only result from the highest clinical accuracy in determining diagnoses.

M.A.

1 online resource (vi, 60 p.)

Psychology

College of Arts and Sciences

Professional credentials Mental health assessments Clinical methods Diagnoses Child maltreatment

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Streptococcus mutans (S. mutans) is the causative agent behind dental caries, an infectious disease also known as tooth decay or dental cavities. S. mutans has a cell wall-attached protein known as Antigen I/II (AgI/II) utilized for bacterial adhesion to the tooth surface. Here we have solved the structures of both amino- and carboxy-terminal regions of the AgI/II molecule using X-ray crystallography. Using this structural information we have now built a tertiary model for AgI/II as a fibrillar protein. Further, we have functionally characterized AgI/II and determined minimal regions of AgI/II that are implicated in its adherence to the salivary agglutinin found on the tooth surface. The following results are presented in this thesis work: 1. We report the high resolution structure (1.8 A° ) of an amino-terminal fragment of AgI/II. This fragment reveals that AgI/II is an elongated molecule with a stalk comprised of - and polyproline type-II (PPII)-helices. The hybrid structure formed from - and PPII helices represents the first example of a new structural class of fibrillar proteins. 2. We report the (2.5 A° ) crystal structure of the complete carboxy-terminus of AgI/II. This structure now shows that the AgI/II carboxy-terminus has three domains that each each adopt the DE-variant immunoglobulin-like fold. 3. Using the amino- and carboxy- terminal structures of AgI/II, biophysical characterizations, and electron microscopic imaging, we have now created an overall tertiary model for AgI/II family of proteins. 4. Adherence studies for AgI/II revealed that AgI/II contains two distinct regions that adhered to human salivary agglutinin (SAG). These regions of AgI/II also adhered non-competitively to SAG. These results now suggest possible models for the S. mutans bacterial adherence to SAG. AgI/II can now be described as an elongated fibrillar protein with globular domains at its termini. The V-region is distal to the cell surface, while three carboxy-terminal domains are close to the cell surface. These globular regions are separated by the alanine-rich and proline-rich repeats of AgI/II that form a unique - and PPII helical hybrid fibril which is revealed for the first time by these structures. This research now provides the first overall structural model for AgI/II as a fibrillar protein.

1 online resource (xiv, 119 p.) : ill., digital, PDF file.

Physiology and Biophysics

Joint Health Sciences;

Streptococcus mutans Antigen I/II fibrillar structure

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Tropical mangrove root communities are some of the most productive and biodiverse on the plant. Sponge mangrove communities inhabit the peat banks and roots of mangroves, often accounting for much of their biomass. Mangroves are threatened worldwide by coastal development, aquaculture, and increased storm intensity. Understanding the population dynamics of these communities is essential to management of this habitat. This thesis compares traditional and taxonomically-sensitive biodiversity indices in comparisons of 1.) mangrove and coral reef sponge communities in Caribbean Panama, 2.) how mangrove sponge communities vary at varying spatial scales across the Caribbean, and 3.) how mangrove sponge communities vary with mangrove islands size. It also makes inferences from incidence functions concerning species-specific dispersal ability, life history strategies, competition, predation, resources, metapopulation stability, and effects of patch removal. The comparisons of traditional and taxonomically-sensitive indices showed mixed performance. Only an analysis of similarity and the most recent taxonomic metric detected a difference between mangrove and reef sponge communities in close proximity to each other. Most of the indices, traditional and modern, showed a significant difference between the mangrove sponges faunas of Panama and Belize. Within Belize, one island was identified by one taxonomic index as having a mangrove sponge fauna significantly different than the rest. Within Panama, the same index identified two islands as significantly different. Incidence functions models identified a putative bimodal relationship between incidence and dispersal ability, with both high and low dispersers present on many islands, and medium dispersers present on few islands. Population simulations demonstrated a range of population fates: extinction, stability, and spreading to all islands. Metapopulation calculations likewise demonstrated a range of islands necessary for each species to maximize their populations. No strong trends were identified that could directly point to trends in the ways sponges may compete with each other and communities assemble. Full ranges were identified for dispersal ability, metapopulation capacities, and population simulations, suggesting a community constantly in flux as species are concurrently remaining stable, going extinct, spreading their ranges, even trading habitats.

M.S.

1 online resource (xi, 132 p.) : ill. (some col.), maps.

Biology

College of Arts and Sciences

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The role of Streptococcus mutans has been extensively studied using a variety of genotyping techniques. Repetitive extragenic palindromic polymerase chain reaction (rep-PCR) is an effective tool for screening large-scale epidemiological studies with high discriminatory power and reproducibility. For this study, multilocus sequence typing (MLST) analysis is used to evaluate genotypes previously identified as unique using rep-PCR. Twenty-two unique S. mutans rep- PCR genotypes were selected from a longitudinal study. Four additional isolates were selected from each genotype group of the 6 most commonly occurring genotypes (n=30) for further analysis. Real-time PCR was performed using eight housekeeping S. mutans gene loci and products sequenced. Sequence data analysis was performed using CLC DNA Workbench with MLST module. Concatenated sequences (3366 bp) were evaluated with MEGA using minimum evolution method with bootstrap. All 22 rep-PCR genotypes were unique by MLST analysis. For rep-PCR genotype groups, MLST groups matched rep-PCR for 3/6 (50%); three groups were further distinguished with MLST analysis. Rep-PCR results were consistent with those found using MLST, although MLST can provide further discrimination for some isolates. Rep-PCR is an effective tool for screening large-scale populations studies of S. mutans for subsequent MLST analysis.

M.S.

1 online resource (xi, 57 p.) : ǂb ill., digital, PDF file.

Dentistry

Dentistry;

MLST rep-PCR genotyping Streptococcus mutans DiversiLab

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In the central nervous system of adult mammals, new neurons are produced throughout life in at least two regions, the subventricular zone and dentate gyrus of the hippocampus. New neurons in the SVZ migrate via the rostral migratory stream and eventually participate in adaptive olfactory processes. In the dentate gyrus, a variety of physiological functions for continued addition of neurons have been proposed, but its role in normal or pathological conditions remains largely unclear. Neurogenesis in the dentate gyrus consists of the stepwise process of generating fully functional granule cells (GCs) from adult neural stem cells. Regulation of neurogenesis can occur at multiple stages by a wide range of physiological or pathological stimuli. Although many factors can influence the differentiation, maturation, and integration of newborn neurons, considerable evidence suggests γ-aminobutyric acid (GABA) signaling is a key regulator. Newborn neurons initially receive synaptic input that is exclusively GABAergic, and normal maturation and synaptic integration is profoundly disrupted when GABA signaling is altered. Hippocampal interneurons are a diverse population of GABA-releasing cells that serve specific inhibitory functions and modulate local circuitry. In the following work, I demonstrate that newborn neurons of the dentate gyrus receive GABAA receptor-mediated input with particularly slow kinetics that result from dedicated presynaptic inputs that also generate slow responses in mature GCs. This characteristically slow GABA signaling in newborn GCs arises from a unique subset of late-spiking hippocampal interneurons of the neurogliaform (NG) cell family. During synchronous activity in the dentate network, late-spiking cells provide robust depolarization to newborn cells while inhibiting other interneurons. Collectively, these data suggest that late-spiking interneurons coordinate local circuitry among new and preexisting GCs, and are poised to manipulate activity-dependent GABAergic regulation of neurogenesis.

1 online resource (viii, 114 p.) : ill., digital, PDF file.

Neurobiology;

Joint Health Sciences;

dentate gyrus GABA granule cell interneuron neurogenesis synapse

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Maintenance of immune homeostasis involves a balance between T cell effector responses to antigen stimulus and reciprocal downregulation of this response through peripheral tolerance mechanisms. Upon exposure to pathogen, cytokine production and signaling serve to tightly coordinate cell-mediated clearance of antigen followed by contraction of the immune response. Interkeukin-2 (IL-2) is a type I family cytokine critical for expansion of activated T cells in vitro and enhancement of T cell memory responses in vivo. Deficiency of IL-2 in vivo also revealed a critical role for IL-2 in immune tolerance through the maintenance of T regulatory cell populations (Treg) in peripheral lymphoid tissues. Thus, regulation of Il2 gene expression and autocrine signaling are central to the balance of immune homeostasis. Defining the regulatory mechanisms associated with Il2 gene expression is crucial for defining the integral role for IL-2 in tolerance and effector immunity. In order to evaluate the role of IL-2 production during the immune response we have engineered a BAC transgenic as well as a gene-targeted knock-in reporter mouse model system to mark Il2 gene activation. Our studies indicate that both mouse models exhibit reporter expression with high fidelity to endogenous Il2 expression patterns while stably marking IL-2-producing cells. Using our Il2 BAC transgenic system (2BiT) system to model inhibition of IL-2 production in responder CD4 T cells by Tregs we describe a model in which Tregs prevent initial activation of Il2 transcription that also subsequently associates with increased responder cell death of non-IL-2 producers. Suppression of naïve activated CD4 T cells by Tregs followed a mechanism consistent with competition for co-stimulation and preventing a threshold of activation rather than cytokine deprivation. Utilizing an Il2 GFP knock-in model we show evidence that IL-21 enhances proliferation and the frequency of IL-2-producing cells in activated naïve CD4 T cells. These results are suggestive of a coordinate relationship between Il2 expression and IL- 21 production and signaling in effector T cell function and fate. Future Il2 expression studies using our novel mouse reporter systems will enable a more in-depth understanding of the role of this cytokine in effector function and immune tolerance.

1 online resource (xvi, 141 p.) : ill., digital, PDF file.

Microbiology;

Joint Health Sciences;

Interleukin-2 T regulatory cells immune tolerance T cell activation gene transcription BAC transgenic and knock-in reporter mice

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The 2001 edition of the American Association of State Highway and Transportation Officials (AASHTO) Standard Specifications for Structural Supports for Highway Signs, Luminaires and Traffic Signals has been revised in its entirety through a major research project conducted under the auspices of the National Cooperative Highway Research Program (NCHRP 17-10). A major part of the revision included updated provisions and criteria for extreme wind loads and new provisions and criteria on fatigue design. These provisions differ considerably from those in previous editions of the specifications, and have remained relatively unchanged in the 2009 edition. The impact of the fatigue criteria on the design of overhead sign structures has not been fully evaluated. The fatigue design loads do not adequately reflect the stresses generated on these structures from wind-induced fatigue loading. In addition, the provisions do not account for the variety of support structures in design, each with different configuration, sizes, shapes, and material properties that influence vibration behavior. As a result, the vulnerability of sign support structures to wind-induced fatigue loading is not fully realized. The main goal of the project was to conduct theoretical and experimental programs of study to evaluate the performance of cantilever-type highway overhead sign support structures subjected to wind induced fatigue loads. A theoretical program was developed that took into account the variety of sign supports structures in design, as well as addressed the vulnerability of these structures to wind-induced fatigue loading. The experimental program was developed to evaluate the accuracy of the theoretical study. A finite element analysis program was conducted to simulate the wind-induced loading environment and the response of sign support structures to this environment. Alterations were made to the model that could not be done experimentally due to costs and time restraints. The results of the finite element analysis were compared to the theoretical and experimental programs of study. The developed information and criteria on fatigue design of sign support structures were used to develop fatigue design loads to provide an improved and more reliable design method. Recommendations are made to update the current specifications to include more reliable fatigue loads.

1 online resource (xxvii, 399 p.) : ill. (some col.)

Civil, Construction and Environmental Engineering

Engineering

Cantilever-type sign support structures Fatigue design Fatigue load Natural wind Truck-induced wind Vibration

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Extracellular matrix (stroma) regulation of mucosal T‐cell function is incompletely understood. Here we uncovered a role for intestinal stromal products in the innate regulation of effector T‐cells. Stroma‐conditioned media (S‐CM) derived from normal human intestinal stroma (TGF‐βhi/IL‐6lo/IL‐1βlo) significantly down‐regulated T‐cell proliferation and IFN‐γ production compared to S‐CM derived from inflamed Crohn’s mucosa (TGF‐βhi/IL‐6hi/IL‐1βhi). Antibody neutralization studies showed that TGF‐β in normal S‐CM inhibited T‐cell proliferation and IFN‐γ production, whereas IL‐6 plus IL‐1β in Crohn’s S‐CM promoted T‐cell proliferation, and the IL‐1β alone promoted IFN‐γ and IL‐17 release. Importantly, stromal cells in normal tissue produce TGF‐β and contribute to mucosal homeostasis and tolerance to antigenic stimulation. In contrast, stromal cells in Crohn’s mucosa produce high levels of IL‐6 and IL‐1β in addition to TGF‐β and are hyper‐responsive to antigenic stimulation. These findings implicate an important role for stromal regulation of immune responses in normal mucosa through the production of TGF‐β and in promoting inflammatory responses in Crohn’s disease through the production of IL‐ 6 and IL‐1β and TGF‐β.

1 online resource (x, 100 p.) : ill., digital, PDF file.

Microbiology;

Joint Health Sciences;

intestine Immune regulation T-cell Stroma Human Crohn's disease

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Heme oxygenase-1 (HO-1) is a critical enzyme catalyzing the degradation of heme and generating carbon monoxide, iron, and biliverdin. In addition to heme degradation, HO-1 expression is known to protect against various cellular insults and disease states including acute kidney injury, atherosclerosis, vascular restenosis, and others. Human HO-1 gene expression is tightly regulated at the level of transcription. The main goal of this study is to explore the transcriptional regulation of the human HO-1 gene in renal epithelial cells. Chromosome Conformation Capture (3C) demonstrates that multiple regulatory regions within the HO-1 promoter and enhancer regions are physically interacting with each other by forming chromatin loops and this looping is required for the initiation of the human HO-1 gene transcription. ChIP-Loop assay reveals that these regions share several common transcription factors such as Sp1, USF-1, and JunB. Sp1 binds to the intronic enhancer which interacts with the -4.5kb promoter region by chromatin looping. Inhibition of Sp1 by siRNA abolishes this interaction and reduces HO-1 transcription. To study human HO-1 transcription in vivo, a HO-1 bacterial artificial chromosome (BAC) transgenic mouse was generated by integrating a 87 kb BAC DNA (a portion of the human chromosome 22 including HO-1 gene and its regulatory regions) into the mouse genome. Global overexpression of HO-1 mRNA and protein in tissues of HO-1 BAC transgenic mice were detected. Moreover, using this HO- 1 BAC transgenic mouse, a “humanized” HO-1 BAC transgenic mouse (hHO-1 BAC) was generated by crossing HO-1 BAC mice with HO-1 knockout (HO-1-/-) mice. In addition to the overexpression of human-specific HO-1 mRNA and protein expression, the human HO-1 gene in hHO-1 BAC mice rescued the abnormal phenotype observed in the HO-1-/- mice such as increased incidence of abortion and embryonic lethality, heightened sensitivity to acute kidney injury, iron overload, anemia, and splenomegaly. These studies provide not only functional insights for the regulation of the human HO-1 gene but also the molecular architecture of the human chromosome containing the HO-1 gene and promoter in renal epithelial cells.

1 online resource (xiv, 136 p.) : ill., digital, PDF file.

Joint Health Sciences;

Heme oxygenase-1 Chromatin looping Transgenic mice Acute kidney injury rhabdomyolysis chromosome conformation capture

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Posttranslational modifications of histones regulate important chromatin and cellular functions. Among them, ubiquitination of histone H2A is correlated to transcriptional repression, such as HOX gene silencing and X chromosome inactiviation. Little was known about the removal of ubiquitin from histones, the enzyme(s) involved and its function in chromatin dynamics. We have identified the protein Ubp-M (USP16) to be the H2A- and nucleosome-specific deubiquitinase. We also demonstrated that Ubp- M-mediated H2A deubiquitination is involved in cell cycle progression to M-phase, HOX gene expression, and posterior development in Xenopus laevis. Furthermore, we have also purified USP12 and USP46 which contain an Ubp-M independent deubiquitinase activity for both uH2A and uH2B. USP12 and USP46 each form a complex with the WD40 repeat-containing protein WDR48, which is required for the deubiquitinase activity. USP12 and USP46 regulate HOX gene expression and gastrulation during Xenopus laevis development. These studies will contribute to the understanding of the regulatory mechanisms of H2A and H2B ubiquitination and deubiquitination, and their biological functions.

1 online resource (x, 90 p.) : ill., digital, PDF file.

Biochemistry and Molecular Genetics;

Joint Health Sciences;

histone H2A ubiquitination deubiquitination Ubp-M

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Non-carious Cervical lesions (NCCL) often encountered in clinical practice, is tooth structure loss at the cemento-enamel junction unrelated to dental caries. NCCL is mostly associated with gingival recession. Restoration of NCCL is challenging due to close periodontal relationship. OBJECTIVE: To develop a non invasive, highly reproducible technique to measure the soft tissue changes and apply the technique to measure the gingival margin position changes after restoration of NCCL. MATERIALS & METHODS: Forty one patients participated in the study. 3 resin composite (Filtek Supreme Plus) restorations were done per patient. GI(Loe & Sillness), PI (Loe & Sillness) , digital images and elastomeric impressions (Aquasil heavy & extra low viscosity) were collected from the three visits ( restoration, 10-15 days first recall, 6 month recall).Gingival phenotype is classified as thick or thin from the photographs. Casts (Fuji Rock type IV die stone) were prepared and a mold was made with putty impression material to hold the cast for imaging. Linear measurements (VHX 600 Keyence digital microscope) were recorded. Follow up visits were also recorded using the same molds as position guides. RESULTS: Intraclass correlation of 0.9963 was seen for the reproducibility of the technique done on 40 samples repeated 8 times. Generalized mixed model analysis of variance was used to evaluate the gingival margin position changes over time and by phenotype. Generalized estimating equations were used to account the GI and the PI. No statistically significant difference in gingival height (p=0.6993), gingival height by phenotype (p=0.9102), and in plaque index (p=0.3092) was noted at the three time intervals. A significant difference was seen in the mean length between the phenotypes (p=0.0211), with thick phenotype having shorter mean length than thin phenotype and in GI (p<0.0001) between GI 1and GI 2 and between GI 1 and GI 3. CONCLUSION: Within the limits of this study it can be concluded that placement of restoration in a NCCL restoration would not change the gingival margin position by time and by phenotype. Resin Composite restoration did not have an effect on plaque accumulation but, it would cause inflammation of the gingiva.

M.S.

1 online resource (xi, 80 p.) : ill., digital, PDF file.

Prosthodontics

Dentistry;

Non-carious cervical lesions linear gingival margin position change measurement

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Growth hormone (GH) and insulin like growth factor-1 (IGF-1) exert profound growth promoting actions during pre and postnatal skeletal muscle development. GH and IGF-1 seem to promote their anabolic actions by influencing skeletal muscle cell proliferation and fusion. However, because GH stimulates the production of IGF-1 from the liver and other GH-responsive peripheral tissues, including skeletal muscle, the individual contributions of these two growth factors to anabolic responses in skeletal muscle remains poorly defined. In this dissertation research, I sought to distinguish the mechanisms responsible for growth hormone’s (GH) anabolic actions in skeletal muscle. To accomplish this, I analyzed the impact of selected genetic alterations in the GH-IGF-1 pathway on skeletal muscle development and function in mice. With the results from these studies, I demonstrate that GH mediates skeletal muscle development by enhancing myoblast fusion in an IGF-1 dependent manner. In addition, I also demonstrate that disruption of the GHR in skeletal muscle leads to alterations in global energy utilization and insulin resistance in an IGF-1 independent manner.

1 online resource (vi, 85 p.) : ill., digital, PDF file.

Pathology

Joint Health Sciences;

GH IGF-1 myoblast fusion insulin sensitivity insulin resistance energy expenditure

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Three reasons to review accumulating data in clinical trials include: ethical issues, financial concerns and administrative concerns. Interim analysis is a good way to monitor accumulating data in clinical trials. Interim analysis allows for the possibility that a study may be terminated early; that is, if the currently observed data convincingly favor the null or the alternative hypothesis then the study ends early. In addition, many clinical trials are conducted to compare a treatment group to a standard group on multiple endpoints. Combining interim analyses with multiple endpoints allows for more information to be provided from the trial than either testing a single endpoint alone or testing multiple endpoints without interim looks. Stochastic curtailment procedures are frequently used in interim monitoring of clinical trials. These methods allow for the possibility of early termination of a study at any interim time point if a significant result (or null result) is highly likely given the current data. One such stochastic curtailment method is conditional power. Conditional power gives the probability of rejecting the null hypothesis at the end of the study given the current data and some fixed parameter of interest. One criticism of conditional power is that it is computed under values of the parameter of interest which may not be supported by the current data. The predictive power method, a mixed Bayesian-frequentist method, is another stochastic curtailment procedure for which this is no longer a concern. The predictive power method extends conditional power to assume that the parameter of interest is random. The conditional power function is averaged with respect to the posterior distribution of the parameter of interest given the observed data. We present an extension of the univariate predictive power method to allow for two correlated endpoints. We assess the properties of the extended predictive power under a variety of conditions, and compare the performance of the extended predictive power method to other commonly used methods for assessing data at interim time points. Finally, we illustrate our extended predictive power method by applying it to data from the Inhaled Nitric Oxide Study.

1 online resource (xiii, 182 p.) : ill., digital, PDF file.

Biostatistics;

Public Health;

predictive power conditional power multiple endpoints interim monitoring clinical trials

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Every year extreme windstorms such as tornadoes and hurricanes have imposed disastrous consequences to the United States community, economy and population. Having a community shelter can protect civilians from these dangerous events. This study focused on providing detailed design guidance in addition to demonstrating the design and analysis of a safe, on-ground, stand-alone community shelter to resist extreme wind forces. The storm shelter must be able to resist 300 mile per hour wind gusts and flying debris impacts of such storms. The primary objective was to develop an innovative and cost-effective Fiber Reinforced Polymer (FRP) panelized construction system. The technique allows the shelter to be sub-divided into basic elements that can be prefabricated and shipped to the construction site, where they can be assembled into the finished structure. The design must meet the requirements recommended by the Federal Emergency Management Agency (FEMA) with life safety as the primary consideration. The design wind pressures for the community shelter were calculated per the American Society of Civil Engineering (ASCE) 7-05 code provision and modeled in the Computational Fluid Dynamic (CFD) software named HYBRID3D. Comparison was made between the ASCE 7-05 and CFD wind pressures to validate the accuracy of the ASCE 7-05 design methodology. Two different FRP materials were proposed for the design and analysis of the FRP panels. The design of FRP panels was based on the performance and minimum wind load design criteria of the ASCE 7-05. The finite element analysis (FEA) software package called ANSYS 11.0 was used to carry out the design of the FRP panels under the wind pressure loading. In addition, the FEA was conducted on the bolted joint connections of the shelter. Further analysis was carried out on the bolted joint connections per the Load Resistance Factor Design (LRFD) code to determine if the bolts had sufficient strength to resist the applied external loadings.

M.S.

1 online resource (xvii, 202 p.) : ill. (chiefly col.), maps.

Civil, Construction and Environmental Engineering

Engineering

Extreme wind FRP ASCE 7-05 FEA Connection Community shelter

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Cystic fibrosis (CF) is a lethal genetic disorder leading to pulmonary decline and premature death. The gene responsible for CF, the cystic fibrosis transmembrane conductance regulator (CFTR), serves as a chloride and bicarbonate channel situated at the apical cell surface of epithelia. The discovery of small molecules that augment channel gating of mutant CFTR (so-called ‘potentiators’) represents a major theme of CF research, and offers hope for new therapeutic interventions. High-throughput screening (HTS) provides a means to test millions of agents in an unbiased manner for CFTR potentiating properties. New agents identified by HTS have undergone extensive preclinical and clinical testing in CF individuals, and shown substantial progress toward clinical advancement. However, novel strategies are required to better understand CFTR potentiators and their applicability in the clinic. In this thesis, we pursued a detailed understanding of emerging CFTR potentiators with high relevance to therapeutic intervention. We describe a set of mechanistic experiments intended to functionally categorize CFTR potentiators based on their biochemical effects on the CFTR regulatory domain (RD), and their activity profiles in cell systems representative of the in vivo environment. Our findings indicate that CFTR potentiators acting independently of RD phosphorylation may be best tailored to rescue cAMP regulation of CFTR carrying the common ΔF508 mutation. In another series of experiments, we show that quercetin, a novel flavonoid, potentiates CFTR mediated anion transport in respiratory epithelia in vitro and in vivo, and may be useful to optimally detect rescue of ΔF508-CFTR. The present project therefore addresses two questions fundamental to both CFTR biology and CF therapeutic intervention: 1. How can knowledge of CFTR modulator mechanism aid in optimization of emerging CFTR potentiators and advance basic understanding of CFTR biology? 2. How can knowledge of a robust class of CFTR activators, the flavonoids, be used to identify compounds best able to activate and detect surface localized and functional CFTR in human subjects with cystic fibrosis? These findings address the increasingly recognized gap between identification of new therapeutic compounds for CF, and a better understanding of agents most suitable for basic and translational cystic fibrosis research.

1 online resource (xv, 115 p.) : ill., digital, PDF file.

Genetics

Joint Health Sciences;

CFTR Cystic Fibrosis potentiators quercetin regulatory-domain cAMP

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This study examines the relationship between electronic health record (EHR) adoption and physicians’ operational productivity and financial performance. The resource-based view of the firm (RBV) was utilized as a theoretical framework to develop and address four hypotheses. Specifically, the first two hypotheses address the impact of EHR adoption status (i.e., electronic- vs. paper-based medical records), and the other two hypotheses focus on the length of EHR adoption (i.e., years of EHR adoption). This cross- sectional study used secondary data from the 2008 physician compensation and production survey conducted by the Medical Group Management Association (MGMA). Multiple linear regression analysis was used to test the hypothesized relationships. The results showed that there was partial evidence that EHR adoption and the length of adoption were negatively related to physicians’ operational productivity. Particularly, while EHR adoption was not related to physician RVU, it was negatively related to the number of encounters. The length of EHR adoption was negatively related to physician RVU. Although EHR adoption and length of adoption were not associated with overall financial performance, the adoption was associated with significantly higher charges. An important implication for scholars is that IT infrastructure might serve as a source of competitive advantage for specific tasks. This suggests that when conducting an IT-performance study, researchers should consider task-specific outcome measures. In addition, managers of ambulatory physician practices can use the findings from this current study to facilitate their decision-making process in EHR adoption. Even though partial evidence suggests that EHR adoption is associated with decreased physicians’ productivity, it is not negatively associated with financial performance. Coupled with the meaningful incentive program currently being offered as part of the HITECH Act, the ability of EHR to improve charge captures should encourage managers to adopt EHR.

3.58MB

Health Services Administration

Health Professions;

electronic health record resource-based view physician practice setting operational productivity financial performance RVU

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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 increase this inhibitory phosphorylation, suggesting that it may be an important mechanism for the regulation of mood. In these studies, we investigate the role of serine phosphorylation of GSK3 in the treatment and pathophysiology of mood disorders. To investigate the mechanisms of mood disorder treatment, we first examined activation of Akt, an upstream regulating kinase of GSK3, in response to serotonin. Both an acute increase in serotonin and chronic antidepressant treatment result in a functional activation of the Akt signaling pathway. Similarly, activation of 5-HT1A receptors were found to increase phosphorylation of GSK3 through activation of the PI3K/Akt pathway, and phosphorylation of GSK3 was found to be necessary for 5-HT1A receptor-mediated inhibition of conditioned fear memories. Antagonism of 5-HT2A receptors was found to inhibit GSK3 through activation of Akt, while activation of 5-HT2A receptors was found to increase inhibitory phosphorylation of GSK3 only in the absence of β-arrestin2. Furthermore, loss of β-arrestin2 potentiates the antidepressant-induced increase in phosphorylated GSK3 as well as the behavioral response to antidepressants. Finally, we investigated the behavioral effects of decreased serine-phosphorylation of GSK3 using knock-in mice with GSK3 that is immune to serine phosphorylation. We found that loss of this phosphorylation resulted in increased behavioral susceptibility to induction of both manic- and depressive-like states. The studies presented here demonstrate that serine phosphorylation of GSK3 plays a critical role in mood disorder pathology. This gives us novel insights into the regulation of mood, and may provide avenues for the development of more effective treatments for mood disorders.

1 online resource (x, 250 p.) : ill., digital, PDF file.

Neurobiology;

Joint Health Sciences;

GSK3 Akt Mood Disorders Serotonin Antidepressants Behavior

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The abundances of ices in planetary environments are obtained through measurements of near-infrared absorption features (˜ν=10,000-4,000 cm−1 , λ=1-2.5 µm), and nearIR measurements of materials present in the interstellar medium are increasingly common. In the studies presented here, the near-IR band strengths for molecules are determined through correlations to their better-known mid-IR characteristics. These strengths are used to determine the column densities of molecules in interstellar dense clouds or other environments from observed data. The first set of experiments focused on the near-IR features of molecules relevant to the study of interstellar icy grain mantles and planetary bodies: CO, CO2, C3O2, CH4, H2O, CH3OH, and NH3. The spectra of these species were studied in the near-IR region from 10,000-4,000 cm−1 and in the mid-IR region from 4,000-400 cm−1 after the slow growth of films at ∼5 K. The results were then used the results to determine the near-IR band strengths of each molecule. Many icy satellites have surfaces that are dominated by either N2 or H2O, and ices in the ISM are primarily composed of H2O. The second set of experiments is focused on the near-IR absorption features of CO, CO2, CH4, and NH3 diluted in H2O and diluted in N2. Since the compositions of icy planetary bodies and interstellar ices are affected by processing due to UV light and proton bombardment, spectra of UV photolyzed and proton irradiated ices of N2 + CO2 and H2O + CO2 have been collected to determine the extent of energetic processing on icy bodies in the outer solar system. These studies have shown that planetary ices are best represented by laboratory analogs comprised of mixed, energetically processed ices.

1 online resource (xix, 154 p.) : ill. (some col.)

Physics

College of Arts and Sciences

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In our present day, the term “chivalry” is understood to define the gentlemanly conduct of a man with respects to a female counterpart. In the fifteenth century, the term “chivalry” is applied in a broader sense, referring to the inter-dynamics of a grouping of knights. “Chivalry” thus examines the bachelorhood of the knight and the magnanimous and egalitarian nature of his position. Italians have been aware of Arthurian legends since at least the eleventh century. In fifteenth century Northern Italy, chivalric literature enjoyed refreshed interest due to an outpouring of Italian and French translations. Borso d’Este (1413-1471), although illegitimate, was the second sovereign son of Niccolò III d’Este of Ferrara. Borso’s illegitimacy and lifestyle made it advantageous for him to embody a knightly persona. In doing so, he employed a variety of artistic campaigns that hyperbolized his pedigree. This thesis focuses on one of these campaigns, the Hall of the Months, in the Palazzo Schifanoia, an Este hunting retreat on the outskirts of Ferrara. Francesco del Cossa and Cosmè Tura painted the Hall of the Months. The program for the fresco cycle is complex. The twelve calendar months run clockwise around the room. Horizontally, the hall is divided into three registers, from bottom to top: earth, corresponding zodiacal signs, and corresponding deities. Considering the 1:1 scaling and expansive proportions of the Hall of the Months (24 m long, 11 m long, and 7.5 m high), the earthly tier illusionistically places viewers outdoors and serve as a reminder of Borso’s place among sovereigns. Themes of civic harmony abated any fear of discord or aggression. Previous scholarship has tended to focus on the astrological aspects of the Hall of the Months. However, its chivalric imagery has either been neglected or not fully explored. Thus, this thesis focuses only on the “earthly” register, whose chivalric imagery promulgates Borso’s carefully crafted persona. By providing a new focus of interest for the Hall of the Months, I hope to open the field to further research about Borso’s biography as well as the importance of chivalric literature in fifteenth-century Italy and in fifteenth-century Italian art.

M.A.

1 online resource (xi, 76 p.) : ill. (chiefly col.), geneal. table, map, plans.

Art and Art History

College of Arts and Sciences

Borso d’Este Chivalry Ferrara Hall of the Months Italian Renaissance Schifanoia

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Type 1 diabetes mellitus (T1D) is most commonly diagnosed in children and young adults, and complications may be life-long as well as life threatening. Management of T1D has proven to be very challenging during adolescence, and parental involvement in diabetes management has been shown to improve adherence and glycemic control in children and adolescents. Middle adolescents should become increasingly responsible for diabetes-related tasks under the supervision and guidance of parents (shared management). However, adolescents spend less time with their family as they get older, resulting in parents’ being unable to validate effective self-management; this inability may lead to anxiety about being separated from their adolescent (parental separation anxiety) and to retention of diabetes task responsibility that would interfere with an effective transfer of responsibility. The purpose of this study was to examine separation anxiety in parents and couples who were parents of adolescents 15 to 17 years of age who had T1D. Specifically, the relationship investigated was that of parental separation anxiety to parental responsibility for diabetes-related tasks and glycemic control. Secondary data analysis was used to examine 61 adolescents and their parents from a larger longitudinal study. Maternal separation anxiety was associated with and was a predictor for maternal responsibility only in 2-parent and 2-parent biological families (p = .008). Maternal separation anxiety was associated with glycemic control in the total sample (p = .042). Findings from multiple regression revealed that maternal separation anxiety was not a significant predictor for maternal responsibility once significant covariates were controlled in the model. Paternal separation anxiety was neither significantly associated with nor a predictor for paternal responsibility or glycemic control. Paired, samples t-tests indicated that maternal separation anxiety and paternal separation anxiety were significantly different in 2-parent biological families (p = .019) but not in 2-parent stepfamilies. Parental separation anxiety was not significantly associated with parental responsibility or glycemic control in the total sample. Bivariate correlations indicated that shared responsibility was not significantly related to glycemic control. Shared responsibility has been associated with improved glycemic control in younger adolescents; however, it does not appear to have the same impact in middle adolescents.

1 online resource (xv, 225 p.) : ill., digital, PDF file.

Nursing;

Nursing;

adolescents diabetes responsibility shared responsibility shared management maternal separation anxiety paternal separation anxiety

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Members of the Fc receptor-like (FCRL) family are cell-surface proteins with ancient conservation, distinct lymphocyte expression patterns, and tyrosine-based signaling capabilities that imply a fundamental role for them in modulating immune responses. Though they share many features with the Fc receptors (FCR) for IgG and IgE, FCRLs have not been found to bind immunoglobulin. In these studies, we sought to characterize the cellular expression pattern, binding partner, and function of a recently identified FCRL family member, human FCRL6. By developing specific monoclonal antibodies (mAbs) we determined that FCRL6 is distinctly expressed by cytotoxic lymphocytes, namely NK cells, CD8+ T cells, γδ T cells, and rare cytotoxic CD4+ T cells. To elucidate its extracellular ligand(s), a cell-based GFP reporter system was developed to assay FCRL6 surface receptor engagement. These studies revealed that FCRL6 binds to HLA-DR, an MHC class II molecule. This interaction was confirmed by generating a panel of HLA-DR-reactive mAbs that blocked the FCRL6/HLA-DR association and by demonstrating that soluble recombinant FCRL6-Fc molecules specifically bind to HLA-DR transductants. The functional relevance of this discovery was also examined. First, by blocking the FCRL6/HLA-DR interaction, CD8+ T cell functions could be enhanced in response to antigenic peptide stimulation. Second, forced expression of FCRL6 in a human NK cell line inhibited its killing of HLA-DR expressing cells. Collectively, these studies demonstrate that FCRL6, a molecule distinctly expressed by cytotoxic lymphocytes, inhibits their effector function upon engagement of its ligand, MHC class II. These findings reveal an intriguing evolutionary relationship between receptors for immunoglobulin and MHC and demonstrate that NK cells and CD8+ T cells, whose activities are traditionally considered to be governed by MHC class I interactions, are also functionally regulated by MHC class II. This newfound interface may have important implications for better understanding HLA class II disease association and its manipulation could be of therapeutic benefit to patients with disorders of cell-mediated immunity.

1 online resource (v, 86 p.) : ill., digital, PDF file.

Microbiology;

Joint Health Sciences;

FCR FCRL FCRL6 MHC class II NK cells CD8+ T cells

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Gossom Switch is a creative nonfiction piece which traces my paternal roots. This narrative explores the family bond, racial segregation, slavery, and civil rights. Although Gossom Switch is a personal journey, my story is also universal and historical. The Zearn Master is a middle-grade fiction novel. While the main purpose of this novel is to entertain, like my creative nonfiction it focuses on family, especially the bond between siblings. This piece is also universal in that it centers around the sport of basketball.

M.A.

1 online resource (vii, 38, 83 p.)

English

College of Arts and Sciences

Fiction Creative nonfiction Middle-grade Basketball Slavery Freedom

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The ubiquitin proteasome system (UPS) is a coordinated process by which the cell can control protein distribution and abundance. Proteins are marked for turnover by the construction of a polyubiquitin chain on the protein substrate. Once engaged by the proteasome, the ubiquitin side-chain is disassembled by proteasomal deubiquitinating enzymes (DUBs), preventing entry of ubiquitin into the proteasome and recycling it for use in future reactions. One of the DUBs that resides on the proteasome is Ubiquitin Specific Protease 14 (Usp14), which is mutated in the ataxia (axJ) mice. This mutation results in pronounced physical deficits and, unexpectedly, a deficit in hippocampal synaptic function. This deficit in the hippocampus was primarily characterized as a reduction in paired pulse facilitation (PPF), a form of synaptic short-term plasticity. The purpose of this project was to understand how the proteasome is able to modulate PPF. To this end we found that the deficit in PPF is due to an increase in the rate of degradation at the proteasome. This change results from the loss of Usp14’s ability to regulate the proteasome, independent of Usp14’s ability to process ubiquitin chains. Surprisingly, the deficit in PPF is not caused by a change in the initial synaptic release probability. Instead, an increased rate of proteasomal degradation results in a significant reduction in the number of docked vesicles at the synaptic terminal. This deficit, combined with a hypothesized homeostatic increase in the release probability per vesicle, accounts for the observed deficit in PPF of the axJ mice.

1 online resource (ix, 144 p.) : ill., digital, PDF file.

Neurobiology;

Joint Health Sciences;

Usp14 Short term plasticity Proteasome PPF UPS

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Sil1 is an Endoplasmic Reticulum (ER) localized protein. SIL1 was initially identified as a UPR-regulated gene. Later studies show Sil1 functions as the nucleotide exchange factor of ER lumenal Hsp70—Bip by directly interacting with the ATPase domain of Bip. Currently, the molecular mechanism how Sil1 catalyzes nucleotide exchange of Bip is still elusive. In this study we determine the complex structure of yeast S.cerevisia Sil1 and Bip (also called Kar2) ATPase domain at 2.3Å resolution by Single-anomalous dispersion (SAD) methods. The Sil1-Bip complex structure reveals that one sil1 molecule interacts with one Bip ATPase domain molecule to form the complex. Sil1 forms an elongated shape which is entirely comprised of α-helices including four Armadillo-like repeats. In the complex structure, Sil1 wraps around the subdomain IIb of the Bip ATPase domain and acts in a “clamp” model. The binding of Sil1 forces a ~13.5° outward rotation of subdomain IIb away from the nucleotide-binding cleft. The complex formation also induces a ~3.7° rotation of subdomain Ib to the opposite direction. These conformational changes open up the nucleotide-binding cleft of Bip ATPase domain, disrupt the hydrogen bonds between Bip ATPase domain and bound ADP, and eventually promote the ADP release and the subsequent ATP binding. A group of interface residues from Sil1 are mutated. Two single mutants H163A and E390A result in complete loss of Sil1-Bip interaction. All the other mutants compromise binding between two proteins to various extents. The ATPase activity assay results show all the Sil1 mutants lose the ability to stimulate the ATPase activity of Bip. The results are consistent with that of the reduced binding affinities between Sil1 mutants and Bip ATPase domain. Utilizing the structural and functional data, a reasonable mechanism for Sil1 functioning as the nucleotide exchange factor of Bip has been proposed.

1 online resource (xi, 78 p.) : ill., digital, PDF file.

Cell Biology;

Joint Health Sciences;

Sil1 Bip ATPase activity

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Ovarian cancer remains the most lethal gynecological malignancy in the U.S. Conventional therapies have limited therapeutic value due to advanced stage of the dis-ease at diagnosis. Conditionally-replicating adenoviruses (CRAds) are promising, novel anti-cancer agents that are designed to selectively replicate in and lyse tumor cells. In clinical trials, CRAds exhibited limited efficacy thus far. Second generation CRAds are being developed to express a therapeutic protein to further enhance antitumor efficacy. One attractive target in ovarian tumor microenvironment is the matrix metalloproteinases (MMPs) that degrade the extracellular matrix. Thus, tissue inhibitor of metalloproteinase 2 (TIMP2), an endogenous inhibitor of MMPs, is a promising candidate to arm a CRAd intended to treat ovarian cancer. We hypothesize that a CRAD armed with TIMP2 will inhibit ovarian cancer progression through two distinct mechanisms. First, specific repli-cation in tumor cells should lead to oncolysis. Second, secretion of TIMP2 into the tu-mor microenvironment should inhibit excess extracellular MMPs and activate other MMP-independent signaling pathways to inhibit tumor growth, angiogenesis and metas-tasis. A targeted and armed CRAd, Ad5/3-CXCR4-TIMP2 was developed using the CXCR4 promoter for enhanced replication, expressing the TIMP2 transgene. First, we confirmed the secretion and functional activity of TIMP2, as demonstrated by the inhibi- tion of gelatin degradation by MMPs. In addition, arming with TIMP2 did not inhibit viral replication nor oncolytic potency, as the TIMP2 armed viruses showed enhanced killing of cancer cells when compared to the unarmed viruses. Examination of viral rep-lication in primary stage III and IV ovarian cancer samples revealed a consistent high level of viral replication with Ad5/3-CXCR4-TIMP2. The therapeutic efficacy of the TIMP2-armed CRAd was then evaluated in an orthotropic model of ovarian cancer, in which athymic mice were intraperitoneally injected with human ovarian cancer cells. The results demonstrated that the Ad5/3-CXCR4-TIMP2 delayed tumor growth and sig-nificantly increased survival when compared to the unarmed CRAd. This effect was me-diated through inhibition of MMPs. Collectively, the present study demonstrated the en-hanced therapeutic efficacy of the dual-action, TIMP2-armed CRAd in vivo and the trans-lational potential of using Ad5/3-CXCR4-TIMP2 for treatment in patients with advanced ovarian cancer.

1 online resource (xiv, 113 p.) : ill., digital, PDF file.

Pathology;

Joint Health Sciences;

CRAds CXCR4 TIMP2 ovarian cancer

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For the past several decades, the prevalence of Type 2 Diabetes and the metabolic syndrome has been increasing. Insulin resistance is the central pathogenic event for these diseases. We previously reported that the NR4A family of orphan nuclear receptors augments insulin sensitivity in adipocytes. We now found that lentiviral mediated NR4A3 hyper-expression increased insulin stimulated glucose transport (ISGT) in C2C12 myocytes while NR4A3 knock-down exhibited opposite effect. We also examined the effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation in C2C12 myocytes. PGA2 augmented ISGT and insulin stimulated AKT phosphorylation in C2C12 myocytes. Importantly, PGA2 treatment led to increased ISGT in NR4A3 over-expressing C2C12 myocytes while the sensitizing effect of PGA2 was diminished in NR4A3 knock-down myocytes. These novel results suggest that a working model that PGA2 augments insulin action in myocytes via a mechanism involving NR4A3, which provides a proof of principle for future anti-diabetic medication development. Exercise is used therapeutically to reverse insulin resistance. Interestingly, exercise was also reported to induce NR4A mRNA expression. Given the established role of NR4As in insulin sensitivity modulation, it was imperative to explore whether exercise regulates NR4A protein expression. Therefore, we measured muscle NR4A protein in 16 healthy young and 11 old males following acute (AE) and chronic (CE) resistance exercise. Muscle biopsies were performed at baseline and 24 hr after both AE and CE. NR4A1 levels are similar in young and old at baseline, increased by AE in young only, and reduced in young and old following chronic resistance training. NR4A3 protein levels are diminished in elderly subjects but are not affected by AE or CE. Our data indicate differential effects of age and exercise on muscle NR4A protein expression, which may shed a light to address whether NR4As are involved in the beneficiary effects of exercise.

1 online resource (viii, 131 p.) : ill., digital, PDF file.

Cell Biology;

Joint Health Sciences;

NR4A3 MINOR insulin sensitivity prostaglandin A2 glucose transport skeletal muscle C2C12 cells insulin action exercise NR4A1

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Calreticulin (CRT), classically known for its chaperone functions in the endoplasmic reticulum and as a Ca2+ 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 of cell surface CRT on signaling through its co-receptor, low density lipoprotein receptor-related protein-1 (LRP1), in response to thrombospondin 1 (TSP1). TSP1 signaling through CRT and LRP1 causes focal adhesion disassembly, cell migration, and anoikis resistance. We found that TSP1 causes LRP1 phosphorylation, which may contribute to its cell signaling capabilities. TSP1, CRT, and LRP1 also have been implicated in cancer development. Therefore, we explored the role of TSP1 binding to CRT and signaling through LRP1 in breast cancer invasion. Our findings do not support a role for TSP1 signaling through CRT and LRP1 in breast cancer invasion. In conclusion, these studies demonstrate that CRT regulates fibrillar collagens. In addition, TSP1 signaling through cell surface CRT and LRP1 induces tyrosine phosphorylation of LRP1.

1 online resource (xvi, 154 p.) : ill., digital, PDF file.

Pathology

Joint Health Sciences;

calreticulin collagen low density lipoprotein receptor-related protein-1 thrombospondin 1

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Introduction: The digital revolution has arrived and is propelling the field of orthodontics into a new age of continually evolving technology. Digital impression technology is now available to produce digital replications directly from a patient’s mouth through laser scanning. The purpose of this preliminary study of the Cadent iTero digital impression system was to determine how the accuracy and reliability of linear measurements made using digital models compare with measurements obtained from control and plaster models. Methods: Nine different polyurethane typodonts demonstrating common occlusal conditions were used as control models through which traditional plaster models and digital models were reproduced and compared. Twentyfour linear measurements were recorded for each typodont (1-9) and model type (control, digital, plaster). Measurements were repeated by the same operator at three separate timepoints (intervals at least one week apart). Results: Mean linear measurements differed significantly by model type – p <0.0001. Tukey’s test demonstrated the mean value for digital models differed significantly from those of control and plaster models while means of control and plaster models were not significantly different. Measurements obtained from each model type were highly correlated and repeatable based on intraclass correlation evaluation (>0.99). Conclusions: Linear measurements obtained from digital models produced through the iTero digital impression system appear to be both accurate and reliable. Though statistically significant differences were demonstrated in this study, the magnitude of the differences was 0.06mm and is considered clinically insignificant by current orthodontic literature standards. The iTero digital impression system for creating digital models therefore appears to be an acceptable digital model development technique.

M.S.

1 online resource (viii, 57 p.) : ill., digital, PDF file.

Orthodontics;

Dentistry;

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Provided that a good enamel bonding procedure has taken place, in vitro and in vivo failure of orthodontic brackets most often takes place at the bracket base-cement interface.1 Current innovations in metal bracket base designs, therefore, most often have focused on improving bond strengths at this interface. Manufacturers claim their particular bracket base design will provide better bond strengths with less bracket failure than their competitors’ design. The purpose of this study was to evaluate the effect bracket base design on mean shear bond strength (SBS) at the bracket base-cement interface. The following four types of metal brackets were compared, ie, 20 Smart Clip brackets (80- gauge single-mesh base), 20 In-Ovation R brackets (SuperMesh, 81.50-gauge doublemesh base), 20 Quick brackets (machined, integral, microetched 3D hook base), and 20 T3 brackets (machined, integral, microetched base with mechanical undercuts). Ten bracketcylinders of each type were debonded after 30 minutes, to simulate initial arch wire engagement. The remaining bracket-cylinders (10 of each type) were debonded after 24 hours and 2,500 rounds of thermocycling. The mean SBS for 30 minute and 24 hour time intervals were as follows: SmartClip, 14.66 ± 2.0 MPa and 25.55 ± 3.6 MPa; In-Ovation R, 14.56 ± 5.0 MPa and 24.94 ± 2.3 MPa; Quick, 11.82 ± 3.9 MPa and 26.82 ± 4.2 MPa; and T3, 24.24 ± 3.8 MPa and 36.86 ± 3.7 MPa. Debonded specimens were examined using 10X magnification to determine adhesive remnants on the acrylic cylinders and bracket bases. The modified adhesive remnant index (MARI) comparisons indicated that three of the bracket types (SmartClip, In-Ovation R, Quick) had similar bracket failure modes, ie, higher frequencies of MARI score 3 (more than half of the adhesive remained on the cylinders and was removed from the bracket). However, the T3 bracket had higher incidence of MARI score 2 (more than half of the adhesive remained on the bracket and was removed from the cylinder). Bracket base design variations were found to significantly influence SBS. The T3 bracket had significantly higher bond strengths than the other bracket types (1-way ANOVA, P ≤ .05) at both 30 minutes and 24 hours. The Quick bracket had significantly lower SBS than the other bracket types at 30 minutes, but SBS values were not significantly different from the mesh-based brackets at 24 hours (P ≤ .05). All four bracket types showed a significant increase in SBS from 30 minutes to 24 hours (2-way ANOVA, P ≤ .05).

M.S.

1 online resource (vii, 34 p.) : ill., digital, PDF file.

Clinical Dentistry;

Dentistry;

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Bacteriophage can mediate the transfer of unrelated mobile genetic elements (MGE) from a carrier bacterial cell to the susceptible population around it. This transfer results in the spread of virulence or other accessory genes encoded on the MGE. During viral particle assembly, the MGE can discourage the formation of viable bacteriophage progeny by limiting the size of the particles to those large enough to encapsidate the MGE, but too small to fit the complete bacteriophage genome which is three times larger. Here, I present models for size determination by an external scaffolding protein which is independent of and dominant over the native bacteriophage scaffold, and for size determination by a pair of internal scaffolding proteins which function in combination with each other and with the native bacteriophage scaffold. Finally, I show distinct patterns of size determination in closely related paradigms.

PhD

1 online resource (ix, 113 p.) :ill., digital, PDF file.

Microbiology;

Joint Health Sciences;

bacteriophage, pathogenicity island, horizontal gene transfer, size determination, scaffold

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