Doctor of Philosophy

dissertationOver three decades have passed since the discovery of human immunodeficiency virus (HIV), and with no viable vaccine, new technologies to prevent the spread of the virus are urgently needed. Pre-exposure prophylaxis, the concept of chemically interrupting HIV transmission, effectively reduced HIV incidence in a number of clinical trials. However, it has been difficult to achieve high and consistent effectiveness in clinical trials due to variable adherence to the dosing regimens requiring frequent administration. This, along with the disproportionate burden of the HIV/AIDS pandemic in young women in sub- Saharan Africa, has catalyzed the research into long-acting, antiretroviral eluting drug delivery systems like intravaginal rings (IVR) in an attempt to increase adherence over dosage forms that require frequent administration, and provide a more consistent drug concentration where transmission occurs. However, IVR technology is generally limited to releasing small quantities of hydrophobic, low molecular weight species that can diffuse through the IVR elastomer. This dissertation describes two adaptable drug delivery platforms that increased the diversity of the drugs that can be delivered from IVRs. Polyether urethane reservoir IVRs were engineered for the delivery of the thermally and hydrolytically unstable prodrug tenofovir disoproxil fumarate. This drug presents a unique design challenge to minimize the hydrolytic drug degradation in the IVR core while also promoting hydration to solubilize and release the drug. This design delivered mg/day quantities of drug and conferred complete protection in macaques from multiple vaginal viral exposures. Next, we engineered a system that uncouples the mechanism of drug release from the interaction of the drug with the elastomer and provides nearly constant release of any stable molecule. In this system, orifices control the hydration rate of the hydrophilic matrix contained within the core of the IVR, and release of the drug-containing gel. We evaluated the utility of this system for the topical delivery of macromolecules, and multiple different small molecule antiretrovirals, specifically for the delivery of drug microparticles. This work describes the design and evaluation of antiretroviral eluting IVR systems that provide adaptable platforms for vaginal drug delivery

Doctor of Philosophy

dissertationThe objective of this study was to investigate the contribution of multiple demographic and religiosity variables as predictors of ambivalent sexism toward women in a sample of LDS adults. A nationwide sample of 3563 active or former LDS participants were recruited through online social media sites and email. The research design was correlational and used survey instruments. The main findings demonstrated that gender was significantly related to the endorsement of sexism. Overall, men had greater benevolent and hostilely sexist attitudes than women. Gender also moderated the relationship between religiosity and benevolent sexism when LDS activity and affiliation were predictors, such that men's endorsement of sexism increased at a greater rate than women's. Conversely, gender moderated the relationship between all religiosity measures and hostile sexism, such that as religiosity increased, women's endorsement of hostilely sexist attitudes increased more than men's did

Flow visualization and flow field measurements of a 1/12 scale tilt rotor aircraft in hover

The results are given of flow visualization studies and inflow velocity field measurements performed on a 1/12 scale model of the XV-15 tilt rotor aircraft in the hover mode. The complex recirculating flow due to the rotor-wake-body interactions characteristic of tilt rotors was studied visually using neutrally buoyant soap bubbles and quantitatively using hot wire anemometry. Still and video photography were used to record the flow patterns. Analysis of the photos and video provided information on the physical dimensions of the recirculating fountain flow and on details of the flow including the relative unsteadiness and turbulence characteristics of the flow. Recirculating flows were also observed along the length of the fuselage. Hot wire anemometry results indicate that the wing under the rotor acts to obstruct the inflow causing a deficit in the inflow velocities over the inboard region of the model. Hot wire anemometry also shows that the turbulence intensities in the inflow are much higher in the recirculating fountain reingestion zone

Defect tolerance of friction stir welds in DH36 steel

Friction stir welding of steel is in the early stages of development. The aim to commercialise this process creates a trade-off between welding time, cost and quality of the joint produced. Therefore, it becomes critical to analyse the lower quality bound of steel friction stir welds in conventional square edge butt welding configuration. Work has been undertaken to evaluate the microstructure and fatigue performance of 6 mm thick DH36 steel plates friction stir welded with sub-optimal process conditions, resulting in the development of embedded and surface breaking flaws. The defective weldments were characterised to understand the nature of the flaws and a programme of mechanical testing was undertaken (including fatigue assessment) to determine the relationship between the flaw geometry, location and weld quality. A number of characteristic flaws were identified and seen to interact with the samples’ fatigue fracture mechanisms. Samples with wormholes at the weld root produced the lowest fatigue performance. Fracture from incomplete fusion paths at the retreating side of the welds’ top surface was seen to correspond to the highest recorded fatigue lives. The work provides an insight into the complex nature of characteristic flaws in steel friction stir welds and their interaction with fatigue behaviour

Auditory and Visual Statistical Learning Are Not Related to ADHD Symptomatology: Evidence From a Research Domain Criteria (RDoC) Approach

Statistical learning is an implicit process that allows individuals to track and predict incoming events from their environment. Given that information is highly structured over time, events become predictable, allowing these individuals to make better sense of their environment. Among the studies that have examined statistical learning in attention deficit/hyperactivity disorder (ADHD), findings have been mixed. Our goal was to examine whether increased ADHD symptomatology related to decreased auditory and visual statistical learning abilities. To investigate this, we examined the entire range of ADHD symptomatology using a Research Domain Criteria approach with a clinically reliable questionnaire in addition to well-established auditory and visual statistical learning paradigms. Total ADHD symptomatology was not related to auditory and visual statistical learning. An identical pattern emerged when inattention and hyperactivity components were separated, indicating that neither of these distinct behavioral symptoms of ADHD are related to statistical learning abilities. Findings from the current study converge with other studies but go beyond finding a lack of a significant relationship – through Bayesian analyses, these data provide novel evidence directly supporting the hypothesis that ADHD symptomatology and statistical learning are decoupled. This finding held for overall levels of ADHD symptomatology as well as the subdomains of inattention and hyperactivity, suggesting that the ability to pick up on patterns in both auditory and visual domains is intact in ADHD. Future work should consider investigating statistical learning in ADHD across ages and beyond auditory and visual domains

Auditory Sensory Filtering and Development in Children with Autism Spectrum Disorder

Sensory filtering is the process of separating and distilling relevant sensory information from irrelevant, which in turn greatly reduces the quantity of sensory information that is fully processed and leads to significant increases in efficiency. Atypical sensory filtering can result in sensory hypo- or hypersensitivity — atypical sensory filtering and hypo/hypersensitivity have been observed in people with autism. Atypical sensory filtering contributes to canonical symptoms in Autism. Sensory filtering can be measured in a few different ways, one of which is the Acoustic Startle Response (ASR). ASR is a reflexively produced muscular reaction to sudden auditory stimuli. Our study aims to manipulate characteristics of auditory stimuli (acoustic reactivity, PPI, and habituation) and observe their subsequent effects on the startle response. Furthermore, observe potential differences in the startle response after these manipulations between ASD and neurotypical children. Differences between these two groups has been observed in prior literature, such as Takahashi et al.\u27s papers in 2014 and 2016, but results have been mixed. Our study hopes to provide more clarity to these mixed findings, through hypothesising that autistic participants will display increased startle compared to neurotypical children under various manipulation\u27s. This research may provide further evidence of sensory filtering differences in ASD, alongside gaining a greater understanding of the underpinnings of symptomology

STABLE ISOTOPES OF HYDROTHERMAL CARBONATE MINERALS IN THE BUTTE PORPHYRY-LODE DEPOSITS, MONTANA

The stable isotopic compositions of over 90 hydrothermal carbonate minerals in the Butte porphyry-lode system were analyzed. These samples came from the underground workings as well as the active Continental Pit area. Most material came from polymetallic “Main Stage” veins which post-date the porphyry Cu-Mo mineralization of Butte. Some samples from late calcite-stellerite veins were also included in the study. Rhodochrosite d13C and d18O values range from -8.3 to -2.9‰ (average of -6.7±1.0‰) and -1.8 to 12.8‰ (average of 3.6 ±3.4‰) respectively, while calcite d13C and d18O values range from -9.0 to -2.6‰ (average of -5.4 ± 1.5‰) and -4.4 to 12.3‰ (average of 6.2±2.8‰) respectively. These values are in agreement with the previous work of Garlick and Epstein (1966). Despite the strong ore-mineral zonation of the Main Stage veins of Butte, no systematic changes in stable isotope composition of carbonate minerals are seen across the district, or with depth. Late calcite samples have similar isotopic composition to carbonate minerals from Main Stage mineralization. Some isotopic re-equilibration with a lower temperature fluid may have taken place, with calcite more susceptible to isotopic resetting compared to less soluble and more abundant rhodochrosite. Based on the observed d18O values of rhodochrosite, and an inferred temperature of formation of Main Stage veins of 200 to 350°C, the vein forming fluids would have had d18O values in the range of -12.6 to 4.1, which suggests mixing of magmatic water with an evolved meteoric water. The stable isotopic composition of vein carbonates from Butte have similar d13C but different d18O values compared to the vein carbonate minerals from the nearby Coeur d’Alene district, Idaho. Whereas the two world-class silver-base metal mining districts may have inherited a similar carbon source, the much heavier d18O values of Coeur d’Alene carbonate suggest involvement of metamorphic fluids, as opposed to the porphyry-meteoric fluids that mineralized the veins of Butte

Flexible Thermoelectric Generators for Biomedical Applications

The market for implantable medical devices is growing rapidly. Research and Markets predicts that by the end of 2015 the market for pacemakers will be 5.1 billion dollars, and a projected growth of 13.82% between 2013 and 2018. The average lifespan of an implantable medical device’s battery is only 5 years, while the projected lifespan of the device itself is 10 years. There is an excess of invasive surgeries occurring to replace these batteries, costing the healthcare system millions of dollars and also causing patients a large degree of discomfort and pain. Thermoelectric generators have the potential to supplement and eventually replace these battery systems, allowing devices to reach their full lifespan. The process for developing thin film, and flexible thermoelectric generators was explored in this study with the intent of designing for biomedical applications. Screen-printing was used as the manufacturing method and several pastes were formulated and tested to compare their thermoelectric potential. A new breed of thermoelectric materials that were built from a bottom-up perspective was the precedent for this research. While they have shown great potential for creating bulk pellets, their application in thin films was still relatively unexplored. The most promising sample created had an electrical conductivity of 6775 S/m, a Seebeck of -125 μV/m and a power factor of 105 μW/m-K2. The potential and limitations of this process are discussed

Presynchronizing PGF2α and GnRH injections before timed artificial insemination CO-Synch + CIDR program

Fixed-time artificial insemination is an effective management tool that reduces the labor associated with more conventional artificial insemination programs requiring detection of estrus. The 7-day CO-Synch + controlled internal drug release (CIDR) insert protocol has been shown to effectively initiate estrus and ovulation in cycling and non-cycling suckled beef cows, producing pregnancy rates at or greater than 50% in beef cows. The gonadotropin-releasing hormone (GnRH) injection that begins the CO-Synch + CIDR program initiates ovulation in a large proportion of cows, particularly anestrous cows. The CIDR, which releases progesterone intravaginally, prevents short estrous cycles that usually follow the first postpartum ovulation in beef cows. Our hypothesis was that inducing estrus with a prostaglandin injection followed 3 days later with a GnRH injection, 7 days before applying the 7-day CO-Synch + CIDR protocol, might increase the percentage of cycling cows that would exhibit synchronous follicular waves after the onset of the CO-Synch + CIDR protocol. We also hypothesized that the additional GnRH injection would increase the percentage of anestrous cows that would ovulate, thereby increasing pregnancy outcomes

The Evolution of Gene Regulation in Drosophila.

Differences in gene expression drive phenotypic diversity. At the level of transcription, these differences are largely controlled by the complex interplay between trans-acting factors and the cis-regulatory sequences to which they bind. In this dissertation, I characterized how the regulation of gene expression has evolved both within and between several species of the Drosophila lineage. I began by describing current methodology to accurately quantify allele-specific expression (ASE) from RNA-seq data, comparing two different methods and highlighting sources of bias. Using this methodology, I measured allele-specific differences in F1 hybrids made by reciprocally crossing two strains of D. melanogaster. These two sets of genetically-identical hybrids differed only by which strain contributed the maternal or paternal allele, allowing me to test the hypothesis that D. melanogaster do not imprint their genome. Next, for that same intraspecific comparison as well as two interspecific comparisons, I measured total and allele-specific gene expression to categorize regulatory differences across divergence times ranging from 0.01-2.5 million years ago. This allowed me to test the hypothesis that cis-regulatory differences account for a higher proportion of the total regulatory differences between species, as well as to determine how patterns for inheritance of gene expression differ across an evolutionary timescale. Because all of these comparisons were made using female whole flies, I tested the prevalence of sex- and tissue-specific differences using gene expression data from female and male carcass and gonad tissues between D. pseudoobscura and its closely-related subspecies D. p. bogotana and their F1 hybrids. I determined that one must use caution when inferring patterns of regulatory divergence in whole flies, as the integration over all different tissue types can mask the complexity of gene regulation in individual tissues. The work in this dissertation expands our knowledge of how the regulation of gene expression differs across a well-characterized lineage and will continue to drive further studies of these phenomena in even more distantly-related species.PHDBioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/110328/4/Kraig_Stevenson_Dissertation.pd