GENOME-WIDE ASSOCIATION STUDIES AT THE INTERFACE OF ALZHEIMER’S DISEASE AND EPIDEMIOLOGICALLY RELATED DISORDERS

Genome-wide association studies (GWAS)s provide an unbiased means of exploring the landscape of complex genetic disease. As such, these studies have identified genetic variants that are robustly associated with a multitude of conditions. I hypothesize that these genetic variants serve as excellent tools for evaluation of the genetic interface between epidemiologically related conditions. Herein, I test the association between SNPs associated with either (i) plasma lipids, (ii) rheumatoid arthritis (RA) or (iii) diabetes mellitus (DM) and late-onset Alzheimer’s disease (AD) to identify shared genetic variants. Regarding the most significantly AD-associated variants, I have also attempted to elucidate their molecular function. Only cholesterol-associated SNPs, as a group, are significantly associated with AD. This association remains after excluding APOE SNPs and suggests that peripheral and or central cholesterol metabolism contribute to AD risk. The general lack of association between RA-associated SNPs and AD is also significant in that these data challenge the hypothesis that genetic variants that increase risk of RA confer protection against AD. Functional studies of variants exhibiting novel associations with AD reveal that the lipid-associated SNP rs3846662 modulates HMGCR exon 13 splicing differentially in different cell types. Although less clear, trends were also observed between the RA-associated rs2837960 and the expression of several BACE2 isoforms, and between the DM-associated rs7804356 and expression of a rare SKAP2 isoform, respectively. In conclusion, the overlap of lipid-, RA- or DM-associated SNPs with AD is modest but in several instances significant. Continued analysis of the interface between GWAS of separate conditions will likely facilitate novel associations missed by conventional GWAS. Furthermore, the identification of functional variants associated with multiple conditions should provide insight into novel mechanisms of disease and may lead to the identification of new therapeutic targets in an era of personalized genomic medicine

Controlling Grain Size in Cold Worked and Annealed 1100 Aluminum to Optimize Ductility in Rocket Diaphragm Systems

Liquid propellant rocket diaphragms require extreme ductility. 1100 Aluminum is used for its high ductility, but the post-processing cold work and subsequent anneal result in excessively large grains. The effect of heat treatment and cold work on grain size in 1100 aluminum was explored. The samples were cold worked to 0, 5, 10, 15 and 30% using tensile elongation. The samples were then heat treated per AMS 2770 with either a Steel Conduction (1000 – 1150°F/min) or a Production (16 – 18°F/min) heating rate. The grain size of the samples were measured using the mean lineal intercept method. The grain diameter ranged from 81 – 189 μm for the Production rate and 83 – 209 μm for the Steel Conduction rate. The 15% cold worked Production rate samples were found to have significantly larger grains than those of the smaller cold work amounts as well as the 15% cold worked Steel Conduction rate samples. This indicated an interaction between the 15% cold work amount and the Production heat treatment which allowed for significant grain growth. The 30% cold worked samples were found to have grain growth in both heat treatments with the largest average grain diameters. The results indicate that the longer times at elevated temperatures during the Production heat treatment allow for significant grain growth at lower cold work amounts. In addition, grain growth is unavoidable for 30% cold work regardless of heating rate

MEMS 411: Lift Demonstration

A portable lift demonstration was requested to get children interested and thinking about what happens with fluid movement. The demonstration had size and weight requirements, which were both met. Accuracy of lift force representation was not requested, but simple force and flow visualizations were required. The demonstration had variable wind speeds, and showed the change in force with change in angle of attack

Validation and Verification of the Wray-Agarwal Turbulence and Algebraic Transition Models for 2D External Airfoil Flows

Validation and verification benchmark test cases are employed in computational fluid dynamics (CFD) to determine the best practices in application of various CFD tools. These cases focus on the geometry modeling, mesh generation, numerical algorithms, and turbulence models to ensure consistent and accurate numerical simulation of physical phenomena. Assessing model accuracy is essential to identify areas of improvement in various turbulence models. Flow past several symmetric NACA airfoils, namely NACA 0012, NACA 0015 and NACA 0018 are standard test cases for validating and evaluating turbulence models’ accuracy since the experimental data is available for these airfoils. Available wind tunnel data allows for testing turbulence models’ capability to predict lift, drag, and pressure distributions for various angles of attack ranging at high Reynolds numbers. In this study, two turbulence models are compared to experimental data for the NACA 0012, 0015, and 0018 airfoils. The two turbulence models are the well-known one equation Spalart-Allmaras (SA) and the recently developed Wray-Agarwal (WA) model. Numerical results show that both turbulence models are capable of accurately predicting lift and pressure coefficients but generally over predict drag. However, the WA model exhibits higher accuracy in predicting lift at high angles of attack for two of the airfoils and peak pressure for NACA 0012 airfoil. The Wray-Agarwal Algebraic Transition (WA-AT) model is a recently proposed new transition model with the goal to obtain similar level or better accuracy with substantially less computational cost compared to existing three (k-kl-ω) or four ( ) equation transition models. The WA-AT model uses the wall distance free version of WA turbulence model (WA2018) in combination with an algebraic transition model. The model has been previously validated for various ERCOFTAC benchmark flat plate cases and for some aerodynamic bodies. To further validate this model, the transitional flows past NACA 0012, 0015, and 0018 airfoils are simulated for a range of Reynolds numbers, turbulence intensities, and angles of attack in ANSYS Fluent. The NACA airfoil cases are simulated at angles of attack from zero to ten degrees, and Reynolds numbers ranging from to , and turbulence intensities ranging from 0.07% to 0.3%. The validation studies show similar or improved predictions using the WA-AT model over the Langtry-Menter’s four equation transition-SST (k –ω – γ - Reθt) model for pressure, drag, lift, and transition location. Overall, the results demonstrate that the WA-AT model offers similar or better accuracy as the four-equation transition-SST model for simulation of transitional flow over NACA 0012, 0015, and 0018 airfoils at much less computational cost. In NASA’s High Fidelity CFD Workshop 2022, the Joukowski airfoil was identified as a benchmark verification case to test the convergence behavior of different turbulence models in different CFD solvers with particular emphasis on SA-neg-QCR 2000 turbulence model. This thesis also studies the accuracy and convergence behavior of Wray-Agarwal (WA) and Spalart-Allmaras (SA) one equation turbulence models by computing the flow past Joukowski airfoil on a sequence of seven workshop specified grids from coarse to fine. The benchmark case has free stream Mach number of 0.15, chord Reynolds number of 3x106 and angle of attack of 0 degree. The goal is to evaluate the convergence behavior of drag coefficient on a sequence of seven grids using WA and original version of SA model in ANSYS Fluent. Both models exhibit nearly first order convergence rates for first order solutions and second order convergence rates for second order solutions. There is no notable difference in the convergence rates between the two turbulence models for both first order and second order implementations

Characterizing the role of MTW1 in the kinetochore of the pathogenic yeast Cryptococcus neoformans

Cryptococcus neoformans is a basidiomycetous yeast with clinical importance due to its role as an opportunistic pathogen in immunocompromised individuals. Upon exposure to C. neoformans patients may develop a disease known as cryptococcosis, a condition associated with pulmonary infections that may result in lethal meningoencephalitis. This disease is often accompanied by aneuploidies of single or multiple chromosomes in a subpopulation of the infecting cells, leading to the idea that missegregation of chromosomes during infection may be a way for this organism to deal with stresses and acquiring antifungal resistance. Because this species is rapidly developing resistance to many of the prevalent antifungal treatments, a need exists for more potent therapies with fewer side effects. The molecular biology concerning cellular reproduction and division in C. neoformans is poorly understood for such an important fungal pathogen. The research performed so far has produced information about such structures as the centromeric DNA of their chromosomes and the kinetochore protein superstructure that links the spindle microtubules to the centromeres. Understanding how chromosome segregation occurs in C. neoformans may bring about better therapies: if it can be shown that homologous proteins perform the same actions in Cryptococcus as they do in other organisms then these proteins may potentially become targets for future studies to determine the mechanism linking the presence of antifungal chemicals to aneuploidy. The kinetochore protein complex is essential for segregation of chromosomes. Previous experiments have described a protein essential to the structure and function of the yeast kinetochore. The necessity of this protein for kinetochore function was first determined using an Schizosaccharomyces pombe strain carrying a temperature-sensitive mutation in the Mis12 gene that causes the protein to malfunction above a certain temperature. It was found that when grown above the restrictive temperature cells were unable to complete mitotic segregation, with the dividing nucleus stuck in the neck between budding cells. A later study described the budding yeast homolog MTW1 (Mis12-like protein) in Saccharomyces cerevisiae using a similar temperature-sensitive mutant and yielded similar results. This protein is part of a subcomplex of kinetochore proteins called the MIND complex. One goal of this project is to characterize the MTW1 homolog in C. neoformans in order to determine whether it maintains the functional importance to kinetochore structure exhibited by the previously described homologs. This has been addressed through the construction of similar temperature-sensitive mutants and by regulating the gene expression through regulatable CTR4 promoter. These strains were created through the use of overlap PCR and biolistic transformation. Molecular and phenotypic characterizations have been performed on these strains and include growth and morphological analyses. Results have confirmed the presence of the desired mutations and have shown some inhibitory effect on growth under restrictive conditions. RNA interference was performed in an effort to demonstrate the necessity of various kinetochore proteins. Initial results indicate that MTW1, along with the outer kinetochore gene DAD2, are not essential whereas several other MIND complex genes (NNF1, DSN1) and inner (CSE4, MIF2) and outer (DAD1) kinetochore genes were shown to be necessary for viability of the yeast cells. These results are in accordance with those obtained through the use of strains with conditional mutations in MTW1. These results imply that while CnMTW1 probably acts in the same capacity as that of its ascomycetous homologs and is necessary for optimal kinetochore function, it is not essential for chromosome segregation

Increasing the intensity and comprehensiveness of aphasia services: identification of key factors influencing implementation across six countries

Background: Aphasia services are currently faced by increasing evidence for therapy of greater intensity and comprehensiveness. Intensive Comprehensive Aphasia Programs (ICAPs) combine these elements in an evidence-based, time-limited group program. The incorporation of new service delivery models in routine clinical practice is, however, likely to pose challenges for both the service provider and administering clinicians. This program of research aims to identify these challenges from the perspective of aphasia clinicians from six countries and will seek to trial potential solutions. Continual advancements in global communication technologies suggest that solutions will be easily shared and accessed across multiple countries. Aims: To identify the perceived and experienced barriers and facilitators to the implementation of 1) intensive aphasia services, 2) comprehensive aphasia services, and 3) ICAPs, from aphasia clinicians across six countries. Methods and procedures: A qualitative enquiry approach included data from six focus groups (n = 34 participants) in Australia, New Zealand, Canada, United States of America (USA), United Kingdom (UK), and Ireland. A thematic analysis of focus group data was informed by the Theoretical Domains Framework (TDF). Outcomes and results: Five prominent theoretical domains from the TDF influenced the implementation of all three aphasia service types across participating countries: environmental context and resources, beliefs about consequences, social/professional role and identity, skills, and knowledge. Four overarching themes assisted the identification and explanation of the key barriers and facilitators: 1. Collaboration, joint initiatives and partnerships, 2. Advocacy, the promotion of aphasia services and evidence-based practice, 3. Innovation, the ability to problem solve challenges, and 4. Culture, the influence of underlying values. Conclusions: The results of this study will inform the development of a theoretically informed intervention to improve health services’ adherence to aphasia best practice recommendations