Delineating the molecular basis of human genetic diseases: Epigenetic and functional studies

Identifying and characterizing the genes responsible for inherited human diseases will ultimately lead to a more holistic understanding of disease pathogenesis, catalyze new diagnostic and treatment modalities, and provide insights into basic biological processes. This dissertation presents research aimed at delineating the genetic and molecular basis of human diseases through epigenetic and functional studies and can be divided into two independent areas of research. The first area of research describes the development of two high-throughput melting curve based methods to assay DNA methylation, referred to as McMSP and McCOBRA. The goal of this project was to develop DNA methylation methods that can be used to rapidly determine the DNA methylation status at a specific locus in a large number of samples. McMSP and McCOBRA provide several advantages over existing methods, as they are simple, accurate, robust, and high-throughput making them applicable to large-scale DNA methylation studies. McMSP and McCOBRA were then used in an epigenetic study of the complex disease Ankylosing spondylitis (AS). Specifically, I tested the hypothesis that aberrant patterns of DNA methylation in five AS candidate genes contribute to disease susceptibility. While no statistically significant methylation differences were observed between cases and controls, this is the first study to investigate the hypothesis that epigenetic variation contributes to AS susceptibility and therefore provides the conceptual framework for future studies. ^ In the second area of research, I performed experiments to better delimit the function of aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), which when mutated causes various forms of inherited blindness such as Leber congenital amaurosis. A yeast two-hybrid screen was performed to identify putative AIPL1-interacting proteins. After screening 2 × 106 bovine retinal cDNA library clones, 6 unique putative AIPL1-interacting proteins were identified. While these 6 AIPL1 protein-protein interactions must be confirmed, their identification is an important step in understanding the functional role of AIPL1 within the retina and will provide insight into the molecular mechanisms underlying inherited blindness. ^

Metro de Madrid rolling stock models and comparative studies relating to comfort

This paper presents the work carried out by Metro de Madrid and the Railway Technology Research Centre (Polytechnic University of Madrid), aimed at setting up rolling stock simulation models with a high level of detail. To do this, the features of the SIMPACK simulation tool used to create models have been briefly outlined, explaining the main features of models in two of the series modelled: 7000 and 8000. Finally, the results obtained from comparing comfort in the 7000 and 8000 series are presented.

Structural and morphological studies on wet-etched InAlGaN barrier HEMT structures

The quaternary nitride-based high electron mobility transistor (HEMT) has been recently a focus of interest because of the possibility to grow lattice-matched barrier to GaN and tune the barrier bandgap at the same time.

Background Measurement Techniques and Sensitivity Studies for the SNO+ Neutrinoless Double Beta Decay Search

The control of radioactive backgrounds will be key in the search for neutrinoless double beta decay at the SNO+ experiment. Several aspects of the SNO+ back- grounds have been studied. The SNO+ tellurium purification process may require ultra low background ethanol as a reagent. A low background assay technique for ethanol was developed and used to identify a source of ethanol with measured 238U and 232Th concentrations below 2.8 10^-13 g/g and 10^-14 g/g respectively. It was also determined that at least 99:997% of the ethanol can be removed from the purified tellurium using forced air ow in order to reduce 14C contamination. In addition, a quality-control technique using an oxygen sensor was studied to monitor 222Rn contamination due to air leaking into the SNO+ scintillator during transport. The expected sensitivity of the technique is 0.1mBq/L or better depending on the oxygen sensor used. Finally, the dependence of SNO+ neutrinoless double beta decay sensitivity on internal background levels was studied using Monte Carlo simulation. The half-life limit to neutrinoless double beta decay of 130Te after 3 years of operation was found to be 4.8 1025 years under default conditions.

IVHS institutional issues and case studies. ADVANCE case study. Final report.

Federal Highway Administration, Washington, D.C.

IVHS institutional issues and case studies. TravTek case study. Final report.

Federal Highway Administration, Washington, D.C.

IVHS institutional issues and case studies. TRANSCOM/TRANSMIT case study. Final report.

Federal Highway Administration, Washington, D.C.

IVHS institutional issues and case studies. Westchester commuter central case study. Final report.

Federal Highway Administration, Washington, D.C.

IVHS institutional issues and case studies. Analysis and lessons learned. Final report.

Federal Highway Administration, Washington, D.C.