Doctor of Philosophy

dissertationCerebral cavernous malformation (CCM), or cavernous angioma, is a common disease that can occur sporadically or familially with autosomal dominant inheritance. CCMs are vascular malformations, predominantly in the brain, consisting of dilated, thinwalled, blood-filled caverns. These lesions can lead to headaches, seizures, focal neurological deficits, and hemorrhagic stroke, but the only available treatment is surgical resection. Familial CCM has been linked to three genes: KRIT1, CCM2, or PDCD10. These genes encode structurally unrelated proteins of poorly understood function, but the three are hypothesized to work as a complex1. Generation of an animal model that faithfully recapitulates CCM disease would greatly benefit the study of the natural history and pathophysiology of CCM and the search for therapeutics. In this dissertation, I demonstrate that Pdcd10 and CCM2 signal through distinct pathways, but that loss of heterozygosity is a common genetic mechanism by which both genes lead to CCM disease. I show that Ccm2 acts to suppress the activity of the small GTPase RhoA, whereas Pdcd10 acts through the GCKIII family of kinases. Studies of knockout mice demonstrate that Ccm2 and Pdcd10 serve essential, but different, functions in the endothelium during development. I also examined Pdcd10 function using the fruitfly Drosophila melanogaster, which has a homolog for PDCD10 but not KRIT1 and CCM2. These studies revealed that Pdcd10 regulates lumen formation in the Drosophila tracheal system and genetically interacts with GCKIII, distinguishing it from Ccm2 and indicating that Pdcd10 can function independently of the other CCM genes. Despite these differences in function, loss of heterozygosity at either locus results in the highly penetrant formation of dilated, vascular caverns in mice that phenocopy human CCM histologically and radiologically. My studies led to the surprising conclusion that the CCM proteins do not share a common signaling mechanism. The distinct pathways, however, lead to a common pathology by the genetic mechanism of loss of heterozygosity. My work has also begun to elucidate the underlying biochemistry behind CCM, which may suggest potential therapies. The establishment of an animal model with highly penetrant disease, similar to human disease, is a powerful first step in developing these therapies

The Attitude of Manitoba High School Principals Toward Physical Education

The purpose of this study was to discover the attitude toward physical education of the one-hundred Manitoba principals of high schools with enrollments over one hundred and fifty. For the basis of evaluation, the Wear Attitude Inventory was incorporated into a questionnaire, to which ninety-one principals responded. Comparisons between different groups of principals to determine attitude differences were also made. These comparisons were made between: Older and younger principals; principals of schools with small enrollment (less than 300) and principals of schools with- larger enrollment; principals with different educational preparation; principals who engaged in personal recreational sports activities and principals who indicated they did not -participate in them; supervisors and non-supervisors; and principals of schools which had a longer class time for physical education and principals of schools with a shorter class time. AS an entire group, the principals had a favorable attitude toward physical education, but the attitude was not highly favorable. No statistically significant attitude differences were found between the different comparison groups

Deconstructing Sins from the Moral Compass of Don Carlos Cobello in F. Sionil Jose’s Sins

The novel “Sins” by F. Sionil Jose depicts the adventurous life of an affluent man whose confessions rationalize the sins he committed as judged only against social standards but ironically narrates the dire consequences as moral concepts. The study aims to deconstruct the prevailing theme of sins as social notions to prove that sins are moral constructs and to teach that morality is an inherent feature of man's mortality. To establish these contradicting ideologies, the study utilized the deconstruction approach in literary criticism by Jacques Derrida. Deconstructionism exposes embedded ideologies by revealing inconsistencies in the text. Specifically, content analysis was integrated to examine words and phrases in-depth to analyze rooted messages. This paper found out that the novel claims incest, premarital sex, and sexual exploitation as sins established only by society and should be judged by it and not beyond it. However, through investigating its instabilities, it was revealed that the novel actually justifies sins against the character's morality because of his belief in mortality as the recipient of suffering, forgiveness, retributive punishments, and even conscience. Thus, the novel inculcates that sins are not just mere social concepts, they are the foremost moral constructs

PD5: a general purpose library for primer design software

BACKGROUND: Complex PCR applications for large genome-scale projects require fast, reliable and often highly sophisticated primer design software applications. Presently, such applications use pipelining methods to utilise many third party applications and this involves file parsing, interfacing and data conversion, which is slow and prone to error. A fully integrated suite of software tools for primer design would considerably improve the development time, the processing speed, and the reliability of bespoke primer design software applications. RESULTS: The PD5 software library is an open-source collection of classes and utilities, providing a complete collection of software building blocks for primer design and analysis. It is written in object-oriented C(++) with an emphasis on classes suitable for efficient and rapid development of bespoke primer design programs. The modular design of the software library simplifies the development of specific applications and also integration with existing third party software where necessary. We demonstrate several applications created using this software library that have already proved to be effective, but we view the project as a dynamic environment for building primer design software and it is open for future development by the bioinformatics community. Therefore, the PD5 software library is published under the terms of the GNU General Public License, which guarantee access to source-code and allow redistribution and modification. CONCLUSIONS: The PD5 software library is downloadable from Google Code and the accompanying Wiki includes instructions and examples: http://code.google.com/p/primer-desig