Redefining military memorials and commemoration and how they have changed since the 19th century with a focus on Anglo-American practice

This thesis is a study of military memorials and commemoration with a focus on Anglo-American practice. The main question is: How has history defined military memorials and commemoration and how have they changed since the 19th century. In an effort to resolve this, the work examines both historic and contemporary forms of memorials and commemoration and establishes that remembrance in sites of collective memory has been influenced by politics, conflicts and religion. Much has been written since the Great War about remembrance and memorialization; however, there is no common lexicon throughout the literature. In order to better explain and understand this complex subject, the work includes an up-to-date literature review and for the first time, terminologies are properly explained and defined. Particular attention is placed on recognizing important military legacies, being familiar with spiritual influences and identifying classic and new signs of remembrance. The thesis contends that commemoration is composed of three key principles – recognition, respect and reflection – that are intractably linked to the fabric of memorials. It also argues that it is time for the study of memorials to come of age and proposes Memorialogy as an interdisciplinary field of study of memorials and associated commemorative practices. Moreover, a more modern, adaptive, General Classification System is presented as a means of identifying and re-defining memorials according to certain groups, types and forms. Lastly, this thesis examines how peacekeeping and peace support operations are being memorialized and how the American tragic events of 11 September 2001 and the war in Afghanistan have forever changed the nature of memorials and commemoration within Canada and elsewhere. This work goes beyond what has been studied and written about over the last century and provides a deeper level of analysis and a fresh approach to understanding the field of Memorialogy.

Molecular and cellular aspects of the SREBP pathway

The SREBP (sterol response element binding proteins) transcription factors are central to regulating de novo biosynthesis of cholesterol and fatty acids. The SREBPs are regulated by retention or escape from the ER to the Golgi where they are proteolytically cleaved into active forms. The SREBP cleavage activating protein (SCAP) and the INSIG proteins are essential in this regulatory process. The aim of this thesis is to further characterise the molecular and cellular aspects surrounding regulation of SREBP processing. SREBP and SCAP are known to interact via their carboxy-terminal regulatory domains (CTDs) but this interaction is poorly characterised. Significant steps were achieved in this thesis towards specific mapping of the interaction site. These included cloning and over expression and partial purification of tagged SREBP1 and SREBP2 CTDs and probing of a SCAP peptide array with the CTDs. Results from the SREBP2 probing were difficult to interpret due to insolubility issues with the protein, however, probing with SREBP1 revealed five potential binding sites which were detected reproducibly. Further research is necessary to overcome SREBP2 insolubility issues and to confirm the identified SREBP1 interaction site(s) on SCAP. INSIG1 has a central role in regulating SREBP processing and in regulating stability of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate limiting enzyme in cholesterol biosynthesis. There are two protein isoforms of human INSIG1 produced through the use of two in-frame alternative start sites. Bioinformatic analysis indicated that the presence of two in-frame start sites within the 5-prime region of INSIG1 mRNA is highly conserved and that production of two isoforms of INSIG1is likely a conserved event. Functional differences between these two isoforms were explored. No difference in either the regulation of SREBP processing or HMGCR degradation between the INSIG1 isoforms was observed and the functional significance of the two isoforms is as yet unclear. The final part of this thesis focused on enhancing the cytotoxicity of statins by targeted inhibition of SREBP processing by oxysterols. Statins have significant potential as anti-cancer agents as they inhibit the activity of HMGCR leading to a deficiency in mevalonate which is essential for cell survival. The levels of HMGCR fluctuate widely due to cholesterol feedback of SREBP processing. The relationship between sterol feedback and statin mediated cell death was investigated in depth in HeLa cells. Down regulation of SREBP processing by sterols significantly enhanced the efficacy of statin mediated cell death. Investigation of sterol feedback in additional cancer cell lines showed that sterol feedback was absent in cell lines A- 498, DU-145, MCF-7 and MeWo but was present in cell lines HT-29, HepG2 and KYSE-70. In the latter inhibition of SREBP processing using oxysterols significantly enhanced statin cytotoxicity. The results indicate that this approach is valid to enhance statin cytotoxicity in cancer cells, but may be limited by deregulation of SREBP processing and off target effects of statins, which were observed for some of the cancer cell lines screened.