Investigation of the genetic susceptibility to osteoporosis in the Irish population

Osteoporosis is a complex skeletal disorder characterized by compromised bone strength. Variation in bone mineral density (BMD) is a contributing factor. The aim of this research as to select informative single nucleotide polymorphisms (SNPs) in potential candidate genes from loci suggestively linked to BMD variation for fine mapping. The gene regulated by oestrogen in breast cancer 1 (GREB1), located at 2p25.1, was selected. GREB1 transcription is initiated early in the oestrogen receptor alpha regulated pathway. There was significant association between GREB1_03 and BMD variation at the lumbar spine and femoral neck (FN) in the discovery cohort. Significant association was observed between GREB1_04 and FN BMD in the replication cohort. The development and differentiation enhancing factor 2, the integrin cytoplasmic domain associated protein 1 and A-disintegrin and metalloprotease 17 were selected due to their respective roles in cell mobility and adhesion. There was no linkage or association observed between the Chr2 cluster SNPs and BMD. Two factors in bone remodelling are the attraction of bone cell precursors and endocrine regulation of the process, primarily through the action of parathyroid hormone (PTH). The C-C chemokine receptor type 3 (CCR3) encodes a CC chemokine receptor expressed in osteoclast precursors. The PTH receptor type 1 (PTHR1) encodes a G-protein coupled receptor for PTH. Association was observed between CCR3 haplotypes and BMD variation at the FN. There was no linkage or association observed between PTHR1 SNPs and BMD variation. Population genetic studies with complex phenotypes endeavour to elucidate the traits genetic architecture. This study presents evidence of association between GREB1 and BMD variation and as such, introduces GREB1 as a novel gene target for osteoporosis genetics studies. It affirms that common genomic variants in PTHR1 are not associated with BMD variation in Caucasians and supports the evidence that CCR3 may be contributing to BMD variation

The examination of the traditional femininity and women’s lives in ancient China

This thesis explores the evolution of the concept of traditional Chinese femininity in relation to women’s lives in ancient China (221 BCE – A.D.1840). It proposes that the traditional Chinese femininity had been trying to seek a balance between the permanent principles and contingency plans for the stability and development of the society, which caused women’s humiliation and freedom. In reality, politicians and thinkers in ancient China had been transforming the concept of femininity itself to make it more adaptable to the social conditions of that time. This may be discussed in terms of three aspects. Firstly, the traditional concept of Chinese human relationships, including the ethical order, always emphasised the influence of individual behaviour on others and the overall stability and linked development of family, society and nation. Thus, both men and women, must be placed within this interrelated, interacting and cooperating relationship. Secondly, the association of family and country created an overlap of family and public affairs, which, objectively, facilitated the movement of women from the inner to the public arena. Thirdly, the notions of political and ethical morality and of men’s virtues and women’s virtues were integrated because of the union of family and nation. Therefore, typically virtuous women could be a source of encouragement for men and, furthermore, men formulated their virtues in the public space by formulating women’s virtues in the private space. The shaping of the gender image and concept of women in ancient China reflected the country’s changing cultural and gender norms. Chinese femininity and lifestyles, like Chinese history, were a continuous presence in the society but were also constantly changing. Through this study, it could be noted that Chinese women were not hidden and that their subjectivity and the concepts motivating them were not merely devised by a male-dominated society and culture.

Investigation of the function of the LNX family of E3 ubiquitin ligases in the nervous system

The Lnx1 (Ligand of Numb protein X 1) and Lnx2 genes belong to a family of PDZ domain-containing RING finger domain E3 ubiquitin ligases. mRNA expression for both genes have been reported in early murine central nervous system. However, there have been limited reports with regards to the expression patterns for both the proteins in vivo. Hence, we have attempted to characterize the significance of these proteins in the context of morphology and physiology of the central nervous system. Through our studies, we have attempted to examine closely the expression of these two genes in the murine central nervous system. We have also looked at novel interacting ligands for both proteins. Interacting partners have been examined with particular relevance to possible roles of their interactions with LNX1 and LNX2 in the functioning of the nervous system. Moreover, we have performed loss-of-function studies by way of creation and characterization of knockout mice.