Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics

Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.

Female sexuality in Ireland 1920 to 1940: Construction and regulation

The central objective of this study is an examination of discourses of Irish female sexuality and of the apparatuses of control designed for its surveillance and regulation in the period nineteen-twenty to nineteen-forty. It is argued that during this period sexuality, and in particular female sexuality, became established as an icon of national identity. This thesis demonstrated that this identity was given symbolic embodiment in the discursive construction of an idealised, feminine subject, a subject who had purity and sexual morality as her defining characteristics. It is argued that female roles and in particular female sexuality, emerged as contested issues in post-colonial Ireland. This is not unusual given that women are frequently constructed in nationalist discourses as repositories of cultural heritage and symbols of national identity (Kandiyoti 1993). This thesis demonstrates that the Catholic Church played a central role in this process of establishing female sexuality as a national icon. Furthermore, it illustrates that through a process of identification and classification, women, whose behaviour contested the prescribed sexual norm, were categorized and labeled as 'wayward girls' 'unmarried mothers' or 'prostitutes'and mechanisms for their control were set in place. Finally, this thesis reveals that the development of these control apparatuses was mediated by class, with the sexuality of working class women being a primary target of surveillance, regulation and indeed reformation.

The senior female international managerial career move: a qualitative study in a European context

Research investigating the position of women in management has, largely, been confined within national boundaries. Over the last fifteen years, empirical studies of women in international management have been undertaken, predominantly in North America. In this research field, many questions remain unanswered or have been only partially addressed. The particular focus of this study is on the senior female international managerial career move in Europe — a relatively unexplored area. Fifty senior female expatriate managers were interviewed, representing a wide range of industry and service sectors. The study, for the first time, assesses an exclusively senior sample of female managers who have made at least one international career move. This study of senior females in international management makes a theoretical contribution, not only to the analysis of gender and international human resource management, but also to wider debates within the contemporary women in management and career theory literatures. The aims of the study were to develop an understanding of the senior female international career move in a European context in order to more fully understand both the covert and overt barriers that may limit women’s international career opportunities. The results of the study show that the senior international career move has largely been developed along a linear male model of career progression, a development which, taken together with gender disparity both in organisations and family responsibilities, frequently prevents women employees from reaching senior managerial positions. The study proposes a model of the senior female international managerial career move, thereby contributing primarily to the international human resource management literature. The implications of the study for research literatures in women in management and career theory are also explored and a future research agenda developed.

Vascular calcification and mineral bone disorder in chronic kidney disease

Chronic Kidney Disease (CKD), osteoporosis and mild hyponatremia are all prevalent chronic conditions that may coexist and are often under-recognized. Mineral-Bone Disorder begins early in the natural history of CKD and results in complex abnormalities of bone which ultimately confers a well-established increased risk of fragility fractures in End Stage Kidney Disease. Hyponatremia is a novel, usually renal mediated metabolic perturbation, that most commonly occurs independently of the stage of renal dysfunction but which may also predispose to increased fracture risk. The extent -if any- to which either early stages of renal dysfunction or the presence of hyponatremia contribute to fracture occurrence in the general population, independently of osteoporosis, is unclear. Renal transplantation is the treatment of choice for ESKD and although it restores endogenous renal function it typically fails to normalize either the long term cardiovascular or fracture risk. One potential mechanism contributing to these elevated long-term risks and to diminished Health Related Quality of Life is persistent, post-transplant hyperparathyroidism. In this study we retrospectively examine the association of renal function and serum sodium with Bone Mineral Density and fracture occurrence in a retrospective cohort of 1930 female members of the general population who underwent routine DXA scan. We then prospectively recruited a cohort of 90 renal transplant recipients in order to examine the association of post transplant parathyroid hormone (PTH) level with measures of CKD Mineral Bone Disorder, including, DXA Bone Mineral Density, Vascular Calcification (assessed using both abdominal radiography and CT techniques, as well as indirectly by carotid-femoral Pulse Wave Velocity) and Quality of Life (using the Short Form-12 and a PTH specific symptom score). In the retrospective DXA cohort, moderate CKD (eGFR 30-59ml/min/1.73m2) and hyponatremia (<135mmol/L) were associated with fracture occurrence, independently of BMD, with an adjusted Odds Ratio (95% Confidence Interval), of 1.37 (1.0, 1.89) and 2.25 (1.24, 4.09) respectively. In the renal transplant study, PTH was independently associated with the presence of osteoporosis, adjusted Odds Ratio (95% Confidence Interval), 1.15 (per 10ng/ml increment), (1.04, 1.26). The presence of osteoporosis but not PTH was independently associated with measures of vascular calcification, adjusted ß (95% Confidence Interval), 12.45, (1.16, 23.75). Of the eight quality-of-life domains examined, post-transplant PTH (per 10ng/ml increment), was only significantly and independently associated with reduced Physical Functioning, (95% Confidence Interval), 1.12 (1.01, 1.23). CKD and hyponatremia are both common health problems that may contribute to fracture occurrence in the general population, a major on-going public health concern. PTH and decreased Bone Mineral Density may signal sub-optimal long-term outcomes post renal transplantation, influencing bone and vascular health and to a limited extent long term Health Related Quality of Life

Molecular analysis of inflammatory mechanisms associated with Escherichia coli and inflammatory bowel diseases

Inflammatory bowel diseases (IBD), encompasses a range of chronic, immune-mediated inflammatory disorders that are usually classified under two major relapsing conditions, Crohn’s Disease (CD) and ulcerative colitis (UC). Extensive studies in the last decades have suggested that the etiology of IBD involves environmental and genetic factors that lead to dysfunction of epithelial barrier with consequent deregulation of the mucosal immune system and inadequate responses to gut microbiota.Over the last decade, the microbial species that has attracted the most attention, with respect to CD etiology, is Eschericia coli. In CD tissue, E. coli antigens have also been identified in macrophages within the lamina propria, granulomas, and in the germinal centres of mesenteric lymph nodes of patients. They have been shown to adhere to and invade intestinal epithelial cells whilst also being able to extensively replicate within macrophages. Through the work of genome-wide association studies (GWAS), there is growing evidence to suggest that the microbial imbalance between commensal and pathogenic bacteria in the gut is aided by a defect in the innate immune system. Autophagy represents a recently investigated pathway that is believed to contribute to the pathogenesis of CD, with studies identified a variant of the autophagy gene, ATG16L1, as a susceptibility gene. The aim of my thesis was to study the cellular and molecular mechanism promoted by E.coli strains in epithelial cells and to assess their contribution to IBD pathology. To achieve this we focused on developing both an in vitro and in vivo model of AIEC infection. This allowed us to further our knowledge on possible mechanisms utilised by AIEC that promoted their survival, as well as developing a better understanding of host reactions. We demonstrate a new survival mechanism promoted by E.coli HM605, whereby it induces the expression of the anti-apoptotic proteins Bcl-XL and BCL2, all of which is exacerbated in an autophagy deficient system. We have also demonstrated the presence of AIEC-induced inflammasome responses in epithelial cells which are exacerbated in an autophagy deficient system and expression of NOD-like receptors (NLRs) which might mediate inflammasome responses in vivo. Finally, we used the Citrobacter rodentium model of infectious colitis to identify Pellino3 as an important mediator in the NOD2 pathway and regulator of intestinal inflammation. In summary, we have developed robust and versatile models of AIEC infection as well as provide new insights into AIEC mediated survival pathways. The collected data provides a new perception into why AIEC bacteria are able to prosper in conditions associated with Crohn’s disease patients with a defect in autophagy.

"Ladyes, damesels, and jantilwomen": female autonomy and authority in Sir Thomas Malory's Morte Darthur

Popular medieval English romances were composed and received within the social consciousness of a distinctly patriarchal culture. This study examines the way in which the dynamic of these texts is significantly influenced by the consequences of female endeavour, in the context of an autonomous feminine presence in both the real and imagined worlds of medieval England, and the authority with which this is presented in various narratives, with a particular focus on Sir Thomas Malory’s Morte Darthur. Chapter One of this study establishes the social and economic positioning of the female in fifteenth-century England, and her capacity for literary engagement; I will then apply this model of female autonomy and authority to a wider discussion of texts contemporary with Malory in Chapters Two and Three, in anticipation of a more detailed study of Le Morte Darthur in Chapters Four and Five. My research explores the female presence and influence in these texts according to certain types: namely the lover, the victim, the ruler, and the temptress. In the case of Malory, the crux of my observations centres on the paradox of the capacity for power in perceived vulnerability, incorporating the presentation of women in this patriarchal culture as being vulnerable and in need of protection, while simultaneously acting as a significant threat to chivalric society by manipulating this apparent fragility, to the detriment of the chivalric knight. In this sense, women can be perceived as being an architect of the romance world, while simultaneously acting as its saboteur. In essence, this study offers an innovative interpretation of female autonomy and authority in medieval romance, presenting an exploration of the physical, intellectual, and emotional placement of women in both the historical and literary worlds of fifteenth-century England, while examining the implications of female conduct on Malory’s Arthurian society.