3 resultados para 1250
em CORA - Cork Open Research Archive - University College Cork - Ireland
Resumo:
This thesis is about a class of literate professionals that served as hereditary brehons, poets and doctors to the Gaelic aristocracy over a period from c.1250-c.1630. My investigation into these families brings together evidence from Gaelic and English sources to highlight the work these families did for their patrons, their status in society and their subsequent fall in the seventeenth century. Such a broad canvas allows us to observe the vibrancy of Gaelic literary culture as these families adapted to the changing political landscape to absorb new Anglo-Norman patrons and assimilated English and Continental ideas while maintaining their distinctive identity. I want to look beyond the ideology espoused by these families to look at the practical choices members of these families made to maintain their status and relevance in a changing social context. To do this I have chosen to focus on each of the three professions in individual chapters to highlight the continuities and changes within the professions and ultimately by comparing the three groups to gauge the success or failure of these professional families to adapt to the encroachment of the New English and the ultimate collapse of the Gaelic world. This thesis takes a holistic approach to these families by including branches of these families not engaged in the hereditary profession. It seeks to provide a broader picture of Gaelic society below the level of the aristocracy by looking at the geographic distribution of these families, their proximity to centres of power, and to land and sea routes that can indicate their involvement in alternative economic activities.
Resumo:
Background: Rates of self-harm are high and have recently increased. This trend and the repetitive nature of self-harm pose a significant challenge to mental health services. Aims: To determine the efficacy of a structured group problem-solving skills training (PST) programme as an intervention approach for self-harm in addition to treatment as usual (TAU) as offered by mental health services. Method: A total of 433 participants (aged 18-64 years) were randomly assigned to TAU plus PST or TAU alone. Assessments were carried out at baseline and at 6-week and 6-month follow-up and repeated hospital-treated self-harm was ascertained at 12-month follow-up. Results: The treatment groups did not differ in rates of repeated self-harm at 6-week, 6-month and 12-month follow-up. Both treatment groups showed significant improvements in psychological and social functioning at follow-up. Only one measure (needing and receiving practical help from those closest to them) showed a positive treatment effect at 6-week (P = 0.004) and 6-month (P = 0.01) follow-up. Repetition was not associated with waiting time in the PST group. Conclusions: This brief intervention for self-harm is no more effective than treatment as usual. Further work is required to establish whether a modified, more intensive programme delivered sooner after the index episode would be effective.
Resumo:
The Insulin-like Growth Factor 1 Receptor (IGF-1R) has an essential function in normal cell growth and in cancer progression. However, anti-IGF-1R therapies have mostly been withdrawn from clinical trials owing to a lack of efficacy and predictive biomarkers. IGF-1R activity and signalling in cancer cells is regulated by its C-terminal tail, and in particular, by a motif that encompasses tyrosines 1250 and 1251 flanked by serines 1248 and 1252 (1248- SFYYS-1252). Mutation of Y1250/1251 greatly reduces IGF-1-promoted cell migration, interaction with the scaffolding protein RACK1 in the context Integrin signalling, and IGF- 1R kinase activity. Here we investigated the phosphorylation of the SFYYS motif and characterise the conditions under which this motif may be phosphorylated under. As phosphorylated residues, the SFYYS motif may also serve to recruit interacting proteins to the IGF-1R. To this end we identified a novel IGF-1R interacting partner which requires phosphorylated residues in the SFYYS motif to interact with the IGF-1R. This interaction was found to be IGF-1-dependent, and required the scaffold protein RACK1. The interaction of this binding protein with the IGF-1R likely functions to promote maximal phosphorylation of Shc and ERK in IGF-1-stimulated cell migration, and may be important for IGF-1 signalling in cancer cells. Lastly, we have investigated possible kinases that may confer resistance or sensitivity to the IGF-1R kinase inhibitor BMS-754807. In this screen we identified ATR as a mediator of resistance and showed that suppression or chemical inhibition of ATR synergised with BMS-754807 to reduce colony formation. This work has contributes to our understanding of IGF-1R kinase regulation and signalling and suggests that administration of anti-IGF-1R drugs with ATR inhibitors may have therapeutic benefit.