Mícheál Coimín agus a shaothar

Is é a chuirim romham a dhéanamh sa tráchtas seo ná eagar a chur ar shaothar liteartha Mhíchíl Coimín; file agus údar próis a bhí ag saothrú na litríochta i gCill Chorcoráin, Contae an Chláir san ochtú haois déag. D’éag sé sa bhliain 1760 nuair a bhí sé beagnach 90 bliain d’aois. Is féidir a rá go bhfuil an Coimíneach, ó thaobh chanóin litríocht na Gaeilge de i measc na mionscríbhneoirí, agus níl aon dabht faoi ach go bhfuil an-chuid de léitheoirí na Gaeilge sa lá atá inniu ann dall ar a chuid scríbhneoireachta. Tá cáil air mar údar ‘Laoi Oisín i dTír na n-Óg’ ach mar a léireofar sa tráchtas seo, tá gach cuma ar an scéal nárbh é a scríobh. Tá againn óna pheann dornán beag dánta agus dhá scéal rómánsaíochta (‘Eachtra Thoroilbh Mhic Stairn’ agus ‘Eachtra a Thriúr Mac’) a scríobh sé nuair a bhí an traidisiún sin próis ar an dé deiridh. Níl aon chuid dá shaothar ar fáil in eagráin a shásódh léitheoirí an lae inniu ná na critéir scolártha atá i bhfeidhm anois. Níor tháinig aon lámhscríbhinn, i lámh an Choimínigh, anuas chugainn agus dá bhrí sin bhí dúshlán áirithe ag baint leis an bpróiseas eagarthóireachta. Sa tráchtas rinne mé an suirbhé is iomláine go dtí seo ar a shaothar i dtraidisiún na lámhscríbhinní agus ar na scríobhaithe a rinne é a sheachadadh. Bhí sé mar aidhm agam teacht ar na lámhscríbhinní is údarásaí sa traidisiún d’fhonn eagráin a réiteach a bheadh dílis dá bhunshaothar. Chomh maith leis sin tabharfar cuntas ar a bheatha agus ar a chúlra liteartha, agus déanfar iniúchadh criticiúil ar a shaothar próis agus fileata.

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.

Effectuation and its implications for socio-technical design science research in information systems

We study the implications of the effectuation concept for socio-technical artifact design as part of the design science research (DSR) process in information systems (IS). Effectuation logic is the opposite of causal logic. Ef-fectuation does not focus on causes to achieve a particular effect, but on the possibilities that can be achieved with extant means and resources. Viewing so-cio-technical IS DSR through an effectuation lens highlights the possibility to design the future even without set goals. We suggest that effectuation may be a useful perspective for design in dynamic social contexts leading to a more dif-ferentiated view on the instantiation of mid-range artifacts for specific local ap-plication contexts. Design science researchers can draw on this paper’s conclu-sions to view their DSR projects through a fresh lens and to reexamine their re-search design and execution. The paper also offers avenues for future research to develop more concrete application possibilities of effectuation in socio-technical IS DSR and, thus, enrich the discourse.