Textual criticism and medieval Irish studies

Many textual scholars will be aware that the title of the present thesis has been composed in a conscious revisionary relation to Tim William Machan’s influential Textual Criticism and Middle English Texts. (Tim William Machan, Textual Criticism and Middle English Texts (Charlottesville, 1994)). The primary subjects of Machan’s study are works written in English between the fourteenth and sixteenth centuries, the latter part of the period conventionally labelled Middle English. In contrast, the works with which I am primarily concerned are those written by scholars of Old and Middle Irish in the nineteenth, twentieth and twenty-first centuries. Where Machan aims to articulate the textual and cultural factors that characterise Middle English works as Middle English, the purposes of this thesis are (a) to identify the underlying ideological and epistemological perspectives which have informed much of the way in which medieval Irish documents and texts are rendered into modern editions, and (b) to begin to place the editorial theory and methodology of medieval Irish studies within the broader context of Biblical, medieval and modern textual criticism. Hence, the title is Textual Criticism and Medieval Irish Studies, rather than Textual Criticism and Medieval Irish Texts

Conformational states of HIV-1 reverse transcriptase for nucleotide incorporation vs. pyrophosphorolysis – binding of foscarnet

HIV-1 reverse transcriptase (RT) catalytically incorporates individual nucleotides into a viral DNA strand complementing an RNA or DNA template strand; the polymerase active site of RT adopts multiple conformational and structural states while performing this task. The states associated are dNTP binding at the N site, catalytic incorporation of a nucleotide, release of a pyrophosphate, and translocation of the primer 3′-end to the P site. Structural characterization of each of these states may help in understanding the molecular mechanisms of drug activity and resistance and in developing new RT inhibitors. Using a 38-mer DNA template-primer aptamer as the substrate mimic, we crystallized an RT/dsDNA complex that is catalytically active, yet translocation-incompetent in crystals. The ability of RT to perform dNTP binding and incorporation in crystals permitted obtaining a series of structures: (I) RT/DNA (P-site), (II) RT/DNA/AZTTP ternary, (III) RT/AZT-terminated DNA (N-site), and (IV) RT/AZT-terminated DNA (N-site)/foscarnet complexes. The stable N-site complex permitted the binding of foscarnet as a pyrophosphate mimic. The Mg2+ ions dissociated after catalytic addition of AZTMP in the pretranslocated structure III, whereas ions A and B had re-entered the active site to bind foscarnet in structure IV. The binding of foscarnet involves chelation with the Mg2+ (B) ion and interactions with K65 and R72. The analysis of interactions of foscarnet and the recently discovered nucleotide-competing RT inhibitor (NcRTI) α-T-CNP in two different conformational states of the enzyme provides insights for developing new classes of polymerase active site RT inhibitors.