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OBJECTIVES/GOALS: Our preclinical data demonstrate that the principal effects of nilotinib, a multi-tyrosine kinase inhibitor, in models of neurodegeneration is clearance of misfolded proteins via autophagy. Here we aimed to evaluate the effects of nilotinib on microRNAs in the cerebrospinal fluid of Parkinson’s disease patients. METHODS/STUDY POPULATION: Cerebrospinal fluid (CSF) was collected as part of an open label phase I (NCT02281474) (n = 12, 300 mg nilotinib taken orally once daily for 6 months), and a phase II randomized, double-blind, placebo-controlled study (NCT02954978) (n = 75, randomized 1:1:1 into placebo, 150 mg or 300 mg nilotinib taken orally once daily for 12 months). RNA was isolated from CSF and Indexed sequencing libraries were prepared from total RNA plus miRNA. Next generation whole-genome sequencing (single-end 1x75 bp, 25 million raw reads per sample) was performed to identify miRNAs significantly differentially expressed (fold-change ≥ 2, Benjamini-Hochberg FDR p-value ≤ 0.05 or Empirical Bayes FDR ≤ 0.05) with treatment compared to baseline. RESULTS/ANTICIPATED RESULTS: Next generation whole-genome sequencing of microRNAs in the CSF demonstrated that nilotinib significantly increases microRNAs that specifically regulate expression of autophagy and ubiquitination genes in individuals with Parkinson’s disease. In the open label phase I, samples, 28 microRNAs found to regulate autophagy and ubiquitination genes, were significantly altered with treatment (Benjamini-Hochberg FDR p-value ≤ 0.05). In the phase II randomized, double-blind, placebo-controlled study samples, we verified several of those 28 candidate microRNAs had been significantly deferentially expressed with treatment (Empirical Bayes FDR p-value ≤ 0.05). DISCUSSION/SIGNIFICANCE OF IMPACT: Our data provide robust evidence that nilotinib’s effects on misfolded protein clearance is via autophagy and CSF miRNA sequencing is a valid biomarker of nilotinib’s effects in a definitive phase III study to investigate nilotinib in Parkinson’s and other neurodegenerative diseases. CONFLICT OF INTEREST DESCRIPTION: Charbel Moussa is listed as an inventor on several Georgetown University patents for the use of tyrosine kinase inhibitors as a treatment for neurodegenerative diseases
It has frequently been observed that the techniques that Purcell employed in his trio sonatas found a new outlet in his orchestral symphonies and overtures of the 1690s. Giovanni Battista Draghi’s 1687 Cecilian ode had shown how a large-scale work could begin with an Italianate orchestral sinfonia rather than the more conventional English take on the French overture, and in their odes and theatre music of the 1690s Purcell and Blow embraced this feature with enthusiasm. What is not often acknowledged is that, Draghi’s example aside, Purcell was effectively forced to invent this genre for himself, adapting the chamber sonata to the larger orchestral resources available at performances of court odes and in the theatre.
What was Purcell aiming to do when he wrote his Chaconne for two flutes in Act III of The Prophetess, or the History of Dioclesian (1690; see facing page)? Such questions are not always easy to answer, but in this particular case there are strong grounds for optimism. Even without the informative heading, it is quickly obvious how the piece is constructed. Neither the repetitive ground bass nor the canon at the unison between the recorder parts could plausibly have arisen fortuitously, so at least in the context of compositional technique we can disregard many of the usual caveats about intention: in this work, Purcell was seeking to compose a canon ‘Two in one upon a Ground’, with the second recorder following the first, two bars later, at the unison.
In recent years, the cultural background to Purcell’s interest in the trio sonata has become much better understood and far more accessible. Apart from the perennial issue of his likely Italian models, we now recognize a body of ‘Restoration Trio Sonatas’, including works both by English composers (notably John Blow) and by Europeans active in London (among them Giovanni Battista Draghi and the elder Nicola Matteis). The example of Robert King’s ‘Sonetta after the Italion Way’ apparently composed around 1680, even sits alongside Purcell’s sonatas as an example of an explicitly acknowledged attempt to emulate Italian stylistic features.
Having laid out in Part I some of the ways in which Purcell’s instrumental music can be better understood through a historically sensitive approach to analysis, learning from contemporary theoretical discussions – both their contents and their omissions – I turn in Part II of this study to a broader consideration of what the same methods can reveal about some of the best known of the composer’s later works, while at the same time developing tools where necessary to explain the phenomena to be found there.
Some of the most conspicuous moments of artifice in Purcell’s vocal music of the 1690s arise from the deployment of contrapuntal augmentation, or ‘fugeing per augmentation’ as Purcell calls it in ‘The Art of Descant’. This chapter examines this phenomenon largely by delving again into the case of transformative self-borrowing identified at the start of Chapter 6: the relationship between the setting of ‘World without end’ in the orchestral Jubilate of 1694 and its antecedent – in terms of materials and contrapuntal treatment – in the last section of Fantazia XI. The technical resources necessary to devise such sustained passages of imitation per augmentation are worthy of consideration in their own right, and provide a fresh avenue for inquiry into Purcell’s compositional choices.
At the climax of his last great choral work, the orchestral Te Deum and Jubilate in D major for the St Cecilia’s Day celebrations of 1694, Purcell dusted off a contrapuntal motif familiar from the end of his much earlier Fantazia XII (Ex. 6.1). Moreover, he also used exactly the same compositional conceit in his working of this motif – no doubt, in fact, his very choice of materials was motivated by the desire to select an idea suitable for subjection to the extreme contrapuntal augmentation of bars 201–8, an illustration of the words ‘world without end’.
One way we can get at the kinds of creative strategies Purcell employed in his most contrapuntally intricate music is to examine it alongside contemporary theoretical writings, including his own. This chapter, then, is principally concerned with the establishment of a methodological basis for the analysis that follows later. This basis is unfolded in three parallel strands: the examination of theoretical texts by Purcell and his immediate contemporaries, the situation of these within the wider context of Restoration cultural discourse, and the analysis of Purcell’s music in the light of the insights gained from both. It culminates in a more detailed study of the first part of one of Purcell’s most accomplished fantazias, with the aim of recovering the composer’s working methods through a careful analysis of his use of counterpoint, or fugeing, as he called it in ‘The Art of Descant’.
Given that the presence of arcane fugal devices in Purcell’s instrumental music is widely recognized as a stylistic marker of conservatism, it is surprising how little detailed and historically sensitive analytical work there has been in order to support this critical response. If the study of this music is to retain any place in modern musicological discourse it will require strong historiographical and analytical models capable of interrogating such commonplace ideas, and thereby illuminating the music to which they refer. Purcell’s ‘conservatism’, if such it is, is a matter of much more than simple stylistic affinity with music that was, by the 1680s, decidedly old-fashioned: one must consider what it was about such music that attracted Purcell, and how it acquired meaning for him and others in the cultural context of late seventeenth-century London.
Most of Purcell’s sonatas contain at least one fugal movement in duple time, usually the second movement of the sonata and frequently entitled ‘canzona’. In many respects this kind of movement enshrines in miniature the full range of issues behind the varied and contradictory reception of Purcell’s instrumental music examined in the Introduction. It certainly brings into sharp focus the dichotomy between, on the one hand, those who wish to hear in Purcell’s sonatas the echoes of a dying tradition of English consort music and, on the other, those for whom they sound a triumphant herald for the coming of the age of Bach and Handel. For all that Purcell’s canzonas superficially resemble the fugues familiar from eighteenth-century repertoire, however, the techniques he deploys in his canzonas and related movements can be clearly related back to his concern for compositional artifice.