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5 - Ensemble Timing in String Quartets
- Edited by Michelle Phillips, Royal Northern College of Music, Manchester, Matthew Sergeant, Bath Spa University
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- Book:
- Music and Time
- Published by:
- Boydell & Brewer
- Published online:
- 07 October 2022
- Print publication:
- 10 June 2022, pp 73-96
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Summary
In this chapter we examine music ensemble timing. This process, in which musicians watch and listen to sense each other and so adjust the timing of their motor actions in order to maintain good ensemble synchronisation, may be considered an example of sensorimotor synchronisation. We recount how experimental studies of the act of tapping along to a metronome – one of the simplest forms of sensorimotor synchronisation – led to the development of an internal clock model, in which self-perceived errors in synchrony between a person's taps and the metronome's beats drive phase corrections to the timing of that person's internal clock. We go on to expand this model to account for the maintenance of ensemble timing in string quartet performance. We assume each player has their own internal clock which is undergoing constant adjustment according to perceived synchrony errors between them and each of their three colleagues. Such a model is mathematically linear and describes phase correction between players. We conclude the chapter by noting that a recently developed oscillator model points the way towards a complementary, non-linear perspective on these timing adjustments between players. Both the linear and non-linear models make important contributions to our understanding of the science behind music ensemble timing, an understanding that could one day inform new approaches to rehearsal technique, and even stylistic variation, in music-making.
Introduction
Playing music in time – whether to an internally generated pulse or to an external signal such as a click track – is a complex task that relies on a number of cognitive mechanisms including perception, attention, memory, and action. In many musical styles, the desired timing of playing can be quite complex, with intended large-scale or local fluctuations in tempo or purposeful deviations from the beat. Fluctuations in the cognitive mechanisms during performance, as well as changes in neurophysiological factors affecting the muscles such as fatigue and stiffness, may result in additional, unintended variability in an individual musician's timing performance (as also discussed in Chapter 2). Despite this variability, musicians must be able to predict and adjust the temporal progression of their music-making in order to achieve their desired musical expression. When musicians play together in groups, additional challenges are put upon these mechanisms.
4558 Investigating the functional consequences of anaplastic lymphoma kinase (ALK) mutations arising upon Lorlatinib treatment
- Gabriela Maria Witek, Whelton Miller, David Slochower, Esther Berko, Yael Mossé, Mark Lemmon, Ravi Radhakrishnan
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- Journal:
- Journal of Clinical and Translational Science / Volume 4 / Issue s1 / June 2020
- Published online by Cambridge University Press:
- 29 July 2020, pp. 9-10
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- Article
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OBJECTIVES/GOALS: Neuroblastoma (NB) is an embryonal cancer of the sympathetic nervous system that affects mostly infants and young children. The complex genetic background present across NB patients results in diverse clinical response and difficulty in individualizing therapy. Currently, NB patients undergo a regimen of genotoxic chemotherapeutics, radiation therapy, and new immunotherapy that, while effective, has significant side effects, including excruciating pain. One promising avenue for targeted therapy in neuroblastoma focuses on anaplastic lymphoma kinase (ALK), a cell surface neural receptor tyrosine kinase. We previously identified activating point mutations within the tyrosine kinase domain of ALK as the primary cause of hereditary NB, and we and others subsequently showed that these same alterations are the most common somatic single-nucleotide mutations in the sporadic forms of the disease. Crizotinib, a first-generation small molecule ATP-competitive inhibitor of the ALK tyrosine kinase, showed limited anti-tumor activity in patients with relapsed NB harboring ALK F1174 and F1245 mutations. We have demonstrated that lorlatinib, a novel ATP-competitive ALK inhibitor, overcomes this de novo resistance in preclinical models of ALK-driven NB. Recent clinical trials with lorlatinib in patients with non-small cell lung cancer harboring an ALK fusion, and in patients with NB harboring ALK mutations show the emergence of multiple or compound ALK mutations as a mechanism of resistance. We postulate that these compound mutations disrupt the interaction between and ALK and cause resistance. In this study, we employ a computational approach to model mutated ALK in complex with lorlatinib as well as ATP to understand whether the new mutations alter the affinity or mode of lorlatinib/ATP binding to ALK, and thus cause suboptimal ALK inhibition. METHODS/STUDY POPULATION: We employ methods in computational structural biology and drug design, primarily based on molecular modeling, molecular dynamics (MD), and molecular docking. Based on existing crystal structures of wildtype ALK, we model the mutations and perform MD simulations in order to characterize the activation state of the protein as well as perform ensemble docking calculations to assess the binding affinities and modes in ALK-lorlatinib and ALK-ATP complexes. RESULTS/ANTICIPATED RESULTS: We expect that the compound mutations cause resistance to lorlatinib either by lowering protein affinity for the drug or increasing the affinity for ATP. Alternatively, the compound mutations may disrupt the protein activation state, in which case ALK may no longer be active, and another protein/pathway could be driving the resistance. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will enable the understanding of the mechanism of resistance to lorlatinib and facilitate the design of new ALK inhibitors, or help develop more optimal and mechanism-guided therapies aimed to overcome the resistance.