Search

Perception and production of auditory rhythms are key capacities for human behaviors such as speech and music. Auditory rhythms in music range in the complexity of successive tone durations; complex rhythms (based on non-integer duration ratios) are more difficult to perceive and produce than simple rhythms (based on integer ratios). The physiological activity supporting this behavioral difference is not well understood. In a within-subjects design, we addressed how rhythm complexity affects cardiac dynamics during auditory perception and production. Musically trained adults listened to and synchronized with simple and complex auditory rhythms while their cardiac activity was recorded. Participants identified missing tones in the rhythms during the Perception condition and produced finger taps to synchronize with the rhythms in the Synchronization condition. Participants were equally accurate at identifying missing tones in both rhythms during the Perception condition. Tapping synchronization was less accurate and less precise with complex rhythms than with simple rhythms. Linear cardiac analyses showed a slower mean heart rate and greater heart rate variability during perception than production, for both simple and complex rhythms. Individual differences showed that greater heart rate variability was correlated with poorer synchronization. Linear and nonlinear cardiac analyses identified perception / synchronization differences; only nonlinear recurrence quantification analyses captured cardiac differences between simple and complex auditory rhythms. Cardiac dynamics were also more deterministic (predictable) during rhythm perception than synchronization. Overall, these findings suggest that cardiac activity is modulated by both task (auditory perception, production) and by rhythm complexity.

CGG repeat expansions in the FMR1 5’UTR cause the neurodegenerative disease Fragile X-associated tremor/ataxia syndrome (FXTAS). These repeats form stable RNA secondary structures that support aberrant translation in the absence of an AUG start codon (RAN translation), producing aggregate-prone peptides that accumulate within intranuclear neuronal inclusions and contribute to neurotoxicity. Here, we show that the most abundant RAN translation product, FMRpolyG, is markedly less toxic when generated from a construct with a non-repetitive alternating codon sequence in place of the CGG repeat. While exploring the mechanism of this differential toxicity, we observed a +1 translational frameshift within the CGG repeat from the arginine to glycine reading frame. Frameshifts occurred within the first few translated repeats and were triggered predominantly by RNA sequence and structural features. Short chimeric R/G peptides form aggregates distinct from those formed by either pure arginine or glycine, and these chimeras induce toxicity in cultured rodent neurons. Together, this work suggests that CGG repeats support translational frameshifting and that chimeric RAN translated peptides may contribute to CGG repeat-associated toxicity in FXTAS and related disorders.

Repeat-associated non-AUG-initiated translation of expanded CGG repeats (CGG RAN) from the FMR1 5'-leader produces toxic proteins that contribute to neurodegeneration in fragile X-associated tremor/ataxia syndrome. Here we describe how unexpanded CGG repeats and their translation play conserved roles in regulating fragile X protein (FMRP) synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production. Activation of mGluR5 receptors enhances FMRP synthesis. This enhancement requires both the CGG repeat and CGG RAN initiation sites. Using non-cleaving antisense oligonucleotides (ASOs), we selectively blocked CGG RAN. This ASO blockade enhanced endogenous FMRP expression in human neurons. In human and rodent neurons, CGG RAN-blocking ASOs suppressed repeat toxicity and prolonged survival. These findings delineate a native function for CGG repeats and RAN translation in regulating basal and activity-dependent FMRP synthesis, and they demonstrate the therapeutic potential of modulating CGG RAN translation in fragile X-associated disorders.

This Element reviews literature on the physiological influences of music during perception and action. It outlines how acoustic features of music influence physiological responses during passive listening, with an emphasis on comparisons of analytical approaches. It then considers specific behavioural contexts in which physiological responses to music impact perception and performance. First, it describes physiological responses to music that evoke an emotional reaction in listeners. Second, it delineates how music influences physiology during music performance and exercise. Finally, it discusses the role of music perception in pain, focusing on medical procedures and laboratory-induced pain with infants and adults.

The original synthesis of gamma-(2-bromo-2-methylpropionate)-epsilon-caprolactone (BMPCL), in use since 1999, has an overall yield of 17% and uses a Cr(VI) reagent for a key oxidation. Despite these liabilities, this synthetic procedure has been reported in all subsequent uses of BMPCL. This is due to BMPCL’s desirable capacity as an inimer – the tertiary alpha-bromo ester functionality allows initiation of controlled radical polymerization while the strained lactone moiety can act as a monomer in ring-opening polymerizations. These orthogonal capacities make BMPCL useful for the synthesis of complex polymer architectures such as combs. This paper reports a higher yielding, telescoped BMPCL synthesis that reduces the use of toxic reagents. Utilizing a mild and near-quantitative activated-DMSO mechanism, the Swern oxidation, in place of pyridinium chlorochromate increases the yield by approximately half to 25% (average of three trials) while eliminating heavy metal usage. In an additional effort for synthetic efficiency, the number of chromatographic purifications was reduced from three to one.

Transcribed CGG repeat expansions cause neurodegeneration in Fragile X‐associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA‐binding proteins (RBPs) into nuclear foci and undergo repeat‐associated non‐AUG (RAN) translation into toxic peptides. To identify proteins involved in these processes, we employed a CGG repeat RNA‐tagging system to capture repeat‐associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine‐rich) proteins that interact selectively with CGG repeats basally and under cellular stress. These proteins modify toxicity in a Drosophila model of FXTAS. Pharmacologic inhibition of serine/arginine protein kinases (SRPKs), which alter SRSF protein phosphorylation, localization, and activity, directly inhibits RAN translation of CGG and GGGGCC repeats (associated with C9orf72 ALS/FTD) and triggers repeat RNA retention in the nucleus. Lowering SRPK expression suppressed toxicity in both FXTAS and C9orf72 ALS/FTD model flies, and SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. Together, these findings demonstrate roles for CGG repeat RNA binding proteins in RAN translation and repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders., Fragile X‐associated tremor/ataxia syndrome (FXTAS) is an adult‐onset neurodegenerative disease caused by a CGG trinucleotide repeat expansion in FMR1. This study identified CGG repeat RNA binding proteins and their kinases that regulate repeat associated non‐AUG (RAN) translation and neurotoxicity.

We addressed how circadian rhythms influence daily musical activities of performing musicians, who exhibit fine temporal control. Music performances often occur in the evening and late at night; evidence suggests that composing musicians tend to be later chronotypes than non-composing musicians. However, chronotype and daily music-making in performing musicians have yet to be investigated. The current study examined chronotype in actively practicing and/or performing musicians and non-musicians, and whether it was related to the daily timing of music performance. To test influences of daily changes due to the global COVID-19 pandemic, disruptions to musical, athletic, social, and sleep habits were also measured. Performing musicians, active (practicing but non-performing) musicians, inactive musicians, and non-musicians, residing in Canada, completed a 7-day online daily activity and sleep diary in Summer 2020. There were more evening chronotypes than morning chronotypes in the sample. Active/performing musicians tended to be earlier chronotypes than all other groups. Musicians' chronotype, but not nightly sleep timing, predicted the time of day that musicians made music: Late chronotypes made music later in the day and early chronotypes made music earlier in the day. Music performance and practice amount decreased during the COVID-19 period, but the daily timing of these activities did not change. All participants reported later sleep onset during the COVID-19 period; the amount of social interaction decreased during the COVID-19 period, while exercise increased for some and decreased for others. No changes in the daily timing of exercise, social interaction, or morning wake-up were reported. These findings suggest that performing musicians may be slightly earlier chronotypes than non-performing musicians and non-musicians, despite music performances often occurring in the evening. Chronotype was related to the time of day of music-making independent of nightly sleep timing, suggesting that times of day for making music reflect an individual's circadian rhythm.

Repeat-associated non-AUG (RAN) translation is a noncanonical translation initiation event that occurs at nucleotide-repeat expansion mutations that are associated with several neurodegenerative diseases, including fragile X-associated tremor ataxia syndrome (FXTAS), ALS, and frontotemporal dementia (FTD). Translation of expanded repeats produces toxic proteins that accumulate in human brains and contribute to disease pathogenesis. Consequently, RAN translation constitutes a potentially important therapeutic target for managing multiple neurodegenerative disorders. Here, we adapted a previously developed RAN translation assay to a high-throughput format to screen 3,253 bioactive compounds for inhibition of RAN translation of expanded CGG repeats associated with FXTAS. We identified five diverse small molecules that dose-dependently inhibited CGG RAN translation, while relatively sparing canonical translation. All five compounds also inhibited RAN translation of expanded GGGGCC repeats associated with ALS and FTD. Using CD and native gel analyses, we found evidence that three of these compounds, BIX01294, CP-31398, and propidium iodide, bind directly to the repeat RNAs. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a transcribed CGG repeat expansion in the 5’ UTR ofFMR1. Expanded CGG repeat RNAs both sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic homopolymeric peptides. RBPs that interact with CGG repeats may play a pivotal role in foci formation and/or RAN translation. Here we employed a CGG repeat RNA-tagging system to capture and identify CGG repeat binding RBPsin vivounder different cellular conditions. We found that several SR (serine/arginine-rich domain) proteins interact with CGG repeat RNAs basally and under cellular stress. These same proteins strongly modify toxicity in a Drosophila model of FXTAS, improving eye degeneration and survival. Furthermore, genetic or pharmacological targeting of the serine/arginine protein kinases (SRPKs) suppresses RAN translation in cellular reporters and toxicity in fly models of FXTAS and C9orf72 ALS/FTD. Finally, pharmacological targeting of SRPK1 supressed CGG repeat toxicity and enhanced survival in rodent neurons. Taken together, these findings demonstrate roles for CGG repeat RNA binding proteins in both RAN translation and repeat toxicity and suggest SRPK inhibition may serve as a possible therapeutic strategy in repeat expansion disorders.

Repeat associated non-AUG (RAN) initiated translation of FMR1 5’ UTR CGG repeats produces toxic homo-polymeric proteins that accumulate within ubiquitinated inclusions in Fragile X-associated tremor/ataxia syndrome (FXTAS) patient brains and model systems. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG codon located 5’ to the repeat. Methods to accurately measure FMRpolyG in FXTAS patients are lacking. Here we used data dependent acquisition (DDA) and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides (SIS) to identify potential signature FMRpolyG fragments in patient cells and tissues. Following immunoprecipitation enrichment, we detected FMRpolyG signature peptides by PRM in transfected cells, FXTAS human samples and patient derived stem cells, but not in controls. Surprisingly, we identified two amino-terminal peptides: Ac-MEAPLPGGVR, initiating at an ACG, and Ac-TEAPLPGGVR, initiating at a GUG, along with evidence for RAN translation initiation within the CGG repeat itself. Initiation at all three sites was upregulated in response to cellular stress, downregulated following eIF1 overexpression and dependent on the initiation factor helicase, eIF4A. Use of the two initiation sites upstream of the repeat decreased following loss of the eIF2 alternative factor eIF2A. These data demonstrate that FMRpolyG is quantifiable in human samples and that RAN translation on FMR1 initiates via similar mechanisms at both near-cognate codons and within the repeat itself through processes dependent on available initiation factors and the cellular environment.

Musicians display individual differences in their spontaneous performance rates (tempo) for simple melodies, but the factors responsible are unknown. Previous research suggests that musical tempo modulates listeners' cardiovascular activity. We report an investigation of musicians' melody performances measured over a 12-h day and subsequent changes in the musicians' physiological activity. Skilled pianists completed four testing sessions in a single day as cardiac activity was recorded during an initial 5 min of baseline rest and during performances of familiar and unfamiliar melodies. Results indicated slower tempi for familiar and unfamiliar melodies at early testing times. Performance rates at 09 h were predicted by differences in participants' alertness and musical training; these differences were not explained by sleep patterns, chronotype, or cardiac activity. Individual differences in pianists' performance tempo were consistent across testing sessions: participants with a faster tempo at 09 h maintained a faster tempo at later testing sessions. Cardiac measures at early testing times indicated increased heart rates and more predictable cardiac dynamics during music performance than baseline rest, and during performances of unfamiliar melodies than familiar melodies. These findings provide the first evidence of cardiac dynamics that are unique to music performance contexts.