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Over a third of the human genome is comprised of repetitive sequences, including more than a million short tandem repeats (STRs). While studies of the pathologic consequences of repeat expansions that cause syndromic human diseases are extensive, the potential native functions of STRs are often ignored. Here, we summarize a growing body of research into the normal biological functions for repetitive elements across the genome, with a particular focus on the roles of STRs in regulating gene expression. We propose reconceptualizing the pathogenic consequences of repeat expansions as aberrancies in normal gene regulation. From this altered viewpoint, we predict that future work will reveal broader roles for STRs in neuronal function and as risk alleles for more common human neurological diseases.

Accurate perception and production of auditory rhythms are key for human behaviors such as speech and music. Auditory rhythms in music range in their complexity: complex rhythms (based on non-integer ratios between successive tone durations) 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 tapped on a keyboard to synchronize with the rhythms in the Synchronization condition. Participants were equally accurate at identifying missing tones in simple and complex 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 synchronization for both simple and complex rhythms; only nonlinear recurrence quantification analyses reflected cardiac differences between simple and complex auditory rhythms. Nonlinear cardiac dynamics were also more deterministic (predictable) during rhythm perception than synchronization. Individual differences during tapping showed that greater heart rate variability was correlated with poorer synchronization. Overall, these findings suggest that linear measures of musicians' cardiac activity reflect global task variability while nonlinear measures additionally reflect stimulus rhythm complexity.

Abstract 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.

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.

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.