The five human polycomb (Pc) paralog proteins, chromobox homolog (Cbx) 2/4/6/7/8, are a family of chromodomain containing methyllysine reader proteins that are canonical readers of trimethyllysine 27 on histone 3 (H3K27me3). The aberrant expression of the Cbx7 gene is implicated in several cancers including prostate, gastric, thyroid, pancreas, and colon cancer. Previous reports on antagonizing the molecular recognition of Cbx7–H3K27me3 with chemical inhibitors showed an impact on prostate cancer cell lines. We report here on the design, synthesis, and structure–activity relationships of a series of potent peptidomimetic antagonists that were optimized on a trimethyllysine-containing scaffold to target Cbx7. The ligands were characterized using fluorescence polarization (FP) for their binding efficiency and selectivity against the Pc paralog Cbx proteins. The most selective ligand 9, as indicated by the FP data analysis, was further characterized using the isothermal titration calorimetry (ITC). Compound 9 exhibits a 220 nM potency for Cbx7 and exhibits 3.3, 1.8, 7.3 times selective for Cbx7 over Cbx2/4/8 and 28-fold selective over the HP1 family member Cbx1. Our research provides several potent and partially selective inhibitors for Cbx2/4/7 that do not contain trimethyllysine. Our models and binding data suggest that the aromatic cages of Cbx7/Cbx4 can accommodate larger alkyl groups such as diisobutyl substitution on the lysine nitrogen.

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A growing body of research analyzing musical scores suggests mode’s relationship with other expressive cues has changed over time. However, to the best of our knowledge, the perceptual implications of these changes have not been formally assessed. Here, we explore how compositional choices of 17th- and 19th-century composers (J. S. Bach and F. Chopin, respectively) differentially affect emotional communication. This novel exploration builds on our team’s previous techniques using commonality analysis to decompose intercorrelated cues in unaltered excerpts of influential compositions. In doing so, we offer an important naturalistic complement to traditional experimental work—often involving tightly controlled stimuli constructed to avoid the intercorrelations inherent to naturalistic music. Our data indicate intriguing changes in cues’ effects between Bach and Chopin, consistent with score-based research suggesting mode’s “meaning” changed across historical eras. For example, mode’s unique effect accounts for the most variance in valence ratings of Chopin’s preludes, whereas its shared use with attack rate plays a more prominent role in Bach’s. We discuss the implications of these findings as part of our field’s ongoing effort to understand the complexity of musical communication—addressing issues only visible when moving beyond stimuli created for scientific, rather than artistic, goals.

Auditory alarms are an important component of human–computer interfaces, used in mission-critical industries such as aviation, nuclear power plants, and hospital settings. Unfortunately, problems with recognition, detection, and annoyance continue to hamper their effectiveness. Historically, they appear designed more in response to engineering constraints than principles of hearing science. Here we argue that auditory perception in general and music perception in particular hold valuable lessons for alarm designers. We also discuss ongoing research suggesting that the temporal complexity of musical tones offers promising insight into new ways of addressing widely recognized shortcomings of current alarms.

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