Re-Sounding Alarms: Designing Ergonomic Auditory Interfaces by Embracing Musical Insights.

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.

Structure-Activity Relationships of Cbx7 Inhibitors, Including Selectivity Studies against Other Cbx Proteins.

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.