Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein–ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).

Background: Previous studies have explored how sensor technologies can assist in in the detection, recognition, and prevention of subjective loneliness. These studies have shown a correlation between physiological and behavioral sensor data and the experience of loneliness. However, little research has been conducted on the design requirements from the perspective of older people and stakeholders in technology development. The use of these technologies and infrastructural questions have been insufficiently addressed. Systems generally consist of sensors or software installed in smartphones or homes. However, no studies have attempted to use smart textiles, which are fabrics with integrated electronics. Objective: This study aims to understand the design requirements for a smart textile loneliness monitoring system from the perspectives of older people and stakeholders. Methods: We conducted co-design workshops with 5 users and 6 stakeholders to determine the design requirements for smart textile loneliness monitoring systems. We derived a preliminary product concept of the smart wearable and furniture system. Digital and physical models and a use case were evaluated in a focus group study with older people and stakeholders (n=7). Results: The results provided insights for designing systems that use smart textiles to monitor loneliness in older people and widen their use. The findings informed the general system, wearables and furniture, materials, sensor positioning, washing, sensor synchronization devices, charging, intervention, and installation and maintenance requirements. This study provided the first insight from a human-centered perspective into smart textile loneliness monitoring systems for older people. Conclusions: We recommend more research on the intervention that links to the monitored loneliness in a way that addresses different needs to ensure its usefulness and value to people. Future systems must also reflect on questions of identification of system users and the available infrastructure and life circumstances of people. We further found requirements that included user cooperation, compatibility with other worn medical devices, and long-term durability.

The Aryl-hydrocarbon Receptor (AhR) is implicated in the regulation of several genes, including those encoding CYP1A1. Although it is an orphan receptor, the amount of data about its relationship with skin homeostasis and nosology is constantly increasing. Interestingly, 6-formylindolo[3,2-b]carbazole (6-FICZ), one of the most active AhR inducers and amongst the proposed receptor’s endogenous ligands, has been detected in Malassezia furfur isolates from lesional skin, as well as in skin scales from patients with seborrhoeic dermatitis. Aiming to study the structure–activity relationships of the indolo[3,2-b]carbazole (ICZ) scaffold and to clarify if the formyl group of 6-FICZ has any specific role in AhR induction, a series of analogues of ICZ (substituted at position 6 with methyl, formyl and hydroxymethyl groups) were synthesized and evaluated for their activity on AhR in cell lines of four different species. A new simple method for the synthesis of 6-FICZ was developed. 6-Methylindolo[3,2-b]carbazole (6-MICZ) showed higher activity than 6-FICZ in human, rat and guinea pig cell lines, and all synthesized derivatives showed comparable activity in the mouse cell line. Therefore, the formyl group does not seem to play a significantly specific role in the affinity for AhR, and 6-FICZ seems less likely to be an endogenous ligand.