RESUMEN
The male genitals of internal fertilisers evolve rapidly and divergently, and sexual selection is generally responsible for this. Many sexually selected traits are condition-dependent-with their expression dependent upon the resources available to be allocated to them-as revealed by genetic or environmental manipulations of condition. However, it is not clear whether male genitals are also condition-dependent. Here we manipulate condition in two ways (via inbreeding and diet) to test the condition-dependence of the genital arch of Drosophila simulans. We found that genital size but not genital shape suffered from inbreeding depression, whereas genital size and shape were affected by dietary manipulation of condition. The differential effects of these treatments likely reflect underlying genetic architecture that has been shaped by past selection: inbreeding depression is only expected when traits have a history of directional selection, while diet impacts traits regardless of historical selection. Nonetheless, our results suggest genitals can be condition-dependent like other sexually selected traits.
RESUMEN
Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.