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The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti‐asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver‐related metabolic diseases.
With every glimpse of our eyes, we sample only a small and incomplete fragment of the visual world, which needs to be contextualized and integrated into a coherent scene representation. Here we show that the visual system achieves this contextualization by exploiting spatial schemata, that is our knowledge about the composition of natural scenes. We measured fMRI and EEG responses to incomplete scene fragments and used representational similarity analysis to reconstruct their cortical representations in space and time. We observed a sorting of representations according to the fragments' place within the scene schema, which occurred during perceptual analysis in the occipital place area and within the first 200 ms of vision. This schema-based coding operates flexibly across visual features (as measured by a deep neural network model) and different types of environments (indoor and outdoor scenes). This flexibility highlights the mechanism's ability to efficiently organize incoming information under dynamic real-world conditions.