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Cell-permeable small molecules are powerful tools for unraveling complex cellular pathways. We demonstrate that nuclear hormone receptors can be engineered through mutagenesis to create orthogonal ligand-receptor pairs to control transcription. Mutated residues in the retinoid X receptor (RXR) were chosen from structural analysis of RXR and the retinoic acid receptor (RAR) ligand binding domains. The potential ligands screened for activation of variant receptors are "near drugs"--compounds synthesized during structure-activity studies that are structurally similar to an approved drug yet inactive on the wild-type receptor. One variant, Q275C;I310M;F313I, is poorly activated by ligands for the wild-type receptor but is activated by a "near drug", fulfilling the criteria of an orthogonal ligand-receptor pair. These experiments demonstrate that nuclear hormone receptors are well suited to supply orthogonal ligand-receptor pairs for experimental biology, biotechnology, and gene therapy. Our findings also demonstrate the general principle that inactive compounds synthesized during drug discovery can be combined with mutant proteins to rapidly create new tools for controlling cellular processes.

Previous scholarship has demonstrated the importance of individual characteristics and structural context for understanding social capital formation. However, a developmental approach to social capital formation has, so far, been absent. In this study, I argue that social capital formation must be understood intergenerationally as well as structurally. Using hierarchical linear modeling, I investigate the hypothesized intergenerational transmission of social capital using Waves 1 and 2 of the National Longitudinal Study of Adolescent Health. The results show that, in addition to individual characteristics, neighborhood-level factors, and school-level variables, parental social capital is an important predictor of adolescent social capital. This study also suggests that the intergenerational transmission of social capital functions, in part, through family structure and that structural differences account for only a relatively small share of the variation in adolescent social capital. Potential explanations for these findings are discussed.