Comparative analysis of homology models of the Ah receptor ligand binding domain: Verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness. © 2013 American Chemical Society

How social identity affects entrepreneurs’ desire for control

In order to obtain a better understanding why some entrepreneurs retain more control over their venture than others, this article analyzes the relationship between the social identity of the entrepreneur and her/his desire for control. In fact, entrepreneurs face an important tradeoff between attracting resources required to build company value and retaining decision-making control. Yet, we currently lack insight into whether and how entrepreneurs’ social motivations shape this trade-off. This study draws on social identity theory and a unique sample of 148 buyout entrepreneurs, as this setting confronts aspiring entrepreneurs directly with the value–control tradeoff. In our logistic regression, we find that entrepreneurs with a strong missionary identity, where venture creation revolves around advancing a cause, hold a higher desire for control. We do not observe a significant relationship between entrepreneurs having a Darwinian (driven by economic self-interest) or communitarian (driven by the concern for the community) identity and the desire to control their venture. When adding the moderating role of the portion of personal wealth the entrepreneur is willing to invest in her/his venture, the relationships between having a Darwinian or missionary social identity and the desire for control become significantly positive when the entrepreneur is looking to invest a larger portion of her/his wealth

Disentangling satisfaction of tenants on science parks : a multiple case study in Belgium

While science parks represent one of the most important policy initiatives to stimulate firm development and growth, their contributions are still highly debated. This paper takes a novel customer-oriented approach to disentangle the contributions science parks provide to their tenants. Particularly, we qualitatively explore when and how science park tenants reach customer satisfaction and how tenants cope with low levels of satisfaction. Our study finds that reaching customer satisfaction is contingent on tenants' expectations, perceived service quality, and pre-entry achievements. We further disentangle coping strategies used by tenants when they are confronted with low levels of satisfaction. Our study provides important theoretical contributions to the organizational sponsorship literature by adding new insights from social psychology and holds valuable practical and policy implications

The relationship between organizational interdependency and additionality obtained from innovation ecosystem participation

Despite the increased interest in innovation ecosystems, few studies have assessed the extent to, which the proclaimed benefits from participating in such ecosystems also occur, and under which circumstances they do occur. Uniting the literature on organizational interdependence and social exchange theory, we assess the behavioral and output additionality obtained by innovation ecosystem participants. In doing so, we build upon a sample of 473 innovative Finnish companies, of which 312 participated in an innovation ecosystem. We find a significantly positive relationship between organizational interdependence and output additionality, and find that this relationship is mediated by behavioral additionality. Furthermore, we find that the relationship between behavioral additionality and output additionality is particularly strong when firms appoint members from the innovation ecosystem to their board of directors, pointing to the importance of internalizing the ecosystem. We discuss implications for academia and practice

Key challenges and opportunities associated with the use of in vitro models to detect human DILI: integrated risk assessment and mitigation plans

Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warning and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians in both academia and the pharmaceutical industry for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. In addition, well defined clinical diagnostic criteria and risk factors are missing. This manuscript provides an overview of the current state of DILI preclinical models with provides an emphasis overview on the key challenges associated with data interpretation, practical considerations, model limitations, and the need for an integrated risk assessment. A perspective of the promise of future technology development that may improve DILI prediction is also discussed. As demonstrated through selected initiatives to address other types of toxicities such as QT prolongation or genetic toxicity, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. An example of a precompetitive effort to address this current gap, the Innovative Medicine Initiative (IMI- sponsored Mechanism-based Integrated Prediction of DILI (MIP-DILI), is provided to illustrate the benefits that harmonization and knowledge sharing can generate for pharmaceutical R&D and patients. Disclaimer: The opinions expressed by the authors do not reflect the opinions or policies of their respective institutions. Any statements in this article should not be considered present or future policy of any regulatory agency