Simvastatin Sodium Salt and Fluvastatin Interact with Human Gap Junction Gamma-3 Protein

Finding pleiomorphic targets for drugs allows new indications or warnings for treatment to be identified. As test of concept, we applied a new chemical genomics approach to uncover additional targets for the widely prescribed lipid-lowering pro-drug simvastatin. We used mRNA extracted from internal mammary artery from patients undergoing coronary artery surgery to prepare a viral cardiovascular protein library, using T7 bacteriophage. We then studied interactions of clones of the bacteriophage, each expressing a different cardiovascular polypeptide, with surface-bound simvastatin in 96-well plates. To maximise likelihood of identifying meaningful interactions between simvastatin and vascular peptides, we used a validated photo-immobilisation method to apply a series of different chemical linkers to bind simvastatin so as to present multiple orientations of its constituent components to potential targets. Three rounds of biopanning identified consistent interaction with the clone expressing part of the gene GJC3, which maps to Homo sapiens chromosome 7, and codes for gap junction gamma-3 protein, also known as connexin 30.2/31.3 (mouse connexin Cx29). Further analysis indicated the binding site to be for the N-terminal domain putatively ‘regulating’ connexin hemichannel and gap junction pores. Using immunohistochemistry we found connexin 30.2/31.3 to be present in samples of artery similar to those used to prepare the bacteriophage library. Surface plasmon resonance revealed that a 25 amino acid synthetic peptide representing the discovered N-terminus did not interact with simvastatin lactone, but did bind to the hydrolysed HMG CoA inhibitor, simvastatin acid. This interaction was also seen for fluvastatin. The gap junction blockers carbenoxolone and flufenamic acid also interacted with the same peptide providing insight into potential site of binding. These findings raise key questions about the functional significance of GJC3 transcripts in the vasculature and other tissues, and this connexin’s role in therapeutic and adverse effects of statins in a range of disease states

What is counterintuitive? Religious cognition and natural expectation

What is ‘counterintuitive’? There is general agreement that it refers to a violation of previously held knowledge, but the precise definition seems to vary with every author and study. The aim of this paper is to deconstruct the notion of 'counterintuitive’ and provide a more philosophically rigorous definition congruent with the history of psychology, recent experimental work in ‘minimally counterintuitive’ concepts, the science vs. religion debate, and the developmental and evolutionary background of human beings. We conclude that previous definitions of counterintuitiveness have been flawed and did not resolve the conflict between a believer’s conception of the supernatural entity (an atypical “real kind”) and the non-believer’s conception (empty name/fictional). Furthermore, too much emphasis has been placed on the universality and (presumed) innateness of intuitive concepts (and hence the criteria for what is counterintuitive)—and far too little attention paid to learning and expertise. We argue that many putatively universal concepts are not innate, but mostly learned and defeasible—part of a religious believer’s repertoire of expert knowledge. Nonetheless, the results from empirical studies about the memorability of counterintuitive concepts have been convincing and it is difficult to improve on existing designs and methodologies. However, future studies in counterintuitive concepts need to embed their work in research about context effects, typicality, the psychology of learning and expertise (for example, the formation of expert templates and range defaults), with more attention to the sources of knowledge (direct and indirect knowledge) and a better idea of what ‘default’ knowledge really is