Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release

Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening the repertoire for DAA targets is a major priority. Here we describe the complete structure of the HCV p7 protein as a monomeric hairpin, solved using a novel combination of chemical shift and nuclear Overhauser effect (NOE)-based methods. This represents atomic resolution information for a full-length virus-coded ion channel, or “viroporin,” whose essential functions represent a clinically proven class of antiviral target exploited previously for influenza A virus therapy. Specific drug-protein interactions validate an allosteric site on the channel periphery and its relevance is demonstrated by the selection of novel, structurally diverse inhibitory small molecules with nanomolar potency in culture. Hit compounds represent a 10,000-fold improvement over prototypes, suppress rimantadine resistance polymorphisms at submicromolar concentrations, and show activity against other HCV genotypes. Conclusion: This proof-of-principle that structure-guided design can lead to drug-like molecules affirms p7 as a much-needed new target in the burgeoning era of HCV DAA

Brokering Trust to Enhance Leadership: A Self-Monitoring Approach to Leadership Emergence

What kind of person is likely to emerge as an informal leader in the workplace? Experimental research shows that high self-monitors—who tend to adjust their attitudes and behaviors to the demands of different situations—emerge as informal leaders in temporary groups. By contrast, low self-monitors—who tend to be true to themselves in terms of consistency in attitudes and behaviors across different situations—are less likely to emerge as leaders. But this prior research does not address the criticism that the emergence of high self-monitors as leaders represents ephemeral impression management in the context of laboratory experiments. To address this issue, we collected and analyzed data from a 116-member high-technology firm. Our results show that self-monitoring is related not only to leadership emergence, but also to the provision of advice to co-workers. Further, people who occupied brokerage positions (being trusted by those who did not trust each other) tended to be seen as leaders if they were high rather than low self-monitors. From these results, we build a picture of the high self-monitoring emergent leader as someone who notices problems and ameliorates them through the provision of advice and the brokerage of relationships across social divides. The occupation of a structurally advantageous position may well be more advantageous for some (i.e., high self-monitors) relative to others (i.e., low self-monitors)

On the Importance of Complaint Handling Design : A Multi-Level Analysis of the Impact in Specific Complaint Situations

Given the large investments required for high-quality complaint handling design, managers need practical guidance in understanding its actual importance for their particular company. However, while prior research emphasizes the general relevance of complaint handling design, it fails to provide a more differentiated perspective on this interesting issue. This study, which is based on an integrative multi-level framework and a dyadic dataset, addresses this important gap in research. Results indicate that the impact of a company’s complaint handling design varies significantly depending on the characteristics of the complaining customers with which the firm has to deal. Further, this paper shows that, contingent on these characteristics, a company’s complaint handling design can shape complainants’ fairness perceptions either considerably or only slightly. Overall, findings suggest that companies should apply an adaptive approach to complaint handling to avoid misallocation of attention, energy, and resources

Modeling of negative Poisson’s ratio (auxetic) crystalline cellulose Iβ

Energy minimizations for unstretched and stretched cellulose models using an all-atom empirical force field (Molecular Mechanics) have been performed to investigate the mechanism for auxetic (negative Poisson’s ratio) response in crystalline cellulose Iβ from kraft cooked Norway spruce. An initial investigation to identify an appropriate force field led to a study of the structure and elastic constants from models employing the CVFF force field. Negative values of on-axis Poisson’s ratios nu31 and nu13 in the x1-x3 plane containing the chain direction (x3) were realized in energy minimizations employing a stress perpendicular to the hydrogen-bonded cellobiose sheets to simulate swelling in this direction due to the kraft cooking process. Energy minimizations of structural evolution due to stretching along the x3 chain direction of the ‘swollen’ (kraft cooked) model identified chain rotation about the chain axis combined with inextensible secondary bonds as the most likely mechanism for auxetic response

VPS29 Is Not an Active Metallo-Phosphatase but Is a Rigid Scaffold Required for Retromer Interaction with Accessory Proteins

VPS29 is a key component of the cargo-binding core complex of retromer, a protein assembly with diverse roles in transport of receptors within the endosomal system. VPS29 has a fold related to metal-binding phosphatases and mediates interactions between retromer and other regulatory proteins. In this study we examine the functional interactions of mammalian VPS29, using X-ray crystallography and NMR spectroscopy. We find that although VPS29 can coordinate metal ions Mn2+ and Zn2+ in both the putative active site and at other locations, the affinity for metals is low, and lack of activity in phosphatase assays using a putative peptide substrate support the conclusion that VPS29 is not a functional metalloenzyme. There is evidence that structural elements of VPS29 critical for binding the retromer subunit VPS35 may undergo both metal-dependent and independent conformational changes regulating complex formation, however studies using ITC and NMR residual dipolar coupling (RDC) measurements show that this is not the case. Finally, NMR chemical shift mapping indicates that VPS29 is able to associate with SNX1 via a conserved hydrophobic surface, but with a low affinity that suggests additional interactions will be required to stabilise the complex in vivo. Our conclusion is that VPS29 is a metal ion-independent, rigid scaffolding domain, which is essential but not sufficient for incorporation of retromer into functional endosomal transport assemblies