No abstract

This study examined consumer evaluation of corporate social responsibility (CSR) activities with a focus on the authenticity and fit of CSR activities and analyzed the influence of consumers' individual perception based on CSR involvement. We carried out an empirical survey to test the hypotheses presented by a scenario test using a questionnaire of 315 college students. The results showed that higher CSR fit has a positive effect on CSR authenticity and brand attitude. As a result of verifying the moderating effect of CSR involvement, the higher the CSR involvement is, the lower the impact of CSR fit on CSR authenticity. Therefore, consumers with high CSR involvement are less affected by CSR fit in evaluating the authenticity of CSR.

Transposable elements are one of major sources to cause genomic instability through various mechanisms including de novo insertion, insertion-mediated genomic deletion, and recombination-associated genomic deletion. Among them is Alu element which is the most abundant element, composing ~10% of the human genome. The element emerged in the primate genome 65 million years ago and has since propagated successfully in the human and non-human primate genomes. Alu element is a non-autonomous retrotransposon and therefore retrotransposed using L1-enzyme machinery. The 'master gene' model has been generally accepted to explain Alu element amplification in primate genomes. According to the model, different subfamilies of Alu elements are created by mutations on the master gene and most Alu elements are amplified from the hyperactive master genes. Alu element is frequently involved in genomic rearrangements in the human genome due to its abundance and sequence identity between them. The genomic rearrangements caused by Alu elements could lead to genetic disorders such as hereditary disease, blood disorder, and neurological disorder. In fact, Alu elements are associated with approximately 0.1% of human genetic disorders. The first part of this review discusses mechanisms of Alu amplification and diversity among different Alu subfamilies. The second part discusses the particular role of Alu elements in generating genomic rearrangements as well as human genetic disorders.

Water molecules inside a G-protein coupled receptor (GPCR) have recently been spotlighted in a series of crystal structures. To decipher the dynamics and functional roles of internal water molecules in GPCR activity, we studied the A 2A adenosine receptor using microsecond molecular-dynamics simulations. Our study finds that the amount of water flux across the transmembrane (TM) domain varies depending on the receptor state, and that the water molecules of the TM channel in the active state flow three times more slowly than those in the inactive state. Depending on the location in solvent-protein interface as well as the receptor state, the average residence time of water in each residue varies from~O(10 2 ) ps to~O (10 2 ) ns. Especially, water molecules, exhibiting ultraslow relaxation (~O(10 2 ) ns) in the active state, are found around the microswitch residues that are considered activity hotspots for GPCR function. A continuous allosteric network spanning the TM domain, arising from water-mediated contacts, is unique in the active state, underscoring the importance of slow water molecules in the activation of GPCRs.

No abstract

Inhibition of chymase is likely to divulge therapeutic ways for the treatment of cardiovascular diseases, and fibrotic disorders. To find novel and potent chymase inhibitors and to provide a new idea for drug design, we used both ligand-based and structure-based methods to perform the virtual screening(VS) of commercially available databases. Different pharmacophore models generated from various crystal structures of enzyme may depict diverse inhibitor binding modes. Therefore, multiple pharmacophore-based approach is applied in this study. X-ray crystallographic data of chymase in complex with different inhibitors were used to generate four structure–based pharmacophore models. One ligand–based pharmacophore model was also developed from experimentally known inhibitors. After successful validation, all pharmacophore models were employed in database screening to retrieve hits with novel chemical scaffolds. Drug-like hit compounds were subjected to molecular docking using GOLD and AutoDock. Finally four structurally diverse compounds with high GOLD score and binding affinity for several crystal structures of chymase were selected as final hits. Identification of final hits by three different pharmacophore models necessitates the use of multiple pharmacophore-based approach in VS process. Quantum mechanical calculation is also conducted for analysis of electrostatic characteristics of compounds which illustrates their significant role in driving the inhibitor to adopt a suitable bioactive conformation oriented in the active site of enzyme. In general, this study is used as example to illustrate how multiple pharmacophore approach can be useful in identifying structurally diverse hits which may bind to all possible bioactive conformations available in the active site of enzyme. The strategy used in the current study could be appropriate to design drugs for other enzymes as well.

No abstract

TWIK (tandem-pore domain weak inward rectifying K(+))-related spinal cord K(+) channel, TRESK, a member of the tandem-pore domain K(+) channel family, is the most recently cloned K(2P) channel. TRESK is highly expressed in dorsal root ganglion neuron, a pain sensing neuron, which is a target for analgesics. In this study, a reliable 3D structure for transmembrane (TM) region of mouse TRESK (mTRESK) was constructed, and then the reasonable blocker binding mode of the protein was investigated. The 3D structure of the mTRESK built by homology modeling method was validated with recommend value of stereochemical quality. Based on the validated structure, K(+) channel blocker-bound conformation was obtained by molecular docking and 5ns MD simulation with DPPC lipid bilayer. Our docking study provides the plausible binding mode of known blockers with key interacting residues, especially, F156 and F364. Finally, these modeling results were verified by experimental study with mutation from phenylalanine to alanine (F156A, F364A and F156A/F364A) at the TM2 and TM4. This is the first modeling study for TRESK that can provide structural information of the protein including ligand binding information. These results can be useful in structure based drug design for finding new blockers of the TRESK as potential therapeutic target of pain treatment.