改革攻坚阶段社会危机的心理预警系统

改革攻坚和体制质变时期,体制改革越来越多地触及到原有利益格局的刚性部分,触及到基本社会阶级阶层和社会群体的利益,各种矛盾相互交织、错综复杂。这一切都不可避免地反映到人们的思想意识上,引发不同程度的社会心理压力。如果我们不注意及时调整和化解日渐增强的心理压力,就有可能超出社会成员对改革的心理承受力,造成社会与政治的高度紧张,从而引发严重的社会危机,破坏社会的和谐与稳定。

Molecular mechMolecular mechanism of glucocorticoid resistance in inflammatory bowel disease

Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn’s disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and toxicity.However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormonefree GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/ MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient’s specific genetic background, thus improving on efficacy and safety rates.

Impaired suppressive activities of human MUTYH variant proteins against oxidative mutagenesis

AIM:To investigate the suppressive activity of MUTYH variant proteins against mutations caused by oxidative lesion,8-hydroxyguanine(8OHG),in human cells.METHODS:p.R154H,p.M255V,p.L360P,and p.P377L MUTYH variants,which were previously found in patients with colorectal polyposis and cancer,were selected for use in this study.Human H1299 cancer cell lines inducibly expressing wild-type(WT) MUTYH(type 2) or one of the 4 above-mentioned MUTYH variants were established using the piggyBac transposon vector system,enabling the genomic integration of the transposon sequence for MUTYH expression.MUTYH expression was examined after cumate induction using Western blotting analysis and immunofluorescence analysis.The intracellular localization of MUTYH variants tagged with FLAG was also immunofluorescently examined.Next,the mutation frequency in the supF of the shuttle plasmid pMY189 containing a single 8OHG residue at position 159 of the supF was compared between empty vector cells and cells expressing WT MUTYH or one of the 4 MUTYH variants using a supF forward mutation assay.RESULTS:The successful establishment of human cell lines inducibly expressing WT MUTYH or one of the 4 MUTYH variants was concluded based on the detection of MUTYH expression in these cell lines after treatment with cumate.All of the MUTYH variants and WT MUTYH were localized in the nucleus,and nuclear localization was also observed for FLAG-tagged MUTYH.The mutation frequency of supF was 2.2 × 10-2 in the 8OHG-containing pMY189 plasmid and 2.5 × 10-4 in WT pMY189 in empty vector cells,which was an 86-fold increase with the introduction of 8OHG.The mutation frequency(4.7 × 10-3) of supF in the 8OHG-containing pMY189 plasmid in cells overexpressing WT MUTYH was significantly lower than in the empty vector cells(P < 0.01).However,the mutation frequencies of the supF in the 8OHG-containing pMY189 plasmid in cells overexpressing the p.R154H,p.M255V,p.L360P,or p.P377L MUTYH variant were 1.84 × 10-2,1.55 × 10-2,1.91 × 10-2,and 1.96 × 10-2,respectively,meaning that no significant difference was observed in the mutation frequency between the empty vector cells and cells overexpressing MUTYH mutants.CONCLUSION:The suppressive activities of p.R154H,p.M255V,p.L360P,and p.P377L MUTYH variants against mutations caused by 8OHG are thought to be severely impaired in human cells.

Preparation of a scorpion-shaped di-NBD derivative of cholesterol and its thixotropic property

A scorpion-shaped di-NBD(4-substituted-7-nitrobenzoxadiazole) derivative of cholesterol(Chol-2NBD) was designed and synthesized. The gelation behaviors of the compound in a series of single and mixed liquids were tested. It was shown that the compound is an effective gelator for mixture liquids of THF and benzene at room temperature. Furthermore, FT-IR and temperature-/concentration-dependent 1H NMR spectroscopy studies revealed that hydrogen bonding and π-π stacking among the molecules of Chol-2NBD are two main driving forces for the physical gelation of the mixture liquids. Interestingly, as observed in the gelation test and confirmed by rheological studies, the Chol-2NBD-THF/benzene gel systems, at least the one with 2:8 of the volume ratio of THF to benzene, are mechanically stable, but very sensitive to the stimulus of shear stress, which means that the gel changes into a liquid upon shaking. More interestingly, the liquid returns to gel instantly once the shear stress is removed. This phase transition process could be repeated for many times at room temperature. In addition, primary tests demonstrated that the fluorescence emission of Chol-2NBD is significantly quenched by the presence of water, ammonia water, or ammonia gas, but the emission recovers after evaporation of them. Further detailed investigation is under progress.