Mass Collaboration in Earthquake Risk Management

The mechanism of mass collaboration in risk management was studied during the Sichuan earthquake under a Web-based “PeopleFinder” project, where information is contributed and shared among mass contributors. The case study is provided by a great earthquake that happened in Wenchuan County, Sichuan Province, of southwestern China at 2:28 p.m. on May 12, 2008. We witnessed and experienced the rescue and relief efforts for the great earthquake. In this article, two fundamental frameworks are developed to study the mechanism of mass collaboration. Mass collaboration is proven to be effective in a big public crisis such as the Sichuan earthquake.     

Isotopically sensitive branching in the formation of cyclic monoterpenes: proof that (-)-alpha-pinene and (-)-beta-pinene are synthesized by the same monoterpene cyclase via deprotonation of a common intermediate

To determine whether the bicyclic monoterpene olefins (-)-alpha-pinene and (-)-beta-pinene arise biosynthetically from the same monoterpene cyclase by alternate deprotonations of a common carbocationic intermediate, the product distributions arising from the acyclic precursor [10-2H3,1-3H]geranyl pyrophosphate were compared with those resulting from incubation of [1-3H]geranyl pyrophosphate with (-)-pinene cyclase from Salvia officinalis. Alteration in proportions of the olefinic products generated by the partially purified pinene cyclase resulted from the suppression of the formation of (-)-beta-pinene (C10 deprotonation) by a primary deuterium isotope effect with a compensating stimulation of the formation of (-)-alpha-pinene (C4 deprotonation). (-)-Pinene cyclase as well as (+)-pinene cyclase also exhibited a decrease in the proportion of the acyclic olefin myrcene generated from the deuteriated substrate, accompanied by a corresponding increase in the commitment to cyclized products. The observation of isotopically sensitive branching, in conjunction with quantitation of the magnitude of the secondary deuterium isotope effect on the overall rate of product formation by the (+)- and (-)-pinene cyclases as well as two other monoterpene cyclases from the same tissue, supports the biosynthetic origin of (-)-alpha-pinene and (-)-beta-pinene by alternative deprotonations of a common enzymatic intermediate. A biogenetic scheme consistent with these results is presented, and alternate proposals for the origin of the pinenes are addressed.     

Effect of T-activin on the production of immune interferon

A study was made of the effect of T-activin on the biosynthesis of immune gamma-interferon. It was shown that in 27% of patients with chronic nonspecific pulmonary diseases, production of gamma-interferon by lymphocytes was substantially reduced during exacerbation of inflammatory process in the lungs. It was discovered that T-activin was not an interferon inductor but enhanced its synthesis in patients with a low capacity of producing immune interferon even at small doses of interferon inductor. The preparation does not produce any effect on this process in normal subjects and in patients showing the normal level of gamma-interferon. Thus T-activin can be used for stimulation of interferonogenesis.     

Impact of vaginal microbiome communities on HIV antiretroviral-based pre-exposure prophylaxis (PrEP) drug metabolism

Despite the efficacy of antiretroviral-based pre-exposure prophylactics (PrEP) in men who have sex with men, studies in women have produced widely varying outcomes. Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. Here, we investigate the mechanisms underlying how vaginal bacteria alter PrEP drug levels and impact HIV infection rates ex vivo. Using cervicovaginal lavages (CVLs) from women with or without bacterial vaginosis (BV), we identified microbial metabolism of PrEP drugs in BV samples through LC-MS/MS analysis of soluble drug levels and metabolite formation in dual T-cell cultures. CVL samples were assessed for microbiome analysis using sequencing of bacterial 16S rRNA genes. We also observed non-Lactobacillus bacteria that are associated with BV may potentially impact PrEP efficacy through increased HIV infection rates in co-cultures containing Lactobacillus or BV bacteria, PrEP drugs, CEM-GFP cells, and HIV-1_LAI virus. Finally, we used these data to develop a novel predictive mathematical simulation modeling system to predict these drug interactions for future trials. These studies demonstrate how dysbiotic vaginal microbiota may impact PrEP drugs and provides evidence linking vaginal bacteria to PrEP efficacy in women.     

Testosterone inhibits cAMP-induced de Novo synthesis of Leydig cell cytochrome P-450(17 alpha) by an androgen receptor-mediated mechanism

The regulation of the novo synthesis of the microsomal cytochrome P-450 enzyme, P-450(17 alpha), was studied in mouse Leydig cell cultures. Chronic treatment with 0.05 mM 8-Br-cAMP (cAMP) caused a time-dependent increase in 17 alpha-hydroxylase activity and in the amount of P-450(17 alpha), quantitated by immunoblotting. This increase in both activity and amount was enhanced by inhibiting testosterone production with aminoglutethimide, an inhibitor of cholesterol side-chain cleavage or SU 10603, an inhibitor of 17 alpha-hydroxylase. To examine the mechanism by which cAMP or cAMP plus inhibitors of testosterone production increased the activity and amount of P-450(17 alpha), changes in the rate of de novo synthesis were studied by measuring [35S]methionine incorporation into newly synthesized protein. Treatment with cAMP plus aminoglutethimide or SU 10603 caused a 2-fold or greater increase in the rate of de novo synthesis of P-450(17 alpha) compared to treatment with cAMP only. The addition of exogenous testosterone reversed this increase in the rate of synthesis, indicating that testosterone modulates the extent of cAMP-stimulated induction of P-450(17 alpha). This negative effect of testosterone could be mimicked by the addition of the androgen agonist, mibolerone, and prevented by the addition of the antiandrogen, hydroxyflutamide. Neither estradiol nor dexamethasone had any effect on the synthesis of P-450(17 alpha). Studies on the degradation of newly synthesized P-450(17 alpha) demonstrated that testosterone had no effect on the decay of P-450(17 alpha) during the first 24 h but caused a significant increase in the rate of decay between 24 and 48 h. These data indicate that testosterone produced during cAMP induction of P-450(17 alpha) negatively regulates the amount of this cytochrome P-450 enzyme by two distinct mechanisms: by repressing cAMP-induced synthesis of P-450(17 alpha) by an androgen receptor-mediated mechanism and by increasing the rate of degradation of P-450(17 alpha). A model is proposed for the regulation of P-450(17 alpha) in Leydig cells.     

Conformation of guanosine 5'-diphosphate as bound to a human c-Ha-ras mutant protein: a nuclear Overhauser effect study

1H NMR spectra of a GDP/GTP-binding domain of human c-Ha-ras gene product (residues 1-171) in which glutamine-61 was replaced by leucine [ras(L61/1-171) protein] were analyzed. By one-dimensional and two-dimensional homonuclear Hartmann-Hahn spectroscopy and nuclear Overhauser effect (NOE) spectroscopy of the complex of the ras(L61/1-171) protein and GDP, the ribose H1', H2', H3', and H4' proton resonances of the bound GDP were identified. The guanine H8 proton resonance of the bound GDP was identified by substituting [8-2H]GDP for GDP. The dependences of the H1' and H8 proton resonance intensities on the duration of irradiation of the H1', H2', H3', and H8 protons were measured. By numerical simulation of these time-dependent NOE profiles, the conformation of the protein-bound GDP was elucidated; the guanosine moiety takes the anti form about the N-glycosidic bond with a dihedral angle of chi = -124 +/- 2 degrees and the ribose ring takes the C2'-endo form. Such an analysis of the conformation of a guanine nucleotide as bound to a GTP-binding protein will be useful for further studies on the molecular mechanism of the conformational activation of ras proteins on ligand substitution of GDP with GTP.