Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for Pseudomonas aeruginosa Multiple Virulence Factor Regulator (MvfR)

Multi-drug resistance (MDR) bacterial pathogens pose a threat to global health and warrant the discovery of new therapeutic molecules, particularly those that can neutralize their virulence and stop the evolution of new resistant mechanisms. The superbug nosocomial pathogen, Pseudomonas aeruginosa, uses a multiple virulence factor regulator (MvfR) to regulate the expression of multiple virulence proteins during acute and persistent infections. The present study targeted MvfR with the intention of designing novel anti-virulent compounds, which will function in two ways: first, they will block the virulence and pathogenesis P. aeruginosa by disrupting the quorum-sensing network of the bacteria, and second, they will stop the evolution of new resistant mechanisms. A structure-based virtual screening (SBVS) method was used to screen druglike compounds from the Asinex antibacterial library (~5968 molecules) and the comprehensive marine natural products database (CMNPD) (~32 thousand compounds), against the ligand-binding domain (LBD) of MvfR, to identify molecules that show high binding potential for the relevant pocket. In this way, two compounds were identified: Top-1 (4-((carbamoyloxy)methyl)-10,10-dihydroxy-2,6-diiminiodecahydropyrrolo[1,2-c]purin-9-yl sulfate) and Top-2 (10,10-dihydroxy-2,6-diiminio-4-(((sulfonatocarbamoyl)oxy)methyl)decahydropyrrolo[1,2-c]purin-9-yl sulfate), in contrast to the co-crystallized M64 control. Both of the screened leads were found to show deep pocket binding and interactions with several key residues through a network of hydrophobic and hydrophilic interactions. The docking results were validated by a long run of 200 ns of molecular dynamics simulation and MM-PB/GBSA binding free energies. All of these analyses confirmed the presence of strong complex formation and rigorous intermolecular interactions. An additional analysis of normal mode entropy and a WaterSwap assay were also performed to complement the aforementioned studies. Lastly, the compounds were found to show an acceptable range of pharmacokinetic properties, making both compounds potential candidates for further experimental studies to decipher their real biological potency.     

Production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) from cottonseed oil and valeric acid in batch culture of Ralstonia sp. strain JC-64

A Ralstonia sp. strain JC-64 that is capable of accumulating poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (P[3HB-co-3HV]) from cottonseed oil and valeric acid was isolated. By using a high limiting-nitrogen (HLN) mineral medium as the medium for the second stage of the fermentation process and by adding the two carbon sources at different times, a range of copolymers with 12–62 mol% of 3HV were produced from a series of HLN mineral mediums containing different compositions of cottonseed oil and valeric acid by Ralstonia sp. JC-64. The melting temperature (T _m ) of polyhydroxybutyrate from cottonseed oil was 174°C and that of P(3HB-co-3HV) with the highest 3HV-mol fraction (62%) was 81°C.     

Implicitly restarted and deflated GMRES

We introduce a deflation method that takes advantage of the IRA method, by extracting a GMRES solution from the Krylov basis computed within the Arnoldi process of the IRA method itself. The deflation is well-suited because it is done with eigenvectors associated to the eigenvalues that are closest to zero, which are approximated by IRA very quickly. By a slight modification, we adapt it to the FOM algorithm, and then to GMRES enhanced by imposing constraints within the minimization condition. The use of IRA enables us to reduce the number of matrix-vector products, while keeping a low storage. This revised version was published online in June 2006 with corrections to the Cover Date.     

基于XC2C64A的无线录井绞车信号检测电路设计

采用XC2C64A芯片设计了无线录井系统中绞车传感器的信号检测(包括鉴相、倍频和计数等)电路,给出了电路设计图、仿真波形和测试结果.现场试验表明,该电路采用集成化设计,降低了系统功耗,减少了PCB板面积,而且提高了系统可靠性,满足电池供电无线录井系统的使用要求.