Interaction of heterocyclic thiols/thiones eliminated from cephalosporins with iodine and its biological implications

Hydrolysis of beta-lactam antibiotics by beta-lactamases (e. g., metallo-beta-lactamase, m beta l) is one of the major bacterial defense systems. These enzymes can catalyze the hydrolysis of a variety of antibiotics including the latest generation of cephalosporins, cephamycins and imipenem. It is shown in this paper that the thiol/thione moieties eliminated from certain cephalosporins by m beta l-mediated hydrolysis readily react with molecular iodine to produce ionic compounds having S-I bonds. While the reaction of MTT with iodine produced the corresponding disulfide, MDT and DMETT produced the charge-transfer complexes MDT-I-2 and DMETT-I-2, respectively. Addition of two equivalents of I-2 to MDT produced a novel cationic complex having an almost linear S-I+-S moiety and I-5(-) counter anion.However, this reaction appears to be highly solvent dependent. When the reaction of MDT with I2 was carried out in water, the reaction produced a monocation having I-5(-), indicating the reactivity of MDT toward I2 is very similar to that of the most commonly used antithyroid drug methimazole (MMI). In contrast to MMI, MDT and DMETT, the triazine-based compound MTDT acts as a weak donor toward iodine. (C)2010 Elsevier Ltd. All rights reserved.

Gas amplification in proportional counters

The variation of gas amplification with applied voltage is an important characteristic of a proportional counter. Results of studies on gas amplification for gas fillings of argon quenched with ethane and carbon dioxide are given. The effects of (a) pressure, (b) quenching agent and (c) concentration on A are discussed briefly.

A systems perspective of host-pathogen interactions: predicting disease outcome in tuberculosis

The complex web of interactions between the host immune system and the pathogen determines the outcome of any infection. A computational model of this interaction network, which encodes complex interplay among host and bacterial components, forms a useful basis for improving the understanding of pathogenesis, in filling knowledge gaps and consequently to identify strategies to counter the disease. We have built an extensive model of the Mycobacterium tuberculosis host-pathogen interactome, consisting of 75 nodes corresponding to host and pathogen molecules, cells, cellular states or processes. Vaccination effects, clearance efficiencies due to drugs and growth rates have also been encoded in the model. The system is modelled as a Boolean network. Virtual deletion experiments, multiple parameter scans and analysis of the system's response to perturbations, indicate that disabling processes such as phagocytosis and phagolysosome fusion or cytokines such as TNF-alpha and IFN-gamma, greatly impaired bacterial clearance, while removing cytokines such as IL-10 alongside bacterial defence proteins such as SapM greatly favour clearance. Simulations indicate a high propensity of the pathogen to persist under different conditions.

Mycobacterium tuberculosis UvrD1 and UvrA Proteins Suppress DNA Strand Exchange Promoted by Cognate and Noncognate RecA Proteins

DNA helicases are present in all kingdoms of life and play crucial roles in processes of DNA metabolism such as replication, repair, recombination, and transcription. To date, however, the role of DNA helicases during homologous recombination in mycobacteria remains unknown. In this study, we show that Mycobacterium tuberculosis UvrD1 more efficiently inhibited the strand exchange promoted by its cognate RecA, compared to noncognate Mycobacterium smegmatis or Escherichia coli RecA proteins. The M. tuberculosis UvrD1(Q276R) mutant lacking the helicase and ATPase activities was able to block strand exchange promoted by mycobacterial RecA proteins but not of E. coil RecA. We observed that M. tuberculosis UvrA by itself has no discernible effect on strand exchange promoted by E. coli RecA but impedes the reaction catalyzed by the mycobacterial RecA proteins. Our data also show that M. tuberculosis UvrA and UvrD1 can act together to inhibit strand exchange promoted by mycobacterial RecA proteins. Taken together, these findings raise the possibility that UvrD1 and UvrA might act together in vivo to counter the deleterious effects of RecA nucleoprotein filaments and/or facilitate the dissolution of recombination intermediates. Finally, we provide direct experimental evidence for a physical interaction between M. tuberculosis UvrD1 and RecA on one hand and RecA and UvrA on the other hand. These observations are consistent with a molecular mechanism, whereby M. tuberculosis UvrA and UvrD1, acting together, block DNA strand exchange promoted by cognate and noncognate RecA proteins.

Anti-windup Schemes for Proportional Integral and Proportional Resonant Controller

Problems like windup or rollover arise in a PI controller working under saturation. Hence anti-windup schemes are necessary to minimize performance degradation.Similar situation may occur in a Proportional Resonant(PR)controller in the presence of a sustained error input.Several methods can be employed based on existing knowledge on PI controller to counter this problem.In this paper few such schemes are proposed and implemented in FPGA and MATLAB and from the obtained results their possible use and limitations have been studied.

Optimal resource partitioning in conflicts based on Lanchester (n, 1) attrition model

This paper develops a model for military conflicts where the defending forces have to determine an optimal partitioning of available resources to counter attacks from an adversary from n different fronts. The problem of optimally partitioning the defending forces against the attacking forces is addressed. The Lanchester square law model is used to develop the dynamical equations governing the variation in force strength. Two different allocation schemes-Time-ZeroAllocation (TZA) and Continuous Constant Allocation (CCA) are considered and the optimal solutions for both are obtained analytically. These results generalize other results available in the literature. Numerical examples are given to support the analytical results.

A systems perspective of host-pathogen interactions: predicting disease outcome in tuberculosis

The complex web of interactions between the host immune system and the pathogen determines the outcome of any infection. A computational model of this interaction network, which encodes complex interplay among host and bacterial components, forms a useful basis for improving the understanding of pathogenesis, in filling knowledge gaps and consequently to identify strategies to counter the disease. We have built an extensive model of the Mycobacterium tuberculosis host-pathogen interactome, consisting of 75 nodes corresponding to host and pathogen molecules, cells, cellular states or processes. Vaccination effects, clearance efficiencies due to drugs and growth rates have also been encoded in the model. The system is modelled as a Boolean network. Virtual deletion experiments, multiple parameter scans and analysis of the system's response to perturbations, indicate that disabling processes such as phagocytosis and phagolysosome fusion or cytokines such as TNF-alpha and IFN-gamma, greatly impaired bacterial clearance, while removing cytokines such as IL-10 alongside bacterial defence proteins such as SapM greatly favour clearance. Simulations indicate a high propensity of the pathogen to persist under different conditions.

Mycobacterium tuberculosis UvrD1 and UvrA Proteins Suppress DNA Strand Exchange Promoted by Cognate and Noncognate RecA Proteins

DNA helicases are present in all kingdoms of life and play crucial roles in processes of DNA metabolism such as replication, repair, recombination, and transcription. To date, however, the role of DNA helicases during homologous recombination in mycobacteria remains unknown. In this study, we show that Mycobacterium tuberculosis UvrD1 more efficiently inhibited the strand exchange promoted by its cognate RecA, compared to noncognate Mycobacterium smegmatis or Escherichia coli RecA proteins. The M. tuberculosis UvrD1(Q276R) mutant lacking the helicase and ATPase activities was able to block strand exchange promoted by mycobacterial RecA proteins but not of E. coil RecA. We observed that M. tuberculosis UvrA by itself has no discernible effect on strand exchange promoted by E. coli RecA but impedes the reaction catalyzed by the mycobacterial RecA proteins. Our data also show that M. tuberculosis UvrA and UvrD1 can act together to inhibit strand exchange promoted by mycobacterial RecA proteins. Taken together, these findings raise the possibility that UvrD1 and UvrA might act together in vivo to counter the deleterious effects of RecA nucleoprotein filaments and/or facilitate the dissolution of recombination intermediates. Finally, we provide direct experimental evidence for a physical interaction between M. tuberculosis UvrD1 and RecA on one hand and RecA and UvrA on the other hand. These observations are consistent with a molecular mechanism, whereby M. tuberculosis UvrA and UvrD1, acting together, block DNA strand exchange promoted by cognate and noncognate RecA proteins.

Effect of coordinated ions on structure and flexibility of parallel G-quadruplexes: A molecular dynamics study

ingle tract guanine residues can associate to form stable parallel quadruplex structures in the presence of certain cations. Nanosecond scale molecular dynamics simulations have been performed on fully solvated fibre model of parallel d(G(7)) quadruplex structures with Na+ or K+ ions coordinated in the cavity formed by the O6 atoms of the guanine bases. The AMBER 4.1 force field and Particle Mesh Ewald technique for electrostatic interactions have been used in all simulations. There quadruplex structures are stable during the simulation, with the middle four base tetrads showing root mean square deviation values between 0.5 to 0.8 Angstrom from the initial structure as well the high resolution crystal structure. Even in the absence of any coordinated ion in the initial structure, the G-quadruplex structure remains intact throughout the simulation. During the 1.1 ns MD simulation, one Nai counter ion from the solvent as well as several water molecules enter the central cavity to occupy the empty coordination sites within the parallel quadruplex and help stabilize the structure. Hydrogen bonding pattern depends on the nature of the coordinated ion, with the G-tetrad undergoing local structural variation to accommodate cations of different sizes. in the absence of any coordinated ion. due to strong mutual repulsion, O6 atoms within G-tetrad are forced farther apart from each other, which leads to a considerably different hydrogen bonding scheme within the G-tetrads and very favourable interaction energy between the guanine bases constituting a G-tetrad. However, a coordinated ion between G-tetrads provides extra stacking energy for the G-tetrads and makes the quadruplex structure more rigid. Na+ ions, within the quadruplex cavity, are more mobile than coordinated K+ ions. A number of hydrogen bonded water molecules are observed within the grooves of all quadruplex structures.

Amido binding to ReO3+ core: Synthesis, structure and intermolecular interactions

The light green coloured complexes of general formula [(ReO)-O-V(L)CI(OH2)]Cl have been synthesised in good yields by reacting [RcvOCl(3)(AsPh3)21 with HL in dichloromethane in dinitrogen atmosphere. Here, L- is the deprotonated form of N',N'-bis(2-pyridylmethyl)amine (HL1); N-(2-pyridylmethyl)-N',N'-dimethylethylenediamine (HL2) and N-(2-pyridylmethyl)-N',N-diethylethylenediamine (HL3). Single crystal X-ray structure determination of [(ReO)-O-V(L-1)Cl(OH2)Cl confirms the amido binding of ReO3+ species. In the solid state of [(ReO)-O-V(L-1)Cl(OH2)]Cl, the coordinated and counter chloride ions are engaged in Re-Cl... H-C(ring), Cl...H-C(ring) and Re(OH2)...Cl hydrogen bonding and forming of a supramolecular network in the solid state. The subunit of the supramolecular network consists of one eight-membered and two nine-membered hydrogen bonded rings. The average diameters of eight-membered and nine-membered rings are similar to 3.70 and similar to 5.26 angstrom, respectively.

Evolution of polyembryony: Consequences to the fitness of mother and offspring

Polyembryony, referring here to situations where a nucellar embryo is formed along with the zygotic embryo, has different consequences for the fitness of the maternal parent and offspring. We have developed genetic and inclusive fitness models to derive the conditions that permit the evolution of polyembryony under maternal and offspring control. We have also derived expressions for the optimal allocation (evolutionarily stable strategy, ESS) of resources between zygotic and nucellar embryos. It is seen that (i) Polyembryony can evolve more easily under maternal control than under that of either the offspring or the ‘selfish’ endosperm. Under maternal regulation, evolution of polyembryony can occur for any clutch size. Under offspring control polyembryony is more likely to evolve for high clutch sizes, and is unlikely for low clutch sizes (<3). This conflict between mother and offspring decreases with increase in clutch size and favours the evolution of polyembryony at high clutch sizes, (ii) Polyembryony can evolve for values of “x” (the power of the function relating fitness to seed resource) greater than 0.5758; the possibility of its occurrence increases with “x”, indicating that a more efficient conversion of resource into fitness favours polyembryony. (iii) Under both maternal parent and offspring control, the evolution of polyembryony becomes increasingly unlikely as the level of inbreeding increases, (iv) The proportion of resources allocated to the nucellar embryo at ESS is always higher than that which maximizes the rate of spread of the allele against a non-polyembryonic allele.Finally we argue that polyembryony is a maternal counter strategy to compensate for the loss in her fitness due to brood reduction caused by sibling rivalry. We support this assertion by two empirical evidences: (a) the extent of polyembryony is positively correlated with brood reduction inCitrus, and (b) species exhibiting polyembryony are more often those that frequently exhibit brood reduction.

A nanosecond molecular dynamics study of antiparallel d(G)(7) quadruplex structures: Effect of the coordinated cations

Nanosecond scale molecular dynamics simulations have been performed on antiparallel Greek key type d(G(7)) quadruplex structures with different coordinated ions, namely Na+ and K+ ion, water and Na+ counter ions, using the AMBER force field and Particle Mesh Ewald technique for electrostatic interactions. Antiparallel structures are stable during the simulation, with root mean square deviation values of similar to1.5 Angstrom from the initial structures. Hydrogen bonding patterns within the G-tetrads depend on the nature of the coordinated ion, with the G-tetrad undergoing local structural variation to accommodate different cations. However, alternating syn-anti arrangement of bases along a chain as well as in a quartet is maintained through out the MD simulation. Coordinated Na+ ions, within the quadruplex cavity are quite mobile within the central channel and can even enter or exit from the quadruplex core, whereas coordinated K+ ions are quite immobile. MD studies at 400 K indicate that K+ ion cannot come out from the quadruplex core without breaking the terminal G-tetrads. Smaller grooves in antiparallel structures are better binding sites for hydrated counter ions, while a string of hydrogen bonded water molecules are observed within both the small and large grooves. The hydration free energy for the K+ ion coordinated structure is more favourable than that for the Na+ ion coordinated antiparallel quadruplex structure.

Effect of coordinated ions on structure and flexiblity of parallel G-quandruplexes: a molecular dynamics study

Single tract guanine residues can associate to form stable parallel quadruplex structures in the presence of certain cations. Nanosecond scale molecular dynamics simulations have been performed on fully solvated fibre model of parallel d(G7) quadruplex structures with Na+ or K+ ions coordinated in the cavity formed by the 06 atoms of the guanine bases. The AMBER 4.1 force field and Particle Mesh Ewald technique for electrostatic interactions have been used in all simulations. These quadruplex structures are stable during the simulation, with the middle four base tetrads showing root mean square deviation values between 0.5 to 0.8 A from the initial structure as well the high resolution crystal structure. Even in the absence of any coordinated ion in the initial structure, the G-quadruplex structure remains intact throughout the simulation. During the 1.1 ns MD simulation, one Na+ counter ion from the solvent as well as several water molecules enter the central cavity to occupy the empty coordination sites within the parallel quadruplex and help stabilize the structure. Hydrogen bonding pattern depends on the nature of the coordinated ion, with the G-tetrad undergoing local structural variation to accommodate cations of different sizes. In the absence of any coordinated ion, due to strong mutual repulsion, 06 atoms within G-tetrad are forced farther apart from each other, which leads to a considerably different hydrogen bonding scheme within the G-tetrads and very favourable interaction energy between the guanine bases constituting a G-tetrad. However, a coordinated ion between G-tetrads provides extra stacking energy for the G-tetrads and makes the quadruplex structure more rigid. Na+ ions, within the quadruplex cavity, are more mobile than coordinated K+ ions. A number of hydrogen bonded water molecules are observed within the grooves of all quadruplex structures

Ab initio molecular orbital calculations on ion-molecule and ion pair-molecule complexes of the water-lithium cyanide system

Ab initio molecular orbital (MO) calculations with the 3-21G and 6-31G basis sets were performed on a series of ion-molecule and ion pair-molecule complexes for the H2O + LiCN system. Stabilisation energies (with counter-poise corrections), geometrical parameters, internal force constants and harmonic vibrational frequencies were evaluated for 16 structures of interest. Although the interaction energies are smaller, the geometries and relative stabilities of the monohydrated contact ion pair are reminiscent of those computed for the complexes of the individual ions. Thus, interaction of the oxygen lone pair with lithium leads to a highly stabilised C2v structure, while the coordination of water to the cyanide ion involves a slightly non-linear hydrogen bond. Symmetrical bifurcated structures are computed to be saddle points on the potential energy surface, and to have an imaginary frequency for the rocking mode of the water molecule. On optimisation the geometries of the solvent shared ion pair structures (e.g. Li+cdots, three dots, centered OH2cdots, three dots, centered CN−) revealed a proton transfer from the water molecule leading to hydrogen bonded forms such as Li-O-Hcdots, three dots, centered HCN. The variation in the force constants and harmonic frequencies in the various structures considered are discussed in terms of ion-molecular and ion pair-molecule interactions.

Improving fault detection and reliability in FDDI networks

FDDI (Fibre Distributed Data Interface) is a 100 Mbit/s token ring network with two counter rotating optical rings. In this paper various possible faults (like lost token, link failures, etc.) are considered, and fault detection and the ring recovery process in case of a failure and the reliability mechanisms provided are studied. We suggest a new method to improve the fault detection and ring recovery process. The performance improvement in terms of station queue length and the average delay is compared with the performance of the existing fault detection and ring recovery process through simulation. We also suggest a modification for the physical configuration of the FDDI networks within the guidelines set by the standard to make the network more reliable. It is shown that, unlike the existing FDDI network, full connectivity is maintained among the stations even when multiple single link failures occur. A distributed algorithm is proposed for link reconfiguration of the modified FDDI network when many successive as well as simultaneous link failures occur. The performance of the modified FDDI network under link failures is studied through simulation and compared with that of the existing FDDI network.