Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery

In eubacteria, RecA is essential for recombinational DNA repair and for stalled replication forks to resume DNA synthesis. Recent work has implicated a role for RecA in the development of antibiotic resistance in pathogenic bacteria. Consequently, our goal is to identify and characterize small-molecule inhibitors that target RecA both in vitro and in vivo. We employed ATPase, DNA strand exchange and LexA cleavage assays to elucidate the inhibitory effects of suramin on Mycobacterium tuberculosis RecA. To gain insights into the mechanism of suramin action, we directly visualized the structure of RecA nucleoprotein filaments by atomic force microscopy. To determine the specificity of suramin action in vivo, we investigated its effect on the SOS response by pull-down and western blot assays as well as for its antibacterial activity. We show that suramin is a potent inhibitor of DNA strand exchange and ATPase activities of bacterial RecA proteins with IC50 values in the low micromolar range. Additional evidence shows that suramin inhibits RecA-catalysed proteolytic cleavage of the LexA repressor. The mechanism underlying such inhibitory actions of suramin involves its ability to disassemble RecA-single-stranded DNA filaments. Notably, suramin abolished ciprofloxacin-induced recA gene expression and the SOS response and augmented the bactericidal action of ciprofloxacin. Our findings suggest a strategy to chemically disrupt the vital processes controlled by RecA and hence the promise of small molecules for use against drug-susceptible as well as drug-resistant strains of M. tuberculosis for better infection control and the development of new therapies.

Conducting polymer-carbon black nanocomposite sensor for volatile organic compounds and correlating sensor response by molecular dynamics

Volatile organic compounds (VOCs) are present in our every day used products such as plastics, cosmetics, air fresheners, paint, etc. The determination of amount of VOC present in atmosphere can be carried out via various sensors. In this work a nanocomposite of a novel thiophene based conducting polymer and carbon black is used as a volatile organic compound sensor. The fabricated 2 lead chemiresistor sensor was tested for vapours of toluene, acetone, cylcohexane, and carbon tetrachloride. The sensor responds to all the vapours, however, exhibit maximum response to toluene vapours. The sensor was evaluated for various concentrations of toluene. The lower limit of detection of the sensor is 15 +/- 10 ppm. The study of the effect of humidity on senor response to toluene showed that the response decreases at higher humidity conditions. The surface morphology of the nanocomposite was characterized by scanning electron microscopy. Diffuse reflectance spectroscopy was used to investigate the absorption of vapours by the nanocomposite film. Contact angle measurements were used to present the effect of water vapour on the toluene response of nanocomposite film. Solubility parameter of the conducting polymer is predicted by molecular dynamics. The sensing behaviour of the conducting polymer is correlated with solubility parameter of the polymer. Dispersion interaction of conducting polymer with toluene is believed to be the reason for the selective response towards toluene. (C) 2014 Elsevier B.V. All rights reserved.

Orthorhombic-tetragonal phase coexistence and enhanced piezo-response at room temperature in Zr, Sn, and Hf modified BaTiO3

The effect of Zr, Hf, and Sn in BaTiO3 has been investigated at close composition intervals in the dilute concentration limit. Detailed structural analysis by x-ray and neutron powder diffraction revealed that merely 2mol. % of Zr, Sn, and Hf stabilizes a coexistence of orthorhombic (Amm2) and tetragonal (P4mm) phases at room temperature. As a consequence, all the three systems show substantial enhancement in the longitudinal piezoelectric coefficient (d(33)), with Sn modification exhibiting the highest value similar to 425 pC/N. (C) 2014 AIP Publishing LLC.

Influence of the AgrC-AgrA Complex on the Response Time of Staphylococcus aureus Quorum Sensing

The Staphylococcus aureus agr quorum-sensing system plays a major role in the transition from the persistent to the virulent phenotype. S. aureus agr type I to IV strains are characterized by mutations in the sensor domain of the histidine kinase AgrC and differences in the sequences of the secreted autoinducing peptides (AIP). Here we demonstrate that interactions between the cytosolic domain of AgrC (AgrC(Cyto)) and the response regulator domain of AgrA (AgrA(RR)) dictate the spontaneity of the cellular response to AIP stimuli. The crystal structure of AgrC(Cyto) provided a basis for a mechanistic model of AgrC-AgrA interactions. This model enabled an analysis of the biochemical and biophysical parameters of AgrC-AgrA interactions in the context of the conformational features of the AgrC-AgrA complex. This analysis revealed distinct sequence and conformational features that determine the affinity, specificity, and kinetics of the phosphotransfer reaction. This step, which governs the response time for transcriptional reengineering triggered by an AIP stimulus, is independent of the agr type and similar for agonist and antagonist stimuli. These experimental data could serve as a basis on which to validate simulations of the quorum-sensing response and for strategies that employ the agr quorum-sensing system to combat biofilm formation in S. aureus infections.

Substituent effect on fluorescence signaling of the cell permeable HSO4- receptors through single point to ratiometric response in green solvent

Two new 2-(2-aminophenyl)benzimidazole-based HSO4- ion selective receptors, 6-(4-nitrophenyl)-5,6-dihydrobenzo4,5]imidazo1,2-c]quinazoline (L1H) and 6-(4-methoxyphenyl)-5,6-dihydrobenzo4,5]imidazo1,2-c] quinazoline (L2H), and their 1 : 1 molecular complexes with HSO4- were prepared in a facile synthetic method and characterized by physicochemical and spectroscopic techniques along with the detailed structural analysis of L1H by single crystal X-ray crystallography. Both receptors (L1H and L2H) behave as highly selective chemosensor for HSO4- ions at biological pH in ethanol-water HEPES buffer (1/5) (v/v) medium over other anions such as F-, Cl-, Br-, I-, AcO-, H2PO4-, N-3(-) and ClO4-. Theoretical and experimental studies showed that the emission efficiency of the receptors (L1H and L2H) was tuned successfully through single point to ratiometric detection by employing the substituent effects. Using 3 sigma method the LOD for HSO4- ions were found to be 18.08 nM and 14.11 nM for L1H and L2H, respectively, within a very short responsive time (15-20 s) in 100 mM HEPES buffer (ethanol-water: 1/5, v/v). Comparison of the utility of the probes (L1H and L2H) as biomarkers for the detection of intracellular HSO4- ions concentrations under a fluorescence microscope has also been included and both probes showed no cytotoxic effect.

Levels of Alpha-Toxin Correlate with Distinct Phenotypic Response Profiles of Blood Mononuclear Cells and with agr Background of Community-Associated Staphylococcus aureus Isolates

Epidemiological studies of Staphylococcus aureus have shown a relation between certain clones and the presence of specific virulence genes, but how this translates into virulence-associated functional responses is not fully elucidated. Here we addressed this issue by analyses of community-acquired S. aureus strains characterized with respect to antibiotic resistance, ST types, agr types, and virulence gene profiles. Supernatants containing exotoxins were prepared from overnight bacterial cultures, and tested in proliferation assays using human peripheral blood mononuclear cells (PBMC). The strains displayed stable phenotypic response profiles, defined by either a proliferative or cytotoxic response. Although, virtually all strains elicited superantigen-mediated proliferative responses, the strains with a cytotoxic profile induced proliferation only in cultures with the most diluted supernatants. This indicated that the superantigen-response was masked by a cytotoxic effect which was also confirmed by flow cytometry analysis. The cytotoxic supernatants contained significantly higher levels of alpha-toxin than did the proliferative supernatants. Addition of alpha-toxin to supernatants characterized as proliferative switched the response into cytotoxic profiles. In contrast, no effect of Panton Valentine Leukocidin, delta-toxin or phenol soluble modulin alpha-3 was noted in the proliferative assay. Furthermore, a significant association between agr type and phenotypic profile was found, where agrII and agrIII strains had predominantly a proliferative profile whereas agrI and IV strains had a predominantly cytotoxic profile. The differential response profiles associated with specific S. aureus strains with varying toxin production could possibly have an impact on disease manifestations, and as such may reflect specific pathotypes.

The basics and advances of immunomodulators and antigen presentation: a key to development of potent memory response against pathogens

Introduction: Immunomodulators are agents, which can modulate the immune response to specific antigens, while causing least toxicity to the host system. Being part of the modern vaccine formulations, these compounds have contributed remarkably to the field of therapeutics. Despite the successful record maintained by these agents, the requirement of novel immunomodulators keeps increasing due to the increasing severity of diseases. Hence, research regarding the same holds great importance. Areas covered: In this review, we discuss the role of immunomodulators in improving performance of various vaccines used for counteracting most threatening infectious diseases, mechanisms behind their action and criteria for development of novel immunomodulators. Expert opinion: Understanding the molecular mechanisms underlying immune response is a prerequisite for development of effective therapeutics as these are often exploited by pathogens for their own propagation. Keeping this in mind, the present research in the field of immunotherapy focuses on developing immunomodulators that would not only enhance the protection against pathogen, but also generate a long-term memory response. With the introduction of advanced formulations including combination of different kinds of immunomodulators, one can expect tremendous success in near future.

Nano-ZnO particle addition to monolithic magnesium for enhanced tensile and compressive response

In this study, the effects of nanoscale ZnO reinforcement on the room temperature tensile and compressive response of monolithic Mg were studied. Experimental observations indicated strength properties improvement due to nanoscale ZnO addition. A maximum increment in tensile yield strength by similar to 55% and compressive yield strength by 90% (with reduced tension-compression asymmetry) was achieved when 0.8 vol.% ZnO nanoparticles were added to Mg. While the fracture strain values under tensile loads were found to increase significantly (by similar to 95%, in case of Mg-0.48ZnO), it remained largely unaffected under compressive loads. The microstructural characteristics studied in order to comprehend the mechanical response showed significant grain refinement due to grain boundary pinning effect of nano-ZnO particles which resulted in strengthening of Mg. Texture analysis using X-ray and EBSD methods indicated weakening of basal fibre texture in Mg/ZnO nanocomposites which contributed towards the reduction in tension-compression yield asymmetry and enhancement in tensile ductility when compared to pure Mg. (C) 2014 Elsevier B.V. All rights reserved.

Using heat treatment effects and EBSD analysis to tailor microstructure of hybrid Mg nanocomposite for enhanced overall mechanical response

In this study, a detailed investigation on the effect of heat treatment on the microstructural characteristics, texture evolution and mechanical properties of Mg-(5.6Ti+2.5B(4)C)(BM) hybrid nanocomposite is presented. Optimised heat treatment parameters, namely, heat treatment temperature and heat treatment time, were first identified through grain size and microhardness measurements. Initially, heat treatment of composites was conducted at temperature range between 100 and 300 degrees C for 1 h. Based on optical microscopic analysis and microhardness measurements, it was evident that significant grain growth and reduction in microhardness occurred for temperatures > 200 degrees C. The cutoff temperature that caused significant grain growth/matrix softening was thus identified. Second, at constant temperature (200 degrees C), the effect of variation of heat treatment time was carried out (ranging between 1 and 5 h) so as to identify the range wherein increase in average grain size and reduction in microhardness occurred. Furthering the study, the effect of optimised heat treatment parameters (200 degrees C, 5 h) on the microstructural texture evolution and hence, on the tensile and compressive properties of the Mg-(5.6Ti+2.5B(4)C)(BM) hybrid nanocomposite was carried out. From electron backscattered diffraction (EBSD) analysis, it was identified that the optimised heat treatment resulted in recrystallisation and residual stress relaxation, as evident from the presence of similar to 87% strain free grains, when compared to that observed in the non-heat treated/as extruded condition (i.e. 2.2 times greater than in the as extruded condition). For the heat treated composite, under both tensile and compressive loads, a significant improvement in fracture strain values (similar to 60% increase) was observed when compared to that of the non-heat treated counterpart, with similar to 20% reduction in yield strength. Based on structure-property correlation, the change in mechanical characteristics is identified to be due to: (1) the presence of less stressed matrix/reinforcement interface due to the relief of residual stresses and (2) texture weakening due to matrix recrystallisation effects, both arising due to heat treatment.

Decentralized demand-supply matching using community microgrids and consumer demand response: A scenario analysis

Developing countries constantly face the challenge of reliably matching electricity supply to increasing consumer demand. The traditional policy decisions of increasing supply and reducing demand centrally, by building new power plants and/or load shedding, have been insufficient. Locally installed microgrids along with consumer demand response can be suitable decentralized options to augment the centralized grid based systems and plug the demand-supply gap. The objectives of this paper are to: (1) develop a framework to identify the appropriate decentralized energy options for demand supply matching within a community, and, (2) determine which of these options can suitably plug the existing demand-supply gap at varying levels of grid unavailability. A scenario analysis framework is developed to identify and assess the impact of different decentralized energy options at a community level and demonstrated for a typical urban residential community Vijayanagar, Bangalore in India. A combination of LPG based CHP microgrid and proactive demand response by the community is the appropriate option that enables the Vijayanagar community to meet its energy needs 24/7 in a reliable, cost-effective manner. The paper concludes with an enumeration of the barriers and feasible strategies for the implementation of community microgrids in India based on stakeholder inputs. (C) 2014 Elsevier Ltd. All rights reserved.

Tailoring viscoelastic response of carbon nanotubes cellular structure using electric field

Cellular structures of carbon nanotubes (CNT) are novel engineering materials, which are finding applications due to their remarkable structural and functional properties. Here, we report the effects of electric field, one of the most frequently used stimulants for harnessing the functional properties of CNT, on the viscoelastic response, an important design consideration for the structural applications of a cellular CNT sample. The application of an electric field results in electrostriction induced large actuation in freestanding CNT samples; however, if the CNT are prohibited to expand, an electric field dependent force is exerted by the sample on the constraining platens. In addition, the above force monotonically decreases with the pre-compressive strain imposed onto the sample. The viscoelastic recovery reveals a decrease in the stress relaxation with an increase in the pre-compressive strain in both the presence and absence of the electric field; however, the stress relaxation was significantly higher in the presence of the electric field. A model, based on a simple linear viscoelastic solid incorporating electric field, is developed to understand the experimental observations.

Precipitation response of the magnesium alloy WE43 in strained and unstrained conditions

The precipitation behavior of the magnesium alloy WE43 (Mg-4%Y-2.3%Nd-0.5%Zr) has been studied in strained and unstrained conditions using Transmission Electron Microscopy (TEM). Ageing treatments were carried out at three temperatures, namely 210 degrees C, 230 degrees C and 260 degrees C. The precipitation sequence during static aging of solution treated (ST) samples has been identified as ST —> beta'' —> beta' followed by the formation of beta(1) and equilibrium beta precipitates form after very long ageing periods. Dynamic precipitation was observed during high temperature deformation, leading to the formation of beta' and intermediate beta(1) precipitates. The strained samples, when further heat treated, resulted in the transformation of beta(1) into beta equilibrium precipitates. The sequence of dynamic precipitation is ST —> beta(1) —> beta and ST —> beta'. (C) 2014 Elsevier B.V. All rights reserved.

A quinazoline derivative as quick-response red-shifted reporter for nanomolar Al3+ and applicable to living cell staining

A newly synthesized and structurally characterized quinazoline derivative (L) has been shown to act as a quick-response chemosensor for Al3+ with a high selectivity over other metal ions in water-DMSO. In the presence of Al3+, L shows a red-shifted ratiometric enhancement in fluorescence as a result of internal charge transfer and chelation-enhanced fluorescence through the inhibition of a photo-induced electron transfer mechanism. This probe detects Al3+ at concentrations as low as 1.48 nM in 100 mM HEPES buffer (DMSO-water, 1 : 9 v/v) at biological pH with a very short response time (15-20 s). L was applied to biological imaging to validate its utility as a fluorescent probe for monitoring Al3+ ions in living cells, illustrating its value in practical environmental and biological systems.

Polarization switching and high piezoelectric response in Sn-modified BaTiO3

BaTiO3 is shown to exhibit anomalous piezoelectric response, comparable to that of lead-zirconate titanate, by dilute Sn modification (1-4 mol%). Using a newly discovered powder poling technique it is shown that the mechanism associated with this anomalous strain response involves electric-field-induced switching of polarization vector from 001] towards 101] pseudocubic direction. This switchability is significantly enhanced by tuning the tetragonal-orthorhombic first-order criticality near to room temperature.