In silico classification of HERG channel blockers: a knowledge-based strategy

The blockage of the hERG potassium channel by a wide number of diverse compounds has become a major pharmacological safety concern as it can lead to sudden cardiac death. In silico models can be potent tools to screen out potential hERG blockers as early as possible during the drug-discovery process. In this study, predictive models developed using the recursive partitioning method and created using diverse datasets from 203 molecules tested on the hERG channel are described. The first model was built with hERG compounds grouped into two classes, with a separation limit set at an IC50 value of 1 microm, and reaches an overall accuracy of 81%. The misclassification of molecules having a range of activity between 1 and 10 microM led to the generation of a tri-class model able to correctly classify high, moderate, and weak hERG blockers with an overall accuracy of 90%. Another model, constructed with the high and weak hERG-blocker categories, successfully increases the accuracy to 96%. The results reported herein indicate that a combination of precise, knowledge management resources and powerful modeling tools are invaluable to assessing potential cardiotoxic side effects related to hERG blockage.     

In the eye of the beholder: Reply to Wilson and Shadish (2006) and Radin, Nelson, Dobyns, and Houtkooper (2006).

H. B?sch, F. Steinkamp, and E. Boller's (see record 2006-08436-001) meta-analysis, which demonstrated (a) a small but highly significant overall effect, (b) a small-study effect, and (c) extreme heterogeneity, has provoked widely differing responses. After considering D. B. Wilson and W. R. Shadish's see record 2006-08436-002) and D. Radin, R. Nelson, Y. Dobyns, and J. Houtkooper's see record 2006-08436-003) concerns about the possible effects of psychological moderator variables, the potential for missing data, and the difficulties inherent in any meta-analytic data, the authors reaffirm their view that publication bias is the most parsimonious model to account for all 3 findings. However, until compulsory registration of trials occurs, it cannot be proven that the effect is in fact attributable to publication bias, and it remains up to the individual reader to decide how the results are best and most parsimoniously interpreted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The plant wound hormone systemin binds with the N-terminal part to its receptor but needs the C-terminal part to activate it

Suspension-cultured cells of Lycopersicon peruvianum respond with rapid medium alkalinization and a strong increase of a MAP kinase-like activity when treated with subnanomolar concentrations of the plant wound hormone systemin. Systemin fragments comprising the N-terminal 14 amino acids (syst1-14) or the C-terminal four amino acids (syst15-18), added singly or in combination, were inactive as inducers of these responses. Syst1-14 but not syst15-18 antagonized activity of intact systemin in a competitive manner. Likewise, intact systemin showed stimulatory, syst1-14 antagonistic activity, and syst15-18 showed no activity in leaf pieces of tomato (L. esculentum) plants assayed for the induction of ethylene biosynthesis. To study the molecular basis of perception, we extended the C-terminal end of systemin by a tyrosine residue and radioiodinated it to yield systemin-125I-iodotyrosine. In membrane preparations of L. peruvianum, this radioligand exhibited rapid, saturable, and reversible binding to a single class of binding sites. Binding showed a dissociation constant of approximately 1 nM, and binding of radioligand was efficiently competed by unlabeled systemin but not by syst15-18 or structurally unrelated peptides. Binding was also competed by the systemin antagonists syst1-14 and syst-Ala-17 (IC50 of 500 and 1000 nM, respectively). Thus, this binding site exhibits the characteristics expected for a functional systemin receptor. Based on these results, we propose a two-step mechanism for systemin action, with binding of the N-terminal part to the receptor as the first step and activation of responses with the C-terminal part as the second step.     

All-optical regeneration techniques

Basic principles of all-optical signal regeneration are presented, and main state-of-art techniques are reviewed. Optical fiber and semiconductor based devices are addressed, and some recently reported 2R and 3R signal regeneration experiments are discussed.     

Preparation of nano‐sized silica/poly(methyl methacrylate) composite latexes by heterocoagulation: comparison of three synthetic routes

Continuing earlier work, 2,2′‐azobis(isobutyramidine) dihydrochloride (AIBA) was used as a cationic initiator to generate positively charged polymers, and promote interaction of these polymers with the negatively charged surface of colloidal silica particles in aqueous solution. Three different synthetic routes have been investigated. In a first route, emulsion polymerization of MMA, initiated by AIBA, was performed directly in an aqueous suspension of the silica beads using a non‐ionic polyoxyethylenic surfactant (NP₃₀). In a second route, AIBA was first adsorbed on the silica surface, and the free amount of initiator was discarded from the suspension. The silica‐adsorbed AIBA adduct was suspended in water with the help of surfactant, and used to initiate the emulsion polymerization of MMA. In a third route, cationic PMMA particles were synthesized separately and subsequently adsorbed on the silica surface. Whatever the approach used for their elaboration, the colloidal nanocomposites were shown to exhibit a raspberry‐like morphology. Quantitative determination of the amount of surface polymer enabled us to evaluate the efficiency of the heterocoagulation process and establish a comparison among the three synthetic routes. Copyright © 2004 Society of Chemical Industry     

Supercritical CO2 as an efficient medium for layered silicate organomodification: Preparation of thermally stable organoclays and dispersion in polyamide 6

In this study, the preparation of organoclays via a new process using supercritical carbon dioxide is described. This method turns out to be very efficient with various surfactants, in particular nonwater-soluble alkylphosphonium salts. The influence of the surfactant as well as of the clay nature on the thermal stability of the organoclay is evaluated by thermogravimetric analysis. Phosphonium-based montmorillonites are up to 90 °C more stable than ammonium-based montmorillonites. Moreover, the use of hectorite adds another 40 °C of thermal stability to the phosphonium-modified clays. These organomodified clays have been melt-blended with polyamide 6 and morphology as well as fire properties of the nanocomposites are discussed, in terms of influence of the stability of organoclays. For the first time, comparison of nanocomposites based on clay organomodified by ammonium and phosphonium salts of the very same structure is reported.     

Miniemulsions using static mixers: A feasibility study using simple in‐line static mixers

The feasibility of using simple static mixers (SM) to produce polymerisable miniemulsion dispersions, and the influence of the emulsification conditions on the diameter of the resulting methylmethacrylate droplets were examined. It was shown that these simple mixers could be used to generate droplets with diameters on the order of 150–300 nm, and that these droplets could be successfully polymerised. As expected, increasing the flow rate through the mixers led to a decrease in the average droplet size. Doubling the number of mixers in series did not have a significant influence on the droplet size but did decrease the time needed to achieve a steady final value of the average diameter. On the contrary, changing the surfactant concentration had an observable effect on the droplet sizes obtained, with higher surfactant concentrations yielding smaller droplets. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Influence of an O2 Type Oxidizing Environment on SiCf/SiC Composites: Properties/Microstructure Relationship

Ceramic matrix composites have been identified as a potential material of core structure for the fourth generation of fission nuclear reactors. Regarding their excellent mechanical behavior in very harsh conditions (high temperature and high irradiation flux), the CVI–SiC_f/SiC composites with pyrocarbon interlayer are of prime interest for the fuel cladding in the gas-cooled fast reactor. Although the working atmosphere is helium in these advanced reactors, the presence of oxidizing impurities could have a significant role on the mechanical behavior of materials subjected to long-term exposures. Within this framework, this study was intended to investigate the influence of oxidation on the SiC_f/SiC composites mechanical properties. Different pre-damage states were intentionally introduced by mechanical tensile tests on plate specimens before performing an oxidation treatment of 1,000 h at 1,000 °C under helium with 10 ppm of O₂. The degradation of the composite was determined from the mechanical behavior of post-exposure specimens. Results were correlated both with microstructural observations of the damage and with characterizations of the generated oxides at the surface of the composites. The most severe decline of mechanical properties occurs for the higher predamaged loadings. Indeed in this case, the silica formed during the oxidation of SiC is not in sufficient quantities to fill the cracks.     

Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples

Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method to detect the use of PPARβ/δ agonists. We analyzed in primary human T cells the in vitro effect of PPARβ/δ activation on fatty acid oxidation (FAO) and on their differentiation into regulatory T cells (Tregs). Furthermore, we conducted studies in mice assigned to groups according to an 8-week exercise training program and/or a 6-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist, in order to (1) determine the immune impact of the treatment on secondary lymphoid organs and to (2) validate a blood signature. Our results show that PPARβ/δ activation increases FAO potential in human and mouse T cells and mouse secondary lymphoid organs. This was accompanied by increased Treg polarization of human primary T cells. Moreover, Treg prevalence in mouse lymph nodes was increased when PPARβ/δ activation was combined with exercise training. Lastly, PPARβ/δ activation increased FAO potential in mouse blood T cells. Unfortunately, this signature was masked by training in mice. In conclusion, beyond the fact that it is unlikely that this signature could be used as a doping-control strategy, our results suggest that the use of PPARβ/δ agonists could have potential detrimental immune effects that may not be detectable in blood samples.     

Mechanism of iron corrosion in water-polyethylene glycol (PEG 400) mixtures

The properties of water-polyethylene glycol (PEG 400) solutions vary with the PEG content. The highest acidity and conductivity values were observed in 20% PEG 400 solutions. Oxygen solubility in such solutions decreased as the PEG 400 content increased. Adsorption of PEG 400, estimated by EQCM, varied with the PEG 400 concentration, also reaching a maximum in 20% PEG 400 solutions, with the weight of the adsorbed layer reaching 3.5 μg cm⁻².Iron corrosion in water-PEG 400 solutions was studied by monitoring the corrosion potential and the polarization curves. Iron corrosion was highest in the 20% PEG 400 solution due to the compromise between the evolution of acidity, dissolved oxygen content and the adsorption and complexation properties of the PEG solutions. Through adaptation of the Bockris mechanism, PEG adsorption at the metal surface constituted the first stage in the iron corrosion mechanism. Iron (ions)/PEG complexes were then formed, which diffused in solution.