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Pengyu Ren - One of the best experts on this subject based on the ideXlab platform.
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Elucidating the Phosphate Binding Mode of Phosphate-Binding Protein: The Critical Effect of Buffer Solution
The Journal of Physical Chemistry B, 2018Co-Authors: Zhifeng Jing, Chengwen Liu, Jean-philip Piquemal, Kevin N. Dalby, Pengyu RenAbstract:Phosphate is an essential component of cell functions, and the specific transport of phosphorus into a cell is mediated by phosphate-binding protein (PBP). The mechanism of PBP-phosphate recognition remains controversial: on the basis of similar binding affinities at acidic and basic pHs, it is believed that the hydrogen network in the binding site is flexible to adapt to different protonation states of phosphates. However, only hydrogen (1H) phosphate was observed in the sub-angstrom X-ray structures. To address this inconsistency, we performed molecular dynamics simulations using the AMOEBA polarizable force field. Structural and free energy data from simulations suggested that 1H phosphate was the preferred bound form at both pHs. The binding of dihydrogen (2H) phosphate disrupted the hydrogen-bond network in the PBP pocket, and the computed affinity was much weaker than that of 1H phosphate. Furthermore, we showed that the discrepancy in the studies described above is resolved if the interaction betwe...
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Elucidating the Phosphate Binding Mode of Phosphate-Binding Protein: The Critical Effect of Buffer Solution
2018Co-Authors: Zhifeng Jing, Chengwen Liu, Jean-philip Piquemal, Kevin N. Dalby, Pengyu RenAbstract:Phosphate is an essential component of cell functions, and the specific transport of phosphorus into a cell is mediated by phosphate-binding protein (PBP). The mechanism of PBP-phosphate recognition remains controversial: on the basis of similar binding affinities at acidic and basic pHs, it is believed that the hydrogen network in the binding site is flexible to adapt to different protonation states of phosphates. However, only hydrogen (1H) phosphate was observed in the sub-angstrom X-ray structures. To address this inconsistency, we performed molecular dynamics simulations using the AMOEBA polarizable force field. Structural and free energy data from simulations suggested that 1H phosphate was the preferred bound form at both pHs. The binding of dihydrogen (2H) phosphate disrupted the hydrogen-bond network in the PBP pocket, and the computed affinity was much weaker than that of 1H phosphate. Furthermore, we showed that the discrepancy in the studies described above is resolved if the interaction between phosphate and the buffer agent is taken into account. The calculated apparent binding affinities are in excellent agreement with experimental measurements. Our results suggest the high specificity of PBP for 1H phosphate and highlight the importance of the buffer solution for the binding of highly charged ligands
Melanie Guerard - One of the best experts on this subject based on the ideXlab platform.
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correction to an appraisal of Critical Effect sizes for the benchmark dose approach to assess dose response relationships in genetic toxicology
Archives of Toxicology, 2017Co-Authors: Andreas Zeller, Gonzalo Duranpacheco, Melanie GuerardAbstract:In the original publication, Table 1 was incorrect (differences in the numerators of the fractions). The correct version of Table 1 (sums in the numerators) is given below.
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a proposal for a novel rationale for Critical Effect size in dose response analysis based on a multi endpoint in vivo study with methyl methanesulfonate
Mutagenesis, 2016Co-Authors: Andreas Zeller, Leilei Tang, Stephen D Dertinger, Juergen Funk, Gonzalo Duranpacheco, Melanie GuerardAbstract:Methyl methanesulfonate, a well-known direct-acting genotoxicant, was assessed in a multi-endpoint study in rats using six closely spaced dose levels. The main goal of the study was to investigate the genotoxic response at very low doses and to analyse this response with dedicated statistical tools in order to find a Point of Departure (PoD) and related metrics. Software packages like PROAST or EPA-BMDS require the toxicologist to define a so-called Critical Effect size (CES) or benchmark response (BMR) and this choice has a large impact on the result of the PoD calculation. Currently, increases of 5%, 10% or 1 standard deviation over concurrent vehicle controls have been proposed for CES/BMR, values that may or may not be suited for all genotoxicity endpoints. Based on the data obtained in this study, we propose an endpoint specific CES approach that reflects the typical evaluation process of a regulatory acceptable genotoxicology study. However, we are aware that this ratio-based CES strategy will need to be more fully developed with additional experimentation and should be mainly seen as a starting point for scientific discussion.
Monique Rennen - One of the best experts on this subject based on the ideXlab platform.
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derivation of the minimal magnitude of the Critical Effect size for continuous toxicological parameters from within animal variation in control group data
Regulatory Toxicology and Pharmacology, 2009Co-Authors: Harrie Buist, Jan Telman, Frhr G Von Bolcshazy, M Dammann, Monique RennenAbstract:Assuming that temporal fluctuations in physiological parameters (e.g. haematology, biochemistry) in individual healthy non-exposed animals are non-adverse, the minimal magnitude of the Critical Effect Size (CES) for a number of continuous parameters of toxicity studies was derived. A total of 36 studies (19 pharmaceutical preclinical studies in dogs and 17 chemical risk assessment studies in rats) were analysed to determine within-animal variation in their control groups. Minimal CES-values were derived for each group of studies, differentiating where necessary between strains and sexes, using the 2.5 percentile (lower limit) and/or 97.5 percentile (upper limit) of the distribution of the within-animal variation around the mean of each parameter. We concluded that minimal CES-values for continuous clinical chemistry and haematology parameters should be established separately per species, strain, sex and study duration investigated. Grouping of minimal CES-values, leading to more or less "general" values, seems possible for those parameters that are subject to tight homeostatic control and consequently show little within-animal variation. Nearly a quarter of the proposed CES-values is ≤5%, nearly a quarter range from 6% to 10%, a quarter is 15% or 20%, and nearly 30% of the proposed values is ≥20% of the mean of the control animals. © 2009 Elsevier Inc. All rights reserved.
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within animal variation as an indication of the minimal magnitude of the Critical Effect size for continuous toxicological parameters applicable in the benchmark dose approach
Risk Analysis, 2006Co-Authors: Susan Dekkers, Jan Telman, Monique Rennen, Marco J Appel, Cees De HeerAbstract:In this study, the within-animal variation in routinely studied continuous toxicological parameters was estimated from temporal fluctuations in individual healthy nonexposed animals. Assuming that these fluctuations are nonadverse, this within-animal variation may be indicative of the minimal magnitude of the Critical Effect size (CES). The CES is defined as the breaking point between adverse and nonadverse changes in a continuous toxicological parameter, at the level of the individual organism. The total variation in the data from individual nonexposed animals was divided in variation parts due to known factors (differences in sex, animal, and day) and a residual variation, by means of analysis of variance. Using the residual variation and the estimated analytical measurement error of a toxicological parameter, the within-animal variation can be estimated. The data showed within-animal variations ranging between 0.6% and 34% for different clinical chemistry and hematological parameters in 90-day rat studies. This indicates that different (minimal) CES values may be applicable for different parameters. © 2006 Society for Risk Analysis.
Paulo Waldir Tardioli - One of the best experts on this subject based on the ideXlab platform.
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preparation of crosslinked enzyme aggregates of a thermostable cyclodextrin glucosyltransferase from thermoanaerobacter sp Critical Effect of the crosslinking agent
Catalysts, 2019Co-Authors: Mayerlenis J Rojas, Murilo Amaralfonseca, Gisella Maria Zanin, Roberto Fernandezlafuente, Raquel L C Giordano, Paulo Waldir TardioliAbstract:This work was financed by National Council for Scientific and Technology Development (CNPq, grant 483947/2012-1, and doctorate fellowship of M.J.R.), and in part by the Coordenacao de Aperfeicoamento Pessoal de Nivel Superior—Brazil (CAPES), Finance Code 001. We also gratefully recognize all support from the Project MINECO from Spanish Government, (project number CTQ2017-86170-R).
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Preparation of Crosslinked Enzyme Aggregates of a Thermostable Cyclodextrin Glucosyltransferase from Thermoanaerobacter sp. Critical Effect of the Crosslinking Agent
MDPI AG, 2019Co-Authors: Mayerlenis J Rojas, Gisella Maria Zanin, Raquel De ,lima Camargo Giordano, Murilo Amaral-fonseca, Roberto Fernandez-lafuente, Paulo Waldir TardioliAbstract:Crosslinked enzyme aggregates (CLEAs) of a thermostable cyclodextrin glucosyltransferase (CGTase) from Thermoanaerobacter sp. have been prepared for the production of cyclodextrins (CDs). Different parameters in the precipitation (nature and concentration of precipitant) and crosslinking steps (time of reaction with cross-linker, nature and concentration of the crosslinker) were evaluated on the production of CLEAs of CGTase. Among the seven studied precipitants, acetone with a 75% (v/v) concentration produced the aggregates of CGTase with higher activity, which retained 97% of the initial activity. Concerning the cross-linker (glutaraldehyde, starch⁻aldehyde, and pectin⁻aldehyde), starch⁻aldehyde produced the most active CLEAs. The use of bovine serum albumin as co-feeder decreased the expressed activity. Addition of polyethylenimine at the end of cross-linking step prevented the leakage of the enzyme and the subsequent Schiff’s bases reduction with sodium borohydride permitted to maintain 24% of the initial activity even with the large dextrin as substrate. The optimal conditions for the immobilization process required were defined as 75% (v/v) acetone as precipitation reagent for 1 h at 20 °C, 20 mM starch⁻aldehyde as crosslinking reagent for 2 h at 20 °C, treatment with 1 mg/mL of polyethylenimine for 5 min, reduction with 1 mg/mL of sodium borohydride. The CLEAs of CGTase were active catalyst (similarly to the free enzyme) in the production of cyclodextrins at 50 °C and pH 6.0 for 6 h reaction, maintaining intact their structures. Besides this, after five cycles of 3 h the total cyclodextrin yield was 80% of the initial value (first batch, with around 45% CD yield)
Cees De Heer - One of the best experts on this subject based on the ideXlab platform.
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within animal variation as an indication of the minimal magnitude of the Critical Effect size for continuous toxicological parameters applicable in the benchmark dose approach
Risk Analysis, 2006Co-Authors: Susan Dekkers, Jan Telman, Monique Rennen, Marco J Appel, Cees De HeerAbstract:In this study, the within-animal variation in routinely studied continuous toxicological parameters was estimated from temporal fluctuations in individual healthy nonexposed animals. Assuming that these fluctuations are nonadverse, this within-animal variation may be indicative of the minimal magnitude of the Critical Effect size (CES). The CES is defined as the breaking point between adverse and nonadverse changes in a continuous toxicological parameter, at the level of the individual organism. The total variation in the data from individual nonexposed animals was divided in variation parts due to known factors (differences in sex, animal, and day) and a residual variation, by means of analysis of variance. Using the residual variation and the estimated analytical measurement error of a toxicological parameter, the within-animal variation can be estimated. The data showed within-animal variations ranging between 0.6% and 34% for different clinical chemistry and hematological parameters in 90-day rat studies. This indicates that different (minimal) CES values may be applicable for different parameters. © 2006 Society for Risk Analysis.