837 research outputs found

    Nose cone mounted heat resistant antenna Patent

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    Nose cone mounted heat resistant antenna comprising plurality of adjacent layers of silica not introducing paths of high thermal conductivity through ablative shiel

    Tabu Search for Frequency Assignment in Mobile Radio Networks

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    Investigating the interaction between Organic Anion Transporter 1 and Ochratoxin A: an in silico structural study to depict early molecular events of substrate recruitment and the impact of single point mutations

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    Organic anion transporters (OATs) belong to a subgroup of the solute carrier 22 transporter family. OATs have a central role in xenobiotic disposition affecting the toxicokinetics of its substrates and inter-individual differences in their expression, activity and function impact both toxicokinetics and toxicodynamics. Amongst OATs, OAT1 (solute carrier family 22 member 6) is involved in the urinary excretion of many xenobiotics bringing substrates into renal proximal tubular cells which can then be secreted across the apical membrane into the tubule lumen. The mycotoxin ochratoxin A has been shown to have a high affinity for OAT1, which is an important renal transporter involved in its urinary excretion. Nowadays, molecular modeling techniques are widely applied to assess protein-ligand interactions and may provide a tool to depict the mechanistic of xenobiotic action be it toxicokinetics or toxicodynamics. This work provides a structured pipeline consisting of docking and molecular dynamic simulations to study OAT1-ligand interactions and the impact of OAT1 polymorphisms on such interactions. Such a computational structure-based analytical framework allowed to: i) model OAT1-substrate complex formation and depict the features correlating its sequence, structure and its capability to recruit substrates; and ii) investigate the impact of OAT1 missense mutations on substrate recruitment. Perspectives on applying such a structured pipeline to xenobiotic-metabolising enzymes are discussed

    Investigating the interaction between organic anion transporter 1 and ochratoxin A: An in silico structural study to depict early molecular events of substrate recruitment and the impact of single point mutations

    Get PDF
    Organic anion transporters (OATs) belong to a subgroup of the solute carrier 22 transporter family. OATs have a central role in xenobiotic disposition affecting the toxicokinetics of its substrates and inter-individual differences in their expression, activity and function impact both toxicokinetics and toxicodynamics. Amongst OATs, OAT1 (solute carrier family 22 member 6) is involved in the urinary excretion of many xenobiotics bringing substrates into renal proximal tubular cells which can then be secreted across the apical membrane into the tubule lumen. The mycotoxin ochratoxin A has been shown to have a high affinity for OAT1, which is an important renal transporter involved in its urinary excretion. Nowadays, molecular modeling techniques are widely applied to assess protein-ligand interactions and may provide a tool to depict the mechanic of xenobiotic action be it toxicokinetics or toxicodynamics. This work provides a structured pipeline consisting of docking and molecular dynamic simulations to study OAT1-ligand interactions and the impact of OAT1 polymorphisms on such interactions. Such a computational structure-based analytical framework allowed to: i) model OAT1-substrate complex formation and depict the features correlating its sequence, structure and its capability to recruit substrates; and ii) investigate the impact of OAT1 missense mutations on substrate recruitment. Perspectives on applying such a structured pipeline to xenobiotic-metabolising enzymes are discussed

    Integrating in silico models and read-across methods for predicting toxicity of chemicals: A step-wise strategy

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    Abstract In silico methods and models are increasingly used for predicting properties of chemicals for hazard identification and hazard characterisation in the absence of experimental toxicity data. Many in silico models are available and can be used individually or in an integrated fashion. Whilst such models offer major benefits to toxicologists, risk assessors and the global scientific community, the lack of a consistent framework for the integration of in silico results can lead to uncertainty and even contradictions across models and users, even for the same chemicals. In this context, a range of methods for integrating in silico results have been proposed on a statistical or case-specific basis. Read-across constitutes another strategy for deriving reference points or points of departure for hazard characterisation of untested chemicals, from the available experimental data for structurally-similar compounds, mostly using expert judgment. Recently a number of software systems have been developed to support experts in this task providing a formalised and structured procedure. Such a procedure could also facilitate further integration of the results generated from in silico models and read-across. This article discusses a framework on weight of evidence published by EFSA to identify the stepwise approach for systematic integration of results or values obtained from these "non-testing methods". Key criteria and best practices for selecting and evaluating individual in silico models are also described, together with the means to combining the results, taking into account any limitations, and identifying strategies that are likely to provide consistent results

    Generic physiologically based kinetic modelling for farm animals: Part I. Data collection of physiological parameters in swine, cattle and sheep

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    Abstract Physiologically based kinetic (PBK) models for farm animals are of growing interest in food and feed safety with key applications for regulated compounds including quantification of tissue concentrations, kinetic parameters and the setting of safe exposure levels on an internal dose basis. The development and application of these models requires data for physiological, anatomical and chemical specific parameters. Here, we present the results of a structured data collection of anatomical and physiological parameters in three key farm animal species (swine, cattle and sheep). We performed an extensive literature search and meta-analyses to quantify intra-species variability and associated uncertainty of the parameters. Parameters were collected for organ weights and blood flows in all available breeds from 110 scientific publications, of which 29, 48 and 33 for cattle, sheep, and swine, respectively. Organ weights were available in literature for all three species. Blood flow parameter values were available for all organs in sheep but were scarcer in swine and cattle. Furthermore, the parameter values showed a large intra-species variation. Overall, the parameter values and associated variability provide reference values which can be used as input for generic PBK models in these species

    The design of an omnidirectional antenna system for the Apollo spacecraft

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    Omnidirectional radio antenna system design for Apollo command modul

    Preventing the Interaction between Coronaviruses Spike Protein and Angiotensin I Converting Enzyme 2: An In Silico Mechanistic Case Study on Emodin as a Potential Model Compound

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    Emodin, a widespread natural anthraquinone, has many biological activities including health-protective and adverse effects. Amongst beneficial effects, potential antiviral activity against coronavirus responsible for the severe acute respiratory syndrome outbreak in 2002–2003 has been described associated with the inhibition of the host cells target receptors recognition by the viral Spike protein. However, the inhibition mechanisms have not been fully characterized, hindering the rational use of emodin as a model compound to develop more effective analogues. This work investigates emodin interaction with the Spike protein to provide a mechanistic explanation of such inhibition. A 3D molecular modeling approach consisting of docking simulations, pharmacophoric analysis and molecular dynamics was used. The plausible mechanism is described as an interaction of emodin at the protein–protein interface which destabilizes the viral protein-target receptor complex. This analysis has been extended to the Spike protein of the coronavirus responsible for the current pandemic hypothesizing emodin’s functional conservation. This solid knowledge-based foothold provides a possible mechanistic rationale of the antiviral activity of emodin as a future basis for the potential development of efficient antiviral cognate compounds. Data gaps and future work on emodin-related adverse effects in parallel to its antiviral pharmacology are explored
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