Prediction of hERG inhibition of drug discovery compounds using biomimetic HPLC measurements

The major causes of failure of drug discovery compounds in clinics are the lack of efficacy and toxicity. To reduce late-stage failures in the drug discovery process, it is essential to estimate early the probability of adverse effects and potential toxicity. Cardiotoxicity is one of the most often observed problems related to a compound\u27s inhibition of the hERG channel responsible for the potassium cation flux. Biomimetic HPLC methods can be used for the early screening of a compound\u27s lipophilicity, protein binding and phospholipid partition. Based on the published hERG pIC50 data of 90 marketed drugs and their measured biomimetic properties, a model has been developed to predict the hERG inhibition using the measured binding of compounds to alpha-1-acid-glycoprotein (AGP) and immobilised artificial membrane (IAM). A representative test set of 16 compounds was carefully selected. The training set, involving the remaining compounds, served to establish the linear model. The mechanistic model supports the hypothesis that compounds have to traverse the cell membrane and bind to the hERG ion channel to cause the inhibition. The AGP and the hERG ion channel show structural similarity, as both bind positively charged compounds with strong shape selectivity. In contrast, a good IAM partition is a prerequisite for cell membrane traversal. For reasons of comparison, a corresponding model was derived by replacing the measured biomimetic properties with calculated physicochemical properties. The model established with the measured biomimetic binding properties proved to be superior and can explain over 70% of the variance of the hERG pIC50 values

Stiffness and Damping Properties of Cellular Shear Walls with Viscoelastic Fillers

Aiming to enhance the stiffness and damping properties of cellular materials, the idea of inserting viscoelastic fillers into the gaps of cells is developed. A representative volume element of typical hexagonal honeycomb cells with and without inclusions is examined under dynamic shear loading, in order to define the mechanical properties of the proposed composite material. Within each cell the viscoelastic material is either through viscoelastic shell elements or through viscoelastic bars attached to the hexagonal cell apexes. The calibrated viscoelastic bar RVE model is, by extent, implemented to a shear wall, tested under dynamic shear loading, to verify the efficiency of the viscoelastic inclusions. Finally, different viscoelastic filler patterns are explored to study the proposed system's performance

Characterisation of Medipix3 Silicon Detectors in a Charged-Particle Beam

While designed primarily for X-ray imaging applications, the Medipix3 ASIC can also be used for charged-particle tracking. In this work, results from a beam test at the CERN SPS with irradiated and non-irradiated sensors are presented and shown to be in agreement with simulation, demonstrating the suitability of the Medipix3 ASIC as a tool for characterising pixel sensors.Comment: 16 pages, 13 figure

Fairness Aware Counterfactuals for Subgroups

In this work, we present Fairness Aware Counterfactuals for Subgroups (FACTS), a framework for auditing subgroup fairness through counterfactual explanations. We start with revisiting (and generalizing) existing notions and introducing new, more refined notions of subgroup fairness. We aim to (a) formulate different aspects of the difficulty of individuals in certain subgroups to achieve recourse, i.e. receive the desired outcome, either at the micro level, considering members of the subgroup individually, or at the macro level, considering the subgroup as a whole, and (b) introduce notions of subgroup fairness that are robust, if not totally oblivious, to the cost of achieving recourse. We accompany these notions with an efficient, model-agnostic, highly parameterizable, and explainable framework for evaluating subgroup fairness. We demonstrate the advantages, the wide applicability, and the efficiency of our approach through a thorough experimental evaluation of different benchmark datasets

Immobilized artificial membrane chromatography: from medicinal chemistry to environmental sciences

Immobilized Artificial Membrane (IAM) chromatography constitutes a valuable tool for medicinal chemists to prioritize drug candidates in early drug development. The retention on IAM stationary phases encodes lipophilicity, electrostatic and other secondary interactions contrary to traditional octanol-water partitioning. An increasing number of publications in recent years have suggested that IAM indices, including isocratic log k(IAM) or extrapolated log kw(IAM) retention factors, chromatographic hydrophobicity index CHI(IAM) or the polarity parameter Δlog kw(IAM) can successfully model the passage of xeniobiotics through biological membranes and barriers and predict pharmacokinetic properties, often in combination with additional descriptors. Examples referring to the modeling of human oral absorption, blood-brain penetration and skin partition are described. More recently, IAM chromatography has been applied to estimate toxicological endpoints in regard to drug safety, such as phospholipidosis potential, or in regard to chemical risk hazards including the bioconcentration factor and aquatic organisms’ toxicity. The promising results in both medicinal chemistry and in environmental science in combination with the speed, reproducibility and low analyte consumption suggest that a broader application of IAM chromatography in the early drug discovery process and in ecotoxicity may save time and money in initial drug candidate selection and will contribute to a reduced risk hazard of chemicals

Dothistroma septosporum identified in Greece on Pinus brutia and Pinus nigra plantations

No abstract available.http://apsjournals.apsnet.org/loi/pdishb201

Mouse phenotyping with near-infrared fluorescence lymphatic imaging

We demonstrate the ability to non-invasively and quantitatively image lymphatic architecture and contractile function using dynamic near-infrared (NIR) fluorescence imaging with injection of indocyanine green in normal and transgenic mice. Unlike normal mice, which showed well defined lymphatic drainage patterns and orthograde propagation of contraction waves, we observed tortuous and mispatterned lymphatic vessels and persistent retrograde lymph flow in mice with deficiency in Prox1, a transcription factor essential for lymphatic vascular development. NIR fluorescence imaging provides a method for quantifying lymphatic function for future studies designed to discern differences in lymphatic function in murine models of human lymphatic disease

Novel species of Huntiella from naturally-occurring forest trees in Greece and South Africa

Huntiella species are wood-infecting, filamentous ascomycetes that occur in fresh wounds on a wide variety of tree species. These fungi are mainly known as saprobes although some have been associated with disease symptoms. Six fungal isolates with typical culture characteristics of Huntiella spp. were collected from wounds on native forest trees in Greece and South Africa. The aim of this study was to identify these isolates, using morphological characters and multigene phylogenies of the rRNA internal transcribed spacer (ITS) region, portions of the β-tubulin (BT1) and translation elongation factor 1α (TEF-1α) genes. The mating strategies of these fungi were also determined through PCR amplification of mating type genes. The study revealed two new species; one from Platanus orientalis in Greece and one from Colophospermum mopane and Senegalia nigrescens in South Africa. These novel taxa have been provided with the names, H. hellenica sp. nov. and H. krugeri sp. nov., respectively. The former species was found to have a homothallic and the latter a heterothallic mating system.Supplementary material 1 : Figure S1. ML tree of Huntiella species generated from the ITS DNA sequence data Authors: FeiFei Liu, Seonju Marincowitz, ShuaiFei Chen, Michael Mbenoun, Panaghiotis Tsopelas, Nikoleta Soulioti, Michael J. Wingfield Data type: phylogenetic tree Explanation note: Sequences generated from this study are printed in bold type. Bold branches indicate posterior probabilities values ≥ 0.9. Bootstrap values and posterior probabilities value are presented above branches as ML/MP/BI. Bootstrap value < 50% or probabilities values < 0.9 are marked with *. Nodes lacking the support value are marked with -. Ceratocystis cercfabiensis (CMW 43029) represents the outgroup. Copyright notice: This dataset is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0/). The Open Database License (ODbL) is a license agreement intended to allow users to freely share, modify, and use this Dataset while maintaining this same freedom for others, provided that the original source and author(s) are credited. Link: https://doi.org/10.3897/mycokeys.69.53205.suppl1Supplementary material 2 : Figure S2. ML tree of Huntiella species generated from the BT1 DNA sequence data Authors: FeiFei Liu, Seonju Marincowitz, ShuaiFei Chen, Michael Mbenoun, Panaghiotis Tsopelas, Nikoleta Soulioti, Michael J. Wingfield Data type: phylogenetic tree Explanation note: Sequences generated from this study are printed in bold type. Bold branches indicate posterior probabilities values ≥ 0.9. Bootstrap values and posterior probabilities values are presented above branches as ML/MP/BI. Bootstrap value < 50% or probabilities values < 0.9 are marked with *. Nodes lacking the support value are marked with -. Ceratocystis cercfabiensis (CMW 43029) represents the outgroup. Copyright notice: This dataset is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0/). The Open Database License (ODbL) is a license agreement intended to allow users to freely share, modify, and use this Dataset while maintaining this same freedom for others, provided that the original source and author(s) are credited. Link: https://doi.org/10.3897/mycokeys.69.53205.suppl2 52 FeiFei Liu et al. / MycoKeys 69: 33–52 (2020)Supplementary material 3 : Figure S3. ML tree of Huntiella species generated from the TEF-1α DNA sequence data Authors: FeiFei Liu, Seonju Marincowitz, ShuaiFei Chen, Michael Mbenoun, Panaghiotis Tsopelas, Nikoleta Soulioti, Michael J. Wingfield Data type: phylogenetic tree Explanation note: Sequences generated from this study are printed in bold type. Bold branches indicate posterior probabilities values ≥ 0.9. Bootstrap values and posterior probabilities values are presented above branches as ML/MP/BI. Bootstrap value < 50% or probabilities values < 0.9 are marked with *. Nodes lacking the support value are marked with -. Ceratocystis cercfabiensis (CMW 43029) represents the outgroup. Copyright notice: This dataset is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0/). The Open Database License (ODbL) is a license agreement intended to allow users to freely share, modify, and use this Dataset while maintaining this same freedom for others, provided that the original source and author(s) are credited. Link: https://doi.org/10.3897/mycokeys.69.53205.suppl3Members of Tree Protection and Cooperation Programme (TPCP) and the National Research Foundation (NRF), South Africa.https://mycokeys.pensoft.netam2021BiochemistryForestry and Agricultural Biotechnology Institute (FABI)GeneticsMicrobiology and Plant Patholog