Dmytro Kevorkov

An efficient method for the detection and elimination of systematic error in high-throughput screening

MOTIVATION High-throughput screening (HTS) is an early-stage process in drug discovery which allows thousands of chemical compounds to be tested in a single study. We report a method for correcting HTS data prior to the hit selection process (i.e. selection of active compounds). The proposed correction minimizes the impact of systematic errors which may affect the hit selection in HTS. The introduced method, called a well correction, proceeds by correcting the distribution of measurements within wells of a given HTS assay. We use simulated and experimental data to illustrate the advantages of the new method compared to other widely-used methods of data correction and hit selection in HTS. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Statistical Analysis of Systematic Errors in High-Throughput Screening

High-throughput screening (HTS) is an efficient technology for drug discovery. It allows for screening of more than 100,000 compounds a day per screen and requires effective procedures for quality control. The authors have developed a method for evaluating a background surface of an HTS assay; it can be used to correct raw HTS data. This correction is necessary to take into account systematic errors that may affect the procedure of hit selection. The described method allows one to analyze experimental HTS data and determine trends and local fluctuations of the corresponding background surfaces. For an assay with a large number of plates, the deviations of the background surface from a plane are caused by systematic errors. Their influence can be minimized by the subtraction of the systematic background from the raw data. Two experimental HTS assays from the ChemBank database are examined in this article. The systematic error present in these data was estimated and removed from them. It enabled the authors to correct the hit selection procedure for both assays.

Experimental investigation and thermodynamic calculation of ternary Al–Ca–Mg phase equilibria

The ternary Al-Ca-Mg phase equlibria were investigated using X-ray diffraction methods, metallography, scanning electron microscopy with energy- and wave-length-dispersive X-ray microanalysis, and differential thermal analysis. The phase diagram was determined in the complete composition range. Large ternary solubilities were found for the binary phases CaMg 2 , Al 2 Ca and Al 3 Ca 8 . Microstructures of samples with compositions near the ternary monovariant eutectic L → CaMg 2 + Al 2 Ca show remarkable rod-like crystals that are identified as intergrowth between CaMg 2 and Al 2 Ca. A consistent thermodynamic model was developed using the Calphad method incorporating all experimental data. It was used to calculate all pertinent phase equilibria of the Al-Ca-Mg system.

HTS-Corrector: software for the statistical analysis and correction of experimental high-throughput screening data

MOTIVATION High-throughput screening (HTS) plays a central role in modern drug discovery, allowing for testing of >100,000 compounds per screen. The aim of our work was to develop and implement methods for minimizing the impact of systematic error in the analysis of HTS data. To the best of our knowledge, two new data correction methods included in HTS-Corrector are not available in any existing commercial software or freeware. RESULTS This paper describes HTS-Corrector, a software application for the analysis of HTS data, detection and visualization of systematic error, and corresponding correction of HTS signals. Three new methods for the statistical analysis and correction of raw HTS data are included in HTS-Corrector: background evaluation, well correction and hit-sigma distribution procedures intended to minimize the impact of systematic errors. We discuss the main features of HTS-Corrector and demonstrate the benefits of the algorithms.

Phylogenetic Network Construction Approaches

This chapter presents a review of the mathematical techniques available to construct phytogenies and to represent reticulate evolution. Phytogenies can be estimated using distance-based, maximum parsimony, or maximum likelihood methods. Bayesian methods have recently become available to construct phytogenies. Reticulate evolution includes horizontal gene transfer between taxa, hybridization events, and homoplasy. Genetic recombination also creates reticulate evolution within lineages. Several methods are now available to construct reticulated networks of various kinds. Twelve such methods and the accompanying software are described in this review chapter.

Experimental study of the Ca-Mg-Zn system using diffusion couples and key alloys

Abstract Nine diffusion couples and 32 key samples were prepared to map the phase diagram of the Ca–Mg–Zn system. Phase relations and solubility limits were determined for binary and ternary compounds using scanning electron microscopy, electron probe microanalysis and x-ray diffraction (XRD). The crystal structure of the ternary compounds was studied by XRD and electron backscatter diffraction. Four ternary intermetallic (IM) compounds were identified in this system: Ca3MgxZn15−x (4.6x12 at 335 °C, IM1), Ca14.5Mg15.8Zn69.7 (IM2), Ca2Mg5Zn13 (IM3) and Ca1.5Mg55.3Zn43.2 (IM4). Three binary compounds were found to have extended solid solubility into ternary systems: CaZn11, CaZn13 and Mg2Ca form substitutional solid solutions where Mg substitutes for Zn atoms in the first two compounds, and Zn substitutes for both Ca and Mg atoms in Mg2Ca. The isothermal section of the Ca–Mg–Zn phase diagram at 335 °C was constructed on the basis of the obtained experimental results. The morphologies of the diffusion couples in the Ca–Mg–Zn phase diagram at 335 °C were studied. Depending on the terminal compositions of the diffusion couples, the two-phase regions in the diffusion zone have either a tooth-like morphology or contain a matrix phase with isolated and/or dendritic precipitates.

Influence of impact speed on water droplet erosion of TiAl compared with Ti6Al4V.

Water Droplet Erosion (WDE) as a material degradation phenomenon has been a concern in power generation industries for decades. Steam turbine blades and the compressor blades of gas turbines that use water injection usually suffer from WDE. The present work focuses on studying erosion resistance of TiAl as a potential alloy for turbine blades compared to Ti6Al4V, a frequently used blade alloy. Their erosion behaviour is investigated at different droplet impact speeds to determine the relation between erosion performance and impact speed. It is found that the relationship is governed by a power law equation, ER ~ Vn, where the speed exponent is 7–9 for Ti6Al4V and 11–13 for TiAl. There is a contrast between the observed speed exponent in this work and the ones reported in the literature for Ti6Al4V. It is attributed to the different erosion setups and impingement conditions such as different droplet sizes. To verify this, the erosion experiments were performed at two different droplet sizes, 464 and 603 μm. TiAl showed superior erosion resistance in all erosion conditions; however, its erosion performance exhibits higher sensitivity to the impact speed compared to Ti6Al4V. It means that aggressive erosion conditions decrease the WDE resistance superiority of TiAl.

Comparison of the interaction of components in the La–Co–Zn and Ce–Co–Zn ternary systems at 470 K

Abstract Interaction of the components in the La–Co–Zn and Ce–Co–Zn ternary systems has been investigated by means of X-ray analysis. The isothermal sections of the phase diagrams have been determined over the entire composition range at 470 K. Seven new ternary compounds have been found in each system and the crystal structure has been determined for most of them.

Phase Equilibria and Magnetic Phases in the Ce-Fe-Co-B System

Ce-Fe-Co-B is a promising system for permanent magnets. A high-throughput screening method combining diffusion couples, key alloys, Scanning Electron Microscope/Wavelength Dispersive X-ray Spectroscope (SEM/WDS), and Magnetic Force Microscope (MFM) is used in this research to understand the phase equilibria and to explore promising magnetic phases in this system. Three magnetic phases were detected and their homogeneity ranges were determined at 900 °C, which were presented by the formulae: Ce2Fe14−xCoxB (0 ≤ x ≤ 4.76), CeCo4−xFexB (0 ≤ x ≤ 3.18), and Ce3Co11−x FexB4 (0 ≤ x ≤ 6.66). The phase relations among the magnetic phases in this system have been studied. Ce2(Fe, Co)14B appears to have stronger magnetization than Ce(Co, Fe)4B and Ce3(Co, Fe)11B4 from MFM analysis when comparing the magnetic interactions of selected key alloys. Also, a non-magnetic CeCo12−xFexB6 (0 ≤ x ≤ 8.74) phase was detected in this system. A boron-rich solid solution with Ce13FexCoyB45 (32 ≤ x ≤ 39, 3 ≤ y ≤ 10) chemical composition was also observed. However, the crystal structure of this phase could not be found in the literature. Moreover, ternary solid solutions ε1 (Ce2Fe17−xCox (0 ≤ x ≤ 12.35)) and ε2 (Ce2Co17−xFex (0 ≤ x ≤ 3.57)) were found to form between Ce2Fe17 and Ce2Co17 in the Ce-Fe-Co ternary system at 900 °C.

The ternary Gd-Li-Mg system: Phase diagram study and computational evaluation

The binary Gd-Li and the ternary Gd-Li-Mg systems were studied experimentally by thermal analysis and phase equilibration and also by thermodynamic calculations using the CALPHAD method. Ternary phase equilibria at 250 °C were studied with 55 different alloys that were annealed for 400 h and analyzed by x-ray diffractometry. A thermodynamic assessment of the binary Gd-Li system was also performed and the calculated phase diagram is presented. In the Gd-Li-Mg system, ternary solubilities of Li in GdMg (up to 5 at.% Li), GdMg2 (up to approximately 3 at.% Li), and GdMg3 (up to 5 at.% Li) were found at 250 °C. No ternary compound was observed. Lattice parameters for different compositions are given for these phases. Thermal analysis using a ternary key sample of composition near the invariant reaction L′=L+(βGd)+GdMg provided the data that were needed to determine a thermodynamic parameter for the ternary liquid. Thermodynamic data sets for the ternary solid solution phases were also developed. Based on the present data sets and those of the binary Gd-Mg and Li-Mg systems from the literature, the phase equilibria in the entire ternary system were calculated. Isothermal and vertical sections of the phase diagram and the projection of the liquidus surface are shown. These calculated phase diagrams are well supported by the experimental data.