Towards Automated Binding Affinity Prediction Using an Iterative Linear Interaction Energy Approach

Binding affinity prediction of potential drugs to target and off-target proteins is an essential asset in drug development. These predictions require the calculation of binding free energies. In such calculations, it is a major challenge to properly account for both the dynamic nature of the protein and the possible variety of ligand-binding orientations, while keeping computational costs tractable. Recently, an iterative Linear Interaction Energy (LIE) approach was introduced, in which results from multiple simulations of a protein-ligand complex are combined into a single binding free energy using a Boltzmann weighting-based scheme. This method was shown to reach experimental accuracy for flexible proteins while retaining the computational efficiency of the general LIE approach. Here, we show that the iterative LIE approach can be used to predict binding affinities in an automated way. A workflow was designed using preselected protein conformations, automated ligand docking and clustering, and a (semi-)automated molecular dynamics simulation setup. We show that using this workflow, binding affinities of aryloxypropanolamines to the malleable Cytochrome P450 2D6 enzyme can be predicted without a priori knowledge of dominant protein-ligand conformations. In addition, we provide an outlook for an approach to assess the quality of the LIE predictions, based on simulation outcomes only.     

High-speed single cable synchronization system for data-converters

A clock-cycle accurate synchronization technique for fully integrated data-converters is presented. Only a single cable is needed to distribute both the required synchronization signal and the converter clock. Different possible implementations, both to generate and decompose the distributed signal, are presented. A discrete component generator circuit is discussed. To avoid setup and hold time violations, on-chip signal reconstruction is unavoidable. A 40 nm CMOS recovery circuit was developed. Simulation results, including layout parasitics, show the wide frequency operating range of the proposed technique.     

Social Exclusion in Later Life: A Systematic Review of the Literature

In the last decade, there has been a growing awareness regarding social exclusion. Considering the ageing population and the likelihood of older people being socially excluded, the aims of this article are to: (1) review existing studies concerning social exclusion in later life; and (2) identify how environmental and life-course perspectives are presented in studies focusing on social exclusion in later life. A systematic review in seven scientific databases was conducted to explore the peer-reviewed evidence. In total, 26 articles were included and analysed. Findings describe the variety of methods, conceptualisation, dimensions and measures used in this recent area of research. Determinants of social exclusion in later life are discussed and life-course and environmental perspectives are examined. The discussion highlights the complex character of the concept and measurement of social exclusion, and the presence of general and age-specific dimensions of social exclusion in later life. The time and context relativity and the need for life-course and environmental perspectives on social exclusion in later life are discussed. Finally, future directions of research are discussed.     

Properties and Printability of Inkjet and Screen-Printed Silver Patterns for RFID Antennas

We report the modeling, and geometrical and electrical characterization, of inkjet and screen-printed patterns on different polymeric substrates for use as antennas in radio-frequency identification (RFID) applications. We compared the physical and electrical characteristics of two silver nanoparticle-based commercial inkjet-printable inks and one screen-printable silver paste, when deposited on polyimide (PI), polyethylene terephthalate (PET), and polyetherimide (PEI) substrates. First, the thickness of the inkjet-printed patterns was predicted by use of an analytical model based on printing conditions and ink composition. The predicted thickness was confirmed experimentally, and geometrical characterization of the lines was completed by measuring the root-mean-square roughness of the patterns. Second, direct-current electrical characterization was performed to identify the printing conditions yielding the lowest resistivity and sheet resistance. The minimum resistivity for the inkjet-printing method was 8.6 ± 0.8 μΩ cm, obtained by printing four stacked layers of one of the commercial inks on PEI, whereas minimum resistivity of 44 ± 7 μΩ cm and 39 ± 4 μΩ cm were obtained for a single layer of screen-printed ink on polyimide (PI) with 140 threads/cm mesh and 90 threads/cm mesh, respectively. In every case, these minimum values of resistivity were obtained for the largest tested thickness. Coplanar waveguide transmission lines were then designed and characterized to analyze the radio-frequency (RF) performance of the printed patterns; minimum transmission losses of 0.0022 ± 0.0012 dB/mm and 0.0016 ± 0.0012 dB/mm measured at 13.56 MHz, in the high-frequency (HF) band, were achieved by inkjet printing on PEI and screen printing on PI, respectively. At 868 MHz, in the ultra-high-frequency band, the minimum values of transmission loss were 0.0130 ± 0.0014 dB/mm for inkjet printing on PEI and 0.0100 ± 0.0014 dB/mm for screen printing on PI. Although the resistivity achieved is lower for inkjet printing than for screen printing, RF losses for inkjetted patterns were larger than for screen-printed patterns, because thicker layers were obtained by screen printing. Finally, several coil inductors for the HF band were also fabricated by use of both printing techniques, and were used as antennas for semi-passive smart RFID tags on plastic foil capable of measuring temperature and humidity.     

The Al-Rich Part of the Fe-Al Phase Diagram

The Al-rich part of the Fe-Al phase diagram between 50 and 80 at.% Al including the complex intermetallic phases Fe₅Al₈ (ε), FeAl₂, Fe₂Al₅, and Fe₄Al₁₃ was re-investigated in detail. A series of 19 alloys was produced and heat-treated at temperatures in the range from 600 to 1100 °C for up to 5000 h. The obtained data were further complemented by results from a number of diffusion couples, which helped to determine the homogeneity ranges of the phases FeAl₂, Fe₂Al₅, and Fe₄Al₁₃. All microstructures were inspected by scanning electron microscopy (SEM), and chemical compositions of the equilibrium phases as well as of the alloys were obtained by electron probe microanalysis (EPMA). Crystal structures and the variation of the lattice parameters were studied by x-ray diffraction (XRD) and differential thermal analysis (DTA) was applied to measure all types of transition temperatures. From these results, a revised version of the Al-rich part of the phase diagram was constructed.     

Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood‐Stage Antimalarial Compounds

Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1‐benzyl‐4‐piperidyl)[6,7‐dimethoxy‐2‐(4‐methyl‐1,4‐diazepin‐1‐yl)‐4‐quinazolinyl]amine (BIX01294; 1 ), a known human G9a inhibitor, together with its dose‐dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC₅₀ values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.     

Nanohybrid Materials with Tunable Birefringence via Cation Exchange in Polymer Films

In this work, a nanohybrid material based on a freestanding polymeric liquid crystal network capable of postmodification via cation exchange to tune birefringence is proposed. The smectic liquid crystal films can be infiltrated with a variety of cations, thereby changing the refractive indices (n_e and n_o) and the effective birefringence (Δn) of the nanohybrid material, with reversible cation infiltration occurring within minutes. Birefringence could be tuned between values of 0.06 and 0.19, depending on the cation infiltrated into the network. Upon infiltration, a decrease in the smectic layer spacing is found with layer contraction independent of the induced change in birefringence. Potential applications are in the field of specialty optical devices, such as flexible, retunable reflective filters.     

Characterization of Micro-Powders for the Fabrication of Compression Molded THz Lenses

We investigate different micro-powders that can be used as base materials for THz lenses fabricated by compression molding. For this application materials with a very weak THz absorbance and low dispersion are required. By measuring the THz absorption coefficient and refractive index of pellets pressed from the different micro-powders, we identify several materials that are well suited for the fabrication of compression molded THz lenses (CMLs). In addition, a considerable range of the refractive index is covered by the samples, which will allow for the fabrication of CMLs with different focal lengths for one and the same lens design.     

The role of technological availability for the distributive impacts of climate change mitigation policy

The impacts of the availability of low-carbon technologies on the regional distribution of mitigation costs are analyzed in a global multi-regional integrated assessment model. Three effects on regional consumption losses are distinguished: domestic measures, trade of fossil energy carriers and trade of emission permits. Key results are: (i) GDP losses and a redirection of investments in the energy system towards capital-intensive technologies are major contributions to regional consumption losses. (ii) A devaluation of tradable fossil energy endowments contributes largely to the mitigation costs of fossil fuel exporters. (iii) In case of reduced availability of low-carbon technologies, the permit market volume and associated monetary redistributions increase. The results suggest that the availability of a broad portfolio of low-carbon technologies could facilitate negotiations on the permit allocation scheme in a global cap-and-trade system.