Introducing the vectorial Kappa: An index to quantify congruence between vectorial mosaics

This paper introduces the vectorial Kappa (κ_v) that one can utilize to assess congruence between two vectorial mosaics. The vectorial Kappa extends for vectorial mosaics the approach of the so-called Cohen's Kappa index, commonly used to compare raster mosaics. By comparing both approaches, we aim to demonstrate how efficient and convenient a vector-based congruence may be when working on vectorial mosaics.     

Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC₅₀ values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC₅₀ > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.     

The impact of demographic changes on the epidemiology of herpes zoster: Spain as a case study

Varicella zoster virus (VZV) causes varicella upon first exposure and may reactivate later in life into herpes zoster (HZ), with a risk that is thought to be reduced by re-exposures to VZV. Given the decades-long time scales of reactivation and its dependence on the accumulation of re-exposure episodes, adopting a long-term perspective may be useful to correctly interpret current epidemiological trends of VZV. In this study, we investigate the possible impact of demographic changes on varicella and HZ in Spain, using an age-structured mathematical model informed with historical demographic data and calibrated against age-specific profiles of varicella seroprevalence and HZ incidence data. The model qualitatively reproduces the remarkable growth of HZ incidence observed in Spain between 1997 and 2004, before the introduction of varicella vaccination programmes. We demonstrate that this growth may be partially ascribed to the reduction of varicella circulation that followed the overall decline of the birth rate in the twentieth century. Model predictions further suggest that, even under the most optimistic projections, HZ incidence will continue its rise until at least 2040. Considering the effect of demographic changes can help interpreting variations in epidemiological trends of HZ, contributing to a more accurate evaluation of vaccination programmes against VZV.     

Validation of radiocarpal joint contact models based on images from a clinical MRI scanner

This study was undertaken to assess magnetic resonance imaging (MRI)-based radiocarpal surface contact models of functional loading in a clinical MRI scanner for future in vivo studies, by comparison with experimental measures from three cadaver forearm specimens. Experimental data were acquired using a Tekscan sensor during simulated light grasp. Magnetic resonance (MR) images were used to obtain model geometry and kinematics (image registration). Peak contact pressures (PPs) and average contact pressures (APs), contact forces and contact areas were determined in the radiolunate and radioscaphoid joints. Contact area was also measured directly from MR images acquired with load and compared with model data. Based on the validation criteria (within 25% of experimental data), out of the six articulations (three specimens with two articulations each), two met the criterion for AP (0%, 14%); one for peak pressure (20%); one for contact force (5%); four for contact area with respect to experiment (8%, 13%, 19% and 23%), and three contact areas met the criterion with respect to direct measurements (14%, 21% and 21%). Absolute differences between model and experimental PPs were reasonably low (within 2.5 MPa). Overall, the results indicate that MRI-based models generated from 3T clinical MR scanner appear sufficient to obtain clinically relevant data.     

Analysis of non-peptidic compounds as potential malarial inhibitors against Plasmodial cysteine proteases via integrated virtual screening workflow

Falcipain-2 (FP-2) and falcipain-3 (FP-3), haemoglobin-degrading enzymes in Plasmodium falciparum, are validated drug targets for the development of effective inhibitors against malaria. However, no commercial drug-targeting falcipains has been developed despite their central role in the life cycle of the parasites. In this work, in silico approaches are used to identify key structural elements that control the binding and selectivity of a diverse set of non-peptidic compounds onto FP-2, FP-3 and homologues from other Plasmodium species as well as human cathepsins. Hotspot residues and the underlying non-covalent interactions, important for the binding of ligands, are identified by interaction fingerprint analysis between the proteases and 2-cyanopyridine derivatives (best hits). It is observed that the size and chemical type of substituent groups within 2-cyanopyridine derivatives determine the strength of protein–ligand interactions. This research presents novel results that can further be exploited in the structure-based molecular-guided design of more potent antimalarial drugs.