Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Zika Virus Growth in Human Kidney Cells Is Restricted by an Elevated Glucose Level

Mosquito-borne Zika virus (ZIKV) became a real threat to human health due to the lack of vaccine and effective antiviral treatment. The virus has recently been responsible for a global outbreak leading to millions of infected cases. ZIKV complications were highlighted in adults with Guillain–Barré syndrome and in newborns with increasing numbers of congenital disorders ranging from mild developmental delays to fatal conditions. The ability of ZIKV to establish a long-term infection in diverse organs including the kidneys has been recently documented but the consequences of such a viral infection are still debated. Our study aimed to determine whether the efficiency of ZIKV growth in kidney cells relates to glucose concentration. Human kidney HK-2 cells were infected with different ZIKV strains in presence of normal and high glucose concentrations. Virological assays showed a decrease in viral replication without modifying entry steps (viral binding, internalization, fusion) under high glucose conditions. This decrease replication was associated with a lower virus progeny and increased cell viability when compared to ZIKV-infected HK-2 cells in normal glucose concentration. In conclusion, we showed for the first time that an elevated glucose level influences ZIKV replication level with an effect on kidney cell survival.     

Macroscopic and Microscopic Structures of Cesium Lead Iodide Perovskite from Atomistic Simulations

A first‐principles‐based effective Hamiltonian is developed and employed to investigate finite‐temperature structural properties of a prototype of perovskite halides, that is CsPbI₃. Such simulations, when using first‐principles‐extracted coefficients, successfully reproduce the existence of an orthorhombic Pnma state and its iodine octahedral tilting angles around room temperature. However, they also yield a direct transformation from Pnma to cubic $Pm\overline{3}m$ upon heating, unlike measurements that reported the occurrence of an intermediate long‐range‐tilted tetragonal P4/mbm phase in‐between the orthorhombic and cubic phases. Such disagreement, which may cast some doubts about the extent to which first‐principle methods can be trusted to mimic hybrid perovskites, can be resolved by “only” changing one short‐range tilting parameter in the whole set of effective Hamiltonian coefficients. In such a case, some reasonable values of this specific parameter result in the predictions that i) the intermediate P4/mbm state originates from fluctuations over many different tilted states; and ii) the cubic $Pm\overline{3}m$ phase is highly locally distorted and develops strong transverse antiphase correlation between first‐nearest neighbor iodine octahedral tiltings, before undergoing a phase transition to P4/mbm under cooling.     

Alteration of the Route to Menaquinone towards Isochorismate-Derived Metabolites

Chorismate and isochorismate constitute branch-point intermediates in the biosynthesis of many aromatic metabolites in microorganisms and plants. To obtain unnatural compounds, we modified the route to menaquinone in Escherichia coli. We propose a model for the binding of isochorismate to the active site of MenD ((1R,2S, 5S,6S)-2-succinyl-5-enolpyruvyl-6-hydroxycyclohex-3-ene-1-carboxylate (SEPHCHC) synthase) that explains the outcome of the native reaction with α-ketoglutarate. We have rationally designed variants of MenD for the conversion of several isochorismate analogues. The double-variant Asn117Arg–Leu478Thr preferentially converts (5S,6S)-5,6-dihydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHD), the hydrolysis product of isochorismate, with a >70-fold higher ratio than that for the wild type. The single-variant Arg107Ile uses (5S,6S)-6-amino-5-hydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHA) as substrate with >6-fold conversion compared to wild-type MenD. The novel compounds have been made accessible in vivo (up to 5.3 g L⁻¹). Unexpectedly, as the identified residues such as Arg107 are highly conserved (>94 %), some of the designed variations can be found in wild-type SEPHCHC synthases from other bacteria (Arg107Lys, 0.3 %). This raises the question for the possible natural occurrence of as yet unexplored branches of the shikimate pathway.     

Software assurance practices for mobile applications

Mobile software applications have to cope with a particular environment that involves small size, limited resources, high autonomy requirements, competitive business models and many other challenges. To provide development guidelines that respond to these needs, several practices have been introduced; however, it is not clear how these guidelines may contribute to solve the issues present in the mobile domain. Furthermore, the rapid evolution of the mobile ecosystem challenges many of the premises upon which the proposed practices were designed. In this paper, we present a survey of the literature on software assurance practices for mobile applications, with the objective of describing them and assessing their contribution and success. We identified, organized and reviewed a body of research that spans in three levels: software development processes, software product assurance practices, and software implementation practices. By carrying out this literature survey, we reviewed the different approaches that researchers on Software Engineering have provided to address the needs that raise in the mobile software development arena. Moreover, we review the evolution of these practices, identifying how the constant changes and modernization of the mobile execution environment has impacted the methods proposed in the literature. Finally, we introduced discussion on the application of these practices in a real productive setting, opening an area for further research that may determine if practitioners have followed the proposed assurance paradigms.     

Intrinsic CFRP-metal-hybrids with rubber interface for the improvement of the damping behaviour

This paper presents an integrated passive damping approach in hybrid metal-CFRP parts for structural applications. In this concept a viscoelastic material is embedded in the joint zone of the hybrid component. To examine the connection strength single-lap-joint specimens were produced and tested and the influence of the used material combinations, different surface structures, and different process parameters i.e. the moment of cross-linking were evaluated. Afterwards, the metal-CFRP hybrids were tested in quasi-static tests to assess their connection strength and failure behaviour. Dynamic cyclic tensile tests with step-wise increased loading conditions were performed to determine the specimens damping behaviour and to estimate their fatigue performance. Finally, these results are compared to a state of the art metal-CFRP hybrid with rivets connecting both materials.     

On stochastic comparisons of finite mixtures for some semiparametric families of distributions

In this paper, we consider the classical finite mixture model, which is an effective tool for modeling lifetime distributions for random samples from heterogeneous populations. We discuss new results on stochastic comparison for two finite mixtures when each of them is drawn from one of the following semiparametric families, i.e., proportional hazards, accelerated lifetime and proportional reversed hazards.