Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification

One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated K_i ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification.     

Submicron droplet formation in the human lung

The exhaled breath of humans contains droplets originating from the lung lining fluid. An analysis of these droplets for non-volatile proteinaceous biomarkers holds potential as a non-invasive diagnosis of lung diseases. To ease the interpretation of the diagnostic results, the source strength of the particles should be known und therefore an understanding of the particle generation process is required. It is assumed that during reopening of a collapsed terminal airway a liquid bridge of the lung lining fluid ruptures and droplets are generated. The objective of our experimental and theoretical study was to clarify the mechanisms of droplet generation for quiet breathing patterns by investigating in detail the number flux and the particle size distribution in the exhaled breath. The process of liquid film rupture is modelled by computational fluid dynamics analysis from which the droplet size distribution is calculated. In addition the number emission flux and the droplet size distribution are systematically measured in the exhaled breath of healthy volunteers. The strong increase of the particle emission flux with tidal volume and the good agreement between measured and calculated droplet number distribution both showing droplets primarily in the submicron range confirm the present hypothesis that reopening of collapsed airway structures associated with the rupture of a surfactant film is the physical mechanism of droplet generation. This was hypothesized previously in the literature.     

Microstraining in titania-, alumina- and silica-supported V2O5-catalysts

Commonly used catalysts in industry are compositions of highly dispersed particles. Typical systems consist of precious metals or transition metal oxides like V₂O₅ on oxide supports, especially TiO₂, Al₂O₃ and SiO₂. Support and active compound show a different chemical and material behaviour. A very important influence of the support on the active compound is the formation of microstrains due to the different thermal expansion behaviour. On the surface of a stiff linear elastic support the active compound is certainly strain hindered. In order to monitor the development of strain hindrance and further effects, in situ experiments were carried out at temperature both in an X-ray and in a neutron powder diffractometer. The width of the reflexes indicated a strong influence of the thermal expansion mismatch on peak width. The strain hindrance creates mismatch stresses high enough to overcome the yield stress of V₂O₅. The Williamson–Hall plots showed both a particle size effect as well as a stress widening but the measurements were difficult because of the materials anisotropy. The TEM work showed again very fine particles which agrees with the X-ray measurements. The support effect may be seen as thermal stress induced formation of a mosaic structure in the active compound. Moreover, the peak width correlated with the catalytic activity. The low ordered regimes in the mosaic structure are acting as further active centres for the catalytic reaction.     

Process engineering parameters and type of n-octenylsuccinate-derivatised starch affect oxidative stability of microencapsulated long chain polyunsaturated fatty acids

Aim of the present study was to investigate the impact of the emulsifying carrier matrix constituent, n-octenylsuccinate-derivatised (OSA)-starch, and process conditions on physical characteristics and oxidative stability of microencapsulated fish oil. Furthermore, the effect of the drying medium, i.e. air or nitrogen, on lipid oxidation during spray-drying and subsequent storage was investigated. Particle characteristics and lipid oxidation of microencapsulated fish oil were both influenced by the type of OSA-starch and the drying conditions. The highest oxidative stability was observed for fish oil microencapsulated in OSA-starch with the lowest average molecular weight and glucose syrup spray-dried at a moderate temperature setting. Particle characteristics of the microcapsules were not attributable for differences in lipid oxidation during storage. In spray-dried carrier matrix particles, the particle size increased with increasing average molecular weight of the OSA-starch and was attributed to an increase in air inclusion. Thus differences in lipid oxidation of the microencapsulated fish oil were attributed to differences in air inclusion as affected by the type of OSA-starch. In terms of spray-drying under inert conditions and in the presence of air, lipid oxidation of microencapsulated fish oil was rather attributed to oxygen availability in the feed emulsion than in the drying gas.     

Integrated energy in Germany–A critical look at the development and state of integrated energies in Germany

In the face of global warming and a scarcity of resources, future energy systems are urged to undergo a major and radical transformation. The recognition of the need to embrace renewable energy technologies and to move toward decarbonization has led to significant changes in the German energy generation, consumption and infrastructure. Ambitious German national plans to decrease carbon dioxide emissions on one side, and the unpredictable and volatile nature of renewable energy sources on the other side have elevated the importance of integrated energies in recent years. The deployment of integrated technologies as a solution to interlink various infrastructures creates opportunities for increasing the reliability of energy systems, minimizing environmental impacts and maximizing the share of renewable resources. This paper discusses the role of integrated energy systems in supporting of sustainable solutions for future energy transitions. Moreover, the reinforcement of this movement with the help of different technologies will be discussed and the development of integrated energy systems in Germany will be reviewed.     

Quantifying Pathways and Friction of Nanoparticles During Controlled Manipulation by Contact-Mode Atomic Force Microscopy

Measuring interfacial friction during the manipulation of nanoparticles is becoming an increasingly important approach in nanotribology research. In this work, antimony and gold particles deposited on flat graphite surfaces have been translated by the tip of an atomic force microscope in contact mode along defined pathways. Two different manipulation techniques are discussed with respect to pathway control and friction quantification. The first technique includes pushing the particles from the side, which often results in a loss of the particle during translation due to unwanted sidewards motion. We analyze this phenomenon with an analytical model and find good agreement with experiments. An alternative approach is to move the particle while the tip remains on its top. We demonstrate that this approach allows better manipulation pathway control and that simultaneous interfacial friction measurements are in quantitative agreement with the first manipulation method.     

On Floating‐Point Normal Vectors

In this paper we analyze normal vector representations. We derive the error of the most widely used representation, namely 3D floating‐point normal vectors. Based on this analysis, we show that, in theory, the discretization error inherent to single precision floating‐point normals can be achieved by 2^50.2 uniformly distributed normals, addressable by 51 bits. We review common sphere parameterizations and show that octahedron normal vectors perform best: they are fast and stable to compute, have a controllable error, and require only 1 bit more than the theoretical optimal discretization with the same error.