Drug discovery from Nature: automated high-quality sample preparation

Secondary metabolites from plants, animals and microorganisms have been proven to be an outstanding source for new and innovative drugs and show a striking structural diversity that supplements chemically synthesized compounds or libraries in drug discovery programs. Unfortunately, extracts from natural sources are usually complex mixtures of compounds:: often generated in time consuming and for the most part manual processes. As quality and quantity of the provided samples play a pivotal role in the success of high-throughput screening programs this poses serious problems. In order to make samples of natural origin competitive with synthetic compound libraries, we devised a novel, automated sample preparation procedure based on solid-phase extraction (SPE). By making use of a modified Zymark RapidTrace^® SPE workstation an easy-to-handle and effective fractionation method has been developed which allows the generation of highquality samples from natural origin, fulfilling the requirements of an integration into high-throughput screening programs.     

High-Temperature Electrical Insulation Behavior of Alumina Films Prepared at Room Temperature by Aerosol Deposition and Influence of Annealing Process and Powder Impurities

Alumina (Al₂O₃) is a widely used material for highly insulating films due to its very low electrical conductivity, even at high temperatures. Typically, alumina films have to be sintered far above 1200 °C, which precludes the coating of lower melting substrates. The aerosol deposition method (ADM), however, is a promising method to manufacture ceramic films at room temperature directly from the ceramic raw powder. In this work, alumina films were deposited by ADM on a three-electrode setup with guard ring and the electrical conductivity was measured between 400 and 900 °C by direct current measurements according to ASTM D257 or IEC 60093. The effects of film annealing and of zirconia impurities in the powder on the electrical conductivity were investigated. The conductivity values of the ADM films correlate well with literature data and can even be improved by annealing at 900 °C from 4.5?×?10^?12 S/cm before annealing up to 5.6?×?10^?13 S/cm after annealing (measured at 400 °C). The influence of zirconia impurities is very low as the conductivity is only slightly elevated. The ADM-processed films show a very good insulation behavior represented by an even lower electrical conductivity than conventional alumina substrates as they are commercially available for thick-film technology.     

Investigations of spherulitic growth in industrial crystallization

The discrimination between crystal growth and aggregation is of crucial importance for the control of morphology and particle size in crystallization processes, as they are influenced in very different ways by the industrial processing environment. A collection of resembling solution-grown polycrystalline particles that differ widely in chemical nature, like elemental nickel, calcium and sodium carbonate, l-glutamic acid and an aromatic amine have been identified to grow by a spherulitic growth mechanism usually only associated with the crystallization of polymers or melts. The particles are not growing by agglomeration of small individual crystals, as often claimed in the literature. The effect of initial supersaturation, temperature and solvent composition on the spherulitic growth of calcium carbonate (vaterite) has been used to demonstrate how spherulites can grow from solution both by central multidirectional growth (in water) and by unidirectional growth followed by low angle branching (in 90 wt% ethylene glycol). The progression of non-crystallographic branching could be monitored as a function of time at intermediate initial supersaturation values, supplying direct visual evidence for spherulitic growth in this system. A reduction in initial supersaturation and temperature resulted in insufficient branching and dumbbell particles, whereas increased levels of supersaturation rapidly produced fully grown spherulites.     

Graphene Nanocomposites Prepared From Blends of Polymer Latex with Chemically Reduced Graphite Oxide Dispersions

Graphene nanocomposites are prepared by chemical reduction of graphite oxide (GO) dispersion with vitamin C in the presence of SAN latex followed by melt compounding. In this process, GO is well dispersed in an aqueous SAN emulsion before reduction. During reduction the SAN latex is adsorbed on the graphene sheets of the chemically reduced GO (CRGO). After melt compounding of such hybrid particles with SAN, the nanocomposites show uniform dispersion of CRGO in SAN resulting in improved stiffness with respect to SAN/graphite. The reduction of GO in the presence of polymer latex represents a versatile route to graphene masterbatches and does not require either drying of GO or thermal GO expansion at high temperatures.

     

Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery and the epigenome are closely interconnected, we investigated whether these alterations may affect the epigenomes of CLL patients. While an overall hypomethylation during CLL carcinogenesis has been observed, the interplay between the epigenetic stage of the originating B cells and SF3B1 mutations, and the subsequent effect of the mutations on methylation alterations in CLL, have not been investigated. We profiled the genome-wide DNA methylation patterns of 27 CLL patients with and without SF3B1 mutations and identified local decreases in methylation levels in SF3B1^mut CLL patients at 67 genomic regions, mostly in proximity to telomeric regions. These differentially methylated regions (DMRs) were enriched in gene bodies of cancer-related signaling genes, e.g., NOTCH1, HTRA3, and BCL9L. In our study, SF3B1 mutations exclusively emerged in two out of three epigenetic stages of the originating B cells. However, not all the DMRs could be associated with the methylation programming of B cells during development, suggesting that mutations in SF3B1 cause additional epigenetic aberrations during carcinogenesis.     

Electronic-level interactions of tungsten oxide with unsupported Se/Ru electrocatalytic nanoparticles

Se/Ru nanoparticles - a potent non-platinum catalyst towards oxygen reduction reaction - were modified by hydrated WO₃ and investigated using the rotating disk/ring electrode methods and by synchrotron X-ray photoelectron spectroscopy. The modification resulted in an enhanced catalytic activity towards oxygen reduction reaction (ORR). Our data indicate that the oxygen reduction current starts ca. 70 mV more positive and formation of undesirable hydrogen peroxide has significantly decreased following the modification of Se/Ru with WO₃. X-ray photoelectron spectroscopy reveals that WO₃ interacts electronically with Se/Ru as the W 4f and Se 3d line-shapes change. We therefore conclude that the electronic interactions between Se/Ru and WO₃ are primarily responsible for the increase in activity and selectivity of the WO₃-modified Se/Ru towards ORR.     

Time‐ and Temperature‐Dependent Fracture Mechanics of Polymers: General Aspects at Monotonic Quasi‐Static and Impact Loading Conditions

Well‐defined correlations exist between the maxima in mechanical loss factor and the local maxima in temperature‐ or loading‐speed‐dependent fracture toughness. The non‐linear viscoelastic fracture processes and small‐strain deformations are characterised by the same Arrhenius‐type activation enthalpies. The local increase in toughness is linearly correlated with the relaxation strength of molecular relaxation processes. Stable crack propagation can be understood as a three‐phase process resulting in steady‐state stable crack growth. The normalised steady‐state crack‐tip‐opening displacement is independent of matrix material, temperature and loading speed.