Detailed Structure–Function Correlations of Bacillus subtilis Acetolactate Synthase

Isobutanol is deemed to be a next‐generation biofuel and a renewable platform chemical. 1 Non‐natural biosynthetic pathways for isobutanol production have been implemented in cell‐based and in vitro systems with Bacillus subtilis acetolactate synthase (AlsS) as key biocatalyst. 2 – 6 AlsS catalyzes the condensation of two pyruvate molecules to acetolactate with thiamine diphosphate and Mg²⁺ as cofactors. AlsS also catalyzes the conversion of 2‐ketoisovalerate into isobutyraldehyde, the immediate precursor of isobutanol. Our phylogenetic analysis suggests that the ALS enzyme family forms a distinct subgroup of ThDP‐dependent enzymes. To unravel catalytically relevant structure‐function relationships, we solved the AlsS crystal structure at 2.3 Å in the presence of ThDP, Mg²⁺ and in a transition state with a 2‐lactyl moiety bound to ThDP. We supplemented our structural data by point mutations in the active site to identify catalytically important residues.     

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non‐aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane‐ and cubane‐containing analogues were found to possess higher themodynamic solubility, whereas cubane‐ and cyclohexyl‐containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP‐B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off‐target effects.     

Development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine D3 receptor ligands

Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.     

Switchable Plasmonic Metasurface Utilizing the Electro-Optic Kerr Effect of a Blue Phase Liquid Crystal

A switchable metasurface composed of plasmonic split ring resonators and a polymer-stabilized liquid crystal blue phase is developed. Owing to field-induced birefringence (electro-optic Kerr effect), the state of polarization of the incident near infrared radiation changes, when a voltage is applied to the liquid crystal. Thus, different resonant modes of the split ring resonators can be addressed and the transmission spectrum changes accordingly. In comparison with other liquid crystal phases, blue phases have several advantages. For example, they are optically isotropic in the field-off state, so that no alignment layer is required. The results of the present study indicate that the advantages of these mesophases can be utilized for switchable metasurfaces.     

Suspension Plasma Spraying: Process Characteristics and Applications

Suspension plasma spraying (SPS) offers the manufacture of unique microstructures which are not possible with conventional powdery feedstock. Due to the considerably smaller size of the droplets and also the further fragmentation of these in the plasma jet, the attainable microstructural features like splat and pore sizes can be downsized to the nanometer range. Our present understanding of the deposition process including injection, suspension plasma plume interaction, and deposition will be outlined. The drawn conclusions are based on analysis of the coating microstructures in combination with particle temperature and velocity measurements as well as enthalpy probe investigations. The last measurements with the water cooled stagnation probe gives valuable information on the interaction of the carrier fluid with the plasma plume. Meanwhile, different areas of application of SPS coatings are known. In this paper, the focus will be on coatings for energy systems. Thermal barrier coatings (TBCs) for modern gas turbines are one important application field. SPS coatings offer the manufacture of strain-tolerant, segmented TBCs with low thermal conductivity. In addition, highly reflective coatings, which reduce the thermal load of the parts from radiation, can be produced. Further applications of SPS coatings as cathode layers in solid oxide fuel cells (SOFC) and for photovoltaic (PV) applications will be presented.     

Separation of Extracellular Esterases from Pellet Cultures of the Basidiomycete Pleurotus sapidus by Foam Fractionation

Two extracellular esterases were produced in submerged cultures of the basidiomycete Pleurotus sapidus. A foam fractionation device was designed and employed for the isolation of the esterolytic enzymes. The recovery of enzyme activity in the liquefied foam strongly depended on the superficial gas velocity. High purification and enrichment factors (E _a = 62.0, P = 15.5) were achieved using nitrogen at 1.87 cm min⁻¹ within 100 min. Increasing the superficial gas velocity to 2.49 cm min⁻¹ improved the recovery of total esterase activity in the foam to >95% at the expense of reduced enrichment and purification factors. Differences in their physicochemical characteristics resulted in differing foaming properties of the two esterases secreted by P. sapidus. By variation of the pH value of the culture medium and addition of Triton X-100, both esterases were successively and quantitatively transferred into the foam in a two-step fractionation process.     

Homology Model Adjustment and Ligand Screening with a Pseudoreceptor of the Human Histamine H4 Receptor

A new pseudoreceptor modeling method (PRPS) was applied to the refinement of a homology model of the human histamine H₄ receptor (H₄R), the prediction of a ligand binding site, and virtual screening. Retrieval of two new H₄R ligands demonstrates the biological relevance of the pseudoreceptor model and provides a means for finding new hits and leads in the early phases of drug discovery.

     

Rheology and properties of melt-processed poly(ether ether ketone)/multi-wall carbon nanotube composites

Poly(ether ether ketone) (PEEK)/multi-wall carbon nanotube (MWNT) composites containing up to 17 wt% filler were prepared using a twin screw extruder. Transmission electron microscopy (TEM) images reveal that the MWNTs were homogeneously dispersed in the PEEK matrix. Linear viscoelastic measurements show that both complex viscosity and moduli increase with increasing MWNT concentration. The storage modulus, G^′ exhibits a dramatic seven order increase in magnitude around 1 wt%, leading to a solid-like low-frequency behaviour at higher loadings; the effect can be attributed to network formation at a rheological percolation threshold. Rheotens measurements show that the melt strength also increases significantly on addition of nanotubes, however, the drawability decreases. An analytical Wagner model was used to calculate the apparent elongational viscosity over a wide range of elongational rates, and to reveal significant increases on addition of MWNTs, with a similar threshold behaviour. The electrical response is also dominated by percolation effects, increasing by nearly 10 orders of magnitude from 10⁻¹¹ to 10⁻¹ S/cm, on the addition of only 2 wt% MWNTs. In contrast, the thermal conductivity and tensile elastic modulus of the composites increased linearly with nanotube content, rising by 130% and 50%, at 17 wt% MWNTs, respectively.