Targeting Oxidative Stress: Novel Coumarin-Based Inverse Agonists of GPR55

Oxidative stress is associated with different neurological and psychiatric diseases. Therefore, development of new pharmaceuticals targeting oxidative dysregulation might be a promising approach to treat these diseases. The G-protein coupled receptor 55 (GPR55) is broadly expressed in central nervous tissues and cells and is involved in the regulation of inflammatory and oxidative cell homeostasis. We have recently shown that coumarin-based compounds enfold inverse agonistic activities at GPR55 resulting in the inhibition of prostaglandin E₂. However, the antioxidative effects mediated by GPR55 were not evaluated yet. Therefore, we investigated the antioxidative effects of two novel synthesized coumarin-based compounds, KIT C and KIT H, in primary mouse microglial and human neuronal SK-N-SK cells. KIT C and KIT H show antioxidative properties in SK-N-SH cells as well as in primary microglia. In GPR55-knockout SK-N-SH cells, the antioxidative effects are abolished, suggesting a GPR55-dependent antioxidative mechanism. Since inverse agonistic GPR55 activation in the brain seems to be associated with decreased oxidative stress, KIT C and KIT H possibly act as inverse agonists of GPR55 eliciting promising therapeutic options for oxidative stress related diseases.     

Influence of the Metal Particle Size on the Ignition of Energetic Materials

A theoretical study of multi‐particle ignition uses a hot spot model which calculates the temperature evolution of individual hot spots in an energetic material. It indicated that ultra‐fine hot particles would be very effective in igniting energetic materials if impinging and penetrating the solid propellant. Igniting mixtures were prepared containing ultra‐fine Ti particles which react fastest compared with coarse particle mixtures, standard B/KNO₃ and black powder. The ultra‐fine particles, however, are obviously oxidized or gasified too fast as to reach the energetic material to be initiated and longer ignition delays are found mainly compared with coarse particle mixtures. An optimized mixture of coarse and ultra‐fine particles would give an improvement of ignition delay times.     

Development of novel metal-supported proton ceramic electrolyser cell with thin film BZY15–Ni electrode and BZY15 electrolyte

Metal supports for planar MS-PCEC were manufactured using tape-casting of low-cost ferritic stainless steel. A coating protecting the metal support against oxidation was applied by vacuum infiltration and a buffer layer of La_0.5Sr_0.5Ti_0.75Ni_0.25O_3–δ (LSTN) was further deposited to smoothen the surface. The BaZr_0.85Y_0.15O_3–δ–NiO (BZY15–NiO) cathode and the BaZr_0.85Y_0.15O_3–δ (BZY15) electrolyte were applied by pulsed laser deposition (PLD) at elevated substrate temperatures (at 700 °C and 600 °C, respectively). The main challenges are related to the restrictions in sintering temperature and atmosphere induced by the metal support, as well as strict demands on the roughness of substrates used for PLD. Reduction treatment of the half cells confirmed that NiO in the BZY15–NiO layer was reduced to Ni, resulting in increased porosity of the BZY15–Ni cathode, while keeping the columnar and dense microstructure of the BZY15 electrolyte. Initial electrochemical testing with a Pt anode showed a total resistance of 40 Ω·cm² at 600 °C. Through this work important advances in using metal supports and thin films in planar PCEC assemblies have been made.     

Impact of grey energy on optimal wall insulation thickness

For decades efforts have been made to reduce the greenhouse gases emissions of buildings by reducing their energy demand with governmental regulations in Europe, pushing towards very low thermal transmittances (U-values) with ever thicker insulation layers for new buildings. However, there is no linear relationship between the insulation thickness and the heat losses. Therefore, above a certain thickness the consumption of buildings does not decrease significantly. Hereafter a life cycle analysis, including emissions before the building becomes operational is applied to evaluate the impact of the increasing thickness of components on the overall emissions. Publicly available product data sheets are used to compare four insulation materials under three scenarios. These analyses yield interesting results showing that energy-intensive insulation materials lead to a negative impact in the overall energy balance after a certain thickness. Even though there is not always a pronounced optimum insulation thickness, it is logical that further reductions in U-value for new buildings should hence be carefully evaluated. The results show that the optimal thickness is around 20 cm for most materials, while the important major savings come from the first 10 cm.     

Underlying solvent-based factors that influence permanent porosity in porous liquids

Porous liquids(PLs)offer the potential to combine the ready handling and mature industry status of liquid absorbents,with the high permanent porosity of metal o...     

Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation

Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis that retromer impairment may be involved in the pathogenesis of NPC and may contribute to increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis observed in NPC disease. Using NPC1-null cells, primary mouse NPC1-deficient neurons and NPC1-deficient mice (BALB/cNctr-Npc1m1N), we show that retromer function is impaired in NPC. This is manifested by altered transport of the retromer core components Vps26, Vps35 and/or retromer receptor sorLA and by retromer accumulation in neuronal processes, such as within axonal swellings. Changes in retromer distribution in NPC1 mouse brains were observed already at the presymptomatic stage (at 4-weeks of age), indicating that the retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Furthermore, we show that cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverts retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. Thus, we characterized retromer dysfunction in NPC and propose that the rescue of retromer impairment may represent a novel therapeutic approach against NPC.     

Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by deficiency of polycystin-1 (PC1) or polycystin-2 (PC2). Altered autophagy has recently been implicated in ADPKD progression, but its exact regulation by PC1 and PC2 remains unclear. We therefore investigated cell death and survival during nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 (PC1KO) or PC2 (PC2KO), and human urine-derived proximal tubular epithelial cells (PTEC) from early-stage ADPKD patients with PC1 mutations versus healthy individuals. Basal autophagy was enhanced in PC1-deficient cells. Similarly, following starvation, autophagy was enhanced and cell death reduced when PC1 was reduced. Autophagy inhibition reduced cell death resistance in PC1KO mIMCDs to the WT level, implying that PC1 promotes autophagic cell survival. Although PC2 expression was increased in PC1KO mIMCDs, PC2 knockdown did not result in reduced autophagy. PC2KO mIMCDs displayed lower basal autophagy, but more autophagy and less cell death following chronic starvation. This could be reversed by overexpression of PC1 in PC2KO. Together, these findings indicate that PC1 levels are partially coupled to PC2 expression, and determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress.     

Burn Rate Models for Gun Propellants

In the past, Vieille's law and minor modifications of it described sufficiently the linear burning rate of gun propellants which governs the design of charges by interior ballistic simulations. Recent developments to increase the performance led to new gun concepts and innovative propellants. These are the electrothermal‐chemical gun, porous and foamed charges as well as formulations exhibiting a temperature independent burning. Vieille's law cannot fully meet experimental results in these cases. Approaches based on the heat flow equation in the solid energetic material give simplified formulas to extend the validity. These burning rate models have the ability to describe the experimentally determined burning behavior at least in a simplified or qualitative way. More sophisticated methods consider complex geometrical structures in the solid or take into account the actual progress in phase behavior and reaction kinetics of heterogeneous combustion. The dependence of the burning rate on initial temperature, on phase transitions, porous structure and gaseous reactions can be described.