Modulation of Muscarinic Signalling in the Central Nervous System by Steroid Hormones and Neurosteroids

Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic receptors represent potential pharmacological targets for various diseases and conditions, such as Alzheimer’s disease, schizophrenia, addiction, epilepsy, or depression. Muscarinic receptors are allosterically modulated by neurosteroids and steroid hormones at physiologically relevant concentrations. In this review, we focus on the modulation of muscarinic receptors by neurosteroids and steroid hormones in the context of diseases and disorders of the central nervous system. Further, we propose the potential use of neuroactive steroids in the development of pharmacotherapeutics for these diseases and conditions.     

Sphingolipid Catabolism and Glycerophospholipid Levels Are Altered in Erythrocytes and Plasma from Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune, inflammatory, degenerative disease of the central nervous system. Changes in lipid metabolism have been suggested to play important roles in MS pathophysiology and progression. In this work we analyzed the lipid composition and sphingolipid-catabolizing enzymes in erythrocytes and plasma from MS patients and healthy controls. We observed reduction of sphingomyelin (SM) and elevation of its products—ceramide (CER) and shingosine (SPH). These changes were supported by the detected up-regulation of the activity of acid sphingomyelinase (ASM) in MS plasma and alkaline ceramidase (ALCER) in erythrocytes from MS patients. In addition, Western blot analysis showed elevated expression of ASM, but not of ALCER. We also compared the ratios between saturated (SAT), unsaturated (UNSAT) and polyunsaturated fatty acids and suggest, based on the significant differences observed for this ratio, that the UNSAT/SAT values could serve as a marker distinguishing erythrocytes and plasma of MS from controls. In conclusion, the application of lipid analysis in the medical practice would contribute to definition of more precise diagnosis, analysis of disease progression, and evaluation of therapeutic strategies. Based on the molecular changes of blood lipids in neurodegenerative pathologies, including MS, clinical lipidomic analytical approaches could become a promising contemporary tool for personalized medicine.     

Dispirooxindole-β-Lactams: Synthesis via Staudinger Ketene-Imine Cycloaddition and Biological Evaluation

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against E. coli strain LPTD.     

Statistical testing for sufficient control chart performances during monitoring of grouped processes

With ISO 7870-8, a standardized application of charting techniques for short runs and small mixed batches was presented in 2017. Similar to various scientific approaches, it requires that sample values from grouped processes follow nearly identical distributions. In practice, however, there tend to be differences between distribution parameters. Moreover, equal parameters do not ensure that distributions are properly aligned to the center line and control limits of the chart. These facts can lead to undesired control chart performances which can be expressed by average run lengths (ARL) during in-control and out-of-control conditions. In this work, a statistical test for sufficient control chart performances during monitoring of grouped processes based on preliminary samples is proposed. Control chart performances are defined as sufficient when they deviate within acceptable ranges from usual performances during single process monitoring in mass production. The ARL resulting from estimated distributions and planned production sequences is used as test statistic and calculated via the Markov chain approach. Exemplary tests are executed for scenarios with individuals and cumulated sum (CUSUM) charts. A simulative determination of error rates resulting from the ARL-based testing demonstrates its effectiveness in testing for sufficient control chart performances compared to an indirect testing with Levene's test and a one-way analysis of variance (ANOVA).     

Synthesis of Calcium Hexaboride by Electrolysis of Molten Salt

Metallurgical and Materials Transactions B - Formation of calcium hexaboride by means of electrodeposition of boron oxide in molten CaCl2 with additives of CaO and B2O3 was analyzed. It was shown...     

Effect of Post-weld Heat Treatment on Microstructure and Mechanical Properties of Laser Beam Welded TiAl-based Alloy

Post-weld heat treatment is carried out on the laser beam welded γ-TiAl-based alloy Ti-48Al-1Cr-1.5Nb-1Mn-0.2Si-0.5B (at. pct). The macro/microstructure and mechanical properties of both as-welded and heat-treated specimens are investigated by radiography, SEM, and tensile tests. Moreover, high energy synchrotron X-ray diffraction is performed to measure the residual stresses and evaluate the microstructure evolution. It is found that the residual stresses are distributed in a three-peak shape in the region of the weld zone and heat-affected zone of the as-welded specimen due to the microstructural transformation and heat softening. The residual stresses are largely relieved after the heat treatment. The heat-treated specimens have a near fully lamellar microstructure and show balanced mechanical properties of strength and ductility. The diffraction shows that the phase transformation from α ₂ to γ takes place under tensile load at 1023 K (750 °C), and the grain size and lamellar spacing are refined in the weld zone. Finally, the fracture mechanisms are found to be controlled by the local stress concentration-induced strain misfit between α ₂ and γ phases in the near γ grains and delamination and debonding in the lamellae. Boride ribbons of 5 μm in the near fully lamellar microstructure are found not to be detrimental to the tensile properties.     

On moving Chaplygin sleigh on a convex surface

We study the problem of moving Chaplygin sleigh along an arbitrary surface. Motion equations for the sleigh are represented as Appel equations. We consider the case when the sleigh moves along a surface of rotation, in particular, along a plane, sphere, and cylinder. We show several cases when the sleigh’s motion equations can be fully integrated.