Impact of neurite alignment on organelle motion

Intracellular transport is pivotal for cell growth and survival. Malfunctions in this process have been associated with devastating neurodegenerative diseases, highlighting the need for a deeper understanding of the mechanisms involved. Here, we use an experimental methodology that leads neurites of differentiated PC12 cells into either one of two configurations: a one-dimensional configuration, where the neurites align along lines, or a two-dimensional configuration, where the neurites adopt a random orientation and shape on a flat substrate. We subsequently monitored the motion of functional organelles, the lysosomes, inside the neurites. Implementing a time-resolved analysis of the mean-squared displacement, we quantitatively characterized distinct motion modes of the lysosomes. Our results indicate that neurite alignment gives rise to faster diffusive and super-diffusive lysosomal motion than the situation in which the neurites are randomly oriented. After inducing lysosome swelling through an osmotic challenge by sucrose, we confirmed the predicted slowdown in diffusive mobility. Surprisingly, we found that the swelling-induced mobility change affected each of the (sub-/super-)diffusive motion modes differently and depended on the alignment configuration of the neurites. Our findings imply that intracellular transport is significantly and robustly dependent on cell morphology, which might in part be controlled by the extracellular matrix.     

Donorsubstituierte 2,4-Diazacyclopentadienone und indigoide 1,3,5,7-Tetraazafulvalene

Donor Substituted 2,4-Diazacyclopentadienones and Indigoid 1,3,5,7-Tetraazafulvalenes Hydrolysis of tris(diethylamino)imidazolylium chloride gives rise to 2,5-bis-diethyl-amino-4H-imidazolin-4-one; thiolysis leads, depending on conditions, to 2,5-bis-diethylamino-4H-imidazolin-4-thione or potassium 2,6-bis-diethylamino-1,3,5,7-tetraazafulvalene-4,8-dithiolate. The latter can be protonated to form green 2,6-bis(dimethylamino)-3,4,7,8-tetrahydro-1,3,5,7-tetraaza-fulvalen-4,8-dithione, a new indigoid compound, and alkylated to give blue 2,6-bis-diethylamino-4,8-bis-alkylthio-1,3,5,7-tetraazafulvalenes. Treatment of 2,5-bis-diethylamino-4H-imidazolin-4-thione with copper furnishes 2,6,4,8-tetrakis-diethylamino-1,3,5,7-tetraazafulvalene. – Oxidation of 2,6-bis-dimethylamino-3,4,7,8-tetrahydro-1,3,5,7-tetraazafulvalen-4,8-dithione gives rise to (2,2′-bis-diethylamino-4,4′-bi(4H-imidazol)-5,5′-dithione, corresponding to dehydroindigo, and reduction leads to a colorless compound, corresponding to leucoindigo.     

Effect of Ions and Sequence Variants on the Antagonist Binding Properties of the Histamine H1 Receptor

The histamine H₁ receptor (H₁R) is a G protein-coupled receptor (GPCR) and represents a main target in the treatment of allergic reactions as well as inflammatory reactions and depressions. Although the overall effect of antagonists on H₁ function has been extensively investigated, rather little is known about the potential modulatory effect of ions or sequence variants on antagonist binding. We investigated the dynamics of a phosphate ion present in the crystal structure and of a sodium ion, for which we determined the position in the allosteric pocket by metadynamics simulations. Both types of ions exhibit significant dynamics within their binding site; however, some key contacts remain stable over the simulation time, which might be exploited to develop more potent drugs targeting these sites. The dynamics of the ions is almost unaffected by the presence or absence of doxepin, as also reflected in their small effect (less than 1 kcal·mol⁻¹) on doxepin binding affinity. We also examined the effect of four H₁R sequence variants observed in the human population on doxepin binding. These variants cause a reduction in doxepin affinity of up to 2.5 kcal·mol⁻¹, indicating that personalized medical treatments that take into account individual mutation patterns could increase precision in the dosage of GPCR-targeting drugs.     

Prudent constraint-handling technique for multiobjective propeller optimisation

The paper presents an alternative constraint-handling technique that converts a nonlinear constrained programming problem into an unconstrained multi-objective optimisation problem. The technique is derived from the behavioural memory constraint-handling method, which was originally implemented for single-objective optimisation with genetic algorithms. We compare our presented technique with two other popular constraint-handling concepts and demonstrate its superiority over them when applied to a propeller optimisation problem. We conclude that the multi-objective behavioural memory constraint-handling technique conjugated with the non-dominated sorting genetic algorithm (NSGA-II) is a prudent method to apply to problems with an infeasible initial design and where constraints have a natural order of satisfaction, which, if not conformed to, would lead to unrealistic designs that impair the search by GA.     

Energy absorption during compression and impact of dry elastic-plastic spherical granules

The discrete modelling and understanding of the particle dynamics in fluidized bed apparatuses, mixers, mills and others are based on the knowledge about the physical properties of particles and their mechanical behaviour during slow, fast and repeated stressing. In this paper model parameters (modulus of elasticity, stiffness, yield pressure, restitution coefficient and strength) of spherical granules (γ-Al₂O₃, zeolites 4A and 13X, sodium benzoate) with different mechanical behaviour have been measured by single particle compression and impact tests. Starting with the elastic compression behaviour of granules as described by Hertz theory, a new contact model was developed to describe the force-displacement behaviour of elastic-plastic granules. The aim of this work is to understand the energy absorption during compression (slow stressing velocity of 0.02 mm/s) and impact (the impact velocity of 0.5–4.5 m/s) of granules. For all examined granules the estimated energy absorption during the impact is found to be far lower than that during compression. Moreover, the measured restitution coefficient is independent of the impact velocity in the examined range and independent of the load intensity by compression (i.e. maximum compressive load). In the case of repeated loading with a constant load amplitude, the granules show cyclic hardening with increasing restitution coefficient up to a certain saturation in the plastic deformation. A model was proposed to describe the increase of the contact stiffness with the number of cycles. When the load amplitude is subsequently increased, further plastic deformation takes place and the restitution coefficient strongly decreases.     

The influence of a corrosive wood-cutting environment on the mechanical properties of hardmetal tools

The influence of a corrosive wood-cutting environment on the strength of hardmetals and on their behaviour under static loading conditions has been investigated. Two commercial hardmetals were tested, which differed in hard phase composition. The results show exposure to this environment to have a highly detrimental influence on the strength of both hardmetals investigated, due to localised corrosive attack which results in the formation of stress raisers. The relative loss in strength as a function of corrosion time is the same for both hardmetals. However, the performance of the two grades differ significantly when a static load is applied in this corrosive environment: the strength of the WC-Co grade remains unaffected by the applied load, while the grade containing a mixed carbide phase exhibits stress corrosion cracking which results in a further reduction in strength.     

Conversion of carbon into CF4 for SI-traceable measurements of absolute carbon isotope amount ratios: a feasibility study

The feasibility of performing SI-traceable carbon isotope amount ratio measurements following conversion of carbon into CF4 was studied. A procedure for the direct fluorination of carbon with elemental fluorine was developed, and the conversion step was checked for losses, blank contributions, and the absence of systematic isotope effects. Gas chromatography was used to identify and quantify the gaseous fluorination products and to isolate CF4 from byproducts. After fluorination of graphite carbon, CF4 and perfluoroalkanes with up to six carbon atoms were observed as reaction products. Within an uncertainty of 10%, the graphite carbon was fully recovered in the gaseous carbon fluorides, with the main product being CF4 (80-90%) and C2F6 as the major byproduct. The fluorination and GC procedures were found to introduce an alteration not bigger than 0.03 +/- 0.04/1000 on the isotopic composition of CF4. Carbon blank contributions introduced during the fluorination procedure were below 0.5% relative to a typical sample of 4 mg of carbon. For two of the materials investigated, the carbon isotope ratios measured on a differential mass spectrometer were reproducible within a standard deviation of approximately 0.1/1000 for several individual fluorinations. For these materials, the developed fluorination procedure is a straightforward process, which can be used as a foundation to establish SI-traceable measurements of carbon isotope amount ratios. However, for the third graphite material the formation of byproducts (C2F6-C6F14) was found to induce significant isotopic fractionation.     

The flip-chip approach for millimeter wave packaging

A particularly critical issue in this regard is module packaging, i.e., the way to assemble and connect several monolithic microwave integrated circuits (MMICs) in a multichip environment in order to build the millimeter-wave front-end. The requirements on the packaging scheme are obvious: the interconnects should provide good millimeter-wave performance (primarily meaning: low reflections and low insertion loss) and, at the same time, they should allow for low-cost fabrication. Among the multichip packaging techniques available, the flip-chip approach is considered to be the most promising candidate to meet these requirements.