The Influences of Sulphation,Salt Type,and Salt Concentration on the Structural Heterogeneity of Glycosaminoglycans

The increasing recognition of the biochemical importance of glycosaminoglycans (GAGs) has in recent times made them the center of attention of recent research investigations. It became evident that subtle conformational factors play an important role in determining the relationship between the chemical composition of GAGs and their activity. Therefore, a thorough understanding of their structural flexibility is needed, which is addressed in this work by means of all-atom molecular dynamics (MD) simulations. Four major GAGs with different substitution patterns, namely hyaluronic acid as unsulphated GAG, heparan-6-sulphate, chondroitin-4-sulphate, and chondroitin-6-sulphate, were investigated to elucidate the influence of sulphation on the dynamical features of GAGs. Moreover, the effects of increasing NaCl and KCl concentrations were studied as well. Different structural parameters were determined from the MD simulations, in combination with a presentation of the free energy landscape of the GAG conformations, which allowed us to unravel the conformational fingerprints unique to each GAG. The largest effects on the GAG structures were found for sulphation at position 6, as well as binding of the metal ions in the absence of chloride ions to the carboxylate and sulphate groups, which both increase the GAG conformational flexibility.     

Dietary fat in the prevention of cardiovascular disease — a review

In developed countries atherosclerotic cardiovascular disease is the reason for about 50% of all deaths. With growing prosperity coronary heart disease (CHD) is becoming the major cause of premature death. Most complications of atherosclerosis occur unexpectedly and more than 50% of the patients developing a myocardial infarction do not survive more than one year. Because of the severe morbidity and high mortality primary prevention is likely to be the only solution. Epidemiological studies show a strong, positive relationship between plasma cholesterol concentrations and the incidence of CHD. People who immigrate from low‐risk to high‐risk areas usually acquire similar plasma cholesterol levels as the native population and a similar CHD risk. This demonstrates that environmental rather than genetic factors lead to the differences in cardiovascular risk and supports the notion that nutrition and lifestyle play a major role. The association between dietary intake of fat and cholesterol and the extent of atherosclerosis and CHD has been recognized in previous studies. The amount of saturated fat in the diet correlates stronger with the incidence of CHD than with total fat intake. The consumption of unsaturated fatty acids, however, appears to be beneficial, since it is inversely correlated with the plasma cholesterol concentration and risk of myocardial infarction. Lately additional nutritional factors like trans fatty acids with a negative influence on risk as well as positive factors like linolenic acid have attracted much attention. In conclusion, as a challenge to public health, preventive medicine needs to focus on changes in dietary habits with priority, particularly fat modification. A nutrition low in total fat primarily avoiding saturated and trans fatty acids, but rich in fruit and vegetables should be recommended.     

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.     

Solid immiscibility in milk fat fractions and methods to determine their occurrence

In this work, the occurrence of solid phase immiscibility during the fractionation process of milk fat is documented. It is shown that solid phase immiscibility occurs in normal fractionation procedures, upon crystallisation at low temperatures and in particular on further fractionation of narrow melting fractions. This phenomenon results in distinct phases of crystallisation. In some cases, the initial phase yields intermediate solid levels independent of increasing supersaturation. The subsequent increase of solids content is solely a contribution of a second, independent crystallisation event. Furthermore, it could be shown that the induction time for the second crystallisation event is not influenced by the presence or absence of the first triacylglyceride group. These results clearly indicate the independence of the crystallisation of the different immiscible fractions in terms of kinetics and thermodynamics. The different processes during the crystallisation process are monitored simply by viscosimetry.     

Fire protection of wood by different gypsum plasterboards

Cone calorimeter tests were performed on specimens made of pieces of wood and pieces of gypsum plasterboards protecting the wood against the heat. The thermal behaviour of the gypsum plasterboards of different origin was studied by determining the time to onset of charring and the charring rate of wood. The specimens were exposed to a constant heat flux of 50 kW/m². The test results show that the time to onset of charring is more dependent on the board thickness than the area weight of the boards. The charring rate is fairly well predicted both by the board thickness and area weight, the latter being slightly better as a prediction parameter. The mechanical board properties needed in order to fully understand the fire protection from gypsum plasterboards were not studied in this investigation. Copyright © 1999 John Wiley & Sons Ltd.     

Doxorubicin Impairs Smooth Muscle Cell Contraction: Novel Insights in Vascular Toxicity

Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 μM DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca²⁺ release from the sarcoplasmic reticulum (0 mM Ca²⁺), but it reduced the subsequent tonic phase characterised by Ca²⁺ influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca²⁺ channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K⁺ and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.     

Microstructure evolution of TiC cermets with ferritic AISI 430L steel binder

From the outlook of healthcare, economic importance and supply risk, utilisation of raw materials like tungsten, cobalt and nickel should be reduced or replaced with other metals. Nontoxic titanium carbide and iron are the top-of-the-line solution for displacing these materials. Our focus was on conventionally fabricated titanium carbide-based cermets with a chromium ferritic steel binder. To study microstructural evolution, specimens were sintered at different temperatures (600–1500°C). We used a scanning electron microscopy, X-ray diffraction and differential scanning calorimetry to analyse the microstructure and phase formation of the cermets. Our results showed that during the solid and liquid phase sintering of the TiC–FeCr cermet, chromium ferrous complex carbides M₇C₃ are formed and as a result, chromium content in the binder phase is decreased. Alloying TiC–FeCr cermets with strong carbide formers improves the structural homogeneity of the cermets. Also, mechanical characteristics (hardness, fracture toughness) were evaluated.