In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.     

The Crosstalk of Adipose-Derived Stem Cells (ADSC), Oxidative Stress,and Inflammation in Protective and Adaptive Responses

The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties.     

A variational approach to magnetoelastic buckling problems for systems of superconducting tori

A variational principle for the magnetoelastic stability problem of superconductors is constructed. Independently, a pair of integral equations is derived, from which the initial and the perturbed field can be computed. The integral equations are solved for in-plane buckling of a slender pair of concentric tori, and out-of-plane buckling of a slender pair of equal coaxial tori. By using the variational principle, it is shown that both cases can become unstable when the currents on the two tori are equally directed, and the pertinent buckling values are calculated. The thus obtained buckling values are compared with the results of an alternative, mathematically less rigorous, method. A good correspondence between the two methods is found (at least as long as the two tori are not too near).     

The cardiovascular interaction between caffeine and nicotine in humans

In a placebo-controlled, double-blind randomized design, we investigated the cardiovascular interaction between caffeine (250 mg intravenously) and nicotine (4 mg chewing gum) in 10 healthy volunteers, both under baseline conditions and during physical and mental stress (standing up and mental arithmetic). Caffeine alone induced a significant increase in blood pressure associated with a decrease in heart rate, whereas nicotine alone increased both blood pressure and heart rate. The combination of caffeine and nicotine increased systolic and diastolic blood pressure by 10.8 +/- 2.0 and 12.4 +/- 1.9 mm Hg, respectively. This pressor response did not differ significantly from the calculated additive effects of caffeine and nicotine on blood pressure, measuring 12.9 +/- 2.0 and 14.2 +/- 2.1 mm Hg, respectively. Heart rate and forearm blood flow also showed a similar response when the combination of caffeine and nicotine was compared with the calculated sum. During physical stress (standing up), blood pressure, heart rate, and plasma catecholamines increased in the placebo test. The pressor response to standing up was less pronounced after the combination of caffeine and nicotine compared with the sum of the separate effects (combination versus sum: delta diastolic blood pressure, 24.7 +/- 1.9 versus 35.2 +/- 2.6 mm Hg [p < 0.01]; delta mean arterial pressure, 22.1 +/- 2.0 mm Hg versus 28.6 +/- 1.6 mm Hg [p < 0.05]). The plasma catecholamine response did not differ between the combination and the sum of both drugs. During mental arithmetic, blood pressure, heart rate, and forearm blood flow increased in the placebo test. The forearm vasodilator response to mental stress was attenuated by the combination of caffeine and nicotine compared with the sum of both drugs (combination versus sum: delta forearm blood flow, -0.1 +/- 0.3 versus 1.4 +/- 0.5 ml/100 ml/min [p < 0.05]). We conclude that the combined administration of caffeine and nicotine shows additive effects on cardiovascular parameters during baseline conditions but less than additive effects during sympathoadrenal stimulation.     

Taming monsters: The cultural domestication of new technology

Central to public discomfort about new technologies is the notion that they are unnatural. Experts often suppose that better knowledge of technology and risks would help overcome public aversion. This assumption turns out to be fairly fruitless, often even increasing social polarization. The pattern of diverging risk assessments about technology might be improved by a better understanding of the moral gut feelings at stake. However, current technology ethics does not seem to be equipped for elaborating theories to explain public discomfort. Either public fear is not taken seriously, or ethical–theoretical rationalizations of moral intuitions lead to unsatisfactory, naturalist constructions, such as the intrinsic value of nature.For a better understanding of current risk controversies, a detour is made to the cultural anthropology of Mary Douglas on pre-modern ideas regarding danger. This offers some clarifying insights into modern perceptions of technological risks. Departing from anthropological observations, a so-called monster theory is sketched, which gives an explanation for the fascination with and aversion towards new technology, leaving aside ‘naturalist’ and ‘nature-skeptic’ explanations of technology ethics. Monster theory offers a point of departure for a new, pragmatic approach to controversies about new technology, the approach being named a pragmatist monster-ethics. It tells us we have to reflect on and shift cultural categories as well as to adapt technologies in order to domesticate our technological ‘monsters’.     

Peroxide crosslinking of rigid poly(vinyl chloride)

Peroxide crosslinking of unplasticized poly(vinyl chloride) with trimethylolpropane trimethacrylate was investigated. Formulations used in this work contained a nontoxic lead‐free stabilizer and showed good color and heat stability. The samples were examined by differential scanning calorimetry, and their tensile properties were measured at room temperature and at 130°C. Gel content or tetrahydrofuran‐insoluble material was measured as an indication of crosslinking. It was shown that premature crosslinking could be avoided during processing and that 190°C was the optimum processing temperature for maximum gel content. The residual unsaturation was monitored by using FTIR spectroscopy. J. VINYL ADDIT. TECHNOL., 2008. © 2008 Society of Plastics Engineers     

Fecal bile acid excretion and composition in response to changes in dietary wheat bran,fat and calcium in the rat

The effect and possible interactive influence of different dietary amounts of wheat bran, fat and calcium on the fecal excretion, concentration and composition of bile acids was studied in Fischer-344 rats. The fecal bile acids were analyzed using gas-liquid chromatography. Dietary wheat bran increased both total bile acid excretion and fecal weight without changes in fecal bile acid concentration. The proportion of fecal hyodeoxycholic acid decreased with increasing dietary fiber, whereas that of lithocholic and deoxycholic acids increased significantly with fiber intake. The percent content of fecal chenodeoxycholic acid did not change. Increasing dietary fat led to an increase in bile acid excretion without changes in either fecal weight or bile acid concentration. In contrast, the level of dietary calcium did not affect the total excretion of bile acids. However, since calcium increased the fecal weight, it consequently diluted bile acids and decreased their fecal concentration. Dietary fat and calcium had no influence on fecal bile acid composition. There were no interactive effects of wheat bran, fat and calcium on fecal bile acids. The finding in this study that dietary fiber, fat and calcium induce significant changes in fecal bile acids may be of relevance to the potential of bile acids to promote carcinogenesis.