Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Adolescent´s perceptions and expectations of parental action on children´s smoking and snus use : national cross sectional data from three decades

Background: Parents play a vital role as children develop tobacco behaviours. Many parents feel unsure about their possibility to influence their teenager's lifestyle. Knowledge about young people's acceptance for parental intervention could increase parental involvement. The overall objective of this study was to explore adolescents' perceptions and expectations of parental action regarding children's smoking and snus use, and whether they have changed over time. To see if there were differences whether the adolescent was a tobacco user or not the adolescents' tobacco use was followed; and described to put the findings on their perceptions and expectations of parental action in a context. Methods: The study used a repeated cross-sectional design, reporting Swedish national data from three decades. Data were collected in 1987, 1994 and 2003 by a questionnaire mailed to homes, in total to 13500 persons. The annual samples, which were random and national representative, consisted of 4500 young people aged 13, 15 and 17 yr, 1500 individuals per age group. The sampling and data collection procedures were done the same way during each survey. Chi2- tests were used to evaluate differences in distributions. Results: Adolescents in all age groups became more positive toward parental action over time. In 2003, more then 86% of the adolescents, including both smokers and non-smokers, strongly supported parental action on their children's smoking by trying to persuade them not to smoke (94%), by not smoking themselves (87%) and by not allowing their children to smoke at home (86%). Both non-smokers and smokers supported the idea of parental action in a similar way. Reduced pocket money had a weak support (42%), especially from girls. Eighty-nine percent of the adolescents expected their parents to act against smoking and 85% against snus use. Smoking was stable at 8% in 1987 and 1994 but decreased to 4% in 2003. In 1987 the snus use prevalence was 4% and in 2003 it was 3%. Snus users were mostly boys while few girls had done more than tried snus. More young people in all age groups had never tried smoking compared to the previous studies. In 2003 57% stated that they had never tried smoking. Conclusion: Adolescent smoking in Sweden has decreased and the proportion who never tried smoking has increased. The results of this study show that a growing majority of adolescents support strong parental intervention to help them refrain from tobacco, but preferably not in a punitive manner. This finding dismisses the notion that adolescents ignore or even disdain parental practices concerning tobacco. Prevention strategies and interventions addressing adolescent tobacco use that involve parents can be improved by using these findings to encourage parents to intervene against their children's tobacco use.Funding from Vasterbotten County Council, Umea, Sweden and the Swedish National Public Health Institute, Stockholm, Sweden, supported research for this article.</p

Sensing current and forces with SPM

Atomic force microscopy (AFM) and scanning tunneling microscopy (STM) are well established techniques to image surfaces and to probe material properties at the atomic and molecular scale. In this review, we show hybrid combinations of AFM and STM that bring together the best of two worlds: the simultaneous detection of atomic scale forces and conduction properties. We illustrate with several examples how the detection of forces during STM and the detection of currents during AFM can give valuable additional information of the nanoscale material properties

A computational framework to integrate high-throughput '-omics' datasets for the identification of potential mechanistic links

International audienceWe recently presented a three-pronged association study that integrated human intestinal microbiome data derived from shotgun-based sequencing with untargeted serum metabolome data and measures of host physiology. Metabolome and microbiome data are high dimensional, posing a major challenge for data integration. Here, we present a step-by-step computational protocol that details and discusses the dimensionality-reduction techniques used and methods for subsequent integration and interpretation of such heterogeneous types of data. Dimensionality reduction was achieved through a combination of data normalization approaches, binning of co-abundant genes and metabolites, and integration of prior biological knowledge. The use of prior knowledge to overcome functional redundancy across microbiome species is one central advance of our method over available alternative approaches. Applying this framework, other investigators can integrate various '-omics' readouts with variables of host physiology or any other phenotype of interest (e.g., connecting host and microbiome readouts to disease severity or treatment outcome in a clinical cohort) in a three-pronged association analysis to identify potential mechanistic links to be tested in experimental settings. Although we originally developed the framework for a human metabolome-microbiome study, it is generalizable to other organisms and environmental metagenomes, as well as to studies including other -omics domains such as transcriptomics and proteomics. The provided R code runs in similar to 1 h on a standard PC