Active Transport of Hepatotoxic Pyrrolizidine Alkaloids in HepaRG Cells

1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring as food contaminants that can cause severe liver damage upon metabolic activation in hepatocytes. However, it is yet unknown how these contaminants enter the cells. The role of hepatic transporters is only at the beginning of being recognized as a key determinant of PA toxicity. Therefore, this study concentrated on assessing the general mode of action of PA transport in the human hepatoma cell line HepaRG using seven structurally different PAs. Furthermore, several hepatic uptake and efflux transporters were targeted with pharmacological inhibitors to identify their role in the uptake of the PAs retrorsine and senecionine and in the disposition of their N-oxides (PANO). For this purpose, PA and PANO content was measured in the supernatant using LC-MS/MS. Also, PA-mediated cytotoxicity was analyzed after transport inhibition. It was found that PAs are taken up into HepaRG cells in a predominantly active and structure-dependent manner. This pattern correlates with other experimental endpoints such as cytotoxicity. Pharmacological inhibition of the influx transporters Na⁺/taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter 1 (SLC22A1) led to a reduced uptake of retrorsine and senecionine into HepaRG cells, emphasizing the relevance of these transporters for PA toxicokinetics.     

The effectiveness of adaptive versus non-adaptive learning with digital educational games

For the training of academic skills, digital educational games with integrated adaptivity are promising. Adaptive games are considered superior to non-adaptive games, because they constantly assess children's performance, and accordingly adapt the difficulty of the tasks corresponding to the children's individual level. However, empirical evidence with regard to the effectivity of adaptive compared to non-adaptive games is limited. A study was conducted with 191 children from the third year of Kinder garten who were enrolled in one of three conditions, that is, playing an adaptive version of the reading game (RG), a non-adaptive version of the RG or training with pen-and-paper exercises. In all three conditions, children trained emergent reading (phonological awareness and letter knowledge) once a week for 30 min over a period of 5 weeks. Children's performance on cognitive (phonological awareness, letter knowledge, reading fluency) and non-cognitive (motivation, self-concept) factors was assessed. Results revealed a significant improvement in phonological awareness and letter knowledge in all conditions. However, no differences between the conditions were observed with respect to children's improvement on phonological awareness and letter knowledge or on their post-test scores for reading fluency. With regard to motivation and self-concept, again, no differences in these non-cognitive factors were observed across conditions.     

Symbolic parametrization of curves

If algebraic varieties like curves or surfaces are to be manipulated by computers, it is essential to be able to represent these geometric objects in an appropriate way. For some applications an implicit representation by algebraic equations is desirable, whereas for others an explicit or parametric representation is more suitable. Therefore, transformation algorithms from one representation to the other are of utmost importance.We investigate the transformation of an implicit representation of a plane algebraic curve into a parametric representation. Various methods for computing a rational parametrization, if one exists, are described. As a new idea we introduce the concept of working with classes of conjugate (singular or simple) points on curves. All the necessary operations, like determining the multiplicity and the character of the singular points or passing a linear system of curves through these points, can be applied to such classes of conjugate points. Using this idea one can parametrize a curve if one knows only one simple point on it. We do not propose any new method for finding such a simple point. By classical methods a rational point on a rational curve can be computed, if such a point exists. Otherwise, one can express the coordinates of such a point in an algebraic extension of degree 2 over the ground field.     

Hypertension and pulmonary edema associated with subconjunctival phenylephrine in a 2-month-old child during cataract extraction

We have analysed trends in male:female ratios among newborns between 1950 and 1990 in 29 countries from five continents. The numbers of liveborn males and females over the period 1950-1994 were derived from the World Health Organization (WHO) database. Countries for which reliable data were available included 20 major European countries (excluding the former Soviet Union, Albania and a few small countries), Canada, the USA, selected countries of Central and South America, Japan, Australia and New Zealand. From the original numbers of males and females, we computed the proportion of males among liveborns for each country and for selected broader areas within Europe. In most countries the proportion of male liveborns was constant during the study period. In particular, the proportion of male newborns in the European Union was 0.515 in 1950-1954, 0.514 in 1970-1974 and 0.514 in 1990-1994. In the USA, corresponding values were 0.513, 0.513 and 0.512. In Japan the ratios were 0.513 in 1950-1954, 0.516 and 1970-1974 and 0.514 in 1990-1994. Decreasing ratios were observed in some northern and eastern European countries plus Greece and Portugal and, particularly, in Mexico. In contrast, the proportion of male liveborns tended to increase in southern Europe and Australia. Overall, among the 29 countries considered, the proportion of males declined in 16, increased in six, and remained stable in seven.