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.     

Design of novel urogenital pharmabiotic formulations containing lactobacilli,salivaricin CRL 1328 and non-microbial compounds with different functionalities

Context: The administration of pharmabiotics is a promising alternative to antimicrobial drugs for the treatment and/or prevention of female urogenital infections.

Objective: To design pharmabiotic formulations including bioactive ingredients of microbial origin combined with non-microbial substances and then to evaluate the stability of the combinations during freeze-drying and storage.

Materials and methods: Different formulations including Lactobacillus gasseri CRL 1263, Lactobacillus salivarius CRL 1328, salivaricin CRL 1328 (a bacteriocin) and non-microbial compounds (lactose, inulin and ascorbic acid) were assayed, and the ingredients were freeze-dried together or separately. The formulations were stored in gelatin capsules at 4?°C for 360?d.

Results: The viability of lactobacilli was affected to different extents depending on the strains and on the formulations assayed. L. salivarius and ascorbic acid were successfully combined only after the freeze-drying process. Salivaricin activity was not detected in formulations containing L. gasseri. However, when combined with ascorbic acid, lactose, inulin or L. salivarius, the bacteriocin maintained its activity for 360?d. The selected microorganisms proved to be compatible for their inclusion in multi-strain formulations together with lactose, inulin and ascorbic acid. Salivaricin could be included only in a L. salivarius CRL 1328 single-strain formulation together with non-microbial substances.

Conclusions: This study provides new insights into the design of urogenital pharmabiotics combining beneficial lactobacilli, salivaricin CRL 1328 and compounds with different functionalities.     

Brennstoffzellen

For two applications of fuel cells (SOFC and IMFC) system configurations and energy balances are presented. A decentralized combined heat and power plant on SOFC basis can be designed as a flexible system with high efficiency. A drive system with methanol reformer and fuel cell (IMFC) in comparison with a natural gas combustion engine has lower energy comsumption and much lower emissions.     

A process-dependent real-time controller for sequencing batch reactor plants: results of full-scale operation.

This paper presents results of a research project, in which a process-dependent real-time control (RTC) strategy for a sequencing batch reactor plant was realised in full-scale. The cycle controller is based on NH4 analysers, NO3 probes, TSS probes and sludge level probes. With this new RTC strategy it was possible to increase the treatment capacity by 50%. By implementation of the new controller the TN, TP and NH4-N treatment efficiency could be improved significantly, too. The treatment efficiency concerning COD is comparable.     

Comparative molecular field analysis of the antitumor activity of 9H-thioxanthen-9-one derivatives against pancreatic ductal carcinoma 03

The present study establishes correlations of in vivo growth inhibition of a solid tumor, pancreatic ductal adenocarcinoma (Panc03), of mice with the steric and electrostatic fields and the hydrophobic parameter log P of a series (32) of 1-[[2-(dialkylamino)alkyl]amino]- 9H-thioxanthen-9-ones by the 3D-QSAR method comparative molecular field analysis (CoMFA). The template molecular model was hycanthone methanesulfonate (19), the structure of which had been established previously by X-ray crystallography. The hycanthone base is protonated at the terminal nitrogen N(2), and an intramolecular hydrogen bond is present between the proximal nitrogen N(1) and carbonyl oxygen O(1) atoms. Crystallographic data also indicate a planar arrangement of bonds around N(1). However, the molecular geometry of 19, optimized by semiempirical molecular orbital methods (PM3, MNDO, AM1), showed the expected trigonal-pyramidal configuration for N(1). A comparison of MO and ab initio methods applied to a model compound, 1-amino-9H-thioxanthen-9-one, led to the selection of PM3 as the method for full geometry optimization of first the cationic and then the neutral forms of 1-32, whereas AM1 provided atomic charges for these same structures save those incorporating a sulfonamide moiety (5, 7, 20, 25, 26, 29, 31, and 32). Acceptable values for the latter were obtained from ab initio calculations. Structures were aligned by minimizing root-mean-square (rms) differences in the fitting of structures to 19 using the FIT option of SYBYL. An alternative strategy of alignment, steric and electrostatic alignment (SEAL), was invoked to provide a comparison of statistical data generated with the rms alignment. The rms-fit alignment of structures produced slightly better cross-validated and conventional r2 values than those generated with the SEAL method. In addition, the rms-fit data indicate that a shift in the lattice of one-half of its spacing has a much smaller effect on the CoMFA data for a lattice of 1 A than one of 2 A. Inclusion of log P in a CoMFA of the neutral structures effected a small (ca. 8-10%) but significant improvement in cross-validated r2 values. The relative contributions of the hydrophobic effects and the steric and electrostatic fields to the conventional r2 values were 16%, 42%, and 42%, respectively. By contrast, incorporation of frontier molecular orbital (HOMO and LUMO) energies or their gaps in the PLS analyses failed to enhance correlation coefficients derived for either the charged or uncharged compounds.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of sudden pressure changes in the surrounding gas phase on flow properties of bulk solids

The variation in the behaviour of bulk solids as a result of sudden pressure changes in the surrounding gas phase is of interest in the application of lock hoppers for transfer of bulk solids into pressure vessels. By using such sluice systems, problems occur due to consolidation of the pressurized bulk solids. This paper presents the results of experimental and theoretical research, which allow to describe the influence of several parameters on pressure compensation and the degree of consolidation. With reference to the forces and mechanisms responsible for consolidation, it is possible to describe the different consolidation behaviour of incompressible (limestone) and compressible (hard coal) bulk solids.     

The effect of lidocaine on growth of cells of head and neck squamous cell carcinoma

The relation between 21 absolute body dimensions as well as 20 anthropometric indices and the length as well as the regularity of the menstrual cycle have been investigated in 156 patients of the hormone ambulance of the I. Universit?ts-Frauenklinik in Vienna. It turned out, that the length as well as the regularity of the menstrual cycle significantly negatively with the amount of the subcutaneous fat tissue. With an increasing amount of adipose tissue, the cycle became shorter and more regular. The importance of the subcutaneous fat tissue as a secondary hormonal gland has been discussed as one cause for these significant connections. Regarding the length- and height dimensions and the menstrual cycle patterns, no statistically significantly relationship could be observed between these two trait system. This is also true for the relationship between body built and the bleeding duration.     

Adaptive flexibility and maladaptive routines in selecting fast and frugal decision strategies.

Decision routines unburden the cognitive capacity of the decision maker. In changing environments, however, routines may become maladaptive. In 2 experiments with a hypothetical stock market game (n = 241), the authors tested whether decision routines tend to persist at the level of decision strategies rather than at the level of options in strategy selection. The payoff structure of the task was changed after 80 decision trials, rendering a new strategy optimal with respect to expected payoff. Whereas most participants detected the appropriate strategy at the beginning of the task, they tended to retain it even when it was no longer optimal. A hint about a possible change had only a small influence on this maladaptive routine; a monetary incentive had none. Switching to a similar but not identical task relaxed the routine, but not much. (PsycINFO Database Record (c) 2010 APA, all rights reserved)