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.     

Chemoenzymatic Asymmetric Synthesis of Pyridine-Based α-Fluorinated Secondary Alcohols

Fluoro-substituted and heteroaromatic compounds are valuable intermediates for a variety of applications in pharma- and agrochemistry and synthetic chemistry. This study investigates the chemoenzymatic preparation of chiral alcohols bearing a heteroaromatic ring with an increasing degree of fluorination in α-position. Starting from readily available picoline derivatives prochiral α-halogenated acyl moieties were introduced with excellent selectivity and 64–95 % yield. The formed carbonyl group was subsequently reduced to the corresponding alcohols using the alcohol dehydrogenase from Lactobacillus kefir, yielding an enantiomeric excess of 95–>99 % and up to 98 % yield.     

Uncertainties in the determination of pyrrolizidine alkaloid levels in naturally contaminated honeys and comparison of results obtained by different analytical approaches

The contamination of honey with hepatotoxic pyrrolizidine alkaloids (PAs) is a well-known hazard for food safety. While management strategies and controls of the honey industry aim to reduce the PA levels, uncertainties remain with regard to the safety of regionally produced and marketed honey. In addition, a previous study showed large differences of results obtained after various periods of storage and apparent differences between the analytical results of different laboratories. Therefore, this study aimed at examining these uncertainties by monitoring the impact of storage on the PA and PA N-oxide (PANO) content of two freshly harvested honeys and on possible demixing effects caused by pollen settling. Additionally, three analytical approaches – target analysis with matrix-matched calibration or standard addition and a sum parameter method – were applied for a comparative analysis of 20 honeys harvested in summer 2016. All samples originated from Schleswig-Holstein in Northern Germany where the PA plant Jacobaea vulgaris is currently observed on a massive scale. The results of the time series analyses showed that PANO levels markedly decreased within a few weeks and practically reached the LOD 16 weeks after harvest. Tertiary PAs, by contrast, remained stable and did not increase as a consequence of PANO decrease. The experiments on a putative demixing, which may result in a heterogeneous distribution of PAs/PANOs, revealed that there was no such effect during storage of up to 12 weeks. A comparison of the PA/PANO levels obtained by different analytical approaches showed that in some cases the sum parameter method yielded much higher levels than the target approaches, whereas in other cases, the target analysis with standard addition found higher levels than the other two methods. In summary, the results of this study highlight uncertainties regarding the validity and comparability of analytical results and consequently regarding health risk assessment.     

The beginning of immigrant settlement in the Helsinki metropolitan area and the role of social housing

Finland has experienced a rapid increase inimmigration since the beginning of the 1990s.Almost half of the foreign population isconcentrated in the metropolitan area of thecapital, Helsinki. The development andexplanations of their settlement patterns havenot yet been thoroughly studied. It ishypothesised in this study that social housingcan explain the settlement patterns. Indices ofdissimilarity were calculated to study thelevel and development of spatial segregation ofimmigrant groups in the Helsinki metropolitanarea in 1995–99, and the association betweenthe settlement patterns of immigrants andsocial housing was studied by regressionanalysis. Neighbourhood-level data were used.The results indicate that the Helsinkimetropolitan area has avoided extreme ethnicsegregation so far and that segregation isdecreasing. Especially immigrants from poorcountries are clearly associated with socialhousing in their settlement patterns, evenafter adjustment for socio-economic anddemographic differentiation. Also newconstruction of social housing seems to haveaffected the spatial distribution of thisgroup. Despite this dependence, the group isnot extremely segregated, which is probablybecause the social housing sector is nottotally marginalised.     

Applications of the discrete element method in mechanical engineering

Compared to other fields of engineering, in mechanical engineering, the Discrete Element Method (DEM) is not yet a well known method. Nevertheless, there is a variety of simulation problems where the method has obvious advantages due to its meshless nature. For problems where several free bodies can collide and break after having been largely deformed, the DEM is the method of choice. Neighborhood search and collision detection between bodies as well as the separation of large solids into smaller particles are naturally incorporated in the method. The main DEM algorithm consists of a relatively simple loop that basically contains the three substeps contact detection, force computation and integration. However, there exists a large variety of different algorithms to choose the substeps to compose the optimal method for a given problem. In this contribution, we describe the dynamics of particle systems together with appropriate numerical integration schemes and give an overview over different types of particle interactions that can be composed to adapt the method to fit to a given simulation problem. Surface triangulations are used to model complicated, non-convex bodies in contact with particle systems. The capabilities of the method are finally demonstrated by means of application examples. Commemorative Contribution.     

Finnish general contracting in the USSR

When dealing with a Soviet client, tendering, scheduling, consideration of available resources, management responsibilities, start-up and hand-over must be approached from a slightly different angle than when dealing with Western clients. Aspects of project management from feasibility analysis to hand-over are described, based on the experience of a Finnish general contractor, Finn Stroi.     

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Book reviews

     

A new technique for on-line and off-line high speed computation

A novel technique for both online and offline computation is presented. With this technique, a reconstruction analysis in elementary particle physics, otherwise prohibitively long, has been accomplished. It will be used online in an upcoming Fermilab experiment to reconstruct more than 100000 events per second and to trigger on the basis of that information. The technique delivers 40 gigaoperations per second, has a bandwidth on the order of gigabytes per second, and has a modest cost. An overview of the program, details of the system, and performance measurements are presented     

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