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.     

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research.     

Uncertainty Matters: Computer Models at the Science–Policy Interface

The use of computer models offers a general and flexible framework that can help to deal with some of the complexities and difficulties associated with the development of water management plans as prescribed by the Water Framework Directive. However, despite the advantages modelling presents, the integration of information derived from models into policy is far away from being trivial or the norm. Part of the difficulties of this integration is rooted in the lack of confidence policy makers have on the incorporation of modelling information into policy formulation. In this paper we examine the reasons for this apparent lack of confidence and explore how some tools, presently in use, address this problem. We conclude that public confidence in models is highly dependent on the way uncertainties are addressed and suggest possible directions of action to improve the current situation. Four real case studies illustrate how computer models have been used in The Netherlands for carrying out management plans at regional and national scale. We suggest that the solution to integrate modelling information into policy formulation lies on both the modelling and the policy-making communities.     

Die Wasserkraftschnecke – Praxis, Prüfstand und Potenzial

Since 2001 Archimedean screws have been used for commercial power generation. However, due to a lack of distribution, this comparatively new, ultra-low-head technology is essentially still a niche product. This work examines their potential, combining an operator survey, field measurements as well as laboratory tests. In extensive lab experiments, efficiencies were measured and compared for seven different screw types at varying speed-to-flow-rate combinations and inclination angles. Here, both excellent efficiencies and the impact of different parameters were observed and significant potential for improvement on the state of the art was found. This article summarizes the area of application, practical experience to date, and the latest developments concerning this highly efficient, low-maintenance, and ecologically promising low-head technology. In doing so, it also provides a well-founded basis for decision-making involving turbine selection at small hydropower sites.     

Precisely Controlled Microsphere Design via Visible‐Light Cross‐Linking of Functional Prepolymers

A new strategy for particle synthesis is enabled by utilizing modern synthetic, polymer, and photochemical techniques to facilitate the synthesis of highly narrow–disperse multifunctional microspheres from visible‐light induced crosslinking of prepolymers in both a single and dual polymer system. The approach requires no stabilizers, bases, or initiators, and proceeds at ambient temperature to yield microspheres with a tunable size range (0.25–5 µm) in less than 4 h, depending largely on solvent composition, but also polymer concentration (2–10 mg mL^?1), ratio, and irradiation intensity (3–20 W). Critically, the visible‐light induced dimerization reaction exploited herein enables simple functional particle syntheses via a single polymer system. Underpinned by an in‐depth kinetic analysis of the particle formation as well as a detailed small molecule study, the mechanism for particle formation is also elucidated. Importantly, inherent advantages of the system are exploited for surface functionalization of residual acrylate and hydroxyl groups (generating inherently fluorescent particles).     

Introducing Widget-based IMS Client Applications

Classic telecommunication methods and Internet services are converging. For this reason Telecommunication companies are looking for new ways to include their services in Web 2.0 applications. A strong candidate for the telecommunication infrastructure of the future is the IP Multimedia Subsystem (IMS), an all IP telecommunication core network. In the last few years a new kind of application has increasingly gained popularity: they are known as widgets. Widgets are small but fancy applications based on Web technologies that are very easy to develop. This paper describes a new approach to combining widgets with telecommunication features, such as Voice over IP calls or messaging, using IMS. Our solution includes a new abstraction layer with interfaces for the different telecommunication capabilities. Moreover, we implemented a widget engine that makes these telecommunication interfaces available to its widgets. Our solution allows the rapid development of new IMS client applications and a short time-to-market. The combination of other Web 2.0 services with IMS features becomes an exploitable opportunity.     

Reconstruction of graphs based on random walks

The analysis of complex networks is of major interest in various fields of science. In many applications we face the challenge that the exact topology of a network is unknown but we are instead given information about distances within this network. The theoretical approaches to this problem have so far been focusing on the reconstruction of graphs from shortest path distance matrices. Often, however, movements in networks do not follow shortest paths but occur in a random fashion. In these cases an appropriate distance measure can be defined as the mean length of a random walk between two nodes — a quantity known as the mean first hitting time.In this contribution we investigate whether a graph can be reconstructed from its mean first hitting time matrix and put forward an algorithm for solving this problem. A heuristic method to reduce the computational effort is described and analyzed. In the case of trees we can even give an algorithm for reconstructing graphs from incomplete random walk distance matrices.     

A 3D moisture-stress FEM analysis for time dependent problems in timber structures

This paper presents a 3D moisture-stress numerical analysis for timber structures under variable humidity and load conditions. An orthotropic viscoelastic-mechanosorptive material model is specialized on the basis of previous models. Both the constitutive model and the equations needed to describe the moisture flow across the structure are implemented into user subroutines of the Abaqus finite element code and a coupled moisture-stress analysis is performed for several types of mechanical loads and moisture changes. The presented computational approach is validated by analyzing some wood tests described in the literature and comparing the computational results with the reported experimental data.