A general introduction to glucocorticoid biology

Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of the GR. We will explain the SEDIGRAM concept, which was launched based on our research results

Construction of planar 4-connected triangulations

In this article we describe a recursive structure for the class of 4-connected triangulations or - equivalently - cyclically 4-connected plane cubic graphs

Tourist trip planning functionalities : state-of-the-art and future

When tourists visit a city or region, they cannot visit every point of interest available, as they are constrained in time and budget. Tourist recommender applications help tourists by presenting a personal selection. Providing adequate tour scheduling support for these kinds of applications is a daunting task for the application developer. The objective of this paper is to demonstrate how existing models from the field of Operations Research (OR) fit this scheduling problem, and enable a wide range of tourist trip planning functionalities. Using the Orienteering Problem (OP) and its extensions to model the tourist trip planning problem, allows to deal with a vast number of practical planning problems

Evidence for rapid uptake of d-galacturonic acid in the yeast Saccharomyces cerevisiae by a channel-type transport system

Abstractd-Galacturonic acid is a major component of pectins but cannot be metabolized by Saccharomyces cerevisiae. It is assumed not to be taken up. We show that yeast displays surprisingly rapid low-affinity uptake of d-galacturonic acid, strongly increasing with decreasing extracellular pH and without saturation up to 1.5M. There was no intracellular concentration above the extracellular level and transport was reversible. Among more than 160 single and multiple deletion mutants in channels and transporters, no strain was affected in d-galacturonic acid uptake. The uptake was not inhibited by any compound tested as candidate competitive inhibitor, including d-glucuronic acid, which was also transported. The characteristics of d-galacturonic acid uptake are consistent with involvement of a channel-type system, probably encoded by multiple genes

Dynamic Collection Scheduling Using Remote Asset Monitoring: Case Study in the UK Charity Sector

Remote sensing technology is now coming onto the market in the waste collection sector. This technology allows waste and recycling receptacles to report their fill levels at regular intervals. This reporting enables collection schedules to be optimized dynamically to meet true servicing needs in a better way and so reduce transport costs and ensure that visits to clients are made in a timely fashion. This paper describes a real-life logistics problem faced by a leading UK charity that services its textile and book donation banks and its high street stores by using a common fleet of vehicles with various carrying capacities. Use of a common fleet gives rise to a vehicle routing problem in which visits to stores are on fixed days of the week with time window constraints and visits to banks (fitted with remote fill-monitoring technology) are made in a timely fashion so that the banks do not become full before collection. A tabu search algorithm was developed to provide vehicle routes for the next day of operation on the basis of the maximization of profit. A longer look-ahead period was not considered because donation rates to banks are highly variable. The algorithm included parameters that specified the minimum fill level (e.g., 50%) required to allow a visit to a bank and a penalty function used to encourage visits to banks that are becoming full. The results showed that the algorithm significantly reduced visits to banks and increased profit by up to 2.4%, with the best performance obtained when the donation rates were more variable

A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation

It has been suggested that glucocorticoid receptor (GR) agonists that promote GR homodimerization more than standard glucocorticoids such as Dexamethasone could be more effective anti-inflammatory molecules against acute and life-threatening inflammatory conditions. To test this hypothesis, we set up a screening pipeline aimed at discovering such Selective Dimerizing GR Agonists and Modulators (SEDIGRAM). The pipeline consists of a reporter gene assay based on a palindromic glucocorticoid responsive element (GRE). This assay represents GR dimerization in human A549 lung epithelial cells. In the pipeline, this is followed by analysis of endogenous GRE-driven gene expression, a FRET assay confirming dimerization, and monitoring of in vitro and in vivo anti-inflammatory activity. In a proof of principle experiment, starting from seven candidate compounds, we identified two potentially interesting compounds (Cortivazol and AZD2906) that confer strong protection in a mouse model of aggressive TNF-induced lethal inflammation. A screening pipeline for SEDIGRAM may assist the search for compounds that promote GR dimerization and limit overwhelming acute inflammatory responses

Effect of simplicity and attractiveness on route selection for different journey types

This study investigated the effects of six attributes, associated with simplicity or attractiveness, on route preference for three pedestrian journey types (everyday, leisure and tourist). Using stated choice preference experiments with computer generated scenes, participants were asked to choose one of a pair of routes showing either two levels of the same attribute (experiment 1) or different attributes (experiment 2). Contrary to predictions, vegetation was the most influential for both everyday and leisure journeys, and land use ranked much lower than expected in both cases. Turns ranked higher than decision points for everyday journeys as predicted, but the positions of both were lowered by initially unranked attributes. As anticipated, points of interest were most important for tourist trips, with the initially unranked attributes having less influence. This is the first time so many attributes have been compared directly, providing new information about the importance of the attributes for different journeys. © 2014 Springer International Publishing

Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice

TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs