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.     

Describing and predicting alcohol use-related harm: an analysis of the Yukon Alcohol and Drug Survey

During 1990 the Yukon Bureau of Statistics conducted an alcohol and drug survey with a sample of 1,348 residents of the Territory, aged 15 and over. Over three-quarters of the sample reported experiencing at least one type of harm from others' drinking during the past year, and over a half experienced two or more types of harm. Among the main predictors of prevalence and extent of harm were respondents' age (younger), a greater number of drinks per occasion, close associates with alcohol problems, and residing in smaller communities. The results are discussed in terms of their relevance to identifying vulnerable groups and informing policy aimed at reducing alcohol use-related harm.     

Cataract surgery and YAG-laser capsulotomy following vitrectomy for diabetic retinopathy

The present study was initiated to assess time-course and risk factors for the development of cataract and posterior-capsule opacification as well as complications of cataract surgery and YAG-laser capsulotomy following vitrectomy for diabetic retinopathy. The charts of all patients undergoing vitrectomy for diabetic retinopathy during a 5-year period in a university eye hospital were retrospectively reviewed. The course of 306 consecutive eyes in which the lens was retained during vitrectomy was analyzed for subsequent cataract surgery and YAG-laser capsulotomy. The first 6 months after cataract or YAG-laser surgery were examined for the occurrence of complications. Data were analyzed with regard to the time course using Kaplan-Meier life-table analysis. The proportion of eyes that underwent cataract surgery after vitrectomy increased nearly linearly with time, approaching 75% after 5 years. Silicone tamponade (relative risk 1.9; P = 0.0005) and transscleral retinal cryotherapy (relative risk 1.4; P = 0.003) were risk factors for subsequent cataract surgery. No significant cataractogenous effect of intravitreal gas as compared with balanced salt solution was found. YAG-laser capsulotomy was performed in 60% of vitrectomized diabetic eyes within 2 years but in only 10% of nondiabetic controls (P < 0.0001). Within 6 months of extracapsular cataract surgery with implantation of an intraocular lens (IOL) in 54 eyes, no serious complication was observed. After YAG-laser capsulotomy, vitreous hemorrhage occurred within 6 months in 6 of 21 eyes. In conclusion, cataract surgery was performed in 75% of the phakic eyes within 5 years of vitrectomy for diabetic retinopathy. Posterior capsular opacification is particularly common in this subset of eyes. No serious complication was observed after extracapsular cataract surgery with IOL implantation, but YAG-laser capsulotomy was associated with an increased risk for vitreous hemorrhage.     

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)     

Hereditary macular dystrophies

BACKGROUND: Orthostatic hypotension is a common phenomenon in the elderly. Hormonal changes during orthostatic stress have been described in elderly normotensive people and in those with essential hypertension. However, the hormonal response in elderly people who have systolic hypertension during orthostasis has not yet been quantified. METHODS: In this study we investigated 14 non-diabetic men, aged 60 to 75 years, with untreated systolic hypertension who were subjected to 45 degrees passive head-up incline on a tilt table for 15 min. Their hormonal profile and hemodynamic changes were analyzed before and after the stress. RESULTS: In the supine position, plasma levels of norepinephrine, atrial natriuretic peptide and aldosterone were in the normal range, while the plasma renin activity was low. Immediately upon tilt the systolic blood pressure fell but it reverted to baseline values after 15 min of orthostasis. At that time the cardiac output decreased while the systemic vascular resistance and the plasma norepinephrine concentration rose. The atrial natriuretic peptide appeared to fall, and the renin-aldosterone level did not change. CONCLUSION: The physiologic response to orthostatic stress in elderly people with systolic hypertension is comparable to that of elderly normotensive people and those with essential hypertension, i.e. a decrease in cardiac output and an increase in plasma norepinephrine levels. The atrial natriuretic peptide appeared to fall appropriately. The response of the renin-aldosterone system mimicked that in elderly patients with low renin essential isolated hypertension. These observations may have a bearing on the management of elderly people with systolic hypertension who also have orthostatic symptoms; they may not require a different approach from that needed for others of the same age group.     

On enabling integrated process compliance with semantic constraints in process management systems

Key to broad use of process management systems (PrMS) in practice is their ability to foster and ease the implementation, execution, monitoring, and adaptation of business processes while still being able to ensure robust and error-free process enactment. To meet these demands a variety of mechanisms has been developed to prevent errors at the structural level (e.g., deadlocks). In many application domains, however, processes often have to comply with business level rules and policies (i.e., semantic constraints) as well. Hence, to ensure error-free executions at the semantic level, PrMS need certain control mechanisms for validating and ensuring the compliance with semantic constraints. In this paper, we discuss fundamental requirements for a comprehensive support of semantic constraints in PrMS. Moreover, we provide a survey on existing approaches and discuss to what extent they are able to meet the requirements and which challenges still have to be tackled. In order to tackle the particular challenge of providing integrated compliance support over the process lifecycle, we introduce the SeaFlows framework. The framework introduces a behavioural level view on processes which serves a conceptual process representation for constraint specification approaches. Further, it provides general compliance criteria for static compliance validation but also for dealing with process changes. Altogether, the SeaFlows framework can serve as formal basis for realizing integrated support of semantic constraints in PrMS.     

Polycyclic Aromatic Hydrocarbons Activate the Aryl Hydrocarbon Receptor and the Constitutive Androstane Receptor to Regulate Xenobiotic Metabolism in Human Liver Cells

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism by upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) by activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual PAHs may also interact with the constitutive androstane receptor (CAR). Here, we studied ten PAHs, different in carcinogenicity classification, for their potential to activate AHR- and CAR-dependent luciferase reporter genes in human liver cells. The majority of investigated PAHs activated AHR, while non-carcinogenic PAHs tended to activate CAR. We further characterized gene expression, protein abundancies and activities of the AHR targets CYP1A1 and 1A2, and the CAR target CYP2B6 in human HepaRG hepatoma cells. Enzyme induction patterns strongly resembled the profiles obtained at the receptor level, with AHR-activating PAHs inducing CYP1A1/1A2 and CAR-activating PAHs inducing CYP2B6. In summary, this study provides evidence that beside well-known activation of AHR, some PAHs also activate CAR, followed by subsequent expression of respective target genes. Furthermore, we found that an increased PAH ring number is associated with AHR activation as well as the induction of DNA double-strand breaks, whereas smaller PAHs activated CAR but showed no DNA-damaging potential.     

Analysis of the Structure and Biosynthesis of the Lipopolysaccharide Core Oligosaccharide of Pseudomonas syringae pv. tomato DC3000

Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, is important for bacterial viability in general and host–pathogen interactions in particular. Negative charges at its core oligosaccharide (core-OS) contribute to membrane integrity through bridging interactions with divalent cations. The molecular structure and synthesis of the core-OS have been resolved in various bacteria including the mammalian pathogen Pseudomonas aeruginosa. A few core-OS structures of plant-associated Pseudomonas strains have been solved to date, but the genetic components of the underlying biosynthesis remained unclear. We conducted a comparative genome analysis of the core-OS gene cluster in Pseudomonas syringae pv. tomato (Pst) DC3000, a widely used model pathogen in plant–microbe interactions, within the P. syringae species complex and to other plant-associated Pseudomonas strains. Our results suggest a genetic and structural conservation of the inner core-OS but variation in outer core-OS composition within the P. syringae species complex. Structural analysis of the core-OS of Pst DC3000 shows an uncommonly high phosphorylation and presence of an O-acetylated sugar. Finally, we combined the results of our genomic survey with available structure information to estimate the core-OS composition of other Pseudomonas species.