Functional Characterisation of Three Glycine N-Acyltransferase Variants and the Effect on Glycine Conjugation to Benzoyl–CoA

The glycine conjugation pathway in humans is involved in the metabolism of natural substrates and the detoxification of xenobiotics. The interactions between the various substrates in this pathway and their competition for the pathway enzymes are currently unknown. The pathway consists of a mitochondrial xenobiotic/medium-chain fatty acid: coenzyme A (CoA) ligase (ACSM2B) and glycine N-acyltransferase (GLYAT). The catalytic mechanism and substrate specificity of both of these enzymes have not been thoroughly characterised. In this study, the level of evolutionary conservation of GLYAT missense variants and haplotypes were analysed. From these data, haplotype variants were selected (156Asn > Ser, [17Ser > Thr,156Asn > Ser] and [156Asn > Ser,199Arg > Cys]) in order to characterise the kinetic mechanism of the enzyme over a wide range of substrate concentrations. The 156Asn > Ser haplotype has the highest frequency and the highest relative enzyme activity in all populations studied, and hence was used as the reference in this study. Cooperative substrate binding was observed, and the kinetic data were fitted to a two-substrate Hill equation. The coding region of the GLYAT gene was found to be highly conserved and the rare 156Asn > Ser,199Arg > Cys variant negatively affected the relative enzyme activity. Even though the 156Asn > Ser,199Arg > Cys variant had a higher affinity for benzoyl-CoA (s_0.5,benz = 61.2 µM), k_cat was reduced to 9.8% of the most abundant haplotype 156Asn > Ser (s_0.5,benz = 96.6 µM), while the activity of 17Ser > Thr,156Asn > Ser (s_0.5,benz = 118 µM) was 73% of 156Asn > Ser. The in vitro kinetic analyses of the effect of the 156Asn > Ser,199Arg > Cys variant on human GLYAT enzyme activity indicated that individuals with this haplotype might have a decreased ability to metabolise benzoate when compared to individuals with the 156Asn > Ser variant. Furthermore, the accumulation of acyl-CoA intermediates can inhibit ACSM2B leading to a reduction in mitochondrial energy production.     

Global Intensity Correction in Dynamic Scenes

Changing image intensities causes problems for many computer vision applications operating in unconstrained environments. We propose generally applicable algorithms to correct for global differences in intensity between images recorded with a static or slowly moving camera, regardless of the cause of intensity variation. The proposed intensity correction is based on intensity-quotient estimation. Various intensity estimation methods are compared. Usability is evaluated with background classification as example application. For this application we introduced the PIPE error measure evaluating performance and robustness to parameter setting. Our approach retains local intensity information, is always operational and can cope with fast changes in intensity. We show that for intensity estimation, robustness to outliers is essential for dynamic scenes. For image sequences with changing intensity, the best performing algorithm (MofQ) improves foreground-background classification results up to a factor two to four on real data.     

Stress Generation, Avoidance Coping, and Depressive Symptoms: A 10-Year Model.

This study examined (a) the role of avoidance coping in prospectively generating both chronic and acute life stressors and (b) the stress-generating role of avoidance coping as a prospective link to future depressive symptoms. Participants were 1,211 late-middle-aged individuals (500 women and 711 men) assessed 3 times over a 10-year period. As predicted, baseline avoidance coping was prospectively associated with both more chronic and more acute life stressors 4 years later. Furthermore, as predicted, these intervening life stressors linked baseline avoidance coping and depressive symptoms 10 years later, controlling for the influence of initial depressive symptoms. These findings broaden knowledge about the stress-generation process and elucidate a key mechanism through which avoidance coping is linked to depressive symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parallel global optimization with the particle swarm algorithm

Present day engineering optimization problems often impose large computational demands, resulting in long solution times even on a modern high-end processor. To obtain enhanced computational throughput and global search capability, we detail the coarse-grained parallelization of an increasingly popular global search method, the particle swarm optimization (PSO) algorithm. Parallel PSO performance was evaluated using two categories of optimization problems possessing multiple local minima-large-scale analytical test problems with computationally cheap function evaluations and medium-scale biomechanical system identification problems with computationally expensive function evaluations. For load-balanced analytical test problems formulated using 128 design variables, speedup was close to ideal and parallel efficiency above 95% for up to 32 nodes on a Beowulf cluster. In contrast, for load-imbalanced biomechanical system identification problems with 12 design variables, speedup plateaued and parallel efficiency decreased almost linearly with increasing number of nodes. The primary factor affecting parallel performance was the synchronization requirement of the parallel algorithm, which dictated that each iteration must wait for completion of the slowest fitness evaluation. When the analytical problems were solved using a fixed number of swarm iterations, a single population of 128 particles produced a better convergence rate than did multiple independent runs performed using sub-populations (8 runs with 16 particles, 4 runs with 32 particles, or 2 runs with 64 particles). These results suggest that (1) parallel PSO exhibits excellent parallel performance under load-balanced conditions, (2) an asynchronous implementation would be valuable for real-life problems subject to load imbalance, and (3) larger population sizes should be considered when multiple processors are available.     

Tests of the dynamic field theory and the spatial precision hypothesis: Capturing a qualitative developmental transition in spatial working memory.

This study tested a dynamic field theory (DFT) of spatial working memory and an associated spatial precision hypothesis (SPH). Between 3 and 6 years of age, there is a qualitative shift in how children use reference axes to remember locations: 3-year-olds’ spatial recall responses are biased toward reference axes after short memory delays, whereas 6-year-olds’ responses are biased away from reference axes. According to the DFT and the SPH, quantitative improvements over development in the precision of excitatory and inhibitory working memory processes lead to this qualitative shift. Simulations of the DFT in Experiment 1 predict that improvements in precision should cause the spatial range of targets attracted toward a reference axis to narrow gradually over development, with repulsion emerging and gradually increasing until responses to most targets show biases away from the axis. Results from Experiment 2 with 3- to 5-year-olds support these predictions. Simulations of the DFT in Experiment 3 quantitatively fit the empirical results and offer insights into the neural processes underlying this developmental change. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term patterns and predictors of successful stressor resolution in later life.

At 1 year, 4 years, and 10 years after baseline, late-middle-aged adults reported whether they had successfully resolved their most important stressor of the past year. Compared to individuals who never resolved focal stressors over the 10-year interval, those who always did consistently showed less negative stressor appraisal, less reliance on avoidance coping, and less use of exploratory relative to directed coping responses, independent of type and severity of focal stressor. Less use of exploratory relative to directed coping and having more social resources, fewer health problems, and fewer depressive symptoms at baseline predicted more stressor resolution over the next 10 years. These predictors are promising foci for prospective efforts to optimize ways in which aging adults manage late-life stressors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Predicting the development of late-life late-onset drinking problems: a 7-year prospective study

There has been little empirical study of risk factors for the development of late-life late-onset drinking problems. In the current prospective study, we compare two groups of older adults who, at a baseline assessment, were nonproblem drinkers: individuals who developed drinking problems over the course of the next 7 years (n = 77) and those who did not (n = 197). Late-onset problem drinkers reported mild to moderate drinking problems and spontaneous remission rates were high. Compared with stable nonproblem drinkers, late-onset problem drinkers at baseline were more likely to report incipient problems, heavier alcohol consumption, greater friend approval of drinking, more reliance on avoidance coping strategies, were more likely to smoke, and were less likely to have acute medical conditions that could potentially be complicated by alcohol consumption. Contrary to expectation, life stressors did not predict drinking problem onset. However, compared with stable nonproblem drinkers, late-onset problem drinkers were more likely to have a history of responding to stressors and negative affect with increased alcohol consumption.     

Pharmacotherapeutic compass 1998

The Central Medical Pharmaceutical Committee of the Health Insurance Council informs the medical profession annually about the effects of drugs through the Pharmacotherapeutical Compass. The 1998 edition now contains a chapter on pharmacokinetics as well. Compared with previous editions the main alterations of the contents concern an introduction and advice on the antidepressants, two protocols with respect to the medical treatment of patients suffering from epilepsy, advice with respect to oral drugs for the treatment of inflammatory bowel disease, an introduction and advice regarding the treatment of allergic rhinitis, the treatment of patients suffering from AIDS with antiretroviral drugs, the treatment of genital herpes, the taking of insulin lispro by patients with diabetes and the taking of bisphosphonates to prevent or to treat osteoporosis. Two corrections to the 1998 edition are given.     

In vitro characterization of microdialysis sampling of macromolecules

Experiments were performed to characterize the in vitro collection of macromolecules using microdialysis. Fluorescently labeled proteins and dextrans ranging from 3000 to 150 000 were sampled using a 10-mm, 100 000 molecular weight cutoff, polyethersulfone microdialysis probe. Published models describing microdialysis mass transport of small molecules were examined to determine their appropriateness for sampling of macromolecules. Collection efficiencies, reported as relative recoveries, for macromolecules from 3000 to 70 000 ranged from 5 to 44%. Collection efficiencies determined for microdialysis sampling of macromolecules follow the functionality of published models, although experimental mass transport resistances are to some extent smaller than predicted. Implications of the current study for in vivo microdialysis sampling of cytokines and growth factors are discussed.