Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3mg/kg, p.o.; n=7) or placebo (n=6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.

A Systems-Level Approach to Human Epileptic Seizures

Epileptic seizures are due to the pathological collective activity of large cellular assemblies. A better understanding of this collective activity is integral to the development of novel diagnostic and therapeutic procedures. In contrast to reductionist analyses, which focus solely on small-scale characteristics of ictogenesis, here we follow a systems-level approach, which combines both small-scale and larger-scale analyses. Peri-ictal dynamics of epileptic networks are assessed by studying correlation within and between different spatial scales of intracranial electroencephalographic recordings (iEEG) of a heterogeneous group of patients suffering from pharmaco-resistant epilepsy. Epileptiform activity as recorded by a single iEEG electrode is determined objectively by the signal derivative and then subjected to a multivariate analysis of correlation between all iEEG channels. We find that during seizure, synchrony increases on the smallest and largest spatial scales probed by iEEG. In addition, a dynamic reorganization of spatial correlation is observed on intermediate scales, which persists after seizure termination. It is proposed that this reorganization may indicate a balancing mechanism that decreases high local correlation. Our findings are consistent with the hypothesis that during epileptic seizures hypercorrelated and therefore functionally segregated brain areas are re-integrated into more collective brain dynamics. In addition, except for a special sub-group, a highly significant association is found between the location of ictal iEEG activity and the location of areas of relative decrease of localised EEG correlation. The latter could serve as a clinically important quantitative marker of the seizure onset zone (SOZ).

The effect of demand, tank parameters, and pumping stations on energy use in municipal drinking water distribution systems

Two of the indicators of the UN Millennium Development Goals ensuring environmental sustainability are energy use and per capita carbon dioxide emissions. The increasing urbanization and increasing world population may require increased energy use in order to transport enough safe drinking water to communities. In addition, the increase in water use would result in increased energy consumption, thereby resulting in increased green-house gas emissions that promote global climate change. The study of multiple Municipal Drinking Water Distribution Systems (MDWDSs) that relates various MDWDS aspects--system components and properties--to energy use is strongly desirable. The understanding of the relationship between system aspects and energy use aids in energy-efficient design. In this study, components of a MDWDS, and/or the characteristics associated with the component are termed as MDWDS aspects (hereafter--system aspects). There are many aspects of MDWDSs that affect the energy usage. Three system aspects (1) system-wide water demand, (2) storage tank parameters, and (3) pumping stations were analyzed in this study. The study involved seven MDWDSs to understand the relationship between the above-mentioned system aspects in relation with energy use. A MDWDSs model, EPANET 2.0, was utilized to analyze the seven systems. Six of the systems were real and one was a hypothetical system. The study presented here is unique in its statistical approach using seven municipal water distribution systems. The first system aspect studied was system-wide water demand. The analysis involved analyzing seven systems for the variation of water demand and its impact on energy use. To quantify the effects of water use reduction on energy use in a municipal water distribution system, the seven systems were modeled and the energy usage quantified for various amounts of water conservation. It was found that the effect of water conservation on energy use was linear for all seven systems and that all the average values of all the systems' energy use plotted on the same line with a high R 2 value. From this relationship, it can be ascertained that a 20% reduction in water demand results in approximately a 13% savings in energy use for all seven systems analyzed. This figure might hold true for many similar systems that are dominated by pumping and not gravity driven. The second system aspect analyzed was storage tank(s) parameters. Various tank parameters: (1) tank maximum water levels, (2) tank elevation, and (3) tank diameter were considered in this part of the study. MDWDSs use a significant amount of electrical energy for the pumping of water from low elevations (usually a source) to higher ones (usually storage tanks). The use of electrical energy has an effect on pollution emissions and, therefore, potential global climate change as well. Various values of these tank parameters were modeled on seven MDWDSs of various sizes using a network solver and the energy usage recorded. It was found that when averaged over all seven analyzed systems (1) the reduction of maximum tank water level by 50% results in a 2% energy reduction, (2) energy use for a change in tank elevation is system specific, and (2) a reduction of tank diameter of 50% results in approximately a 7% energy savings. The third system aspect analyzed in this study was pumping station parameters. A pumping station consists of one or more pumps. The seven systems were analyzed to understand the effect of the variation of pump horsepower and the number of booster stations on energy use. It was found that adding booster stations could save energy depending upon the system characteristics. For systems with flat topography, a single main pumping station was found to use less energy. In systems with a higher-elevation neighborhood, however, one or more booster pumps with a reduced main pumping station capacity used less energy. The energy savings for the seven systems was dependent on the number of boosters and ranged from 5% to 66% for the analyzed five systems with higher elevation neighborhoods (S3, S4, S5, S6, and S7). No energy savings was realized for the remaining two flat topography systems, S1, and S2. The present study analyzed and established the relationship between various system aspects and energy use in seven MDWDSs. This aids in estimating the amount of energy savings in MDWDSs. This energy savings would ultimately help reduce Greenhouse gases (GHGs) emissions including per capita CO 2 emissions thereby potentially lowering the global climate change effect. This will in turn contribute to meeting the MDG of ensuring environmental sustainability.

Change-Enabled Software Systems

Few real software systems are built completely from scratch nowadays. Instead, systems are built iteratively and incrementally, while integrating and interacting with components from many other systems. Adaptation, reconfiguration and evolution are normal, ongoing processes throughout the lifecycle of a software system. Nevertheless the platforms, tools and environments we use to develop software are still largely based on an outmoded model that presupposes that software systems are closed and will not significantly evolve after deployment. We claim that in order to enable effective and graceful evolution of modern software systems, we must make these systems more amenable to change by (i) providing explicit, first-class models of software artifacts, change, and history at the level of the platform, (ii) continuously analysing static and dynamic evolution to track emergent properties, and (iii) closing the gap between the domain model and the developers' view of the evolving system. We outline our vision of dynamic, evolving software systems and identify the research challenges to realizing this vision.

PyGirl: Generating Whole-System VMs from High-Level Prototypes Using PyPy

Virtual machines (VMs) emulating hardware devices are generally implemented in low-level languages for performance reasons. This results in unmaintainable systems that are difficult to understand. In this paper we report on our experience using the PyPy toolchain to improve the portability and reduce the complexity of whole-system VM implementations. As a case study we implement a VM prototype for a Nintendo Game Boy, called PyGirl, in which the high-level model is separated from low-level VM implementation issues. We shed light on the process of refactoring from a low-level VM implementation in Java to a high-level model in RPython. We show that our whole-system VM written with PyPy is significantly less complex than standard implementations, without substantial loss in performance.

An economic assessment of drought effects on three grassland systems in Switzerland

This paper analyzes the economic impacts of summer drought on Swiss grassland production. We combine field trial data from drought experiments in three different grasslands in Switzerland with site-specific information on economic costs and benefits. The analysis focuses on the economic implications of drought effects on grassland yields as well as grassland composition. In agreement with earlier studies, we found rather heterogeneous yield effects of drought on Swiss grassland systems, with significantly reduced yields as a response to drought at the lowland and sub-alpine sites, but increased yields at the wetter pre-alpine site. Relative yield losses were highest at the sub-alpine site (with annual yield losses of up to 37 %). However, because income from grassland production at extensive sites relies to a large extent on ecological direct payments, even large yield losses had only limited implications in terms of relative profit reductions. In contrast, negative drought impacts at the most productive, intensively managed lowland site were dominant, with average annual drought-induced profit margin reductions of about 28 %. This is furthermore emphasized if analyzing the farm level perspective of drought impacts. Combining site-specific effects at the farm level, we found that in particular farms with high shares of lowland grassland sites suffer from summer droughts in terms of farm-level fodder production and profit margins. Moreover, our results showed that the higher competitiveness of weeds (broad-leaved dock) under drought conditions will require increasing attention on weed control measures in future grassland production systems. Taking into account that the risk of drought occurrence is expected to increase in the coming years, additional instruments to cope with drought risks in fodder production and finally farmers’ income have to be developed.

Learning to drive: learners' self-reported cognitive failure level predicts driving instructor's observation rating of driving performance

OBJECTIVES Evidence increases that cognitive failure may be used to screen for drivers at risk. Until now, most studies have relied on driving learners. This exploratory pilot study examines self-report of cognitive failure in driving beginners and error during real driving as observed by driving instructors. METHODS Forty-two driving learners of 14 driving instructors filled out a work-related cognitive failure questionnaire. Driving instructors observed driving errors during the next driving lesson. In multiple linear regression analysis, driving errors were regressed on cognitive failure with the number of driving lessons as an estimator of driving experience controlled. RESULTS Higher cognitive failure predicted more driving errors (p < .01) when age, gender and driving experience were controlled in analysis. CONCLUSIONS Cognitive failure was significantly associated with observed driving errors. Systematic research on cognitive failure in driving beginners is recommended.

Pelagic molybdenum concentration anomalies and the impact of sediment resuspension on the molybdenum budget in two tidal systems of the North Sea

The seasonal dynamics of molybdenum (Mo) were studied in the water column of two tidal basins of the German Wadden Sea (Sylt-Rømø and Spiekeroog) between 2007 and 2011. In contrast to its conservative behaviour in the open ocean, both, losses of more than 50% of the usual concentration level of Mo in seawater and enrichments up to 20% were observed repeatedly in the water column of the study areas. During early summer, Mo removal by adsorption on algae-derived organic matter (e.g. after Phaeocystis blooms) is postulated to be a possible mechanism. Mo bound to organic aggregates is likely transferred to the surface sediment where microbial decomposition enriches Mo in the pore water. First δ98/95Mo data of the study area disclose residual Mo in the open water column being isotopically heavier than MOMo (Mean Ocean Molybdenum) during a negative Mo concentration anomaly, whereas suspended particulate matter shows distinctly lighter values. Based on field observations a Mo isotope enrichment factor of ε = −0.3‰ has been determined which was used to argue against sorption on metal oxide surfaces. It is suggested here that isotope fractionation is caused by biological activity and association to organic matter. Pelagic Mo concentration anomalies exceeding the theoretical salinity-based concentration level, on the other hand, cannot be explained by replenishment via North Sea waters alone and require a supply of excess Mo. Laboratory experiments with natural anoxic tidal flat sediments and modelled sediment displacement during storm events suggest fast and effective Mo release during the resuspension of anoxic sediments in oxic seawater as an important process for a recycling of sedimentary sulphide bound Mo into the water column.

Migrant Background and Higher Education Participation in Europe. The Effect of the Educational Systems

The main aim of this article is to shed light on the extent to which differences in higher education participation between people with and without a migrant background of low/higher social origin can be explained by two macro-level characteristics of national educational institutions: stratification of the secondary school system and provision of alternative access to higher education. General assumptions are that people with a migrant background of low social origin benefit in low-stratified secondary school systems and in systems that provide alternative access to institutions of higher education more than their native peers in the same social stratum, owing to primary and secondary effects of migrant background. Database is a pooled dataset of the five waves of the European Social Survey. Results of logistic multi-level analyses indicate that a low-stratified secondary school system improves the probability of people with a migrant background/low social origin attaining a higher education degree. On the other hand, a stratified secondary school system reduces their chances regarding this educational stage. The provision of alternative access to an institution of higher education improves their likelihood of becoming higher education graduates.

SLA-Driven Simulation of Multi-Tenant Scalable Cloud-Distributed Enterprise Information Systems

Cloud Computing is an enabler for delivering large-scale, distributed enterprise applications with strict requirements in terms of performance. It is often the case that such applications have complex scaling and Service Level Agreement (SLA) management requirements. In this paper we present a simulation approach for validating and comparing SLA-aware scaling policies using the CloudSim simulator, using data from an actual Distributed Enterprise Information System (dEIS). We extend CloudSim with concurrent and multi-tenant task simulation capabilities. We then show how different scaling policies can be used for simulating multiple dEIS applications. We present multiple experiments depicting the impact of VM scaling on both datacenter energy consumption and dEIS performance indicators.

Predicting 3-year mortality after percutaneous coronary intervention: updated logistic clinical SYNTAX score based on patient-level data from 7 contemporary stent trials

OBJECTIVES This study aimed to update the Logistic Clinical SYNTAX score to predict 3-year survival after percutaneous coronary intervention (PCI) and compare the performance with the SYNTAX score alone. BACKGROUND The SYNTAX score is a well-established angiographic tool to predict long-term outcomes after PCI. The Logistic Clinical SYNTAX score, developed by combining clinical variables with the anatomic SYNTAX score, has been shown to perform better than the SYNTAX score alone in predicting 1-year outcomes after PCI. However, the ability of this score to predict long-term survival is unknown. METHODS Patient-level data (N = 6,304, 399 deaths within 3 years) from 7 contemporary PCI trials were analyzed. We revised the overall risk and the predictor effects in the core model (SYNTAX score, age, creatinine clearance, and left ventricular ejection fraction) using Cox regression analysis to predict mortality at 3 years. We also updated the extended model by combining the core model with additional independent predictors of 3-year mortality (i.e., diabetes mellitus, peripheral vascular disease, and body mass index). RESULTS The revised Logistic Clinical SYNTAX models showed better discriminative ability than the anatomic SYNTAX score for the prediction of 3-year mortality after PCI (c-index: SYNTAX score, 0.61; core model, 0.71; and extended model, 0.73 in a cross-validation procedure). The extended model in particular performed better in differentiating low- and intermediate-risk groups. CONCLUSIONS Risk scores combining clinical characteristics with the anatomic SYNTAX score substantially better predict 3-year mortality than the SYNTAX score alone and should be used for long-term risk stratification of patients undergoing PCI.