International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

Considering tourist perceptions and network configuration in destination management

The competitiveness of tourism destinations is a relevant issue for tourism studies, moreso, is a key element on the daily basis of tourism destinations. In this sense, the management of tourism destinations is essential to maintain competitive advantages. In this article tourism destination is considered as a relational network, where interaction and cooperation is needed among tourist agents, to achieve major levels of competitive advantage and a more effective destination management system. In addition, the perceptions of tourists are obtained from two main sources. The first one is the social construction of a tourism destination previous to the visit and the second one is obtained from the interaction between tourists and tourism destination agents during the visit. In this sense, the management of tourism destination to emit a homogenous and collective image is a factor that can reduce the gap if dissatisfaction from the previous and real tourist perception. The discussion is centered on the relationship within a destination, between the supply network and the targeted demand, considering these two approaches jointly, to benefit destination management. The main result is a conceptual model that shows how tourism agents and tourists in the tourism destination interact to improve the destination competitiveness

Fluctuation-Driven Neural Dynamics Reproduce Drosophila Locomotor Patterns.

The neural mechanisms determining the timing of even simple actions, such as when to walk or rest, are largely mysterious. One intriguing, but untested, hypothesis posits a role for ongoing activity fluctuations in neurons of central action selection circuits that drive animal behavior from moment to moment. To examine how fluctuating activity can contribute to action timing, we paired high-resolution measurements of freely walking Drosophila melanogaster with data-driven neural network modeling and dynamical systems analysis. We generated fluctuation-driven network models whose outputs-locomotor bouts-matched those measured from sensory-deprived Drosophila. From these models, we identified those that could also reproduce a second, unrelated dataset: the complex time-course of odor-evoked walking for genetically diverse Drosophila strains. Dynamical models that best reproduced both Drosophila basal and odor-evoked locomotor patterns exhibited specific characteristics. First, ongoing fluctuations were required. In a stochastic resonance-like manner, these fluctuations allowed neural activity to escape stable equilibria and to exceed a threshold for locomotion. Second, odor-induced shifts of equilibria in these models caused a depression in locomotor frequency following olfactory stimulation. Our models predict that activity fluctuations in action selection circuits cause behavioral output to more closely match sensory drive and may therefore enhance navigation in complex sensory environments. Together these data reveal how simple neural dynamics, when coupled with activity fluctuations, can give rise to complex patterns of animal behavior.

Very high-resolution digital elevation models: are multi-scale-derived variables ecologically relevant?

1. Digital elevation models (DEMs) are often used in landscape ecology to retrieve elevation or first derivative terrain attributes such as slope or aspect in the context of species distribution modelling. However, DEM-derived variables are scale-dependent and, given the increasing availability of very high-resolution (VHR) DEMs, their ecological relevancemust be assessed for different spatial resolutions. 2. In a study area located in the Swiss Western Alps, we computed VHR DEMs-derived variables related to morphometry, hydrology and solar radiation. Based on an original spatial resolution of 0.5 m, we generated DEM-derived variables at 1, 2 and 4 mspatial resolutions, applying a Gaussian Pyramid. Their associations with local climatic factors, measured by sensors (direct and ambient air temperature, air humidity and soil moisture) as well as ecological indicators derived fromspecies composition, were assessed with multivariate generalized linearmodels (GLM) andmixed models (GLMM). 3. Specific VHR DEM-derived variables showed significant associations with climatic factors. In addition to slope, aspect and curvature, the underused wetness and ruggedness indices modelledmeasured ambient humidity and soilmoisture, respectively. Remarkably, spatial resolution of VHR DEM-derived variables had a significant influence on models' strength, with coefficients of determination decreasing with coarser resolutions or showing a local optimumwith a 2 mresolution, depending on the variable considered. 4. These results support the relevance of using multi-scale DEM variables to provide surrogates for important climatic variables such as humidity, moisture and temperature, offering suitable alternatives to direct measurements for evolutionary ecology studies at a local scale.

Entry Regulation Asymmetries and Gasoline Competition in a Mixed Motorway Network

Regulatory and funding asymmetries in the Spanish motorway network produce huge differences in the structure of gasoline markets by motorway type: free or toll. While competition is encouraged among gas stations on free motorways, the regulations for toll motorways allow private concessionaires to auction all gas stations to the same provider, thereby limiting competition and consolidating market power. This paper reports how this regulatory asymmetry results in higher prices and fewer gas stations. Specifically, we show that competition is constrained on toll motorways by the granting of geographical monopolies, resulting in a small number of rivals operating in close proximity to each other, and allowing gas stations to operate as local monopolies. The lack of competition would seem to account for the price differential between toll and free motorways. According to available evidence, deregulation measures affecting toll motorway concessions could help to mitigate price inefficiencies and increase consumer welfare.

Privatization and PPPS in transportation infrastructure: Network effects of increasing user fees

PPPS: Problem: Public-private-partnerships in transport infrastructure characteristically increase user-fees. Purpose: We aim to identify the network effects of the use of PPPs and increased user tolls in road infrastructure. Methods: We study the increases in user tolls on motorways due to the use of PPPs in the US. Results and conclusions: Among other things, the monetization of motorways is associated with an increase in toll levels that has consequences for their users, and also for the rest of the sections of the network.

Performance Management of a Next Generation Network

Today's communication networks consist of numerous interdependent network components. To manage these networks and to ensure their reliable and efficient operation to meet the increasing customer usability demands, extensive network management tools are required from the service provider. The goal of this study was to adapt the Next Generation Network (NGN) providing VoIP services within a performance oriented network management system. This study focuses only on NGN network and the project was implemented as an assignment of the Network Operations Center of Elisa Corporation. The theoretical part of this study introduces the network environment of the Elisa NGN platform: its components and used signalling protocols as well as other exploitable communication protocols. In addition, the Simple Network Management Protocol (SNMP) is closely examined since it is commonly used as the basis of IP (Internet Protocol) network management. Also some primary applications enabled by the NGN technology are introduced. The empirical part of this study contains a short overview of the implemented network performance management system and its properties. The most crucial monitored MIB modules, SNMP parameters and implemented performance measurements are described. The trap topology and the role of the traps for management of the NGN platform are considered and finally, the conclusion based on the several disquisitions is made supported with suggestions for future improvements.

Europeanisation and Conflict Resolution: The Case of Cyprus

This paper investigates the example of Cyprus as a case study for the Europeanisation of conflict resolution. The argument advanced is that the European Union (EU) impacts the positions of the parts of the conflict (here, Greek Cypriots, Turkish Cypriots and Turkey) but not always towards the resolution of the dispute and compliance with EU conditionality. Conformity with EU conditionality depends on its credibility, which is decreased by the internalisation of the conflict into the EU. In this context, this work contributes to the discussion on Europeanisation and the aptitude of the EU in conflict resolution as well as the role of the EU in the Cyprus conflict during the post-accession years.

Infrastructure and nation building: The regulation and financing of network transportation infrastructures in Spain (1720-2010)

This paper analyzes Spanish infrastructure policy since the early 1700s: Road building in the eighteenth century, railway creation and expansion in the nineteenth, motorway expansion in the twentieth, and high speed rail development in the twenty-first. The analysis reveals a long-term pattern, in which infrastructure policy in Spain has been driven not by the requirements of commerce and economic activity, but rather by the desire to centralize transportation around the country’s political capital.

Price rivalry in airline markets: A study of a successful strategy of a network carrier against a low-cost carrier

Competition in airline markets may be tough. In this context, network carriers have two alternative strategies to compete with low-cost carriers. First, they may establish a low-cost subsidiary. Second, they may try to reduce costs using the main brand. This paper examines a successful strategy of the first type implemented by Iberia in the Spanish domestic market. Our analysis of data and the estimation of a pricing equation show that Iberia has been able to charge lower prices than rivals with its low-cost subsidiary. The pricing policy of the Spanish network carrier has been particularly aggressive in less dense routes and shorter routes.

Predicting richness and composition in mountain insect communities at high resolution: a new test of the SESAM framework

Aim The aim of this study was to test different modelling approaches, including a new framework, for predicting the spatial distribution of richness and composition of two insect groups. Location The western Swiss Alps. Methods We compared two community modelling approaches: the classical method of stacking binary prediction obtained fromindividual species distribution models (binary stacked species distribution models, bS-SDMs), and various implementations of a recent framework (spatially explicit species assemblage modelling, SESAM) based on four steps that integrate the different drivers of the assembly process in a unique modelling procedure. We used: (1) five methods to create bS-SDM predictions; (2) two approaches for predicting species richness, by summing individual SDM probabilities or by modelling the number of species (i.e. richness) directly; and (3) five different biotic rules based either on ranking probabilities from SDMs or on community co-occurrence patterns. Combining these various options resulted in 47 implementations for each taxon. Results Species richness of the two taxonomic groups was predicted with good accuracy overall, and in most cases bS-SDM did not produce a biased prediction exceeding the actual number of species in each unit. In the prediction of community composition bS-SDM often also yielded the best evaluation score. In the case of poor performance of bS-SDM (i.e. when bS-SDM overestimated the prediction of richness) the SESAM framework improved predictions of species composition. Main conclusions Our results differed from previous findings using community-level models. First, we show that overprediction of richness by bS-SDM is not a general rule, thus highlighting the relevance of producing good individual SDMs to capture the ecological filters that are important for the assembly process. Second, we confirm the potential of SESAM when richness is overpredicted by bS-SDM; limiting the number of species for each unit and applying biotic rules (here using the ranking of SDM probabilities) can improve predictions of species composition

An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

Although approximately 50% of Down Syndrome (DS) patients have heart abnormalities, they exhibit an overprotection against cardiac abnormalities related with the connective tissue, for example a lower risk of coronary artery disease. A recent study reported a case of a person affected by DS who carried mutations in FBN1, the gene causative for a connective tissue disorder called Marfan Syndrome (MFS). The fact that the person did not have any cardiac alterations suggested compensation effects due to DS. This observation is supported by a previous DS meta-analysis at the molecular level where we have found an overall upregulation of FBN1 (which is usually downregulated in MFS). Additionally, that result was cross-validated with independent expression data from DS heart tissue. The aim of this work is to elucidate the role of FBN1 in DS and to establish a molecular link to MFS and MFS-related syndromes using a computational approach. To reach that, we conducted different analytical approaches over two DS studies (our previous meta-analysis and independent expression data from DS heart tissue) and revealed expression alterations in the FBN1 interaction network, in FBN1 co-expressed genes and FBN1-related pathways. After merging the significant results from different datasets with a Bayesian approach, we prioritized 85 genes that were able to distinguish control from DS cases. We further found evidence for several of these genes (47%), such as FBN1, DCN, and COL1A2, being dysregulated in MFS and MFS-related diseases. Consequently, we further encourage the scientific community to take into account FBN1 and its related network for the study of DS cardiovascular characteristics.

Interactome analysis reveals that FAM161A, deficient in recessive retinitis pigmentosa, is a component of the Golgi-centrosomal network.

Defects in FAM161A, a protein of unknown function localized at the cilium of retinal photoreceptor cells, cause retinitis pigmentosa, a form of hereditary blindness. By using different fragments of this protein as baits to screen cDNA libraries of human and bovine retinas, we defined a yeast two-hybrid-based FAM161A interactome, identifying 53 bona fide partners. In addition to statistically significant enrichment in ciliary proteins, as expected, this interactome revealed a substantial bias towards proteins from the Golgi apparatus, the centrosome and the microtubule network. Validation of interaction with key partners by co-immunoprecipitation and proximity ligation assay confirmed that FAM161A is a member of the recently recognized Golgi-centrosomal interactome, a network of proteins interconnecting Golgi maintenance, intracellular transport and centrosome organization. Notable FAM161A interactors included AKAP9, FIP3, GOLGA3, KIFC3, KLC2, PDE4DIP, NIN and TRIP11. Furthermore, analysis of FAM161A localization during the cell cycle revealed that this protein followed the centrosome during all stages of mitosis, likely reflecting a specific compartmentalization related to its role at the ciliary basal body during the G0 phase. Altogether, these findings suggest that FAM161A's activities are probably not limited to ciliary tasks but also extend to more general cellular functions, highlighting possible novel mechanisms for the molecular pathology of retinal disease.

Imaging the time-integrated cerebral metabolic activity with subcellular resolution through nanometer-scale detection of biosynthetic products deriving from (13)C-glucose.

Glucose is the primary source of energy for the brain but also an important source of building blocks for proteins, lipids, and nucleic acids. Little is known about the use of glucose for biosynthesis in tissues at the cellular level. We demonstrate that local cerebral metabolic activity can be mapped in mouse brain tissue by quantitatively imaging the biosynthetic products deriving from [U-(13)C]glucose metabolism using a combination of in situ electron microscopy and secondary ion mass-spectroscopy (NanoSIMS). Images of the (13)C-label incorporated into cerebral ultrastructure with ca. 100nm resolution allowed us to determine the timescale on which the metabolic products of glucose are incorporated into different cells, their sub-compartments and organelles. These were mapped in astrocytes and neurons in the different layers of the motor cortex. We see evidence for high metabolic activity in neurons via the nucleus (13)C enrichment. We observe that in all the major cell compartments, such as e.g. nucleus and Golgi apparatus, neurons incorporate substantially higher concentrations of (13)C-label than astrocytes.