The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor ? through spatial relocalization at helix 7 of its ligand-binding domain

Peroxisome proliferator-activated receptor ? (PPAR?) is a transcription factor that promotes differentiation and cell survival in the stomach. PPAR? upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPAR? is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPAR? signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPAR? and enhanced nuclear translocation and ligand-independent transcription of PPAR? target genes. In contrast, Cav1 overexpression sequestered PPAR? in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPAR?'s ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPAR? and to inhibit cell proliferation. Ligand-activated PPAR? also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPAR? regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPAR? to ligands, limiting proliferation of gastric epithelial cells.

Callosal connections of primary visual cortex predict the spatial spreading of binocular rivalry across the visual hemifields

In binocular rivalry, presentation of different images to the separate eyes leads to conscious perception alternating between the two possible interpretations every few seconds. During perceptual transitions, a stimulus emerging into dominance can spread in a wave-like manner across the visual field. These traveling waves of rivalry dominance have been successfully related to the cortical magnification properties and functional activity of early visual areas, including the primary visual cortex (V1). Curiously however, these traveling waves undergo a delay when passing from one hemifield to another. In the current study, we used diffusion tensor imaging (DTI) to investigate whether the strength of interhemispheric connections between the left and right visual cortex might be related to the delay of traveling waves across hemifields. We measured the delay in traveling wave times (ΔTWT) in 19 participants and repeated this test 6 weeks later to evaluate the reliability of our behavioral measures. We found large interindividual variability but also good test-retest reliability for individual measures of ΔTWT. Using DTI in connection with fiber tractography, we identified parts of the corpus callosum connecting functionally defined visual areas V1-V3. We found that individual differences in ΔTWT was reliably predicted by the diffusion properties of transcallosal fibers connecting left and right V1, but observed no such effect for neighboring transcallosal visual fibers connecting V2 and V3. Our results demonstrate that the anatomical characteristics of topographically specific transcallosal connections predict the individual delay of interhemispheric traveling waves, providing further evidence that V1 is an important site for neural processes underlying binocular rivalry.

Phylogenetic and virulence analysis of tick-borne encephalitis virus field isolates from Switzerland

Tick-borne encephalitis (TBE) is an endemic disease in Switzerland, with about 110-120 reported human cases each year. Endemic areas are found throughout the country. However, the viruses circulating in Switzerland have not been characterized so far. In this study, the complete envelope (E) protein sequences and phylogenetic classification of 72 TBE viruses found in Ixodes ricinus ticks sampled at 39 foci throughout Switzerland were analyzed. All isolates belonged to the European subtype and were highly related (mean pairwise sequence identity of 97.8% at the nucleotide and 99.6% at the amino acid level of the E protein). Sixty-four isolates were characterized in vitro with respect to their plaque phenotype. More than half (57.8%) of isolates produced a mixture of plaques of different sizes, reflecting a heterogeneous population of virus variants. Isolates consistently forming plaques of small size were associated with recently detected endemic foci with no or only sporadic reports of clinical cases. All of six virus isolates investigated in an in vivo mouse model were highly neurovirulent (100% mortality) but exhibited a relatively low level of neuroinvasiveness, with mouse survival rates ranging from 50% to 100%. Therefore, TBE viruses circulating in Switzerland belong to the European subtype and are closely related. In vitro and in vivo surrogates suggest a high proportion of isolates with a relatively low level of virulence, which is in agreement with a hypothesized high proportion of subclinical or mild TBE infections.

Linking physiology with behaviour: Functional specialisation of the visual field is reflected in gaze patterns during visual search

Based on neurophysiological findings and a grid to score binocular visual field function, two hypotheses concerning the spatial distribution of fixations during visual search were tested and confirmed in healthy participants and patients with homonymous visual field defects. Both groups showed significant biases of fixations and viewing time towards the centre of the screen and the upper screen half. Patients displayed a third bias towards the side of their field defect, which represents oculomotor compensation. Moreover, significant correlations between the extent of these three biases and search performance were found. Our findings suggest a new, more dynamic view of how functional specialisation of the visual field influences behaviour.

Scalp field maps and their characterization

The present chapter gives a comprehensive introduction into the display and quantitative characterization of scalp field data. After introducing the construction of scalp field maps, different interpolation methods, the effect of the recording reference and the computation of spatial derivatives are discussed. The arguments raised in this first part have important implications for resolving a potential ambiguity in the interpretation of differences of scalp field data. In the second part of the chapter different approaches for comparing scalp field data are described. All of these comparisons can be interpreted in terms of differences of intracerebral sources either in strength, or in location and orientation in a nonambiguous way. In the present chapter we only refer to scalp field potentials, but mapping also can be used to display other features, such as power or statistical values. However, the rules for comparing and interpreting scalp field potentials might not apply to such data. Generic form of scalp field data Electroencephalogram (EEG) and event-related potential (ERP) recordings consist of one value for each sample in time and for each electrode. The recorded EEG and ERP data thus represent a two-dimensional array, with one dimension corresponding to the variable “time” and the other dimension corresponding to the variable “space” or electrode. Table 2.1 shows ERP measurements over a brief time period. The ERP data (averaged over a group of healthy subjects) were recorded with 19 electrodes during a visual paradigm. The parietal midline Pz electrode has been used as the reference electrode.

Statistical analysis of multichannel scalp field data

High density spatial and temporal sampling of EEG data enhances the quality of results of electrophysiological experiments. Because EEG sources typically produce widespread electric fields (see Chapter 3) and operate at frequencies well below the sampling rate, increasing the number of electrodes and time samples will not necessarily increase the number of observed processes, but mainly increase the accuracy of the representation of these processes. This is namely the case when inverse solutions are computed. As a consequence, increasing the sampling in space and time increases the redundancy of the data (in space, because electrodes are correlated due to volume conduction, and time, because neighboring time points are correlated), while the degrees of freedom of the data change only little. This has to be taken into account when statistical inferences are to be made from the data. However, in many ERP studies, the intrinsic correlation structure of the data has been disregarded. Often, some electrodes or groups of electrodes are a priori selected as the analysis entity and considered as repeated (within subject) measures that are analyzed using standard univariate statistics. The increased spatial resolution obtained with more electrodes is thus poorly represented by the resulting statistics. In addition, the assumptions made (e.g. in terms of what constitutes a repeated measure) are not supported by what we know about the properties of EEG data. From the point of view of physics (see Chapter 3), the natural “atomic” analysis entity of EEG and ERP data is the scalp electric field

Comparison of climate field reconstruction techniques: Application to Europe

This paper presents a comparison of principal component (PC) regression and regularized expectation maximization (RegEM) to reconstruct European summer and winter surface air temperature over the past millennium. Reconstruction is performed within a surrogate climate using the National Center for Atmospheric Research (NCAR) Climate System Model (CSM) 1.4 and the climate model ECHO-G 4, assuming different white and red noise scenarios to define the distortion of pseudoproxy series. We show how sensitivity tests lead to valuable “a priori” information that provides a basis for improving real world proxy reconstructions. Our results emphasize the need to carefully test and evaluate reconstruction techniques with respect to the temporal resolution and the spatial scale they are applied to. Furthermore, we demonstrate that uncertainties inherent to the predictand and predictor data have to be more rigorously taken into account. The comparison of the two statistical techniques, in the specific experimental setting presented here, indicates that more skilful results are achieved with RegEM as low frequency variability is better preserved. We further detect seasonal differences in reconstruction skill for the continental scale, as e.g. the target temperature average is more adequately reconstructed for summer than for winter. For the specific predictor network given in this paper, both techniques underestimate the target temperature variations to an increasing extent as more noise is added to the signal, albeit RegEM less than with PC regression. We conclude that climate field reconstruction techniques can be improved and need to be further optimized in future applications.

Characterization of microfluidic systems with Doppler optical coherence tomography

Doppler Optical Coherence Tomography (DOCT) is a biomedical imaging technique that allows simultaneous structural imaging and flow monitoring inside biological tissues and materials with spatial resolution in the micrometer scale. It has recently been applied to the characterization of microfluidic systems. Structural and flow imaging of novel microfluidics platforms for cytotoxicologic applications were obtained with a real-time, Near Infrared Spectral Domain DOCT system. Characteristics such as flow homogeneity in the chamber, which is one of the most important parameters for cell culture, are investigated. OCT and DOCT images were used to monitor flow inside a specific platform that is based on microchannel division for a better flow homogeneity. In particular, the evolution of flow profile at the transition between the microchannel structure and the chamber is studied.

Faces and emotions: brain electric field sources during covert emotional processing

Covert brain activity related to task-free, spontaneous (i.e. unrequested), emotional evaluation of human face images was analysed in 27-channel averaged event-related potential (ERP) map series recorded from 18 healthy subjects while observing random sequences of face images without further instructions. After recording, subjects self-rated each face image on a scale from “liked” to “disliked”. These ratings were used to dichotomize the face images into the affective evaluation categories of “liked” and “disliked” for each subject and the subjects into the affective attitudes of “philanthropists” and “misanthropists” (depending on their mean rating across images). Event-related map series were averaged for “liked” and “disliked” face images and for “philanthropists” and “misanthropists”. The spatial configuration (landscape) of the electric field maps was assessed numerically by the electric gravity center, a conservative estimate of the mean location of all intracerebral, active, electric sources. Differences in electric gravity center location indicate activity of different neuronal populations. The electric gravity center locations of all event-related maps were averaged over the entire stimulus-on time (450 ms). The mean electric gravity center for disliked faces was located (significant across subjects) more to the right and somewhat more posterior than for liked faces. Similar differences were found between the mean electric gravity centers of misanthropists (more right and posterior) and philanthropists. Our neurophysiological findings are in line with neuropsychological findings, revealing visual emotional processing to depend on affective evaluation category and affective attitude, and extending the conclusions to a paradigm without directed task.

Impacts of out-migration on land management in mountain areas

INTRODUCTION Out-migration from mountain areas is leaving behind half families and elderly to deal with managing the land alongside daily life challenges. A potential reduction of labour force as well as expertise on cropping practices, maintenance of terraces and irrigation canals, slope stabilization, grazing, forest and other land management practices are further challenged by changing climate conditions and increased environmental threats. An understanding of the resilience of managed land resources in order to enhance adaptation to environmental and socio-economic variability, and evidence of the impact of Sustainable Land Management (SLM) on the mitigation of environmental threats have so far not sufficiently been tackled. The study presented here aims to find out how land management in mountains is being affected by migration in the context of natural hazards and climate change in two study sites, namely Quillacollo District of Bolivia and Panchase area of Western Nepal, and which measures are needed to increase resilience of livelihoods and land management practices. The presentation includes draft results from first field work periods in both sites. A context of high vulnerability According to UNISDR, vulnerability is defined as “the characteristics and circumstances of a community, system or asset that make it susceptible to the damaging effects of a hazard”.Hazards are another threat affecting people’s livelihood in mountainous area. They can be either natural or human induced. Landslides, debris flow and flood are affecting peopleGood land management can significantly reduce occurrence of hazards. In the opposite bad land management or land abandonment can lead to negative consequences on the land, and thus again increase vulnerability of people’s livelihoods. METHODS The study integrates bio-physical and socio-economic data through a case study as well as a mapping approach. From the social sciences, well-tested participatory qualitative methodologies, typically used in Vulnerability and Capacity Analyses, such as semi-structured interviews with so-called ‘key informants’, transect walks, participatory risk and social resource mapping are applied. The bio-physical analysis of the current environmental conditions determining hazards and structural vulnerability are obtained from remote sensing analysis, field work studies, and GIS analysis The assessment of the consequences of migration in the area of origin is linked with a mapping and appraisal of land management practices (www.wocat.net, Schwilch et al., 2011). The WOCAT mapping tool (WOCAT/LADA/DESIRE 2008) allows capturing the major land management practices / technologies, their spread, effectiveness and impact within a selected area. Data drawn from a variety of sources are compiled and harmonised by a team of experts, consisting of land degradation and conservation specialists working in consultation with land users from various backgrounds. The specialists’ and land users’ knowledge is combined with existing datasets and documents (maps, GIS layers, high-resolution satellite images, etc.) in workshops that are designed to build consensus regarding the variables used to assess land degradation and SLM. This process is also referred to as participatory expert assessment or consensus mapping. The WOCAT mapping and SLM documentation methodologies are used together with participatory mapping and other socio-economic data collection (interviews, questionnaires, focus group discussions, expert consultation) to combine information about migration types and land management issues. GIS and other spatial visualization tools (e.g. Google maps) will help to represent and understand these links. FIRST RESULTS Nepal In Nepal, migration is a common strategy to improve the livelihoods. Migrants are mostly men and they migrate to other Asian countries, first to India and then to the Gulf countries. Only a few women are migrating abroad. Women migrate essentially to main Nepali cities when they can afford it. Remittances are used primarily for food and education; however they are hardly used for agricultural purposes. Besides traditional agriculture being maintained, only few new practices are emerging, such as vegetable farming or agroforestry. The land abandonment is a growing consequence of outmigration, resulting in the spreading of invasive species. However, most impacts of migration on land management are not yet clear. Moreover, education is a major concern for the respondents; they want their children having a better education and get better opportunities. Linked to this, unemployment is another major concern of the respondents, which in turn is “solved” through outmigration. Bolivia Migration is a common livelihood strategy in Bolivia. In the area of study, whole families are migrating downward to the cities of the valleys or to other departments of Bolivia, especially to Chapare (tropics) for the coca production and to Santa Cruz. Some young people are migrating abroad, mostly to Argentina. There are few remittances and if those are sent to the families in the mountain areas, then they are mainly used for agriculture purpose. The impacts of migration on land management practices are not clear although there are some important aspects to be underlined. The people who move downward are still using their land and coming back during part of the week to work on it. As a consequence of this multi-residency, there is a tendency to reduce land management work or to change the way the land is used. As in Nepal, education is a very important issue in this area. There is no secondary school, and only one community has a primary school. After the 6th grade students have therefore to go down into the valley towns to study. The lack of basic education is pushing more and more people to move down and to leave the mountains. CONCLUSIONS This study is on-going, more data have to be collected to clearly assess the impacts of out-migration on land management in mountain areas. The first results of the study allow us to present a few interesting findings. The two case studies are very different, however in both areas, young people are not staying anymore in the mountains and leave behind half families and elderly to manage the land. Additionally in both cases education is a major reason for moving out, even though the causes are not always the same. More specifically, in the case of Nepal, the use of remittances underlines the fact that investment in agriculture is not the first choice of a family. In the case of Bolivia, some interesting findings showed that people continue to work on their lands even if they move downward. The further steps of the study will help to explore these interesting issues in more detail. REFERENCES Schwilch G., Bestelmeyer B., Bunning S., Critchley W., Herrick J., Kellner K., Liniger H.P., Nachtergaele F., Ritsema C.J., Schuster B., Tabo R., van Lynden G., Winslow M. 2011. Experiences in Monitoring and Assessment of Sustainable Land Management. Land Degradation & Development 22 (2), 214-225. Doi 10.1002/ldr.1040 WOCAT/LADA/DESIRE 2008. A Questionnaire for Mapping Land Degradation and Sustainable Land Management. Liniger H.P., van Lynden G., Nachtergaele F., Schwilch G. (eds), Centre for Development and Environment, Institute of Geography, University of Berne, Berne

Synchrotron x ray induced axonal transections in the brain of rats assessed by high-field diffusion tensor imaging tractography

Since approximately two thirds of epileptic patients are non-eligible for surgery, local axonal fiber transections might be of particular interest for them. Micrometer to millimeter wide synchrotron-generated X-ray beamlets produced by spatial fractionation of the main beam could generate such fiber disruptions non-invasively. The aim of this work was to optimize irradiation parameters for the induction of fiber transections in the rat brain white matter by exposure to such beamlets. For this purpose, we irradiated cortex and external capsule of normal rats in the antero-posterior direction with a 4 mm×4 mm array of 25 to 1000 µm wide beamlets and entrance doses of 150 Gy to 500 Gy. Axonal fiber responses were assessed with diffusion tensor imaging and fiber tractography; myelin fibers were examined histopathologically. Our study suggests that high radiation doses (500 Gy) are required to interrupt axons and myelin sheaths. However, a radiation dose of 500 Gy delivered by wide minibeams (1000 µm) induced macroscopic brain damage, depicted by a massive loss of matter in fiber tractography maps. With the same radiation dose, the damage induced by thinner microbeams (50 to 100 µm) was limited to their paths. No macroscopic necrosis was observed in the irradiated target while overt transections of myelin were detected histopathologically. Diffusivity values were found to be significantly reduced. A radiation dose ≤ 500 Gy associated with a beamlet size of < 50 µm did not cause visible transections, neither on diffusion maps nor on sections stained for myelin. We conclude that a peak dose of 500 Gy combined with a microbeam width of 100 µm optimally induced axonal transections in the white matter of the brain.

The Protection and Promotion of Cultural Diversity in a Digital Networked Environment : Mapping Possible Advances to Coherence

The present paper is the result of a four-year-long project examining the concept and the policies of cultural diversity and the impact of digital media upon the regulatory environment where the goal of cultural diversity is to be achieved. The focus of the project was primarily on the international level and in particular on the World Trade Organization (WTO) and the United Nations Educational Scientific and Cultural Organization (UNESCO), which also epitomise the often framed as opposing pair of trade and culture. In the broad context of the project, we sought to pinpoint the essential elements of an international trade-and-culture conducive framework that can also overcome the existing fragmentation in the field of international law and move towards more coherent solutions. In a narrower context, we sketched some possible improvements to the WTO law that can make it more suitable to the digital networked environment and to the objective of diverse media that some states aspire. . Our key messages are: (1) Neither the WTO nor UNESCO currently offers appropriate solutions to the trade and culture predicament and allows for efficient protection and promotion of cultural diversity; (2) The trade and culture discourse is overly politicised and due to the related path dependencies, a number of feasible solutions appears presently blocked; (3) The digital networked environment has profoundly changed the ways cultural content is created, distributed, accessed and consumed, and may thus offer good reasons to reassess and readjust the present models of governance; (4) Access to information appears to be the most appropriate focus of the discussions with view to protecting and promoting cultural diversity in the new digital media setting, both in local and global contexts; (5) This new focal point demands also broadening and interconnecting the policy discussions, which should go beyond the narrow scope of audiovisual media services, but cautiously account for the developments at the network and applications levels, as well as in other domains, such as most notably intellectual property rights protection; (6) There are various ways in which the WTO can be made more conducive to cultural policy considerations and these include, among others, improved and updated services classifications; enhanced legal certainty with regard to digitally transferred goods and services; incorporation of rules on subsidies for services and on competition.

Coherent control of terahertz meta-materials

We present coherent control of a THz meta-material. Specifically, we show in detail the time and frequency dependent response of a single and a double split ring resonator upon excitation with a shaped THz field. Through far- and near-field measurements, we confirm the coherence transfer from the tailored THz field to the system and back to the radiated field and we demonstrate selective excitation of a designated system resonance with a suitably shaped THz pulse.

Spatial and temporal patterns of greenness on the Yamal Peninsula, Russia: interactions of ecological and social factors affecting the Arctic normalized difference vegetation index

The causes of a greening trend detected in the Arctic using the normalized difference vegetation index (NDVI) are still poorly understood. Changes in NDVI are a result of multiple ecological and social factors that affect tundra net primary productivity. Here we use a 25 year time series of AVHRR-derived NDVI data (AVHRR: advanced very high resolution radiometer), climate analysis, a global geographic information database and ground-based studies to examine the spatial and temporal patterns of vegetation greenness on the Yamal Peninsula, Russia. We assess the effects of climate change, gas-field development, reindeer grazing and permafrost degradation. In contrast to the case for Arctic North America, there has not been a significant trend in summer temperature or NDVI, and much of the pattern of NDVI in this region is due to disturbances. There has been a 37% change in early-summer coastal sea-ice concentration, a 4% increase in summer land temperatures and a 7% change in the average time-integrated NDVI over the length of the satellite observations. Gas-field infrastructure is not currently extensive enough to affect regional NDVI patterns. The effect of reindeer is difficult to quantitatively assess because of the lack of control areas where reindeer are excluded. Many of the greenest landscapes on the Yamal are associated with landslides and drainage networks that have resulted from ongoing rapid permafrost degradation. A warming climate and enhanced winter snow are likely to exacerbate positive feedbacks between climate and permafrost thawing. We present a diagram that summarizes the social and ecological factors that influence Arctic NDVI. The NDVI should be viewed as a powerful monitoring tool that integrates the cumulative effect of a multitude of factors affecting Arctic land-cover change.

Territorial Cohesion through Spatial Policies: An Analysis with Cultural Theory and Clumsy Solutions

The European Territorial Cohesion Policy has been the subject of numerous debates in recent years. Most contributions focus on understanding the term itself and figuring out what is behind it, or arguing for or against a stronger formal competence of the European Union in this field. This article will leave out these aspects and pay attention to (undefined and legally non-binding) conceptual elements of territorial cohesion, focusing on the challenge of linking it within spatial policies and organising the relations. Therefore, the theoretical approach of Cultural Theory and its concept of clumsy solution are applied to overcome the dilemma of typical dichotomies by adding a third and a fourth (but not a fifth) perspective. In doing so, normative contradictions between different rational approaches can be revealed, explained and approached with the concept of ‘clumsy solutions’. This contribution aims at discussing how this theoretical approach helps us explain and frame a coalition between the Territorial Cohesion Policy and spatial policies. This approach contributes to finding the best way of linking and organising policies, although the solution might be clumsy according to the different rationalities involved.