TRANSCRIPTIONAL AND POST-TRANSLATIONAL MECHANISMS CONTRIBUTE TO MAINTENANCE OF REST IN NEURAL TUMORS

The RE-1 silencing transcription factor (REST) is an important regulator of normal nervous system development. It negatively regulates neuronal lineage specification in neural progenitors by binding to its consensus RE-1 element(s) located in the regulatory region of its target neuronal differentiation genes. The developmentally coordinated down-regulation of REST mRNA and protein in neural progenitors triggers terminal neurogenesis. REST is overexpressed in pediatric neural tumors such as medulloblastoma and neuroblastoma and is associated with poor neuronal differentiation. High REST protein correlate with poor prognosis for patients with medulloblastoma, however similar studies have not been done with neuroblastoma patients. Mechanism(s) underlying elevated REST levels medulloblastoma and neuroblastoma are unclear, and is the focus of this thesis project. We discovered that transcriptional and post-translational mechanisms govern REST mis-regulation in medulloblastoma and neuroblastoma. In medulloblastoma, REST transcript is aberrantly elevated in a subset of patient samples. Using loss of function and gain of function experiments, we provide evidence that the Hairy Enhancer of Split (HES1) protein represses REST transcription in medulloblastoma cell lines, modulates the expression of neuronal differentiation genes, and alters the survival potential of these cells in vitro. We also show that REST directly represses its own expression in an auto-regulatory feedback loop. Interestingly, our studies identified a novel interaction between REST and HES1. We also observed their co-occupancy at the RE-1 sites, thereby suggesting potential for co-regulation of REST expression. Our pharmacological studies in neuroblastoma using retinoic acid revealed that REST levels are controlled by transcriptional and post-transcriptional mechanisms. Post-transcriptional mechanisms are mediated by modulation of E3 ligase or REST, SCFβ-TRCP, and contribute to resistance of some cells to retinoic acid treatment.

Signaling pathways in the transcriptional and post-translational regulation of the human glutathione S -transferase P1 gene

The human glutathione S-transferase P1 (GSTP1) protein is an endogenous inhibitor of c-jun N-terminal kinases (JNKs) and an important phase II detoxification enzyme. ^ Recent identification of a cAMP response element (CRE) in the 5 ′-region of the human GSTP1 gene and several putative phosphorylation sites for the Ser/Thr protein kinases, including, cAMP-dependent protein kinases (PKAs), protein kinases C (PKCs), and JNKs in the GSTP1 protein raised the possibility that signaling pathways may play an important role in the transcriptional and post-translational regulation of GSTP1 gene. This study examined (a) whether the signaling pathway mediated by CAMP, via the GSTP1 CRE, is involved in the transcriptional regulation of the GSTP1 gene, (b) whether signaling pathways mediated by the Ser/Thr protein kinases (PKAs, PKCs, and JNKs) induce post-translational modification, viz. phosphorylation of the GSTP1 protein, and (c) whether such phosphorylation of the GSTP1 protein alters its functions in metabolism and in JNK signaling. ^ The first major finding in this study is the establishment of the human GSTP1 gene as a novel CAMP responsive gene in which transcription is activated via an interaction between PKA activated CRE binding protein-1 (CREB-1) and the CRE in the 5′-regulatory region. ^ The second major finding in this study is the observation that the GSTP1 protein undergoes phosphorylation and functionally activated by second messenger-activated protein kinases, PKA and PKC, in tumor cells with activated signaling pathways. Following phosphorylation by PKA or PKC, the catalytic activity of the GSTP1 protein was significantly enhanced, as indicated by a decrease in its Km (2- to 3.6-fold) and an increase in Kcat/ Km (1.6- to 2.5-fold) for glutathione. Given the frequent over-expression of GSTP1 and the aberrant PKA/PKC signaling cascade observed in tumors, these findings suggest that phosphorylation of GSTP1 may contribute to the malignant progression and drug-resistant phenotype of these tumors. ^ The third major finding in this study is that the GSTP1 protein, an inhibitor of JNKs, undergoes significant phosphorylation in tumor cells with activated JNK signaling pathway and in those under oxidative stress. Following phosphorylation by JNK, the ability of GSTP1 to inhibit JNK downstream function, i.e. c-jun phosphorylation, was significantly enhanced, suggesting a feedback mechanism of regulation of JNK-mediated cellular signaling. (Abstract shortened by UMI.) ^

Mid-Wisconsin to Holocene permafrost and landscape dynamics based on a drained lake basin core from the northern Seward Peninsula, Northwest Alaska

Permafrost-related processes drive regional landscape dynamics in the Arctic terrestrial system. A better understanding of past periods indicative of permafrost degradation and aggradation is important for predicting the future response of Arctic landscapes to climate change. Here, we used a multi-proxy approach to analyze a ~4 m long sediment core from a drained thermokarst lake basin on the northern Seward Peninsula in western Arctic Alaska (USA). Sedimentological, biogeochemistical, geochronological, micropaleontological (ostracoda, testate amoeba) and tephra analyses were used to determine the long-term environmental Early-Wisconsin to Holocene history preserved in our core for Central Beringia. Yedoma accumulation dominated throughout the Early to Late-Wisconsin but was interrupted by wetland formation from 44.5 to 41.5 ka BP. The latter was terminated by deposition of 1 m of volcanic tephra, most likely originating from the South Killeak Maar eruption at about 42 ka BP. Yedoma deposition continued until 22.5 ka BP and was followed by a depositional hiatus in the sediment core between 22.5 and 0.23 ka BP. We interpret this hiatus as due to intense thermokarst activity in the areas surrounding the site, which served as a sediment source during the Late-Wisconsin to Holocene climate transition. The lake forming the modern basin on the upland initiated around 0.23 ka BP, which drained catastrophically in spring 2005. The present study emphasizes that Arctic lake systems and periglacial landscapes are highly dynamic and permafrost formation as well as degradation in Central Beringia was controlled by regional to global climate patterns and as well as by local disturbances.

Robust trends of landscape dynamics in the Arctic Lena Delta with temporally dense Landsat time-series stacks, with links to GeoTIFFs

Arctic permafrost landscapes are among the most vulnerable and dynamic landscapes globally, but due to their extent and remoteness most of the landscape changes remain unnoticed. In order to detect disturbances in these areas we developed an automated processing chain for the calculation and analysis of robust trends of key land surface indicators based on the full record of available Landsat TM, ETM +, and OLI data. The methodology was applied to the ~ 29,000 km**2 Lena Delta in Northeast Siberia, where robust trend parameters (slope, confidence intervals of the slope, and intercept) were calculated for Tasseled Cap Greenness, Wetness and Brightness, NDVI, and NDWI, and NDMI based on 204 Landsat scenes for the observation period between 1999 and 2014. The resulting datasets revealed regional greening trends within the Lena Delta with several localized hot-spots of change, particularly in the vicinity of the main river channels. With a 30-m spatial resolution various permafrost-thaw related processes and disturbances, such as thermokarst lake expansion and drainage, fluvial erosion, and coastal changes were detected within the Lena Delta region, many of which have not been noticed or described before. Such hotspots of permafrost change exhibit significantly different trend parameters compared to non-disturbed areas. The processed dataset, which is made freely available through the data archive PANGAEA, will be a useful resource for further process specific analysis by researchers and land managers. With the high level of automation and the use of the freely available Landsat archive data, the workflow is scalable and transferrable to other regions, which should enable the comparison of land surface changes in different permafrost affected regions and help to understand and quantify permafrost landscape dynamics.

The Landscape of Ontology Reuse in Linked Data

Abstract. The uptake of Linked Data (LD) has promoted the proliferation of datasets and their associated ontologies for describing different domains. Ac-cording to LD principles, developers should reuse as many available terms as possible to describe their data. Importing ontologies or referring to their terms’ URIs are the two main ways to reuse knowledge from available ontologies. In this paper, we have analyzed 18589 terms appearing within 196 ontologies in-cluded in the Linked Open Vocabularies (LOV) registry with the aim of under-standing the current state of ontology reuse in the LD context. In order to char-acterize the landscape of ontology reuse in this context, we have extracted sta-tistics about currently reused elements, calculated ratios for reuse, and drawn graphs about imports and references between ontologies. Keywords: ontology, vocabulary, reuse, linked data, ontology import

Translational research combining orthologous genes and human diseases with the OGOLOD dataset

OGOLOD is a Linked Open Data dataset derived from different biomedical resources by an automated pipeline, using a tailored ontology as a scaffold. The key contribution of OGOLOD is that it links, in new RDF triples, genetic human diseases and orthologous genes, paving the way for a more efficient translational biomedical research exploiting the Linked Open Data cloud.

Teaching in Landscape

“We, the landscape architects, concerned with the future development of our landscapes in a fast changing world, believe that everything, influencing the way in which the outdoor environment is created, used, and maintained is fundamental to sustainable development and human well-being. We, being responsible for the improvement of the education of future landscape architects to enable them to work for a sustainable environment within the context of our natural and cultural heritage”. (IFLA/UNESCO 2005) CHARTER FOR LANDSCAPE ARCHITECTURAL EDUCATION) Nowadays, respect and appreciation of the landscape sustainably grow. Landscape Architecture professionals are makers encourage and guide this growth. However, there is still no legal recognition of the landscape profession in Spain. For this reason we present this paper that shows the current framework in which appear a professional educated with masters and specialized courses, but it lacks a defined work area and unique in its business learned. We present the demands of both IFLA and the EFLA and teaching lines proposed by these organizations at European level are distinguished. Furthermore, we analyze the national scene and major training centres are distinguished.

Assessing the landscape value of public works: validation of the method in the lowlands of the middle section of the Tajo river (Spain)

This paper proposes a method of landscape characterisation and assessment of public works associated with fluvial landscapes, which is validated in the middle section of the Tajo River. In this method, a set of criteria is identified that unifies various characteristics of the landscape associated to the infrastructures. A specific weight is then assigned to each criterion in such a way as to produce a semi-quantitative value ranging from a minimum value of 0 to a maximum value of 10. Taken together, these criteria enable us to describe and assess the value of the public works selected for study, in this case helping us to evaluate the sections of the River Tajo analysed in our study area. Accordingly, the value of all the infrastructures associated to a stretch of the river covering several hundred kilometres was determined and after dividing this stretch into sections, they were compared under equivalent conditions to provide a hierarchal ranking.

Mapping the visual landscape quality in Europe using physical attributes

he inclusion of environmental care data in the decision-making process should be based on the results obtained after scienti?cally evaluating different environmental variables. Herein, a European landscape geographic model is presented. This landscape map would allow the environmental care variable ?visual landscape?, along with other information related to vegetation, geology, soils, cultural variables, etc., to be integrated into the planning process. The methodology used is not new since it has already been tested in Spain by the authors. Nevertheless, the model was adapted to cope with the much more extensive territory of the European Union. This meant dealing with computational dif?culties, and a lack of information. The result of this work is a raster map (100 m cell size) that evaluates landscape quality in Europe by dividing the area into seven visual quality classes. This is a practical tool for territorial development that will facilitate the environmental assessment of plans, such as infrastructure plans, within a strategic pan-European framework.

The Current Landscape of Pitfalls in Ontologies

A growing number of ontologies are already available thanks to development initiatives in many different fields. In such ontology developments, developers must tackle a wide range of difficulties and handicaps, which can result in the appearance of anomalies in the resulting ontologies. Therefore, ontology evaluation plays a key role in ontology development projects. OOPS! is an on-line tool that automatically detects pitfalls, considered as potential errors or problems, and thus may help ontology developers to improve their ontologies. To gain insight in the existence of pitfalls and to assess whether there are differences among ontologies developed by novices, a random set of already scanned ontologies, and existing well-known ones, data of 406 OWL ontologies were analysed on OOPS!’s 21 pitfalls, of which 24 ontologies were also examined manually on the detected pitfalls. The various analyses performed show only minor differences between the three sets of ontologies, therewith providing a general landscape of pitfalls in ontologies.

Understanding landscape and the values of traditional architecture and construction

Ponencia presentada en el congreso internacional organizado por el Comité Internacional de Arquitectura Vernácula de ICOMOS - UNESCO.

Estimation of nitrogen budgets for contrasting catchments at the landscape scale.

A comprehensive assessment of nitrogen (N) flows at the landscape scale is fundamental to understand spatial interactions in the N cascade and to inform the development of locally optimised N management strategies. To explore these interactions, complete N budgets were estimated for two contrasting hydrological catchments (dominated by agricultural grassland vs. semi-natural peat-dominated moorland), forming part of an intensively studied landscape in southern Scotland. Local scale atmospheric dispersion modelling and detailed farm and field inventories provided high resolution estimations of input fluxes. Direct agricultural inputs (i.e. grazing excreta, N2 fixation, organic and synthetic fertiliser) accounted for most of the catchment N inputs, representing 82% in the grassland and 62% in the moorland catchment, while atmospheric deposition made a significant contribution, particularly in the moorland catchment, contributing 38% of the N inputs. The estimated catchment N budgets highlighted areas of key uncertainty, particularly N2 exchange and stream N export. The resulting N balances suggest that the study catchments have a limited capacity to store N within soils, vegetation and groundwater. The "catchment N retention", i.e. the amount of N which is either stored within the catchment or lost through atmospheric emissions, was estimated to be 13% of the net anthropogenic input in the moorland and 61% in the grassland catchment. These values contrast with regional scale estimates: Catchment retentions of net anthropogenic input estimated within Europe at the regional scale range from 50% to 90%, with an average of 82% (Billen et al., 2011). This study emphasises the need for detailed budget analyses to identify the N status of European landscapes.

Heterogeneity of atmosfpheric ammonia at the landscape scale and consequences for environmental impact assessment.

We examined the consequences of the spatial heterogeneity of atmospheric ammonia (NH3) by measuring and modelling NH3 concentrations and deposition at 25 m grid resolution for a rural landscape containing intensive poultry farming, agricultural grassland, woodland and moorland. The emission pattern gave rise to a high spatial variability of modelled mean annual NH3 concentrations and dry deposition. Largest impacts were predicted for woodland patches located within the agricultural area, while larger moorland areas were at low risk, due to atmospheric dispersion, prevailing wind direction and low NH3 background. These high resolution spatial details are lost in national scale estimates at 1 km resolution due to less detailed emission input maps. The results demonstrate how the spatial arrangement of sources and sinks is critical to defining the NH3 risk to semi-natural ecosystems. These spatial relationships provide the foundation for local spatial planning approaches to reduce environmental impacts of atmospheric NH3.