Renal Involvement in Systemic Sclerosis

Scleroderma renal crisis (SRC) is classical renal disease in systemic sclerosis (SSc). SRC is a relatively rare manifestation, approximately in 5% of patients. In terms of severity, manifestation in the form of SRC is the most common cause of acute organ failure. In SSc patients, SRC is defined as a new onset of accelerated arterial hypertension and rapidly progressive anuric or oliguric renal failure. SRC is primarily vascular injury with increased activity of the renin-angiotensin activity. These events lead to release or activation of cytokines and growth factors that result in the typical proliferative vascular lesions. Successful approach is routine use of angiotensin-converting enzyme inhibitors in the treatment of SRC (except prevention) and other advances in renal replacement therapy in SSc management. It is crucial to detect manifestations of SRC early and to manage appropriately in collaboration with intensive care medicine, cardiologists, and nephrologists. In contrast to SRC, clinical presentation of interstitial renal disease is poor, often without evidence of renal abnormality. Interestingly, other renal manifestations are glomerulonephritis and vasculitis. These manifestations are associated with overlapping mechanisms. The objective of this chapter is to focus on actual knowledge about the renal involvement in SSc and current treatment principles and possibilities

Landscape fragmentation in Europe. Joint EEA-FOEN report. EEA Report No 2/2011.

Landscape fragmentation in Europe Landscape fragmentation caused by transportation infrastructure and built-up areas has a number of ecological effects. It contributes significantly to the decline and loss of wildlife populations and to the increasing endangerment of species in Europe, for example through the dissection and isolation of populations, and affects the water regime and the recreational quality of landscapes. In spite of the planning concept of preserving large unfragmented areas, fragmentation has continued to increase during the last 20 years, and many more new transportation infrastructure projects are planned, in particular in eastern Europe, which will further increase the level of landscape fragmentation significantly. Therefore, data on the degree of landscape fragmentation are needed that are suitable for comparing different regions, especially in relation to different natural landscape types and different socioeconomic conditions. This report quantitatively investigates the degree of landscape fragmentation in 28 countries in Europe for the first time for three different fragmentation geometries at three levels. The three levels include countries, regions (NUTS-X, according to the Nomenclature of Statistical Territorial Units), and a grid of 1 km2 cells (LEAC grid, which is used for Land and Ecosystem Accounting activities). The report applies the method of 'effective mesh density' which quantifies the degree to which the possibilities for movement of wildlife in the landscape are interrupted by barriers. The effective mesh density values across the 28 investigated countries cover a large range, from low values in large parts of Scandinavia to very high values in western and central Europe. Many highly fragmented regions are located in Belgium, the Netherlands, Denmark, Germany, France, Poland and the Czech Republic. High fragmentation values are mostly found in the vicinity of large urban areas and along major transportation corridors. The lowest levels of fragmentation are usually associated with mountain ranges or remoteness. Fragmentation geometry B2 'Fragmentation of non-mountainous land areas' which includes highways up to class 4, railways and urban areas, is the most important fragmentation geometry, as it is suitable for comparing regions with differing geographical conditions like different amounts of mountains or lakes; it also encompasses the most complete set of physical barriers that may affect a large number of species. Predictive models of landscape fragmentation In the second part, this report investigates potential causes that contribute to an increased or decreased degree of landscape fragmentation and determines their relative importance. The density of the transportation network and the extent of landscape fragmentation are largely a function of interacting socioeconomic drivers such as population density and geophysical factors such as topography. Current levels of landscape fragmentation need to be interpreted within the context of these regional socioeconomic and geophysical conditions. Therefore, this report applies a set of statistical models to determine which of these factors drive the process of landscape fragmentation in Europe. We analysed the statistical relationships between landscape fragmentation and a range of predictive variables, applied these relationships to predict the likely fragmentation values for all regions in our study area, and compared actual values with predicted values. In general, the most relevant variables affecting landscape fragmentation were population density, gross domestic product per capita, volume passenger density, and the quantity of goods loaded and unloaded per capita. The amount of variation in the level of fragmentation that was explained by the predictor variables was high, ranging from 46 % to 91 % in different parts of Europe. The statistical relationships indicated that different drivers of landscape fragmentation are important in different parts of Europe. Efforts for curtailing landscape fragmentation should take these differences into account. Relevance for monitoring systems and policymaking The results demonstrate that there is an urgent need for action. Large discrepancies between predicted and observed fragmentation values provide a basis for identifying areas for prioritising management action. Such data also provide a starting point for scenarios for the future development of landscape fragmentation in Europe. There is an increasing need and interest in including indicators of landscape fragmentation in monitoring systems of sustainable development, biodiversity, and landscape quality. We recommend that the results presented in this report be used for this purpose and be updated on a regular basis to detect trends in the development of landscape fragmentation. Therefore, this report discusses the use of fragmentation analysis presented in this report as a tool for performance review in transportation planning and regional planning and recommends a set of measures to control landscape fragmentation, such as more effective protection of remaining unfragmented areas and wildlife corridors, the setting of targets and limits and a European defragmentation strategy. This study provides for the first time an accurate measurement of landscape fragmentation for most of the European continent, which supports managers and policymakers in allocating resources towards the protection and restoration of biodiversity and landscape quality. The report also identifies future research needs

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes

Urban Sprawl in Europe. Joint EEA-FOEN report. No 11/2016.

Executive summary Urban sprawl is associated with a number of ecological, economic and social effects. Some of these relate to people's desires, for example, to live in single-family homes with gardens. However, urban sprawl has detrimental and long-lasting effects. For example, urban sprawl contributes significantly to the loss of fertile farmland, to soil sealing and to the loss of ecological soil functions. The increase in built-up areas reduces the size of wildlife habitats and increases landscape fragmentation and the spread of invasive species. Urban sprawl leads to higher greenhouse gas emissions, higher infrastructure costs for transport, water and electrical power, the loss of open landscapes, and the degradation of various ecosystem services. Despite various efforts to address this problem, urban sprawl has increased rapidly in Europe in recent decades. Thus, urban sprawl presents a major challenge with regard to sustainable land use, as the International Year of Soils 2015 highlighted. Sprawl is a result not only of population growth but also of lifestyles that take up more space. Accordingly, urban sprawl has increased even in regions with a declining human population. Many more urban development and transport infrastructure projects are planned for the future, in particular in the European Union (EU) Member States which joined after 2004. Consequently, further increases in urban sprawl in the future will be significant. Therefore, consistent data on the degree of urban sprawl are needed, particularly data that are suitable for the comparison of regions across Europe. This report investigates the degree of urban sprawl in 32 countries in Europe by considering two points in time (2006 and 2009) at three levels. The three levels include the country level, the NUTS-2 region level (based on the Nomenclature of Territorial Units for Statistics (NUTS)) and the 1-km2 cell level (based on the Land and Ecosystem Accounting (LEAC) grid). The comparison of two points in time allowed an assessment of temporal changes in urban sprawl. This report applies the method of 'weighted urban proliferation' (WUP), which quantifies the degree of urban sprawl for any given landscape through a combination of three components: (1) the size of the built-up areas; (2) the spatial configuration (dispersion) of the built-up areas in the landscape; and (3) the uptake of built-up area per inhabitant or job. The report provides, for the first time, an assessment of urban sprawl in all EU and European Free Trade Association (EFTA) countries using the WUP method. The urban sprawl values obtained cover a large range, from low values for large parts of Scandinavia ( 4 UPU/m2) and very high values for large parts of western and central Europe (> 6 UPU/m2). The two largest clusters of high-sprawl values in Europe are located in (1) north-eastern France, Belgium, the Netherlands and part of western Germany; and (2) in the United Kingdom between London and the Midlands. The analysis of sprawl at the 1-km2-grid level shows that sprawl is most pronounced in wide rings around city centres, along large transport corridors, and along many coastlines (particularly in the Mediterranean countries). The lowest levels of sprawl are mainly associated with mountain ranges or remote areas. The level of sprawl, as measured by WUP, increased in all European countries between 2006 and 2009. The overall WUP value for Europe (all 32 countries combined) increased from 1.56 urban permeation units (UPU)/m2 in 2006 to 1.64 UPU/m2 in 2009, that is by 5 % in 3 years or by 1.7 % per year. In most countries, the increase was higher than 1 % per year, and in many countries WUP increased by more than 2 % per year. This was also the case for most NUTS-2 regions. Future studies using additional time-points will allow more detailed temporal comparisons. Base data for 2012 will be available in 2016 and these could be analysed in a follow-up project. Driving forces and predictive models of urban sprawl The level of urban sprawl is largely a function of socio-economic and demographic drivers, and the geophysical context. Current levels of urban sprawl need to be interpreted within the context of regional socio-economic and geophysical conditions. Therefore, the second part of this study investigated the potential factors that may contribute to an increase or decrease in the degree of urban sprawl, and determined their relative importance. The report applied a set of statistical models to determine which of these factors drive the process of urban sprawl in Europe. We analysed the statistical relationships between urban sprawl and a range of explanatory variables (14 variables at the country level and 12 at the NUTS-2 level). We also applied these relationships to predict the expected sprawl values for all regions in our study area and compared actual values with predicted values. Most of our hypotheses about the likely driving forces of urban sprawl were confirmed by the statistical analyses. The relevant variables identified as affecting urban sprawl are population density, road density, railway density, household size, governmental effectiveness, the number of cars per 1 000 inhabitants and two environmental factors (i.e. net primary production and relief energy). This result was consistent for both of the years (2006 and 2009) considered in the analysis. The results indicate that economic development has, largely, not been decoupled from increases in urban sprawl. A high amount of variation in the level of urban sprawl, as measured by WUP, was explained by the predictor variables: 72–80 % at the country level and 80–81 % at the NUTS-2 level. The variation explained for the three components of WUP ranged between 67 % and 94 % at the NUTS-2 level. Efforts to control urban sprawl should take these driving forces into account. Relevance for monitoring and policymaking The results provided by this study are intended to contribute to more sustainable political decision- making and planning throughout Europe. In the last 15 years (2000–2015), several projects and programmes at the European level have proposed a suite of concepts and measures to address urban sprawl and promote more sustainable land use. The most recent (2014), and perhaps most important, of these is the Seventh Environment Action Programme (7EAP), which calls for indicators of resource efficiency to be established in order to guide public and private decision-makers. Although the urgent challenge presented by urban sprawl has been recognised, there is still no monitoring in place for European urban sprawl. This report aims to help close this gap. The results confirm the conclusion of earlier reports (e.g. EEA, 2006a; EEA, 2006b) namely that there is an increasingly urgent need for action. Large discrepancies between the predicted and observed levels of urban sprawl provide a basis for identifying areas for prioritising management action. Our data also provide a basis for scenarios regarding the future development of urban sprawl in Europe. There is an increasing need and interest in including indicators of urban sprawl in systems for monitoring sustainable development, the state of the environment, biodiversity and landscape quality. The results presented in this report are intended for this purpose and can be updated on a regular basis in order to detect trends in urban sprawl. This report also demonstrates the usefulness of the WUP method as a tool for urban and regional planning and for performance review based on benchmarks, targets and limits. This study provides a comparable measurement of urban sprawl for most of the European continent using a consistent data set across Europe. The results will support managers and policymakers with the allocation of resources for the better protection of agricultural soils and landscape quality, and more sustainable political decision-making related to land use. The report also identifies the most immediate priorities and future research needs

Annexes 1-5: Urban Sprawl in Europe. Joint EEA-FOEN report. No 11/2016.

See main report "Urban Sprawl in Europe. Joint EEA-FOEN report"

Zersiedelung in Europa: Ländervergleich und treibende Kräfte. (Urban sprawl in Europe: Comparison of countries and driving forces.)

Steigende Zersiedelung steht im Widerspruch zu den Prinzipien und dem Geist von Nachhaltigkeit. Daten zur Zersiedelung werden benötigt, um die Wirksamkeit von Maßnahmen und Verordnungen zu überprüfen, welche die Zersiedelung begrenzen sollen. Die Autoren haben die Methode der „gewichteten Zersiedelung“ (Weighted Urban Proliferation, WUP) auf 32 Länder in Europa angewendet, um die Zersiedelung zu messen. Dazu wurden die europäischen HRL-Imperviousness-Daten von 2006 und 2009 verwendet. Die Ergebnisse zeigen, dass große Teile Europas von Zersiedelung betroffen sind. Der Gesamtwert von WUP für Europa beträgt 1,64 Durchsiedlungseinheiten/m2 (2009). Er ist zwischen 2006 und 2009 deutlich angestiegen, aber die Werte der einzel- nen Länder unterscheiden sich stark voneinander. Außerdem wurde der Zusammenhang mit zwölf potenziellen Treibern der Zersiedelung statistisch untersucht. Dieses Projekt ist die erste Analyse der Zersiedelung und ihrer zeitlichen Veränderung für einen gesamten Kontinent mit WUP. Der Beitrag stellt erste Ergebnisse vor und weist auf die Veröffentlichungen hin, die derzeit in Vorbereitung sind

Copernicus for urban resilience in Europe

The urban community faces a significant obstacle in effectively utilising Earth Observation (EO) intelligence, particularly the Copernicus EO program of the European Union, to address the multifaceted aspects of urban sustainability and bolster urban resilience in the face of climate change challenges. In this context, here we present the efforts of the CURE project, which received funding under the European Union’s Horizon 2020 Research and Innovation Framework Programme, to leverage the Copernicus Core Services (CCS) in supporting urban resilience. CURE provides spatially disaggregated environmental intelligence at a local scale, demonstrating that CCS can facilitate urban planning and management strategies to improve the resilience of cities. With a strong emphasis on stakeholder engagement, CURE has identified eleven cross-cutting applications between CCS that correspond to the major dimensions of urban sustainability and align with user needs. These applications have been integrated into a cloud-based platform known as DIAS (Data and Information Access Services), which is capable of delivering reliable, usable and relevant intelligence to support the development of downstream services towards enhancing resilience planning of cities throughout Europe

Telomere Attrition Occurs during Ex Vivo Expansion of Human Dental Pulp Stem Cells

We provide a detailed characteristic of stem cells isolated and expanded from the human dental pulp. Dental pulp stem cells express mesenchymal cell markers STRO-1, vimentin, CD29, CD44, CD73, CD90, CD166, and stem cell markers Sox2, nestin, and nucleostemin. They are multipotent as shown by their osteogenic and chondrogenic potential. We measured relative telomere length in 11 dental pulp stem cell lines at different passages by quantitative real-time PCR. Despite their large proliferative capacity, stable viability, phenotype, and genotype over prolonged cultivation, human dental pulp stem cells suffer from progressive telomere shortening over time they replicate in vitro. Relative telomere length (T/S) was inversely correlated with cumulative doubling time. Our findings indicate that excessive ex vivo expansion of adult stem cells should be reduced at minimum to avoid detrimental effects on telomere maintenance and measurement of telomere length should become a standard when certificating the status and replicative age of stem cells prior therapeutic applications

Development of submicromolar 17β-HSD10 inhibitors and their in vitro and in vivo evaluation

Funding: This study was supported by the Ministry of Education, Youth, and Sports of the Czech Republic (project ESF no. CZ.02.1.01/0.0/0.0/18_069/0010054), by the University of Hradec Kralove (Faculty of Science, no. SV2103‐2022), by Charles University, Prague, Czech Republic (project Cooperatio, research area Neurosciences), by the project MH CZ-DRO VFN64165, and by MH CZ - DRO (UHHK, 00179906), by the Ministry of Defence of the Czech Republic (Faculty of Military Health Sciences Hradec Kralove) under the grant entitled the “Long-term organization development plan - Medical Aspects of Weapons of Mass Destruction”, and by the RS MacDonald Charitable Trust and Rosetrees Trust.17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial enzyme and putative drug target for the treatment of various pathologies including Alzheimer's disease or some types of hormone-dependent cancer. In this study, a series of new benzothiazolylurea-based inhibitors were developed based on the structure-activity relationship (SAR) study of previously published compounds and predictions of their physico-chemical properties. This led to the identification of several submicromolar inhibitors (IC50 ∼0.3 μM), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17β-HSD10 was further confirmed by differential scanning fluorimetry and the best molecules were found to be cell penetrable. In addition, the best compounds weren't found to have additional effects for mitochondrial off-targets and cytotoxic or neurotoxic effects. The two most potent inhibitors 9 and 11 were selected for in vivo pharmacokinetic study after intravenous and peroral administration. Although the pharmacokinetic results were not fully conclusive, it seemed that compound 9 was bioavailable after peroral administration and could penetrate into the brain (brain-plasma ratio 0.56).Peer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field