Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis

In many human carcinomas, expression of the lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) correlates with up-regulated lymphangiogenesis and regional lymph node metastasis. Here, we have used the Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis to investigate the functional role of VEGF-D in the induction of lymphangiogenesis and tumor progression. Expression of VEGF-D in beta cells of single-transgenic Rip1VEGF-D mice resulted in the formation of peri-insular lymphatic lacunae, often containing leukocyte accumulations and blood hemorrhages. When these mice were crossed to Rip1Tag2 mice, VEGF-D-expressing tumors also exhibited peritumoral lymphangiogenesis with lymphocyte accumulations and hemorrhages, and they frequently developed lymph node and lung metastases. Notably, tumor outgrowth and blood microvessel density were significantly reduced in VEGF-D-expressing tumors. Our results demonstrate that VEGF-D induces lymphangiogenesis, promotes metastasis to lymph nodes and lungs, and yet represses hemangiogenesis and tumor outgrowth. Because a comparable transgenic expression of vascular endothelial growth factor-C (VEGF-C) in Rip1Tag2 has been shown previously to provoke lymphangiogenesis and lymph node metastasis in the absence of any distant metastasis, leukocyte infiltration, or angiogenesis-suppressing effects, these results reveal further functional differences between VEGF-D and VEGF-C.

Direct and indirect associations between plant species richness and productivity in grasslands: regional differences preclude simple generalization of productivity-biodiversity relationships

Plant species richness of permanent grasslands has often been found to be significantly associated with productivity. Concentrations of nutrients in biomass can give further insight into these productivity- plant species richness relationships, e.g. by reflecting land use or soil characteristics. However, the consistency of such relationships across different regions has rarely been taken into account, which might significantly compromise our potential for generalization. We recorded plant species richness and measured above-ground biomass and concentrations of nutrients in biomass in 295 grasslands in three regions in Germany that differ in soil and climatic conditions. Structural equation modelling revealed that nutrient concentrations were mostly indirectly associated with plant species richness via biomass production. However, negative associations between the concentrations of different nutrients and biomass and plant species richness differed considerably among regions. While in two regions, more than 40% of the variation in plant species richness could be attributed to variation in biomass, K, P, and to some degree also N concentrations, in the third region only 15% of the variation could be explained in this way. Generally, highest plant species richness was recorded in grasslands where N and P were co-limiting plant growth, in contrast to N or K (co-) limitation. But again, this pattern was not recorded in the third region. While for two regions land-use intensity and especially the application of fertilizers are suggested to be the main drivers causing the observed negative associations with productivity, in the third region the little variance accounted for, low species richness and weak relationships implied that former intensive grassland management, ongoing mineralization of peat and fluctuating water levels in fen grasslands have overruled effects of current land-use intensity and productivity. Finally, we conclude that regional replication is of major importance for studies seeking general insights into productivity-diversity relationships.

Tree growth response along an elevational gradient: climate or genetics?

Environment and genetics combine to influence tree growth and should therefore be jointly considered when evaluating forest responses in a warming climate. Here, we combine dendroclimatology and population genetic approaches with the aim of attributing climatic influences on growth of European larch (Larix decidua) and Norway spruce (Picea abies). Increment cores and genomic DNA samples were collected from populations along a ~900-m elevational transect where the air temperature gradient encompasses a ~4 °C temperature difference. We found that low genetic differentiation among populations indicates gene flow is high, suggesting that migration rate is high enough to counteract the selective pressures of local environmental variation. We observed lower growth rates towards higher elevations and a transition from negative to positive correlations with growing season temperature upward along the elevational transect. With increasing elevation there was also a clear increase in the explained variance of growth due to summer temperatures. Comparisons between climate sensitivity patterns observed along this elevational transect with those from Larix and Picea sites distributed across the Alps reveal good agreement, and suggest that tree-ring width (TRW) variations are more climate-driven than genetics-driven at regional and larger scales. We conclude that elevational transects are an extremely valuable platform for understanding climatic-driven changes over time and can be especially powerful when working within an assessed genetic framework.

Socioeconomic, Temporal and Regional Variation in Body Mass Index among 188,537 Swiss Male Conscripts Born between 1986 and 1992

BACKGROUND Rising levels of overweight and obesity are important public-health concerns worldwide. The purpose of this study is to elucidate their prevalence and trends in Switzerland by analyzing variations in Body Mass Index (BMI) of Swiss conscripts. METHODS The conscription records were provided by the Swiss Army. This study focussed on conscripts 18.5-20.5 years of age from the seven one-year birth cohorts spanning the period 1986-1992. BMI across professional status, area-based socioeconomic position (abSEP), urbanicity and regions was analyzed. Two piecewise quantile regression models with linear splines for three birth-cohort groups were used to examine the association of median BMI with explanatory variables and to determine the extent to which BMI has varied over time. RESULTS The study population consisted of 188,537 individuals. Median BMI was 22.51 kg/m2 (22.45-22.57 95% confidence interval (CI)). BMI was lower among conscripts of high professional status (-0.46 kg/m2; 95% CI: -0.50, -0.42, compared with low), living in areas of high abSEP (-0.11 kg/m2; 95% CI: -0.16, -0.07 compared to medium) and from urban communities (-0.07 kg/m2; 95% CI: -0.11, -0.03, compared with peri-urban). Comparing with Midland, median BMI was highest in the North-West (0.25 kg/m2; 95% CI: 0.19-0.30) and Central regions (0.11 kg/m2; 95% CI: 0.05-0.16) and lowest in the East (-0.19 kg/m2; 95% CI: -0.24, -0.14) and Lake Geneva regions (-0.15 kg/m2; 95% CI: -0.20, -0.09). Trajectories of regional BMI growth varied across birth cohorts, with median BMI remaining high in the Central and North-West regions, whereas stabilization and in some cases a decline were observed elsewhere. CONCLUSIONS BMI of Swiss conscripts is associated with individual and abSEP and urbanicity. Results show regional variation in the levels and temporal trajectories of BMI growth and signal their possible slowdown among recent birth cohorts.

Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome.

BACKGROUND Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments. METHODS AND RESULTS We studied inflammatory and transforming growth factor-β (TGF-β) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-β1, TGF-β2, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-β2, whereas downstream canonical/noncanonical TGF-β signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity. CONCLUSIONS These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-β signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-β1. Finally, we found a novel role for dysregulated TGF-β2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.

A novel approach for assessing shifting cultivation dynamics in a regional conservation hotspot - insights from nort-eastern Madagascar

The north-eastern escarpment of Madagascar has been deemed a global hotspot of biodiversity due to its high levels of endemic speciesbeing heavily threatened by accelerated deforestation rates and landscape changes. The main concern for conservation of the remaining humid primary forests is the shifting cultivation practices of local smallholder farmers for rice production. According to the mainstream narrative, human population growth leads to a shortening of crop-fallow cycles and thus to the accelerated conversion of forests to agricultural land. However, little is currently known about the dynamic changes between forest and shifting cultivation systems at the regional level. Existing land cover change analyses in this area have so far only focused on binary forest to non-forest changes and have therefore failed to account for the dynamic nature of the change processes between forest and different agriculture land use systems. This can be partly explained by the significant challenge to delineate shifting cultivation systems on land cover maps using traditional remote sensing classification approaches. To address this gap we therefore applied a novel GIS approach, that was originally developed for the assessment of shifting cultivation dynamics in Laos and has so far never been applied elsewhere, to map shifting cultivation of different crop-fallow lengths as well as permanent agriculture land use at the regional level. Change analyses of land use maps between 1995 and 2011 allowed us to comprehend the general trends of land use trajectories and their spatial variation. This more detailed understanding of land use change dynamics is key to plan for successful interventions to slow forest loss while at the same time improving local livelihoods. We further believe that this approach holds great potential for conservation monitoring in this resource-rich but povertyprone conservation hotspot.

Legal Framework for Cross-Regional Networks: The Case of Services and Migration

Paper prepared by Marion Panizzon and Charlotte Sieber-Gasser for the International Conference on the Political Economy of Liberalising Trade in Services, Hebrew University of Jerusalem, 14-15 June 2010 Recent literature has shed light on the economic potential of cross-border networks. These networks, consisting of expatriates and their acquaintances from abroad and at home, provide the basis for the creation of cross-border value added chains and therewith the means for turning brain drain into brain circulation. Both aspects are potentially valuable for economic growth in the developing world. Unilateral co-development policies operating through co-funding of expatriate business ventures, but also bilateral agreements liberalising circular migration for a limited set of per-sons testify to the increasing awareness of governments about the potential, which expatriate networks hold for economic growth in developing countries. Whereas such punctual efforts are valuable, viewed from a long term perspective, these top-down, government mandated Diaspora stimulation programs, will not replace, this paper argues, the market-driven liberalisation of infrastructure and other services in developing countries. Nor will they carry, in the case of circular labour migration, the political momentum to liberalise labour market admission for those non-nationals, who will eventually emerge as the future transnational entrepreneurs. It will take a combination of mode 4 and infrastructure services openings-cum regulation for countries at both sides of the spectrum to provide the basis and precondition for transnational business and entrepreneurial networks to emerge and translate into cross-border, value added production chains. Two key issues are of particular relevance in this context: (i) the services sector, especially in infrastructure, tends to suffer from inefficiencies, particularly in developing countries, and (ii) labour migration, a highly complex issue, still faces disproportionately rigid barriers despite well-documented global welfare gains. Both are hindrances for emerging markets to fully take advantage of the potential of these cross-border networks. Adapting the legal framework for enhancing the regulatory and institutional frameworks for services trade, especially in infrastructure services sectors (ISS) and labour migration could provide the incentives necessary for brain circulation and strengthen cross-border value added chains by lowering transaction costs. This paper analyses the shortfalls of the global legal framework – the shallow status quo of GATS commitments in ISS and mode 4 particular – in relation to stimulating brain circulation and the creation of cross-border value added chains in emerging markets. It highlights the necessity of adapting the legal framework, both on the global and the regional level, to stimulate broader and wider market access in the four key ISS sectors (telecommunications, transport, professional and financial services) in developing countries, as domestic supply capacity, global competitiveness and economic diversification in ISS sectors are necessary for mobilising expatriate re-turns, both physical and virtual. The paper argues that industrialised, labour receiving countries need to offer mode 4 market access to wider categories of persons, especially to students, graduate trainees and young professionals from abroad. Further-more, free trade in semi-finished products and mode 4 market access are crucial for the creation of cross-border value added chains across the developing world. Finally, the paper discusses on the basis of a case study on Jordan why the key features of trade agreements, which promote circular migration and the creation of cross-border value added chains, consist of trade liberalisation in services and liberal migration policies.