Dll4-Notch signaling as a therapeutic target in tumor angiogenesis

Tumor angiogenesis is an important target for cancer therapy, with most current therapies designed to block the VEGF signaling pathway. However, clinical resistance to anti-VEGF therapy highlights the need for targeting additional tumor angiogenesis signaling pathways. The endothelial Notch ligand Dll4 (delta-like 4) has recently emerged as a critical regulator of tumor angiogenesis and thus as a promising new therapeutic anti-angiogenesis target. Blockade of Dll4-Notch signaling in tumors results in excessive, non-productive angiogenesis with resultant inhibitory effects on tumor growth, even in some tumors that are resistant to anti-VEGF therapies. As Dll4 inhibitors are entering clinical cancer trials, this review aims to provide current perspectives on the function of the Dll4-Notch signaling axis during tumor angiogenesis and as a target for anti-angiogenic cancer therapy

Analyse der wirtschaftlichen Lage ökologisch wirtschaftender Betriebe im Wirtschaftsjahr 2021/22

Im deutschen Testbetriebsnetz des Bundesministeriums für Ernährung und Landwirtschaft (BMEL) wird auch die wirtschaftliche Lage von ökologisch wirtschaftenden Betrieben in Deutschland erfasst. Das Thünen-Institut für Betriebswirtschaft wertet die Daten jährlich aus und erstellt einen Ergebnisbericht. Der aktuelle Bericht fasst die wichtigsten Ergebnisse des Wirtschaftsjahres 2021/22 zusammen

Dissolved silicon isotope dynamics in large river estuaries

Estuarine systems are of key importance for the riverine input of silicon (Si) to the ocean, which is a limiting factor of diatom productivity in coastal areas. This study presents a field dataset of surface dissolved Si isotopic compositions (30SiSi(OH)4) obtained in the estuaries of three of the world’s largest rivers, the Amazon (ARE), Yangtze (YRE), and Pearl (PRE), which cover different climate zones. While 30SiSi(OH)4 behaved conservatively in the YRE and PRE supporting a dominant control by water mass mixing, significantly increased 30SiSi(OH)4 signatures due to diatom utilization of Si(OH)4 were observed in the ARE and reflected a Si isotopic enrichment factor 30 of −1.0±0.4‰ (Rayleigh model) or −1.6±0.4‰ (steady state model). In addition, seasonal variability of Si isotope behavior in the YRE was observed by comparison to previous work and most likely resulted from changes in water residence time, temperature, and light level. Based on the 30 value obtained for the ARE, we estimate that the global average 30SiSi(OH)4 entering the ocean is 0.2-0.3‰ higher than that of the rivers due to Si retention in estuaries. This systematic modification of riverine Si isotopic compositions during estuarine mixing, as well as the seasonality of Si isotope dynamics in single estuaries, needs to be taken into account for better constraining the role of large river estuaries in the oceanic Si cycle

Synchronous and proportional deglacial changes in Atlantic meridional overturning and northeast Brazilian precipitation

Changes in heat transport associated with fluctuations in the strength of the Atlantic meridional overturning circulation (AMOC) are widely considered to affect the position of the Intertropical Convergence Zone (ITCZ), but the temporal immediacy of this teleconnection has to date not been resolved. Based on a high-resolution marine sediment sequence over the last deglaciation, we provide evidence for a synchronous and near-linear link between changes in the Atlantic interhemispheric sea surface temperature difference and continental precipitation over northeast Brazil. The tight coupling between AMOC strength, sea surface temperature difference, and precipitation changes over northeast Brazil unambiguously points to a rapid and proportional adjustment of the ITCZ location to past changes in the Atlantic meridional heat transport

Effects of input data aggregation on simulated crop yields in temperate and Mediterranean climates

The modelling exercise for this study was highly supported by partner universities and research institutes in the framework of the MACSUR project and financially supported by the German Federal Ministry of Education and Research BMBF (FKZ 2815ERA01J) in the framework of the funding measure “Soil as a Sustainable Resource for the Bioeconomy – BonaRes”, project “BonaRes (Module B): BonaRes Centre for Soil Research (FKZ BOMA03037514, 031B0026A and 031A608A) and by the Ministry of Agriculture and Food (BMEL) in the framework of the MACSUR project (FKZ 2815ERA01J). In addition, the relevant co-authors from the partner institutes are separately financed by their respective projects. AV, EC, and EL were supported by The Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (220-2007-1218) and by the strategic funding ‘Soil-Water-Landscape’ from the faculty of Natural Resources and Agricultural Sciences (Swedish University of Agricultural Sciences). JC thank the INRA ACCAF metaprogramm for funding. KCK, CN, XS and TS were supported by MACSUR2 (FKZ 031B0039C). MK thanks for the funding by the UK BBSRC (BB/N004922/1) and the MAXWELL HPC team of the University of Aberdeen for providing equipment and support for the DailyDayCent simulations. FE acknowledges support by the German Science Foundation (project EW 119/5-1). GRM, TG, and FE thank Andreas Enders and Gunther Krauss (INRES, University of Bonn) for support. The authors also would like to acknowledge the support provided by the BMBF and the valuable comments of the scientists of the Institut für Nutzpflanzenwissenschaften und Ressourcenschutz (INRES), University of Bonn, Germany.Peer reviewedPostprin

Impact of Spatial Soil and Climate Input Data Aggregation on Regional Yield Simulations

This work was financially supported by the German Federal Ministry of Food and Agriculture (BMEL) through the Federal Office for Agriculture and Food (BLE), (2851ERA01J). FT and RPR were supported by FACCE MACSUR (3200009600) through the Finnish Ministry of Agriculture and Forestry (MMM). EC, HE and EL were supported by The Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (220-2007-1218) and by the strategic funding ‘Soil-Water-Landscape’ from the faculty of Natural Resources and Agricultural Sciences (Swedish University of Agricultural Sciences) and thank professor P-E Jansson (Royal Institute of Technology, Stockholm) for support. JC, HR and DW thank the INRA ACCAF metaprogramm for funding and Eric Casellas from UR MIAT INRA for support. CB was funded by the Helmholtz project “REKLIM—Regional Climate Change”. CK was funded by the HGF Alliance “Remote Sensing and Earth System Dynamics” (EDA). FH was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) under the Grant FOR1695. FE and SS acknowledge support by the German Science Foundation (project EW 119/5-1). HH, GZ, SS, TG and FE thank Andreas Enders and Gunther Krauss (INRES, University of Bonn) for support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption

The consolidated European synthesis of CH4 and N2O emissions for the European Union and United Kingdom : 1990-2019

Funding Information: We thank Aurélie Paquirissamy, Géraud Moulas and the ARTTIC team for the great managerial support offered during the project. FAOSTAT statistics are produced and disseminated with the support of its member countries to the FAO regular budget. Annual, gap-filled and harmonized NGHGI uncertainty estimates for the EU and its member states were provided by the EU GHG inventory team (European Environment Agency and its European Topic Centre on Climate change mitigation). Most top-down inverse simulations referred to in this paper rely for the derivation of optimized flux fields on observational data provided by surface stations that are part of networks like ICOS (datasets: 10.18160/P7E9-EKEA , Integrated Non-CO Observing System, 2018a, and 10.18160/B3Q6-JKA0 , Integrated Non-CO Observing System, 2018b), AGAGE, NOAA (Obspack Globalview CH: 10.25925/20221001 , Schuldt et al., 2017), CSIRO and/or WMO GAW. We thank all station PIs and their organizations for providing these valuable datasets. We acknowledge the work of other members of the EDGAR group (Edwin Schaaf, Jos Olivier) and the outstanding scientific contribution to the VERIFY project of Peter Bergamaschi. Timo Vesala thanks ICOS-Finland, University of Helsinki. The TM5-CAMS inversions are available from https://atmosphere.copernicus.eu (last access: June 2022); Arjo Segers acknowledges support from the Copernicus Atmosphere Monitoring Service, implemented by the European Centre for Medium-Range Weather Forecasts on behalf of the European Commission (grant no. CAMS2_55). This research has been supported by the European Commission, Horizon 2020 Framework Programme (VERIFY, grant no. 776810). Ronny Lauerwald received support from the CLand Convergence Institute. Prabir Patra received support from the Environment Research and Technology Development Fund (grant no. JPMEERF20182002) of the Environmental Restoration and Conservation Agency of Japan. Pierre Regnier received financial support from the H2020 project ESM2025 – Earth System Models for the Future (grant no. 101003536). David Basviken received support from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (METLAKE, grant no. 725546). Greet Janssens-Maenhout received support from the European Union's Horizon 2020 research and innovation program (CoCO, grant no. 958927). Tuula Aalto received support from the Finnish Academy (grants nos. 351311 and 345531). Sönke Zhaele received support from the ERC consolidator grant QUINCY (grant no. 647204).Peer reviewedPublisher PD