TY - JOUR A1 - Allan, Eric A1 - Manning, Pete A1 - Alt, Fabian A1 - Binkenstein, Julia A1 - Blaser, Stefan A1 - Blüthgen, Nico A1 - Böhm, Stefan A1 - Grassein, Fabrice A1 - Hölzel, Norbert A1 - Klaus, Valentin H. A1 - Kleinebecker, Till A1 - Morris, E. Kathryn A1 - Oelmann, Yvonne A1 - Prati, Daniel A1 - Renner, Swen C. A1 - Rillig, Matthias C. A1 - Schaefer, Martin A1 - Schloter, Michael A1 - Schmitt, Barbara A1 - Schöning, Ingo A1 - Schrumpf, Marion A1 - Solly, Emily A1 - Sorkau, Elisabeth A1 - Steckel, Juliane A1 - Steffen-Dewenter, Ingolf A1 - Stempfhuber, Barbara A1 - Tschapka, Marco A1 - Weiner, Christiane N. A1 - Weisser, Wolfgang W. A1 - Werner, Michael A1 - Westphal, Catrin A1 - Wilcke, Wolfgang A1 - Fischer, Markus T1 - Land use intensification alters ecosystem multifunctionality via loss of biodiversity and changes to functional composition JF - Ecology letters N2 - Global change, especially land-use intensification, affects human well-being by impacting the delivery of multiple ecosystem services (multifunctionality). However, whether biodiversity loss is a major component of global change effects on multifunctionality in real-world ecosystems, as in experimental ones, remains unclear. Therefore, we assessed biodiversity, functional composition and 14 ecosystem services on 150 agricultural grasslands differing in land-use intensity. We also introduce five multifunctionality measures in which ecosystem services were weighted according to realistic land-use objectives. We found that indirect land-use effects, i.e. those mediated by biodiversity loss and by changes to functional composition, were as strong as direct effects on average. Their strength varied with land-use objectives and regional context. Biodiversity loss explained indirect effects in a region of intermediate productivity and was most damaging when land-use objectives favoured supporting and cultural services. In contrast, functional composition shifts, towards fast-growing plant species, strongly increased provisioning services in more inherently unproductive grasslands. KW - Biodiversity-ecosystem functioning KW - ecosystem services KW - global change KW - land use KW - multifunctionality Y1 - 2015 U6 - https://doi.org/10.1111/ele.12469 SN - 1461-023X SN - 1461-0248 VL - 18 IS - 8 SP - 834 EP - 843 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Soliveres, Santiago A1 - van der Plas, Fons A1 - Manning, Peter A1 - Prati, Daniel A1 - Gossner, Martin M. A1 - Renner, Swen C. A1 - Alt, Fabian A1 - Arndt, Hartmut A1 - Baumgartner, Vanessa A1 - Binkenstein, Julia A1 - Birkhofer, Klaus A1 - Blaser, Stefan A1 - Blüthgen, Nico A1 - Boch, Steffen A1 - Böhm, Stefan A1 - Börschig, Carmen A1 - Buscot, Francois A1 - Diekötter, Tim A1 - Heinze, Johannes A1 - Hölzel, Norbert A1 - Jung, Kirsten A1 - Klaus, Valentin H. A1 - Kleinebecker, Till A1 - Klemmer, Sandra A1 - Krauss, Jochen A1 - Lange, Markus A1 - Morris, E. Kathryn A1 - Müller, Jörg A1 - Oelmann, Yvonne A1 - Overmann, Jörg A1 - Pasalic, Esther A1 - Rillig, Matthias C. A1 - Schaefer, H. Martin A1 - Schloter, Michael A1 - Schmitt, Barbara A1 - Schöning, Ingo A1 - Schrumpf, Marion A1 - Sikorski, Johannes A1 - Socher, Stephanie A. A1 - Solly, Emily F. A1 - Sonnemann, Ilja A1 - Sorkau, Elisabeth A1 - Steckel, Juliane A1 - Steffan-Dewenter, Ingolf A1 - Stempfhuber, Barbara A1 - Tschapka, Marco A1 - Türke, Manfred A1 - Venter, Paul C. A1 - Weiner, Christiane N. A1 - Weisser, Wolfgang W. A1 - Werner, Michael A1 - Westphal, Catrin A1 - Wilcke, Wolfgang A1 - Wolters, Volkmar A1 - Wubet, Tesfaye A1 - Wurst, Susanne A1 - Fischer, Markus A1 - Allan, Eric T1 - Biodiversity at multiple trophic levels is needed for ecosystem multifunctionality JF - Nature : the international weekly journal of science Y1 - 2016 U6 - https://doi.org/10.1038/nature19092 SN - 0028-0836 SN - 1476-4687 VL - 536 SP - 456 EP - + PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Soliveres, Santiago A1 - Manning, Peter A1 - Prati, Daniel A1 - Gossner, Martin M. A1 - Alt, Fabian A1 - Arndt, Hartmut A1 - Baumgartner, Vanessa A1 - Binkenstein, Julia A1 - Birkhofer, Klaus A1 - Blaser, Stefan A1 - Bluethgen, Nico A1 - Boch, Steffen A1 - Boehm, Stefan A1 - Boerschig, Carmen A1 - Buscot, Francois A1 - Diekoetter, Tim A1 - Heinze, Johannes A1 - Hoelzel, Norbert A1 - Jung, Kirsten A1 - Klaus, Valentin H. A1 - Klein, Alexandra-Maria A1 - Kleinebecker, Till A1 - Klemmer, Sandra A1 - Krauss, Jochen A1 - Lange, Markus A1 - Morris, E. Kathryn A1 - Mueller, Joerg A1 - Oelmann, Yvonne A1 - Overmann, Jörg A1 - Pasalic, Esther A1 - Renner, Swen C. A1 - Rillig, Matthias C. A1 - Schaefer, H. Martin A1 - Schloter, Michael A1 - Schmitt, Barbara A1 - Schoening, Ingo A1 - Schrumpf, Marion A1 - Sikorski, Johannes A1 - Socher, Stephanie A. A1 - Solly, Emily F. A1 - Sonnemann, Ilja A1 - Sorkau, Elisabeth A1 - Steckel, Juliane A1 - Steffan-Dewenter, Ingolf A1 - Stempfhuber, Barbara A1 - Tschapka, Marco A1 - Tuerke, Manfred A1 - Venter, Paul A1 - Weiner, Christiane N. A1 - Weisser, Wolfgang W. A1 - Werner, Michael A1 - Westphal, Catrin A1 - Wilcke, Wolfgang A1 - Wolters, Volkmar A1 - Wubet, Tesfaye A1 - Wurst, Susanne A1 - Fischer, Markus A1 - Allan, Eric T1 - Locally rare species influence grassland ecosystem multifunctionality JF - Philosophical transactions of the Royal Society of London : B, Biological sciences N2 - Species diversity promotes the delivery of multiple ecosystem functions (multifunctionality). However, the relative functional importance of rare and common species in driving the biodiversity multifunctionality relationship remains unknown. We studied the relationship between the diversity of rare and common species (according to their local abundances and across nine different trophic groups), and multifunctionality indices derived from 14 ecosystem functions on 150 grasslands across a land use intensity (LUI) gradient. The diversity of above- and below-ground rare species had opposite effects, with rare above-ground species being associated with high levels of multifunctionality, probably because their effects on different functions did not trade off against each other. Conversely, common species were only related to average, not high, levels of multifunctionality, and their functional effects declined with LUI. Apart from the community level effects of diversity, we found significant positive associations between the abundance of individual species and multifunctionality in 6% of the species tested. Species specific functional effects were best predicted by their response to LUI: species that declined in abundance with land use intensification were those associated with higher levels of multifunctionality. Our results highlight the importance of rare species for ecosystem multifunctionality and help guiding future conservation priorities. KW - biodiversity KW - common species KW - ecosystem function KW - identity hypothesis KW - land use KW - multitrophic Y1 - 2016 U6 - https://doi.org/10.1098/rstb.2015.0269 SN - 0962-8436 SN - 1471-2970 VL - 371 SP - 3175 EP - 3185 PB - Royal Society CY - London ER - TY - JOUR A1 - Edlich, Alexander A1 - Gerecke, Christian A1 - Giulbudagian, Michael A1 - Neumann, Falko A1 - Hedtrich, Sarah A1 - Schaefer-Korting, Monika A1 - Ma, Nan A1 - Calderon, Marcelo A1 - Kleuser, Burkhard T1 - Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin JF - European Journal of Pharmaceutics and Biopharmaceutics N2 - Engineered nanogels are of high value for a targeted and controlled transport of compounds due to the ability to change their chemical properties by external stimuli. As it has been indicated that nanogels possess a high ability to penetrate the stratum corneum, it cannot be excluded that nanogels interact with dermal dendritic cells, especially in diseased skin. In this study the potential crosstalk of the thermore-sponsive nanogels (tNGs) with the dendritic cells of the skin was investigated with the aim to determine the immunotoxicological properties of the nanogels. The investigated tNGs were made of dendritic polyglycerol (dPG) and poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)), as polymer conferring thermoresponsive properties. Although the tNGs were taken up, they displayed neither cytotoxic and genotoxic effects nor any induction of reactive oxygen species in the tested cells. Interestingly, specific uptake mechanisms of the tNGs by the dendritic cells were depending on the nanogels cloud point temperature (Tcp), which determines the phase transition of the nanoparticle. The study points to caveolae-mediated endocytosis as being the major tNGs uptake mechanism at 37 degrees C, which is above the Tcp of the tNGs. Remarkably, an additional uptake mechanism, beside caveolae-mediated endocytosis, was observed at 29 degrees C, which is the Tcp of the tNGs. At this temperature, which is characterized by two different states of the tNGs, macropinocytosis was involved as well. In summary, our study highlights the impact of thermoresponsivity on the cellular uptake mechanisms which has to be taken into account if the tNGs are used as a drug delivery system. KW - Dendritic cells KW - Drug delivery systems KW - Nanogel KW - Nanoparticle KW - Nanoparticle uptake KW - Nanotoxicology Y1 - 2017 U6 - https://doi.org/10.1016/j.ejpb.2016.12.016 SN - 0939-6411 SN - 1873-3441 VL - 116 SP - 155 EP - 163 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Heneghan, Carl A1 - Ward, Alison A1 - Perera, Rafael A1 - Bankhead, Clare A1 - Fuller, Alice A1 - Stevens, Richard A1 - Bradford, Kairen A1 - Tyndel, Sally A1 - Alonso-Coello, Pablo A1 - Ansell, Jack A1 - Beyth, Rebecca A1 - Bernardo, Artur A1 - Christensen, Thomas Decker A1 - Cromheecke, Manon A1 - Edson, Robert G A1 - Fitzmaurice, David A1 - Gadisseur, Alain PA A1 - Garcia-Alamino, Josep M A1 - Gardiner, Chris A1 - Hasenkam, Michael A1 - Jacobson, Alan A1 - Kaatz, Scott A1 - Kamali, Farhad A1 - Khan, Tayyaba Irfan A1 - Knight, Eve A1 - Kortke, Heinrich A1 - Levi, Marcel A1 - Matchar, David Bruce A1 - Menendez-Jandula, Barbara A1 - Rakovac, Ivo A1 - Schaefer, Christian A1 - Siebenhofer, Andrea A1 - Souto, Juan Carlos A1 - Sunderji, Rubina A1 - Gin, Kenneth A1 - Shalansky, Karen A1 - Völler, Heinz A1 - Wagner, Otto A1 - Zittermann, Armin T1 - Self-monitoring of oral anticoagulation systematic review and meta-analysis of individual patient data JF - The lancet N2 - Background Uptake of self-testing and self-management of oral coagulation has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. Methods We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. Findings Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12 800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0.51; 95% CI 0.31-0.85) but not for major haemorrhagic events (0.88, 0.74-1.06) or death (0.82, 0.62-1.09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0.33, 95% CI 0.17-0.66), as did participants with mechanical heart valve (0.52, 0.35-0.77). Analysis of major outcomes in the very elderly (age >= 85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. Interpretation Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. Y1 - 2012 U6 - https://doi.org/10.1016/S0140-6736(11)61294-4 SN - 0140-6736 VL - 379 IS - 9813 SP - 322 EP - 334 PB - Elsevier CY - New York ER - TY - JOUR A1 - Mayer, Magnus C. A1 - Schauenburg, Linda A1 - Thompson-Steckel, Greta A1 - Dunsing, Valentin A1 - Kaden, Daniela A1 - Voigt, Philipp A1 - Schaefer, Michael A1 - Chiantia, Salvatore A1 - Kennedy, Timothy E. A1 - Multhaup, Gerhard T1 - Amyloid precursor-like protein 1 (APLP1) exhibits stronger zinc-dependent neuronal adhesion than amyloid precursor protein and APLP2 JF - Journal of neurochemistry N2 - The amyloid precursor protein (APP) and its paralogs, amyloid precursor-like protein 1 (APLP1) and APLP2, are metalloproteins with a putative role both in synaptogenesis and in maintaining synapse structure. Here, we studied the effect of zinc on membrane localization, adhesion, and secretase cleavage of APP, APLP1, and APLP2 in cell culture and rat neurons. For this, we employed live-cell microscopy techniques, a microcontact printing adhesion assay and ELISA for protein detection in cell culture supernatants. We report that zinc induces the multimerization of proteins of the amyloid precursor protein family and enriches them at cellular adhesion sites. Thus, zinc facilitates the formation of de novo APP and APLP1 containing adhesion complexes, whereas it does not have such influence on APLP2. Furthermore, zinc-binding prevented cleavage of APP and APLPs by extracellular secretases. In conclusion, the complexation of zinc modulates neuronal functions of APP and APLPs by (i) regulating formation of adhesion complexes, most prominently for APLP1, and (ii) by reducing the concentrations of neurotrophic soluble APP/APLP ectodomains. KW - amyloid precursor protein KW - amyloid precursor-like protein KW - neuronal adhesion KW - number and brightness KW - zinc Y1 - 2016 U6 - https://doi.org/10.1111/jnc.13540 SN - 0022-3042 SN - 1471-4159 VL - 137 SP - 266 EP - 276 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Kralemann, Bjoern A1 - Fruehwirth, Matthias A1 - Pikovskij, Arkadij A1 - Rosenblum, Michael A1 - Kenner, Thomas A1 - Schaefer, Jochen A1 - Moser, Maximilian T1 - In vivo cardiac phase response curve elucidates human respiratory heart rate variability JF - Nature Communications N2 - Recovering interaction of endogenous rhythms from observations is challenging, especially if a mathematical model explaining the behaviour of the system is unknown. The decisive information for successful reconstruction of the dynamics is the sensitivity of an oscillator to external influences, which is quantified by its phase response curve. Here we present a technique that allows the extraction of the phase response curve from a non-invasive observation of a system consisting of two interacting oscillators-in this case heartbeat and respiration-in its natural environment and under free-running conditions. We use this method to obtain the phase-coupling functions describing cardiorespiratory interactions and the phase response curve of 17 healthy humans. We show for the first time the phase at which the cardiac beat is susceptible to respiratory drive and extract the respiratory-related component of heart rate variability. This non-invasive method for the determination of phase response curves of coupled oscillators may find application in many scientific disciplines. Y1 - 2013 U6 - https://doi.org/10.1038/ncomms3418 SN - 2041-1723 VL - 4 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Gerecke, Christian A1 - Edlich, Alexander A1 - Giulbudagian, Michael A1 - Schumacher, Fabian A1 - Zhang, Nan A1 - Said, Andre A1 - Yealland, Guy A1 - Lohan, Silke B. A1 - Neumann, Falko A1 - Meinke, Martina C. A1 - Ma, Nan A1 - Calderon, Marcelo A1 - Hedtrich, Sarah A1 - Schaefer-Korting, Monika A1 - Kleuser, Burkhard T1 - Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes JF - Nanotoxicology N2 - Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery. KW - Drug delivery KW - nanoparticles KW - particle characterization KW - keratinocytes KW - nanotoxicology Y1 - 2017 U6 - https://doi.org/10.1080/17435390.2017.1292371 SN - 1743-5390 SN - 1743-5404 VL - 11 SP - 267 EP - 277 PB - Routledge, Taylor & Francis Group CY - Abingdon ER -