TY - JOUR A1 - Schurr, Frank Martin A1 - Bossdorf, Oliver A1 - Milton, Sue J. A1 - Schumacher, J. T1 - Spatial pattern formation in semi-arid shrubland : a priori predicted versus observed pattern characteristics N2 - Ecologists increasingly use spatial statistics to study vegetation patterns. Mostly, however, these techniques are applied in a purely descriptive fashion without a priori statements on the pattern characteristics expected. We formulated such a priori predictions in a study of spatial pattern in a semi-arid Karoo shrubland, South Africa. Both seed dispersal and root competition have been discussed as processes shaping the spatial structure of this community. If either of the two processes dominates pattern formation, patterns within and between shrub functional groups are expected to show distinct deviations from null models. We predicted the type and scale of these deviations and compared predicted to observed pattern characteristics. As predicted by the seed dispersal hypothesis, small-scale co-occurrence within and between groups of colonisers and successors was increased as compared to complete spatially random arrangement of shrubs. The root competition predictions, however, were not met as shrubs of similar rooting depth co- occurred more frequently than expected under random shrub arrangement. Since the distribution of rooting groups to the given shrub locations also failed to match the root competition predictions, there was little evidence for dominance of root competition in pattern formation. Although other processes may contribute to small-scale plant co-occurrence, the sufficient and most parsimonious explanation for the observed pattern is that its formation was dominated by seed dispersal. To characterise point patterns we applied both cumulative (uni- and bivariate K-function) and local (pair- and mark-correlation function) techniques. Based on our results we recommend that future studies of vegetation patterns include local characteristics as they independently describe a pattern at different scales and can be easily related to processes changing with interplant distance in a predictable fashion. Y1 - 2004 ER - TY - JOUR A1 - Schweigert, Florian J. A1 - Buchholz, Ingeborg A1 - Schumacher, A. A1 - Gropp, J. T1 - Effect of dietary ß-carotene on the accumulation of ß-carotene and vitamin A in plasma and tissues of gilts Y1 - 2001 ER - TY - GEN A1 - Beckmann, Nadine A1 - Becker, Katrin Anne A1 - Kadow, Stephanie A1 - Schumacher, Fabian A1 - Kramer, Melanie A1 - Kühn, Claudine A1 - Schulz-Schaeffer, Walter J. A1 - Edwards, Michael J. A1 - Kleuser, Burkhard A1 - Gulbins, Erich A1 - Carpinteiro, Alexander T1 - Acid sphingomyelinase deficiency ameliorates Farber disease T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1087 KW - Farber disease KW - lysosomal storage disorders KW - acid ceramidase KW - acid sphingomyelinase KW - amitriptyline Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-441282 SN - 1866-8372 IS - 1087 ER - TY - JOUR A1 - Beckmann, Nadine A1 - Becker, Katrin Anne A1 - Kadow, Stephanie A1 - Schumacher, Fabian A1 - Kramer, Melanie A1 - Kuehn, Claudine A1 - Schulz-Schaeffer, Walter J. A1 - Edwards, Michael J. A1 - Kleuser, Burkhard A1 - Gulbins, Erich A1 - Carpinteiro, Alexander T1 - Acid Sphingomyelinase Deficiency Ameliorates Farber Disease JF - International journal of molecular sciences N2 - Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients. KW - Farber disease KW - lysosomal storage disorders KW - acid ceramidase KW - acid sphingomyelinase KW - amitriptyline Y1 - 2019 U6 - https://doi.org/10.3390/ijms20246253 SN - 1422-0067 VL - 20 IS - 24 PB - MDPI CY - Basel ER - TY - JOUR A1 - Zalden, Peter A1 - Quirin, Florian A1 - Schumacher, Mathias A1 - Siegel, Jan A1 - Wei, Shuai A1 - Koc, Azize A1 - Nicoul, Matthieu A1 - Trigo, Mariano A1 - Andreasson, Pererik A1 - Enquist, Henrik A1 - Shu, Michael J. A1 - Pardini, Tommaso A1 - Chollet, Matthieu A1 - Zhu, Diling A1 - Lemke, Henrik A1 - Ronneberger, Ider A1 - Larsson, Jörgen A1 - Lindenberg, Aaron M. A1 - Fischer, Henry E. A1 - Hau-Riege, Stefan A1 - Reis, David A. A1 - Mazzarello, Riccardo A1 - Wuttig, Matthias A1 - Sokolowski-Tinten, Klaus T1 - Femtosecond x-ray diffraction reveals a liquid-liquid phase transition in phase-change materials JF - Science N2 - In phase-change memory devices, a material is cycled between glassy and crystalline states. The highly temperature-dependent kinetics of its crystallization process enables application in memory technology, but the transition has not been resolved on an atomic scale. Using femtosecond x-ray diffraction and ab initio computer simulations, we determined the time-dependent pair-correlation function of phase-change materials throughout the melt-quenching and crystallization process. We found a liquid-liquid phase transition in the phase-change materials Ag4In3Sb67Te26 and Ge15Sb85 at 660 and 610 kelvin, respectively. The transition is predominantly caused by the onset of Peierls distortions, the amplitude of which correlates with an increase of the apparent activation energy of diffusivity. This reveals a relationship between atomic structure and kinetics, enabling a systematic optimization of the memory-switching kinetics. Y1 - 2019 U6 - https://doi.org/10.1126/science.aaw1773 SN - 0036-8075 SN - 1095-9203 VL - 364 IS - 6445 SP - 1062 EP - 1067 PB - American Assoc. for the Advancement of Science CY - Washington, DC ER - TY - INPR A1 - Baret, Jean-Christophe A1 - Belder, Detlev A1 - Bier, Frank Fabian A1 - Cao, Jialan A1 - Gruschke, Oliver A1 - Hardt, Steffen A1 - Kirschbaum, Michael A1 - Koehler, J. Michael A1 - Schumacher, Soeren A1 - Urban, G. A. A1 - Viefhues, Martina T1 - Contributors to the 10th Anniversary Germany issue T2 - LAB on a chip : miniaturisation for chemistry and biology Y1 - 2012 U6 - https://doi.org/10.1039/c1lc90139g SN - 1473-0197 VL - 12 IS - 3 SP - 419 EP - 421 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Lindemann, Marcus A1 - Schmid, Simone A1 - Gronau, Norbert A1 - Schumacher, J. T1 - Marktstudie zur kundenorientierten Weiterentwicklung von MES Y1 - 2006 ER - TY - JOUR A1 - Peter, Martin G. A1 - Ley, J. P. A1 - Petersen, Stefan A1 - Londershausen, M. A1 - Schumacher-Wandersleb, Michael H. M. G. A1 - Spindler, Klaus-Dieter A1 - Spindler-Barth, Margarethe A1 - Turberg, Andreas T1 - Synthesis of chitinase inhibitors Y1 - 1994 ER - TY - JOUR A1 - Beckmann, Nadine A1 - Kadow, Stephanie A1 - Schumacher, Fabian A1 - Goethert, Joachim R. A1 - Kesper, Stefanie A1 - Draeger, Annette A1 - Schulz-Schaeffer, Walter J. A1 - Wang, Jiang A1 - Becker, Jan U. A1 - Kramer, Melanie A1 - Kuehn, Claudine A1 - Kleuser, Burkhard A1 - Becker, Katrin Anne A1 - Gulbins, Erich A1 - Carpinteiro, Alexander T1 - Pathological manifestations of Farber disease in a new mouse model JF - Biological chemistry N2 - Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies. KW - acid ceramidase KW - ceramide KW - Farber disease KW - lysosomal storage disorders Y1 - 2018 U6 - https://doi.org/10.1515/hsz-2018-0170 SN - 1431-6730 SN - 1437-4315 VL - 399 IS - 10 SP - 1183 EP - 1202 PB - De Gruyter CY - Berlin ER - TY - JOUR A1 - Gulbins, Anne A1 - Schumacher, Fabian A1 - Becker, Katrin Anne A1 - Wilker, Barbara A1 - Soddemann, Matthias A1 - Boldrin, Francesco A1 - Müller, Christian P. A1 - Edwards, Michael J. A1 - Goodman, Michael A1 - Caldwell, Charles C. A1 - Kleuser, Burkhard A1 - Kornhuber, Johannes A1 - Szabo, Ildiko A1 - Gulbins, Erich T1 - Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide JF - Molecular psychiatry N2 - Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days. Y1 - 2018 U6 - https://doi.org/10.1038/s41380-018-0090-9 SN - 1359-4184 SN - 1476-5578 VL - 23 IS - 12 SP - 2324 EP - 2346 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Seitz, Aaron P. A1 - Schumacher, Fabian A1 - Baker, Jennifer A1 - Soddemann, Matthias A1 - Wilker, Barbara A1 - Caldwell, Charles C. A1 - Gobble, Ryan M. A1 - Kamler, Markus A1 - Becker, Katrin Anne A1 - Beck, Sascha A1 - Kleuser, Burkhard A1 - Edwards, Michael J. A1 - Gulbins, Erich T1 - Sphingosine-coating of plastic surfaces prevents ventilator-associated pneumonia JF - Journal of molecular medicine N2 - Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in critically ill patients. Here, we employed the broad antibacterial effects of sphingosine to prevent VAP by developing a novel method of coating surfaces of endotracheal tubes with sphingosine and sphingosine analogs. Sphingosine and phytosphingosine coatings of endotracheal tubes prevent adherence and mediate killing of Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus, even in biofilms. Most importantly, sphingosine-coating of endotracheal tubes also prevented P. aeruginosa and S. aureus pneumonia in vivo. Coating of the tubes with sphingosine was stable, without obvious side effects on tracheal epithelial cells and did not induce inflammation. In summary, we describe a novel method to coat plastic surfaces and provide evidence for the application of sphingosine and phytosphingosine as novel antimicrobial coatings to prevent bacterial adherence and induce killing of pathogens on the surface of endotracheal tubes with potential to prevent biofilm formation and VAP.Key messagesNovel dip-coating method to coat plastic surfaces with lipids.Sphingosine and phytosphingosine as novel antimicrobial coatings on plastic surface.Sphingosine coatings of endotracheal tubes prevent bacterial adherence and biofilms.Sphingosine coatings of endotracheal tubes induce killing of pathogens.Sphingosine coatings of endotracheal tubes ventilator-associated pneumonia. KW - Coating KW - Plastic surfaces KW - Sphingosine KW - Ventilation KW - Acinetobacter baumannii KW - Pseudomonas aeruginosa KW - Staphylococcus aureus Y1 - 2019 U6 - https://doi.org/10.1007/s00109-019-01800-1 SN - 0946-2716 SN - 1432-1440 VL - 97 IS - 8 SP - 1195 EP - 1211 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Kachler, Katerina A1 - Bailer, Maximilian A1 - Heim, Lisanne A1 - Schumacher, Fabian A1 - Reichel, Martin A1 - Holzinger, Corinna D. A1 - Trump, Sonja A1 - Mittler, Susanne A1 - Monti, Juliana A1 - Trufa, Denis I. A1 - Rieker, Ralf J. A1 - Hartmann, Arndt A1 - Sirbu, Horia A1 - Kleuser, Burkhard A1 - Kornhuber, Johannes A1 - Finotto, Susetta T1 - Enhanced acid sphingomyelinase activity drives immune evasion and tumor growth in non-small cell lung carcinoma JF - Cancer research N2 - The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and-extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. (C) 2017 AACR. Y1 - 2017 U6 - https://doi.org/10.1158/0008-5472.CAN-16-3313 SN - 0008-5472 SN - 1538-7445 VL - 77 IS - 21 SP - 5963 EP - 5976 PB - American Association for Cancer Research CY - Philadelphia ER - TY - JOUR A1 - Gutbier, Birgitt A1 - Schönrock, Stefanie M. A1 - Ehrler, Carolin A1 - Haberberger, Rainer A1 - Dietert, Kristina A1 - Gruber, Achim D. A1 - Kummer, Wolfgang A1 - Michalick, Laura A1 - Kuebler, Wolfgang M. A1 - Hocke, Andreas C. A1 - Szymanski, Kolja A1 - Letsiou, Eleftheria A1 - Lüth, Anja A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Mitchell, Timothy J. A1 - Bertrams, Wilhelm A1 - Schmeck, Bernd A1 - Treue, Denise A1 - Klauschen, Frederick A1 - Bauer, Torsten T. A1 - Tönnies, Mario A1 - Weissmann, Norbert A1 - Hippenstiel, Stefan A1 - Suttorp, Norbert A1 - Witzenrath, Martin T1 - Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2 JF - Critical care medicine N2 - Objectives: Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia. Design: Controlled, in vitro, ex vivo, and in vivo laboratory study. Subjects: Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells. Interventions: Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin. Measurements and Main Results: Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1(-/-) mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase. Conclusions: Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury. KW - acute lung injury KW - pneumococcal pneumonia KW - sphingosine kinase 1 KW - sphingosine-1-phosphate KW - sphingosine-1-phosphate receptor 2 Y1 - 2018 U6 - https://doi.org/10.1097/CCM.0000000000002916 SN - 0090-3493 SN - 1530-0293 VL - 46 IS - 3 SP - e258 EP - e267 PB - Lippincott Williams & Wilkins CY - Philadelphia ER -