TY - JOUR A1 - Imeri, Faik A1 - Fallegger, Daniel A1 - Zivkovic, Aleksandra A1 - Schwalm, Stephanie A1 - Enzmann, Gaby A1 - Blankenbach, Kira A1 - Heringdorf, Dagmar Meyer Zu A1 - Homann, Thomas A1 - Kleuser, Burkhard A1 - Pfeilschifter, Josef A1 - Engelhardt, Britta A1 - Stark, Holger A1 - Huwiler, Andrea T1 - Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice JF - Neuropharmacology N2 - The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P(1) and S1P(3), but not S1P(2), receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNF alpha-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNF alpha-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases. (C) 2014 Elsevier Ltd. All rights reserved. KW - Fingolimod KW - ST-968 KW - ST-1071 KW - Sphingosine 1-phosphate KW - Endothelial cells KW - Permeability KW - Multiple sclerosis Y1 - 2014 U6 - https://doi.org/10.1016/j.neuropharm.2014.05.012 SN - 0028-3908 SN - 1873-7064 VL - 85 SP - 314 EP - 327 PB - Elsevier CY - Oxford ER - TY - GEN A1 - Seyrich, Maximilian A1 - Alirezaeizanjani, Zahra A1 - Beta, Carsten A1 - Stark, Holger T1 - Statistical parameter inference of bacterial swimming strategies T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - We provide a detailed stochastic description of the swimming motion of an E. coli bacterium in two dimension, where we resolve tumble events in time. For this purpose, we set up two Langevin equations for the orientation angle and speed dynamics. Calculating moments, distribution and autocorrelation functions from both Langevin equations and matching them to the same quantities determined from data recorded in experiments, we infer the swimming parameters of E. coli. They are the tumble rate lambda, the tumble time r(-1), the swimming speed v(0), the strength of speed fluctuations sigma, the relative height of speed jumps eta, the thermal value for the rotational diffusion coefficient D-0, and the enhanced rotational diffusivity during tumbling D-T. Conditioning the observables on the swimming direction relative to the gradient of a chemoattractant, we infer the chemotaxis strategies of E. coli. We confirm the classical strategy of a lower tumble rate for swimming up the gradient but also a smaller mean tumble angle (angle bias). The latter is realized by shorter tumbles as well as a slower diffusive reorientation. We also find that speed fluctuations are increased by about 30% when swimming up the gradient compared to the reversed direction. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 914 KW - E. coli KW - run and tumble KW - chemotaxis KW - stochastic processes KW - bacterial swimming strategies KW - parameter inference Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-446214 SN - 1866-8372 IS - 914 ER - TY - JOUR A1 - Seyrich, Maximilian A1 - Alirezaeizanjani, Zahra A1 - Beta, Carsten A1 - Stark, Holger T1 - Statistical parameter inference of bacterial swimming strategies JF - New journal of physics : the open-access journal for physics N2 - We provide a detailed stochastic description of the swimming motion of an E. coli bacterium in two dimension, where we resolve tumble events in time. For this purpose, we set up two Langevin equations for the orientation angle and speed dynamics. Calculating moments, distribution and autocorrelation functions from both Langevin equations and matching them to the same quantities determined from data recorded in experiments, we infer the swimming parameters of E. coli. They are the tumble rate lambda, the tumble time r(-1), the swimming speed v(0), the strength of speed fluctuations sigma, the relative height of speed jumps eta, the thermal value for the rotational diffusion coefficient D-0, and the enhanced rotational diffusivity during tumbling D-T. Conditioning the observables on the swimming direction relative to the gradient of a chemoattractant, we infer the chemotaxis strategies of E. coli. We confirm the classical strategy of a lower tumble rate for swimming up the gradient but also a smaller mean tumble angle (angle bias). The latter is realized by shorter tumbles as well as a slower diffusive reorientation. We also find that speed fluctuations are increased by about 30% when swimming up the gradient compared to the reversed direction. KW - E.coli KW - run and tumble KW - chemotaxis KW - stochastic processes KW - bacterial swimming strategies KW - parameter inference Y1 - 2018 U6 - https://doi.org/10.1088/1367-2630/aae72c SN - 1367-2630 VL - 20 PB - IOP Publ. Ltd. CY - Bristol ER - TY - JOUR A1 - Stepanovska, Bisera A1 - Zivkovic, Aleksandra A1 - Enzmann, Gaby A1 - Tietz, Silvia A1 - Homann, Thomas A1 - Kleuser, Burkhard A1 - Engelhardt, Britta A1 - Stark, Holger A1 - Huwiler, Andrea T1 - Morpholino analogues of fingolimod as novel and selective S1P1 ligands with in vivo efficacy in a mouse model of experimental antigen-induced encephalomyelitis JF - International journal of molecular sciences N2 - Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) which is associated with lower life expectancy and disability. The experimental antigen-induced encephalomyelitis (EAE) in mice is a useful animal model of MS, which allows exploring the etiopathogenetic mechanisms and testing novel potential therapeutic drugs. A new therapeutic paradigm for the treatment of MS was introduced in 2010 through the sphingosine 1-phosphate (S1P) analogue fingolimod (FTY720, Gilenya(R)), which acts as a functional S1P(1) antagonist on T lymphocytes to deplete these cells from the blood. In this study, we synthesized two novel structures, ST-1893 and ST-1894, which are derived from fingolimod and chemically feature a morpholine ring in the polar head group. These compounds showed a selective S1P(1) activation profile and a sustained S1P(1) internalization in cultures of S1P(1)-overexpressing Chinese hamster ovary (CHO)-K1 cells, consistent with a functional antagonism. In vivo, both compounds induced a profound lymphopenia in mice. Finally, these substances showed efficacy in the EAE model, where they reduced clinical symptoms of the disease, and, on the molecular level, they reduced the T-cell infiltration and several inflammatory mediators in the brain and spinal cord. In summary, these data suggest that S1P(1)-selective compounds may have an advantage over fingolimod and siponimod, not only in MS but also in other autoimmune diseases. KW - ST-1893 KW - ST-1894 KW - morpholino analogues of fingolimod KW - sphingosine KW - 1-phosphate KW - immunomodulator KW - lymphopenia KW - multiple sclerosis KW - experimental antigen-induced encephalomyelitis Y1 - 2020 U6 - https://doi.org/10.3390/ijms21186463 SN - 1422-0067 VL - 21 IS - 18 PB - MDPI CY - Basel ER - TY - JOUR A1 - Theves, Matthias A1 - Taktikos, Johannes A1 - Zaburdaev, Vasily A1 - Stark, Holger A1 - Beta, Carsten T1 - A bacterial swimmer with two alternating speeds of propagation JF - Biophysical journal N2 - We recorded large data sets of swimming trajectories of the soil bacterium Pseudomonas putida. Like other prokaryotic swimmers, P. putida exhibits a motion pattern dominated by persistent runs that are interrupted by turning events. An in-depth analysis of their swimming trajectories revealed that the majority of the turning events is characterized by an angle of phi(1) = 180 degrees (reversals). To a lesser extent, turning angles of phi(2 Sigma Sigma Sigma Sigma) = 00 are also found. Remarkably, we observed that, upon a reversal, the swimming speed changes by a factor of two on average a prominent feature of the motion pattern that, to our knowledge, has not been reported before. A theoretical model, based on the experimental values for the average run time and the rotational diffusion, recovers the mean-square displacement of P. putida if the two distinct swimming speeds are taken into account. Compared to a swimmer that moves with a constant intermediate speed, the mean-square displacement is strongly enhanced. We furthermore observed a negative dip in the directional autocorrelation at intermediate times, a feature that is only recovered in an extended model, where the nonexponential shape of the run-time distribution is taken into account. Y1 - 2013 U6 - https://doi.org/10.1016/j.bpj.2013.08.047 SN - 0006-3495 SN - 1542-0086 VL - 105 IS - 8 SP - 1915 EP - 1924 PB - Cell Press CY - Cambridge ER -