TY - JOUR A1 - Asthana, Manish Kumar A1 - Brunhuber, Bettina A1 - Mühlberger, Andreas A1 - Reif, Andreas A1 - Schneider, Simone A1 - Herrmann, Martin J. T1 - Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism JF - International Journal of Neuropsychopharmacology N2 - Background: Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. Methods: An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. Results: The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Conclusions: Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans. KW - BDNF KW - brain derived neurotrophic factor KW - fear conditioning KW - genetics memory KW - reconsolidation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166217 VL - 19 IS - 6 ER - TY - JOUR A1 - Verma, Pramod Kumar A1 - Steinbacher, Andreas A1 - Schmiedel, Alexander A1 - Nuernberger, Patrick A1 - Brixner, Tobias T1 - Excited-state intramolecular proton transfer of 2-acetylindan-1,3-dione studied by ultrafast absorption and fluorescence spectroscopy JF - Structural Dynamics N2 - We employ transient absorption from the deep-UV to the visible region and fluorescence upconversion to investigate the photoinduced excited-state intramolecular proton-transfer dynamics in a biologically relevant drug molecule, 2-acetylindan-1,3-dione. The molecule is a ß-diketone which in the electronic ground state exists as exocyclic enol with an intramolecular H-bond. Upon electronic excitation at 300 nm, the first excited state of the exocyclic enol is initially populated, followed by ultrafast proton transfer (≈160 fs) to form the vibrationally hot endocyclic enol. Subsequently, solvent-induced vibrational relaxation takes place (≈10 ps) followed by decay (≈390 ps) to the corresponding ground state. KW - time resolved spectroscopy KW - ground states KW - fluorescence spectra KW - absorption spectra KW - ultraviolet light KW - hydrogen bonding KW - excited states KW - reaction mechanisms KW - fluorescence KW - solvents Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181301 VL - 3 ER - TY - JOUR A1 - Rasche, Leo A1 - Kumar, Manoj A1 - Gershner, Grant A1 - Samant, Rohan A1 - Van Hemert, Rudy A1 - Heidemeier, Anke A1 - Lapa, Constantin A1 - Bley, Thorsten A1 - Buck, Andreas A1 - McDonald, James A1 - Hillengass, Jens A1 - Epstein, Joshua A1 - Thanendrarajan, Sharmilan A1 - Schinke, Carolina A1 - van Rhee, Frits A1 - Zangari, Maurizio A1 - Barlogie, Bart A1 - Davies, Faith E. A1 - Morgan, Gareth J. A1 - Weinhold, Niels T1 - Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis? JF - Theranostics N2 - Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10(-10)) and International Staging System 3 (P=0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions: The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM. KW - multiple myeloma KW - diffusion weighted mri KW - spleen KW - tumor burden KW - high risk KW - extramedullary hematopoiesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224982 VL - 9 IS - 16 ER - TY - THES A1 - Kumar, Andreas T1 - Expression und Aufreinigung von intrazellulären Anteilen des Interleukin-4-Rezeptors als GST-Fusionsproteine und Messung von Protein-Protein-Wechselwirkungen T1 - Expression and Purification of Intracellular Parts of the Interleukin-4-Receptor as GST-Fusion-Proteins and Detection of Protein-Protein-Interactions N2 - In dieser Doktorarbeit wurden zwei intrazelluläre Anteile des IL-4 Rezeptors als GST-Fusionsproteine exprimiert. GST-E1, in dem das cytoplasmatische membranproximale 1/3 von IL-4Ralpha (173 AS) einschließlich des Box 1 Motivs an GST fusioniert ist, konnte nach differenzierter De- und Renaturierung und Bindung an Glutathion-Sepharose Matrix in elektrophoretisch reiner Form aufgereinigt werden. GST-gammainP5D4, in dem die intrazelluläre Domäne von gamma c an GST gebunden vorliegt, konnte nur als heterogenes Gemisch mit 4 C-terminal verkürzten Fraktionen erhalten werden. Mit diesen rekombinanten Fusionsproteinen wurden Immunpräzipitationsversuche in Lysaten IL-4R-transfizierter Ba/F3 Zellen vor und nach Stimulation mit IL-4 durchgeführt. Für GST-E1 wurde eine Wechselwirkung mit Jak1 nachgewiesen, die dem bisherigen Kenntnisstand entspricht; für GST-ginP5D4 hingegen konnte eine Wechselwirkung mit Jak3 nicht gezeigt werden. Beide Proteine sind in der Lage, STAT5 zu präzipitieren; diese Bindung erscheint unabhängig von der IL-4 Stimulation der Zellen und läßt neue Spekulationen über den Mechanismus der Signaltransduktion durch STAT5 zu. Danach könnten nach den hier gewonnenen Informationen beide IL-4-Rezeptorketten jeweils ein STAT5 Molekül zur STAT5-Dimerisirerung nach Rezeptoraktivierung beitragen. Es ist somit gelungen, ein in-vitro-Modell zur Messung von Protein-Protein-Wechselwirkungen am IL-4 Rezeptor zu etablieren, welches für weitere Untersuchungen eingesetzt werden kann. N2 - Two intracellular parts of the interleukin-4-receptor were expressed as GST-fusion-proteins. GST-E1, which comprises the cytoplasmic membrane-proximal 1/3 of IL-4Ralpha (173 AS) including the box1-motif fused to GST, could be purified electrophoretically clean after differential denaturation and renaturation and specific binding to Glutathion-Sepharose Matrix. GSTgammainP5D4, which comprises the intracellular domain of gamma c fused to GST, could only be purified as a heterogenous mixture with 4 C-terminally truncated proteins. Immunoprecipitation experiments were performed in lysates of IL-4R transfected Ba/F3 cells before and after stimulation with IL-4. For GST-E1, an interaction with Jak1 was shown, reflecting the current state of knowledge; however, an interaction with Jak3 could not be shown for GSTgamma in P5D4. Both proteins are able tp precipitate STAT5; this binding appears independet of IL-4 stimulation of the cells and allows for new speculations on the signal transduction mechanism by STAT5. According to the information gained in this work, both IL-4-receptor chains could contribute one STAT5 molecule to STAT5 dimerisation after receptor activation. Therefore, the goal was achieved to establish an in-vitro-model for the detection of protein-protein interactions on the interleukin-4-receptor, which can be used for further investigations. KW - Interleukin-4 KW - Rezeptor KW - Signaltransduktion KW - GST-Fusionsprotein KW - Jak/ STAT KW - Interleukin-4 KW - receptor KW - signal transduction KW - GST fusion protein KW - Jak/ STAT Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5338 ER -