TY - JOUR A1 - Levy, Marion J. F. A1 - Boulle, Fabien A1 - Emerit, Michel Boris A1 - Poilbout, Corinne A1 - Steinbusch, Harry W. M. A1 - Van den Hove, Daniel L. A. A1 - Kenis, Gunter A1 - Lanfumey, Laurence T1 - 5-HTT independent effects of fluoxetine on neuroplasticity JF - Scientific Reports N2 - Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB. KW - depression KW - neurotrophic factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236759 VL - 9 ER - TY - JOUR A1 - Kurabi, Arwa A1 - Schaerer, Daniel A1 - Noack, Volker A1 - Bernhardt, Marlen A1 - Pak, Kwang A1 - Alexander, Thomas A1 - Husseman, Jacob A1 - Nguyen, Quyen A1 - Harris, Jeffrey P. A1 - Ryan, Allen F. T1 - Active Transport of Peptides Across the Intact Human Tympanic Membrane JF - Scientific Reports N2 - We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients. KW - assay systems KW - biological models Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230929 VL - 8 ER - TY - JOUR A1 - López, Cristina A1 - Kleinheinz, Kortine A1 - Aukema, Sietse M. A1 - Rohde, Marius A1 - Bernhart, Stephan H. A1 - Hübschmann, Daniel A1 - Wagener, Rabea A1 - Toprak, Umut H. A1 - Raimondi, Francesco A1 - Kreuz, Markus A1 - Waszak, Sebastian M. A1 - Huang, Zhiqin A1 - Sieverling, Lina A1 - Paramasivam, Nagarajan A1 - Seufert, Julian A1 - Sungalee, Stephanie A1 - Russell, Robert B. A1 - Bausinger, Julia A1 - Kretzmer, Helene A1 - Ammerpohl, Ole A1 - Bergmann, Anke K. A1 - Binder, Hans A1 - Borkhardt, Arndt A1 - Brors, Benedikt A1 - Claviez, Alexander A1 - Doose, Gero A1 - Feuerbach, Lars A1 - Haake, Andrea A1 - Hansmann, Martin-Leo A1 - Hoell, Jessica A1 - Hummel, Michael A1 - Korbel, Jan O. A1 - Lawerenz, Chris A1 - Lenze, Dido A1 - Radlwimmer, Bernhard A1 - Richter, Julia A1 - Rosenstiel, Philip A1 - Rosenwald, Andreas A1 - Schilhabel, Markus B. A1 - Stein, Harald A1 - Stilgenbauer, Stephan A1 - Stadler, Peter F. A1 - Szczepanowski, Monika A1 - Weniger, Marc A. A1 - Zapatka, Marc A1 - Eils, Roland A1 - Lichter, Peter A1 - Loeffler, Markus A1 - Möller, Peter A1 - Trümper, Lorenz A1 - Klapper, Wolfram A1 - Hoffmann, Steve A1 - Küppers, Ralf A1 - Burkhardt, Birgit A1 - Schlesner, Matthias A1 - Siebert, Reiner T1 - Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma JF - Nature Communications N2 - Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing. KW - cancer genomics KW - lymphocytes KW - lymphoid tissues KW - oncology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237281 VL - 10 ER - TY - JOUR A1 - Lu, Yuan A1 - Boswell, Wiliam A1 - Boswell, Mikki A1 - Klotz, Barbara A1 - Kneitz, Susanne A1 - Regneri, Janine A1 - Savage, Markita A1 - Mendoza, Cristina A1 - Postlethwait, John A1 - Warren, Wesley C. A1 - Schartl, Manfred A1 - Walter, Ronald B. T1 - Application of the Transcriptional Disease Signature (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model JF - Scientific Reports N2 - Cell culture and protein target-based compound screening strategies, though broadly utilized in selecting candidate compounds, often fail to eliminate candidate compounds with non-target effects and/or safety concerns until late in the drug developmental process. Phenotype screening using intact research animals is attractive because it can help identify small molecule candidate compounds that have a high probability of proceeding to clinical use. Most FDA approved, first-in-class small molecules were identified from phenotypic screening. However, phenotypic screening using rodent models is labor intensive, low-throughput, and very expensive. As a novel alternative for small molecule screening, we have been developing gene expression disease profiles, termed the Transcriptional Disease Signature (TDS), as readout of small molecule screens for therapeutic molecules. In this concept, compounds that can reverse, or otherwise affect known disease-associated gene expression patterns in whole animals may be rapidly identified for more detailed downstream direct testing of their efficacy and mode of action. To establish proof of concept for this screening strategy, we employed a transgenic strain of a small aquarium fish, medaka (Oryzias latipes), that overexpresses the malignant melanoma driver gene xmrk, a mutant egfr gene, that is driven by a pigment cell-specific mitf promoter. In this model, melanoma develops with 100% penetrance. Using the transgenic medaka malignant melanoma model, we established a screening system that employs the NanoString nCounter platform to quantify gene expression within custom sets of TDS gene targets that we had previously shown to exhibit differential transcription among xmrk-transgenic and wild-type medaka. Compound-modulated gene expression was identified using an internet-accessible custom-built data processing pipeline. The effect of a given drug on the entire TDS profile was estimated by comparing compound-modulated genes in the TDS using an activation Z-score and Kolmogorov-Smirnov statistics. TDS gene probes were designed that target common signaling pathways that include proliferation, development, toxicity, immune function, metabolism and detoxification. These pathways may be utilized to evaluate candidate compounds for potential favorable, or unfavorable, effects on melanoma-associated gene expression. Here we present the logistics of using medaka to screen compounds, as well as, the development of a user-friendly NanoString data analysis pipeline to support feasibility of this novel TDS drug-screening strategy. KW - bioinformatics KW - phenotypic screening Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237322 VL - 9 ER - TY - JOUR A1 - Meral, Derya A1 - Provasi, Davide A1 - Prada-Gracia, Diego A1 - Möller, Jan A1 - Marino, Kristen A1 - Lohse, Martin J. A1 - Filizola, Marta T1 - Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations JF - Scientific Reports N2 - Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer. Analysis of these computations identifies kinetically distinct macrostates comprising several different short-lived dimeric configurations of either inactive or activated MOR. Calculated kinetic rates and fractions of dimers at different MOR concentrations suggest a negligible population of MOR homodimers at physiological concentrations, which is supported by acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments. This study provides a rigorous, quantitative explanation for some conflicting experimental data on GPCR oligomerization. KW - computational biophysics KW - fluorescence resonance energy transfer Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223995 VL - 8 ER - TY - JOUR A1 - Medler, Juliane A1 - Nelke, Johannes A1 - Weisenberger, Daniela A1 - Steinfatt, Tim A1 - Rothaug, Moritz A1 - Berr, Susanne A1 - Hünig, Thomas A1 - Beilhack, Andreas A1 - Wajant, Harald T1 - TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity JF - Cell Death & Disease N2 - Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed. KW - biologics KW - proteins Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223948 VL - 10 ER - TY - THES A1 - Hahn, Sarah T1 - Investigating non-canonical, 5' UTR-dependent translation of MYC and its impact on colorectal cancer development T1 - Untersuchung der nicht-kanonischen, 5' UTR-abhängigen Translation von MYC und ihres Einflusses auf die Entwicklung von Darmkrebs N2 - Colorectal cancer (CRC) is the second most common tumour disease in Germany, with the sequential accumulation of certain mutations playing a decisive role in the transition from adenoma to carcinoma. In particular, deregulation of the Wnt signalling pathway and the associated deregulated expression of the MYC oncoprotein play a crucial role. Targeting MYC thus represents an important therapeutic approach in the treatment of tumours. Since direct inhibition of MYC is challenging, various approaches have been pursued to date to target MYC indirectly. The MYC 5' UTR contains an internal ribosomal entry site (IRES), which has a particular role in the initiation of MYC translation, especially in multiple myeloma. As basis for this work, it was hypothesised on the basis of previous data that translation of MYC potentially occurs via its IRES in CRC as well. Based on this, two IRES inhibitors were tested for their potential to regulate MYC expression in CRC cells. In addition, alternative, 5’ UTR-dependent translation of MYC and interacting factors were investigated. EIF3D was identified as a MYC 5' UTR binding protein which has the potential to regulate MYC expression in CRC. The results of this work suggest that there is a link between eIF3D and MYC expression/translation, rendering eIF3D a potential therapeutic target for MYC-driven CRCs. N2 - Das kolorektale Karzinom (KRK) ist die zweithäufigste Tumorerkrankung in Deutschland, wobei die sequenzielle Akkumulation bestimmter Mutationen eine entscheidende Rolle beim Übergang vom Adenom zum Karzinom spielt. Insbesondere die Deregulation des Wnt-Signalweges und die damit verbundene deregulierte Expression des MYC-Onkoproteins spielen eine entscheidende Rolle. MYC ist ein zentraler Vermittler von Zellfunktionen und reguliert als Transkriptionsfaktor die Expression fast aller Gene sowie verschiedener RNA-Spezies. Selbst kleine Veränderungen der zellulären MYC-Konzentration können das Proliferationsverhalten beeinflussen und die Entstehung und das Fortschreiten von Tumoren fördern. Die gezielte Beeinflussung von MYC stellt daher einen wichtigen therapeutischen Ansatz für die Behandlung von Tumoren dar. Da eine direkte Hemmung von MYC aufgrund seiner Struktur herausfordernd ist, wurden bisher verschiedene Ansätze verfolgt, um MYC indirekt zu beeinflussen, etwa über seinen Interaktionspartner MAX oder auf Ebene der Stabilität, Transkription oder Translation. In unserer eigenen Forschungsgruppe lag der Schwerpunkt in den letzten Jahren speziell auf der Translation von MYC im KRK. Es konnte gezeigt werden, dass die Hemmung der kanonischen cap-abhängigen Translation nicht wie erwartet zu einer Verringerung der zellulären MYC-Level führt, was auf einen alternativen Mechanismus der MYC-Translation hindeutet, der unabhängig vom eIF4F-Komplex abläuft. Die 5'-UTR von MYC enthält eine interne ribosomale Eintrittsstelle (IRES), die eine besondere Rolle bei der Initiierung der MYC-Translation spielt, insbesondere im Multiplen Myelom. Als Grundlage für diese Arbeit wurde daher die Hypothese aufgestellt, dass die Translation von MYC im KRK möglicherweise ebenfalls über die IRES erfolgt. Auf dieser Grundlage wurden zunächst zwei publizierte IRES-Inhibitoren auf ihr Potenzial zur Regulierung der MYC-Expression in KRK-Zellen getestet. J007-IRES hatte keine Auswirkungen auf die MYC-Proteinmenge, und Cymarin scheint weitaus globalere Auswirkungen zu haben, die nicht ausschließlich auf die Verringerung der MYC-Proteinmenge zurückzuführen sind. Daher wurde weiter untersucht, inwieweit die alternative Translation von MYC generell von der 5'-UTR und damit interagierenden Faktoren abhängig ist. EIF3D wurde als MYC-5'-UTR-Bindungsprotein identifiziert, dessen Knockdown zu reduzierten MYC-Leveln, einem Proliferationsdefizit sowie einer Verringerung der globalen Proteinsynthese in KRK-Zellen führte. Darüber hinaus führte die Depletion von EIF3D zu ähnlichen Veränderungen im zellulären Genexpressionsmuster wie die Depletion von MYC, wobei viele tumorassoziierte Signalwege betroffen waren. Mittels eCLIP-seq wurde die Bindung von eIF3D an die MYC mRNA nachgewiesen, der genaue Mechanismus einer möglicherweise durch eIF3D vermittelten Translation von MYC muss jedoch weiter untersucht werden. Die Ergebnisse dieser Arbeit deuten darauf hin, dass eine Verbindung zwischen eIF3D und der MYC-Expression/Translation besteht, wodurch eIF3D zu einem potenziellen therapeutischen Ziel für MYC-getriebene KRKs wird. KW - Myc KW - Translation KW - Colorectal cancer KW - 5' UTR Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364202 ER - TY - THES A1 - Bönninger, Solveig Eva T1 - Förderliche und hinderliche Faktoren im Trauerprozess von Nahestehenden eines*r Verstorbenen T1 - Supporting and Hindering Factors in the Grieving Process of Close Relatives of a Deceased Person N2 - Laut Statistischem Bundesamt (Destatis) starben allein im Jahr 2020 zirka 985.500 Menschen. Die häufigsten Todesursachen waren Herz-Kreislauf- und Krebs-Erkrankungen (vgl. Destatis 2020). Die meisten Menschen haben den Wunsch zuhause zu sterben, doch die Mehrheit stirbt in Krankenhäusern, Alten- und Pflegeheimen (vgl. DHPV 2017; Dasch et al. 2015). Der Tod eines nahestehenden Menschen kann bei Hinterbliebenen zu großen Belastungen, gesundheitlichen Problemen sowie einer gesteigerten Mortalität führen (vgl. Stroebe et al. 2007). Ziel dieser Arbeit war es, mit Hilfe von halbstandardisierten Interviews mit 30 Trauernden Faktoren herauszuarbeiten, die sich förderlich oder hinderlich auf den Trauerprozess auswirken können. Die Interviews wurden mit der Transkriptionssoftware f4transkript verschriftlicht und mittels qualitativer Inhaltsanalyse nach Mayring ausgewertet. Es entstand ein Kategoriensystem mit je vier Oberkategorien innerhalb der zwei Hauptkategorien, Förderliche und Hinderliche Faktoren. Folgende Faktoren konnten identifiziert werden: Förderliche Faktoren in der Oberkategorie Betreuung der erkrankten und trauernden Person sind eine gute Symptomkontrolle sowie der verständnisvolle Umgang mit den Nahestehenden, während mangelhafte Kommunikation wiederum hinderlich für eine positive Trauerbewältigung ist. In der Oberkategorie Intrapersonale Faktoren sind die Antizipation des Todes sowie die Auseinandersetzung mit der Trauer förderlich, während negative Gefühle (z.B. Schuldgefühle, Hilfslosigkeit) sich in besagter Hinsicht hinderlich auswirken. In der Oberkategorie Beziehung zur verstorbenen Person können die optimale Nutzung der verbliebenen Zeit sowie der offene Umgang mit der Erkrankung förderliche Faktoren darstellen, während ein “schwieriger“ Abschied sowie ungeklärte Konflikte oder offene Fragen Hindernisse für den Trauerprozess sein können. In der Oberkategorie Soziales Umfeld sind die unaufgeforderte Unterstützung, die emotionale Begleitung sowie ein flexibler Arbeitgeber förderlich. Streitigkeiten innerhalb der Familie und Unverständnis der Mitmenschen dagegen sind hinderlich. Eine gute und würdevolle Sterbebegleitung, wie sie in der Palliativmedizin in der Regel gewährleistet ist, ist von großer Bedeutung für einen gelingenden Trauerprozess. Daher sollte eine palliative Haltung disziplinübergreifend vorangebracht und ausgebaut werden. In der Gesellschaft sollte Trauernden mehr Toleranz und Verständnis entgegengebracht und offen mit dem Thema Tod und Sterben umgegangen werden. N2 - According to the German Federal Statistical Office (Destatis), approximately 985,500 people died in the year 2020 in Germany. The most common causes of death were cardiovascular diseases and cancer (cf. Destatis 2020). Most people wish to die at home, but the majority die in hospitals and care facilities (cf. DHPV 2017; Dasch et al. 2015). The death of a close person can lead to significant difficulties, health problems, and increased mortality among the bereaved (cf. Stroebe et al. 2007). The aim of this study was to identify factors that can have a supporting or hindering effect on the grieving process by conducting semi-structured interviews with 30 mourners. The interviews were transcribed using the f4transkript transcription software and evaluated using qualitative content analysis according to Mayring. A category system was developed with four subcategories within the two main categories, Supporting and Hindering Factors. The following factors were identified: Supporting factors in the subcategory "Care of the sick and grieving person" include good symptom control and understanding treatment of the relatives, while poor communication, in turn, is a hindrance to positive grief coping. In the subcategory "Intrapersonal factors", the anticipation of death and dealing with grief are supportive, while negative emotions (e.g., feelings of guilt, helplessness) have a hindering effect in this regard. In the subcategory "Relationship with the deceased person", optimal use of the remaining time and open handling of the illness can be supporting factors, while a "difficult" farewell and unresolved conflicts or open questions can be obstacles to the grieving process. In the subcategory "Social environment", unsolicited support, emotional companionship, and a flexible employer are supporting. Family disputes and a lack of understanding from others, on the other hand, are hindering. Good and dignified end-of-life care, as is generally ensured in palliative medicine, is of great importance for a successful grieving process. Therefore, a palliative attitude should be promoted and expanded across disciplines. In society, more tolerance and understanding should be shown to mourners, and the topic of death and dying should be dealt with openly. KW - Trauer KW - Trauerarbeit KW - Prolonged grief disorder KW - Trauerprozess KW - Soziales Umfeld KW - Beziehung zur verstorbenen Person KW - Medizinisch-psychologische Betreuung KW - Intrapersonale Faktoren KW - Milieu Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364319 ER - TY - THES A1 - Morabbian, Jasamin T1 - Etablierung von Stammzell-Sphäroiden mit inkorporierten Biokeramik-Partikeln zur Förderung der osteogenen Differenzierung T1 - Establishment of stem cell spheroids with incorporated bioceramic particles for the promotion of osteogenic differentiation N2 - In der vorliegenden Dissertationsarbeit wurden Sphäroide aus mesenchymalen Stammzellen aus dem Fettgewebe oder dem Knochenmark mittels der Micromold-Methode hergestellt. Den Sphäroiden wurden entweder Calciumphosphat- oder Calcium-Magnesium-Phosphat-Partikel hinzugefügt. Zum einen sollte überprüft werden, ob die Zugabe von Partikeln die osteogene Differenzierung der Sphäroide fördert und somit zur weiteren Entwicklung von körpereigenem Knochenersatzmaterial in der regenerativen Medizin beiträgt. Zum anderen sollte festgestellt werden, ob eine der beiden Biokeramiken hinsichtlich der osteogenen Differenzierung überlegen ist. N2 - In this dissertation, spheroids were produced from mesenchymal stem cells from adipose tissue or bone marrow using the micromold method. Either calcium phosphate or calcium magnesium phosphate particles were added to the spheroids. On the one hand, it was to be examined whether the addition of particles promotes the osteogenic differentiation of the spheroids and thus contributes to the further development of endogenous bone replacement material in regenerative medicine. Secondly, to determine whether one of the two bioceramics is superior in terms of osteogenic differentiation. KW - Stammzelle KW - Calciumphosphat KW - Spheroid KW - Knochenzement KW - Knochenersatzmaterial KW - Calcium-Magnesium-Phosphat Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369256 ER - TY - THES A1 - Yabe, Marie T1 - Untersuchung des Mental Rotation-Paradigmas bei Patienten mit fokaler Dystonie T1 - Mental Rotation performance in patients with focal dystonia N2 - Das mR-Paradigma beschreibt die Fähigkeit Objekte gedanklich zu drehen und erfordert dabei komplexe neuronale Prozesse. Bisherige Studien konnten nicht klären, ob es ein spezifisches Muster der Beeinträchtigung im mR-Test bei fokalen Dystonien gibt. Die übergeordnete Fragestellung der vorliegenden Arbeit war, ob eine verlangsamte Reaktion bei der mR von körperlichen Abbildungen einen stabilen Endophänotyp fokaler Dystonien darstellt. Die Zielsetzung war die Überprüfung der Hypothesen, 1) dass bisherige Ergebnisse, die eine verlängerte Reaktionszeit von CD-Patienten bei der mR von körperlichen Abbildungen aufzeigten, reproduzierbar sind und 2) dass eine erhöhte Reaktionszeit bei der mR von körperlichen Abbildungen auch bei Patienten mit BSP vorliegt. Um dabei die mR möglichst spezifisch zu untersuchen, wurden folgende sekundäre Hypothesen formuliert: a) die kognitive Leistungsfähigkeit und b) das allgemeine Reaktionsvermögen der Teilnehmer stellen potenzielle Störfaktoren für die Reaktionszeit bei der mR-Aufgabe dar. Diese wurden neben der Händigkeit und der allgemeinen Geschicklichkeit systematisch erhoben. 23 CD-Patienten und 23 gesunde Kontrollpersonen sowie 21 BSP- und 19 HFS-Patienten wurden hinsichtlich Geschlechterverteilung, Alter und Bildungsstand verglichen. Zudem wurden Händigkeit, Fingergeschicklichkeit, allgemeine Reaktionszeit und kognitiver Status jedes Teilnehmers erhoben. Im mR-Test wurden Fotos von Körperteilen (Hand, Fuß oder Kopf) und einem nicht-körperlichen Objekt (Auto) gezeigt, die in sechs verschiedene Winkelgrade um die eigene Achse in der Bildebene rotiert waren. Die Teilnehmer wurden gebeten, die Lateralität des dargestellten Bildes per Tastendruck anzugeben. Bewertet wurden sowohl Geschwindigkeit als auch Richtigkeit der Antworten. Im Vergleich zu gesunden Kontrollpersonen schnitten CD- und HFS-Patienten bei der mR der Hände schlechter ab, während die BSP-Patienten vergleichbare Leistungen zeigten. Es bestand ein signifikanter Zusammenhang zwischen einer verlängerten mR-Reaktionszeit und reduzierten MoCA-Scores sowie einer erhöhten mR-Reaktionszeit und verlängerter allgemeiner Reaktionszeit. Nach Ausschluss der Patienten mit MCI zeigten CD-Patienten, nicht jedoch HFS-Patienten, im Vergleich zur gesunden Kontrollgruppe weiterhin verlangsamte Reaktionszeiten der Hände. Die vorliegende Studie konnte die Frage, ob eine verlangsamte Reaktion bei der mR von körperlichen Abbildungen einen stabilen Endophänotyp fokaler Dystonien darstellt, nicht sicher beantworten. Es stellte sich jedoch heraus, dass Kognition und allgemeine Reaktionszeit starke Einflussfaktoren bei der mR-Aufgabe sind. Dies wurde in den früheren Arbeiten nicht berücksichtigt und stellt daher ein neues und wichtiges Ergebnis dar. Die verlangsamte Reaktion bei der mR der Hände bei CD-Patienten auch nach Ausschluss von Patienten mit MCI lässt ein spezifisches Defizit der Fähigkeit der mR vermuten. Das Vorliegen einer tiefergreifenden zugrundeliegenden Netzwerkstörung, die sich auf die Leistung im mR-Test auswirkt, wäre dabei denkbar. N2 - Mental rotation (mR) describes the ability to rotate objects in mind. Previous studies could not clarify whether there is a specific pattern of mR impairment in focal dystonia. This study aimed to investigate whether patients with cervical dystonia (CD) and blepharospasm (BSP) show an increased reaction time (RT) in mR of body parts. Besides the study aimed to assess potential confounders such as cognitive performance and general reaction time. 23 CD patients and 23 healthy controls (K) as well as 21 BSP and 19 hemifacial spasm (HFS) patients were matched for sex, age, and education level. Disease severity was evaluated by clinical scales. Besides handedness, finger dexterity, general reaction time, and cognitive status were assessed. The mR-task included photographs of body parts (hand, foot or head) and a non-corporal object (car) displayed at different angles rotated within their plane. Subjects were asked to judge laterality of the presented image by keystroke. Both speed and correctness were evaluated. CD and HFS patients showed increased RT in mR of hands compared to K, whereas BSP group showed comparable performance. There was a significant association of prolonged mR-RT with reduced MoCA scores and with increased general reaction time. After exclusion of patients with mild cognitive impairment, increased RT in the mR of hands was confined to CD group, but not HFS. The present study could not clarify whether a prolonged RT in mR of body parts defines a dystonic endophenotype. However, it showed that cognition and general reaction time have strong influence on mR. The increased RT in the mR of the hands in CD patients, even after exclusion of patients with mild cognitive impairment, implicate a specific deficit in mR ability. Thereby an underlying network disorder that affects mR performance is conceivable. KW - mental rotation KW - fokale Dystonie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363927 ER - TY - THES A1 - Laqua, Caroline T1 - Association of myocardial tissue characteristics and functional outcome in biopsy-verified myocarditis assessed by cardiac magnetic resonance imaging T1 - Zusammenhänge zwischen geweblichen Eigenschaften des Myokards und funktionellem Outcome bei biopsie-verifizierter Myokarditis im Kardio-MRT N2 - The relation between LV function and cardiac MRI tissue characteristics in separate myocardial segments and their change over time has yet to be explored in myocarditis. Thus, our research aimed to investigate possible associations between global and regional myocardial T1 and T2 times and peak strain in patients with suspected myocarditis. From 2012 to 2015, 129 patients with clinically suspected myocarditis of the prospective, observational MyoRacer-Trial underwent systematic biventricular EMB at baseline and cardiac MRI at baseline and after three months as a follow-up. We divided the LV myocardium into 17 segments and estimated the segmental myocardial strain using FT. We registered T1 and T2 maps to the cine sequences and transferred the segmentations used for FT to ensure conformity of the myocardial segments. Multi-level multivariable linear mixed effects regression was applied to investigate the relation of segmental myocardial strain to relaxation times and their respective change from baseline to follow-up. We found a significant improvement in myocardial peak strain from baseline to follow-up (p < 0.001; all p-values given for likelihood ratio tests) and significant associations between higher T1 and T2 times and lower segmental myocardial peak strain (p ranging from < 0.001 to 0.049). E.g., regression coefficient (Reg. coef.) for segmental radial peak strain in short axis view (SRPS_SAX) and T1 time: -1.9, 95% CI (-2.6;-1.2) %/100 ms, p < 0.001. A decrease in T1 and T2 times from baseline to follow-up was also significantly related to a recovery of segmental peak strains (p ranging from < 0.001 to 0.050). E.g., Reg. coef. for SRPS_SAX per ΔT1: -1.8, 95% CI (-2.5;-1.0) %/100 ms, p < 0.001. Moreover, the higher the baseline T1 time, the more substantial the functional recovery from baseline to follow-up (p ranging from 0.004 to 0.042, e.g., for SRPS_SAX: Reg. coef. 1.3, 95% CI (0.4;2.1) %/100 ms, p 0.004). We did not find an effect modification by the presence of myocarditis in the EMB (p > 0.1). Our cross-sectional and longitudinal analyses provide evidence of dose-dependent correlations between T1 and T2 relaxation times and myocardial peak strain in patients with clinical presentation of myocarditis, regardless of the EMB result. Thus, assessing strain values and mapping relaxation times helps estimate the functional prognosis in patients with clinically suspected myocarditis. N2 - Die Zusammenhänge zwischen der kardialen linksventrikulären (LV) Funktion und magnetresonanztomographisch erhebbaren Parametern des Myokards sowie deren jeweiligen Entwicklungen im zeitlichen Verlauf einer Myokarditis sind bisher nicht umfassend untersucht. Daher beschäftigt sich die vorliegende Arbeit mit der Erforschung des Verhältnisses von globalen und regionalen peak strain-Werten und T1 und T2 Zeiten des LV Myokards in der Magnetresonanztomographie (MRT) bei Patienten mit Verdacht auf Myokarditis. Die MyoRacer-Studie ist eine prospektive Beobachtungsstudie, die von 2012 bis 2015 am Herzzentrum des Universitätsklinikums Leipzig durchgeführt wurde. Dabei wurden 129 Patienten mit klinischem Verdacht auf Myokarditis mittels biventrikulärer Myokardbiopsie sowie kardialer MRT untersucht. Drei Monate nach der Erstuntersuchung (EU) erfolgte eine MRT-Folgeuntersuchung (FU). Für unsere Analysen unterteilten wir das LV Myokard standardmäßig in 17 Segmente, um mithilfe der Technik des feature trackings den segmentalen peak strain zu evaluieren. Weiterhin registrierten wir T1 und T2 maps gegen cine-Sequenzen der MRT und übertrugen die Segmentierungen aus den cine-Sequenzen zwecks Übereinstimmung in die MRT maps. Anschließend analysierten wir die Zusammenhänge zwischen segmentalem strain und T1 und T2 Zeiten und deren jeweiligen Veränderungen im zeitlichen Verlauf mithilfe eines hierarchischen, multivariablen, gemischten linearen Regressionsmodells. Unsere Ergebnisse zeigen eine signifikante Verbesserung der peak strain-Werte von der EU zur FU (p < 0.001; alle p-Werte für likelihood ratio tests angegeben) sowie eine signifikante Assoziation von erhöhten T1 und T2 Zeiten mit verminderten segmentalen peak strain-Werten (p zwischen < 0.001 und 0.049). Weiterhin war ein Abfall der T1 und T2 Zeiten von der EU zur FU signifikant mit einer Erholung der segmentalen peak strain-Werte verknüpft (p zwischen < 0.001 und 0.050). Je höher die T1 Zeiten bei der EU ausfielen, desto stärker erholte bzw. verbesserte sich der peak strain von der EU zur FU (p zwischen 0.004 und 0.042). Eine Effektmodifikation durch den bioptischen Nachweis einer Myokarditis war nicht zu beobachten (p > 0.1). Unsere Quer- und Längsschnittanalysen belegen dosisabhängige Zusammenhänge zwischen T1 und T2 Zeiten und myokardialen peak strain-Werten bei Patienten mit dem klinischen Bild einer Myokarditis, unabhängig vom Ergebnis der Myokardbiopsie. Daher ist die Bestimmung von T1 und T2 Zeiten und myokardialem strain mittels kardialer MRT zur Abschätzung der funktionellen Prognose bei Patienten mit klinischem Verdacht auf Myokarditis hilfreich. KW - Myokarditis KW - Kernspintomografie KW - T1-Zeit KW - T2-Zeit KW - strain KW - t1 time KW - t2 time KW - myocarditis KW - MRI Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363903 ER - TY - JOUR A1 - Snaebjornsson, Marteinn T A1 - Schulze, Almut T1 - Non-canonical functions of enzymes facilitate cross-talk between cell metabolic and regulatory pathways JF - Experimental & Molecular Medicine N2 - The metabolic rewiring that occurs during cell transformation is a hallmark of cancer. It is diverse in different cancers as it reflects different combinations of oncogenic drivers, tumor suppressors, and the microenvironment. Metabolic rewiring is essential to cancer as it enables uncontrolled proliferation and adaptation to the fluctuating availability of nutrients and oxygen caused by poor access to the vasculature due to tumor growth and a foreign microenvironment encountered during metastasis. Increasing evidence now indicates that the metabolic state in cancer cells also plays a causal role in tumor growth and metastasis, for example through the action of oncometabolites, which modulate cell signaling and epigenetic pathways to promote malignancy. In addition to altering the metabolic state in cancer cells, some multifunctional enzymes possess non-metabolic functions that also contribute to cell transformation. Some multifunctional enzymes that are highly expressed in cancer, such as pyruvate kinase M2 (PKM2), have non-canonical functions that are co-opted by oncogenic signaling to drive proliferation and inhibit apoptosis. Other multifunctional enzymes that are frequently downregulated in cancer, such as fructose-bisphosphatase 1 (FBP1), are tumor suppressors, directly opposing mitogenic signaling via their non-canonical functions. In some cases, the enzymatic and non-canonical roles of these enzymes are functionally linked, making the modulation of non-metabolic cellular processes dependent on the metabolic state of the cell. KW - cancer metabolism Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238763 VL - 50 ER - TY - JOUR A1 - Sirtl, Simon A1 - Knoll, Gertrud A1 - Dieu Thuy, Trinh A1 - Lang, Isabell A1 - Siegmund, Daniela A1 - Gross, Stefanie A1 - Schuler-Thurner, Beatrice A1 - Neubert, Patrick A1 - Jantsch, Jonathan A1 - Wajant, Harald A1 - Ehrenschwender, Martin T1 - Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors JF - Oncogene N2 - Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens. KW - apoptosis KW - cancer microenvironment KW - cytokines Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238327 VL - 37 ER - TY - JOUR A1 - Stegmann, Yannik A1 - Reicherts, Philipp A1 - Andreatta, Marta A1 - Pauli, Paul A1 - Wieser, Matthias J. T1 - The effect of trait anxiety on attentional mechanisms in combined context and cue conditioning and extinction learning JF - Scientific Reports N2 - Sensory processing and attention allocation are shaped by threat, but the role of trait-anxiety in sensory processing as a function of threat predictability remains incompletely understood. Therefore, we measured steady-state visual evoked potentials (ssVEPs) as an index of sensory processing of predictable and unpredictable threat cues in 29 low (LA) and 29 high (HA) trait-anxious participants during a modified NPU-paradigm followed by an extinction phase. Three different contextual cues indicated safety (N), predictable (P) or unpredictable threat (U), while foreground cues signalled shocks in the P-condition only. All participants allocated increased attentional resources to the central P-threat cue, replicating previous findings. Importantly, LA individuals exhibited larger ssVEP amplitudes to contextual threat (U and P) than to contextual safety cues, while HA individuals did not differentiate among contextual cues in general. Further, HA exhibited higher aversive ratings of all contexts compared to LA. These results suggest that high trait-anxious individuals might be worse at discriminating contextual threat stimuli and accordingly overestimate the probability and aversiveness of unpredictable threat. These findings support the notion of aberrant sensory processing of unpredictable threat in anxiety disorders, as this processing pattern is already evident in individuals at risk of these disorders. KW - attention KW - fear conditioning Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239394 VL - 9 ER - TY - JOUR A1 - Solimando, A G A1 - Brandl, A A1 - Mattenheimer, K A1 - Graf, C A1 - Ritz, M A1 - Ruckdeschel, A A1 - Stühmer, T A1 - Mokhtari, Z A1 - Rudelius, M A1 - Dotterweich, J A1 - Bittrich, M A1 - Desantis, V A1 - Ebert, R A1 - Trerotoli, P A1 - Frassanito, M A A1 - Rosenwald, A A1 - Vacca, A A1 - Einsele, H A1 - Jakob, F A1 - Beilhack, A T1 - JAM-A as a prognostic factor and new therapeutic target in multiple myeloma JF - Leukemia N2 - Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification. KW - haematological cancer KW - myeloma Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239069 VL - 32 ER - TY - JOUR A1 - Siegmund, Daniela A1 - Ehrenschwender, Martin A1 - Wajant, Harald T1 - TNFR2 unlocks a RIPK1 kinase activity-dependent mode of proinflammatory TNFR1 signaling JF - Cell Death & Disease N2 - TNF is not only a major effector molecule of PAMP/DAMP-activated macrophages, but also regulates macrophage function and viability. We recently demonstrated that TNFR2 triggers necroptosis in macrophages with compromised caspase activity by two cooperating mechanisms: induction of endogenous TNF with subsequent stimulation of TNFR1 and depletion of cytosolic TRAF2-cIAP complexes. Here we show that TNFR2 activation in caspase-inhibited macrophages results in the production of endogenous TNF and TNFR1 stimulation followed by upregulation of A20, TRAF1, IL-6, and IL-1β. Surprisingly, TNFR1-mediated induction of IL-6 and IL-1β was clearly evident in response to TNFR2 stimulation but occurred not or only weakly in macrophages selectively and directly stimulated via TNFR1. Moreover, TNFR2-induced TNFR1-mediated gene induction was largely inhibited by necrostatin-1, whereas upregulation of A20 and TRAF1 by direct and exclusive stimulation of TNFR1 remained unaffected by this compound. Thus, treatment with TNFR2/ZVAD enables TNFR1 in macrophages to stimulate gene induction via a pathway requiring RIPK1 kinase activity. TNFR2/ZVAD-induced production of IL-6 and IL-1β was largely blocked in necroptosis-resistant MLKL- and RIPK3-deficient macrophages, whereas induction of A20 and TRAF1 remained unaffected. In sum, our results show that in caspase-inhibited macrophages TNFR2 not only triggers TNF/TNFR1-mediated necroptosis but also TNF/TNFR1-mediated RIPK3/MLKL-dependent and -independent gene induction. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238034 VL - 9 ER - TY - JOUR A1 - Vaeth, Martin A1 - Wang, Yin-Hu A1 - Eckstein, Miriam A1 - Yang, Jun A1 - Silverman, Gregg J. A1 - Lacruz, Rodrigo S. A1 - Kannan, Kasthuri A1 - Feske, Stefan T1 - Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels JF - Nature Communications N2 - T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells. KW - gene regulation in immune cells KW - lymphocytes KW - regulatory T cells KW - signal transduction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232148 VL - 10 ER - TY - JOUR A1 - Sulzer, David A1 - Cassidy, Clifford A1 - Horga, Guillermo A1 - Kang, Un Jung A1 - Fahn, Stanley A1 - Casella, Luigi A1 - Pezzoli, Gianni A1 - Langley, Jason A1 - Hu, Xiaoping P. A1 - Zucca, Fabio A. A1 - Isaias, Ioannis U. A1 - Zecca, Luigi T1 - Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease JF - npj Parkinson's Disease N2 - The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240207 VL - 4 ER - TY - JOUR A1 - Ullrich, M A1 - Weber, M A1 - Post, A M A1 - Popp, S A1 - Grein, J A1 - Zechner, M A1 - González, H Guerrero A1 - Kreis, A A1 - Schmitt, A G A1 - Üҫeyler, N A1 - Lesch, K-P A1 - Schuh, K T1 - OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency JF - Molecular Psychiatry N2 - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD. KW - molecular biology KW - neuroscience KW - physiology KW - psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232096 VL - 23 ER - TY - JOUR A1 - Trautz, Florian A1 - Franke, Heike A1 - Bohnert, Simone A1 - Hammer, Niels A1 - Müller, Wolf A1 - Stassart, Ruth A1 - Tse, Rexson A1 - Zwirner, Johann A1 - Dreßler, Jan A1 - Ondruschka, Benjamin T1 - Survival-time dependent increase in neuronal IL-6 and astroglial GFAP expression in fatally injured human brain tissue JF - Scientific Reports N2 - Knowledge on trauma survival time prior to death following a lethal traumatic brain injury (TBI) may be essential for legal purposes. Immunohistochemistry studies might allow to narrow down this survival interval. The biomarkers interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) are well known in the clinical setting for their usability in TBI prediction. Here, both proteins were chosen in forensics to determine whether neuronal or glial expression in various brain regions may be associated with the cause of death and the survival time prior to death following TBI. IL-6 positive neurons, glial cells and GFAP positive astrocytes all concordantly increase with longer trauma survival time, with statistically significant changes being evident from three days post-TBI (p < 0.05) in the pericontusional zone, irrespective of its definite cortical localization. IL-6 staining in neurons increases significantly in the cerebellum after trauma, whereas increasing GFAP positivity is also detected in the cortex contralateral to the focal lesion. These systematic chronological changes in biomarkers of pericontusional neurons and glial cells allow for an estimation of trauma survival time. Higher numbers of IL-6 and GFAP-stained cells above threshold values in the pericontusional zone substantiate the existence of fatal traumatic changes in the brain with reasonable certainty. KW - cell death in the nervous system KW - diagnostic markers KW - outcomes research Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229037 VL - 9 ER -