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 - Breun, Maria A1 - Monoranu, Camelia M. A1 - Kessler, Almuth F. A1 - Matthies, Cordula A1 - Löhr, Mario A1 - Hagemann, Carsten A1 - Schirbel, Andreas A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Buck, Andreas K. A1 - Wester, Hans-Jürgen A1 - Ernestus, Ralf-Ingo A1 - Lapa, Constantin T1 - [\(^{68}\)Ga]-Pentixafor PET/CT for CXCR4-mediated imaging of vestibular schwannomas JF - Frontiers in Oncology N2 - We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor. Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients. Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors. Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression. KW - vestibular schwannoma KW - CXCR4 KW - PET/CT KW - molecular imaging KW - Pentixafor Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201863 VL - 9 IS - 503 ER - TY - JOUR A1 - Drescher, Nora A1 - Klein, Alexandra-Maria A1 - Schmitt, Thomas A1 - Leonhardt, Sara Diana T1 - A clue on bee glue: New insight into the sources and factors driving resin intake in honeybees (Apis mellifera) JF - PLoS ONE N2 - Honeybees (Apis mellifera) are threatened by numerous pathogens and parasites. To prevent infections they apply cooperative behavioral defenses, such as allo-grooming and hygiene, or they use antimicrobial plant resin. Resin is a chemically complex and highly variable mixture of many bioactive compounds. Bees collect the sticky material from different plant species and use it for nest construction and protection. Despite its importance for colony health, comparatively little is known about the precise origins and variability in resin spectra collected by honeybees. To identify the botanical resin sources of A. mellifera in Western Europe we chemically compared resin loads of individual foragers and tree resins. We further examined the resin intake of 25 colonies from five different apiaries to assess the effect of location on variation in the spectra of collected resin. Across all colonies and apiaries, seven distinct resin types were categorized according to their color and chemical composition. Matches between bee-collected resin and tree resin indicated that bees used poplar (Populus balsamifera, P. x canadensis), birch (Betula alba), horse chestnut (Aesculus hippocastanum) and coniferous trees (either Picea abies or Pinus sylvestris) as resin sources. Our data reveal that honeybees collect a comparatively broad and variable spectrum of resin sources, thus assuring protection against a variety of antagonists sensitive to different resins and/or compounds. We further unravel distinct preferences for specific resins and resin chemotypes, indicating that honeybees selectively search for bioactive resin compounds. KW - Honey bees KW - Poplars KW - Trees KW - Forests KW - Chemical composition KW - Bees KW - Conifers KW - Phenols Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200935 VL - 14 IS - 2 ER - TY - JOUR A1 - Richter, Gesa M. A1 - Kruppa, Jochen A1 - Munz, Matthias A1 - Wiehe, Ricarda A1 - Häsler, Robert A1 - Franke, Andre A1 - Martins, Orlando A1 - Jockel-Schneider, Yvonne A1 - Bruckmann, Corinna A1 - Dommisch, Henrik A1 - Schaefer, Arne S. T1 - A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers JF - Clinical Epigenetics N2 - Background The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. Results Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1. Conclusion This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa. KW - EWAS KW - Methylation KW - Expression KW - Masticatory mucosa KW - CYP1B1 KW - AHRR KW - Cytochrome P 450 pathway KW - OSCC KW - Smoking Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226175 VL - 11 ER - TY - JOUR A1 - Paelecke-Habermann, Yvonne A1 - Paelecke, Marko A1 - Mauth, Juliane A1 - Tschisgale, Juliane A1 - Lindenmeyer, Johannes A1 - Kübler, Andrea T1 - A comparison of implicit and explicit reward learning in low risk alcohol users versus people who binge drink and people with alcohol dependence JF - Addictive Behaviors Reports N2 - Chronic alcohol use leads to specific neurobiological alterations in the dopaminergic brain reward system, which probably are leading to a reward deficiency syndrome in alcohol dependence. The purpose of our study was to examine the effects of such hypothesized neurobiological alterations on the behavioral level, and more precisely on the implicit and explicit reward learning. Alcohol users were classified as dependent drinkers (using the DSM-IV criteria), binge drinkers (using criteria of the USA National Institute on Alcohol Abuse and Alcoholism) or low-risk drinkers (following recommendations of the Scientific board of trustees of the German Health Ministry). The final sample (n = 94) consisted of 36 low-risk alcohol users, 37 binge drinkers and 21 abstinent alcohol dependent patients. Participants were administered a probabilistic implicit reward learning task and an explicit reward- and punishment-based trial-and-error-learning task. Alcohol dependent patients showed a lower performance in implicit and explicit reward learning than low risk drinkers. Binge drinkers learned less than low-risk drinkers in the implicit learning task. The results support the assumption that binge drinking and alcohol dependence are related to a chronic reward deficit. Binge drinking accompanied by implicit reward learning deficits could increase the risk for the development of an alcohol dependence. KW - Alcohol dependence KW - Binge drinking KW - Low risk alcohol use KW - Implicit and explicit reward learning Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201406 VL - 9 ER - TY - JOUR A1 - Groll, J A1 - Burdick, J A A1 - Cho, D-W A1 - Derby, B A1 - Gelinsky, M A1 - Heilshorn, S C A1 - Jüngst, T A1 - Malda, J A1 - Mironov, V A A1 - Nakayama, K A1 - Ovsianikov, A A1 - Sun, W A1 - Takeuchi, S A1 - Yoo, J J A1 - Woodfield, T B F T1 - A definition of bioinks and their distinction from biomaterial inks JF - Biofabrication N2 - Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384–402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks. KW - bioink KW - biomaterial ink KW - definition Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-253993 VL - 11 IS - 1 ER - TY - JOUR A1 - Steuer Costa, Wagner A1 - Van der Auwera, Petrus A1 - Glock, Caspar A1 - Liewald, Jana F. A1 - Bach, Maximilian A1 - Schüler, Christina A1 - Wabnig, Sebastian A1 - Oranth, Alexandra A1 - Masurat, Florentin A1 - Bringmann, Henrik A1 - Schoofs, Liliane A1 - Stelzer, Ernst H. K. A1 - Fischer, Sabine C. A1 - Gottschalk, Alexander T1 - A GABAergic and peptidergic sleep neuron as a locomotion stop neuron with compartmentalized Ca2+ dynamics JF - Nature Communications N2 - Animals must slow or halt locomotion to integrate sensory inputs or to change direction. In Caenorhabditis elegans, the GABAergic and peptidergic neuron RIS mediates developmentally timed quiescence. Here, we show RIS functions additionally as a locomotion stop neuron. RIS optogenetic stimulation caused acute and persistent inhibition of locomotion and pharyngeal pumping, phenotypes requiring FLP-11 neuropeptides and GABA. RIS photoactivation allows the animal to maintain its body posture by sustaining muscle tone, yet inactivating motor neuron oscillatory activity. During locomotion, RIS axonal Ca2+ signals revealed functional compartmentalization: Activity in the nerve ring process correlated with locomotion stop, while activity in a branch correlated with induced reversals. GABA was required to induce, and FLP-11 neuropeptides were required to sustain locomotion stop. RIS attenuates neuronal activity and inhibits movement, possibly enabling sensory integration and decision making, and exemplifies dual use of one cell across development in a compact nervous system. KW - cellular neuroscience KW - neural circuits Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223273 VL - 10 ER - TY - JOUR A1 - Rayner, Christopher A1 - Coleman, Jonathan R. I. A1 - Purves, Kirstin L. A1 - Hodsoll, John A1 - Goldsmith, Kimberley A1 - Alpers, Georg W. A1 - Andersson, Evelyn A1 - Arolt, Volker A1 - Boberg, Julia A1 - Bögels, Susan A1 - Creswell, Cathy A1 - Cooper, Peter A1 - Curtis, Charles A1 - Deckert, Jürgen A1 - Domschke, Katharina A1 - El Alaoui, Samir A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Grocholewski, Anja A1 - Hahlweg, Kurt A1 - Hamm, Alfons A1 - Hedman, Erik A1 - Heiervang, Einar R. A1 - Hudson, Jennifer L. A1 - Jöhren, Peter A1 - Keers, Robert A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lavebratt, Catharina A1 - Lee, Sang-hyuck A1 - Lester, Kathryn J. A1 - Lindefors, Nils A1 - Margraf, Jürgen A1 - Nauta, Maaike A1 - Pané-Farré, Christiane A. A1 - Pauli, Paul A1 - Rapee, Ronald M. A1 - Reif, Andreas A1 - Rief, Winfried A1 - Roberts, Susanna A1 - Schalling, Martin A1 - Schneider, Silvia A1 - Silverman, Wendy K. A1 - Ströhle, Andreas A1 - Teismann, Tobias A1 - Thastum, Mikael A1 - Wannemüller, Andre A1 - Weber, Heike A1 - Wittchen, Hans-Ulrich A1 - Wolf, Christiane A1 - Rück, Christian A1 - Breen, Gerome A1 - Eley, Thalia C. T1 - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders JF - Translational Psychiatry N2 - Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits. KW - Human behaviour KW - Personalized medicine KW - Prognostic markers KW - Psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048 VL - 9 IS - 150 ER - TY - JOUR A1 - Walker, Brian A. A1 - Mavrommatis, Konstantinos A1 - Wardell, Christopher P. A1 - Ashby, T. Cody A1 - Bauer, Michael A1 - Davies, Faith A1 - Rosenthal, Adam A1 - Wang, Hongwei A1 - Qu, Pingping A1 - Hoering, Antje A1 - Samur, Mehmet A1 - Towfic, Fadi A1 - Ortiz, Maria A1 - Flynt, Erin A1 - Yu, Zhinuan A1 - Yang, Zhihong A1 - Rozelle, Dan A1 - Obenauer, John A1 - Trotter, Matthew A1 - Auclair, Daniel A1 - Keats, Jonathan A1 - Bolli, Niccolo A1 - Fulciniti, Mariateresa A1 - Szalat, Raphael A1 - Moreau, Phillipe A1 - Durie, Brian A1 - Stewart, A. Keith A1 - Goldschmidt, Hartmut A1 - Raab, Marc S. A1 - Einsele, Hermann A1 - Sonneveld, Pieter A1 - San Miguel, Jesus A1 - Lonial, Sagar A1 - Jackson, Graham H. A1 - Anderson, Kenneth C. A1 - Avet-Loiseau, Herve A1 - Munshi, Nikhil A1 - Thakurta, Anjan A1 - Morgan, Gareth T1 - A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis JF - Leukemia N2 - Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches. KW - cancer genomics KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233299 VL - 33 ER - TY - JOUR A1 - Farrell, Jeffrey M. A1 - Grande, Vincenzo A1 - Schmidt, David A1 - Würthner, Frank T1 - A Highly Warped Heptagon-Containing sp\(^2\) Carbon Scaffold via Vinylnaphthyl π-Extension JF - Angewandte Chemie International Edition N2 - A new strategy is demonstrated for the synthesis of warped, negatively curved, all‐sp\(^2\)‐carbon π‐scaffolds. Multifold C−C coupling reactions are used to transform a polyaromatic borinic acid into a saddle‐shaped polyaromatic hydrocarbon (2 ) bearing two heptagonal rings. Notably, this Schwarzite substructure is synthesized in only two steps from an unfunctionalized alkene. A highly warped structure of 2 was revealed by X‐ray crystallographic studies and pronounced flexibility of this π‐scaffold was ascertained by experimental and computational studies. Compound 2 exhibits excellent solubility, visible range absorption and fluorescence, and readily undergoes two reversible one‐electron oxidations at mild potentials. KW - arenes KW - carbon KW - C-C coupling KW - curvature KW - polycyclic aromatic hydrocarbons Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206682 VL - 58 IS - 46 ER -