@article{GriesbeckMichailRauchetal.2019, author = {Griesbeck, Stefanie and Michail, Evripidis and Rauch, Florian and Ogasawara, Hiroaki and Wang, Chenguang and Sato, Yoshikatsu and Edkins, Robert M. and Zhang, Zuolun and Taki, Masayasu and Lambert, Christoph and Yamaguchi, Shigehiro and Marder, Todd B.}, title = {The Effect of Branching on the One- and Two-Photon Absorption, Cell Viability, and Localization of Cationic Triarylborane Chromophores with Dipolar versus Octupolar Charge Distributions for Cellular Imaging}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, number = {57}, doi = {10.1002/chem.201902461}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212887}, pages = {13164 -- 13175}, year = {2019}, abstract = {Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two-photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two-photon excited fluorescence (TPEF) live-cell imaging.}, language = {en} } @article{GriesbeckMichailRauchetal.2019, author = {Griesbeck, Stefanie and Michail, Evripidis and Rauch, Florian and Ogasawara, Hiroaki and Wang, Chenguang and Sato, Yoshikatsu and Edkins, Robert M. and Zhang, Zuolun and Taki, Masayasu and Lambert, Christoph and Yamaguchi, Shigehiro and Marder, Todd B.}, title = {The Effect of Branching on One- and Two-Photon Absorption, Cell Viability and Localization of Cationic Triarylborane Chromophores with Dipolar versus Octupolar Charge Distributions for Cellular Imaging}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, number = {57}, doi = {10.1002/chem.201902461}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204829}, pages = {13164-13175}, year = {2019}, abstract = {Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two-photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two-photon excited fluorescence (TPEF) live-cell imaging.}, language = {en} } @article{Zonneveld2019, author = {Zonneveld, Ben J. M.}, title = {The DNA weights per nucleus (genome size) of more than 2350 species of the Flora of The Netherlands, of which 1370 are new to science, including the pattern of their DNA peaks}, series = {Forum Geobotanicum}, volume = {8}, journal = {Forum Geobotanicum}, issn = {1867-9315}, doi = {10.3264/FG.2019.1022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189724}, pages = {24-78}, year = {2019}, abstract = {Besides external characteristics and reading a piece of DNA (barcode), the DNA weight per nucleus (genome size) via flow cytometry is a key value to detect species and hybrids and determine ploidy. In addition, the DNA weight appears to be related to various properties, such as the size of the cell and the nucleus, the duration of mitosis and meiosis and the generation time. Sometimes it is even possible to distinguish between groups or sections, which can lead to new classification of the genera. The variation in DNA weight is also useful to analyze biodiversity, genome evolution and relationships between related taxa. Moreover, it is important to know how large a genome is before one determines the base sequence of the DNA of a plant. Flow cytometry is also important for understanding fundamental processes in plants such as growth and development and recognizing chimeras. In the literature, DNA weight measurements are usually limited to one genus and often only locally (Siljak et al. 2010; Bai et al. 2012). In this study, however, it was decided to investigate all vascular plants from one country. This can also contribute to the protection of rare plants. This study is the first flora in the world whose weight of DNA per nucleus and peak patterns has been determined. More than 6400 plants, representing more than 2350 (sub)species (more than 90\%) have been collected, thanks to the help of almost 100 volunteers of Floristisch Onderzoek Nederland (Floron). Multiple specimens of many species have therefore been measured, preferably from different populations, in some cases more than fifty. For 1370 species, these values were not previously published. Moreover, a good number of the remaining 45\% are new for The Netherlands. In principle, each species has a fixed weight of DNA per nucleus. It has also been found that, especially between the genera, there are strong differences in the number of peaks that determine the DNA weight, from one to five peaks. This indicates that in a plant or organ there are sometimes nuclei with multiples of its standard DNA weight (multiple ploidy levels). It is impossible to show graphs of more than 2350 species. Therefore, we have chosen to show the peak pattern in a new way in a short formula. Within most genera there are clear differences in the DNA weights per nucleus between the species, in some other genera the DNA weight is hardly variable. Based on about twenty genera that were previously measured completely in most cases ('t Hart et al. 2003: Veldkamp and Zonneveld 2011; Soes et al. 2012; Dirkse et al. 2014, 2015; Verloove et al. 2017; Zonneveld [et al.] 2000-2018), it can be noted that even if all species of a genus have the same number of chromosomes, there can still be a difference of up to three times in the weight of the DNA. Therefore, a twice larger DNA weight does not have to indicate four sets of chromosomes. Finally, this research has also found clues to examine further the current taxonomy of a number of species or genera.}, subject = {Pflanzen}, language = {en} } @article{TarauBerlinCurcioetal.2019, author = {Tarau, Ioana-Sandra and Berlin, Andreas and Curcio, Christine A. and Ach, Thomas}, title = {The cytoskeleton of the retinal pigment epithelium: from normal aging to age-related macular degeneration}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms20143578}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201781}, year = {2019}, abstract = {The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, adjacent to the fenestrated capillaries of the choriocapillaris. It shows strong apical (towards photoreceptors) to basal/basolateral (towards Bruch membrane) polarization. Multiple functions are bound to a complex structure of highly organized and polarized intracellular components: the cytoskeleton. A strong connection between the intracellular cytoskeleton and extracellular matrix is indispensable to maintaining the function of the RPE and thus, the photoreceptors. Impairments of these intracellular structures and the regular architecture they maintain often result in a disrupted cytoskeleton, which can be found in many retinal diseases, including age-related macular degeneration (AMD). This review article will give an overview of current knowledge on the molecules and proteins involved in cytoskeleton formation in cells, including RPE and how the cytoskeleton is affected under stress conditions — especially in AMD.}, language = {en} } @article{AlbertAndreAnghinolfietal.2019, author = {Albert, A. and Andr{\´e}, M. and Anghinolfi, M. and Anton, G. and Ardid, M. and Aubert, J.-J. and Aublin, J. and Avgitas, T. and Baret, B. and Barrios-Mart{\´i}t, J. and Basa, S. and Belhorma, B. and Bertin, V. and Biagi, S. and Bormuth, R. and Boumaaza, J and Bourret, S. and Bouwhuis, M. C. and Br{\^a}nzas, H. and Bruijn, R. and Brunner, J. and Busto, J. and Capone, A. and Caramete, L. and Carr, J. and Celli, S. and Chabab, M. and Cherkaoui El Moursli, R. and Chiarusi, T. and Circella, M. and Coelho, J. A. B. and Coleiro, A. and Colomer, M and Coniglione, R. and Costantini, H. and Coyle, P. and Creusot, A. and D{\´i}az, A. F. and Deschamps, A. and Distefano, C. and Di Palma, I. and Domi, A. and Donzaud, C. and Dornic, D. and Drouhin, D. and Eberl, T. and El Bojaddaini, I. and El Khayati, N. and Els{\"a}sser, D. and Enzenh{\"o}fer, A. and Ettahiri, A. and Fassi, F. and Felis, I. and Fermani, P. and Ferrara, G. and Fusco, L. A. and Gay, P. and Glotin, H. and Gr{\´e}goire, T. and Gracia Ruiz, R. and Graf, K. and Hallmann, S. and van Haren, H. and Heijboer, A. J. and Hello, Y. and Hern{\´a}ndez-Rey, J. J. and H{\"o}ßl, J. and Hofest{\"a}dt, J. and Illuminati, G. and de Jong, M. and Jongen, M. and Kadler, M. and Kalekin, O. and Katz, U. and Khan-Chowdhury, N. R. and Kouchner, A. and Kreter, M. and Kreykenbohm, I. and Kulikovskiy, V. and Lachaud, C. and Lahmann, R. and Lef{\`e}vre, D. and Leonora, E. and Levi, G. and Lotze, M. and Loucatos, S. and Marcelin, M. and Margiotta, A. and Marinelli, A. and Mart{\´i}nez-Mora, J. A. and Mele, R. and Melis, K. and Migliozzi, P. and Moussa, A. and Navas, S. and Nezri, E. and Nu{\~n}ez, A. and Organokov, M. and Pavalas, G. E. and Pellegrino, C. and Piattelli, P. and Popa, V. and Pradier, T. and Quinn, L. and Racca, C. and Randazzo, N. and Riccobene, G. and S{\´a}nchez-Losa, A. and Salda{\~n}a, M. and Salvadori, I. and Samtleben, D. F. E. and Sanguineti, M. and Sapienza, P. and Sch{\"u}ssler, F. and Spurio, M. and Stolarczyk, Th. and Taiuti, M. and Tayalati, Y. and Trovato, A. and Vallage, B. and Van Elewyck, V. and Versari, F. and Vivolo, D. and Wilms, J. and Zaborov, D. and Zornoza, J. D. and Z{\´u}{\~n}iga, J.}, title = {The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope}, series = {European Physical Journal C}, volume = {78}, journal = {European Physical Journal C}, doi = {10.1140/epjc/s10052-018-6451-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227802}, pages = {1-9}, year = {2019}, abstract = {One of the main objectives of the ANTARES telescope is the search for point- like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliableway to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i. e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, theMoon shadow is observed with 3.5s statistical significance. The detector angular resolution for downwardgoing muons is 0.73. +/- 0.14.. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.}, language = {en} } @article{BeerSchenkHelfrichFoersteretal.2019, author = {Beer, Katharina and Schenk, Mariela and Helfrich-F{\"o}rster, Charlotte and Holzschuh, Andrea}, title = {The circadian clock uses different environmental time cues to synchronize emergence and locomotion of the solitary bee Osmia bicornis}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-54111-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202721}, pages = {17748}, year = {2019}, abstract = {Life on earth adapted to the daily reoccurring changes in environment by evolving an endogenous circadian clock. Although the circadian clock has a crucial impact on survival and behavior of solitary bees, many aspects of solitary bee clock mechanisms remain unknown. Our study is the first to show that the circadian clock governs emergence in Osmia bicornis, a bee species which overwinters as adult inside its cocoon. Therefore, its eclosion from the pupal case is separated by an interjacent diapause from its emergence in spring. We show that this bee species synchronizes its emergence to the morning. The daily rhythms of emergence are triggered by temperature cycles but not by light cycles. In contrast to this, the bee's daily rhythms in locomotion are synchronized by light cycles. Thus, we show that the circadian clock of O. bicornis is set by either temperature or light, depending on what activity is timed. Light is a valuable cue for setting the circadian clock when bees have left the nest. However, for pre-emerged bees, temperature is the most important cue, which may represent an evolutionary adaptation of the circadian system to the cavity-nesting life style of O. bicornis.}, language = {en} } @article{HornMitesserHovestadtetal.2019, author = {Horn, Melanie and Mitesser, Oliver and Hovestadt, Thomas and Yoshii, Taishi and Rieger, Dirk and Helfrich-F{\"o}rster, Charlotte}, title = {The circadian clock improves fitness in the fruit fly, Drosophila melanogaster}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, number = {1374}, issn = {1664-042X}, doi = {10.3389/fphys.2019.01374}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195738}, year = {2019}, abstract = {It is assumed that a properly timed circadian clock enhances fitness, but only few studies have truly demonstrated this in animals. We raised each of the three classical Drosophila period mutants for >50 generations in the laboratory in competition with wildtype flies. The populations were either kept under a conventional 24-h day or under cycles that matched the mutant's natural cycle, i.e., a 19-h day in the case of pers mutants and a 29-h day for perl mutants. The arrhythmic per0 mutants were grown together with wildtype flies under constant light that renders wildtype flies similar arrhythmic as the mutants. In addition, the mutants had to compete with wildtype flies for two summers in two consecutive years under outdoor conditions. We found that wildtype flies quickly outcompeted the mutant flies under the 24-h laboratory day and under outdoor conditions, but perl mutants persisted and even outnumbered the wildtype flies under the 29-h day in the laboratory. In contrast, pers and per0 mutants did not win against wildtype flies under the 19-h day and constant light, respectively. Our results demonstrate that wildtype flies have a clear fitness advantage in terms of fertility and offspring survival over the period mutants and - as revealed for perl mutants - this advantage appears maximal when the endogenous period resonates with the period of the environment. However, the experiments indicate that perl and pers persist at low frequencies in the population even under the 24-h day. This may be a consequence of a certain mating preference of wildtype and heterozygous females for mutant males and time differences in activity patterns between wildtype and mutants.}, language = {en} } @article{AktasUpcinHenkeetal.2019, author = {Aktas, Bertal H. and Upcin, Berin and Henke, Erik and Padmasekar, Manju and Qin, Xuebin and Erg{\"u}n, S{\"u}leyman}, title = {The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells}, series = {Stem Cells International}, journal = {Stem Cells International}, doi = {10.1155/2019/1608787}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227769}, pages = {1-20}, year = {2019}, abstract = {Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks.}, language = {en} } @article{WenNowakKrolNagleretal.2019, author = {Wen, Xinbo and Nowak-Kr{\´o}l, Agnieszka and Nagler, Oliver and Kraus, Felix and Zhu, Na and Zheng, Nan and M{\"u}ller, Matthias and Schmidt, David and Xie, Zengqi and W{\"u}rthner, Frank}, title = {Tetrahydroxy-perylene bisimide embedded in zinc oxide thin film as electron transporting layer for high performance non-fullerene organic solar cells}, series = {Angewandte Chemie International Edition}, volume = {58}, journal = {Angewandte Chemie International Edition}, number = {37}, doi = {10.1002/anie.201907467}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204723}, pages = {13051-13055}, year = {2019}, abstract = {By introduction of four hydroxy (HO) groups into the two perylene bisimide (PBI) bay areas, new HO-PBI ligands were obtained which upon deprotonation can complex ZnII ions and photosensitize semiconductive zinc oxide thin films. Such coordination is beneficial for dispersing PBI photosensitizer molecules evenly into metal oxide films to fabricate organic-inorganic hybrid interlayers for organic solar cells. Supported by the photoconductive effect of the ZnO:HO-PBI hybrid interlayers, improved electron collection and transportation is achieved in fullerene and non-fullerene polymer solar cell devices, leading to remarkable power conversion efficiencies of up to 15.95 \% for a non-fullerene based organic solar cell.}, language = {en} } @article{SchmalzlPlumhoffGilbertetal.2019, author = {Schmalzl, Jonas and Plumhoff, Piet and Gilbert, Fabian and Gohlke, Frank and Konrads, Christian and Brunner, Ulrich and Jakob, Franz and Ebert, Regina and Steinert, Andre F.}, title = {Tendon-derived stem cells from the long head of the biceps tendon}, series = {Bone \& Joint Research}, volume = {8}, journal = {Bone \& Joint Research}, number = {9}, doi = {10.1302/2046-3758.89.BJR-2018-0214.R2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200370}, pages = {414-424}, year = {2019}, abstract = {Objectives The long head of the biceps (LHB) is often resected in shoulder surgery and could therefore serve as a cell source for tissue engineering approaches in the shoulder. However, whether it represents a suitable cell source for regenerative approaches, both in the inflamed and non-inflamed states, remains unclear. In the present study, inflamed and native human LHBs were comparatively characterized for features of regeneration. Methods In total, 22 resected LHB tendons were classified into inflamed samples (n = 11) and non-inflamed samples (n = 11). Proliferation potential and specific marker gene expression of primary LHB-derived cell cultures were analyzed. Multipotentiality, including osteogenic, adipogenic, chondrogenic, and tenogenic differentiation potential of both groups were compared under respective lineage-specific culture conditions. Results Inflammation does not seem to affect the proliferation rate of the isolated tendon-derived stem cells (TDSCs) and the tenogenic marker gene expression. Cells from both groups showed an equivalent osteogenic, adipogenic, chondrogenic and tenogenic differentiation potential in histology and real-time polymerase chain reaction (RT-PCR) analysis. Conclusion These results suggest that the LHB tendon might be a suitable cell source for regenerative approaches, both in inflamed and non-inflamed states. The LHB with and without tendinitis has been characterized as a novel source of TDSCs, which might facilitate treatment of degeneration and induction of regeneration in shoulder surgery.}, language = {en} } @article{OdorferWindZeller2019, author = {Odorfer, Thorsten M. and Wind, Teresa and Zeller, Daniel}, title = {Temporal discrimination thresholds and proprioceptive performance: impact of age and nerve conduction}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {1241}, issn = {1662-453X}, doi = {10.3389/fnins.2019.01241}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195648}, year = {2019}, abstract = {Background Increasing attention is payed to the contribution of somatosensory processing in motor control. In particular, temporal somatosensory discrimination has been found to be altered differentially in common movement disorders. To date, there have only been speculations as to how impaired temporal discrimination and clinical motor signs may relate to each other. Prior to disentangling this relationship, potential confounders of temporal discrimination, in particular age and peripheral nerve conduction, should be assessed, and a quantifiable measure of proprioceptive performance should be established. ObjectiveTo assess the influence of age and polyneuropathy (PNP) on somatosensory temporal discrimination threshold (STDT), temporal discrimination movement threshold (TDMT), and behavioral measures of proprioception of upper and lower limbs. Methods STDT and TDMT were assessed in 79 subjects (54 healthy, 25 with PNP; age 30-79 years). STDT was tested with surface electrodes over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpi radialis (FCR) and tibialis anterior (TA) muscle. Goniometer-based devices were used to assess limb proprioception during (i) active pointing to LED markers, (ii) active movements in response to variable visual cues, and (iii) estimation of limb position following passive movements. Pointing (or estimation) error was taken as a measure of proprioceptive performance. Results In healthy subjects, higher age was associated with higher STDT and TDMT at upper and lower extremities, while age did not correlate with proprioceptive performance. Patients with PNP showed higher STDT and TDMT values and decreased proprioceptive performance in active pointing tasks compared to matched healthy subjects. As an additional finding, there was a significant correlation between performance in active pointing tasks and temporal discrimination thresholds. Conclusion Given their notable impact on measures of temporal discrimination, age and peripheral nerve conduction need to be accounted for if STDT and TDMT are applied in patients with movement disorders. As a side observation, the correlation between measures of proprioception and temporal discrimination may prompt further studies on the presumptive link between these two domains.}, language = {en} } @article{WajantBeilhack2019, author = {Wajant, Harald and Beilhack, Andreas}, title = {Targeting regulatory T cells by addressing tumor necrosis factor and its receptors in allogeneic hematopoietic cell transplantation and cancer}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {2040}, doi = {10.3389/fimmu.2019.02040}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201578}, year = {2019}, abstract = {An intricate network of molecular and cellular actors orchestrates the delicate balance between effector immune responses and immune tolerance. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) proves as a pivotal protagonist promoting but also suppressing immune responses. These opposite actions are accomplished through specialist cell types responding to TNF via TNF receptors TNFR1 and TNFR2. Recent findings highlight the importance of TNFR2 as a key regulator of activated natural FoxP3+ regulatory T cells (Tregs) in inflammatory conditions, such as acute graft-vs.-host disease (GvHD) and the tumor microenvironment. Here we review recent advances in our understanding of TNFR2 signaling in T cells and discuss how these can reconcile seemingly conflicting observations when manipulating TNF and TNFRs. As TNFR2 emerges as a new and attractive target we furthermore pinpoint strategies and potential pitfalls for therapeutic targeting of TNFR2 for cancer treatment and immune tolerance after allogeneic hematopoietic cell transplantation.}, language = {en} } @article{SchuhmannKraftBieberetal.2019, author = {Schuhmann, Michael K. and Kraft, Peter and Bieber, Michael and Kollikowski, Alexander M. and Schulze, Harald and Nieswandt, Bernhard and Pham, Mirko and Stegner, David and Stoll, Guido}, title = {Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms20082019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201700}, year = {2019}, abstract = {Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{-/-}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.}, language = {en} } @article{KhayenkoMaric2019, author = {Khayenko, Vladimir and Maric, Hans Michael}, title = {Targeting GABA\(_A\)R-associated proteins: new modulators, labels and concepts}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, number = {162}, doi = {10.3389/fnmol.2019.00162}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201876}, year = {2019}, abstract = {γ-aminobutyric acid type A receptors (GABA\(_A\)Rs) are the major mediators of synaptic inhibition in the brain. Aberrant GABA\(_A\)R activity or regulation is observed in various neurodevelopmental disorders, neurodegenerative diseases and mental illnesses, including epilepsy, Alzheimer's and schizophrenia. Benzodiazepines, anesthetics and other pharmaceutics targeting these receptors find broad clinical use, but their inherent lack of receptor subtype specificity causes unavoidable side effects, raising a need for new or adjuvant medications. In this review article, we introduce a new strategy to modulate GABAeric signaling: targeting the intracellular protein interactors of GABA\(_A\)Rs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABA\(_A\)R subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABA\(_A\)R-associated proteins can be successfully targeted through diverse molecules, including recombinant proteins, intrabodies, peptide-based probes and small molecules. Small-molecule artemisinins and peptides derived from endogenous interactors, that specifically target the universal receptor binding site of gephyrin, acutely affect synaptic GABA\(_A\)R numbers and clustering, modifying neuronal transmission. Interference with GABA\(_A\)R trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABA\(_A\)R to AP2 increase the surface concentration of GABA\(_A\)R clusters and enhance GABAergic signaling. Engineering of gephyrin binding peptides delivered superior means to interrogate neuronal structure and function. Fluorescent peptides, designed from gephyrin binders, enable live neuronal staining and visualization of gephyrin in the post synaptic sites with submicron resolution. We anticipate that in the future, novel fluorescent probes, with improved size and binding efficiency, may find wide application in super resolution microscopy studies, enlightening the nanoscale architecture of the inhibitory synapse. Broader studies on GABA\(_A\)R accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABA\(_A\)R modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs.}, language = {en} } @article{OttoSchmidtKastneretal.2019, author = {Otto, C. and Schmidt, S. and Kastner, C. and Denk, S. and Kettler, J. and M{\"u}ller, N. and Germer, C.T. and Wolf, E. and Gallant, P. and Wiegering, A.}, title = {Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells}, series = {Neoplasia}, volume = {21}, journal = {Neoplasia}, number = {11}, doi = {10.1016/j.neo.2019.10.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202451}, pages = {1110-1120}, year = {2019}, abstract = {The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.}, language = {en} } @article{KuehnischHerbstAl‐Wakeel‐Marquardetal.2019, author = {K{\"u}hnisch, Jirko and Herbst, Christopher and Al-Wakeel-Marquard, Nadya and Dartsch, Josephine and Holtgrewe, Manuel and Baban, Anwar and Mearini, Giulia and Hardt, Juliane and Kolokotronis, Konstantinos and Gerull, Brenda and Carrier, Lucie and Beule, Dieter and Schubert, Stephan and Messroghli, Daniel and Degener, Franziska and Berger, Felix and Klaassen, Sabine}, title = {Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3}, series = {Clinical Genetics}, volume = {96}, journal = {Clinical Genetics}, number = {6}, doi = {10.1111/cge.13645}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213958}, pages = {549 -- 559}, year = {2019}, abstract = {The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38\%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.}, language = {en} } @article{HeidenreichWengDonhauseretal.2019, author = {Heidenreich, Julius F. and Weng, Andreas M. and Donhauser, Julian and Greiser, Andreas and Chow, Kelvin and Nordbeck, Peter and Bley, Thorsten A. and K{\"o}stler, Herbert}, title = {T1- and ECV-mapping in clinical routine at 3 T: differences between MOLLI, ShMOLLI and SASHA}, series = {BMC Medical Imaging}, volume = {19}, journal = {BMC Medical Imaging}, doi = {10.1186/s12880-019-0362-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201999}, pages = {59}, year = {2019}, abstract = {Background T1 mapping sequences such as MOLLI, ShMOLLI and SASHA make use of different technical approaches, bearing strengths and weaknesses. It is well known that obtained T1 relaxation times differ between the sequence techniques as well as between different hardware. Yet, T1 quantification is a promising tool for myocardial tissue characterization, disregarding the absence of established reference values. The purpose of this study was to evaluate the feasibility of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T. Methods Native and post-contrast T1 mapping data acquired on a 3 T full-body scanner using the three pulse sequences 5(3)3 MOLLI, ShMOLLI and SASHA in 19 patients with clinical indication for contrast enhanced MRI were compared. We analyzed global and segmental T1 relaxation times as well as respective extracellular volumes and compared the emerged differences between the used pulse sequences. Results T1 times acquired with MOLLI and ShMOLLI exhibited systematic T1 deviation compared to SASHA. Myocardial MOLLI T1 times were 19\% lower and ShMOLLI T1 times 25\% lower compared to SASHA. Native blood T1 times from MOLLI were 13\% lower than SASHA, while post-contrast MOLLI T1-times were only 5\% lower. ECV values exhibited comparably biased estimation with MOLLI and ShMOLLI compared to SASHA in good agreement with results reported in literature. Pathology-suspect segments were clearly differentiated from remote myocardium with all three sequences. Conclusion Myocardial T1 mapping yields systematically biased pre- and post-contrast T1 times depending on the applied pulse sequence. Additionally calculating ECV attenuates this bias, making MOLLI, ShMOLLI and SASHA better comparable. Therefore, myocardial T1 mapping is a powerful clinical tool for classification of soft tissue abnormalities in spite of the absence of established reference values.}, language = {en} } @article{RauschenbergerSchmittAzeemetal.2019, author = {Rauschenberger, Tabea and Schmitt, Viola and Azeem, Muhammad and Klein-Hessling, Stefan and Murti, Krisna and Gr{\"a}n, Franziska and Goebeler, Matthias and Kerstan, Andreas and Klein, Matthias and Bopp, Tobias and Serfling, Edgar and Muhammad, Khalid}, title = {T cells control chemokine secretion by keratinocytes}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {1917}, issn = {1664-3224}, doi = {10.3389/fimmu.2019.01917}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195695}, year = {2019}, abstract = {The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8\(^+\)T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8\(^+\)T cells. One key molecule is IFN-γ that is synthesized by CD8\(^+\)T cells under the control of NFATc1 and NFATc2. CD8\(^+\)T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8\(^+\)T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.}, language = {en} } @article{VillalobosWieseImhoffetal.2019, author = {Villalobos, Alvaro S. and Wiese, Jutta and Imhoff, Johannes F. and Dorador, Cristina and Keller, Alexander and Hentschel, Ute}, title = {Systematic affiliation and genome analysis of Subtercola vilae DB165T with particular emphasis on cold adaptation of an isolate from a high-altitude cold volcano lake}, series = {Microorganisms}, volume = {7}, journal = {Microorganisms}, number = {4}, issn = {2076-2607}, doi = {10.3390/microorganisms7040107}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197394}, year = {2019}, abstract = {Among the Microbacteriaceae the species of Subtercola and Agreia form closely associated clusters. Phylogenetic analysis demonstrated three major phylogenetic branches of these species. One of these branches contains the two psychrophilic species Subtercola frigoramans and Subtercola vilae, together with a larger number of isolates from various cold environments. Genomic evidence supports the separation of Agreia and Subtercola species. In order to gain insight into the ability of S. vilae to adapt to life in this extreme environment, we analyzed the genome with a particular focus on properties related to possible adaptation to a cold environment. General properties of the genome are presented, including carbon and energy metabolism, as well as secondary metabolite production. The repertoire of genes in the genome of S. vilae DB165\(^T\) linked to adaptations to the harsh conditions found in Llullaillaco Volcano Lake includes several mechanisms to transcribe proteins under low temperatures, such as a high number of tRNAs and cold shock proteins. In addition, S. vilae DB165\(^T\) is capable of producing a number of proteins to cope with oxidative stress, which is of particular relevance at low temperature environments, in which reactive oxygen species are more abundant. Most important, it obtains capacities to produce cryo-protectants, and to combat against ice crystal formation, it produces ice-binding proteins. Two new ice-binding proteins were identified which are unique to S. vilae DB165\(^T\). These results indicate that S. vilae has the capacity to employ different mechanisms to live under the extreme and cold conditions prevalent in Llullaillaco Volcano Lake.}, language = {en} } @article{GrebinykPrylutskaChepurnaetal.2019, author = {Grebinyk, Anna and Prylutska, Svitlana and Chepurna, Oksana and Grebinyk, Sergii and Prylutskyy, Yuriy and Ritter, Uwe and Ohulchanskyy, Tymish Y. and Matyshevska, Olga and Dandekar, Thomas and Frohme, Marcus}, title = {Synergy of chemo- and photodynamic therapies with C\(_{60}\) Fullerene-Doxorubicin nanocomplex}, series = {Nanomaterials}, volume = {9}, journal = {Nanomaterials}, number = {11}, issn = {2079-4991}, doi = {10.3390/nano9111540}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193140}, year = {2019}, abstract = {A nanosized drug complex was explored to improve the efficiency of cancer chemotherapy, complementing it with nanodelivery and photodynamic therapy. For this, nanomolar amounts of a non-covalent nanocomplex of Doxorubicin (Dox) with carbon nanoparticle C\(_{60}\) fullerene (C\(_{60}\)) were applied in 1:1 and 2:1 molar ratio, exploiting C\(_{60}\) both as a drug-carrier and as a photosensitizer. The fluorescence microscopy analysis of human leukemic CCRF-CEM cells, in vitro cancer model, treated with nanocomplexes showed Dox's nuclear and C\(_{60}\)'s extranuclear localization. It gave an opportunity to realize a double hit strategy against cancer cells based on Dox's antiproliferative activity and C\(_{60}\)'s photoinduced pro-oxidant activity. When cells were treated with 2:1 C\(_{60}\)-Dox and irradiated at 405 nm the high cytotoxicity of photo-irradiated C\(_{60}\)-Dox enabled a nanomolar concentration of Dox and C\(_{60}\) to efficiently kill cancer cells in vitro. The high pro-oxidant and pro-apoptotic efficiency decreased IC\(_{50}\) 16, 9 and 7 × 10\(^3\)-fold, if compared with the action of Dox, non-irradiated nanocomplex, and C\(_{60}\)'s photodynamic effect, correspondingly. Hereafter, a strong synergy of therapy arising from the combination of C\(_{60}\)-mediated Dox delivery and C\(_{60}\) photoexcitation was revealed. Our data indicate that a combination of chemo- and photodynamic therapies with C\(_{60}\)-Dox nanoformulation provides a promising synergetic approach for cancer treatment.}, language = {en} } @article{ElhfnawyVolkmannSchliesseretal.2019, author = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix}, title = {Symptomatic vs. asymptomatic 20-40\% internal carotid artery stenosis: Does the plaque size matter?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {960}, doi = {10.3389/fneur.2019.00960}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201262}, year = {2019}, abstract = {Background: Around 9-15\% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50\%. However, the extent to which ICA-stenosis <50\% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20-40\%. Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of W{\"u}rzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20-40\%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans. Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20-40\%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21-0.69) cm2 and 0.27 (0.21-0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71\% and a specificity of 76\% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95\% CI) of 5.54 (1.2-25.6), p = 0.028 and 1.78 (0.36-8.73), p = 0.48, respectively, for symptomatic ICA-stenosis. Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20-40\%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment.}, language = {en} } @article{JansenHeintelJordanetal.2019, author = {Jansen, Hendrik and Heintel, Timo M. and Jordan, Martin and Meffert, Rainer H. and Frey, Soenke P.}, title = {Survived traumatic hemipelvectomy with salvage of the limb in a 14  months old toddler}, series = {Trauma Case Reports}, volume = {22}, journal = {Trauma Case Reports}, doi = {10.1016/j.tcr.2019.100220}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202207}, pages = {100220}, year = {2019}, abstract = {We report on a 14 months old toddler who sustained a traumatic hemipelvectomy by being crushed between a car and a stone wall. After stabilization in the resuscitation room he was treated operatively by laparotomy, osteosynthesis of the pelvic ring, reconstruction of the both external iliac vessels and the urethra and reposition of the testicles. After 66 days he was discharged into rehabilitation. Implants were removed after eight months. 20 months after the injury, the leg was plegic, initial radiological signs of femoral head necrosis showed up but the infant was able to walk with an orthesis and a walker. Up to our knowledge, this is the youngest patient described in the literature with a survived traumatic hemipelvectomy and salvaged limb.}, language = {en} } @article{WagnerEikenHaubitzetal.2019, author = {Wagner, Johanna and Eiken, Barbara and Haubitz, Imme and Lichthardt, Sven and Matthes, Niels and L{\"o}b, Stefan and Klein, Ingo and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Suprapubic bladder drainage and epidural catheters following abdominal surgery—a risk for urinary tract infections?}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0209825}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177731}, pages = {e0209825}, year = {2019}, abstract = {Background Epidural catheters are state of the art for postoperative analgesic in abdominal surgery. Due to neurolysis it can lead to postoperative urinary tract retention (POUR), which leads to prolonged bladder catheterization, which has an increased risk for urinary tract infections (UTI). Our aim was to identify the current perioperative management of urinary catheters and, second, to identify the optimal time of suprapubic bladder catheter removal in regard to the removal of the epidural catheter. Methods We sent a questionnaire to 102 German hospitals and analyzed the 83 received answers to evaluate the current handling of bladder drainage and epidural catheters. Then, we conducted a retrospective study including 501 patients, who received an epidural and suprapubic catheter after abdominal surgery at the University Hospital W{\"u}rzburg. We divided the patients into three groups according to the point in time of suprapubic bladder drainage removal in regard to the removal of the epidural catheter and analyzed the onset of a UTI. Results Our survey showed that in almost all hospitals (98.8\%), patients received an epidural catheter and a bladder drainage after abdominal surgery. The point in time of urinary catheter removal was equally distributed between before, simultaneously and after the removal of the epidural catheter (respectively: ~28-29\%). The retrospective study showed a catheter-associated UTI in 6.7\%. Women were affected significantly more often than men (10,7\% versus 2,5\%, p<0.001). There was a non-significant trend to more UTIs when the suprapubic catheter was removed after the epidural catheter (before: 5.7\%, after: 8.4\%). Conclusion The point in time of suprapubic bladder drainage removal in relation to the removal of the epidural catheter does not seem to correlate with the rate of UTIs. The current handling in Germany is inhomogeneous, so further studies to standardize treatment are recommended.}, language = {en} } @article{SchlegelPetersDooseetal.2019, author = {Schlegel, Jan and Peters, Simon and Doose, S{\"o}ren and Schubert-Unkmeir, Alexandra and Sauer, Markus}, title = {Super-resolution microscopy reveals local accumulation of plasma membrane gangliosides at Neisseria meningitidis Invasion Sites}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {194}, doi = {10.3389/fcell.2019.00194}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201639}, year = {2019}, abstract = {Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for epidemic meningitis and sepsis worldwide. A critical step in the development of meningitis is the interaction of bacteria with cells forming the blood-cerebrospinal fluid barrier, which requires tight adhesion of the pathogen to highly specialized brain endothelial cells. Two endothelial receptors, CD147 and the β2-adrenergic receptor, have been found to be sequentially recruited by meningococci involving the interaction with type IV pilus. Despite the identification of cellular key players in bacterial adhesion the detailed mechanism of invasion is still poorly understood. Here, we investigated cellular dynamics and mobility of the type IV pilus receptor CD147 upon treatment with pili enriched fractions and specific antibodies directed against two extracellular Ig-like domains in living human brain microvascular endothelial cells. Modulation of CD147 mobility after ligand binding revealed by single-molecule tracking experiments demonstrates receptor activation and indicates plasma membrane rearrangements. Exploiting the binding of Shiga (STxB) and Cholera toxin B (CTxB) subunits to the two native plasma membrane sphingolipids globotriaosylceramide (Gb3) and raft-associated monosialotetrahexosylganglioside GM1, respectively, we investigated their involvement in bacterial invasion by super-resolution microscopy. Structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM) unraveled accumulation and coating of meningococci with GM1 upon cellular uptake. Blocking of CTxB binding sites did not impair bacterial adhesion but dramatically reduced bacterial invasion efficiency. In addition, cell cycle arrest in G1 phase induced by serum starvation led to an overall increase of GM1 molecules in the plasma membrane and consequently also in bacterial invasion efficiency. Our results will help to understand downstream signaling events after initial type IV pilus-host cell interactions and thus have general impact on the development of new therapeutics targeting key molecules involved in infection.}, language = {en} } @article{SteinmetzgerBessiLenzetal.2019, author = {Steinmetzger, Christian and Bessi, Irene and Lenz, Ann-Kathrin and H{\"o}bartner, Claudia}, title = {Structure-fluorescence activation relationships of a large Stokes shift fluorogenic RNA aptamer}, series = {Nucleic Acids Research}, journal = {Nucleic Acids Research}, doi = {10.1093/nar/gkz1084/5628921}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-192340}, pages = {gkz1084}, year = {2019}, abstract = {The Chili RNA aptamer is a 52 nt long fluorogen-activating RNA aptamer (FLAP) that confers fluorescence to structurally diverse derivatives of fluorescent protein chromophores. A key feature of Chili is the formation of highly stable complexes with different ligands, which exhibit bright, highly Stokes-shifted fluorescence emission. In this work, we have analyzed the interactions between the Chili RNA and a family of conditionally fluorescent ligands using a variety of spectroscopic, calorimetric and biochemical techniques to reveal key structure - fluorescence activation relationships (SFARs). The ligands under investigation form two categories with emission maxima of ~540 nm or ~590 nm, respectively, and bind with affinities in the nanomolar to low-micromolar range. Isothermal titration calorimetry was used to elucidate the enthalpic and entropic contributions to binding affinity for a cationic ligand that is unique to the Chili aptamer. In addition to fluorescence activation, ligand binding was also observed by NMR spectroscopy, revealing characteristic signals for the formation of a G-quadruplex only upon ligand binding. These data shed light on the molecular features required and responsible for the large Stokes shift and the strong fluorescence enhancement of red and green emitting RNA-chromophore complexes.}, language = {en} } @article{KasaragodSchindelin2019, author = {Kasaragod, Vikram Babu and Schindelin, Hermann}, title = {Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, issn = {1662-5099}, doi = {10.3389/fnmol.2019.00191}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189308}, pages = {191}, year = {2019}, abstract = {γ-Aminobutyric acid type A receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABAARs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABAARs are key drug targets. The majority of synaptic GABAARs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3-M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABAAR provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABAARs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABAARs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.}, language = {en} } @article{KasaragodSchindelin2019, author = {Kasaragod, Vikram Babu and Schindelin, Hermann}, title = {Structure of heteropentameric GABA\(_A\) receptors and receptor-anchoring properties of gephyrin}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, number = {191}, doi = {10.3389/fnmol.2019.00191}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201886}, year = {2019}, abstract = {γ-Aminobutyric acid type A receptors (GABA\(_A\)Rs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABA\(_A\)Rs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABA\(_A\)Rs are key drug targets. The majority of synaptic GABA\(_A\)Rs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3-M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABA\(_A\)R provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABA\(_A\)Rs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABA\(_A\)Rs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.}, language = {en} } @article{WutzlerKrogiasGrauetal.2019, author = {Wutzler, Alexander and Krogias, Christos and Grau, Anna and Veltkamp, Roland and Heuschmann, Peter U. and Haeusler, Karl Georg}, title = {Stroke prevention in patients with acute ischemic stroke and atrial fibrillation in Germany - a cross sectional survey}, series = {BMC Neurology}, volume = {19}, journal = {BMC Neurology}, doi = {10.1186/s12883-019-1249-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201078}, pages = {25}, year = {2019}, abstract = {Background Atrial fibrillation (AF) is present in 15-20\% of patients with acute ischemic stroke. Oral anticoagulation reduces the risk of AF-related recurrent stroke but clinical guideline recommendations are rather vague regarding its use in the acute phase of stroke. We aimed to assess the current clinical practice of medical stroke prevention in AF patients during the acute phase of ischemic stroke. Methods In April 2017, a standardized anonymous questionnaire was sent to clinical leads of all 298 certified stroke units in Germany. Results Overall, 154 stroke unit leads participated (response rate 52\%). Anticoagulation in the acute phase of stroke is considered feasible in more than 90\% of AF patients with ischemic stroke. Clinicians assume that about two thirds of all AF patients (range 20-100\%) are discharged on oral anticoagulation. According to local preferences, acetylsalicylic acid is given orally in the majority of patients with delayed initiation of oral anticoagulation. A non-vitamin K-dependent oral anticoagulant (NOAC) is more often prescribed than a vitamin K-dependent oral anticoagulant (VKA). VKA is more often chosen in patients with previous VKA intake than in VKA naive patients. In the minority of patients, stroke unit leads discuss the prescription of a specific oral anticoagulant with the treating general practitioner. Adherence to medical stroke prevention after hospital discharge is not assessed on a regular basis in any patient by the majority of participating stroke centers. Conclusions Early secondary stroke prevention in AF patients in German stroke units is based on OAC use but prescription modalities vary in clinical practice.}, language = {en} } @article{KimMcDonaghDengetal.2019, author = {Kim, Brandon J. and McDonagh, Maura A. and Deng, Liwen and Gastfriend, Benjamin D. and Schubert-Unkmeir, Alexandra and Doran, Kelly S. and Shusta, Eric V.}, title = {Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells}, series = {Fluids and Barriers of the CNS}, volume = {16}, journal = {Fluids and Barriers of the CNS}, doi = {10.1186/s12987-019-0146-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201895}, pages = {26}, year = {2019}, abstract = {Bacterial meningitis is a serious life threatening infection of the CNS. To cause meningitis, blood-borne bacteria need to interact with and penetrate brain endothelial cells (BECs) that comprise the blood-brain barrier. BECs help maintain brain homeostasis and they possess an array of efflux transporters, such as P-glycoprotein (P-gp), that function to efflux potentially harmful compounds from the CNS back into the circulation. Oftentimes, efflux also serves to limit the brain uptake of therapeutic drugs, representing a major hurdle for CNS drug delivery. During meningitis, BEC barrier integrity is compromised; however, little is known about efflux transport perturbations during infection. Thus, understanding the impact of bacterial infection on P-gp function would be important for potential routes of therapeutic intervention. To this end, the meningeal bacterial pathogen, Streptococcus agalactiae, was found to inhibit P-gp activity in human induced pluripotent stem cell-derived BECs, and live bacteria were required for the observed inhibition. This observation was correlated to decreased P-gp expression both in vitro and during infection in vivo using a mouse model of bacterial meningitis. Given the impact of bacterial interactions on P-gp function, it will be important to incorporate these findings into analyses of drug delivery paradigms for bacterial infections of the CNS.}, language = {en} } @article{SchlottmannSchickeKruegeretal.2019, author = {Schlottmann, Elisabeth and Schicke, David and Kr{\"u}ger, Felix and Lingnau, Benjamin and Schneider, Christian and H{\"o}fling, Sven and L{\"u}dge, Kathy and Porte, Xavier and Reitzenstein, Stephan}, title = {Stochastic polarization switching induced by optical injection in bimodal quantum-dot micropillar lasers}, series = {Optics Express}, volume = {27}, journal = {Optics Express}, number = {20}, doi = {10.1364/OE.27.028816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228603}, pages = {28816-28831}, year = {2019}, abstract = {Mutual coupling and injection locking of semiconductor lasers is of great interest in non-linear dynamics and its applications for instance in secure data communication and photonic reservoir computing. Despite its importance, it has hardly been studied in microlasers operating at mu W light levels. In this context, vertically emitting quantum dot micropillar lasers are of high interest. Usually, their light emission is bimodal, and the gain competition of the associated linearly polarized fundamental emission modes results in complex switching dynamics. We report on selective optical injection into either one of the two fundamental mode components of a bimodal micropillar laser. Both modes can lock to the master laser and influence the non-injected mode by reducing the available gain. We demonstrate that the switching dynamics can be tailored externally via optical injection in very good agreement with our theory based on semi-classical rate equations. (C) 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement}, language = {en} } @article{LenczykRoyNitschetal.2019, author = {Lenczyk, Carsten and Roy, Dipak Kumar and Nitsch, J{\"o}rn and Radacki, Krzysztof and Rauch, Florian and Dewhurst, Rian D. and Bickelhaupt, F. Matthias and Marder, Todd B. and Braunschweig, Holger}, title = {Steric Effects Dictate the Formation of Terminal Arylborylene Complexes of Ruthenium from Dihydroboranes}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, number = {59}, issn = {1521-3765}, doi = {10.1002/chem.201902890}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219537}, pages = {13566-13571}, year = {2019}, abstract = {The steric and electronic properties of aryl substituents in monoaryl borohydrides (Li[ArBH\(_3\)]) and dihydroboranes were systematically varied and their reactions with [Ru(PCy\(_3\))\(_2\)HCl(H\(_2\))] (Cy: cyclohexyl) were studied, resulting in bis(σ)-borane or terminal borylene complexes of ruthenium. These variations allowed for the investigation of the factors involved in the activation of dihydroboranes in the synthesis of terminal borylene complexes. The complexes were studied by multinuclear NMR spectroscopy, mass spectrometry, X-ray diffraction analysis, and density functional theory (DFT) calculations. The experimental and computational results suggest that the ortho-substitution of the aryl groups is necessary for the formation of terminal borylene complexes.}, language = {en} } @article{ZhangMichailSaaletal.2019, author = {Zhang, Fangyuan and Michail, Evripidis and Saal, Fridolin and Krause, Ana-Maria and Ravat, Prince}, title = {Stereospecific Synthesis and Photophysical Properties of Propeller-Shaped C\(_{90}\)H\(_{48}\) PAH}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, number = {71}, doi = {10.1002/chem.201904962}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208682}, pages = {16241-16245}, year = {2019}, abstract = {Herein, we have synthesized an enantiomerically pure propeller-shaped PAH, C\(_{90}\)H\(_{48}\), possessing three [7]helicene and three [5]helicene subunits. This compound can be obtained in gram quantities in a straightforward manner. The photophysical and chiroptical properties were investigated using UV/Vis absorption and emission, optical rotation and circular dichroism spectroscopy, supported by DFT calculations. The nonlinear optical properties were investigated by two-photon absorption measurements using linearly and circularly polarized light. The extremely twisted structure and packing of the homochiral compound were investigated by single-crystal X-ray diffraction analysis.}, language = {en} } @article{ElhfnawyHeuschmannPhametal.2019, author = {Elhfnawy, Ahmed Mohamed and Heuschmann, Peter U. and Pham, Mirko and Volkmann, Jens and Fluri, Felix}, title = {Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {317}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196225}, year = {2019}, abstract = {Background and Purpose: Internal carotid artery stenosis (ICAS)≥70\% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70\% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70\% (Spearman correlation coefficient ρ = -0.57, p < 0.001, n = 51) but neither for sICAS<70\% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70\% and ≥70\% was 17 (15-20) and 15 (12-19) mm (p = 0.06), respectively, while that for sICAS<90\% and sICAS 90\% was 18 (15-21) and 13 (10-16) mm, respectively (p < 0.001). Among patients with ICAS <70\%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1\% and 51.1\%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6\%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70\% to be longer than that of sICAS≥70\%. Moreover, the ultrasound-measured length of sICAS<90\% was significantly longer than that of sICAS 90\%. Among patients with sICAS≥70\%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results.}, language = {en} } @article{BratengeierHolubyevWegener2019, author = {Bratengeier, Klaus and Holubyev, Kostyantyn and Wegener, Sonja}, title = {Steeper dose gradients resulting from reduced source to target distance—a planning system independent study}, series = {Journal of Applied Clinical Medical Physics}, volume = {20}, journal = {Journal of Applied Clinical Medical Physics}, number = {1}, doi = {10.1002/acm2.12490}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177424}, pages = {89-100}, year = {2019}, abstract = {Purpose: To quantify the contribution of penumbra in the improvement of healthy tissue sparing at reduced source-to-axis distance (SAD) for simple spherical target and different prescription isodoses (PI). Method: A TPS-independent method was used to estimate three-dimensional (3D) dose distribution for stereotactic treatment of spherical targets of 0.5 cm radius based on single beam two-dimensional (2D) film dosimetry measurements. 1 cm target constitutes the worst case for the conformation with standard Multi-Leaf Collimator (MLC) with 0.5 cm leaf width. The measured 2D transverse dose cross-sections and the profiles in leaf and jaw directions were used to calculate radial dose distribution from isotropic beam arrangement, for both quadratic and circular beam openings, respectively. The results were compared for standard (100 cm) and reduced SAD 70 and 55 cm for different PI. Results: For practical reduction of SAD using quadratic openings, the improvement of healthy tissue sparing (HTS) at distances up to 3 times the PTV radius was at least 6\%-12\%; gradient indices (GI) were reduced by 3-39\% for PI between 40\% and 90\%. Except for PI of 80\% and 90\%, quadratic apertures at SAD 70 cm improved the HTS by up to 20\% compared to circular openings at 100 cm or were at least equivalent; GI were 3\%-33\% lower for reduced SAD in the PI range 40\%-70\%. For PI = 80\% and 90\% the results depend on the circular collimator model. Conclusion: Stereotactic treatments of spherical targets delivered at reduced SAD of 70 or 55 cm using MLC spare healthy tissue around the target at least as good as treatments at SAD 100 cm using circular collimators. The steeper beam penumbra at reduced SAD seems to be as important as perfect target conformity. The authors argue therefore that the beam penumbra width should be addressed in the stereotactic studies.}, language = {en} } @article{WickHarteltPuppe2019, author = {Wick, Christoph and Hartelt, Alexander and Puppe, Frank}, title = {Staff, symbol and melody detection of Medieval manuscripts written in square notation using deep Fully Convolutional Networks}, series = {Applied Sciences}, volume = {9}, journal = {Applied Sciences}, number = {13}, issn = {2076-3417}, doi = {10.3390/app9132646}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197248}, year = {2019}, abstract = {Even today, the automatic digitisation of scanned documents in general, but especially the automatic optical music recognition (OMR) of historical manuscripts, still remains an enormous challenge, since both handwritten musical symbols and text have to be identified. This paper focuses on the Medieval so-called square notation developed in the 11th-12th century, which is already composed of staff lines, staves, clefs, accidentals, and neumes that are roughly spoken connected single notes. The aim is to develop an algorithm that captures both the neumes, and in particular its melody, which can be used to reconstruct the original writing. Our pipeline is similar to the standard OMR approach and comprises a novel staff line and symbol detection algorithm based on deep Fully Convolutional Networks (FCN), which perform pixel-based predictions for either staff lines or symbols and their respective types. Then, the staff line detection combines the extracted lines to staves and yields an F\(_1\) -score of over 99\% for both detecting lines and complete staves. For the music symbol detection, we choose a novel approach that skips the step to identify neumes and instead directly predicts note components (NCs) and their respective affiliation to a neume. Furthermore, the algorithm detects clefs and accidentals. Our algorithm predicts the symbol sequence of a staff with a diplomatic symbol accuracy rate (dSAR) of about 87\%, which includes symbol type and location. If only the NCs without their respective connection to a neume, all clefs and accidentals are of interest, the algorithm reaches an harmonic symbol accuracy rate (hSAR) of approximately 90\%. In general, the algorithm recognises a symbol in the manuscript with an F\(_1\) -score of over 96\%.}, language = {en} } @article{RadevaWalterStachetal.2019, author = {Radeva, Mariya Y. and Walter, Elias and Stach, Ramona Alexandra and Yazdi, Amir S. and Schlegel, Nicolas and Sarig, Ofer and Sprecher, Eli and Waschke, Jens}, title = {ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.00770}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224910}, pages = {770, 1-11}, year = {2019}, abstract = {Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1 alpha, IL-6, TNF alpha, and IFN-gamma was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1 alpha and IL-6 was enhanced in some experiments but not in others whereas release of TNF-alpha dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling.}, language = {en} } @article{StrengGoettlerHaerleinetal.2019, author = {Streng, Andrea and Goettler, David and Haerlein, Miriam and Lehmann, Lisa and Ulrich, Kristina and Prifert, Christiane and Krempl, Christine and Weißbrich, Benedikt and Liese, Johannes G.}, title = {Spread and clinical severity of respiratory syncytial virus A genotype ON1 in Germany, 2011-2017}, series = {BMC Infectious Diseases}, volume = {19}, journal = {BMC Infectious Diseases}, doi = {10.1186/s12879-019-4266-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201516}, pages = {613}, year = {2019}, abstract = {Background The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings. Methods During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes. Results A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6\%) were infected with RSV-A, 235 (39.0\%) with RSV-B, and one child (0.2\%) with both RSV-A and RSV-B; in 26 (4.3\%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4\%), NA1 in 92 (26.9\%), and GA5 in 2 children (0.6\%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7-12 vs. 7 days, IQR 5-9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4-9 vs. 4 days, IQR 2-6; p = 0.03) for children infected with RSV-A ON1. Conclusions In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar.}, language = {en} } @article{SierraSanchezGutierrezetal.2019, author = {Sierra, Miguel A. and S{\´a}nchez, David and Gutierrez, Rafael and Cuniberti, Gianaurelio and Dom{\´i}nguez-Adame, Francisco and D{\´i}az, Elena}, title = {Spin-polarized electron transmission in DNA-like systems}, series = {Biomolecules}, volume = {10}, journal = {Biomolecules}, number = {1}, issn = {2218-273X}, doi = {10.3390/biom10010049}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193813}, year = {2019}, abstract = {The helical distribution of the electronic density in chiral molecules, such as DNA and bacteriorhodopsin, has been suggested to induce a spin-orbit coupling interaction that may lead to the so-called chirality-induced spin selectivity (CISS) effect. Key ingredients for the theoretical modelling are, in this context, the helically shaped potential of the molecule and, concomitantly, a Rashba-like spin-orbit coupling due to the appearance of a magnetic field in the electron reference frame. Symmetries of these models clearly play a crucial role in explaining the observed effect, but a thorough analysis has been largely ignored in the literature. In this work, we present a study of these symmetries and how they can be exploited to enhance chiral-induced spin selectivity in helical molecular systems.}, language = {en} } @article{LohrTerekhovWengetal.2019, author = {Lohr, David and Terekhov, Maxim and Weng, Andreas Max and Schroeder, Anja and Walles, Heike and Schreiber, Laura Maria}, title = {Spin echo based cardiac diffusion imaging at 7T: An ex vivo study of the porcine heart at 7T and 3T}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0213994}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201376}, pages = {e0213994}, year = {2019}, abstract = {Purpose of this work was to assess feasibility of cardiac diffusion tensor imaging (cDTI) at 7 T in a set of healthy, unfixed, porcine hearts using various parallel imaging acceleration factors and to compare SNR and derived cDTI metrics to a reference measured at 3 T. Magnetic resonance imaging was performed on 7T and 3T whole body systems using a spin echo diffusion encoding sequence with echo planar imaging readout. Five reference (b = 0 s/mm\(^2\)) images and 30 diffusion directions (b = 700 s/mm\(^2\)) were acquired at both 7 T and 3 T using a GRAPPA acceleration factor R = 1. Scans at 7 T were repeated using R = 2, R = 3, and R = 4. SNR evaluation was based on 30 reference (b = 0 s/mm\(^2\)) images of 30 slices of the left ventricle and cardiac DTI metrics were compared within AHA segmentation. The number of hearts scanned at 7 T and 3 T was n = 11. No statistically significant differences were found for evaluated helix angle, secondary eigenvector angle, fractional anisotropy and apparent diffusion coefficient at the different field strengths, given sufficiently high SNR and geometrically undistorted images. R≥3 was needed to reduce susceptibility induced geometric distortions to an acceptable amount. On average SNR in myocardium of the left ventricle was increased from 29±3 to 44±6 in the reference image (b = 0 s/mm\(^2\)) when switching from 3 T to 7 T. Our study demonstrates that high resolution, ex vivo cDTI is feasible at 7 T using commercial hardware.}, language = {en} } @article{AvotadeLiraSchneiderSchaulies2019, author = {Avota, Elita and de Lira, Maria Nathalia and Schneider-Schaulies, Sibylle}, title = {Sphingomyelin breakdown in T cells: role of membrane compartmentalization in T cell signaling and interference by a pathogen}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {152}, issn = {2296-634X}, doi = {10.3389/fcell.2019.00152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199168}, year = {2019}, abstract = {Sphingolipids are major components of cellular membranes, and at steady-state level, their metabolic fluxes are tightly controlled. On challenge by external signals, they undergo rapid turnover, which substantially affects the biophysical properties of membrane lipid and protein compartments and, consequently, signaling and morphodynamics. In T cells, external cues translate into formation of membrane microdomains where proximal signaling platforms essential for metabolic reprograming and cytoskeletal reorganization are organized. This review will focus on sphingomyelinases, which mediate sphingomyelin breakdown and ensuing ceramide release that have been implicated in T-cell viability and function. Acting at the sphingomyelin pool at the extrafacial or cytosolic leaflet of cellular membranes, acid and neutral sphingomyelinases organize ceramide-enriched membrane microdomains that regulate T-cell homeostatic activity and, upon stimulation, compartmentalize receptors, membrane proximal signaling complexes, and cytoskeletal dynamics as essential for initiating T-cell motility and interaction with endothelia and antigen-presenting cells. Prominent examples to be discussed in this review include death receptor family members, integrins, CD3, and CD28 and their associated signalosomes. Progress made with regard to experimental tools has greatly aided our understanding of the role of bioactive sphingolipids in T-cell biology at a molecular level and of targets explored by a model pathogen (measles virus) to specifically interfere with their physiological activity.}, language = {en} } @article{GraebGeidel2019, author = {Gr{\"a}b, Patrick and Geidel, Ekkehard}, title = {Spectroscopic studies of food colorings}, series = {World Journal of Chemical Education}, volume = {7}, journal = {World Journal of Chemical Education}, number = {2}, doi = {10.12691/wjce-7-2-13}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201908}, pages = {136-144}, year = {2019}, abstract = {In chemical education, it is often a challenge to understand the basic principles of spectroscopic techniques due to missing connections to the real world. Therefore, the present contribution offers context-based applications of UV/Vis spectroscopy for analytics of food colorings with which learners can improve their skills regarding this method. The spectroscopic determination of food colorings seems to be a promising approach due to the long tradition and omnipresence of dyes in supermarket products. The therefor-required spectral data for commonly used dyes are provided for educational usage. Qualitative and quantitative analytics of food colorings in four different lemonades and chocolate beans have been used to introduce learners to important analytical techniques like sample preparation or elimination of confounding factors. These analytics also display the limitations of the method in the visible range of light in the case of tartrazine and curcumin. By applying Lambert-Beer-Bouguer's Law in different variations, typical calculations of concentrations can be studied in quantitative analyses. The studied food samples demonstrate the different usage of food colorings depending on the country of sale. Finally, a 3D-printable low-cost photometer suitable for the discussed quantitative analytics in educational contexts is presented.}, language = {en} } @article{NickelMueller2019, author = {Nickel, Joachim and Mueller, Thomas D.}, title = {Specification of BMP signaling}, series = {Cells}, volume = {8}, journal = {Cells}, number = {12}, issn = {2073-4409}, doi = {10.3390/cells8121579}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193869}, pages = {1579}, year = {2019}, abstract = {Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.}, language = {en} } @article{StreinzerChakravortyNeumayeretal.2019, author = {Streinzer, Martin and Chakravorty, Jharna and Neumayer, Johann and Megu, Karsing and Narah, Jaya and Schmitt, Thomas and Bharti, Himender and Spaethe, Johannes and Brockmann, Axel}, title = {Species composition and elevational distribution of bumble bees (Hymenoptera, Apidae, Bombus Latreille) in the East Himalaya, Arunachal Pradesh, India}, series = {ZooKeys}, volume = {851}, journal = {ZooKeys}, doi = {10.3897/zookeys.851.32956}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201937}, pages = {71-89}, year = {2019}, abstract = {The East Himalaya is one of the world's most biodiverse ecosystems. However, very little is known about the abundance and distribution of many plant and animal taxa in this region. Bumble bees are a group of cold-adapted and high elevation insects that fulfil an important ecological and economical function as pollinators of wild and agricultural flowering plants and crops. The Himalayan mountain range provides ample suitable habitats for bumble bees. Systematic study of Himalayan bumble bees began a few decades ago and the main focus has centred on the western region, while the eastern part of the mountain range has received little attention and only a few species have been verified. During a three-year survey, more than 700 bumble bee specimens of 21 species were collected in Arunachal Pradesh, the largest of the north-eastern states of India. The material included a range of species that were previously known from a limited number of collected specimens, which highlights the unique character of the East Himalayan ecosystem. Our results are an important first step towards a future assessment of species distribution, threat, and conservation. Clear elevation patterns of species diversity were observed, which raise important questions about the functional adaptations that allow bumble bees to thrive in this particularly moist region in the East Himalaya.}, language = {en} } @article{LangePauli2019, author = {Lange, Bastian and Pauli, Paul}, title = {Social anxiety changes the way we move—A social approach-avoidance task in a virtual reality CAVE system}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0226805}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200528}, pages = {e0226805}, year = {2019}, abstract = {Investigating approach-avoidance behavior regarding affective stimuli is important in broadening the understanding of one of the most common psychiatric disorders, social anxiety disorder. Many studies in this field rely on approach-avoidance tasks, which mainly assess hand movements, or interpersonal distance measures, which return inconsistent results and lack ecological validity. Therefore, the present study introduces a virtual reality task, looking at avoidance parameters (movement time and speed, distance to social stimulus, gaze behavior) during whole-body movements. These complex movements represent the most ecologically valid form of approach and avoidance behavior. These are at the core of complex and natural social behavior. With this newly developed task, the present study examined whether high socially anxious individuals differ in avoidance behavior when bypassing another person, here virtual humans with neutral and angry facial expressions. Results showed that virtual bystanders displaying angry facial expressions were generally avoided by all participants. In addition, high socially anxious participants generally displayed enhanced avoidance behavior towards virtual people, but no specifically exaggerated avoidance behavior towards virtual people with a negative facial expression. The newly developed virtual reality task proved to be an ecological valid tool for research on complex approach-avoidance behavior in social situations. The first results revealed that whole body approach-avoidance behavior relative to passive bystanders is modulated by their emotional facial expressions and that social anxiety generally amplifies such avoidance.}, language = {en} } @article{RufBeerKoestleretal.2019, author = {Ruf, Katharina and Beer, Meinrad and K{\"o}stler, Herbert and Weng, Andreas Max and Neubauer, Henning and Klein, Alexander and Platek, Kathleen and Roth, Kristina and Beneke, Ralph and Hebestreit, Helge}, title = {Size-adjusted muscle power and muscle metabolism in patients with cystic fibrosis are equal to healthy controls - a case control study}, series = {BMC Pulmonary Medicine}, volume = {19}, journal = {BMC Pulmonary Medicine}, doi = {10.1186/s12890-019-1039-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200981}, pages = {269}, year = {2019}, abstract = {Background Skeletal muscle function dysfunction has been reported in patients with cystic fibrosis (CF). Studies so far showed inconclusive data whether reduced exercise capacity is related to intrinsic muscle dysfunction in CF. Methods Twenty patients with CF and 23 age-matched controls completed an incremental cardiopulmonary cycling test. Further, a Wingate anaerobic test to assess muscle power was performed. In addition, all participants completed an incremental knee-extension test with 31P magnetic resonance spectroscopy to assess muscle metabolism (inorganic phosphate (Pi) and phosphocreatinine (PCr) as well as intracellular pH). In the MRI, muscle cross-sectional area of the M. quadriceps (qCSA) was also measured. A subgroup of 15 participants (5 CF, 10 control) additionally completed a continuous high-intensity, high-frequency knee-extension exercise task during 31P magnetic resonance spectroscopy to assess muscle metabolism. Results Patients with CF showed a reduced exercise capacity in the incremental cardiopulmonary cycling test (VO2peak: CF 77.8 ± 16.2\%predicted (36.5 ± 7.4 ml/qCSA/min), control 100.6 ± 18.8\%predicted (49.1 ± 11.4 ml/qCSA/min); p < 0.001), and deficits in anaerobic capacity reflected by the Wingate test (peak power: CF 537 ± 180 W, control 727 ± 186 W; mean power: CF 378 ± 127 W, control 486 ± 126 W; power drop CF 12 ± 5 W, control 8 ± 4 W. all: p < 0.001). In the knee-extension task, patients with CF achieved a significantly lower workload (p < 0.05). However, in a linear model analysing maximal work load of the incremental knee-extension task and results of the Wingate test, respectively, only muscle size and height, but not disease status (CF or not) contributed to explaining variance. In line with this finding, no differences were found in muscle metabolism reflected by intracellular pH and the ratio of Pi/PCr at submaximal stages and peak exercise measured through MRI spectroscopy. Conclusions The lower absolute muscle power in patients with CF compared to controls is exclusively explained by the reduced muscle size in this study. No evidence was found for an intrinsic skeletal muscle dysfunction due to primary alterations of muscle metabolism.}, language = {en} } @article{BohmannKurkaduMesnildeRochemontetal.2019, author = {Bohmann, Ferdinand O. and Kurka, Natalia and du Mesnil de Rochemont, Richard and Gruber, Katharina and Guenther, Joachim and Rostek, Peter and Rai, Heike and Zickler, Philipp and Ertl, Michael and Berlis, Ansgar and Poli, Sven and Mengel, Annerose and Ringleb, Peter and Nagel, Simon and Pfaff, Johannes and Wollenweber, Frank A. and Kellert, Lars and Herzberg, Moriz and Koehler, Luzie and Haeusler, Karl Georg and Alegiani, Anna and Schubert, Charlotte and Brekenfeld, Caspar and Doppler, Christopher E. J. and Onur, Oezguer A. and Kabbasch, Christoph and Manser, Tanja and Pfeilschifter, Waltraud}, title = {Simulation-based training of the rapid evaluation and management of acute stroke (STREAM) — a prospective single-arm multicenter trial}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00969}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369239}, year = {2019}, abstract = {Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2-3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period. Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the "door-to-needle" time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire. Interventions: We are applying a multi-level intervention in cooperation with three "STREAM multipliers" from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2-3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings. Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.}, language = {en} } @article{SaddiqueUsmanBernhofer2019, author = {Saddique, Naeem and Usman, Muhammad and Bernhofer, Christian}, title = {Simulating the impact of climate change on the hydrological regimes of a sparsely gauged mountainous basin, northern Pakistan}, series = {Water}, volume = {11}, journal = {Water}, number = {10}, issn = {2073-4441}, doi = {10.3390/w11102141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193175}, year = {2019}, abstract = {Projected climate changes for the 21st century may cause great uncertainties on the hydrology of a river basin. This study explored the impacts of climate change on the water balance and hydrological regime of the Jhelum River Basin using the Soil and Water Assessment Tool (SWAT). Two downscaling methods (SDSM, Statistical Downscaling Model and LARS-WG, Long Ashton Research Station Weather Generator), three Global Circulation Models (GCMs), and two representative concentration pathways (RCP4.5 and RCP8.5) for three future periods (2030s, 2050s, and 2090s) were used to assess the climate change impacts on flow regimes. The results exhibited that both downscaling methods suggested an increase in annual streamflow over the river basin. There is generally an increasing trend of winter and autumn discharge, whereas it is complicated for summer and spring to conclude if the trend is increasing or decreasing depending on the downscaling methods. Therefore, the uncertainty associated with the downscaling of climate simulation needs to consider, for the best estimate, the impact of climate change, with its uncertainty, on a particular basin. The study also resulted that water yield and evapotranspiration in the eastern part of the basin (sub-basins at high elevation) would be most affected by climate change. The outcomes of this study would be useful for providing guidance in water management and planning for the river basin under climate change.}, language = {en} } @article{DechaudVolffSchartletal.2019, author = {Dechaud, Corentin and Volff, Jean-Nicolas and Schartl, Manfred and Naville, Magali}, title = {Sex and the TEs: transposable elements in sexual development and function in animals}, series = {Mobile DNA}, volume = {10}, journal = {Mobile DNA}, doi = {10.1186/s13100-019-0185-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202510}, pages = {42}, year = {2019}, abstract = {Transposable elements are endogenous DNA sequences able to integrate into and multiply within genomes. They constitute a major source of genetic innovations, as they can not only rearrange genomes but also spread ready-to-use regulatory sequences able to modify host gene expression, and even can give birth to new host genes. As their evolutionary success depends on their vertical transmission, transposable elements are intrinsically linked to reproduction. In organisms with sexual reproduction, this implies that transposable elements have to manifest their transpositional activity in germ cells or their progenitors. The control of sexual development and function can be very versatile, and several studies have demonstrated the implication of transposable elements in the evolution of sex. In this review, we report the functional and evolutionary relationships between transposable elements and sexual reproduction in animals. In particular, we highlight how transposable elements can influence expression of sexual development genes, and how, reciprocally, they are tightly controlled in gonads. We also review how transposable elements contribute to the organization, expression and evolution of sexual development genes and sex chromosomes. This underscores the intricate co-evolution between host functions and transposable elements, which regularly shift from a parasitic to a domesticated status useful to the host.}, language = {en} } @article{WaiderPoppMlinaretal.2019, author = {Waider, Jonas and Popp, Sandy and Mlinar, Boris and Montalbano, Alberto and Bonfiglio, Francesco and Aboagye, Benjamin and Thuy, Elisabeth and Kern, Raphael and Thiel, Christopher and Araragi, Naozumi and Svirin, Evgeniy and Schmitt-B{\"o}hrer, Angelika G. and Corradetti, Renato and Lowry, Christopher A. and Lesch, Klaus-Peter}, title = {Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {245}, issn = {1662-453X}, doi = {10.3389/fnins.2019.00245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196077}, year = {2019}, abstract = {Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.}, language = {en} } @article{ThoelkenThammErbacheretal.2019, author = {Th{\"o}lken, Clemens and Thamm, Markus and Erbacher, Christoph and Lechner, Marcus}, title = {Sequence and structural properties of circular RNAs in the brain of nurse and forager honeybees (Apis mellifera)}, series = {BMC Genomics}, volume = {20}, journal = {BMC Genomics}, doi = {10.1186/s12864-018-5402-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241302}, year = {2019}, abstract = {Background The honeybee (Apis mellifera) represents a model organism for social insects displaying behavioral plasticity. This is reflected by an age-dependent task allocation. The most protruding tasks are performed by young nurse bees and older forager bees that take care of the brood inside the hive and collect food from outside the hive, respectively. The molecular mechanism leading to the transition from nurse bees to foragers is currently under intense research. Circular RNAs, however, were not considered in this context so far. As of today, this group of non-coding RNAs was only known to exist in two other insects, Drosophila melanogaster and Bombyx mori. Here we complement the state of circular RNA research with the first characterization in a social insect. Results We identified numerous circular RNAs in the brain of A. mellifera nurse bees and forager bees using RNA-Seq with exonuclease enrichment. Presence and circularity were verified for the most abundant representatives. Back-splicing in honeybee occurs further towards the end of transcripts and in transcripts with a high number of exons. The occurrence of circularized exons is correlated with length and CpG-content of their flanking introns. The latter coincides with increased DNA-methylation in the respective loci. For two prominent circular RNAs the abundance in worker bee brains was quantified in TaqMan assays. In line with previous findings of circular RNAs in Drosophila, circAmrsmep2 accumulates with increasing age of the insect. In contrast, the levels of circAmrad appear age-independent and correlate with the bee's task. Its parental gene is related to amnesia-resistant memory. Conclusions We provide the first characterization of circRNAs in a social insect. Many of the RNAs identified here show homologies to circular RNAs found in Drosophila and Bombyx, indicating that circular RNAs are a common feature among insects. We find that exon circularization is correlated to DNA-methylation at the flanking introns. The levels of circAmrad suggest a task-dependent abundance that is decoupled from age. Moreover, a GO term analysis shows an enrichment of task-related functions. We conclude that circular RNAs could be relevant for task allocation in honeybee and should be investigated further in this context.}, language = {en} }