@article{FoersterKoziolSchaeferetal.2019, author = {F{\"o}rster, Sabine and Koziol, Uriel and Sch{\"a}fer, Tina and Duvoisin, Raphael and Cailliau, Katia and Vanderstraete, Mathieu and Dissous, Colette and Brehm, Klaus}, title = {The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction}, series = {PLoS Neglected Tropical Diseases}, volume = {13}, journal = {PLoS Neglected Tropical Diseases}, doi = {10.1371/journal.pntd.0006959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228190}, year = {2019}, abstract = {Background Alveolar echinococcosis (AE) is a lethal zoonosis caused by the metacestode larva of the tapeworm Echinococcus multilocularis. The infection is characterized by tumour-like growth of the metacestode within the host liver, leading to extensive fibrosis and organ-failure. The molecular mechanisms of parasite organ tropism towards the liver and influences of liver cytokines and hormones on parasite development are little studied to date. Methodology/Principal findings We show that the E. multilocularis larval stage expresses three members of the fibroblast growth factor (FGF) receptor family with homology to human FGF receptors. Using the Xenopus expression system we demonstrate that all three Echinococcus FGF receptors are activated in response to human acidic and basic FGF, which are present in the liver. In all three cases, activation could be prevented by addition of the tyrosine kinase (TK) inhibitor BIBF 1120, which is used to treat human cancer. At physiological concentrations, acidic and basic FGF significantly stimulated the formation of metacestode vesicles from parasite stem cells in vitro and supported metacestode growth. Furthermore, the parasite's mitogen activated protein kinase signalling system was stimulated upon addition of human FGF. The survival of metacestode vesicles and parasite stem cells were drastically affected in vitro in the presence of BIBF 1120. Conclusions/Significance Our data indicate that mammalian FGF, which is present in the liver and upregulated during fibrosis, supports the establishment of the Echinococcus metacestode during AE by acting on an evolutionarily conserved parasite FGF signalling system. These data are valuable for understanding molecular mechanisms of organ tropism and host-parasite interaction in AE. Furthermore, our data indicate that the parasite's FGF signalling systems are promising targets for the development of novel drugs against AE.}, language = {en} } @article{NagyCusumanoAndreattaetal.2019, author = {Nagy, D{\´o}ra and Cusumano, Paola and Andreatta, Gabriele and Martin Anduaga, Ane and Hermann-Luibl, Christiane and Reinhard, Nils and Gesto, Jo{\~a}o and Wegener, Christian and Mazzotta, Gabriella and Rosato, Ezio and Kyriacou, Charalambos P. and Helfrich-F{\"o}rster, Charlotte and Costa, Rodolfo}, title = {Peptidergic signaling from clock neurons regulates reproductive dormancy in Drosophila melanogaster}, series = {PLoS Genetics}, volume = {15}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1008158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231681}, year = {2019}, abstract = {With the approach of winter, many insects switch to an alternative protective developmental program called diapause. Drosophila melanogaster females overwinter as adults by inducing a reproductive arrest that is characterized by inhibition of ovarian development at previtellogenic stages. The insulin producing cells (IPCs) are key regulators of this process, since they produce and release insulin-like peptides that act as diapause-antagonizing hormones. Here we show that in D. melanogaster two neuropeptides, Pigment Dispersing Factor (PDF) and short Neuropeptide F (sNPF) inhibit reproductive arrest, likely through modulation of the IPCs. In particular, genetic manipulations of the PDF-expressing neurons, which include the sNPF-producing small ventral Lateral Neurons (s-LNvs), modulated the levels of reproductive dormancy, suggesting the involvement of both neuropeptides. We expressed a genetically encoded cAMP sensor in the IPCs and challenged brain explants with synthetic PDF and sNPF. Bath applications of both neuropeptides increased cAMP levels in the IPCs, even more so when they were applied together, suggesting a synergistic effect. Bath application of sNPF additionally increased Ca2+ levels in the IPCs. Our results indicate that PDF and sNPF inhibit reproductive dormancy by maintaining the IPCs in an active state.}, language = {en} } @article{LiLiuVanselowetal.2019, author = {Li, Ying H. and Liu, Xianhui and Vanselow, Jens T. and Zheng, Haiyan and Schlosser, Andreas and Chiu, Joanna C.}, title = {O-GlcNAcylation of PERIOD regulates its interaction with CLOCK and timing of circadian transcriptional repression}, series = {PLoS Genetics}, volume = {15}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1007953}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236826}, year = {2019}, abstract = {Circadian clocks coordinate time-of-day-specific metabolic and physiological processes to maximize organismal performance and fitness. In addition to light and temperature, which are regarded as strong zeitgebers for circadian clock entrainment, metabolic input has now emerged as an important signal for clock entrainment and modulation. Circadian clock proteins have been identified to be substrates of O-GlcNAcylation, a nutrient sensitive post-translational modification (PTM), and the interplay between clock protein O-GlcNAcylation and other PTMs is now recognized as an important mechanism by which metabolic input regulates circadian physiology. To better understand the role of O-GlcNAcylation in modulating clock protein function within the molecular oscillator, we used mass spectrometry proteomics to identify O-GlcNAcylation sites of PERIOD (PER), a repressor of the circadian transcriptome and a critical biochemical timer of the Drosophila clock. In vivo functional characterization of PER O-GlcNAcylation sites indicates that O-GlcNAcylation at PER(S942) reduces interactions between PER and CLOCK (CLK), the key transcriptional activator of clock-controlled genes. Since we observe a correlation between clock-controlled daytime feeding activity and higher level of PER O-GlcNAcylation, we propose that PER(S942) O-GlcNAcylation during the day functions to prevent premature initiation of circadian repression phase. This is consistent with the period-shortening behavioral phenotype of per(S942A) flies. Taken together, our results support that clock-controlled feeding activity provides metabolic signals to reinforce light entrainment to regulate circadian physiology at the post-translational level. The interplay between O-GlcNAcylation and other PTMs to regulate circadian physiology is expected to be complex and extensive, and reach far beyond the molecular oscillator.}, language = {en} } @article{BreitenbachLiangBeyersdorfetal.2019, author = {Breitenbach, Tim and Liang, Chunguang and Beyersdorf, Niklas and Dandekar, Thomas}, title = {Analyzing pharmacological intervention points: A method to calculate external stimuli to switch between steady states in regulatory networks}, series = {PLoS Computational Biology}, volume = {15}, journal = {PLoS Computational Biology}, doi = {10.1371/journal.pcbi.1007075}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220385}, year = {2019}, abstract = {Once biological systems are modeled by regulatory networks, the next step is to include external stimuli, which model the experimental possibilities to affect the activity level of certain network's nodes, in a mathematical framework. Then, this framework can be interpreted as a mathematical optimal control framework such that optimization algorithms can be used to determine external stimuli which cause a desired switch from an initial state of the network to another final state. These external stimuli are the intervention points for the corresponding biological experiment to obtain the desired outcome of the considered experiment. In this work, the model of regulatory networks is extended to controlled regulatory networks. For this purpose, external stimuli are considered which can affect the activity of the network's nodes by activation or inhibition. A method is presented how to calculate a selection of external stimuli which causes a switch between two different steady states of a regulatory network. A software solution based on Jimena and Mathworks Matlab is provided. Furthermore, numerical examples are presented to demonstrate application and scope of the software on networks of 4 nodes, 11 nodes and 36 nodes. Moreover, we analyze the aggregation of platelets and the behavior of a basic T-helper cell protein-protein interaction network and its maturation towards Th0, Th1, Th2, Th17 and Treg cells in accordance with experimental data.}, language = {en} } @article{SteimleMenzBenderetal.2019, author = {Steimle, Alex and Menz, Sarah and Bender, Annika and Ball, Brianna and Weber, Alexander N. R. and Hagemann, Thomas and Lange, Anna and Maerz, Jan K. and Perusel, Raphael and Michaelis, Lena and Sch{\"a}fer, Andrea and Yao, Hans and L{\"o}w, Hanna-Christine and Beier, Sina and Mebrhatu, Mehari Tesfazgi and Gronbach, Kerstin and Wagner, Samuel and Voehringer, David and Schaller, Martin and Fehrenbacher, Birgit and Autenrieth, Ingo B. and Oelschlaeger, Tobias A. and Frick, Julia-Stefanie}, title = {Flagellin hypervariable region determinessymbiotic properties of commensalEscherichia coli strains}, series = {PLoS Biology}, volume = {17}, journal = {PLoS Biology}, doi = {10.1371/journal.pbio.3000334}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239501}, year = {2019}, abstract = {Escherichia coli represents a classical intestinal gram-negative commensal. Despite this commensalism, different E. coli strains can mediate disparate immunogenic properties in a given host. Symbiotic E. coli strains such as E. coli Nissle 1917 (EcN) are attributed beneficial properties, e.g., promotion of intestinal homeostasis. Therefore, we aimed to identify molecular features derived from symbiotic bacteria that might help to develop innovative therapeutic alternatives for the treatment of intestinal immune disorders. This study was performed using the dextran sodium sulphate (DSS)-induced colitis mouse model, which is routinely used to evaluate potential therapeutics for the treatment of Inflammatory Bowel Diseases (IBDs). We focused on the analysis of flagellin structures of different E. coli strains. EcN flagellin was found to harbor a substantially longer hypervariable region (HVR) compared to other commensal E. coli strains, and this longer HVR mediated symbiotic properties through stronger activation of Toll-like receptor (TLR)5, thereby resulting in interleukin (IL)-22-mediated protection of mice against DSS-induced colitis. Furthermore, using bone-marrow-chimeric mice (BMCM), CD11c+ cells of the colonic lamina propria (LP) were identified as the main mediators of these flagellin-induced symbiotic effects. We propose flagellin from symbiotic E. coli strains as a potential therapeutic to restore intestinal immune homeostasis, e.g., for the treatment of IBD patients.}, language = {en} } @article{HerpinSchmidtKneitzetal.2019, author = {Herpin, Amaury and Schmidt, Cornelia and Kneitz, Susanne and Gob{\´e}, Clara and Regensburger, Martina and Le Cam, Aur{\´e}lie and Montfort, J{\´e}rome and Adolfi, Mateus C. and Lillesaar, Christina and Wilhelm, Dagmar and Kraeussling, Michael and Mourot, Brigitte and Porcon, B{\´e}atrice and Pannetier, Ma{\"e}lle and Pailhoux, Eric and Ettwiller, Laurence and Dolle, Dirk and Guiguen, Yann and Schartl, Manfred}, title = {A novel evolutionary conserved mechanism of RNA stability regulates synexpression of primordial germ cell-specific genes prior to the sex-determination stage in medaka}, series = {PLoS Biology}, volume = {17}, journal = {PLoS Biology}, doi = {10.1371/journal.pbio.3000185}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320011}, year = {2019}, abstract = {Dmrt1 is a highly conserved transcription factor, which is critically involved in regulation of gonad development of vertebrates. In medaka, a duplicate of dmrt1—acting as master sex-determining gene—has a tightly timely and spatially controlled gonadal expression pattern. In addition to transcriptional regulation, a sequence motif in the 3′ UTR (D3U-box) mediates transcript stability of dmrt1 mRNAs from medaka and other vertebrates. We show here that in medaka, two RNA-binding proteins with antagonizing properties target this D3U-box, promoting either RNA stabilization in germ cells or degradation in the soma. The D3U-box is also conserved in other germ-cell transcripts, making them responsive to the same RNA binding proteins. The evolutionary conservation of the D3U-box motif within dmrt1 genes of metazoans—together with preserved expression patterns of the targeting RNA binding proteins in subsets of germ cells—suggest that this new mechanism for controlling RNA stability is not restricted to fishes but might also apply to other vertebrates.}, language = {en} } @article{OPUS4-31406, title = {Search for heavy long-lived multicharged particles in proton-proton collisions at √\(s\)=13 TeV using the ATLAS detector}, series = {Physical Review D}, volume = {99}, journal = {Physical Review D}, number = {5}, organization = {The ATLAS Collaboration}, doi = {10.1103/PhysRevD.99.052003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314061}, pages = {1-26}, year = {2019}, abstract = {A search for heavy long-lived multicharged particles is performed using the ATLAS detector at the LHC. Data with an integrated luminosity of 36.1 fb(-1) collected in 2015 and 2016 from proton-proton collisions at root s = 13 TeV are examined. Particles producing anomalously high ionization, consistent with long-lived massive particles with electric charges from vertical bar q vertical bar = 2e to vertical bar q vertical bar = 7e, are searched for. No events are observed, and 95\% confidence level cross-section upper limits are interpreted as lower mass limits for a Drell-Yan production model. Multicharged particles with masses between 50 and 980-1220 GeV (depending on their electric charge) are excluded.}, language = {en} } @article{AndreattaPauli2019, author = {Andreatta, Marta and Pauli, Paul}, title = {Generalization of appetitive conditioned responses}, series = {Psychophysiology}, volume = {56}, journal = {Psychophysiology}, doi = {10.1111/psyp.13397}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221132}, year = {2019}, abstract = {A stimulus (conditioned stimulus, CS) associated with an appetitive unconditioned stimulus (US) acquires positive properties and elicits appetitive conditioned responses (CR). Such associative learning has been examined extensively in animals with food as the US, and results are used to explain psychopathologies (e.g., substance-related disorders or obesity). Human studies on appetitive conditioning exist, too, but we still know little about generalization processes. Understanding these processes may explain why stimuli not associated with a drug, for instance, can elicit craving. Forty-seven hungry participants underwent an appetitive conditioning protocol during which one of two circles with different diameters (CS+) became associated with an appetitive US (chocolate or salty pretzel, according to participants' preference) but never the other circle (CS-). During generalization, US were delivered twice and the two CS were presented again plus four circles (generalization stimuli, GS) with gradually increasing diameters from CS- to CS+. We found successful appetitive conditioning as reflected in appetitive subjective ratings (positive valence, higher contingency) and physiological responses (startle attenuation and larger skin conductance responses) to CS+ versus CS-, and, importantly, both measures confirmed generalization as indicated by generalization gradients. Small changes in CS-US contingency during generalization may have weakened generalization processes on the physiological level. Considering that appetitive conditioned responses can be generalized to non-US-associated stimuli, a next important step would be to investigate risk factors that mediate overgeneralization.}, language = {en} } @article{Chevalier‐RoignantFlathTrigeorgis2019, author = {Chevalier-Roignant, Beno{\^i}t and Flath, Christoph M. and Trigeorgis, Lenos}, title = {Disruptive Innovation, Market Entry and Production Flexibility in Heterogeneous Oligopoly}, series = {Production and Operations Management}, volume = {28}, journal = {Production and Operations Management}, doi = {10.1111/poms.12995}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-356226}, pages = {1641-1657}, year = {2019}, abstract = {We develop a model of oligopoly competition involving innovation effort, market entry and production flexibility under demand uncertainty. Several heterogeneous firms make efforts to develop new prototypes; if they succeed, they hold a shared option to enter a new market under stochastic demand. We derive analytic results for the Markov perfect equilibrium accounting for development effort, market entry and production decisions and complement these by numerical analyses. Firm value—which embeds real options—is not convex increasing in demand but exhibits "competitive waves" due to market entries by rivals. A firm with a development advantage ("innovator") exerts greater innovation effort if the market is a niche, whereas another benefiting from economies of scale ("incumbent") invests more if the market is larger. Positive externalities benefit the incumbent in the development stage, whereas the innovator is better off in counteracting negative externalities. Demand volatility raises firm incentives to innovate as it enhances the value of firm market-entry and production flexibility.}, language = {en} } @article{HuangWaadtNuhkatetal.2019, author = {Huang, Shouguang and Waadt, Rainer and Nuhkat, Maris and Kollist, Hannes and Hedrich, Rainer and Roelfsema, M. Rob G.}, title = {Calcium signals in guard cells enhance the efficiency by which abscisic acid triggers stomatal closure}, series = {New Phytologist}, volume = {224}, journal = {New Phytologist}, doi = {10.1111/nph.15985}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322716}, pages = {177-187}, year = {2019}, abstract = {During drought, abscisic acid (ABA) induces closure of stomata via a signaling pathway that involves the calcium (Ca2+)-independent protein kinase OST1, as well as Ca2+-dependent protein kinases. However, the interconnection between OST1 and Ca2+ signaling in ABA-induced stomatal closure has not been fully resolved. ABA-induced Ca2+ signals were monitored in intact Arabidopsis leaves, which express the ratiometric Ca2+ reporter R-GECO1-mTurquoise and the Ca2+-dependent activation of S-type anion channels was recorded with intracellular double-barreled microelectrodes. ABA triggered Ca2+ signals that occurred during the initiation period, as well as in the acceleration phase of stomatal closure. However, a subset of stomata closed in the absence of Ca2+ signals. On average, stomata closed faster if Ca2+ signals were elicited during the ABA response. Loss of OST1 prevented ABA-induced stomatal closure and repressed Ca2+ signals, whereas elevation of the cytosolic Ca2+ concentration caused a rapid activation of SLAC1 and SLAH3 anion channels. Our data show that the majority of Ca2+ signals are evoked during the acceleration phase of stomatal closure, which is initiated by OST1. These Ca2+ signals are likely to activate Ca2+-dependent protein kinases, which enhance the activity of S-type anion channels and boost stomatal closure.}, language = {en} }