TY - JOUR A1 - Koeniger, Tobias A1 - Kuerten, Stefanie T1 - Splitting the "unsplittable": Dissecting resident and infiltrating macrophages in experimental autoimmune encephalomyelitis JF - International Journal of Molecular Sciences N2 - Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS. KW - CNS KW - distinction KW - experimental autoimmune encephalomyelitis KW - inflammation KW - macrophages KW - markers KW - microglia KW - monocytes Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285067 SN - 1422-0067 VL - 18 IS - 10 ER - TY - JOUR A1 - Hibar, Derrek P. A1 - Adams, Hieab H.H. A1 - Jahanshad, Neda A1 - Chauhan, Ganesh A1 - Stein, Jason L A1 - Hofer, Edith A1 - Renteria, Miguel E. A1 - Bis, Joshua C. A1 - Arias-Vasquez, Alejandro A1 - Ikram, M. Kamran A1 - Desrivières, Sylvane A1 - Vernooij, Meike W. A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Amin, Najaf A1 - Andersson, Micael A1 - Arfanakis, Konstantinos A1 - Aribisala, Benjamin S. A1 - Armstrong, Nicola J. A1 - Athanasiu, Lavinia A1 - Axelsson, Tomas A1 - Beecham, Ashley H. A1 - Beiser, Alexa A1 - Bernard, Manon A1 - Blanton, Susan H. A1 - Bohlken, Marc M. A1 - Boks, Marco P. A1 - Bralten, Janita A1 - Brickman, Adam M. A1 - Carmichael, Owen T1 - Novel genetic loci associated with hippocampal volume JF - Nature Communications N2 - The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (r\(_g\)=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. KW - brain KW - hippocampal formation KW - neuropsychiatric disorders KW - Alzheimer’s disease KW - genetic loci KW - hippocampal volume Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-182115 VL - 8 ER - TY - JOUR A1 - Vargas Casanova, Yerly A1 - Rodríguez Guerra, Jorge Antonio A1 - Umaña Pérez, Yadi Adriana A1 - Leal Castro, Aura Lucía A1 - Almanzar Reina, Giovanni A1 - García Castañeda, Javier Eduardo A1 - Rivera Monroy, Zuly Jenny T1 - Antibacterial synthetic peptides derived from bovine lactoferricin exhibit cytotoxic effect against MDA-MB-468 and MDA-MB-231 breast cancer cell lines JF - Molecules N2 - Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B, containing the RRWQWR motif, were designed, synthesized, purified, and characterized using RP-HPLC chromatography and MALDI-TOF mass spectrometry. The antibacterial activity of the designed peptides against E. coli (ATCC 11775 and 25922) and their cytotoxic effect against MDA-MB-468 and MDA-MB-231 breast cancer cell lines were evaluated. Dimeric and tetrameric peptides showed higher antibacterial activity in both bacteria strains than linear peptides. The dimeric peptide (RRWQWR)\(_2\)K-Ahx exhibited the highest antibacterial activity against the tested bacterial strains. Furthermore, the peptides with high antibacterial activity exhibited significant cytotoxic effect against the tested breast cancer cell lines. This cytotoxic effect was fast and dependent on the peptide concentration. The tetrameric molecule containing RRWQWR motif has an optimal cytotoxic effect at a concentration of 22 µM. The evaluated dimeric and tetrameric peptides could be considered as candidates for developing new therapeutic agents against breast cancer. Polyvalence of linear sequences could be considered as a novel and versatile strategy for obtaining molecules with high anticancer activity. KW - lactoferricin B KW - E. coli KW - breast cancer KW - cytotoxic effect KW - antibacterial activity KW - synthetic peptides Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173887 VL - 22 IS - 10 ER - TY - JOUR A1 - Vangeel, Elise Beau A1 - Pishva, Ehsan A1 - Hompes, Titia A1 - van den Hove, Daniel A1 - Lambrechts, Diether A1 - Allegaert, Karel A1 - Freson, Kathleen A1 - Izzi, Benedetta A1 - Claes, Stephan T1 - Newborn genome-wide DNA methylation in association with pregnancy anxiety reveals a potential role for \(GABBR1\) JF - Clinical Epigenetics N2 - Background: There is increasing evidence for the role of prenatal stress in shaping offspring DNA methylation and disease susceptibility. In the current study, we aimed to identify genes and pathways associated with pregnancy anxiety using a genome-wide DNA methylation approach. Methods: We selected 22 versus 23 newborns from our Prenatal Early Life Stress (PELS) cohort, exposed to the lowest or highest degree of maternal pregnancy anxiety, respectively. Cord blood genome-wide DNA methylation was assayed using the HumanMethylation450 BeadChip (HM450, n = 45) and candidate gene methylation using EpiTYPER (n = 80). Cortisol levels were measured at 2, 4, and 12 months of age to test infant stress system (re)activity. Results: Data showed ten differentially methylated regions (DMR) when comparing newborns exposed to low versus high pregnancy anxiety scores. We validated a top DMR in the GABA-B receptor subunit 1 gene (GABBR1) revealing the association with pregnancy anxiety particularly in male newborns (most significant CpG Pearson R = 0.517, p = 0.002; average methylation Pearson R = 0.332, p = 0.039). Cord blood GABBR1 methylation was associated with infant cortisol levels in response to a routine vaccination at 4 months old. Conclusions: In conclusion, our results show that pregnancy anxiety is associated with differential DNA methylation patterns in newborns and that our candidate gene GABBR1 is associated with infant hypothalamic-pituitary-adrenal axis response to a stressor. Our findings reveal a potential role for GABBR1 methylation in association with stress and provide grounds for further research. KW - DNA methylation KW - GABBR1 KW - gender differences KW - HPA axis KW - pregnancy anxiety KW - prenatal stress Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173825 VL - 9 ER - TY - JOUR A1 - Salker, Madhuri S. A1 - Singh, Yogesh A1 - Zeng, Ni A1 - Chen, Hong A1 - Zhang, Shaqiu A1 - Umbach, Anja T. A1 - Fakhri, Hajar A1 - Kohlhofer, Ursula A1 - Quintanilla-Martinez, Leticia A1 - Durairaj, Ruban R. Peter A1 - Barros, Flavio S. V. A1 - Vrljicak, Pavle A1 - Ott, Sascha A1 - Brucker, Sara Y. A1 - Wallwiener, Diethelm A1 - Madunić, Ivana Vrhovac A1 - Breljak, Davorka A1 - Sabolić, Ivan A1 - Koepsell, Hermann A1 - Brosens, Jan J. A1 - Lang, Florian T1 - Loss of endometrial sodium glucose cotransporter SGLT1 is detrimental to embryo survival and fetal growth in pregnancy JF - Scientific Reports N2 - Embryo implantation requires a hospitable uterine environment. A key metabolic change that occurs during the peri-implantation period, and throughout early pregnancy, is the rise in endometrial glycogen content. Glycogen accumulation requires prior cellular uptake of glucose. Here we show that both human and murine endometrial epithelial cells express the high affinity Na\(^+\)-coupled glucose carrier SGLT1. Ussing chamber experiments revealed electrogenic glucose transport across the endometrium in wild type (\(Slc5a1^{+/+}\)) but not in SGLT1 defcient (\(Slc5a1^{−/−}\)) mice. Endometrial glycogen content, litter size and weight of offspring at birth were signifcantly lower in \(Slc5a1^{−/−}\) mice. In humans, \(SLC5A1\) expression was upregulated upon decidualization of primary endometrial stromal cells. Endometrial \(SLC5A1\) expression during the implantation window was attenuated in patients with recurrent pregnancy loss when compared with control subjects. Our fndings reveal a novel mechanism establishing adequate endometrial glycogen stores for pregnancy. Disruption of this histiotrophic pathway leads to adverse pregnancy outcome. KW - biology KW - embryology KW - intrauterine growth KW - paediatric research Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173814 VL - 7 ER - TY - JOUR A1 - Cerna-Velazco, Nhell A1 - Faber, Thomas A1 - Jones-Pérez, Joel A1 - Porod, Werner T1 - Constraining sleptons at the LHC in a supersymmetric low-scale seesaw scenario JF - European Physical Journal C N2 - We consider a scenario inspired by natural supersymmetry, where neutrino data is explained within a low-scale seesaw scenario. We extend the Minimal Supersymmetric Standard Model by adding light right-handed neutrinos and their superpartners, the R-sneutrinos, and consider the lightest neutralinos to be higgsino-like. We consider the possibilities of having either an R-sneutrino or a higgsino as lightest supersymmetric particle. Assuming that squarks and gauginos are heavy, we systematically evaluate the bounds on slepton masses due to existing LHC data. KW - physics KW - particle physics KW - neutrino KW - R-sneutrino KW - supersymmetry (SUSY) KW - supersymmetric model KW - standard seesaw KW - inverse seesaw KW - minimal supersymmetric standard model (MSSM) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173809 VL - 77 ER - TY - JOUR T1 - Search for triboson \({W^\pm}{W^\pm}{W^\mp}\) production in \(pp\) collisions at \(\sqrt{s}\) = 8 TeV with the ATLAS detector JF - European Physical Journal C N2 - This paper reports a search for triboson \({W^\pm}{W^\pm}{W^\mp}\) production in two decay channels (\({W^\pm}{W^\pm}{W^\mp}\) → \({ℓ^\pm}{νℓ^\pm}{νℓ^\mp}{ν}\) and \({W^\pm}{W^\pm}{W^\mp}\) → \({ℓ^\pm}{νℓ^\pm}{νjj}\) with \(ℓ=e,μ\)) in proton-proton collision data corresponding to an integrated luminosity of 20.3 fb\(^{−1}\) at a centre-of-mass energy of 8 TeV with the ATLAS detector at the Large Hadron Collider. Events with exactly three charged leptons, or two leptons with the same electric charge in association with two jets, are selected. The total number of events observed in data is consistent with the Standard Model (SM) predictions. The observed 95% confidence level upper limit on the SM \({W^\pm}{W^\pm}{W^\mp}\) production cross section is found to be 730 fb with an expected limit of 560 fb in the absence of SM \({W^\pm}{W^\pm}{W^\mp}\) production. Limits are also set on \(WWWW\) anomalous quartic gauge couplings. KW - high energy physics KW - triboson production KW - triple gauge couplings (TGCs) KW - quartic gauge couplings (QGCs) KW - decay channels Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173710 VL - 77 IS - 141 ER - TY - JOUR T1 - A measurement of the calorimeter response to single hadrons and determination of the jet energy scale uncertainty using LHC Run-1 \(pp\)-collision data with the ATLAS detector JF - European Physical Journal C N2 - A measurement of the calorimeter response to isolated charged hadrons in the ATLAS detector at the LHC is presented. This measurement is performed with 3.2 nb\(^{−1}\) of proton–proton collision data at \(\sqrt{s}\) = 7 TeV from 2010 and 0.1 nb\(^{−1}\) of data at \(\sqrt{s}\) = 8 TeV from 2012. A number of aspects of the calorimeter response to isolated hadrons are explored. After accounting for energy deposited by neutral particles, there is a 5% discrepancy in the modelling, using various sets of GEANT4 hadronic physics models, of the calorimeter response to isolated charged hadrons in the central calorimeter region. The description of the response to anti-protons at low momenta is found to be improved with respect to previous analyses. The electromagnetic and hadronic calorimeters are also examined separately, and the detector simulation is found to describe the response in the hadronic calorimeter well. The jet energy scale uncertainty and correlations in scale between jets of different momenta and pseudorapidity are derived based on these studies. The uncertainty is 2–5% for jets with transverse momenta above 2 TeV, where this method provides the jet energy scale uncertainty for ATLAS. KW - high energy physics KW - ATLAS detector KW - hadronic calorimeter KW - charged hadron response KW - identified particle response KW - hadronic physics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173690 VL - 77 IS - 26 ER - TY - JOUR A1 - Chiesa, Mauro A1 - Greiner, Nicolas A1 - Schönherr, Marek A1 - Tramontano, Francesco T1 - Electroweak corrections to diphoton plus jets JF - Journal of High Energy Physics N2 - We calculate the next-to-leading order electroweak corrections to the production of a photon pair in association with zero, one and two jets at the LHC. We use GoSam and Sherpa to obtain the results in a fully automated way. For a typical set of fiducial cuts the electroweak corrections lead to a modification of the total cross section of up to 3%, depending on the jet multiplicity. We find substantial contributions in differential distributions, leading to tens of per cent corrections for phase space regions within the reach of the LHC. Furthermore we investigate the importance of photon induced processes as well as subleading contributions. Photon induced processes are found to be negligible, subleading contributions can have a sizeable impact however they can be removed by appropriate phase space cuts. KW - NLO computations Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173512 IS - 10 ER - TY - JOUR A1 - Leopold, Stephanie A. A1 - Zeilbeck, Ludwig F. A1 - Weber, Gregor A1 - Seitz, Roswitha A1 - Bösl, Michael R. A1 - Jägle, Herbert A1 - Fuchshofer, Rudolf A1 - Tamm, Ernst R. A1 - Ohlmann, Andreas T1 - Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma JF - Scientific Reports N2 - Norrin is a secreted signaling molecule activating the Wnt/β-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA/2J/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA/2J/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA/2J/Pax6-Norrin mice, which showed a β-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt/β-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma. KW - glaucoma KW - neurotrophic factors Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173494 VL - 7 ER -