TY  - JOUR
A1  - Mitjans, M.
A1  - Begemann, M.
A1  - Ju, A.
A1  - Dere, E.
A1  - Wüstefeld, L.
A1  - Hofer, S.
A1  - Hassouna, I.
A1  - Balkenhol, J.
A1  - Oliveira, B.
A1  - Van der Auwera, S.
A1  - Tammer, R.
A1  - Hammerschmidt, K.
A1  - Völzke, H.
A1  - Homuth, G.
A1  - Cecconi, F.
A1  - Chowdhury, K.
A1  - Grabe, H.
A1  - Frahm, J.
A1  - Boretius, S.
A1  - Dandekar, T.
A1  - Ehrenreich, H.
T1  - Sexual dimorphism of \(AMBRA1\)-related autistic features in human and mouse
JF  - Translational Psychiatry
N2  - \(Ambra1\) is linked to autophagy and neurodevelopment. Heterozygous \(Ambra1\) deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of \(AMBRA1\) for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal \(AMBRA1\) genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower \(AMBRA1\) mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by \(in\) \(silico\) analysis. Searching for further autism-relevant characteristics in \(Ambra1^{+/−}\) mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an \(in\) \(vivo\) readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of \(AMBRA1/Ambra1\) partial loss-of-function genotypes for female autistic traits. Moreover, they suggest \(Ambra1\) heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.
KW  - biology
KW  - clinical genetics
KW  - molecular neuroscience
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173782
VL  - 2017
IS  - 7
ER  - 
TY  - JOUR
A1  - Min, Chul-Hee
A1  - Goth, F.
A1  - Lutz, P.
A1  - Bentmann, H.
A1  - Kang, B.Y.
A1  - Cho, B.K.
A1  - Werner, J.
A1  - Chen, K.-S.
A1  - Assaad, F.
A1  - Reinert, F.
T1  - Matching DMFT calculations with photoemission spectra of heavy fermion insulators: universal properties of the near-gap spectra of SmB\(_{6}\)
JF  - Scientific Reports
N2  - Paramagnetic heavy fermion insulators consist of fully occupied quasiparticle bands inherent to Fermi liquid theory. The gap emergence below a characteristic temperature is the ultimate sign of coherence for a many-body system, which in addition can induce a non-trivial band topology. Here, we demonstrate a simple and efficient method to compare a model study and an experimental result for heavy fermion insulators. The temperature dependence of the gap formation in both local moment and mixed valence regimes is captured within the dynamical mean field (DMFT) approximation to the periodic Anderson model (PAM). Using the topological coherence temperature as the scaling factor and choosing the input parameter set within the mixed valence regime, we can unambiguously link the theoretical energy scales to the experimental ones. As a particularly important result, we find improved consistency between the scaled DMFT density of states and the photoemission near-gap spectra of samarium hexaboride (SmB\(_{6}\)).
KW  - SmB\(_{6}\)
KW  - heavy fermion insulators
KW  - dynamical mean field
KW  - samarium hexaboride
KW  - near-gap spectra
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170328
VL  - 7
IS  - 11980
ER  - 
TY  - JOUR
A1  - Milanos, Sinem
A1  - Elsharif, Shaimaa A.
A1  - Janzen, Dieter
A1  - Buettner, Andrea
A1  - Villmann, Carmen
T1  - Metabolic Products of Linalool and Modulation of GABA\(_{A}\) Receptors
JF  - Frontiers in Chemistry
N2  - Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory α1β2 GABA\(_{A}\) receptors in various expression systems. However, in plants or humans, i.e., following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives. Here, we analyzed the modulatory potential of linalool derivatives at α1β2γ2 GABA\(_{A}\) receptors upon transient overexpression. Following receptor expression control, electrophysiological recordings in a whole cell configuration were used to determine the chloride influx upon co-application of GABA EC\(_{10-30}\) together with the modulatory substance. Our results show that only oxygenated linalool metabolites at carbon 8 positively affect GABAergic currents whereas derivatives hydroxylated or carboxylated at carbon 8 were rather ineffective. Acetylated linalool derivatives resulted in non-significant changes of GABAergic currents. We can conclude that metabolism of linalool reduces its positive allosteric potential at GABAA receptors compared to the significant potentiation effects of the parent molecule linalool itself.
KW  - Cys-loop receptor
KW  - GABA\(_{A}\)
KW  - receptor
KW  - linalool
KW  - linalyl acetate
KW  - oxygenation
KW  - patch-clamp
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170779
VL  - 5
IS  - 46
ER  - 
TY  - JOUR
A1  - Mielich-Süss, Benjamin
A1  - Wagner, Rabea M.
A1  - Mietrach, Nicole
A1  - Hertlein, Tobias
A1  - Marincola, Gabriella
A1  - Ohlsen, Knut
A1  - Geibel, Sebastian
A1  - Lopez, Daniel
T1  - Flotillin scaffold activity contributes to type VII secretion system assembly in Staphylococcus aureus
JF  - PLoS Pathogens
N2  - Scaffold proteins are ubiquitous chaperones that promote efficient interactions between partners of multi-enzymatic protein complexes; although they are well studied in eukaryotes, their role in prokaryotic systems is poorly understood. Bacterial membranes have functional membrane microdomains (FMM), a structure homologous to eukaryotic lipid rafts. Similar to their eukaryotic counterparts, bacterial FMM harbor a scaffold protein termed flotillin that is thought to promote interactions between proteins spatially confined to the FMM. Here we used biochemical approaches to define the scaffold activity of the flotillin homolog FloA of the human pathogen Staphylococcus aureus, using assembly of interacting protein partners of the type VII secretion system (T7SS) as a case study. Staphylococcus aureus cells that lacked FloA showed reduced T7SS function, and thus reduced secretion of T7SS-related effectors, probably due to the supporting scaffold activity of flotillin. We found that the presence of flotillin mediates intermolecular interactions of T7SS proteins. We tested several small molecules that interfere with flotillin scaffold activity, which perturbed T7SS activity in vitro and in vivo. Our results suggest that flotillin assists in the assembly of S. aureus membrane components that participate in infection and influences the infective potential of this pathogen.
KW  - flotillin
KW  - scaffold protein
KW  - Staphylococcus aureus
KW  - type VII secretion system
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170035
VL  - 13
IS  - 11
ER  - 
TY  - JOUR
A1  - Middelhoff, Frederike
T1  - Literary autozoographies: contextualizing species life in german animal autobiography
JF  - Humanities
N2  - What does it mean to take animal autobiography seriously and how can we account for the representation of life-narrating animals? The article investigates animal autobiographies as ‘literary autozoographies’, drawing attention to both the generic contexts and the epistemological premises of these texts. Adopting a double-bind approach stemming from autobiographical research as well as cultural animal studies, the article focuses on early nineteenth-century equine autozoographies from the German-speaking tradition. These texts are discussed exemplarily in relation to the parameters of fictional autobiographies, before they are contextualized with historical discourses regarding horses in natural history and so-called ‘horse-science’. Due to the fact that the poetics and aesthetics of the genre are modeled on the templates of factual autobiographies, the article argues that literary autozoographies can be read as fictional autobiographies as well as meta-auto/biographical discourse undermining autobiographical conventions. Furthermore, it shows that literary autozoography and zoology share a common historical and ideological epistemology accounting for the representation of animals in both fields. Literary autozoographies thus participate in the negotiation and production of species-specific knowledge. Reading Life of the Mecklenburg Mare Amante (1804), Life of a Job Horse (1807) and Life of a Worn-Out Hack (1819) alongside equine-centric discourses around 1800, the article demonstrates in what ways these texts can be regarded as part of a regime of knowledge attributing emotions and cognitive capacities to horses, while simultaneously arguing for humane treatment on the basis of interspecies homologies.
KW  - animal autobiography
KW  - fictional autobiography
KW  - meta-autobiography
KW  - life writing
KW  - contextualist narratology
KW  - cultural and literary animal studies
KW  - poetics of knowledge
KW  - zoology
KW  - natural history
KW  - equine autozoography
KW  - horse-science
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198052
SN  - 2076-0787
VL  - 6
IS  - 2
PB  - MDPI
ER  - 
TY  - JOUR
A1  - Mende, Daniel R.
A1  - Letunic, Ivica
A1  - Huerta-Cepas, Jaime
A1  - Li, Simone S.
A1  - Forslund, Kristoffer
A1  - Sunagawa, Shinichi
A1  - Bork, Peer
T1  - proGenomes: a resource for consistent functional and taxonomic annotations of prokaryotic genomes
JF  - Nucleic Acids Research
N2  - The availability of microbial genomes has opened many new avenues of research within microbiology. This has been driven primarily by comparative genomics approaches, which rely on accurate and consistent characterization of genomic sequences. It is nevertheless difficult to obtain consistent taxonomic and integrated functional annotations for defined prokaryotic clades. Thus, we developed proGenomes, a resource that provides user-friendly access to currently 25 038 high-quality genomes whose sequences and consistent annotations can be retrieved individually or by taxonomic clade. These genomes are assigned to 5306 consistent and accurate taxonomic species clusters based on previously established methodology. proGenomes also contains functional information for almost 80 million protein-coding genes, including a comprehensive set of general annotations and more focused annotations for carbohydrate-active enzymes and antibiotic resistance genes. Additionally, broad habitat information is provided for many genomes. All genomes and associated information can be downloaded by user-selected clade or multiple habitat-specific sets of representative genomes. We expect that the availability of high-quality genomes with comprehensive functional annotations will promote advances in clinical microbial genomics, functional evolution and other subfields of microbiology. proGenomes is available at http://progenomes.embl.de.
KW  - biology
KW  - genomic sequence
KW  - prokaryotic clade
KW  - proGenomes
KW  - habitat information
KW  - taxonomic description
KW  - genome collection
KW  - comparative genomics
KW  - genomics research
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171987
VL  - 45
IS  - D1
ER  - 
TY  - JOUR
A1  - Memmel, Simon
A1  - Sisario, Dmitri
A1  - Zöller, Caren
A1  - Fiedler, Vanessa
A1  - Katzer, Astrid
A1  - Heiden, Robin
A1  - Becker, Nicholas
A1  - Eing, Lorenz
A1  - Ferreira, Fábio L.R.
A1  - Zimmermann, Heiko
A1  - Sauer, Markus
A1  - Flentje, Michael
A1  - Sukhorukov, Vladimir L.
A1  - Djuzenova, Cholpon S.
T1  - Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities
JF  - Oncotarget
N2  - High invasiveness and resistance to chemo- and radiotherapy of glioblastoma multiforme (GBM) make it the most lethal brain tumor. Therefore, new treatment strategies for preventing migration and invasion of GBM cells are needed. Using two different migration assays, Western blotting, conventional and super-resolution (dSTORM) fluorescence microscopy we examine the effects of the dual PI3K/mTOR-inhibitor PI-103 alone and in combination with the Hsp90 inhibitor NVP-AUY922 and/or irradiation on the migration, expression of marker proteins, focal adhesions and F-actin cytoskeleton in two GBM cell lines (DK-MG and SNB19) markedly differing in their invasive capacity. Both lines were found to be strikingly different in morphology and migration behavior. The less invasive DK-MG cells maintained a polarized morphology and migrated in a directionally persistent manner, whereas the highly invasive SNB19 cells showed a multipolar morphology and migrated randomly. Interestingly, a single dose of 2 Gy accelerated wound closure in both cell lines without affecting their migration measured by single-cell tracking. PI-103 inhibited migration of DK-MG (p53 wt, PTEN wt) but not of SNB19 (p53 mut, PTEN mut) cells probably due to aberrant reactivation of the PI3K pathway in SNB19 cells treated with PI-103. In contrast, NVP-AUY922 exerted strong anti-migratory effects in both cell lines. Inhibition of cell migration was associated with massive morphological changes and reorganization of the actin cytoskeleton. Our results showed a cell line-specific response to PI3K/mTOR inhibition in terms of GBM cell motility. We conclude that anti-migratory agents warrant further preclinical investigation as potential therapeutics for treatment of GBM.
KW  - chemotherapy
KW  - glioblastoma multiforme
KW  - migration
KW  - treatment
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170719
VL  - 8
IS  - 28
ER  - 
TY  - JOUR
A1  - Meininger, Susanne
A1  - Blum, Carina
A1  - Schamel, Martha
A1  - Barralet, Jake E.
A1  - Ignatius, Anita
A1  - Gbureck, Uwe
T1  - Phytic acid as alternative setting retarder enhanced biological performance of dicalcium phosphate cement in vitro
JF  - Scientific Reports
N2  - Dicalcium phosphate cement preparation requires the addition of setting retarders to meet clinical requirements regarding handling time and processability. Previous studies have focused on the influence of different setting modifiers on material properties such as mechanical performance or injectability, while ignoring their influence on biological cement properties as they are used in low concentrations in the cement pastes and the occurrence of most compounds in human tissues. Here, analyses of both material and biological behavior were carried out on samples with common setting retardants (citric acid, sodium pyrophosphate, sulfuric acid) and novel (phytic acid). Cytocompatibility was evaluated by in vitro tests with osteoblastic (hFOB 1.19) and osteoclastic (RAW 264.7) cells. We found cytocompatibility was better for sodium pyrophosphate and phytic acid with a three-fold cell metabolic activity by WST-1 test, whereas samples set with citric acid showed reduced cell number as well as cell activity. The compressive strength (CS) of cements formed with phytic acid (CS = 13 MPa) were nearly equal to those formed with citric acid (CS = 15 MPa) and approximately threefold higher than for other setting retardants. Due to a proven cytocompatibility and high mechanical strength, phytic acid seems to be a candidate replacement setting retardant for dicalcium phosphate cements.
KW  - implants
KW  - biomedical materials
KW  - dicalcium phosphate cement
KW  - phytic acid
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171047
VL  - 7
IS  - 558
ER  - 
TY  - JOUR
A1  - Maurer, Jana
A1  - Hupp, Sabrina
A1  - Bischoff, Carolin
A1  - Foertsch, Christina
A1  - Mitchell, Timothy J.
A1  - Chakraborty, Trinad
A1  - Iliev, Asparouh I.
T1  - Distinct neurotoxicity profile of listeriolysin O from \(Listeria\) \(monocytogenes\)
JF  - Toxins
N2  - Cholesterol-dependent cytolysins (CDCs) are protein toxins that originate from Gram-positive bacteria and contribute substantially to their pathogenicity. CDCs bind membrane cholesterol and build prepores and lytic pores. Some effects of the toxins are observed in non-lytic concentrations. Two pathogens, \(Streptococcus\) \(pneumoniae\) and \(Listeria\) \(monocytogenes\), cause fatal bacterial meningitis, and both produce toxins of the CDC family—pneumolysin and listeriolysin O, respectively. It has been demonstrated that pneumolysin produces dendritic varicosities (dendrite swellings) and dendritic spine collapse in the mouse neocortex, followed by synaptic loss and astrocyte cell shape remodeling without elevated cell death. We utilized primary glial cultures and acute mouse brain slices to examine the neuropathological effects of listeriolysin O and to compare it to pneumolysin with identical hemolytic activity. In cultures, listeriolysin O permeabilized cells slower than pneumolysin did but still initiated non-lytic astrocytic cell shape changes, just as pneumolysin did. In an acute brain slice culture system, listeriolysin O produced dendritic varicosities in an NMDA-dependent manner but failed to cause dendritic spine collapse and cortical astrocyte reorganization. Thus, listeriolysin O demonstrated slower cell permeabilization and milder glial cell remodeling ability than did pneumolysin and lacked dendritic spine collapse capacity but exhibited equivalent dendritic pathology.
KW  - medicine
KW  - listeriolysin O
KW  - meningitis
KW  - acute slices
KW  - variocosities
KW  - dendritic spines
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172130
VL  - 9
IS  - 1
ER  - 
TY  - JOUR
A1  - Maierhofer, Anna
A1  - Flunkert, Julia
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Schindler, Detlev
A1  - Nanda, Indrajit
A1  - Haaf, Thomas
T1  - Analysis of global DNA methylation changes in primary human fibroblasts in the early phase following X-ray irradiation
JF  - PLoS ONE
N2  - Epigenetic alterations may contribute to the generation of cancer cells in a multi-step process of tumorigenesis following irradiation of normal body cells. Primary human fibroblasts with intact cell cycle checkpoints were used as a model to test whether X-ray irradiation with 2 and 4 Gray induces direct epigenetic effects (within the first cell cycle) in the exposed cells. ELISA-based fluorometric assays were consistent with slightly reduced global DNA methylation and hydroxymethylation, however the observed between-group differences were usually not significant. Similarly, bisulfite pyrosequencing of interspersed LINE-1 repeats and centromeric α-satellite DNA did not detect significant methylation differences between irradiated and non-irradiated cultures. Methylation of interspersed ALU repeats appeared to be slightly increased (one percentage point; p = 0.01) at 6 h after irradiation with 4 Gy. Single-cell analysis showed comparable variations in repeat methylation among individual cells in both irradiated and control cultures. Radiation-induced changes in global repeat methylation, if any, were much smaller than methylation variation between different fibroblast strains. Interestingly, α-satellite DNA methylation positively correlated with gestational age. Finally, 450K methylation arrays mainly targeting genes and CpG islands were used for global DNA methylation analysis. There were no detectable methylation differences in genic (promoter, 5' UTR, first exon, gene body, 3' UTR) and intergenic regions between irradiated and control fibroblast cultures. Although we cannot exclude minor effects, i.e. on individual CpG sites, collectively our data suggest that global DNA methylation remains rather stable in irradiated normal body cells in the early phase of DNA damage response.
KW  - DNA methylation
KW  - fibroblasts
KW  - methylation
KW  - alu elements
KW  - DNA damage
KW  - epigenetics
KW  - cancer treatment
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170895
VL  - 12
IS  - 5
ER  - 
TY  - JOUR
A1  - Lüningschrör, Patrick
A1  - Binotti, Beyenech
A1  - Dombert, Benjamin
A1  - Heimann, Peter
A1  - Perez-Lara, Angel
A1  - Slotta, Carsten
A1  - Thau-Habermann, Nadine
A1  - von Collenberg, Cora R.
A1  - Karl, Franziska
A1  - Damme, Markus
A1  - Horowitz, Arie
A1  - Maystadt, Isabelle
A1  - Füchtbauer, Annette
A1  - Füchtbauer, Ernst-Martin
A1  - Jablonka, Sibylle
A1  - Blum, Robert
A1  - Üçeyler, Nurcan
A1  - Petri, Susanne
A1  - Kaltschmidt, Barbara
A1  - Jahn, Reinhard
A1  - Kaltschmidt, Christian
A1  - Sendtner, Michael
T1  - Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
JF  - Nature Communications
N2  - Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.
KW  - autophagy
KW  - synaptic vesicles
KW  - Pleckstrin homology containing family member 5 (Plekhg5)
KW  - regulation
KW  - motoneuron disease
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170048
VL  - 8
IS  - 678
ER  - 
TY  - JOUR
A1  - Lutz, Manfred B.
A1  - Strobl, Herbert
A1  - Schuler, Gerold
A1  - Romani, Nikolaus
T1  - GM-CSF monocyte-derived cells and Langerhans cells as part of the dendritic cell family
JF  - Frontiers in Immunology
N2  - Dendritic cells (DCs) and macrophages (Mph) share many characteristics as components of the innate immune system. The criteria to classify the multitude of subsets within the mononuclear phagocyte system are currently phenotype, ontogeny, transcription patterns, epigenetic adaptations, and function. More recently, ontogenetic, transcriptional, and proteomic research approaches uncovered major developmental differences between Flt3L-dependent conventional DCs as compared with Mphs and monocyte-derived DCs (MoDCs), the latter mainly generated in vitro from murine bone marrow-derived DCs (BM-DCs) or human CD14\(^{+}\) peripheral blood monocytes. Conversely, in vitro GM-CSF-dependent monocyte-derived Mphs largely resemble MoDCs whereas tissue-resident Mphs show a common embryonic origin from yolk sac and fetal liver with Langerhans cells (LCs). The novel ontogenetic findings opened discussions on the terminology of DCs versus Mphs. Here, we bring forward arguments to facilitate definitions of BM-DCs, MoDCs, and LCs. We propose a group model of terminology for all DC subsets that attempts to encompass both ontogeny and function.
KW  - macrophages
KW  - dendritic cells
KW  - GM-CSF
KW  - monocytes
KW  - Langerhans cells
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158730
VL  - 8
IS  - 1388
ER  - 
TY  - JOUR
A1  - Lukeš, Tomáš
A1  - Glatzová, Daniela
A1  - Kvíčalová, Zuzana
A1  - Levet, Florian
A1  - Benda, Aleš
A1  - Letschert, Sebastian
A1  - Sauer, Markus
A1  - Brdička, Tomáš
A1  - Lasser, Theo
A1  - Cebecauer, Marek
T1  - Quantifying protein densities on cell membranes using super-resolution optical fluctuation imaging
JF  - Nature Communications
N2  - Quantitative approaches for characterizing molecular organization of cell membrane molecules under physiological and pathological conditions profit from recently developed super-resolution imaging techniques. Current tools employ statistical algorithms to determine clusters of molecules based on single-molecule localization microscopy (SMLM) data. These approaches are limited by the ability of SMLM techniques to identify and localize molecules in densely populated areas and experimental conditions of sample preparation and image acquisition. We have developed a robust, model-free, quantitative clustering analysis to determine the distribution of membrane molecules that excels in densely labeled areas and is tolerant to various experimental conditions, i.e. multiple-blinking or high blinking rates. The method is based on a TIRF microscope followed by a super-resolution optical fluctuation imaging (SOFI) analysis. The effectiveness and robustness of the method is validated using simulated and experimental data investigating nanoscale distribution of CD4 glycoprotein mutants in the plasma membrane of T cells.
KW  - biology
KW  - fluorescence imaging
KW  - imaging the immune system
KW  - super-resolution microscopy
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172993
VL  - 8
ER  - 
TY  - JOUR
A1  - Lueken, U
A1  - Kuhn, M
A1  - Yang, Y
A1  - Straube, B
A1  - Kircher, T
A1  - Wittchen, H-U
A1  - Pfleiderer, B
A1  - Arolt, V
A1  - Wittmann, A
A1  - Ströhle, A
A1  - Weber, H
A1  - Reif, A
A1  - Domschke, K
A1  - Deckert, J
A1  - Lonsdorf, TB
T1  - Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach
JF  - Translational Psychiatry
N2  - Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain’s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.
KW  - glycine receptor beta subunit
KW  - neural fear network activation
KW  - intermediate phenotype approach
KW  - defensive system reactivity
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-182381
VL  - 7
IS  - e1227
ER  - 
TY  - JOUR
A1  - Ludwigs, Markus
A1  - Amann, Hannah
T1  - Klausur im Kommunalrecht: Ausschluss aus dem Gemeinderat
JF  - JURA - Juristische Ausbildung
N2  - Kein Abstract verfügbar.
KW  - Kommunalrecht
KW  - Klausur
KW  - Gemeinderat
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195589
SN  - 1612-7021
SN  - 0170-1452
N1  - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
VL  - 39
IS  - 9
SP  - 1106
EP  - 1115
ER  - 
TY  - JOUR
A1  - Lohse, Christian
A1  - Bock, Andreas
A1  - Maiellaro, Isabella
A1  - Hannawacker, Annette
A1  - Schad, Lothar R.
A1  - Lohse, Martin J.
A1  - Bauer, Wolfgang R.
T1  - Experimental and mathematical analysis of cAMP nanodomains
JF  - PLoS ONE
N2  - In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. These complex tasks demand a highly organized orchestration of spatially and temporally confined cAMP action which should be best achieved by compartmentalization of the latter. A great body of evidence suggests that cAMP compartments may be established and maintained by cAMP degrading enzymes, e.g. phosphodiesterases (PDEs). However, the molecular and biophysical details of how PDEs can orchestrate cAMP gradients are entirely unclear. In this paper, using fusion proteins of cAMP FRET-sensors and PDEs in living cells, we provide direct experimental evidence that the cAMP concentration in the vicinity of an individual PDE molecule is below the detection limit of our FRET sensors (<100nM). This cAMP gradient persists in crude cytosol preparations. We developed mathematical models based on diffusion-reaction equations which describe the creation of nanocompartments around a single PDE molecule and more complex spatial PDE arrangements. The analytically solvable equations derived here explicitly determine how the capability of a single PDE, or PDE complexes, to create a nanocompartment depend on the cAMP degradation rate, the diffusive mobility of cAMP, and geometrical and topological parameters. We apply these generic models to our experimental data and determine the diffusive mobility and degradation rate of cAMP. The results obtained for these parameters differ by far from data in literature for free soluble cAMP interacting with PDE. Hence, restricted cAMP diffusion in the vincinity of PDE is necessary to create cAMP nanocompartments in cells.
KW  - fluorescence resonance energy transfer
KW  - yellow fluorescent protein
KW  - radii
KW  - adenylyl cyclase signaling cascade
KW  - cell fusion
KW  - cytosol
KW  - isoproterenol
KW  - absorption
KW  - cyclic nucleotides such as cyclic adenosine monophosphate
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170972
VL  - 12
IS  - 4
ER  - 
TY  - JOUR
A1  - Liu, Han
A1  - Chen, Chunhai
A1  - Gao, Zexia
A1  - Min, Jiumeng
A1  - Gu, Yongming
A1  - Jian, Jianbo
A1  - Jiang, Xiewu
A1  - Cai, Huimin
A1  - Ebersberger, Ingo
A1  - Xu, Meng
A1  - Zhang, Xinhui
A1  - Chen, Jianwei
A1  - Luo, Wei
A1  - Chen, Boxiang
A1  - Chen, Junhui
A1  - Liu, Hong
A1  - Li, Jiang
A1  - Lai, Ruifang
A1  - Bai, Mingzhou
A1  - Wei, Jin
A1  - Yi, Shaokui
A1  - Wang, Huanling
A1  - Cao, Xiaojuan
A1  - Zhou, Xiaoyun
A1  - Zhao, Yuhua
A1  - Wei, Kaijian
A1  - Yang, Ruibin
A1  - Liu, Bingnan
A1  - Zhao, Shancen
A1  - Fang, Xiaodong
A1  - Schartl, Manfred
A1  - Qian, Xueqiao
A1  - Wang, Weimin
T1  - The draft genome of blunt snout bream (Megalobrama amblycephala) reveals the development of intermuscular bone and adaptation to herbivorous diet
JF  - GigaScience
N2  - The blunt snout bream Megalobrama amblycephala is the economically most important cyprinid fish species. As an herbivore, it can be grown by eco-friendly and resource-conserving aquaculture. However, the large number of intermuscular bones in the trunk musculature is adverse to fish meat processing and consumption. As a first towards optimizing this aquatic livestock, we present a 1.116-Gb draft genome of M. amblycephala, with 779.54 Mb anchored on 24 linkage groups. Integrating spatiotemporal transcriptome analyses, we show that intermuscular bone is formed in the more basal teleosts by intramembranous ossification and may be involved in muscle contractibility and coordinating cellular events. Comparative analysis revealed that olfactory receptor genes, especially of the beta type, underwent an extensive expansion in herbivorous cyprinids, whereas the gene for the umami receptor T1R1 was specifically lost in M. amblycephala. The composition of gut microflora, which contributes to the herbivorous adaptation of M. amblycephala, was found to be similar to that of other herbivores. As a valuable resource for the improvement of M. amblycephala livestock, the draft genome sequence offers new insights into the development of intermuscular bone and herbivorous adaptation.
KW  - Megalobrama amblycephala
KW  - whole genome
KW  - herbivorous diet
KW  - intermuscular bone
KW  - transcriptome
KW  - gut microflora
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170844
VL  - 6
IS  - 7
ER  - 
TY  - JOUR
A1  - Lischke, Alexander
A1  - Herpertz, Sabine C.
A1  - Berger, Christoph
A1  - Domes, Gregor
A1  - Gamer, Matthias
T1  - Divergent effects of oxytocin on (para-)limbic reactivity to emotional and neutral scenes in females with and without borderline personality disorder
JF  - Social Cognitive and Affective Neuroscience
N2  - Borderline personality disorder (BPD) patients’ hypersensitivity for emotionally relevant stimuli has been suggested be due to abnormal activity and connectivity in (para-)limbic and prefrontal brain regions during stimulus processing. The neuropeptide oxytocin has been shown to modulate activity and functional connectivity in these brain regions, thereby optimizing the processing of emotional and neutral stimuli. To investigate whether oxytocin would be capable of attenuating BPD patients’ hypersensitivity for such stimuli, we recorded brain activity and gaze behavior during the processing of complex scenes in 51 females with and 48 without BPD after intranasal application of either oxytocin or placebo. We found divergent effects of oxytocin on BPD and healthy control (HC) participants’ (para-)limbic reactivity to emotional and neutral scenes: Oxytocin decreased amygdala and insula reactivity in BPD participants but increased it in HC participants, indicating an oxytocin-induced normalization of amygdala and insula activity during scene processing. In addition, oxytocin normalized the abnormal coupling between amygdala activity and gaze behavior across all scenes in BPD participants. Overall, these findings suggest that oxytocin may be capable of attenuating BPD patients’ hypersensitivity for complex scenes, irrespective of their valence.
KW  - psychology
KW  - oxytocin
KW  - amygdala
KW  - insula
KW  - borderline personality disorder
KW  - functional magnetic resonance imaging
KW  - eye tracking
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173309
VL  - 12
IS  - 11
ER  - 
TY  - JOUR
A1  - Lindert, J. M.
A1  - Pozzorini, S.
A1  - Boughezal, R.
A1  - Campbell, J. M.
A1  - Denner, A.
A1  - Dittmaier, S.
A1  - Gehrmann-De Ridder, A.
A1  - Gehrmann, T.
A1  - Glover, N.
A1  - Huss, A.
A1  - Kallweit, S.
A1  - Maierhöfer, P.
A1  - Mangano, M. L.
A1  - Morgan, T. A.
A1  - Mück, A.
A1  - Petriello, F.
A1  - Salam, G. P.
A1  - Schönherr, M.
A1  - Williams, C.
T1  - Precise predictions for \(V+\)jets dark matter backgrounds
JF  - European Physical Journal C
N2  - High-energy jets recoiling against missing transverse energy (MET) are powerful probes of dark matter at the LHC. Searches based on large MET signatures require a precise control of the \({Z(ν\overline{ν})}+\) jet background in the signal region. This can be achieved by taking accurate data in control regions dominated by \(Z(ℓ^+ℓ^−)+\) jet, \(W(ℓν)+\) jet and \(γ+\) jet production, and extrapolating to the \({Z(ν\overline{ν})}+\) jet background by means of precise theoretical predictions. In this context, recent advances in perturbative calculations open the door to significant sensitivity improvements in dark matter searches. In this spirit, we present a combination of state-of-the-art calculations for all relevant \(V+\) jets processes, including throughout NNLO QCD corrections and NLO electroweak corrections supplemented by Sudakov logarithms at two loops. Predictions at parton level are provided together with detailed recommendations for their usage in experimental analyses based on the reweighting of Monte Carlo samples. Particular attention is devoted to the estimate of theoretical uncertainties in the framework of dark matter searches, where subtle aspects such as correlations across different \(V+\) jet processes play a key role. The anticipated theoretical uncertainty in the \({Z(ν\overline{ν})}+\) jet background is at the few percent level up to the TeV range.
KW  - Physics
KW  - High energy physics
KW  - High-energy jets
KW  - Dark matter
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172555
VL  - 77
ER  - 
TY  - JOUR
A1  - Lilla, Nadine
A1  - Füllgraf, Hannah
A1  - Stetter, Christian
A1  - Köhler, Stefan
A1  - Ernestus, Ralf-Ingo
A1  - Westermaier, Thomas
T1  - First Description of Reduced Pyruvate Dehydrogenase Enzyme Activity Following Subarachnoid Hemorrhage (SAH)
JF  - Frontiers in Neuroscience
N2  - Object: 
Several previous studies reported metabolic derangements and an accumulation of metabolic products in the early phase of experimental subarachnoid hemorrhage (SAH), which may contribute to secondary brain damage. This may be a result of deranged oxygen utilization due to enzymatic dysfunction in aerobic glucose metabolism. This study was performed to investigate, if pyruvate dehydrogenase enzyme (PDH) is affected in its activity giving further hints for a derangement of oxidative metabolism.
Methods: 
Eighteen male Sprague-Dawley rats were randomly assigned to one of two experimental groups (n = 9): (1) SAH induced by the endovascular filament model and (2) sham-operated controls. Mean arterial blood pressure (MABP), intracranial pressure (ICP), and local cerebral blood flow (LCBF; laser-Doppler flowmetry) were continuously monitored from 30 min before until 3 h after SAH. Thereafter, the animals were sacrificed and PDH activity was measured by ELISA.
Results: 
PDH activity was significantly reduced in animals subjected to SAH compared to controls.
Conclusion: The results of this study demonstrate for the first time a reduction of PDH activity following SAH, independent of supply of substrates and may be an independent factor contributing to a derangement of oxidative metabolism, failure of oxygen utilization, and secondary brain damage.
KW  - secondary brain damage
KW  - aerobic glycolysis
KW  - CBF
KW  - metabolism
KW  - PDH
KW  - SAH
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157636
VL  - 11
IS  - 37
ER  -