TY  - JOUR
A1  - Hines, Rochelle M.
A1  - Maric, Hans Michael
A1  - Hines, Dustin J.
A1  - Modgil, Amit
A1  - Panzanelli, Patrizia
A1  - Nakamura, Yasuko
A1  - Nathanson, Anna J.
A1  - Cross, Alan
A1  - Deeb, Tarek
A1  - Brandon, Nicholas J.
A1  - Davies, Paul
A1  - Fritschy, Jean-Marc
A1  - Schindelin, Hermann
A1  - Moss, Stephen J.
T1  - Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin
JF  - Nature Communications
N2  - Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.
KW  - cellular neuroscience
KW  - ion channels in the nervous system
KW  - neurotransmitters
KW  - synaptic development
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320719
VL  - 9
ER  - 
TY  - JOUR
A1  - Hernández, Gonzalo
A1  - José Ramírez, María
A1  - Minguillón, Jordi
A1  - Quiles, Paco
A1  - Ruiz de Garibay, Gorka
A1  - Aza-Carmona, Miriam
A1  - Bogliolo, Massimo
A1  - Pujol, Roser
A1  - Prados-Carvajal, Rosario
A1  - Fernández, Juana
A1  - García, Nadia
A1  - López, Adrià
A1  - Gutiérrez-Enríquez, Sara
A1  - Diez, Orland
A1  - Benítez, Javier
A1  - Salinas, Mónica
A1  - Teulé, Alex
A1  - Brunet, Joan
A1  - Radice, Paolo
A1  - Peterlongo, Paolo
A1  - Schindler, Detlev
A1  - Huertas, Pablo
A1  - Puente, Xose S.
A1  - Lázaro, Conxi
A1  - Àngel Pujana, Miquel
A1  - Surrallés, Jordi
T1  - Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1
JF  - Nature Communications
N2  - BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.
KW  - cancer
KW  - double-strand DNA breaks
KW  - genomic instability
KW  - RNA metabolism
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319929
VL  - 9
ER  - 
TY  - JOUR
T1  - Combination of inclusive and differential t(t)over-bar charge asymmetry measurements using ATLAS and CMS data at root S=7 and 8 TeV
JF  - Journal of High Energy Physics
N2  - This paper presents combinations of inclusive and differential measurements of the charge asymmetry (A(C)) in top quark pair (t(t)over-bar) events with a lepton+jets signature by the ATLAS and CMS Collaborations, using data from LHC proton-proton collisions at centre-of-mass energies of 7 and 8 TeV. The data correspond to integrated luminosities of about 5 and 20 fb(-1) for each experiment, respectively. The resulting combined LHC measurements of the inclusive charge asymmetry are A(C)(LHC7) = 0.005 +/- 0.007 (stat) +/- 0.006 (syst) at 7 TeV and A(C)(LHC8) = 0.0055 +/- 0.0023 (stat) +/- 0.0025 (syst) at 8 TeV. These values, as well as the combination of A(C) measurements as a function of the invariant mass of the t(t)over-bar system at 8 TeV, are consistent with the respective standard model predictions.
KW  - Hadron-Hadron scattering (experiments)
KW  - Patron distributions
KW  - Top physics
KW  - PP Collisions
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312669
VL  - 33
IS  - 4
ER  - 
TY  - JOUR
A1  - Kreinberg, Sören
A1  - Porte, Xavier
A1  - Schicke, David
A1  - Lingnau, Benjamin
A1  - Schneider, Christian
A1  - Höfling, Sven
A1  - Kanter, Ido
A1  - Lüdge, Kathy
A1  - Reitzenstein, Stephan
T1  - Mutual coupling and synchronization of optically coupled quantum-dot micropillar lasers at ultra-low light levels
JF  - Nature Communications
N2  - Synchronization of coupled oscillators at the transition between classical physics and quantum physics has become an emerging research topic at the crossroads of nonlinear dynamics and nanophotonics. We study this unexplored field by using quantum dot microlasers as optical oscillators. Operating in the regime of cavity quantum electrodynamics (cQED) with an intracavity photon number on the order of 10 and output powers in the 100 nW range, these devices have high β-factors associated with enhanced spontaneous emission noise. We identify synchronization of mutually coupled microlasers via frequency locking associated with a sub-gigahertz locking range. A theoretical analysis of the coupling behavior reveals striking differences from optical synchronization in the classical domain with negligible spontaneous emission noise. Beyond that, additional self-feedback leads to zero-lag synchronization of coupled microlasers at ultra-low light levels. Our work has high potential to pave the way for future experiments in the quantum regime of synchronization.
KW  - nanoscale devices
KW  - quantum optics
KW  - semiconductor lasers
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229811
VL  - 10
ER  - 
TY  - JOUR
A1  - Kremer, Mark
A1  - Biesenthal, Tobias
A1  - Maczewsky, Lukas J.
A1  - Heinrich, Matthias
A1  - Thomale, Ronny
A1  - Szameit, Alexander
T1  - Demonstration of a two-dimensional PT-symmetric crystal
JF  - Nature Communications
N2  - With the discovery of PT-symmetric quantum mechanics, it was shown that even non-Hermitian systems may exhibit entirely real eigenvalue spectra. This finding did not only change the perception of quantum mechanics itself, it also significantly influenced the field of photonics. By appropriately designing one-dimensional distributions of gain and loss, it was possible to experimentally verify some of the hallmark features of PT-symmetry using electromagnetic waves. Nevertheless, an experimental platform to study the impact of PT-symmetry in two spatial dimensions has so far remained elusive. We break new grounds by devising a two-dimensional PT-symmetric system based on photonic waveguide lattices with judiciously designed refractive index landscape and alternating loss. With this system at hand, we demonstrate a non-Hermitian two-dimensional topological phase transition that is closely linked to the emergence of topological mid-gap edge states.
KW  - micro-optics
KW  - optical materials and structures
KW  - topological matter
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230132
VL  - 10
ER  - 
TY  - JOUR
A1  - Kraus, Michael
A1  - Grimm, Clemens
A1  - Seibel, Jürgen
T1  - Reversibility of a Point Mutation Induced Domain Shift: Expanding the Conformational Space of a Sucrose Phosphorylase
JF  - Scientific Reports
N2  - Despite their popularity as enzyme engineering targets structural information about Sucrose Phosphorylases remains scarce. We recently clarified that the Q345F variant of Bifidobacterium adolescentis Sucrose Phosphorylase is able to accept large polyphenolic substrates like resveratrol via a domain shift. Here we present a crystal structure of this variant in a conformation suitable for the accommodation of the donor substrate sucrose in excellent agreement with the wild type structure. Remarkably, this conformation does not feature the previously observed domain shift which is therefore reversible and part of a dynamic process rather than a static phenomenon. This crystallographic snapshot completes our understanding of the catalytic cycle of this useful variant and will allow for a more rational design of further generations of Sucrose Phosphorylase variants.
KW  - biocatalysis
KW  - X-ray crystallography
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224845
VL  - 8
ER  - 
TY  - JOUR
A1  - Müller, Laura S. M.
A1  - Cosentino, Raúl O.
A1  - Förstner, Konrad U.
A1  - Guizetti, Julien
A1  - Wedel, Carolin
A1  - Kaplan, Noam
A1  - Janzen, Christian J.
A1  - Arampatzi, Panagiota
A1  - Vogel, Jörg
A1  - Steinbiss, Sascha
A1  - Otto, Thomas D.
A1  - Saliba, Antoine-Emmanuel
A1  - Sebra, Robert P.
A1  - Siegel, T. Nicolai
T1  - Genome organization and DNA accessibility control antigenic variation in trypanosomes
JF  - Nature
N2  - Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host1. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility2,3. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding4. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses—Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing—that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation.
KW  - histone variants
KW  - genome architecture
KW  - single molecule real time (SMRT)
KW  - brucei genome
KW  - distance-dependent decay
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224265
VL  - 563
ER  - 
TY  - JOUR
A1  - Munz, Matthias
A1  - Richter, Gesa M.
A1  - Loos, Bruno G.
A1  - Jepsen, Søren
A1  - Divaris, Kimon
A1  - Offenbacher, Steven
A1  - Teumer, Alexander
A1  - Holtfreter, Birte
A1  - Kocher, Thomas
A1  - Bruckmann, Corinna
A1  - Jockel-Schneider, Yvonne
A1  - Graetz, Christian
A1  - Munoz, Loreto
A1  - Bhandari, Anita
A1  - Tennstedt, Stephanie
A1  - Staufenbiel, Ingmar
A1  - van der Velde, Nathalie
A1  - Uitterlinden, André G.
A1  - de Groot, Lisette C. P. G. M.
A1  - Wellmann, Jürgen
A1  - Berger, Klaus
A1  - Krone, Bastian
A1  - Hoffmann, Per
A1  - Laudes, Matthias
A1  - Lieb, Wolfgang
A1  - Andre, Franke
A1  - Dommisch, Henrik
A1  - Erdmann, Jeanette
A1  - Schaefer, Arne S.
T1  - Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus
JF  - Scientific Reports
N2  - Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (PAgP-Ger < 0.05; PCAD < 5 × 10−8; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02–1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05–1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.
KW  - vesicle-associated membrane protein 8 (VAMP8)
KW  - ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS7)
KW  - shared genetic basis
KW  - genome-wide association studies (GWAS)
KW  - GWAS meta-analysis
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231647
VL  - 8
ER  - 
TY  - JOUR
A1  - Morimoto, Yoshiro
A1  - Shimada-Sugimoto, Mihoko
A1  - Otowa, Takeshi
A1  - Yoshida, Shintaro
A1  - Kinoshita, Akira
A1  - Mishima, Hiroyuki
A1  - Yamaguchi, Naohiro
A1  - Mori, Takatoshi
A1  - Imamura, Akira
A1  - Ozawa, Hiroki
A1  - Kurotaki, Naohiro
A1  - Ziegler, Christiane
A1  - Domschke, Katharina
A1  - Deckert, Jürgen
A1  - Umekage, Tadashi
A1  - Tochigi, Mamoru
A1  - Kaiya, Hisanobu
A1  - Okazaki, Yuji
A1  - Tokunaga, Katsushi
A1  - Sasaki, Tsukasa
A1  - Yoshiura, Koh-ichiro
A1  - Ono, Shinji
T1  - Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder
JF  - Translational Psychiatry
N2  - Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case–control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case–control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.
KW  - clinical genetics
KW  - medical genetics
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224192
VL  - 8
ER  - 
TY  - JOUR
A1  - Schneider, Christian
A1  - Glazov, Mikhail M.
A1  - Korn, Tobias
A1  - Höfling, Sven
A1  - Urbaszek, Bernhard
T1  - Two-dimensional semiconductors in the regime of strong light-matter coupling
JF  - Nature Communications
N2  - The optical properties of transition metal dichalcogenide monolayers are widely dominated by excitons, Coulomb-bound electron–hole pairs. These quasi-particles exhibit giant oscillator strength and give rise to narrow-band, well-pronounced optical transitions, which can be brought into resonance with electromagnetic fields in microcavities and plasmonic nanostructures. Due to the atomic thinness and robustness of the monolayers, their integration in van der Waals heterostructures provides unique opportunities for engineering strong light-matter coupling. We review first results in this emerging field and outline future opportunities and challenges.
KW  - optical physics
KW  - two-dimensional materials
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231295
VL  - 9
ER  -