TY  - JOUR
A1  - Robertson, Kevin A.
A1  - Hsieh, Wei Yuan
A1  - Forster, Thorsten
A1  - Blanc, Mathieu
A1  - Lu, Hongjin
A1  - Crick, Peter J.
A1  - Yutuc, Eylan
A1  - Watterson, Steven
A1  - Martin, Kimberly
A1  - Griffiths, Samantha J.
A1  - Enright, Anton J.
A1  - Yamamoto, Mami
A1  - Pradeepa, Madapura M.
A1  - Lennox, Kimberly A.
A1  - Behlke, Mark A.
A1  - Talbot, Simon
A1  - Haas, Jürgen
A1  - Dölken, Lars
A1  - Griffiths, William J.
A1  - Wang, Yuqin
A1  - Angulo, Ana
A1  - Ghazal, Peter
T1  - An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway
JF  - PLoS Biology
N2  - In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.
KW  - microRNA
KW  - sterol pathway
KW  - multihit targeting
KW  - interferon signaling
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166666
VL  - 14
IS  - 3
ER  - 
TY  - JOUR
A1  - Jakobson, Liina
A1  - Vaahtera, Lauri
A1  - Tõldsepp, Kadri
A1  - Nuhkat, Maris
A1  - Wang, Cun
A1  - Wang, Yuh-Shuh
A1  - Hõrak, Hanna
A1  - Valk, Ervin
A1  - Pechter, Priit
A1  - Sindarovska, Yana
A1  - Tang, Jing
A1  - Xiao, Chuanlei
A1  - Xu, Yang
A1  - Talas, Ulvi Gerst
A1  - García-Sosa, Alfonso T.
A1  - Kangasjärvi, Saijaliisa
A1  - Maran, Uko
A1  - Remm, Maido
A1  - Roelfsema, M. Rob G.
A1  - Hu, Honghong
A1  - Kangasjärvi, Jaakko
A1  - Loog, Mart
A1  - Schroeder, Julian I.
A1  - Kollist, Hannes
A1  - Brosché, Mikael
T1  - Natural Variation in Arabidopsis Cvi-0 Accession Reveals an Important Role of MPK12 in Guard Cell CO\(_{2}\) Signaling
JF  - PLoS Biology
N2  - Plant gas exchange is regulated by guard cells that form stomatal pores. Stomatal adjustments are crucial for plant survival; they regulate uptake of CO\(_{2}\) for photosynthesis, loss of water, and entrance of air pollutants such as ozone. We mapped ozone hypersensitivity, more open stomata, and stomatal CO\(_{2}\)-insensitivity phenotypes of the Arabidopsis thaliana accession Cvi-0 to a single amino acid substitution in MITOGEN-ACTIVATED PROTEIN (MAP) KINASE 12 (MPK12). In parallel, we showed that stomatal CO\(_{2}\)-insensitivity phenotypes of a mutant cis (CO\(_{2}\)-insensitive) were caused by a deletion of MPK12. Lack of MPK12 impaired bicarbonate-induced activation of S-type anion channels. We demonstrated that MPK12 interacted with the protein kinase HIGH LEAF TEMPERATURE 1 (HT1)—a central node in guard cell CO\(_{2}\) signaling—and that MPK12 functions as an inhibitor of HT1. These data provide a new function for plant MPKs as protein kinase inhibitors and suggest a mechanism through which guard cell CO\(_{2}\) signaling controls plant water management.
KW  - MPK12
KW  - CO\(_{2}\) signaling
KW  - Arabidopsis thaliana
KW  - Cvi-0
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166657
VL  - 14
IS  - 12
ER  - 
TY  - JOUR
A1  - Adrián-Martínez, S.
A1  - Albert, A.
A1  - André, M.
A1  - Anton, G.
A1  - Ardid, M.
A1  - Aubert, J.-J.
A1  - Avgitas, T.
A1  - Baret, B.
A1  - Barrios-Martí, J.
A1  - Basa, S.
A1  - Bertin, V.
A1  - Biagi, S.
A1  - Bormuth, R.
A1  - Bouwhuis, M.C.
A1  - Bruijn, R.
A1  - Brunner, J.
A1  - Busto, J.
A1  - Capone, A.
A1  - Caramete, L.
A1  - Carr, J.
A1  - Celli, S.
A1  - Chiarusi, T.
A1  - Circella, M.
A1  - Coleiro, A.
A1  - Coniglione, R.
A1  - Costantini, H.
A1  - Coyle, P.
A1  - Creusot, A.
A1  - Deschamps, A.
A1  - De Bonis, G.
A1  - Distefano, C.
A1  - Donzaud, C.
A1  - Dornic, D.
A1  - Drouhin, D.
A1  - Eberl, T.
A1  - El Bojaddaini, I.
A1  - Elsässer, D.
A1  - Enzenhöfer, A.
A1  - Fehn, K.
A1  - Felis, I.
A1  - Fusco, L.A.
A1  - Galatà, S.
A1  - Gay, P.
A1  - Geißelsöder, S.
A1  - Geyer, K.
A1  - Giordano, V.
A1  - Gleixner, A.
A1  - Glotin, H.
A1  - Gracia-Ruiz, R.
A1  - Graf, K.
A1  - Hallmann, S.
A1  - van Haren, H.
A1  - Heijboer, A.J.
A1  - Hello, Y.
A1  - Hernández-Rey, J.J.
A1  - Hößl, J.
A1  - Hofestädt, J.
A1  - Hugon, C.
A1  - Illuminati, G.
A1  - James, C.W.
A1  - de Jong, M.
A1  - Jongen, M.
A1  - Kadler, M.
A1  - Kalekin, O.
A1  - Katz, U.
A1  - Kießling, D.
A1  - Kouchner, A.
A1  - Kreter, M.
A1  - Kreykenbohm, I.
A1  - Kulikovskiy, V.
A1  - Lachaud, C.
A1  - Lahmann, R.
A1  - Lefèvre, D.
A1  - Leonora, E.
A1  - Loucatos, S.
A1  - Marcelin, M.
A1  - Margiotta, A.
A1  - Marinelli, A.
A1  - Martínez-Mora, J.A.
A1  - Mathieu, A.
A1  - Melis, K.
A1  - Michael, T.
A1  - Migliozzi, P.
A1  - Moussa, A.
A1  - Mueller, C.
A1  - Nezri, E.
A1  - Pavalas, G.E.
A1  - Pellegrino, C.
A1  - Perrina, C.
A1  - Piattelli, P.
A1  - Popa, V.
A1  - Pradier, T.
A1  - Racca, C.
A1  - Riccobene, G.
A1  - Roensch, K.
A1  - Saldaña, M.
A1  - Samtleben, D.F.E.
A1  - Sánchez-Losa, A.
A1  - Sanguineti, M.
A1  - Sapienza, P.
A1  - Schnabel, J.
A1  - Schüssler, F.
A1  - Seitz, T.
A1  - Sieger, C.
A1  - Spurio, M.
A1  - Stolarczyk, Th.
A1  - Taiuti, M.
A1  - Tönnis, C.
A1  - Trovato, A.
A1  - Tselengidou, M.
A1  - Turpin, D.
A1  - Vallage, B.
A1  - Vallée, C.
A1  - Van Elewyck, V.
A1  - Vivolo, D.
A1  - Wagner, S.
A1  - Wilms, J.
A1  - Zornoza, J.D.
A1  - Zúñiga, J.
T1  - Limits on dark matter annihilation in the sun using the ANTARES neutrino telescope
JF  - Physics Letters B
N2  - A search for muon neutrinos originating from dark matter annihilations in the Sun is performed using the data recorded by the ANTARES neutrino telescope from 2007 to 2012. In order to obtain the best possible sensitivities to dark matter signals, an optimisation of the event selection criteria is performed taking into account the background of atmospheric muons, atmospheric neutrinos and the energy spectra of the expected neutrino signals. No significant excess over the background is observed and 90% C.L. upper limits on the neutrino flux, the spin-dependent and spin-independent WIMP-nucleon cross-sections are derived for WIMP masses ranging from 50 GeV to 5 TeV for the annihilation channels WIMP + WIMP→ b\(\overline{b}\), W\(^{+}\)W\(^{−}\) and τ\(^{+}\)τ\(^{−}\).
KW  - dark matter
KW  - WIMP
KW  - neutralino
KW  - indirect detection
KW  - neutrino telescope
KW  - sun
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166642
VL  - 759
ER  - 
TY  - JOUR
A1  - Neufang, S.
A1  - Akhrif, A.
A1  - Herrmann, C.G.
A1  - Drepper, C.
A1  - Homola, G.A.
A1  - Nowak, J.
A1  - Waider, J.
A1  - Schmitt, A.G.
A1  - Lesch, K.-P.
A1  - Romanos, M.
T1  - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans
JF  - Translational Psychiatry
N2  - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies.
KW  - Clinical Genetics
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418
IS  - 6
ER  - 
TY  - JOUR
A1  - Adrián-Martínez, S.
A1  - Albert, A.
A1  - André, M.
A1  - Anghinolfi, M.
A1  - Anton, G.
A1  - Ardid, M.
A1  - Aubert, J.-J.
A1  - Avgitas, T.
A1  - Baret, B.
A1  - Barrios-Martí, J.
A1  - Basa, S.
A1  - Bertin, V.
A1  - Biagi, S.
A1  - Bormuth, R.
A1  - Bouwhuis, M.C.
A1  - Bruijn, R.
A1  - Brunner, J.
A1  - Busto, J.
A1  - Capone, A.
A1  - Caramete, L.
A1  - Carr, J.
A1  - Celli, S.
A1  - Chiarusi, T.
A1  - Circella, M.
A1  - Coleiro, A.
A1  - Coniglione, R.
A1  - Constantini, H.
A1  - Coyle, P.
A1  - Creusot, A.
A1  - Deschamps, A.
A1  - De Bonis, G.
A1  - Distefano, C.
A1  - Donzaud, C.
A1  - Dornic, D.
A1  - Drouhin, D.
A1  - Eberl, T.
A1  - El Bojaddaini, I.
A1  - Elsässer, D.
A1  - Enzenhöfer, A.
A1  - Fehn, K.
A1  - Felis, I.
A1  - Fusco, L.A.
A1  - Galatà, S.
A1  - Gay, P.
A1  - Geißelsöder, S.
A1  - Geyer, K.
A1  - Giordano, V.
A1  - Gleixner, A.
A1  - Glotin, H.
A1  - Gracia-Ruiz, R.
A1  - Graf, K.
A1  - Hallmann, S.
A1  - van Haren, H.
A1  - Heijboer, A.J.
A1  - Hello, Y.
A1  - Hernández-Rey, J.J.
A1  - Hößl, J.
A1  - Hofestädt, J.
A1  - Hugon, C.
A1  - Illuminati, G.
A1  - James, C.W.
A1  - de Jong, M.
A1  - Kadler, M.
A1  - Kalekin, O.
A1  - Katz, U.
A1  - Kießling, D.
A1  - Kouchner, A.
A1  - Kreter, M.
A1  - Kreykenbohm, I.
A1  - Kulikovskiy, V.
A1  - Lachaud, C.
A1  - Lahmann, R.
A1  - Lefèvre, D.
A1  - Leonora, E.
A1  - Loucatos, S.
A1  - Marcelin, M.
A1  - Margiotta, A.
A1  - Marinelli, A.
A1  - Martínez-Mora, J.A.
A1  - Mathieu, A.
A1  - Michael, T.
A1  - Migliozzi, P.
A1  - Moussa, A.
A1  - Mueller, C.
A1  - Nezri, E.
A1  - Pavalas, G.E.
A1  - Pellegrino, C.
A1  - Perrina, C.
A1  - Piattelli, P.
A1  - Popa, V.
A1  - Pradier, T.
A1  - Racca, C.
A1  - Riccobene, G.
A1  - Roensch, K.
A1  - Saldaña, M.
A1  - Samtleben, D.F.E.
A1  - Sánchez-Losa, A.
A1  - Sanguineti, M.
A1  - Sapienza, P.
A1  - Schnabel, J.
A1  - Schüssler, F.
A1  - Seitz, T.
A1  - Sieger, C.
A1  - Spurio, M.
A1  - Stolarczyk, Th.
A1  - Taiuti, M.
A1  - Trovato, A.
A1  - Tselengidou, M.
A1  - Turpin, D.
A1  - Tönnis, C.
A1  - Vallage, B.
A1  - Vallée, C.
A1  - Van Elewyck, V.
A1  - Visser, E.
A1  - Vivolo, D.
A1  - Wagner, S.
A1  - Wilms, J.
A1  - Zornoza, J.D.
A1  - Zúñiga, J.
T1  - Constraints on the neutrino emission from the Galactic Ridge with the ANTARES telescope
JF  - Physics Letters B
N2  - A highly significant excess of high-energy astrophysical neutrinos has been reported by the IceCube Collaboration. Some features of the energy and declination distributions of IceCube events hint at a North/South asymmetry of the neutrino flux. This could be due to the presence of the bulk of our Galaxy in the Southern hemisphere. The ANTARES neutrino telescope, located in the Mediterranean Sea, has been taking data since 2007. It offers the best sensitivity to muon neutrinos produced by galactic cosmic ray interactions in this region of the sky. In this letter a search for an extended neutrino flux from the Galactic Ridge region is presented. Different models of neutrino production by cosmic ray propagation are tested. No excess of events is observed and upper limits for different neutrino flux spectral indices Γ are set. For Γ=2.4 the 90% confidence level flux upper limit at 100 TeV for one neutrino flavour corresponds to Φ\(^{1f}_{0}\) (100 TeV) = 2.0 · 10\(^{−17}\) GeV\(^{−1}\) cm\(^{−2}\)s\(^{−1}\)sr\(^{−1}\). Under this assumption, at most two events of the IceCube cosmic candidates can originate from the Galactic Ridge. A simple power-law extrapolation of the Fermi-LAT flux to account for IceCube High Energy Starting Events is excluded at 90% confidence level.
KW  - neutrino emission
KW  - Galactic Ridge
KW  - ANTARES telescope
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166608
VL  - 760
ER  - 
TY  - JOUR
A1  - Kim, Seonghoon
A1  - Zhang, Bo
A1  - Wang, Zhaorong
A1  - Fischer, Julian
A1  - Brodbeck, Sebastian
A1  - Kamp, Martin
A1  - Schneider, Christian
A1  - Höfling, Sven
A1  - Deng, Hui
T1  - Coherent Polariton Laser
JF  - Physical Review X
N2  - The semiconductor polariton laser promises a new source of coherent light, which, compared to conventional semiconductor photon lasers, has input-energy threshold orders of magnitude lower. However, intensity stability, a defining feature of a coherent state, has remained poor. Intensity noise many times the shot noise of a coherent state has persisted, attributed to multiple mechanisms that are difficult to separate in conventional polariton systems. The large intensity noise, in turn, limits the phase coherence. Thus, the capability of the polariton laser as a source of coherence light is limited. Here, we demonstrate a polariton laser with shot-noise-limited intensity stability, as expected from a fully coherent state. This stability is achieved by using an optical cavity with high mode selectivity to enforce single-mode lasing, suppress condensate depletion, and establish gain saturation. Moreover, the absence of spurious intensity fluctuations enables the measurement of a transition from exponential to Gaussian decay of the phase coherence of the polariton laser. It suggests large self-interaction energies in the polariton condensate, exceeding the laser bandwidth. Such strong interactions are unique to matter-wave lasers and important for nonlinear polariton devices. The results will guide future development of polariton lasers and nonlinear polariton devices.
KW  - polariton laser
KW  - condensed matter physics
KW  - photonics
KW  - quantum physics
KW  - coherent light
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166597
VL  - 6
IS  - 011026
ER  - 
TY  - JOUR
A1  - Kernreiter, T.
A1  - Governale, M.
A1  - Zülicke, U.
A1  - Hankiewicz, E. M.
T1  - Anomalous Spin Response and Virtual-Carrier-Mediated Magnetism in a Topological Insulator
JF  - Physical Review X
N2  - We present a comprehensive theoretical study of the static spin response in HgTe quantum wells, revealing distinctive behavior for the topologically nontrivial inverted structure. Most strikingly, the q=0 (long-wavelength) spin susceptibility of the undoped topological-insulator system is constant and equal to the value found for the gapless Dirac-like structure, whereas the same quantity shows the typical decrease with increasing band gap in the normal-insulator regime. We discuss ramifications for the ordering of localized magnetic moments present in the quantum well, both in the insulating and electron-doped situations. The spin response of edge states is also considered, and we extract effective Landé g factors for the bulk and edge electrons. The variety of counterintuitive spin-response properties revealed in our study arises from the system’s versatility in accessing situations where the charge-carrier dynamics can be governed by ordinary Schrödinger-type physics; it mimics the behavior of chiral Dirac fermions or reflects the material’s symmetry-protected topological order.
KW  - spin response
KW  - magnetism
KW  - nanophysics
KW  - topological insulators
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166582
VL  - 6
IS  - 021010
ER  - 
TY  - JOUR
A1  - Read, Hannah M.
A1  - Mills, Grant
A1  - Johnson, Sarah
A1  - Tsai, Peter
A1  - Dalton, James
A1  - Barquist, Lars
A1  - Print, Cristin G.
A1  - Patrick, Wayne M.
A1  - Wiles, Siouxsie
T1  - The in vitro and in vivo effects of constitutive light expression on a bioluminescent strain of the mouse enteropathogen Citrobacter rodentium
JF  - PeerJ
N2  - Bioluminescent reporter genes, such as those from fireflies and bacteria, let researchers use light production as a non-invasive and non-destructive surrogate measure of microbial numbers in a wide variety of environments. As bioluminescence needs microbial metabolites, tagging microorganisms with luciferases means only live metabolically active cells are detected. Despite the wide use of bioluminescent reporter genes, very little is known about the impact of continuous (also called constitutive) light expression on tagged bacteria. We have previously made a bioluminescent strain of Citrobacter rodentium, a bacterium which infects laboratory mice in a similar way to how enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) infect humans. In this study, we compared the growth of the bioluminescent C. rodentium strain ICC180 with its non-bioluminescent parent (strain ICC169) in a wide variety of environments. To understand more about the metabolic burden of expressing light, we also compared the growth profiles of the two strains under approximately 2,000 different conditions. We found that constitutive light expression in ICC180 was near-neutral in almost every non-toxic environment tested. However, we also found that the non-bioluminescent parent strain has a competitive advantage over ICC180 during infection of adult mice, although this was not enough for ICC180 to be completely outcompeted. In conclusion, our data suggest that constitutive light expression is not metabolically costly to C. rodentium and supports the view that bioluminescent versions of microbes can be used as a substitute for their non-bioluminescent parents to study bacterial behaviour in a wide variety of environments.
KW  - bioluminescence
KW  - lux
KW  - luciferase
KW  - biophotonic imaging
KW  - bioluminescence imaging
KW  - enteric pathogens
KW  - animal model
KW  - reporter genes
KW  - phenotypic microarray
KW  - biolog
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166576
VL  - 4
IS  - e2130
ER  - 
TY  - JOUR
A1  - Schupp, Nicole
A1  - Stopper, Helga
A1  - Heidland, August
T1  - DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers
JF  - Oxidative Medicine and Cellular Longevity
N2  - Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients’ burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2′-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker’s potential to predict clinical outcomes.
KW  - chronic kidney disease
KW  - cancer risk
KW  - DNA damage
KW  - biomarkers
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166569
VL  - 2016
IS  - 3592042
ER  - 
TY  - JOUR
A1  - Lenders, Malte
A1  - Weidemann, Frank
A1  - Kurschat, Christine
A1  - Canaan-Kühl, Sima
A1  - Duning, Thomas
A1  - Stypmann, Jörg
A1  - Schmitz, Boris
A1  - Reiermann, Stefanie
A1  - Krämer, Johannes
A1  - Blaschke, Daniela
A1  - Wanner, Christoph
A1  - Brand, Stefan-Martin
A1  - Brand, Eva
T1  - Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant
JF  - Orphanet Journal of Rare Diseases
N2  - Background
Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma.

Methods
To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations.

Results
p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed.

Conclusions
We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.
KW  - Fabry disease
KW  - genotype
KW  - lyso-Gb3
KW  - variant of unknown significance
KW  - GLA mutation
KW  - late-onset
KW  - stroke
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166559
VL  - 11
IS  - 54
ER  - 
TY  - JOUR
A1  - Lenders, Malte
A1  - Hennermann, Julia B.
A1  - Kurschat, Christine
A1  - Rolfs, Arndt
A1  - Canaan-Kühl, Sima
A1  - Sommer, Claudia
A1  - Üçeyler, Nurcan
A1  - Kampmann, Christoph
A1  - Karabul, Nesrin
A1  - Giese, Anne-Katrin
A1  - Duning, Thomas
A1  - Stypmann, Jörg
A1  - Krämer, Johannes
A1  - Weidemann, Frank
A1  - Brand, Stefan-Martin
A1  - Wanner, Christoph
A1  - Brand, Eva
T1  - Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease
JF  - Orphanet Journal of Rare Diseases
N2  - Background
The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines.

Methods
Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed.

Results
Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels.

Conclusion
The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.
KW  - Fabry disease
KW  - females
KW  - lyso-Gb3
KW  - enzyme replacement therapy
KW  - guidelines
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166543
VL  - 11
IS  - 88
ER  - 
TY  - JOUR
A1  - Wente, Sarah
A1  - Schröder, Simone
A1  - Buckard, Johannes
A1  - Büttel, Hans-Martin
A1  - von Deimling, Florian
A1  - Diener, Wilfried
A1  - Häussler, Martin
A1  - Hübschle, Susanne
A1  - Kinder, Silvia
A1  - Kurlemann, Gerhard
A1  - Kretzschmar, Christoph
A1  - Lingen, Michael
A1  - Maroske, Wiebke
A1  - Mundt, Dirk
A1  - Sánchez-Albisua, Iciar
A1  - Seeger, Jürgen
A1  - Toelle, Sandra P.
A1  - Boltshauser, Eugen
A1  - Brockmann, Knut
T1  - Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study
JF  - Orphanet Journal of Rare Diseases
N2  - Background
The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom.

Methods
We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA.

Results
Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups.

Conclusions
Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment.
KW  - congenital ocular motor apraxia
KW  - molar tooth sign
KW  - Joubert syndrome
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166534
VL  - 11
IS  - 104
ER  - 
TY  - JOUR
A1  - Eisenhardt, Anja E.
A1  - Sprenger, Adrian
A1  - Röring, Michael
A1  - Herr, Ricarda
A1  - Weinberg, Florian
A1  - Köhler, Martin
A1  - Braun, Sandra
A1  - Orth, Joachim
A1  - Diedrich, Britta
A1  - Lanner, Ulrike
A1  - Tscherwinski, Natalja
A1  - Schuster, Simon
A1  - Dumaz, Nicolas
A1  - Schmidt, Enrico
A1  - Baumeister, Ralf
A1  - Schlosser, Andreas
A1  - Dengjel, Jörn
A1  - Brummer, Tilman
T1  - Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles
JF  - Oncotarget
N2  - B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase.
KW  - BRAF
KW  - proteomics
KW  - phosphorylation
KW  - sorafenib
KW  - protein-protein interaction
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166529
VL  - 7
IS  - 18
ER  - 
TY  - JOUR
A1  - Vučićević, Dubravka
A1  - Gehre, Maja
A1  - Dhamija, Sonam
A1  - Friis-Hansen, Lennart
A1  - Meierhofer, David
A1  - Sauer, Sascha
A1  - Ørom, Ulf Andersson
T1  - The long non-coding RNA PARROT is an upstream regulator of c-Myc and affects proliferation and translation
JF  - Oncotarget
N2  - Long non-coding RNAs are important regulators of gene expression and signaling pathways. The expression of long ncRNAs is dysregulated in cancer and other diseases. The identification and characterization of long ncRNAs is often challenging due to their low expression level and localization to chromatin. Here, we identify a functional long ncRNA, PARROT (Proliferation Associated RNA and Regulator Of Translation) transcribed by RNA polymerase II and expressed at a relatively high level in a number of cell lines. The PARROT long ncRNA is associated with proliferation in both transformed and normal cell lines. We characterize the long ncRNA PARROT as an upstream regulator of c-Myc affecting cellular proliferation and translation using RNA sequencing and mass spectrometry following depletion of the long ncRNA. PARROT is repressed during senescence of human mammary epithelial cells and overexpressed in some cancers, suggesting an important association with proliferation through regulation of c-Myc. With this study, we add to the knowledge of cytoplasmic functional long ncRNAs and extent the long ncRNA-Myc regulatory network in transformed and normal cells.
KW  - PARROT
KW  - c-Myc
KW  - long ncRNA
KW  - upstream regulator
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166519
VL  - 7
IS  - 23
ER  - 
TY  - JOUR
A1  - Shi, Yaoyao
A1  - Kuai, Yue
A1  - Lei, Lizhen
A1  - Weng, Yuanyuan
A1  - Berberich-Siebelt, Friederike
A1  - Zhang, Xinxia
A1  - Wang, Jinjie
A1  - Zhou, Yuan
A1  - Jiang, Xin
A1  - Ren, Guoping
A1  - Pan, Hongyang
A1  - Mao, Zhengrong
A1  - Zhou, Ren
T1  - The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma
JF  - Oncotarget
N2  - Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (−87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets (PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis.
KW  - LITAF
KW  - BCL6
KW  - apoptosis
KW  - lymphoma
KW  - B-cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166500
VL  - 7
IS  - 47
ER  - 
TY  - JOUR
A1  - Schneider, Anna
A1  - Corona, Angela
A1  - Spöring, Imke
A1  - Jordan, Mareike
A1  - Buchholz, Bernd
A1  - Maccioni, Elias
A1  - Di Santo, Roberto
A1  - Bodem, Jochen
A1  - Tramontano, Enzo
A1  - Wöhrl, Birgitta M.
T1  - Biochemical characterization of a multi-drug resistant HIV-1 subtype AG reverse transcriptase: antagonism of AZT discrimination and excision pathways and sensitivity to RNase H inhibitors
JF  - Nucleic Acids Research
N2  - We analyzed a multi-drug resistant (MR) HIV-1 reverse transcriptase (RT), subcloned from a patient-derived subtype CRF02_AG, harboring 45 amino acid exchanges, amongst them four thymidine analog mutations (TAMs) relevant for high-level AZT (azidothymidine) resistance by AZTMP excision (M41L, D67N, T215Y, K219E) as well as four substitutions of the AZTTP discrimination pathway (A62V, V75I, F116Y and Q151M). In addition, K65R, known to antagonize AZTMP excision in HIV-1 subtype B was present. Although MR-RT harbored the most significant amino acid exchanges T215Y and Q151M of each pathway, it exclusively used AZTTP discrimination, indicating that the two mechanisms are mutually exclusive and that the Q151M pathway is obviously preferred since it confers resistance to most nucleoside inhibitors. A derivative was created, additionally harboring the TAM K70R and the reversions M151Q as well as R65K since K65R antagonizes excision. MR-R65K-K70R-M151Q was competent of AZTMP excision, whereas other combinations thereof with only one or two exchanges still promoted discrimination. To tackle the multi-drug resistance problem, we tested if the MR-RTs could still be inhibited by RNase H inhibitors. All MR-RTs exhibited similar sensitivity toward RNase H inhibitors belonging to different inhibitor classes, indicating the importance of developing RNase H inhibitors further as anti-HIV drugs.
KW  - ribonuclease H
KW  - HIV-1 subtype AG
KW  - azidothymidine
KW  - reverse transcriptase
KW  - multi-drug resistance
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166423
VL  - 44
IS  - 5
ER  - 
TY  - JOUR
A1  - Cui, Huanhuan
A1  - Schlesinger, Jenny
A1  - Schoenhals, Sophia
A1  - Tonjes, Martje
A1  - Dunkel, Ilona
A1  - Meierhofer, David
A1  - Cano, Elena
A1  - Schulz, Kerstin
A1  - Berger, Michael F.
A1  - Haack, Timm
A1  - Abdelilah-Seyfried, Salim
A1  - Bulyk, Martha L.
A1  - Sauer, Sascha
A1  - Sperling, Silke R.
T1  - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA
JF  - Nucleic Acids Research
N2  - DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.
KW  - phosphorylation
KW  - DPF3a
KW  - HEY repressors
KW  - DNA
KW  - cardiac hypertrophy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166391
VL  - 44
IS  - 6
ER  - 
TY  - JOUR
A1  - Schwarz, Roland F.
A1  - Tamuri, Asif U.
A1  - Kultys, Marek
A1  - King, James
A1  - Godwin, James
A1  - Florescu, Ana M.
A1  - Schultz, Jörg
A1  - Goldman, Nick
T1  - ALVIS: interactive non-aggregative visualization and explorative analysis of multiple sequence alignments
JF  - Nucleic Acids Research
N2  - Sequence Logos and its variants are the most commonly used method for visualization of multiple sequence alignments (MSAs) and sequence motifs. They provide consensus-based summaries of the sequences in the alignment. Consequently, individual sequences cannot be identified in the visualization and covariant sites are not easily discernible. We recently proposed Sequence Bundles, a motif visualization technique that maintains a one-to-one relationship between sequences and their graphical representation and visualizes covariant sites. We here present Alvis, an open-source platform for the joint explorative analysis of MSAs and phylogenetic trees, employing Sequence Bundles as its main visualization method. Alvis combines the power of the visualization method with an interactive toolkit allowing detection of covariant sites, annotation of trees with synapomorphies and homoplasies, and motif detection. It also offers numerical analysis functionality, such as dimension reduction and classification. Alvis is user-friendly, highly customizable and can export results in publication-quality figures. It is available as a full-featured standalone version (http://www.bitbucket.org/rfs/alvis) and its Sequence Bundles visualization module is further available as a web application (http://science-practice.com/projects/sequence-bundles).
KW  - visualization
KW  - multiple sequence alignments
KW  - phylogenetic trees
KW  - Alvis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166374
VL  - 44
IS  - 8
ER  - 
TY  - JOUR
A1  - Letunic, Ivica
A1  - Bork, Peer
T1  - Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees
JF  - Nucleic Acids Research
N2  - Interactive Tree Of Life (http://itol.embl.de) is a web-based tool for the display, manipulation and annotation of phylogenetic trees. It is freely available and open to everyone. The current version was completely redesigned and rewritten, utilizing current web technologies for speedy and streamlined processing. Numerous new features were introduced and several new data types are now supported. Trees with up to 100,000 leaves can now be efficiently displayed. Full interactive control over precise positioning of various annotation features and an unlimited number of datasets allow the easy creation of complex tree visualizations. iTOL 3 is the first tool which supports direct visualization of the recently proposed phylogenetic placements format. Finally, iTOL's account system has been redesigned to simplify the management of trees in user-defined workspaces and projects, as it is heavily used and currently handles already more than 500,000 trees from more than 10,000 individual users.
KW  - Interactive Tree Of Life (iTOL)
KW  - phylogenetic trees
KW  - visualization
KW  - tool
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166181
VL  - 44
IS  - W1
ER  - 
TY  - JOUR
A1  - Telorac, Jonas
A1  - Prykhozhij, Sergey V.
A1  - Schöne, Stefanie
A1  - Meierhofer, David
A1  - Sauer, Sascha
A1  - Thomas-Chollier, Morgane
A1  - Meijsing, Sebastiaan H.
T1  - Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements
JF  - Nucleic Acids Research
N2  - Out of the myriad of potential DNA binding sites of the glucocorticoid receptor (GR) found in the human genome, only a cell-type specific minority is actually bound, indicating that the presence of a recognition sequence alone is insufficient to specify where GR binds. Cooperative interactions with other transcription factors (TFs) are known to contribute to binding specificity. Here, we reasoned that sequence signals preventing GR recruitment to certain loci provide an alternative means to confer specificity. Motif analyses uncovered candidate Negative Regulatory Sequences (NRSs) that interfere with genomic GR binding. Subsequent functional analyses demonstrated that NRSs indeed prevent GR binding to nearby response elements. We show that NRS activity is conserved across species, found in most tissues and that they also interfere with the genomic binding of other TFs. Interestingly, the effects of NRSs appear not to be a simple consequence of changes in chromatin accessibility. Instead, we find that NRSs interact with proteins found at sub-nuclear structures called paraspeckles and that these proteins might mediate the repressive effects of NRSs. Together, our studies suggest that the joint influence of positive and negative sequence signals partition the genome into regions where GR can bind and those where it cannot.
KW  - DNA sequencing
KW  - glucocorticoid receptor
KW  - DNA binding
KW  - transcription factors
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166330
VL  - 44
IS  - 13
ER  -