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  - Albert, A.
A1  - André, M.
A1  - Anghinolfi, M.
A1  - Anton, G.
A1  - Ardid, M.
A1  - Aubert, J.-J.
A1  - Aublin, J.
A1  - Avgitas, T.
A1  - Baret, B.
A1  - Barrios-Martít, J.
A1  - Basa, S.
A1  - Belhorma, B.
A1  - Bertin, V.
A1  - Biagi, S.
A1  - Bormuth, R.
A1  - Boumaaza, J
A1  - Bourret, S.
A1  - Bouwhuis, M. C.
A1  - Brânzas, H.
A1  - Bruijn, R.
A1  - Brunner, J.
A1  - Busto, J.
A1  - Capone, A.
A1  - Caramete, L.
A1  - Carr, J.
A1  - Celli, S.
A1  - Chabab, M.
A1  - Cherkaoui El Moursli, R.
A1  - Chiarusi, T.
A1  - Circella, M.
A1  - Coelho, J. A. B.
A1  - Coleiro, A.
A1  - Colomer, M
A1  - Coniglione, R.
A1  - Costantini, H.
A1  - Coyle, P.
A1  - Creusot, A.
A1  - Díaz, A. F.
A1  - Deschamps, A.
A1  - Distefano, C.
A1  - Di Palma, I.
A1  - Domi, A.
A1  - Donzaud, C.
A1  - Dornic, D.
A1  - Drouhin, D.
A1  - Eberl, T.
A1  - El Bojaddaini, I.
A1  - El Khayati, N.
A1  - Elsässer, D.
A1  - Enzenhöfer, A.
A1  - Ettahiri, A.
A1  - Fassi, F.
A1  - Felis, I.
A1  - Fermani, P.
A1  - Ferrara, G.
A1  - Fusco, L. A.
A1  - Gay, P.
A1  - Glotin, H.
A1  - Grégoire, T.
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  - Illuminati, G.
A1  - de Jong, M.
A1  - Jongen, M.
A1  - Kadler, M.
A1  - Kalekin, O.
A1  - Katz, U.
A1  - Khan-Chowdhury, N. R.
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  - Levi, G.
A1  - Lotze, M.
A1  - Loucatos, S.
A1  - Marcelin, M.
A1  - Margiotta, A.
A1  - Marinelli, A.
A1  - Martínez-Mora, J. A.
A1  - Mele, R.
A1  - Melis, K.
A1  - Migliozzi, P.
A1  - Moussa, A.
A1  - Navas, S.
A1  - Nezri, E.
A1  - Nuñez, A.
A1  - Organokov, M.
A1  - Pavalas, G. E.
A1  - Pellegrino, C.
A1  - Piattelli, P.
A1  - Popa, V.
A1  - Pradier, T.
A1  - Quinn, L.
A1  - Racca, C.
A1  - Randazzo, N.
A1  - Riccobene, G.
A1  - Sánchez-Losa, A.
A1  - Saldaña, M.
A1  - Salvadori, I.
A1  - Samtleben, D. F. E.
A1  - Sanguineti, M.
A1  - Sapienza, P.
A1  - Schüssler, F.
A1  - Spurio, M.
A1  - Stolarczyk, Th.
A1  - Taiuti, M.
A1  - Tayalati, Y.
A1  - Trovato, A.
A1  - Vallage, B.
A1  - Van Elewyck, V.
A1  - Versari, F.
A1  - Vivolo, D.
A1  - Wilms, J.
A1  - Zaborov, D.
A1  - Zornoza, J. D.
A1  - Zúñiga, J.
T1  - The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope
JF  - European Physical Journal C
N2  - One of the main objectives of the ANTARES telescope is the search for point- like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliableway to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i. e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, theMoon shadow is observed with 3.5s statistical significance. The detector angular resolution for downwardgoing muons is 0.73. +/- 0.14.. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.
KW  - Atmospheric muons
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227802
VL  - 78
ER  - 
TY  - JOUR
A1  - Prusty, Bhupesh K.
A1  - Chowdhury, Suvagata R.
A1  - Gulve, Nitish
A1  - Rudel, Thomas
T1  - Peptidase Inhibitor 15 (PI15) Regulates Chlamydial CPAF Activity
JF  - Frontiers in Cellular and Infection Microbiology
N2  - Obligate intracellular pathogenic Chlamydia trachomatis express several serine proteases whose roles in chlamydial development and pathogenicity are not completely understood. The chlamydial protease CPAF is expressed during the replicative phase of the chlamydial developmental cycle and is secreted into the lumen of the Chlamydia-containing vacuole called inclusion. How the secreted protease is activated in the inclusion lumen is currently not fully understood. We have identified human serine peptidase inhibitor PI15 as a potential host factor involved in the regulation of CPAF activation. Silencing expression as well as over expression of PI15 affected normal development of Chlamydia. PI15 was transported into the chlamydial inclusion lumen where it co-localized with CPAF aggregates. We show that PI15 binds to the CPAF zymogen and potentially induces CPAF protease activity at low concentrations. However, at high concentrations PI15 inhibits CPAF activity possibly by blocking its protease domain. Our findings shed light on a new aspect of chlamydial host co-evolution which involves the recruitment of host cell proteins into the inclusion to control the activation of bacterial proteases like CPAF that are important for the normal development of Chlamydia.
KW  - chlamydia
KW  - CPAF activation
KW  - peptidase inhibitor PI15
KW  - chlamydial inclusion
KW  - chlamydia serine proteases
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196918
SN  - 2235-2988
VL  - 8
IS  - 183
ER  - 
TY  - JOUR
A1  - Fischer, Annette
A1  - Harrison, Kelly S
A1  - Ramirez, Yesid
A1  - Auer, Daniela
A1  - Chowdhury, Suvagata Roy
A1  - Prusty, Bhupesh K
A1  - Sauer, Florian
A1  - Dimond, Zoe
A1  - Kisker, Caroline
A1  - Hefty, P Scott
A1  - Rudel, Thomas
T1  - Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense
JF  - eLife
N2  - Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl-1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity of C. trachomatis for IFNγ and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense.
KW  - cell-autonomous defense
KW  - Chlamydia trachomatis
KW  - deubiquitinase
KW  - Mcl-1
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171073
VL  - 6
IS  - e21465
ER  -