2024-03-29T00:57:03Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/84042019-08-30T11:32:37Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Liebich, Ines
author
Bode, Jürgen
author
Frisch, Matthias
author
Wingender, Edgar
2007-02-14T15:45:37Z
2002-01-01
Nucleic Acids Research 2002 30(1):372-374
0305-1048
11752340
http://hdl.handle.net/10033/8404
99064
en_US
Copyright © 2002 Oxford University Press
S/MARt DB: a database on scaffold/matrix attached regions
URL
https://hzi.openrepository.com/bitstream/10033/8404/1/Liebich%20et%20al_final.pdf
File
MD5
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Liebich et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8404/7/Liebich%20et%20al_final.pdf.txt
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Liebich et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/84052019-08-30T11:32:37Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Kel-Margoulis, Olga V.
author
Kel, Alexander E.
author
Reuter, Ingmar
author
Deineko, Igor V.
author
Wingender, Edgar
2007-02-14T15:45:59Z
2002-01-01
Nucleic Acids Research 2002 30(1):332-334
0305-1048
11752329
http://hdl.handle.net/10033/8405
99108
en_US
Copyright © 2002 Oxford University Press
TRANSCompel®: a database on composite regulatory elements in eukaryotic genes
URL
https://hzi.openrepository.com/bitstream/10033/8405/1/Kel-Margoulis%20et%20al_final.pdf
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MD5
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Kel-Margoulis et al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/8405/7/Kel-Margoulis%20et%20al_final.pdf.txt
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MD5
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Kel-Margoulis et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/84022019-08-30T11:32:38Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Kel-Margoulis, Olga V.
author
Romashchenko, Aida G.
author
Kolchanov, Nikolay A.
author
Wingender, Edgar
author
Kel, Alexander E.
2007-02-14T15:44:21Z
2000-01-01
Nucleic Acids Research 2000 28(1):311-315
0305-1048
10592258
http://hdl.handle.net/10033/8402
102399
en_US
Copyright © 2000 Oxford University Press
COMPEL: a database on composite regulatory elements providing combinatorial transcriptional regulation
URL
https://hzi.openrepository.com/bitstream/10033/8402/1/Kel-Margoulis%20et%20al_final.pdf
File
MD5
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Kel-Margoulis et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8402/7/Kel-Margoulis%20et%20al_final.pdf.txt
File
MD5
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Kel-Margoulis et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/84092019-08-30T11:32:38Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Wingender, E.
author
Chen, X.
author
Hehl, R.
author
Karas, H.
author
Liebich, I.
author
Matys, V.
author
Meinhardt, T.
author
Prüß, M.
author
Reuter, I.
author
Schacherer, F.
2007-02-14T15:49:55Z
2000-01-01
Nucleic Acids Research 2000 28(1):316-319
0305-1048
10592259
http://hdl.handle.net/10033/8409
102445
en_US
Copyright © 2000 Oxford University Press
TRANSFAC: an integrated system for gene expression regulation
URL
https://hzi.openrepository.com/bitstream/10033/8409/1/Wingender%20et%20al_final.pdf
File
MD5
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Wingender et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8409/7/Wingender%20et%20al_final.pdf.txt
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Wingender et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/85052019-08-30T11:32:38Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Heinemeyer, T
author
Wingender, E
author
Reuter, I
author
Hermjakob, H
author
Kel, A E
author
Kel, O V
author
Ignatieva, E V
author
Ananko, E A
author
Podkolodnaya, O A
author
Kolpakov, F A
author
Podkolodny, N L
author
Kolchanov, N A
2007-02-19T09:02:17Z
1998-01-01
Nucleic Acids Research 1998 26(1):362-367
0305-1048
9399875
http://hdl.handle.net/10033/8505
147251
en_US
Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL.
URL
https://hzi.openrepository.com/bitstream/10033/8505/1/Heinemeyer%20et%20al_final.pdf
File
MD5
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Heinemeyer et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8505/7/Heinemeyer%20et%20al_final.pdf.txt
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Heinemeyer et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/85062019-08-30T11:32:38Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Heinemeyer, T
author
Chen, X
author
Karas, H
author
Kel, A E
author
Kel, O V
author
Liebich, I
author
Meinhardt, T
author
Reuter, I
author
Schacherer, F
author
Wingender, E
2007-02-19T09:09:54Z
1999-01-01
Nucleic Acids Research 1999 27(1):318-322
0305-1048
9847216
http://hdl.handle.net/10033/8506
148171
en_US
Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms.
URL
https://hzi.openrepository.com/bitstream/10033/8506/1/Heinemeyer%20et%20al_final.pdf
File
MD5
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Heinemeyer et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8506/7/Heinemeyer%20et%20al_final.pdf.txt
File
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Heinemeyer et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/85222019-08-30T11:32:38Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Wingender, E
author
Kel, A E
author
Kel, O V
author
Karas, H
author
Heinemeyer, T
author
Dietze, P
author
Knüppel, R
author
Romaschenko, A G
author
Kolchanov, N A
2007-02-19T09:50:15Z
1997-01-01
Nucleic Acids Research 1997 25(1):265-268
0305-1048
9016550
http://hdl.handle.net/10033/8522
146363
en_US
TRANSFAC, TRRD and COMPEL: towards a federated database system on transcriptional regulation.
URL
https://hzi.openrepository.com/bitstream/10033/8522/1/Wingender%20et%20al_final.pdf
File
MD5
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Wingender et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8522/7/Wingender%20et%20al_final.pdf.txt
File
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Wingender et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/86122019-08-30T11:32:39Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Frisch, Matthias
author
Frech, Kornelie
author
Klingenhoff, Andreas
author
Cartharius, Kerstin
author
Liebich, Ines
author
Werner, Thomas
2007-02-20T13:07:44Z
2002-02
Genome Research 2002 12(2):349-354
1088-9051
11827955
10.1101/gr.206602
http://hdl.handle.net/10033/8612
155272
en_US
Copyright © 2002, Cold Spring Harbor Laboratory Press
In Silico Prediction of Scaffold/Matrix Attachment Regions in Large Genomic Sequences
URL
https://hzi.openrepository.com/bitstream/10033/8612/1/Frisch%20et%20al_final.pdf
File
MD5
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Frisch et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8612/7/Frisch%20et%20al_final.pdf.txt
File
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Frisch et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/85372019-08-30T11:32:15Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Münch, Richard
author
Hiller, Karsten
author
Barg, Heiko
author
Heldt, Dana
author
Linz, Simone
author
Wingender, Edgar
author
Jahn, Dieter
2007-02-19T10:43:32Z
2003-01-01
Nucleic Acids Research 2003 31(1):266-269
0305-1048
12519998
http://hdl.handle.net/10033/8537
165484
en_US
Copyright © 2003 Oxford University Press
PRODORIC: prokaryotic database of gene regulation
URL
https://hzi.openrepository.com/bitstream/10033/8537/1/M%c3%bcnch%20et%20al_final.pdf
File
MD5
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251138
application/pdf
Münch et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8537/7/M%c3%bcnch%20et%20al_final.pdf.txt
File
MD5
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Münch et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/85382019-08-30T11:31:48Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Krull, Mathias
author
Voss, Nico
author
Choi, Claudia
author
Pistor, Susanne
author
Potapov, Anatolij
author
Wingender, Edgar
2007-02-19T10:44:45Z
2003-01-01
Nucleic Acids Research 2003 31(1):97-100
0305-1048
12519957
http://hdl.handle.net/10033/8538
165536
en_US
Copyright © 2003 Oxford University Press
TRANSPATH®: an integrated database on signal transduction and a tool for array analysis
URL
https://hzi.openrepository.com/bitstream/10033/8538/1/Krull%20et%20al_final.pdf
File
MD5
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295147
application/pdf
Krull et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8538/7/Krull%20et%20al_final.pdf.txt
File
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Krull et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/85432019-08-30T11:31:48Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Matys, V.
author
Fricke, E.
author
Geffers, Robert
author
Gößling, E.
author
Haubrock, M.
author
Hehl, R.
author
Hornischer, K.
author
Karas, D.
author
Kel, A. E.
author
Kel-Margoulis, O. V.
author
Kloos, D.-U.
author
Land, S.
author
Lewicki-Potapov, B.
author
Michael, H.
author
Münch, R.
author
Reuter, I.
author
Rotert, S.
author
Saxel, H.
author
Scheer, M.
author
Thiele, S.
author
Wingender, E.
2007-02-19T11:32:32Z
2003-01-01
Nucleic Acids Research 2003 31(1):374-378
0305-1048
12520026
http://hdl.handle.net/10033/8543
165555
en_US
Copyright © 2003 Oxford University Press
TRANSFAC®: transcriptional regulation, from patterns to profiles
URL
https://hzi.openrepository.com/bitstream/10033/8543/1/Matys%20et%20al_final.pdf
File
MD5
95ddc189c6af849cbce5332b1321ca0f
243745
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Matys et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8543/7/Matys%20et%20al_final.pdf.txt
File
MD5
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24889
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Matys et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/86752019-08-30T11:31:49Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Sun, Jibin
author
Daniel, Rolf
author
Wagner-Döbler, Irene
author
Zeng, An-Ping
2007-02-20T14:46:07Z
2004-09-29
BMC Evolutionary Biology 2004 4:36
1471-2148
15456522
10.1186/1471-2148-4-36
http://hdl.handle.net/10033/8675
524169
Background Quorum sensing is a process of bacterial cell-to-cell communication involving the production and detection of extracellular signaling molecules called autoinducers. Recently, it has been proposed that autoinducer-2 (AI-2), a furanosyl borate diester derived from the recycling of S-adenosyl-homocysteine (SAH) to homocysteine, serves as a universal signal for interspecies communication. Results In this study, 138 completed genomes were examined for the genes involved in the synthesis and detection of AI-2. Except for some symbionts and parasites, all organisms have a pathway to recycle SAH, either using a two-step enzymatic conversion by the Pfs and LuxS enzymes or a one-step conversion using SAH-hydrolase (SahH). 51 organisms including most Gamma-, Beta-, and Epsilonproteobacteria, and Firmicutes possess the Pfs-LuxS pathway, while Archaea, Eukarya, Alphaproteobacteria, Actinobacteria and Cyanobacteria prefer the SahH pathway. In all 138 organisms, only the three Vibrio strains had strong, bidirectional matches to the periplasmic AI-2 binding protein LuxP and the central signal relay protein LuxU. The initial two-component sensor kinase protein LuxQ, and the terminal response regulator luxO are found in most Proteobacteria, as well as in some Firmicutes, often in several copies. Conclusions The genomic analysis indicates that the LuxS enzyme required for AI-2 synthesis is widespread in bacteria, while the periplasmic binding protein LuxP is only present in Vibrio strains. Thus, other organisms may either use components different from the AI-2 signal transduction system of Vibrio strains to sense the signal of AI-2, or they do not have such a quorum sensing system at all.
en_US
Copyright © 2004 Sun et al; licensee BioMed Central Ltd.
Is autoinducer-2 a universal signal for interspecies communication: a comparative genomic and phylogenetic analysis of the synthesis and signal transduction pathways
URL
https://hzi.openrepository.com/bitstream/10033/8675/1/sun%20et%20al_final.pdf
File
MD5
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547229
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sun et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8675/7/sun%20et%20al_final.pdf.txt
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sun et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/86792019-08-30T11:32:12Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Wiemann, Stefan
author
Weil, Bernd
author
Wellenreuther, Ruth
author
Gassenhuber, Johannes
author
Glassl, Sabine
author
Ansorge, Wilhelm
author
Böcher, Michael
author
Blöcker, Helmut
author
Bauersachs, Stefan
author
Blum, Helmut
author
Lauber, Jürgen
author
Düsterhöft, Andreas
author
Beyer, Andreas
author
Köhrer, Karl
author
Strack, Normann
author
Mewes, Hans-Werner
author
Ottenwälder, Birgit
author
Obermaier, Brigitte
author
Tampe, Jens
author
Heubner, Dagmar
author
Wambutt, Rolf
author
Korn, Bernhard
author
Klein, Michaela
author
Poustka, Annemarie
2007-02-21T08:15:30Z
2001-03
Genome Research 2001 11(3):422-435
1088-9051
11230166
10.1101/gr.154701
http://hdl.handle.net/10033/8679
311072
en_US
Copyright © 2001, Cold Spring Harbor Laboratory Press
Toward a Catalog of Human Genes and Proteins: Sequencing and Analysis of 500 Novel Complete Protein Coding Human cDNAs
URL
https://hzi.openrepository.com/bitstream/10033/8679/1/Wiemann%20et%20al_final.pdf
File
MD5
31c252ffc8257caf49ce5c0edc0c669d
654235
application/pdf
Wiemann et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8679/7/Wiemann%20et%20al_final.pdf.txt
File
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Wiemann et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/86852019-08-30T11:24:26Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Ma, Hong-Wu
author
Kumar, Bharani
author
Ditges, Uta
author
Gunzer, Florian
author
Buer, Jan
author
Zeng, An-Ping
2007-02-21T08:22:34Z
2004
Nucleic Acids Research 2004 32(22):6643-6649
0305-1048
15604458
10.1093/nar/gkh1009
http://hdl.handle.net/10033/8685
545451
en_US
Copyright © 2004 Oxford University Press
An extended transcriptional regulatory network of Escherichia coli and analysis of its hierarchical structure and network motifs
URL
https://hzi.openrepository.com/bitstream/10033/8685/1/Ma%20et%20al_final.pdf
File
MD5
792e8be23f1dd69709d4eeb6914df146
624984
application/pdf
Ma et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8685/7/Ma%20et%20al_final.pdf.txt
File
MD5
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Ma et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/86992019-08-30T11:31:49Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Mertens, Gabriele
author
Hoffmann, Andrea
author
Blöcker, Helmut
author
Frank, Ronald
author
Kahmann, Regine
2007-02-21T08:38:11Z
1984-10
The EMBO Journal 1984 3(10):2415-2421
0261-4189
16453561
http://hdl.handle.net/10033/8699
557702
Images
en_US
© IRL Press Limited, Oxford, England.
Gin-mediated site-specific recombination in bacteriophage Mu DNA: overproduction of the protein and inversion in vitro
URL
https://hzi.openrepository.com/bitstream/10033/8699/1/Mertens%20et%20al_final.pdf
File
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Mertens et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8699/7/Mertens%20et%20al_final.pdf.txt
File
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Mertens et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/87062019-08-30T11:24:27Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Elhariry, Hesham M.
author
Meens, Jochen
author
Stehr, Matthias
author
Auling, Georg
2007-02-21T08:46:36Z
2005-09
Applied and Environmental Microbiology 2005 71(9):5582-5586
0099-2240
10.1128/AEM.71.9.5582-5586.2005
http://hdl.handle.net/10033/8706
1214679
en_US
Copyright © 2005, American Society for Microbiology
S434F in NrdE Generates the Thermosensitive Phenotype of Corynebacterium ammoniagenes CH31 and Enhances Thermolability by Increasing the Surface Hydrophobicity of the NrdE(Ts) Protein
URL
https://hzi.openrepository.com/bitstream/10033/8706/7/Elhariry%20et%20al_final.pdf
File
MD5
adad6d035d8c43b1c3f847904a8054ab
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application/pdf
Elhariry et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8706/8/Elhariry%20et%20al_final.pdf.txt
File
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Elhariry et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/142012019-08-30T11:35:39Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Van den Bulcke, Tim
author
Van Leemput, Koenraad
author
Naudts, Bart
author
van Remortel, Piet
author
Ma, Hongwu
author
Verschoren, Alain
author
De Moor, Bart
author
Marchal, Kathleen
2007-10-23T08:19:09Z
2006
BMC Bioinformatics 2006, 7:43
1471-2105
16438721
10.1186/1471-2105-7-43
http://hdl.handle.net/10033/14201
BACKGROUND: The development of algorithms to infer the structure of gene regulatory networks based on expression data is an important subject in bioinformatics research. Validation of these algorithms requires benchmark data sets for which the underlying network is known. Since experimental data sets of the appropriate size and design are usually not available, there is a clear need to generate well-characterized synthetic data sets that allow thorough testing of learning algorithms in a fast and reproducible manner. RESULTS: In this paper we describe a network generator that creates synthetic transcriptional regulatory networks and produces simulated gene expression data that approximates experimental data. Network topologies are generated by selecting subnetworks from previously described regulatory networks. Interaction kinetics are modeled by equations based on Michaelis-Menten and Hill kinetics. Our results show that the statistical properties of these topologies more closely approximate those of genuine biological networks than do those of different types of random graph models. Several user-definable parameters adjust the complexity of the resulting data set with respect to the structure learning algorithms. CONCLUSION: This network generation technique offers a valid alternative to existing methods. The topological characteristics of the generated networks more closely resemble the characteristics of real transcriptional networks. Simulation of the network scales well to large networks. The generator models different types of biological interactions and produces biologically plausible synthetic gene expression data.
en
SynTReN: a generator of synthetic gene expression data for design and analysis of structure learning algorithms.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/14201/1/Van%20den%20Bulcke%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/145552019-08-30T11:36:05Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Vordermeier, H Martin
author
Huygen, Kris
author
Singh, Mahavir
author
Hewinson, R Glyn
author
Xing, Zhou
2007-11-13T14:31:29Z
2006-02-01
Infect. Immun. 2006, 74(2):1416-8
0019-9567
16428796
10.1128/IAI.74.2.1416-1418.2006
http://hdl.handle.net/10033/14555
Cattle were vaccinated with an adenovirus expressing the mycobacterial antigen 85A (rAd85A), with Mycobacterium bovis BCG followed by rAd85A heterologous boosting, or with rAd85A followed by BCG boosting. BCG/rAd85A resulted in the highest direct gamma interferon responses. Cultured enzyme-linked immunospot assay analysis demonstrated that memory responses were induced by all three protocols but were strongest after BCG/rAd85A and rAd85A/BCG vaccination.
en
Immune responses induced in cattle by vaccination with a recombinant adenovirus expressing Mycobacterial antigen 85A and Mycobacterium bovis BCG.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/14555/1/Vordermeier_fin.pdf
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oai:repository.helmholtz-hzi.de:10033/145752019-08-30T11:35:39Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Reljic, R
author
Clark, S O
author
Williams, A
author
Falero-Diaz, G
author
Singh, M
author
Challacombe, S
author
Marsh, P D
author
Ivanyi, J
2007-11-15T09:34:37Z
2006-03-01
Clin. Exp. Immunol. 2006, 143(3):467-73
0009-9104
16487246
10.1111/j.1365-2249.2006.03012.x
http://hdl.handle.net/10033/14575
Intranasal inoculation of mice with monoclonal IgA against the alpha-crystallin (acr1) antigen can diminish the tuberculous infection in the lungs. As this effect has been observed only over a short-term, we investigated if it could be extended by inoculation of IFNgamma 3 days before infection, and further co-inoculations with IgA, at 2 h before and 2 and 7 days after aerosol infection with Mycobacterium tuberculosis H37Rv. This treatment reduced the lung infection at 4 weeks more than either IgA or IFNgamma alone (i.e. 17-fold, from 4.2 x 10(7) to 2.5 x 10(6) CFU, P = 0.006), accompanied also by lower granulomatous infiltration of the lungs. IFNgamma added prior to infection of mouse peritoneal macrophages with IgA-opsonized bacilli resulted in a synergistic increase of nitric oxide and TNFalpha production and a 2-3 fold decrease in bacterial counts. Our improved results suggest, that combined treatment with IFNgamma and IgA could be developed towards prophylactic treatment of AIDS patients, or as an adjunct to chemotherapy.
en
Intranasal IFNgamma extends passive IgA antibody protection of mice against Mycobacterium tuberculosis lung infection.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/14575/1/Reljic_final.pdf
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oai:repository.helmholtz-hzi.de:10033/153722019-08-30T11:36:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Trujillo, Madia
author
Mauri, PierLuigi
author
Benazzi, Louise
author
Comini, Marcelo
author
De Palma, Antonella
author
Flohé, Leopold
author
Radi, Rafael
author
Stehr, Matthias
author
Singh, Mahavir
author
Ursini, Fulvio
author
Jaeger, Timo
department
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avda. General Flores 2125, UY-11800 Montevideo, Uruguay.
2007-12-18T09:21:20Z
2006-07-21
The mycobacterial thioredoxin peroxidase can act as a one-cysteine peroxiredoxin. 2006, 281 (29):20555-66 J. Biol. Chem.
0021-9258
16682410
10.1074/jbc.M601008200
http://hdl.handle.net/10033/15372
The Journal of biological chemistry
Thioredoxin peroxidase (TPx) has been reported to dominate the defense against H(2)O(2), other hydroperoxides, and peroxynitrite at the expense of thioredoxin (Trx) B and C in Mycobacterium tuberculosis (Mt). By homology, the enzyme has been classified as an atypical 2-C-peroxiredoxin (Prx), with Cys(60) as the "peroxidatic" cysteine (C(P)) forming a complex catalytic center with Cys(93) as the "resolving" cysteine (C(R)). Site-directed mutagenesis confirms Cys(60) to be C(P) and Cys(80) to be catalytically irrelevant. Replacing Cys(93) with serine leads to fast inactivation as seen by conventional activity determination, which is associated with oxidation of Cys(60) to a sulfinic acid derivative. However, in comparative stopped-flow analysis, WT-MtTPx and MtTPx C93S reduce peroxynitrite and react with TrxB and -C similarly fast. Reduction of pre-oxidized WT-MtTPx and MtTPx C93S by MtTrxB is demonstrated by monitoring the redox-dependent tryptophan fluorescence of MtTrxB. Furthermore, MtTPx C93S remains stable for 10 min at a morpholinosydnonimine hydrochloride-generated low flux of peroxynitrite and excess MtTrxB in a dihydrorhodamine oxidation model. Liquid chromatography-tandem mass spectrometry analysis revealed disulfide bridges between Cys(60) and Cys(93) and between Cys(60) and Cys(80) in oxidized WT-MtTPx. Reaction of pre-oxidized WT-MtTPx and MtTPx C93S with MtTrxB C34S or MtTrxC C40S yielded dead-end intermediates in which the Trx mutants are preferentially linked via disulfide bonds to Cys(60) and never to Cys(93) of the TPx. It is concluded that neither Cys(80) nor Cys(93) is required for the catalytic cycle of the peroxidase. Instead, MtTPx can react as a 1-C-Prx with Cys(60) being the site of attack for both the oxidizing and the reducing substrate. The role of Cys(93) is likely to conserve the oxidation equivalents of the sulfenic acid state of C(P) as a disulfide bond to prevent overoxidation of Cys(60) under a restricted supply of reducing substrate.
en
The mycobacterial thioredoxin peroxidase can act as a one-cysteine peroxiredoxin.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/158682019-08-30T11:25:11Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Leeb, Tosso
author
Vogl, Claus
author
Zhu, Baoli
author
de Jong, Pieter J
author
Binns, Matthew M
author
Chowdhary, Bhanu P
author
Scharfe, Maren
author
Jarek, Michael
author
Nordsiek, Gabriele
author
Schrader, Frank
author
Blöcker, Helmut
department
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Bünteweg 17p, 30559 Hannover, Germany. Tosso.Leeb@itz.unibe.ch
2008-01-09T14:10:56Z
2006-06
A human-horse comparative map based on equine BAC end sequences. 2006, 87 (6):772-6 Genomics
0888-7543
16603334
10.1016/j.ygeno.2006.03.002
http://hdl.handle.net/10033/15868
Genomics
In an effort to increase the density of sequence-based markers for the horse genome we generated 9473 BAC end sequences (BESs) from the CHORI-241 BAC library with an average read length of 677 bp. BLASTN searches with the BESs revealed 4036 meaningful hits (E
en
A human-horse comparative map based on equine BAC end sequences.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/15868/1/Leeb%20et%20al_final.pdf
File
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URL
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oai:repository.helmholtz-hzi.de:10033/188722019-08-30T11:36:04Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Udvarnoki, Katalin
author
Cervenak, László
author
Uray, Katalin
author
Hudecz, Ferenc
author
Kacskovics, Imre
author
Spallek, Ralf
author
Singh, Mahavir
author
Füst, George
author
Prohászka, Zoltán
department
Third Department of Medicine, Semmelweis University, H-1125 Budapest, Kútvölgyi st. 4, Hungary.
2008-02-21T14:09:36Z
2007-04
Antibodies against C-reactive protein cross-react with 60-kilodalton heat shock proteins. 2007, 14 (4):335-41 Clin. Vaccine Immunol.
1556-6811
17301219
10.1128/CVI.00155-06
http://hdl.handle.net/10033/18872
Clinical and vaccine immunology : CVI
C-reactive protein (CRP) is an acute-phase reactant frequently used in histochemistry as a marker of ongoing inflammation. Furthermore, CRP is a powerful biomarker for the prediction of coronary artery disease risk. Heat-shock protein 60 (Hsp60) and CRP are complement-activating molecules, and the effect of their interactions on the regulation of complement activation was studied. However, during the first experiments, we learned that polyclonal anti-CRP antibodies cross-react with Hsp60. Therefore, the aim of our present study was to analyze the cross-reactivity of anti-CRP antibodies (Ab) with Hsp60 in solid-phase enzyme immune assays, in epitope studies using a series of overlapping synthetic peptides, and in Ouchterlony analyses. We found that three different commercial rabbit polyclonal antibodies and two monoclonal (9C9 and CRP-8) anti-CRP antibodies specifically recognize recombinant human Hsp60 and recombinant Mycobacterium tuberculosis Hsp65, respectively. Hsp60 was found to inhibit the binding of anti-CRP polyclonal Ab to Hsp60. Six epitope regions of Hsp60 were recognized by the anti-CRP antibodies, and one region (amino acids [AA] 218 to 232) was recognized by monoclonal antibodies CRP-8 and 9C9. This epitope region of Hsp60 displays 26.6% amino acid identity to CRP AA region 77 to 90. These data suggest that the B-cell epitopes shared between CRP and Hsp60 give rise to a true mimicry-based cross-reaction and the induction of cross-reactive antibodies. Our study underlines the importance of thorough study design and careful interpretation of results while using polyclonal anti-CRP antibodies for histochemistry, especially at low dilutions. Furthermore, analytical interference with Hsp60 in CRP assays should also be tested.
en
Antibodies against C-reactive protein cross-react with 60-kilodalton heat shock proteins.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/18872/1/Udvarnoki%20et%20al_final.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/18872/8/Udvarnoki%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/223132019-08-30T11:37:44Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Dinser, R
author
Fousse, M
author
Sester, U
author
Albrecht, K
author
Singh, M
author
Köhler, H
author
Müller-Ladner, U
author
Sester, M
department
Department of Internal Medicine and Rheumatology, Justus-Liebig University of Giessen, Kerckhoff Clinic, Benekestrasse 2-8, D-61231 Bad Nauheim, Germany. r.dinser@kerckhoff-klinik.de
2008-04-04T11:55:57Z
2008-02
Evaluation of latent tuberculosis infection in patients with inflammatory arthropathies before treatment with TNF-alpha blocking drugs using a novel flow-cytometric interferon-gamma release assay. 2008, 47 (2):212-8 Rheumatology (Oxford)
1462-0332
18208824
10.1093/rheumatology/kem351
http://hdl.handle.net/10033/22313
Rheumatology (Oxford, England)
OBJECTIVE: To compare the efficacy of the conventional skin test and a novel flow cytometric whole blood assay in the diagnosis of latent tuberculosis infection (LTBI) in patients with rheumatological diseases evaluated for treatment with TNF-alpha-blocking agents. METHODS: Prospective study of 97 consecutively enrolled patients, who were assessed for the presence of LTBI through clinical history, Mendel-Mantoux skin testing and chest X-ray. In addition, T-cell reactivity towards tuberculin (PPD, purified protein derivative) and the Mycobacterium tuberculosis-specific proteins ESAT-6 and CFP-10 was determined ex vivo using a flow cytometric whole blood assay. RESULTS: After standard screening, 15% of patients receiving TNF-alpha-blocking therapy were pretreated with isoniazide (INH), another 5% of patients did not receive TNF-alpha-blocking therapy because of LTBI. PPD-reactivity in the skin was observed in 14% of patients compared with 39% with the whole blood test. Analysis of the M. tuberculosis-specific response to ESAT-6 and CFP-10 revealed positive results in 16% of patients. Using a decision tree incorporating history, chest X-ray and either skin-test or ESAT-6/CFP-10 results, 18 or 22% of the patients, respectively, were classified as latently infected with M. tuberculosis. Four patients treated with INH because of a positive skin reaction did not show reactivity to ESAT-6/CFP-10 in the whole blood assays. Another six patients not pretreated with INH because of negative skin tests would have received INH, had the results of the whole blood assay been taken into account. CONCLUSION: The Mendel-Mantoux skin test has a low sensitivity and specificity for the diagnosis of LTBI in this cohort of patients, potentially resulting in both over- and under-treatment with prophylactic INH when compared with the flow cytometric analysis of whole blood T-cell reactivity to proteins specific to M. tuberculosis. Use of T-cell based in vitro tests may help to refine diagnostic testing for LTBI.
en
Evaluation of latent tuberculosis infection in patients with inflammatory arthropathies before treatment with TNF-alpha blocking drugs using a novel flow-cytometric interferon-gamma release assay.
Article
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oai:repository.helmholtz-hzi.de:10033/245132019-08-30T11:25:43Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Schnell, Robert
author
Oehlmann, Wulf
author
Singh, Mahavir
author
Schneider, Gunter
department
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
2008-04-30T11:56:12Z
2007-08-10
Structural insights into catalysis and inhibition of O-acetylserine sulfhydrylase from Mycobacterium tuberculosis. Crystal structures of the enzyme alpha-aminoacrylate intermediate and an enzyme-inhibitor complex. 2007, 282 (32):23473-81 J. Biol. Chem.
0021-9258
17567578
10.1074/jbc.M703518200
http://hdl.handle.net/10033/24513
The Journal of biological chemistry
Cysteine biosynthetic genes are up-regulated in the persistent phase of Mycobacterium tuberculosis, and the corresponding enzymes are therefore of interest as potential targets for novel antibacterial agents. cysK1 is one of these genes and has been annotated as coding for an O-acetylserine sulfhydrylase. Recombinant CysK1 is a pyridoxal phosphate (PLP)-dependent enzyme that catalyzes the conversion of O-acetylserine to cysteine. The crystal structure of the enzyme was determined to 1.8A resolution. CysK1 belongs to the family of fold type II PLP enzymes and is similar in structure to other O-acetylserine sulfhydrylases. We were able to trap the alpha-aminoacrylate reaction intermediate and determine its structure by cryocrystallography. Formation of the aminoacrylate complex is accompanied by a domain rotation resulting in active site closure. The aminoacrylate moiety is bound in the active site via the covalent linkage to the PLP cofactor and by hydrogen bonds of its carboxyl group to several enzyme residues. The catalytic lysine residue is positioned such that it can protonate the Calpha-carbon atom of the aminoacrylate only from the si-face, resulting in the formation of L-cysteine. CysK1 is competitively inhibited by a four-residue peptide derived from the C-terminal of serine acetyl transferase. The crystallographic analysis reveals that the peptide binds to the enzyme active site, suggesting that CysK1 forms an bi-enzyme complex with serine acetyl transferase, in a similar manner to other bacterial and plant O-acetylserine sulfhydrylases. The structure of the enzyme-peptide complex provides a framework for the design of strong binding inhibitors.
en
Structural insights into catalysis and inhibition of O-acetylserine sulfhydrylase from Mycobacterium tuberculosis. Crystal structures of the enzyme alpha-aminoacrylate intermediate and an enzyme-inhibitor complex.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/24513/1/Schnell_final.pdf
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oai:repository.helmholtz-hzi.de:10033/711632019-08-30T11:33:05Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Agren, Daniel
author
Stehr, Matthias
author
Berthold, Catrine L
author
Kapoor, Shobhna
author
Oehlmann, Wulf
author
Singh, Mahavir
author
Schneider, Gunter
department
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
2009-06-22T13:53:17Z
2008-04-04
Three-dimensional structures of apo- and holo-L-alanine dehydrogenase from Mycobacterium tuberculosis reveal conformational changes upon coenzyme binding. 2008, 377 (4):1161-73 J. Mol. Biol.
1089-8638
18304579
10.1016/j.jmb.2008.01.091
http://hdl.handle.net/10033/71163
Journal of molecular biology
L-alanine dehydrogenase from Mycobacterium tuberculosis catalyzes the NADH-dependent reversible conversion of pyruvate and ammonia to L-alanine. Expression of the gene coding for this enzyme is up-regulated in the persistent phase of the organism, and alanine dehydrogenase is therefore a potential target for pathogen control by antibacterial compounds. We have determined the crystal structures of the apo- and holo-forms of the enzyme to 2.3 and 2.0 A resolution, respectively. The enzyme forms a hexamer of identical subunits, with the NAD-binding domains building up the core of the molecule and the substrate-binding domains located at the apical positions of the hexamer. Coenzyme binding stabilizes a closed conformation where the substrate-binding domains are rotated by about 16 degrees toward the dinucleotide-binding domains, compared to the open structure of the apo-enzyme. In the structure of the abortive ternary complex with NAD+ and pyruvate, the substrates are suitably positioned for hydride transfer between the nicotinamide ring and the C2 carbon atom of the substrate. The approach of the nucleophiles water and ammonia to pyruvate or the reaction intermediate iminopyruvate, respectively, is, however, only possible through conformational changes that make the substrate binding site more accessible. The crystal structures identified the conserved active-site residues His96 and Asp270 as potential acid/base catalysts in the reaction. Amino acid replacements of these residues by site-directed mutagenesis led to inactive mutants, further emphasizing their essential roles in the enzymatic reaction mechanism.
en
Three-dimensional structures of apo- and holo-L-alanine dehydrogenase from Mycobacterium tuberculosis reveal conformational changes upon coenzyme binding.
Article
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URL
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URL
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oai:repository.helmholtz-hzi.de:10033/929202019-08-30T11:33:05Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Elamin, Ayssar A
author
Stehr, Matthias
author
Oehlmann, Wulf
author
Singh, Mahavir
department
Department of Genome Analysis, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
2010-02-24T13:30:33Z
2009-12
The mycolyltransferase 85A, a putative drug target of Mycobacterium tuberculosis: development of a novel assay and quantification of glycolipid-status of the mycobacterial cell wall. 2009, 79 (3):358-63 J. Microbiol. Methods
1872-8359
19857528
10.1016/j.mimet.2009.10.010
http://hdl.handle.net/10033/92920
Journal of microbiological methods
The enzymes of the antigen 85 complex (Ag85A, B, and C) possess mycolyltransferase activity and catalyze the synthesis of the most abundant glycolipid of the mycobacterial cell wall, the cord factor. The cord factor (trehalose 6,6'-dimycolate, TDM) is essential for the integrity of the mycobacterial cell wall and pathogenesis of the bacillus. Thus, TDM biosynthesis is regarded as a potential drug target for control of Mycobacterium tuberculosis infections. Trehalose 6,6'-dimycolate (TDM) is synthesized from two molecules of trehalose-6'-monomycolate (TMM) by antigen 85A. We report here a novel enzyme assay using the natural substrate TMM. The novel colorimetric assay is based on the quantification of glucose from the degradation of trehalose, which is the product from catalytic activity of antigen 85A. Using the new assay, K(m) and K(cat) were determined with values of 129.6+/-8.1 microM and 65.4+/-4.1 min(-1), respectively. This novel assay is also suitable for robust high-throughput screening (HTS) for compound library screening against mycolyltransferase (antigen 85A). The assay is significantly faster and more convenient to use than all assays currently in use. The assay has a very low coefficient of variance (0.04) in 96-well plates and shows a Z' factor of 0.67-0.73, indicating the robustness of the assay. In addition, this new assay is highly suitable for the quantification of total TMM of the mycobacterial cell envelope.
en
The mycolyltransferase 85A, a putative drug target of Mycobacterium tuberculosis: development of a novel assay and quantification of glycolipid-status of the mycobacterial cell wall.
Article
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oai:repository.helmholtz-hzi.de:10033/941732019-08-30T11:33:57Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Meidtner, Karina
author
Schwarzenbacher, Hermann
author
Scharfe, Maren
author
Severitt, Simone
author
Blöcker, Helmut
author
Fries, Ruedi
department
Chair of Animal Breeding, Technical University of Munich, Hochfeldweg 1, 85354 Freising - Weihenstephan, Germany. karina.meidtner@tierzucht.tum.de
2010-03-12T09:52:44Z
2009
Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness. 2009, 10:76 BMC Genet.
1471-2156
19943979
10.1186/1471-2156-10-76
http://hdl.handle.net/10033/94173
BMC genetics
BACKGROUND: Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD) has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics. RESULTS: Screening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa x Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa x Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-delta mRNA levels. Haplotype 4 significantly increases PPAR-delta mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-delta. CONCLUSION: This study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.
en
Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/94173/1/Meidtner%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/1287912019-08-30T11:30:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Leonhardt, Johannes
author
Kuebler, Joachim F
author
Turowski, Carmen
author
Tschernig, Thomas
author
Geffers, Robert
author
Petersen, Claus
department
Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
2011-04-27T14:27:20Z
2010-02
Susceptibility to experimental biliary atresia linked to different hepatic gene expression profiles in two mouse strains. 2010, 40 (2):196-203 Hepatol. Res.
1386-6346
19788687
10.1111/j.1872-034X.2009.00577.x
http://hdl.handle.net/10033/128791
Hepatology research : the official journal of the Japan Society of Hepatology
Aim: To compare hepatic gene expression during the development of experimental biliary atresia (BA) in two different mouse strains. Methods: Balb/c mice and C57Black/6 (Black/6) mice were infected with rhesus rotavirus (RRV) postpartum, clinical signs of BA and survival were noted. Liver sections were assessed for cluster of differentiation antigen (CD) 3, CD4 and CD8 expression, and the hepatic virus load was determined. Second, mice of both strains were sacrificed three days after infection. Isolated hepatic RNA was subjected to gene expression analysis using Affymetrix Gene Chip MOE 430 2.0. Results: The incidence of BA was significantly lower in Black/6 mice compared to Balb/c mice (13.5% vs. 67%, P < 0.05). The mean virus titers were higher in mice with BA compared to mice without BA. Different gene profiles three days after virus infection were noted, with differential expression of 201 genes, including those regulating apoptosis, nucleic acid binding, transport function and particularly the immune response (chemokine C-C motif ligand 2, toll-like receptor 3, CD antigen 14, chemokine (C-X-C motif) ligands 10 and 11). This correlated with a significant increase of CD4 positive cells only in Balb/c mice with BA compared to healthy mice (13.5 vs. 5.0; P < 0.05). Black/6 mice did not exhibit any significant increase of CD3 or CD4 leukocytes despite cholestasis. Conclusion: The different susceptibility to experimental BA was associated with an increase of CD4 T-cells in the liver of Balb/c mice, which is linked to different gene profiles at the onset of bile duct obstruction.
en
Susceptibility to experimental biliary atresia linked to different hepatic gene expression profiles in two mouse strains.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/1417922019-08-30T11:28:23Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Schenk, Ursula
author
Frascoli, Michela
author
Proietti, Michele
author
Geffers, Robert
author
Traggiai, Elisabetta
author
Buer, Jan
author
Ricordi, Camillo
author
Westendorf, Astrid M
author
Grassi, Fabio
department
Institute for Research in Biomedicine, Bellinzona, Switzerland.
2011-09-06T11:25:54Z
2011
ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. 2011, 4 (162):ra12 Sci Signal
1937-9145
21364186
10.1126/scisignal.2001270
http://hdl.handle.net/10033/141792
Science signaling
Extracellular nucleotides are pleiotropic regulators of mammalian cell function. Adenosine triphosphate (ATP) released from CD4(+) helper T cells upon stimulation of the T cell receptor (TCR) contributes in an autocrine manner to the activation of mitogen-activated protein kinase (MAPK) signaling through purinergic P2X receptors. Increased expression of p2rx7, which encodes the purinergic receptor P2X7, is part of the transcriptional signature of immunosuppressive CD4(+)CD25(+) regulatory T cells (T(regs)). Here, we show that the activation of P2X7 by ATP inhibits the suppressive potential and stability of T(regs). The inflammatory cytokine interleukin-6 (IL-6) increased ATP synthesis and P2X7-mediated signaling in T(regs), which induced their conversion to IL-17-secreting T helper 17 (T(H)17) effector cells in vivo. Moreover, pharmacological antagonism of P2X receptors promoted the cell-autonomous conversion of naïve CD4(+) T cells into T(regs) after TCR stimulation. Thus, ATP acts as an autocrine factor that integrates stimuli from the microenvironment and cellular energetics to tune the developmental and immunosuppressive program of the T cell in adaptive immune responses.
en
ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors.
Article
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oai:repository.helmholtz-hzi.de:10033/1819902019-08-30T11:31:23Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Adhikary, Till
author
Kaddatz, Kerstin
author
Finkernagel, Florian
author
Schönbauer, Anne
author
Meissner, Wolfgang
author
Scharfe, Maren
author
Jarek, Michael
author
Blöcker, Helmut
author
Müller-Brüsselbach, Sabine
author
Müller, Rolf
department
Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.
2011-10-28T10:55:24Z
2011
Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ). 2011, 6 (1):e16344 PLoS ONE
1932-6203
21283829
10.1371/journal.pone.0016344
http://hdl.handle.net/10033/181990
PloS one
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with essential functions in lipid, glucose and energy homeostasis, cell differentiation, inflammation and metabolic disorders, and represent important drug targets. PPARs heterodimerize with retinoid X receptors (RXRs) and can form transcriptional activator or repressor complexes at specific DNA elements (PPREs). It is believed that the decision between repression and activation is generally governed by a ligand-mediated switch. We have performed genomewide analyses of agonist-treated and PPARβ/δ-depleted human myofibroblasts to test this hypothesis and to identify global principles of PPARβ/δ-mediated gene regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq) of PPARβ/δ, H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional profiling enabled the definition of 112 bona fide PPARβ/δ target genes showing either of three distinct types of transcriptional response: (I) ligand-independent repression by PPARβ/δ; (II) ligand-induced activation and/or derepression by PPARβ/δ; and (III) ligand-independent activation by PPARβ/δ. These data identify PPRE-mediated repression as a major mechanism of transcriptional regulation by PPARβ/δ, but, unexpectedly, also show that only a subset of repressed genes are activated by a ligand-mediated switch. Our results also suggest that the type of transcriptional response by a given target gene is connected to the structure of its associated PPRE(s) and the biological function of its encoded protein. These observations have important implications for understanding the regulatory PPAR network and PPARβ/δ ligand-based drugs.
en
Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ).
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/2139692019-08-30T11:29:47Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Su, Fei
author
Yu, Bo
author
Sun, Jibin
author
Ou, Hong-Yu
author
Zhao, Bo
author
Wang, Limin
author
Qin, Jiayang
author
Tang, Hongzhi
author
Tao, Fei
author
Jarek, Michael
author
Scharfe, Maren
author
Ma, Cuiqing
author
Ma, Yanhe
author
Xu, Ping
department
State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People’s Republic of China.
2012-03-02T10:12:39Z
2011-09
Genome sequence of the thermophilic strain Bacillus coagulans 2-6, an efficient producer of high-optical-purity L-lactic acid. 2011, 193 (17):4563-4 J. Bacteriol.
1098-5530
21705584
10.1128/JB.05378-11
http://hdl.handle.net/10033/213969
Journal of bacteriology
Bacillus coagulans 2-6 is an efficient producer of lactic acid. The genome of B. coagulans 2-6 has the smallest genome among the members of the genus Bacillus known to date. The frameshift mutation at the start of the d-lactate dehydrogenase sequence might be responsible for the production of high-optical-purity l-lactic acid.
en
Genome sequence of the thermophilic strain Bacillus coagulans 2-6, an efficient producer of high-optical-purity L-lactic acid.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/213969/1/Su%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2266512019-08-30T11:34:22Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Boppana, Sridhar
author
Scheglov, Alexander
author
Geffers, Robert
author
Tarabykin, Victor
department
Max-Planck-Institute for Experimental Medicine, Hermann-Rein Strasse 3, 37075 Göttingen, Germany. boppansr@umdnj.edu
2012-05-30T08:29:02Z
2012-02
Cellular retinaldehyde-binding protein (CRALBP) is a direct downstream target of transcription factor Pax6. 2012, 1820 (2):151-6 Biochim. Biophys. Acta
0006-3002
21996446
10.1016/j.bbagen.2011.09.015
http://hdl.handle.net/10033/226651
Biochimica et biophysica acta
Transcription factor Pax6 plays an essential role in the expression of other transcription factors, cell adhesion molecules and is crucial for neurogenesis in the developing forebrain. Analysis of gene expression profiles through microarray experiments in Pax6 mutants allowed us to focus on CRALBP, one of the many genes that were downregulated.
en
Archived with thanks to Biochimica et biophysica acta
Cellular retinaldehyde-binding protein (CRALBP) is a direct downstream target of transcription factor Pax6.
Article
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https://hzi.openrepository.com/bitstream/10033/226651/1/Boppana%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/226651/3/Fig2%20Cortex%20eye%20immuno.tif
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URL
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https://hzi.openrepository.com/bitstream/10033/226651/16/Boppana%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/2334552019-08-30T11:33:57Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Schneider, Björn
author
Nagel, Stefan
author
Ehrentraut, Stefan
author
Kaufmann, Maren
author
Meyer, Corinna
author
Geffers, Robert
author
Drexler, Hans G
author
MacLeod, Roderick A F
department
Department of Human and Animal Cell Cultures, DSMZ-German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7b, 38124 Braunschweig, Germany. bjoern.schneider@med.uni-rostock.de
2012-07-12T14:59:19Z
2012-03
Neoplastic MiR-17~92 deregulation at a DNA fragility motif (SIDD). 2012, 51 (3):219-28 Genes Chromosomes Cancer
1098-2264
22072491
10.1002/gcc.20946
http://hdl.handle.net/10033/233455
Genes, chromosomes & cancer
Chromosomal or mutational activation of BCL6 (at 3q27) typifies diffuse large B-cell lymphoma (DLBCL) which in the germinal center subtype may be accompanied by focal amplification of chromosome band 13q31 effecting upregulation of miR-17~92. Using long distance inverse-polymerase chain reaction, we mapped and sequenced six breakpoints of a complex BCL6 rearrangement t(3;13)(q27;q31)t(12;13)(p11;q31) in DLBCL cells, which places miR-17~92 antisense within the resulting ITPR2-BCL6 chimeric fusion gene rearrangement. MiR-17~92 members were upregulated ~15-fold over controls in a copy number independent manner consistent with structural deregulation. MIR17HG and ITPR2-BCL6 were, despite their close configuration, independently expressed, discounting antisense regulation. MIR17HG in t(3;13)t(12;13) cells proved highly responsive to treatment with histone deacetylase inhibitors implicating epigenetic deregulation, consistent with which increased histone-H3 acetylation was detected by chromatin immunoprecipitation near the upstream MIR17HG breakpoint. Remarkably, 5/6 DNA breaks in the t(3;13)t(12;13) precisely cut at stress-induced DNA duplex destabilization (SIDD) peaks reminiscent of chromosomal fragile sites, while the sixth lay 150 bp distant. Extended SIDD profiling showed that additional oncomiRs also map to SIDD peaks. Fluorescence in situ hybridization analysis showed that 11 of 52 (21%) leukemia-lymphoma (L-L) cell lines with 13q31 involvement bore structural rearrangements at/near MIR17HG associated with upregulation. As well as fueling genome instability, SIDD peaks mark regulatory nuclear-scaffold matrix attachment regions open to nucleosomal acetylation. Collectively, our data indict a specific DNA instability motif (SIDD) in chromosome rearrangement, specifically alterations activating miR-17~92 epigenetically via promoter hyperacetylation, and supply a model for the clustering of oncomiRs near cancer breakpoints.
en
Archived with thanks to Genes, chromosomes & cancer
Neoplastic MiR-17~92 deregulation at a DNA fragility motif (SIDD).
Article
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https://hzi.openrepository.com/bitstream/10033/233455/48/Suppl%20Fig%20Legs.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/2369892019-08-30T11:25:43Zcom_10033_311624com_10033_6839com_10033_620636col_10033_311625col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Göhler, Anna-Katharina
author
Kökpinar, Öznur
author
Schmidt-Heck, Wolfgang
author
Geffers, Robert
author
Guthke, Reinhard
author
Rinas, Ursula
author
Schuster, Stefan
author
Jahreis, Knut
author
Kaleta, Christoph
department
Department of Genetics, University of Osnabrück, Osnabrück, Germany.
2012-08-02T10:34:07Z
2011
More than just a metabolic regulator--elucidation and validation of new targets of PdhR in Escherichia coli. 2011, 5:197 BMC Syst Biol
1752-0509
22168595
10.1186/1752-0509-5-197
http://hdl.handle.net/10033/236989
BMC systems biology
The pyruvate dehydrogenase regulator protein (PdhR) of Escherichia coli acts as a transcriptional regulator in a pyruvate dependent manner to control central metabolic fluxes. However, the complete PdhR regulon has not yet been uncovered. To achieve an extended understanding of its gene regulatory network, we combined large-scale network inference and experimental verification of results obtained by a systems biology approach.
en
Archived with thanks to BMC systems biology
More than just a metabolic regulator--elucidation and validation of new targets of PdhR in Escherichia coli.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/236989/1/g%c3%b6hler-k%c3%b6kpinar%20et%20al_final.pdf
File
MD5
d0c4e1d5faa17f91b58ca8c3622f9f42
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göhler-kökpinar et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/236989/8/g%c3%b6hler-k%c3%b6kpinar%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/2399312019-08-30T11:28:51Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Block, Jennifer
author
Breitsprecher, Dennis
author
Kühn, Sonja
author
Winterhoff, Moritz
author
Kage, Frieda
author
Geffers, Robert
author
Duwe, Patrick
author
Rohn, Jennifer L
author
Baum, Buzz
author
Brakebusch, Cord
author
Geyer, Matthias
author
Stradal, Theresia E B
author
Faix, Jan
author
Rottner, Klemens
department
Institute of Genetics, University of Bonn, Karlrobert-Kreiten-Strasse 13, 53115 Bonn, Germany.
2012-08-24T13:12:54Z
2012-06-05
FMNL2 drives actin-based protrusion and migration downstream of Cdc42. 2012, 22 (11):1005-12 Curr. Biol.
1879-0445
22608513
10.1016/j.cub.2012.03.064
http://hdl.handle.net/10033/239931
Current biology : CB
Cell migration entails protrusion of lamellipodia, densely packed networks of actin filaments at the cell front. Filaments are generated by nucleation, likely mediated by Arp2/3 complex and its activator Scar/WAVE. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2, accumulates at lamellipodia and filopodia tips. FMNL2 is cotranslationally modified by myristoylation and regulated by interaction with the Rho-guanosine triphosphatase Cdc42. Abolition of myristoylation or Cdc42 binding interferes with proper FMNL2 activation, constituting an essential prerequisite for subcellular targeting. In vitro, C-terminal FMNL2 drives elongation rather than nucleation of actin filaments in the presence of profilin. In addition, filament ends generated by Arp2/3-mediated branching are captured and efficiently elongated by the formin. Consistent with these biochemical properties, RNAi-mediated silencing of FMNL2 expression decreases the rate of lamellipodia protrusion and, accordingly, the efficiency of cell migration. Our data establish that the FMNL subfamily member FMNL2 is a novel elongation factor of actin filaments that constitutes the first Cdc42 effector promoting cell migration and actin polymerization at the tips of lamellipodia.
en
Archived with thanks to Current biology : CB
FMNL2 drives actin-based protrusion and migration downstream of Cdc42.
Article
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
URL
https://hzi.openrepository.com/bitstream/10033/239931/1/Block%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/239931/2/Block%202012%20Supplement.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/239931/11/Block%202012%20Supplement.pdf.txt
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URL
https://hzi.openrepository.com/bitstream/10033/239931/12/Block%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/2416972019-08-30T11:25:43Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Meier, Karin
author
Mathieu, Eve-Lyne
author
Finkernagel, Florian
author
Reuter, L Maximilian
author
Scharfe, Maren
author
Doehlemann, Gunther
author
Jarek, Michael
author
Brehm, Alexander
department
Institut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, Marburg, Germany.
2012-09-06T11:17:24Z
2012-05
LINT, a novel dL(3)mbt-containing complex, represses malignant brain tumour signature genes. 2012, 8 (5):e1002676 PLoS Genet.
1553-7404
22570633
10.1371/journal.pgen.1002676
http://hdl.handle.net/10033/241697
PLoS genetics
Mutations in the l(3)mbt tumour suppressor result in overproliferation of Drosophila larval brains. Recently, the derepression of different gene classes in l(3)mbt mutants was shown to be causal for transformation. However, the molecular mechanisms of dL(3)mbt-mediated gene repression are not understood. Here, we identify LINT, the major dL(3)mbt complex of Drosophila. LINT has three core subunits-dL(3)mbt, dCoREST, and dLint-1-and is expressed in cell lines, embryos, and larval brain. Using genome-wide ChIP-Seq analysis, we show that dLint-1 binds close to the TSS of tumour-relevant target genes. Depletion of the LINT core subunits results in derepression of these genes. By contrast, histone deacetylase, histone methylase, and histone demethylase activities are not required to maintain repression. Our results support a direct role of LINT in the repression of brain tumour-relevant target genes by restricting promoter access.
en
Archived with thanks to PLoS genetics
LINT, a novel dL(3)mbt-containing complex, represses malignant brain tumour signature genes.
Article
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
URL
https://hzi.openrepository.com/bitstream/10033/241697/1/meier%20et%20al_final.pdf
File
MD5
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URL
https://hzi.openrepository.com/bitstream/10033/241697/8/meier%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/2451832019-08-30T11:28:24Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Mathieu, Eve-Lyne
author
Finkernagel, Florian
author
Murawska, Magdalena
author
Scharfe, Maren
author
Jarek, Michael
author
Brehm, Alexander
department
Institute for Molecular Biology and Tumor Research, Philipps-University, Emil-Mannkopff-Strasse 2, 35037 Marburg, Germany.
2012-09-20T09:47:18Z
2012-06
Recruitment of the ATP-dependent chromatin remodeler dMi-2 to the transcribed region of active heat shock genes. 2012, 40 (11):4879-91 Nucleic Acids Res.
1362-4962
22362736
10.1093/nar/gks178
http://hdl.handle.net/10033/245183
Nucleic acids research
The ATP-dependent chromatin remodeler dMi-2 can play both positive and negative roles in gene transcription. Recently, we have shown that dMi-2 is recruited to the hsp70 gene in a heat shock-dependent manner, and is required to achieve high transcript levels. Here, we use chromatin immunoprecipitation sequencing (ChIP-Seq) to identify other chromatin regions displaying increased dMi-2 binding upon heat shock and to characterize the distribution of dMi-2 over heat shock genes. We show that dMi-2 is recruited to the body of at least seven heat shock genes. Interestingly, dMi-2 binding extends several hundred base pairs beyond the polyadenylation site into the region where transcriptional termination occurs. We find that dMi-2 does not associate with the entire nucleosome-depleted hsp70 locus 87A. Rather, dMi-2 binding is restricted to transcribed regions. Our results suggest that dMi-2 distribution over active heat shock genes are determined by transcriptional activity.
en
Archived with thanks to Nucleic acids research
Recruitment of the ATP-dependent chromatin remodeler dMi-2 to the transcribed region of active heat shock genes.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/245183/1/mathieu%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/245183/8/mathieu%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/2493552019-08-30T11:27:16Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Nagel, Stefan
author
Ehrentraut, Stefan
author
Tomasch, Jürgen
author
Lienenklaus, Stefan
author
Schneider, Björn
author
Geffers, Robert
author
Meyer, Corinna
author
Kaufmann, Maren
author
Drexler, Hans G
author
MacLeod, Roderick A F
department
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. sna@dsmz.de
2012-10-18T11:18:19Z
2012
Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL). 2012, 7 (7):e40747 PLoS ONE
1932-6203
22848398
10.1371/journal.pone.0040747
http://hdl.handle.net/10033/249355
PloS one
Homeobox genes encode transcription factors impacting key developmental processes including embryogenesis, organogenesis, and cell differentiation. Reflecting their tight transcriptional control, homeobox genes are often embedded in large non-coding, cis-regulatory regions, containing tissue specific elements. In T-cell acute lymphoblastic leukemia (T-ALL) homeobox genes are frequently deregulated by chromosomal aberrations, notably translocations adding T-cell specific activatory elements. NKX3-1 is a prostate specific homeobox gene activated in T-ALL patients expressing oncogenic TAL1 or displaying immature T-cell characteristics. After investigating regulation of NKX3-1 in primary cells and cell lines, we report its ectopic expression in T-ALL cells independent of chromosomal rearrangements. Using siRNAs and expression profiling, we exploited NKX3-1 positive T-ALL cell lines as tools to investigate aberrant activatory mechanisms. Our data confirmed NKX3-1 activation by TAL1/GATA3/LMO and identified LYL1 as an alternative activator in immature T-ALL cells devoid of GATA3. Moreover, we showed that NKX3-1 is directly activated by early T-cell homeodomain factor MSX2. These activators were regulated by MLL and/or by IL7-, BMP4- and IGF2-signalling. Finally, we demonstrated homeobox gene SIX6 as a direct leukemic target of NKX3-1 in T-ALL. In conclusion, we identified three major mechanisms of NKX3-1 regulation in T-ALL cell lines which are represented by activators TAL1, LYL1 and MSX2, corresponding to particular T-ALL subtypes described in patients. These results may contribute to the understanding of leukemic transcriptional networks underlying disturbed T-cell differentiation in T-ALL.
en
Archived with thanks to PloS one
Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL).
Article
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https://hzi.openrepository.com/bitstream/10033/249355/1/nagel-ehrentraut%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2648942019-08-30T11:30:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Terrados, Gloria
author
Finkernagel, Florian
author
Stielow, Bastian
author
Sadic, Dennis
author
Neubert, Juliane
author
Herdt, Olga
author
Krause, Michael
author
Scharfe, Maren
author
Jarek, Michael
author
Suske, Guntram
department
Institute of Molecular Biology and Tumor Research, Philipps-University, Emil-Mannkopff-Str. 2, D-35032 Marburg, Germany.
2013-01-11T10:09:50Z
2012-09
Genome-wide localization and expression profiling establish Sp2 as a sequence-specific transcription factor regulating vitally important genes. 2012, 40 (16):7844-57 Nucleic Acids Res.
1362-4962
22684502
10.1093/nar/gks544
http://hdl.handle.net/10033/264894
Nucleic acids research
The transcription factor Sp2 is essential for early mouse development and for proliferation of mouse embryonic fibroblasts in culture. Yet its mechanisms of action and its target genes are largely unknown. In this study, we have combined RNA interference, in vitro DNA binding, chromatin immunoprecipitation sequencing and global gene-expression profiling to investigate the role of Sp2 for cellular functions, to define target sites and to identify genes regulated by Sp2. We show that Sp2 is important for cellular proliferation that it binds to GC-boxes and occupies proximal promoters of genes essential for vital cellular processes including gene expression, replication, metabolism and signalling. Moreover, we identified important key target genes and cellular pathways that are directly regulated by Sp2. Most significantly, Sp2 binds and activates numerous sequence-specific transcription factor and co-activator genes, and represses the whole battery of cholesterol synthesis genes. Our results establish Sp2 as a sequence-specific regulator of vitally important genes.
en
Archived with thanks to Nucleic acids research
Genome-wide localization and expression profiling establish Sp2 as a sequence-specific transcription factor regulating vitally important genes.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/264894/1/Terrados%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/2672722019-08-30T11:29:17Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Neumann, Olaf
author
Kesselmeier, Miriam
author
Geffers, Robert
author
Pellegrino, Rossella
author
Radlwimmer, Bernhard
author
Hoffmann, Katrin
author
Ehemann, Volker
author
Schemmer, Peter
author
Schirmacher, Peter
author
Lorenzo Bermejo, Justo
author
Longerich, Thomas
department
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
2013-01-28T10:30:15Z
2012-11
Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors. 2012, 56 (5):1817-27 Hepatology
1527-3350
22689435
10.1002/hep.25870
http://hdl.handle.net/10033/267272
Hepatology (Baltimore, Md.)
To identify new tumor-suppressor gene candidates relevant for human hepatocarcinogenesis, we performed genome-wide methylation profiling and vertical integration with array-based comparative genomic hybridization (aCGH), as well as expression data from a cohort of well-characterized human hepatocellular carcinomas (HCCs). Bisulfite-converted DNAs from 63 HCCs and 10 healthy control livers were analyzed for the methylation status of more than 14,000 genes. After defining the differentially methylated genes in HCCs, we integrated their DNA copy-number alterations as determined by aCGH data and correlated them with gene expression to identify genes potentially silenced by promoter hypermethylation. Aberrant methylation of candidates was further confirmed by pyrosequencing, and methylation dependency of silencing was determined by 5-aza-2'-deoxycytidine (5-aza-dC) treatment. Methylation profiling revealed 2,226 CpG sites that showed methylation differences between healthy control livers and HCCs. Of these, 537 CpG sites were hypermethylated in the tumor DNA, whereas 1,689 sites showed promoter hypomethylation. The hypermethylated set was enriched for genes known to be inactivated by the polycomb repressive complex 2, whereas the group of hypomethylated genes was enriched for imprinted genes. We identified three genes matching all of our selection criteria for a tumor-suppressor gene (period homolog 3 [PER3], insulin-like growth-factor-binding protein, acid labile subunit [IGFALS], and protein Z). PER3 was down-regulated in human HCCs, compared to peritumorous and healthy liver tissues. 5-aza-dC treatment restored PER3 expression in HCC cell lines, indicating that promoter hypermethylation was indeed responsible for gene silencing. Additionally, functional analysis supported a tumor-suppressive function for PER3 and IGFALS in vitro. CONCLUSION: The present study illustrates that vertical integration of methylation data with high-resolution genomic and transcriptomic data facilitates the identification of new tumor-suppressor gene candidates in human HCC.
en
Archived with thanks to Hepatology (Baltimore, Md.)
Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors.
Article
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oai:repository.helmholtz-hzi.de:10033/2678322019-08-30T11:29:17Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Habig, Christin
author
Geffers, Robert
author
Distl, Ottmar
department
Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover (Foundation), Hannover, Germany.
2013-01-31T12:14:47Z
2012
Differential gene expression from genome-wide microarray analyses distinguishes Lohmann Selected Leghorn and Lohmann Brown layers. 2012, 7 (10):e46787 PLoS ONE
1932-6203
23056453
10.1371/journal.pone.0046787
http://hdl.handle.net/10033/267832
PloS one
The Lohmann Selected Leghorn (LSL) and Lohmann Brown (LB) layer lines have been selected for high egg production since more than 50 years and belong to the worldwide leading commercial layer lines. The objectives of the present study were to characterize the molecular processes that are different among these two layer lines using whole genome RNA expression profiles. The hens were kept in the newly developed small group housing system Eurovent German with two different group sizes. Differential expression was observed for 6,276 microarray probes (FDR adjusted P-value <0.05) among the two layer lines LSL and LB. A 2-fold or greater change in gene expression was identified on 151 probe sets. In LSL, 72 of the 151 probe sets were up- and 79 of them were down-regulated. Gene ontology (GO) enrichment analysis accounting for biological processes evinced 18 GO-terms for the 72 probe sets with higher expression in LSL, especially those taking part in immune system processes and membrane organization. A total of 32 enriched GO-terms were determined among the 79 down-regulated probe sets of LSL. Particularly, these terms included phosphorus metabolic processes and signaling pathways. In conclusion, the phenotypic differences among the two layer lines LSL and LB are clearly reflected in their gene expression profiles of the cerebrum. These novel findings provide clues for genes involved in economically important line characteristics of commercial laying hens.
en
Archived with thanks to PloS one
Differential gene expression from genome-wide microarray analyses distinguishes Lohmann Selected Leghorn and Lohmann Brown layers.
Article
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oai:repository.helmholtz-hzi.de:10033/2703752019-08-30T11:34:22Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Hamisch, Domenica
author
Randewig, Dörte
author
Schliesky, Simon
author
Bräutigam, Andrea
author
Weber, Andreas P M
author
Geffers, Robert
author
Herschbach, Cornelia
author
Rennenberg, Heinz
author
Mendel, Ralf R
author
Hänsch, Robert
department
Institut für Pflanzenbiologie, Technische Universität Braunschweig, Braunschweig, Germany.
2013-02-25T14:46:34Z
2012-12
Impact of SO(2) on Arabidopsis thaliana transcriptome in wildtype and sulfite oxidase knockout plants analyzed by RNA deep sequencing. 2012, 196 (4):1074-85 New Phytol.
1469-8137
23025405
10.1111/j.1469-8137.2012.04331.x
http://hdl.handle.net/10033/270375
The New phytologist
High concentrations of sulfur dioxide (SO(2) ) as an air pollutant, and its derivative sulfite, cause abiotic stress that can lead to cell death. It is currently unknown to what extent plant fumigation triggers specific transcriptional responses. To address this question, and to test the hypothesis that sulfite oxidase (SO) is acting in SO(2) detoxification, we compared Arabidopsis wildtype (WT) and SO knockout lines (SO-KO) facing the impact of 600 nl l(-1) SO(2) , using RNAseq to quantify absolute transcript abundances. These transcriptome data were correlated to sulfur metabolism-related enzyme activities and metabolites obtained from identical samples in a previous study. SO-KO plants exhibited remarkable and broad regulative responses at the mRNA level, especially in transcripts related to sulfur metabolism enzymes, but also in those related to stress response and senescence. Focusing on SO regulation, no alterations were detectable in the WT, whereas in SO-KO plants we found up-regulation of two splice variants of the SO gene, although this gene is not functional in this line. Our data provide evidence for the highly specific coregulation between SO and sulfur-related enzymes like APS reductase, and suggest two novel candidates for involvement in SO(2) detoxification: an apoplastic peroxidase, and defensins as putative cysteine mass storages.
en
Archived with thanks to The New phytologist
Impact of SO(2) on Arabidopsis thaliana transcriptome in wildtype and sulfite oxidase knockout plants analyzed by RNA deep sequencing.
Article
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oai:repository.helmholtz-hzi.de:10033/2713042019-08-30T11:31:23Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Ehrentraut, Stefan
author
Nagel, Stefan
author
Scherr, Michaela E
author
Schneider, Björn
author
Quentmeier, Hilmar
author
Geffers, Robert
author
Kaufmann, Maren
author
Meyer, Corinna
author
Prochorec-Sobieszek, Monika
author
Ketterling, Rhett P
author
Knudson, Ryan A
author
Feldman, Andrew L
author
Kadin, Marshall E
author
Drexler, Hans G
author
Macleod, Roderick A F
department
Leibniz Institute, DSMZ - German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
2013-03-06T13:57:14Z
2013
t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5. 2013, 8 (1):e53767 PLoS ONE
1932-6203
23372669
10.1371/journal.pone.0053767
http://hdl.handle.net/10033/271304
PloS one
Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2-translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.
en
Archived with thanks to PloS one
t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/271304/1/Ehrentraut%20et%20al_final.pdf
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MD5
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https://hzi.openrepository.com/bitstream/10033/271304/8/Ehrentraut%20et%20al_final.pdf.txt
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Ehrentraut et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/2743182019-08-30T11:29:17Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Kindler, Eveline
author
Jónsdóttir, Hulda R
author
Muth, Doreen
author
Hamming, Ole J
author
Hartmann, Rune
author
Rodriguez, Regulo
author
Geffers, Robert
author
Fouchier, Ron A M
author
Drosten, Christian
author
Müller, Marcel A
author
Dijkman, Ronald
author
Thiel, Volker
department
Institute of Immunobiology, Kantonal Hospital, St. Gallen, Switzerland.
2013-03-20T14:02:56Z
2013
Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential. 2013, 4 (1): MBio
2150-7511
23422412
10.1128/mBio.00611-12
http://hdl.handle.net/10033/274318
mBio
ABSTRACT The recent emergence of a novel human coronavirus (HCoV-EMC) in the Middle East raised considerable concerns, as it is associated with severe acute pneumonia, renal failure, and fatal outcome and thus resembles the clinical presentation of severe acute respiratory syndrome (SARS) observed in 2002 and 2003. Like SARS-CoV, HCoV-EMC is of zoonotic origin and closely related to bat coronaviruses. The human airway epithelium (HAE) represents the entry point and primary target tissue for respiratory viruses and is highly relevant for assessing the zoonotic potential of emerging respiratory viruses, such as HCoV-EMC. Here, we show that pseudostratified HAE cultures derived from different donors are highly permissive to HCoV-EMC infection, and by using reverse transcription (RT)-PCR and RNAseq data, we experimentally determined the identity of seven HCoV-EMC subgenomic mRNAs. Although the HAE cells were readily responsive to type I and type III interferon (IFN), we observed neither a pronounced inflammatory cytokine nor any detectable IFN responses following HCoV-EMC, SARS-CoV, or HCoV-229E infection, suggesting that innate immune evasion mechanisms and putative IFN antagonists of HCoV-EMC are operational in the new host. Importantly, however, we demonstrate that both type I and type III IFN can efficiently reduce HCoV-EMC replication in HAE cultures, providing a possible treatment option in cases of suspected HCoV-EMC infection. IMPORTANCE A novel human coronavirus, HCoV-EMC, has recently been described to be associated with severe respiratory tract infection and fatalities, similar to severe acute respiratory syndrome (SARS) observed during the 2002-2003 epidemic. Closely related coronaviruses replicate in bats, suggesting that, like SARS-CoV, HCoV-EMC is of zoonotic origin. Since the animal reservoir and circumstances of zoonotic transmission are yet elusive, it is critically important to assess potential species barriers of HCoV-EMC infection. An important first barrier against invading respiratory pathogens is the epithelium, representing the entry point and primary target tissue of respiratory viruses. We show that human bronchial epithelia are highly susceptible to HCoV-EMC infection. Furthermore, HCoV-EMC, like other coronaviruses, evades innate immune recognition, reflected by the lack of interferon and minimal inflammatory cytokine expression following infection. Importantly, type I and type III interferon treatment can efficiently reduce HCoV-EMC replication in the human airway epithelium, providing a possible avenue for treatment of emerging virus infections.
en
Archived with thanks to mBio
Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/274318/1/Kindler%20et%20al_final.pdf
File
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https://hzi.openrepository.com/bitstream/10033/274318/8/Kindler%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/2884072019-08-30T11:30:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Sundarasetty, Bala Sai
author
Singh, Vijay Kumar
author
Salguero, Gustavo
author
Geffers, Robert
author
Rickmann, Mareike
author
Macke, Laura
author
Borchers, Sylvia
author
Figueiredo, Constanca
author
Schambach, Axel
author
Gullberg, Urban
author
Provasi, Elena
author
Bonini, Chiara
author
Ganser, Arnold
author
Woelfel, Thomas
author
Stripecke, Renata
department
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
2013-05-02T11:03:32Z
2013-02
Lentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia. 2013, 24 (2):220-37 Hum. Gene Ther.
1557-7422
23311414
10.1089/hum.2012.128
http://hdl.handle.net/10033/288407
Human gene therapy
Wilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4) was used to transduce human monocytes ex vivo. Overnight transduction induced self-differentiation of monocytes into immunophenotypically stable "SmartDC/tWT1" (GM-CSF(+), IL-4(+), tWT1(+), IL-6(+), IL-8(+), TNF-α(+), MCP-1(+), HLA-DR(+), CD86(+), CCR2(+), CCR5(+)) that were viable for 3 weeks in vitro. SmartDC/tWT1 were produced with peripheral blood mononuclear cells (PBMC) obtained from an FLT3-ITD(+) AML patient and surplus material from a donor lymphocyte infusion (DLI) and used to expand CD8(+) T cells in vitro. Expanded cytotoxic T lymphocytes (CTLs) showed antigen-specific reactivity against WT1 and against WT1(+) leukemia cells. SmartDC/tWT1 injected s.c. into Nod.Rag1(-/-).IL2rγc(-/-) mice were viable in vivo for more than three weeks. Migration of human T cells (huCTLs) to the immunization site was demonstrated following adoptive transfer of huCTLs into mice immunized with SmartDC/tWT1. Furthermore, SmartDC/tWT1 immunization plus adoptive transfer of T cells reactive against WT1 into mice resulted in growth arrest of a WT1(+) tumor. Gene array analyses of SmartDC/tWT1 demonstrated upregulation of several genes related to innate immunity. Thus, SmartDC/tWT1 can be produced in a single day of ex vivo gene transfer, are highly viable in vivo, and have great potential for use as immunotherapy against malignant transformation overexpressing WT1.
en
Archived with thanks to Human gene therapy
Lentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/288407/1/Sundarasetty%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2989022019-08-30T11:33:57Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Bhuju, Sabin
author
Fonseca, Leila de Souza
author
Marsico, Anna Grazia
author
de Oliveira Vieira, Gisele Betzler
author
Sobral, Luciana Fonseca
author
Stehr, Matthias
author
Singh, Mahavir
author
Saad, Maria Helena Féres
department
Department of Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2013-08-15T13:28:21Z
2013-06-14
Mycobacterium tuberculosis isolates from Rio de Janeiro reveal unusually low correlation between pyrazinamide resistance and mutations in the pncA gene. 2013, 19C:1-6 Infect. Genet. Evol.
1567-7257
23770140
10.1016/j.meegid.2013.06.008
http://hdl.handle.net/10033/298902
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
It has been widely accepted, that pyrazinamide (PZA) resistance in Mycobacterium tuberculosis is correlated with mutations in the pncA gene. But since years researchers have been puzzled by the fact that up to 30% of PZA resistant strains do not show any correlation between PZA resistance and mutations in the pncA gene, and thus may vary with geographic area. The objective of the study was to investigate the correlation between PZA susceptibility and mutations in pncA gene in M. tuberculosis isolates from individuals living in a highly endemic area. Therefore we analyzed drug resistant and multidrug resistant (MDR) isolates from patients in Rio de Janeiro, Brazil. From a total of 97 clinical isolates of M. tuberculosis 35 were identified as PZA resistant, 24/35 strains did not show PZase activity and 15/24 (62.5%) strains possess mutation in the pncA gene. This is a low correlation between PZA resistance and PZase activity (68.6%) and even lower correlation between PZA resistance and the presence of mutation in pncA gene (45.7%). Most of the mutations found were conserved near the active site or metal binding site of PZase. The 146A>C mutation was found both in PZA resistant and susceptible isolates, suggesting that this mutation may not fully associated with PZA resistance. Of the mutations found, three have not been previously described. The insertions 192-193 TCCTCGTC and 388-389 AGGTCGATG, although found before, here was found to be a short tandem repeat and in one strain, insertion of the IS6110 was observed 55nt upstream of the gene. All PZA resistant isolates had no mutation in the gene coding ribosomal protein S1 (rpsA), which has recently been proposed as alternate target for pyrazinoic acid (POA). The results show a low association of PZA resistance and pncA gene mutations in a selected patient group from an highly endemic area. Our findings point out that the phenotypic susceptibility testing remains important for the detection of PZA-resistant M. tuberculosis.
Archived with thanks to Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
Mycobacterium tuberculosis isolates from Rio de Janeiro reveal unusually low correlation between pyrazinamide resistance and mutations in the pncA gene.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/298902/1/Bhuju%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2995072019-08-30T11:27:16Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Günther, Katharina
author
Rust, Mareike
author
Leers, Joerg
author
Boettger, Thomas
author
Scharfe, Maren
author
Jarek, Michael
author
Bartkuhn, Marek
author
Renkawitz, Rainer
department
Institute for Genetics, Justus-Liebig-University, D35392 Giessen, Germany.
2013-08-22T14:30:57Z
2013-03-01
Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. 2013, 41 (5):3010-21 Nucleic Acids Res.
1362-4962
23361464
10.1093/nar/gkt035
http://hdl.handle.net/10033/299507
Nucleic acids research
The heterogeneous collection of nucleosome remodelling and deacetylation (NuRD) complexes can be grouped into the MBD2- or MBD3-containing complexes MBD2-NuRD and MBD3-NuRD. MBD2 is known to bind to methylated CpG sequences in vitro in contrast to MBD3. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here, we show that MBD2-NuRD, in contrast to MBD3-NuRD, converts open chromatin with euchromatic histone modifications into tightly compacted chromatin with repressive histone marks. Genome-wide, a strong enrichment for MBD2 at methylated CpG sequences is found, whereas CpGs bound by MBD3 are devoid of methylation. MBD2-bound genes are generally lower expressed as compared with MBD3-bound genes. When depleting cells for MBD2, the MBD2-bound genes increase their activity, whereas MBD2 plus MBD3-bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes.
en
Archived with thanks to Nucleic acids research
Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences.
Article
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https://hzi.openrepository.com/bitstream/10033/299507/1/G%c3%bcnther%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/299507/8/G%c3%bcnther%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3034622019-08-30T11:30:58Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Buitrago-Molina, Laura Elisa
author
Marhenke, Silke
author
Longerich, Thomas
author
Sharma, Amar Deep
author
Boukouris, Aristeidis E
author
Geffers, Robert
author
Guigas, Bruno
author
Manns, Michael P
author
Vogel, Arndt
department
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
2013-10-15T12:55:57Z
2013-09
The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice. 2013, 58 (3):1143-52 Hepatology
1527-3350
23526443
10.1002/hep.26412
http://hdl.handle.net/10033/303462
Hepatology (Baltimore, Md.)
Hepatocellular carcinoma (HCC) frequently arises in the context of chronic injury that promotes DNA damage and chromosomal aberrations. The cyclin-dependent kinase inhibitor p21 is an important transcriptional target of several tumor suppressors, which promotes cell cycle arrest in response to many stimuli. The aim of this study was to further delineate the role of p21 in the liver during moderate and severe injury and to specify its role in the initiation and progression of HCC. Deletion of p21 led to continuous hepatocyte proliferation in mice with severe injury allowing animal survival but also facilitated rapid tumor development, suggesting that control of compensatory proliferation by high levels of p21 is critical to the prevention of tumor development. Unexpectedly, however, liver regeneration and hepatocarcinogenesis was impaired in p21-deficient mice with moderate injury. Mechanistically, loss of p21 was compensated by activation of Sestrin2, which impaired mitogenic mammalian target of rapamycin (mTOR) signaling and activated cytoprotective Nrf2 signaling. Conclusion: The degree of liver injury and the strength of p21 activation determine its effects on liver regeneration and tumor development in the liver. Moreover, our data uncover a molecular link in the complex mTOR, Nrf2, and p53/p21-signaling network through activation of Sestrin2, which regulates hepatocyte proliferation and tumor development in mice with liver injury. (Hepatology 2013;53:1143-1152).
en
Archived with thanks to Hepatology (Baltimore, Md.)
The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice.
Article
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https://hzi.openrepository.com/bitstream/10033/303462/1/Buitrago-Molina%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/303462/2/Supplementary%20Materials%20and%20Methods.pdf
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https://hzi.openrepository.com/bitstream/10033/303462/22/Supplementary%20Materials%20and%20Methods.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3046762019-08-30T11:34:18Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Hasemeier, Britta
author
Geffers, Robert
author
Bartels, Stephan
author
Schlegelberger, Brigitte
author
Kreipe, Hans
author
Lehmann, Ulrich
department
Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany
2013-10-29T09:29:35Z
2013-09
Archival bone marrow trephines are suitable for high-throughput mutation analysis using next generation sequencing technology. 2013, 98 (9):e115-6 Haematologica
1592-8721
24006411
10.3324/haematol.2013.091652
http://hdl.handle.net/10033/304676
Haematologica
en
Archived with thanks to Haematologica
Archival bone marrow trephines are suitable for high-throughput mutation analysis using next generation sequencing technology.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/304676/1/Hasemeier%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/304676/12/Hasemeier_suppl.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3058762019-08-30T11:30:58Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Schlereth, Katharina
author
Heyl, Charlotte
author
Krampitz, Anna-Maria
author
Mernberger, Marco
author
Finkernagel, Florian
author
Scharfe, Maren
author
Jarek, Michael
author
Leich, Ellen
author
Rosenwald, Andreas
author
Stiewe, Thorsten
department
Molecular Oncology, Philipps-University, Marburg, Germany.
2013-11-28T10:27:54Z
2013-08
Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions. 2013, 9 (8):e1003726 PLoS Genet.
1553-7404
23966881
10.1371/journal.pgen.1003726
http://hdl.handle.net/10033/305876
PLoS genetics
p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context- and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensively profile the cistrome of p53 mutants with reduced or increased cooperativity. The analysis highlighted a particular relevance of cooperativity for extending the p53 cistrome to non-canonical binding sequences characterized by deletions, spacer insertions and base mismatches. Furthermore, it revealed a striking functional separation of the cistrome on the basis of cooperativity; with low cooperativity genes being significantly enriched for cell cycle and high cooperativity genes for apoptotic functions. Importantly, expression of high but not low cooperativity genes was correlated with superior survival in breast cancer patients. Interestingly, in contrast to most p53-activated genes, p53-repressed genes did not commonly contain p53 binding elements. Nevertheless, both the degree of gene activation and repression were cooperativity-dependent, suggesting that p53-mediated gene repression is largely indirect and mediated by cooperativity-dependently transactivated gene products such as CDKN1A, E2F7 and non-coding RNAs. Since both activation of apoptosis genes with non-canonical response elements and repression of pro-survival genes are crucial for p53's apoptotic activity, the cistrome analysis comprehensively explains why p53-induced apoptosis, but not cell cycle arrest, strongly depends on the intermolecular cooperation of p53 molecules as a possible safeguard mechanism protecting from accidental cell killing.
en
Archived with thanks to PLoS genetics
Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/305876/1/schlereth%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3062712019-08-30T11:25:43Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Kaput, Jim
author
Cotton, Richard G H
author
Hardman, Lauren
author
Watson, Michael
author
Al Aqeel, Aida I
author
Al-Aama, Jumana Y
author
Al-Mulla, Fahd
author
Alonso, Santos
author
Aretz, Stefan
author
Auerbach, Arleen D
author
Bapat, Bharati
author
Bernstein, Inge T
author
Bhak, Jong
author
Bleoo, Stacey L
author
Blöcker, Helmut
author
Brenner, Steven E
author
Burn, John
author
Bustamante, Mariona
author
Calzone, Rita
author
Cambon-Thomsen, Anne
author
Cargill, Michele
author
Carrera, Paola
author
Cavedon, Lawrence
author
Cho, Yoon Shin
author
Chung, Yeun-Jun
author
Claustres, Mireille
author
Cutting, Garry
author
Dalgleish, Raymond
author
den Dunnen, Johan T
author
Díaz, Carlos
author
Dobrowolski, Steven
author
dos Santos, M Rosário N
author
Ekong, Rosemary
author
Flanagan, Simon B
author
Flicek, Paul
author
Furukawa, Yoichi
author
Genuardi, Maurizio
author
Ghang, Ho
author
Golubenko, Maria V
author
Greenblatt, Marc S
author
Hamosh, Ada
author
Hancock, John M
author
Hardison, Ross
author
Harrison, Terence M
author
Hoffmann, Robert
author
Horaitis, Rania
author
Howard, Heather J
author
Barash, Carol Isaacson
author
Izagirre, Neskuts
author
Jung, Jongsun
author
Kojima, Toshio
author
Laradi, Sandrine
author
Lee, Yeon-Su
author
Lee, Jong-Young
author
Gil-da-Silva-Lopes, Vera L
author
Macrae, Finlay A
author
Maglott, Donna
author
Marafie, Makia J
author
Marsh, Steven G E
author
Matsubara, Yoichi
author
Messiaen, Ludwine M
author
Möslein, Gabriela
author
Netea, Mihai G
author
Norton, Melissa L
author
Oefner, Peter J
author
Oetting, William S
author
O'Leary, James C
author
de Ramirez, Ana Maria Oller
author
Paalman, Mark H
author
Parboosingh, Jillian
author
Patrinos, George P
author
Perozzi, Giuditta
author
Phillips, Ian R
author
Povey, Sue
author
Prasad, Suyash
author
Qi, Ming
author
Quin, David J
author
Ramesar, Rajkumar S
author
Richards, C Sue
author
Savige, Judith
author
Scheible, Dagmar G
author
Scott, Rodney J
author
Seminara, Daniela
author
Shephard, Elizabeth A
author
Sijmons, Rolf H
author
Smith, Timothy D
author
Sobrido, María-Jesús
author
Tanaka, Toshihiro
author
Tavtigian, Sean V
author
Taylor, Graham R
author
Teague, Jon
author
Töpel, Thoralf
author
Ullman-Cullere, Mollie
author
Utsunomiya, Joji
author
van Kranen, Henk J
author
Vihinen, Mauno
author
Webb, Elizabeth
author
Weber, Thomas K
author
Yeager, Meredith
author
Yeom, Young I
author
Yim, Seon-Hee
author
Yoo, Hyang-Sook
department
Division of Personalised Nutrition and Medicine, FDA/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. James.kaput@fda.hhs.gov
2013-12-04T13:55:25Z
2009-04
Planning the human variome project: the Spain report. 2009, 30 (4):496-510 Hum. Mutat.
1098-1004
19306394
10.1002/humu.20972
http://hdl.handle.net/10033/306271
Human mutation
The remarkable progress in characterizing the human genome sequence, exemplified by the Human Genome Project and the HapMap Consortium, has led to the perception that knowledge and the tools (e.g., microarrays) are sufficient for many if not most biomedical research efforts. A large amount of data from diverse studies proves this perception inaccurate at best, and at worst, an impediment for further efforts to characterize the variation in the human genome. Because variation in genotype and environment are the fundamental basis to understand phenotypic variability and heritability at the population level, identifying the range of human genetic variation is crucial to the development of personalized nutrition and medicine. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) was proposed initially to systematically collect mutations that cause human disease and create a cyber infrastructure to link locus specific databases (LSDB). We report here the discussions and recommendations from the 2008 HVP planning meeting held in San Feliu de Guixols, Spain, in May 2008.
en
Archived with thanks to Human mutation
Planning the human variome project: the Spain report.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/306271/1/Kaput%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/306271/8/Kaput%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3066562019-08-30T11:31:49Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Adhikary, T
author
Brandt, D T
author
Kaddatz, K
author
Stockert, J
author
Naruhn, S
author
Meissner, W
author
Finkernagel, F
author
Obert, J
author
Lieber, S
author
Scharfe, M
author
Jarek, M
author
Toth, P M
author
Scheer, F
author
Diederich, W E
author
Reinartz, S
author
Grosse, R
author
Müller-Brüsselbach, S
author
Müller, R
department
Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
2013-12-10T13:01:17Z
2013-10-31
Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion. 2013, 32 (44):5241-52 Oncogene
1476-5594
23208498
10.1038/onc.2012.549
http://hdl.handle.net/10033/306656
Oncogene
Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARβ/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARβ/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor β (TGFβ)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARβ/δ target in MDA-MB-231 cells, previously implicated in TGFβ-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFβ and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARβ/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands' ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARβ/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARβ/δ-ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARβ/δ agonists is feasible.
en
Archived with thanks to Oncogene
Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/3109752019-08-30T11:25:11Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Stielow, Christina
author
Stielow, Bastian
author
Finkernagel, Florian
author
Scharfe, Maren
author
Jarek, Michael
author
Suske, Guntram
2014-01-07T09:44:26Z
2013-12-24
SUMOylation of the polycomb group protein L3MBTL2 facilitates repression of its target genes. 2013: Nucleic Acids Res.
1362-4962
24369422
10.1093/nar/gkt1317
http://hdl.handle.net/10033/310975
Nucleic acids research
Lethal(3) malignant brain tumour like 2 (L3MBTL2) is an integral component of the polycomb repressive complex 1.6 (PRC1.6) and has been implicated in transcriptional repression and chromatin compaction. Here, we show that L3MBTL2 is modified by SUMO2/3 at lysine residues 675 and 700 close to the C-terminus. SUMOylation of L3MBTL2 neither affected its repressive activity in reporter gene assays nor it's binding to histone tails in vitro. In order to analyse whether SUMOylation affects binding of L3MBTL2 to chromatin, we performed ChIP-Seq analysis with chromatin of wild-type HEK293 cells and with chromatin of HEK293 cells stably expressing either FLAG-tagged SUMOylation-competent or SUMOylation-defective L3MBTL2. Wild-type FLAG-L3MBTL2 and the SUMOylation-defective FLAG-L3MBTL2 K675/700R mutant essentially occupied the same sites as endogenous L3MBTL2 suggesting that SUMOylation of L3MBTL2 does not affect chromatin binding. However, a subset of L3MBTL2-target genes, particularly those with low L3MBTL2 occupancy including pro-inflammatory genes, was de-repressed in cells expressing the FLAG-L3MBTL2 K675/700R mutant. Finally, we provide evidence that SUMOylation of L3MBTL2 facilitates repression of these PRC1.6-target genes by balancing the local H2Aub1 levels established by the ubiquitinating enzyme RING2 and the de-ubiquitinating PR-DUB complex.
Archived with thanks to Nucleic acids research
SUMOylation of the polycomb group protein L3MBTL2 facilitates repression of its target genes.
Article
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https://hzi.openrepository.com/bitstream/10033/310975/1/Stielow%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3110232019-08-30T11:25:43Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Strempel, Nikola
author
Neidig, Anke
author
Nusser, Michael
author
Geffers, Robert
author
Vieillard, Julien
author
Lesouhaitier, Olivier
author
Brenner-Weiss, Gerald
author
Overhage, Joerg
department
Research group genomeanalytics, Helmholtz Centre for infection research, Braunschweig, Germany
2014-01-07T14:31:24Z
2013
Human Host Defense Peptide LL-37 Stimulates Virulence Factor Production and Adaptive Resistance in Pseudomonas aeruginosa. 2013, 8 (12):e82240 PLoS ONE
1932-6203
24349231
10.1371/journal.pone.0082240
http://hdl.handle.net/10033/311023
PloS one
A multitude of different virulence factors as well as the ability to rapidly adapt to adverse environmental conditions are important features for the high pathogenicity of Pseudomonas aeruginosa. Both virulence and adaptive resistance are tightly controlled by a complex regulatory network and respond to external stimuli, such as host signals or antibiotic stress, in a highly specific manner. Here, we demonstrate that physiological concentrations of the human host defense peptide LL-37 promote virulence factor production as well as an adaptive resistance against fluoroquinolone and aminoglycoside antibiotics in P. aeruginosa PAO1. Microarray analyses of P. aeruginosa cells exposed to LL-37 revealed an upregulation of gene clusters involved in the production of quorum sensing molecules and secreted virulence factors (PQS, phenazine, hydrogen cyanide (HCN), elastase and rhamnolipids) and in lipopolysaccharide (LPS) modification as well as an induction of genes encoding multidrug efflux pumps MexCD-OprJ and MexGHI-OpmD. Accordingly, we detected significantly elevated levels of toxic metabolites and proteases in bacterial supernatants after LL-37 treatment. Pre-incubation of bacteria with LL-37 for 2 h led to a decreased susceptibility towards gentamicin and ciprofloxacin. Quantitative Realtime PCR results using a PAO1-pqsE mutant strain present evidence that the quinolone response protein and virulence regulator PqsE may be implicated in the regulation of the observed phenotype in response to LL-37. Further experiments with synthetic cationic antimicrobial peptides IDR-1018, 1037 and HHC-36 showed no induction of pqsE expression, suggesting a new role of PqsE as highly specific host stress sensor.
en
Archived with thanks to PloS one
Human Host Defense Peptide LL-37 Stimulates Virulence Factor Production and Adaptive Resistance in Pseudomonas aeruginosa.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/311023/1/Strempel%20et%20al_final.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/311023/8/Strempel%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3113322019-08-30T11:27:16Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Hämmerle, Monika
author
Gutschner, Tony
author
Uckelmann, Hannah
author
Ozgur, Sevim
author
Fiskin, Evgenij
author
Gross, Matthias
author
Skawran, Britta
author
Geffers, Robert
author
Longerich, Thomas
author
Breuhahn, Kai
author
Schirmacher, Peter
author
Stoecklin, Georg
author
Diederichs, Sven
department
AG Genomanalytic, Hemholtz Centre for Infection research, D38124 Braunschweig, Germany
2014-01-15T09:37:35Z
2013-05-31
Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1). 2013: Hepatology
1527-3350
23728852
10.1002/hep.26537
http://hdl.handle.net/10033/311332
Hepatology (Baltimore, Md.)
Selected long noncoding RNAs (lncRNAs) have been shown to play important roles in carcinogenesis. Although the cellular functions of these transcripts can be diverse, many lncRNAs regulate gene expression. In contrast, factors that control the expression of lncRNAs remain largely unknown. Here we investigated the impact of RNA binding proteins on the expression of the liver cancer-associated lncRNA HULC (highly up-regulated in liver cancer). First, we validated the strong up-regulation of HULC in human hepatocellular carcinoma. To elucidate posttranscriptional regulatory mechanisms governing HULC expression, we applied an RNA affinity purification approach to identify specific protein interaction partners and potential regulators. This method identified the family of IGF2BPs (IGF2 mRNA-binding proteins) as specific binding partners of HULC. Depletion of IGF2BP1, also known as IMP1, but not of IGF2BP2 or IGF2BP3, led to an increased HULC half-life and higher steady-state expression levels, indicating a posttranscriptional regulatory mechanism. Importantly, HULC represents the first IGF2BP substrate that is destabilized. To elucidate the mechanism by which IGF2BP1 destabilizes HULC, the CNOT1 protein was identified as a novel interaction partner of IGF2BP1. CNOT1 is the scaffold of the human CCR4-NOT deadenylase complex, a major component of the cytoplasmic RNA decay machinery. Indeed, depletion of CNOT1 increased HULC half-life and expression. Thus, IGF2BP1 acts as an adaptor protein that recruits the CCR4-NOT complex and thereby initiates the degradation of the lncRNA HULC. Conclusion: Our findings provide important insights into the regulation of lncRNA expression and identify a novel function for IGF2BP1 in RNA metabolism. (Hepatology 2013).
Archived with thanks to Hepatology (Baltimore, Md.)
Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1).
Article
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URL
https://hzi.openrepository.com/bitstream/10033/311332/1/H%c3%a4mmerle%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/311332/8/H%c3%a4mmerle%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3172372019-08-30T11:25:43Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Weiterer, Sebastian
author
Uhle, Florian
author
Bhuju, Sabin
author
Jarek, Michael
author
Weigand, Markus A
author
Bartkuhn, Marek
2014-05-21T13:00:03Z
2014
From Human Monocytes to Genome-Wide Binding Sites - A Protocol for Small Amounts of Blood: Monocyte Isolation/ChIP-Protocol/Library Amplification/Genome Wide Computational Data Analysis. 2014, 9 (4):e94164 PLoS ONE
1932-6203
24732314
10.1371/journal.pone.0094164
http://hdl.handle.net/10033/317237
PloS one
Chromatin immunoprecipitation in combination with a genome-wide analysis via high-throughput sequencing is the state of the art method to gain genome-wide representation of histone modification or transcription factor binding profiles. However, chromatin immunoprecipitation analysis in the context of human experimental samples is limited, especially in the case of blood cells. The typically extremely low yields of precipitated DNA are usually not compatible with library amplification for next generation sequencing. We developed a highly reproducible protocol to present a guideline from the first step of isolating monocytes from a blood sample to analyse the distribution of histone modifications in a genome-wide manner. Conclusion: The protocol describes the whole work flow from isolating monocytes from human blood samples followed by a high-sensitivity and small-scale chromatin immunoprecipitation assay with guidance for generating libraries compatible with next generation sequencing from small amounts of immunoprecipitated DNA.
en
Archived with thanks to PloS one
From Human Monocytes to Genome-Wide Binding Sites - A Protocol for Small Amounts of Blood: Monocyte Isolation/ChIP-Protocol/Library Amplification/Genome Wide Computational Data Analysis.
Article
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
URL
https://hzi.openrepository.com/bitstream/10033/317237/1/Weiterer%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3219712019-08-30T11:36:33Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Habig, Christin
author
Geffers, Robert
author
Distl, Ottmar
2014-06-19T12:37:46Z
2014
A replication study for genome-wide gene expression levels in two layer lines elucidates differentially expressed genes of pathways involved in bone remodeling and immune responsiveness. 2014, 9 (6):e98350 PLoS ONE
1932-6203
24922511
10.1371/journal.pone.0098350
http://hdl.handle.net/10033/321971
PloS one
The current replication study confirmed significant differences in gene expression profiles of the cerebrum among the two commercial layer lines Lohmann Selected Leghorn (LSL) and Lohmann Brown (LB). Microarray analyses were performed for 30 LSL and another 30 LB laying hens kept in the small group housing system Eurovent German. A total of 14,103 microarray probe sets using customized Affymetrix ChiGene-1_0-st Arrays with 20,399 probe sets were differentially expressed among the two layer lines LSL and LB (FDR adjusted P-value <0.05). An at least 2-fold change in expression levels could be observed for 388 of these probe sets. In LSL, 214 of the 388 probe sets were down- and 174 were up-regulated and vice versa for the LB layer line. Among the 174 up-regulated probe sets in LSL, we identified 51 significantly enriched Gene ontology (GO) terms of the biological process category. A total of 63 enriched GO-terms could be identified for the 214 down-regulated probe sets of the layer line LSL. We identified nine genes significantly differentially expressed between the two layer lines in both microarray experiments. These genes play a crucial role in protection of neuronal cells from oxidative stress, bone mineral density and immune response among the two layer lines LSL and LB. Thus, the different regulation of these genes may significantly contribute to phenotypic trait differences among these layer lines. In conclusion, these novel findings provide a basis for further research to improve animal welfare in laying hens and these layer lines may be of general interest as an animal model.
en
Archived with thanks to PloS one
A replication study for genome-wide gene expression levels in two layer lines elucidates differentially expressed genes of pathways involved in bone remodeling and immune responsiveness.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/321971/1/Habig%20et%20al_final.pdf
File
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URL
https://hzi.openrepository.com/bitstream/10033/321971/8/Habig%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3219732019-08-30T11:32:17Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Yun, Haiyang
author
Damm, Frederik
author
Yap, Damian
author
Schwarzer, Adrian
author
Chaturvedi, Anuhar
author
Jyotsana, Nidhi
author
Lübbert, Michael
author
Bullinger, Lars
author
Döhner, Konstanze
author
Geffers, Robert
author
Aparicio, Samuel
author
Humphries, R Keith
author
Ganser, Arnold
author
Heuser, Michael
2014-06-19T13:59:17Z
2014-06-03
Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia. 2014: Haematologica
1592-8721
24895338
10.3324/haematol.2013.101386
http://hdl.handle.net/10033/321973
Haematologica
Hypomethylating agents are widely used in patients with myelodysplastic syndromes and unfit patients with acute myeloid leukemia. However, it is not well understood why only some patients respond to hypomethylating agents. We found previously that the effect of decitabine on hematopoietic stem cell viability differed between Mll5 wildtype and null cells. We therefore investigated the role of MLL5 expression levels on outcome of acute myeloid leukemia patients who were treated with decitabine. MLL5 above the median expression level predicted longer overall survival independent of DNMT3A mutation status in bivariate analysis (median overall survival for high vs. low MLL5 expression, 292 vs. 167 days, P=.026). In patients who received 3 or more courses decitabine, high MLL5 expression and wildtype DNMT3A independently predicted improved overall survival (median overall survival for high vs. low MLL5 expression, 468 vs. 243 days, P=.012). In transformed murine cells, loss of Mll5 was associated with resistance to low-dose decitabine, less global DNA methylation in promoter regions, and reduced DNA demethylation upon decitabine treatment. Together, these data support our clinical observation of improved outcome in decitabine treated patients who express MLL5 at high levels, and suggest a mechanistic role of MLL5 in the regulation of DNA methylation.
Archived with thanks to Haematologica
Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/321973/1/Yun%20et%20al_final.pdf
File
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URL
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oai:repository.helmholtz-hzi.de:10033/3235142019-08-30T11:32:16Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Petersen, Jörn
author
Ludewig, Ann-Kathrin
author
Michael, Victoria
author
Bunk, Boyke
author
Jarek, Michael
author
Baurain, Denis
author
Brinkmann, Henner
2014-07-21T12:43:48Z
2014-03
Chromera velia, endosymbioses and the rhodoplex hypothesis--plastid evolution in cryptophytes, alveolates, stramenopiles, and haptophytes (CASH lineages). 2014, 6 (3):666-84 Genome Biol Evol
1759-6653
24572015
10.1093/gbe/evu043
http://hdl.handle.net/10033/323514
Genome biology and evolution
The discovery of Chromera velia, a free-living photosynthetic relative of apicomplexan pathogens, has provided an unexpected opportunity to study the algal ancestry of malaria parasites. In this work, we compared the molecular footprints of a eukaryote-to-eukaryote endosymbiosis in C. velia to their equivalents in peridinin-containing dinoflagellates (PCD) to reevaluate recent claims in favor of a common ancestry of their plastids. To this end, we established the draft genome and a set of full-length cDNA sequences from C. velia via next-generation sequencing. We documented the presence of a single coxI gene in the mitochondrial genome, which thus represents the genetically most reduced aerobic organelle identified so far, but focused our analyses on five "lucky genes" of the Calvin cycle. These were selected because of their known support for a common origin of complex plastids from cryptophytes, alveolates (represented by PCDs), stramenopiles, and haptophytes (CASH) via a single secondary endosymbiosis with a red alga. As expected, our broadly sampled phylogenies of the nuclear-encoded Calvin cycle markers support a rhodophycean origin for the complex plastid of Chromera. However, they also suggest an independent origin of apicomplexan and dinophycean (PCD) plastids via two eukaryote-to-eukaryote endosymbioses. Although at odds with the current view of a common photosynthetic ancestry for alveolates, this conclusion is nonetheless in line with the deviant plastome architecture in dinoflagellates and the morphological paradox of four versus three plastid membranes in the respective lineages. Further support for independent endosymbioses is provided by analysis of five additional markers, four of them involved in the plastid protein import machinery. Finally, we introduce the "rhodoplex hypothesis" as a convenient way to designate evolutionary scenarios where CASH plastids are ultimately the product of a single secondary endosymbiosis with a red alga but were subsequently horizontally spread via higher-order eukaryote-to-eukaryote endosymbioses.
en
Archived with thanks to Genome biology and evolution
Chromera velia, endosymbioses and the rhodoplex hypothesis--plastid evolution in cryptophytes, alveolates, stramenopiles, and haptophytes (CASH lineages).
Article
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URL
https://hzi.openrepository.com/bitstream/10033/323514/1/Petersen%20et%20al_final.pdf
File
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URL
https://hzi.openrepository.com/bitstream/10033/323514/8/Petersen%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3379622019-08-30T11:32:17Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Bohla, Dorte
author
Herold, Martin
author
Panzer, Imke
author
Buxa, Melanie K
author
Ali, Tamer
author
Demmers, Jeroen
author
Krüger, Marcus
author
Scharfe, Maren
author
Jarek, Michael
author
Bartkuhn, Marek
author
Renkawitz, Rainer
department
Helmholtz Centre for ifection research, Innhoffenstr. 7, D38124 Braunschweig, Germany.
2015-01-09T09:18:43Z
2014
A functional insulator screen identifies NURF and dREAM components to be required for enhancer-blocking. 2014, 9 (9):e107765 PLoS ONE
1932-6203
25247414
10.1371/journal.pone.0107765
http://hdl.handle.net/10033/337962
PloS one
Chromatin insulators of higher eukaryotes functionally divide the genome into active and inactive domains. Furthermore, insulators regulate enhancer/promoter communication, which is evident from the Drosophila bithorax locus in which a multitude of regulatory elements control segment specific gene activity. Centrosomal protein 190 (CP190) is targeted to insulators by CTCF or other insulator DNA-binding factors. Chromatin analyses revealed that insulators are characterized by open and nucleosome depleted regions. Here, we wanted to identify chromatin modification and remodelling factors required for an enhancer blocking function. We used the well-studied Fab-8 insulator of the bithorax locus to apply a genome-wide RNAi screen for factors that contribute to the enhancer blocking function of CTCF and CP190. Among 78 genes required for optimal Fab-8 mediated enhancer blocking, all four components of the NURF complex as well as several subunits of the dREAM complex were most evident. Mass spectrometric analyses of CTCF or CP190 bound proteins as well as immune precipitation confirmed NURF and dREAM binding. Both co-localise with most CP190 binding sites in the genome and chromatin immune precipitation showed that CP190 recruits NURF and dREAM. Nucleosome occupancy and histone H3 binding analyses revealed that CP190 mediated NURF binding results in nucleosomal depletion at CP190 binding sites. Thus, we conclude that CP190 binding to CTCF or to other DNA binding insulator factors mediates recruitment of NURF and dREAM. Furthermore, the enhancer blocking function of insulators is associated with nucleosomal depletion and requires NURF and dREAM.
en
A functional insulator screen identifies NURF and dREAM components to be required for enhancer-blocking.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/337962/1/Bohla%20et%20al_final.pdf
File
MD5
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1886730
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URL
https://hzi.openrepository.com/bitstream/10033/337962/8/Bohla%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3386672019-08-30T11:31:48Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Wingender, E
2015-01-22T14:17:30Z
1988-03-25
Compilation of transcription regulating proteins. 1988, 16 (5):1879-902 Nucleic Acids Res.
0305-1048
3282223
http://hdl.handle.net/10033/338667
Nucleic acids research
en
Compilation of transcription regulating proteins.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/338667/1/Wingender_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3444722019-08-30T11:32:16Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Kehrmann, Jan
author
Tatura, Roman
author
Zeschnigk, Michael
author
Probst-Kepper, Michael
author
Geffers, Robert
author
Steinmann, Joerg
author
Buer, Jan
department
Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Germany.
2015-02-16T13:39:43Z
2014-07
Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells. 2014, 142 (3):384-95 Immunology
1365-2567
24476360
10.1111/imm.12261
http://hdl.handle.net/10033/344472
Immunology
The epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate on human CD4(+) CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage-specifying transcription factors of the major T-cell lineages and their leading cytokines, functional properties and global transcriptome changes were analysed. The FOXP3-TSDR methylation pattern was determined by using deep amplicon bisulphite sequencing. 5-aza-2'-deoxycytidine induced FOXP3-TSDR hypomethylation and expression of the Treg-cell-specific genes FOXP3 and LRRC32. Proliferation of 5-aza-2'-deoxycytidine-treated cells was reduced, but the cells did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of T helper type 1 and type 17 cells were induced. Epigallocatechin-3-gallate induced global DNA hypomethylation to a lesser extent than 5-aza-2'-deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg-cell-specific genes. Neither of the DNA methyltransferase inhibitors induced fully functional human Treg cells. 5-aza-2'-deoxycitidine-treated cells resembled Treg cells, but they did not suppress proliferation of responder cells, which is an essential capability to be used for Treg cell transfer therapy. Using a recently developed targeted demethylation technology might be a more promising approach for the generation of functional Treg cells.
en
Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/344472/1/Kehrmann%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3448112019-08-30T11:33:57Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Jurida, Liane
author
Soelch, Johanna
author
Bartkuhn, Marek
author
Handschick, Katja
author
Müller, Helmut
author
Newel, Doris
author
Weber, Axel
author
Dittrich-Breiholz, Oliver
author
Schneider, Heike
author
Bhuju, Sabin
author
Saul, Vera V
author
Schmitz, M Lienhard
author
Kracht, Michael
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2015-02-23T13:44:13Z
2015-02-04
The Activation of IL-1-Induced Enhancers Depends on TAK1 Kinase Activity and NF-κB p65. 2015: Cell Rep
2211-1247
25660023
10.1016/j.celrep.2015.01.001
http://hdl.handle.net/10033/344811
Cell reports
The inflammatory gene response requires activation of the protein kinase TAK1, but it is currently unknown how TAK1-derived signals coordinate transcriptional programs in the genome. We determined the genome-wide binding of the TAK1-controlled NF-κB subunit p65 in relation to active enhancers and promoters of transcribed genes by chromatin immunoprecipitation sequencing (ChIP-seq) experiments. Out of 35,000 active enhancer regions, 410 H3K4me1-positive enhancers show interleukin 1 (IL-1)-induced H3K27ac and p65 binding. Inhibition of TAK1 or IKK2 or depletion of p65 blocked inducible enhancer activation and gene expression. As exemplified by the CXC chemokine cluster located on chromosome 4, the TAK1-p65 pathway also regulates the recruitment kinetics of the histone acetyltransferase CBP, of NF-κB p50, and of AP-1 transcription factors to both promoters and enhancers. This study provides a high-resolution view of epigenetic changes occurring during the IL-1 response and allows the genome-wide identification of a distinct class of inducible p65 NF-κB-dependent enhancers in epithelial cells.
The Activation of IL-1-Induced Enhancers Depends on TAK1 Kinase Activity and NF-κB p65.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/344811/1/Jurida%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3469882019-08-30T11:33:29Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Ohrnberger, Stefan
author
Thavamani, Abhishek
author
Braeuning, Albert
author
Lipka, Daniel B
author
Kirilov, Milen
author
Geffers, Robert
author
Authenrieth, Stella E
author
Römer, Michael
author
Zell, Andreas
author
Bonin, Michael
author
Schwarz, Michael
author
Schütz, Günther
author
Schirmacher, Peter
author
Plass, Christoph
author
Longerich, Thomas
author
Nordheim, Alfred
department
Helmholtz Centre for infection research, Inhoffenstr. 7., 38124 Braunschweig, Germany.
2015-03-23T13:31:18Z
2015-03
Dysregulated serum response factor triggers formation of hepatocellular carcinoma. 2015, 61 (3):979-89 Hepatology
1527-3350
25266280
10.1002/hep.27539
http://hdl.handle.net/10033/346988
Hepatology (Baltimore, Md.)
The ubiquitously expressed transcriptional regulator serum response factor (SRF) is controlled by both Ras/MAPK (mitogen-activated protein kinase) and Rho/actin signaling pathways, which are frequently activated in hepatocellular carcinoma (HCC). We generated SRF-VP16(iHep) mice, which conditionally express constitutively active SRF-VP16 in hepatocytes, thereby controlling subsets of both Ras/MAPK- and Rho/actin-stimulated target genes. All SRF-VP16(iHep) mice develop hyperproliferative liver nodules that progresses to lethal HCC. Some murine (m)HCCs acquire Ctnnb1 mutations equivalent to those in human (h)HCC. The resulting transcript signatures mirror those of a distinct subgroup of hHCCs, with shared activation of oncofetal genes including Igf2, correlating with CpG hypomethylation at the imprinted Igf2/H19 locus.
en
Dysregulated serum response factor triggers formation of hepatocellular carcinoma.
Article
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oai:repository.helmholtz-hzi.de:10033/3470142019-08-30T11:33:57Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Zschüttig, Anke
author
Auerbach, Christian
author
Meltke, Simone
author
Eichhorn, Christin
author
Brandt, Manuela
author
Blom, Jochen
author
Goesmann, Alexander
author
Jarek, Michael
author
Scharfe, Maren
author
Zimmermann, Kurt
author
Wassenaar, Trudy M
author
Gunzer, Florian
department
Helmholtz Centre for infection research, Inhoffenstr. 7., 38124Braunschweig, Germany.
2015-03-23T14:45:10Z
2015
Complete Sequence of Probiotic Symbioflor 2 Escherichia coli Strain G3/10 and Draft Sequences of Symbioflor 2 E. coli Strains G1/2, G4/9, G5, G6/7, and G8. 2015, 3 (2): Genome Announc
2169-8287
25745009
10.1128/genomeA.01330-14
http://hdl.handle.net/10033/347014
Genome announcements
The complete genome of probiotic Escherichia coli strain G3/10 is presented here. In addition, the probiotic E. coli strains G1/2, G4/9, G5, G6/7, and G8 are presented in draft form. These six strains together comprise the probiotic product Symbioflor 2 (DSM 17252).
en
Complete Sequence of Probiotic Symbioflor 2 Escherichia coli Strain G3/10 and Draft Sequences of Symbioflor 2 E. coli Strains G1/2, G4/9, G5, G6/7, and G8.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/5510002019-08-30T11:33:57Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Weiterer, Sebastian
author
Uhle, Florian
author
Lichtenstern, Christoph
author
Siegler, Benedikt H
author
Bhuju, Sabin
author
Jarek, Michael
author
Bartkuhn, Marek
author
Weigand, Markus A
2015-04-30T09:27:49Z
2015
Sepsis induces specific changes in histone modification patterns in human monocytes. 2015, 10 (3):e0121748 PLoS ONE
1932-6203
25793379
10.1371/journal.pone.0121748
http://hdl.handle.net/10033/551000
PloS one
Sepsis is a global burden and the primary cause of death in intensive care units worldwide. The pathophysiological changes induced by the host's systemic inflammatory response to infection are not yet fully understood. During sepsis, the immune system is confronted with a variety of factors, which are integrated within the individual cells and result in changes of their basal state of responsiveness. Epigenetic mechanisms like histone modifications are known to participate in the control of immune reactions, but so far the situation during sepsis is unknown.
en
Sepsis induces specific changes in histone modification patterns in human monocytes.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/551000/1/weiter%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/5593242019-08-30T11:36:05Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Heussler, Gary E
author
Cady, Kyle C
author
Koeppen, Katja
author
Bhuju, Sabin
author
Stanton, Bruce A
author
O'Toole, George A
2015-07-09T09:38:28Z
2015
Clustered Regularly Interspaced Short Palindromic Repeat-Dependent, Biofilm-Specific Death of Pseudomonas aeruginosa Mediated by Increased Expression of Phage-Related Genes. 2015, 6 (3):e00129-15 MBio
2150-7511
25968642
10.1128/mBio.00129-15
http://hdl.handle.net/10033/559324
mBio
The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (CRISPR/Cas) system is an adaptive immune system present in many archaea and bacteria. CRISPR/Cas systems are incredibly diverse, and there is increasing evidence of CRISPR/Cas systems playing a role in cellular functions distinct from phage immunity. Previously, our laboratory reported one such alternate function in which the type 1-F CRISPR/Cas system of the opportunistic pathogen Pseudomonas aeruginosa strain UCBPP-PA14 (abbreviated as P. aeruginosa PA14) inhibits both biofilm formation and swarming motility when the bacterium is lysogenized by the bacteriophage DMS3. In this study, we demonstrated that the presence of just the DMS3 protospacer and the protospacer-adjacent motif (PAM) on the P. aeruginosa genome is necessary and sufficient for this CRISPR-dependent loss of these group behaviors, with no requirement of additional DMS3 sequences. We also demonstrated that the interaction of the CRISPR system with the DMS3 protospacer induces expression of SOS-regulated phage-related genes, including the well-characterized pyocin operon, through the activity of the nuclease Cas3 and subsequent RecA activation. Furthermore, our data suggest that expression of the phage-related genes results in bacterial cell death on a surface due to the inability of the CRISPR-engaged strain to downregulate phage-related gene expression, while these phage-related genes have minimal impact on growth and viability under planktonic conditions. Deletion of the phage-related genes restores biofilm formation and swarming motility while still maintaining a functional CRISPR/Cas system, demonstrating that the loss of these group behaviors is an indirect effect of CRISPR self-targeting.
en
Clustered Regularly Interspaced Short Palindromic Repeat-Dependent, Biofilm-Specific Death of Pseudomonas aeruginosa Mediated by Increased Expression of Phage-Related Genes.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/5657782019-08-30T11:36:33Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Filkins, Laura M
author
Graber, Jyoti A
author
Olson, Daniel G
author
Dolben, Emily L
author
Lynd, Lee R
author
Bhuju, Sabin
author
O'Toole, George A
2015-08-10T10:43:30Z
2015-07-15
Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model. 2015, 197 (14):2252-64 J. Bacteriol.
1098-5530
25917910
10.1128/JB.00059-15
http://hdl.handle.net/10033/565778
Journal of bacteriology
The airways of patients with cystic fibrosis are colonized with diverse bacterial communities that change dynamically during pediatric years and early adulthood. Staphylococcus aureus is the most prevalent pathogen during early childhood, but during late teens and early adulthood, a shift in microbial composition occurs leading to Pseudomonas aeruginosa community predominance in ∼50% of adults. We developed a robust dual-bacterial in vitro coculture system of P. aeruginosa and S. aureus on monolayers of human bronchial epithelial cells homozygous for the ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) mutation to better model the mechanisms of this interaction. We show that P. aeruginosa drives the S. aureus expression profile from that of aerobic respiration to fermentation. This shift is dependent on the production of both 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) and siderophores by P. aeruginosa. Furthermore, S. aureus-produced lactate is a carbon source that P. aeruginosa preferentially consumes over medium-supplied glucose. We find that initially S. aureus and P. aeruginosa coexist; however, over extended coculture P. aeruginosa reduces S. aureus viability, also in an HQNO- and P. aeruginosa siderophore-dependent manner. Interestingly, S. aureus small-colony-variant (SCV) genetic mutant strains, which have defects in their electron transport chain, experience reduced killing by P. aeruginosa compared to their wild-type parent strains; thus, SCVs may provide a mechanism for persistence of S. aureus in the presence of P. aeruginosa. We propose that the mechanism of P. aeruginosa-mediated killing of S. aureus is multifactorial, requiring HQNO and P. aeruginosa siderophores as well as additional genetic, environmental, and nutritional factors.
en
Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/565778/1/Filikins%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6210322021-07-06T12:05:05Zcom_10033_620636com_10033_622921col_10033_622926col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Jeron, Andreas
author
Hansen, Wiebke
author
Ewert, Franziska
author
Buer, Jan
author
Geffers, Robert
author
Bruder, Dunja
2017-08-02T09:06:27Z
2012-12-17
BMC Genomics. 2012 Dec 17;13(1):705
http://dx.doi.org/10.1186/1471-2164-13-705
Abstract Background The transcription factor (TF) forkhead box P3 (FOXP3) is constitutively expressed at high levels in naturally occurring CD4+CD25+ regulatory T cells (nTregs). It is not only the most accepted marker for that cell population but is also considered lineage determinative. Chromatin immunoprecipitation (ChIP) of TFs in combination with genomic tiling microarray analysis (ChIP-on-chip) has been shown to be an appropriate tool for identifying FOXP3 transcription factor binding sites (TFBSs) on a genome-wide scale. In combination with microarray expression analysis, the ChIP-on-chip technique allows identification of direct FOXP3 target genes. Results ChIP-on-chip analysis of the human FOXP3 expressed in resting and PMA/ionomycin–stimulated Jurkat T cells revealed several thousand putative FOXP3 binding sites and demonstrated the importance of intronic regions for FOXP3 binding. The analysis of expression data showed that the stimulation-dependent down-regulation of IL-22 was correlated with direct FOXP3 binding in the IL-22 promoter region. This association was confirmed by real-time PCR analysis of ChIP-DNA. The corresponding ChIP-region also contained a matching FOXP3 consensus sequence. Conclusions Knowledge of the general distribution patterns of FOXP3 TFBSs in the human genome under resting and activated conditions will contribute to a better understanding of this TF and its influence on direct target genes, as well as its importance for the phenotype and function of Tregs. Moreover, FOXP3-dependent repression of Th17-related IL-22 may be relevant to an understanding of the phenomenon of Treg/Th17 cell plasticity.
en
ChIP-on-chip analysis identifies IL-22 as direct target gene of ectopically expressed FOXP3 transcription factor in human T cells
Journal Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/621032/1/12864_2012_Article_4607.pdf
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oai:repository.helmholtz-hzi.de:10033/6207742019-08-30T11:31:49Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Eckelt, Elke
author
Jarek, Michael
author
Frömke, Cornelia
author
Meens, Jochen
author
Goethe, Ralph
2017-01-27T10:27:41Z
2014-12-06
BMC Genomics. 2014 Dec 06;15(1):1076
http://dx.doi.org/10.1186/1471-2164-15-1076
Abstract Background Maintenance of metal homeostasis is crucial in bacterial pathogenicity as metal starvation is the most important mechanism in the nutritional immunity strategy of host cells. Thus, pathogenic bacteria have evolved sensitive metal scavenging systems to overcome this particular host defence mechanism. The ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) displays a unique gut tropism and causes a chronic progressive intestinal inflammation. MAP possesses eight conserved lineage specific large sequence polymorphisms (LSP), which distinguish MAP from its ancestral M. avium ssp. hominissuis or other M. avium subspecies. LSP14 and LSP15 harbour many genes proposed to be involved in metal homeostasis and have been suggested to substitute for a MAP specific, impaired mycobactin synthesis. Results In the present study, we found that a LSP14 located putative IrtAB-like iron transporter encoded by mptABC was induced by zinc but not by iron starvation. Heterologous reporter gene assays with the lacZ gene under control of the mptABC promoter in M. smegmatis (MSMEG) and in a MSMEG∆furB deletion mutant revealed a zinc dependent, metalloregulator FurB mediated expression of mptABC via a conserved mycobacterial FurB recognition site. Deep sequencing of RNA from MAP cultures treated with the zinc chelator TPEN revealed that 70 genes responded to zinc limitation. Remarkably, 45 of these genes were located on a large genomic island of approximately 90 kb which harboured LSP14 and LSP15. Thirty-five of these genes were predicted to be controlled by FurB, due to the presence of putative binding sites. This clustering of zinc responsive genes was exclusively found in MAP and not in other mycobacteria. Conclusions Our data revealed a particular genomic signature for MAP given by a unique zinc specific locus, thereby suggesting an exceptional relevance of zinc for the metabolism of MAP. MAP seems to be well adapted to maintain zinc homeostasis which might contribute to the peculiarity of MAP pathogenicity.
en
Identification of a lineage specific zinc responsive genomic island in Mycobacterium avium ssp. paratuberculosis
Journal Article
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URL
https://hzi.openrepository.com/bitstream/10033/620774/1/12864_2014_Article_6800.pdf
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oai:repository.helmholtz-hzi.de:10033/6207732018-06-12T23:36:19Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Garbe, Julia
author
Wesche, Andrea
author
Bunk, Boyke
author
Kazmierczak, Marlon
author
Selezska, Katherina
author
Rohde, Christine
author
Sikorski, Johannes
author
Rohde, Manfred
author
Jahn, Dieter
author
Schobert, Max
2017-01-27T10:21:38Z
2010-11-26
BMC Microbiology. 2010 Nov 26;10(1):301
http://dx.doi.org/10.1186/1471-2180-10-301
Abstract Background Pseudomonas aeruginosa causes lung infections in patients suffering from the genetic disorder Cystic Fibrosis (CF). Once a chronic lung infection is established, P. aeruginosa cannot be eradicated by antibiotic treatment. Phage therapy is an alternative to treat these chronic P. aeruginosa infections. However, little is known about the factors which influence phage infection of P. aeruginosa under infection conditions and suitable broad host range phages. Results We isolated and characterized a phage, named JG024, which infects a broad range of clinical and environmental P. aeruginosa strains. Sequencing of the phage genome revealed that the phage JG024 is highly related to the ubiquitous and conserved PB1-like phages. The receptor of phage JG024 was determined as lipopolysaccharide. We used an artificial sputum medium to study phage infection under conditions similar to a chronic lung infection. Alginate production was identified as a factor reducing phage infectivity. Conclusions Phage JG024 is a suitable broad host range phage which could be used in phage therapy. Phage infection experiments under simulated chronic lung infection conditions showed that alginate production reduces phage infection efficiency.
en
Characterization of JG024, a pseudomonas aeruginosa PB1-like broad host range phage under simulated infection conditions
Journal Article
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URL
https://hzi.openrepository.com/bitstream/10033/620773/1/12866_2010_Article_1257.pdf
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oai:repository.helmholtz-hzi.de:10033/6207712019-08-30T11:25:43Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Seifert, Oliver
author
Matussek, Andreas
author
Sjögren, Florence
author
Geffers, Robert
author
Anderson, Chris D
2017-01-27T10:19:06Z
2012-11-09
Journal of Inflammation. 2012 Nov 09;9(1):43
http://dx.doi.org/10.1186/1476-9255-9-43
Abstract Background Gold salts has previously been used in the treatment of rheumatoid arthritis but have been replaced by biologicals such as TNF-α inhibitors. The mechanisms behind the anti-inflammatory effect of metallic gold ions are still unknown, however, recent data showed that charged gold atoms are released from pure metallic gold implants by macrophages via a dissolucytosis membrane, and that gold ions are taken up by local macrophages, mast cells and to some extent fibroblasts. These findings open the question of possible immunomodulatory effects of metallic gold and motivate efforts on a deeper understanding of the effect of metallic gold on key inflammatory cells as macrophages. Methods Human macrophage cells (cell line THP-1) were grown on gold foils and intracellular uptake was analysed by autometallography. The impact of phagocytised gold ions on viability of THP-1 cells was investigated by trypan blue staining and TUNEL assay. The global gene expression profile of THP-1 cells after incorporation of gold ions was studied using microarray analysis comprising approximately 20,000 genes. The gene expression data was confirmed by measurement of secreted proteins. Results Autometallography showed intracellular uptake of gold ions into THP-1 cells. No significant effect on viability of THP-1 cells was demonstrated. Our data revealed a unique gene expression signature of dissolucytotic THP-1 cells that had taken up gold ions. A large number of regulated genes were functionally related to immunomodulation. Gold ion uptake induced downregulation of genes involved in rheumatoid arthritis such as hepatocyte growth factor, tenascin-C, inhibitor of DNA binding 1 and 3 and matrix metalloproteinase 13. Conclusion The data obtained in this study offer new insights into the mode of action of gold ions and suggest for the investigation of effects on other key cells and a possible future role of metallic gold as implants in rheumatoid arthritis or other inflammatory conditions.
en
Gene expression profiling of macrophages: implications for an immunosuppressive effect of dissolucytotic gold ions
Journal Article
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URL
https://hzi.openrepository.com/bitstream/10033/620771/1/12950_2012_Article_255.pdf
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oai:repository.helmholtz-hzi.de:10033/6207302019-08-30T11:37:23Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Meidtner, Karina
author
Schwarzenbacher, Hermann
author
Scharfe, Maren
author
Severitt, Simone
author
Blöcker, Helmut
author
Fries, Ruedi
2017-01-19T09:43:09Z
2009-11-30
BMC Genetics. 2009 Nov 30;10(1):76
http://dx.doi.org/10.1186/1471-2156-10-76
Abstract Background Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD) has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics. Results Screening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa × Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa × Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-δ mRNA levels. Haplotype 4 significantly increases PPAR-δ mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-δ. Conclusion This study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.
en
Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness
Journal Article
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oai:repository.helmholtz-hzi.de:10033/5772442019-08-30T11:36:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Orlik, Johanna
author
Schüngel, Sven
author
Buitrago-Molina, Laura Elisa
author
Marhenke, Silke
author
Geffers, Robert
author
Endig, Jessica
author
Lobschat, Katharina
author
Rössler, Stephanie
author
Goeppert, Benjamin
author
Manns, Michael P
author
Gross, Atan
author
Vogel, Arndt
department
Hannover Medical School, Hannover, Germany.
2015-09-14T14:29:36Z
2015-09
The BH3-only protein BID impairs the p38-mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice. 2015, 62 (3):816-28 Hepatology
1527-3350
25951810
10.1002/hep.27888
http://hdl.handle.net/10033/577244
Hepatology (Baltimore, Md.)
Apoptosis is critical for maintaining tissue homeostasis, and apoptosis evasion is considered as a hallmark of cancer. However, increasing evidence also suggests that proapoptotic molecules can contribute to the development of cancer, including liver cancer. The aim of this study was to further clarify the role of the proapoptotic B-cell lymphoma 2 homology domain 3 (BH3)-only protein BH3 interacting-domain death agonist (BID) for chronic liver injury (CLI) and hepatocarcinogenesis (HCG). Loss of BID significantly delayed tumor development in two mouse models of Fah-mediated and HBsTg-driven HCG, suggesting a tumor-promoting effect of BID. Liver injury as well as basal and mitogen-stimulated hepatocyte proliferation were not modulated by BID. Moreover, there was no in vivo or in vitro evidence that BID was involved in DNA damage response in hepatocytes and hepatoma cells. Our data revealed that CLI was associated with strong activation of oxidative stress (OS) response and that BID impaired full activation of p38 after OS.
en
The BH3-only protein BID impairs the p38-mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/577244/1/Orlik%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/5833992019-08-30T11:31:49Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Fiedler, Jan
author
Breckwoldt, Kaja
author
Remmele, Christian W
author
Hartmann, Dorothee
author
Dittrich, Marcus
author
Pfanne, Angelika
author
Just, Annette
author
Xiao, Ke
author
Kunz, Meik
author
Müller, Tobias
author
Hansen, Arne
author
Geffers, Robert
author
Dandekar, Thomas
author
Eschenhagen, Thomas
author
Thum, Thomas
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2015-12-08T10:45:46Z
2015-11-03
Development of Long Noncoding RNA-Based Strategies to Modulate Tissue Vascularization. 2015, 66 (18):2005-15 J. Am. Coll. Cardiol.
1558-3597
26516004
10.1016/j.jacc.2015.07.081
http://hdl.handle.net/10033/583399
Journal of the American College of Cardiology
Long noncoding ribonucleic acids (lncRNAs) are a subclass of regulatory noncoding ribonucleic acids for which expression and function in human endothelial cells and angiogenic processes is not well studied.
en
Development of Long Noncoding RNA-Based Strategies to Modulate Tissue Vascularization.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/583399/1/Fiedler%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/5942082019-08-30T11:36:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Eddyani, Miriam
author
Vandelannoote, Koen
author
Meehan, Conor J
author
Bhuju, Sabin
author
Porter, Jessica L
author
Aguiar, Julia
author
Seemann, Torsten
author
Jarek, Michael
author
Singh, Mahavir
author
Portaels, Françoise
author
Stinear, Timothy P
author
de Jong, Bouke C
department
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2016-01-19T14:23:32Z
2015-11
A Genomic Approach to Resolving Relapse versus Reinfection among Four Cases of Buruli Ulcer. 2015, 9 (11):e0004158 PLoS Negl Trop Dis
1935-2735
26618509
10.1371/journal.pntd.0004158
http://hdl.handle.net/10033/594208
PLoS neglected tropical diseases
Increased availability of Next Generation Sequencing (NGS) techniques allows, for the first time, to distinguish relapses from reinfections in patients with multiple Buruli ulcer (BU) episodes.
en
A Genomic Approach to Resolving Relapse versus Reinfection among Four Cases of Buruli Ulcer.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/5992542019-08-30T11:36:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Ding, Jie
author
Dirks, Wilhelm G
author
Ehrentraut, Stefan
author
Geffers, Robert
author
MacLeod, Roderick A F
author
Nagel, Stefan
author
Pommerenke, Claudia
author
Romani, Julia
author
Scherr, Michaela
author
Vaas, Lea A I
author
Zaborski, Margarete
author
Drexler, Hans G
author
Quentmeier, Hilmar
department
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2016-02-25T14:59:25Z
2015-06
BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2. 2015, 100 (6):801-9 Haematologica
1592-8721
25769544
10.3324/haematol.2014.120048
http://hdl.handle.net/10033/599254
Haematologica
Genetic heterogeneity is widespread in tumors, but poorly documented in cell lines. According to immunoglobulin hypermutation analysis, the diffuse large B-cell lymphoma cell line U-2932 comprises two subpopulations faithfully representing original tumor subclones. We set out to identify molecular causes underlying subclone-specific expression affecting 221 genes including surface markers and the germinal center oncogenes BCL6 and MYC. Genomic copy number variations explained 58/221 genes differentially expressed in the two U-2932 clones. Subclone-specific expression of the aryl-hydrocarbon receptor (AhR) and the resulting activity of the AhR/ARNT complex underlaid differential regulation of 11 genes including MEF2B. Knock-down and inhibitor experiments confirmed that AhR/ARNT regulates MEF2B, a key transcription factor for BCL6. AhR, MEF2B and BCL6 levels correlated not only in the U-2932 subclones but in the majority of 23 cell lines tested, indicting overexpression of AhR as a novel mechanism behind BCL6 diffuse large B-cell lymphoma. Enforced modulation of BCL6 affected 48/221 signature genes. Although BCL6 is known as a transcriptional repressor, 28 genes were up-regulated, including LMO2 and MYBL1 which, like BCL6, signify germinal center diffuse large B-cell lymphoma. Supporting the notion that BCL6 can induce gene expression, BCL6 and the majority of potential targets were co-regulated in a series of B-cell lines. In conclusion, genomic copy number aberrations, activation of AhR/ARNT, and overexpression of BCL6 are collectively responsible for differential expression of more than 100 genes in subclones of the U-2932 cell line. It is particularly interesting that BCL6 - regulated by AhR/ARNT and wild-type MEF2B - may drive expression of germinal center markers in diffuse large B-cell lymphoma.
en
BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/599254/1/Ding%20et%20al.pdf
File
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oai:repository.helmholtz-hzi.de:10033/6010392019-08-30T11:36:32Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Dai, Haiping
author
Ehrentraut, Stefan
author
Nagel, Stefan
author
Eberth, Sonja
author
Pommerenke, Claudia
author
Dirks, Wilhelm G
author
Geffers, Robert
author
Kalavalapalli, Srilaxmi
author
Kaufmann, Maren
author
Meyer, Corrina
author
Faehnrich, Silke
author
Chen, Suning
author
Drexler, Hans G
author
MacLeod, Roderick A F
department
Helmholtz Centre for infection research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.
2016-03-09T15:18:54Z
2015
Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines. 2015, 10 (11):e0139663 PLoS ONE
1932-6203
26599546
10.1371/journal.pone.0139663
http://hdl.handle.net/10033/601039
PloS one
Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2-10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings highlight biallelic deletions as a major class of chromosomal lesion in PMBL cell lines, while endorsing the latter as preclinical models for hunting and testing new biomarkers and actionable targets.
en
Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines.
Article
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oai:repository.helmholtz-hzi.de:10033/6060822019-08-30T11:29:17Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Elgohary, Nahla
author
Pellegrino, Rossella
author
Neumann, Olaf
author
Elzawahry, Heba M
author
Saber, Magdy M
author
Zeeneldin, Ahmed A
author
Geffers, Robert
author
Ehemann, Volker
author
Schemmer, Peter
author
Schirmacher, Peter
author
Longerich, Thomas
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-04-20T14:03:46Z
2015-02
Protumorigenic role of Timeless in hepatocellular carcinoma. 2015, 46 (2):597-606 Int. J. Oncol.
1791-2423
25405317
10.3892/ijo.2014.2751
http://hdl.handle.net/10033/606082
International journal of oncology
The mammalian timeless (TIM) protein interacts with proteins of the endogenous clock and essentially contributes to the circadian rhythm. In addition, TIM is involved in maintenance of chromosome integrity, growth control and development. Thus, we hypothesized that TIM may exert a potential protumorigenic function in human hepatocarcinogenesis. TIM was overexpressed in a subset of human HCCs both at the mRNA and the protein level. siRNA-mediated knockdown of TIM reduced cell viability due to the induction of apoptosis and G2 arrest. The latter was mediated via CHEK2 phosphorylation. In addition, siRNA-treated cells showed a significantly reduced migratory capacity and reduced expression levels of various proteins. Mechanistically, TIM directly interacts with the eukaryotic elongation factor 1A2 (EEF1A2), which binds to actin filaments to promote tumor cell migration. siRNA-mediated knockdown of TIM reduced EEF1A2 protein levels thereby affecting ribosomal protein biosynthesis. Thus, overexpression of TIM exerts oncogenic function in human HCCs, which is mediated via CHEK2 and EEF1A2.
en
Protumorigenic role of Timeless in hepatocellular carcinoma.
Article
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URL
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URL
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Elgohary et al.pdf.txt
oai:repository.helmholtz-hzi.de:10033/6132012019-08-30T11:28:51Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Ehrentraut, Stefan
author
Schneider, Björn
author
Nagel, Stefan
author
Pommerenke, Claudia
author
Quentmeier, Hilmar
author
Geffers, Robert
author
Feist, Maren
author
Kaufmann, Maren
author
Meyer, Corinna
author
Kadin, Marshall E
author
Drexler, Hans G
author
MacLeod, Roderick A F
department
German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
2016-06-15T12:51:54Z
2016-04-28
Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma. 2016: Oncotarget
1949-2553
27144517
10.18632/oncotarget.9077
http://hdl.handle.net/10033/613201
Oncotarget
We propose that deregulated T-helper-cell (Th) signaling underlies evolving Th17 cytokine expression seen during progression of cutaneous T-cell lymphoma (CTCL). Accordingly, we developed a lymphoma progression model comprising cell lines established at indolent (MAC-1) and aggressive (MAC-2A) CTCL stages. We discovered activating JAK3 (V722I) mutations present at indolent disease, reinforced in aggressive disease by novel compound heterozygous SOCS1 (G78R/D105N) JAK-binding domain inactivating mutations. Though isogenic, indolent and aggressive-stage cell lines had diverged phenotypically, the latter expressing multiple Th17 related cytokines, the former a narrower profile. Importantly, indolent stage cells remained poised for Th17 cytokine expression, readily inducible by treatment with IL-2 - a cytokine which mitigates Th17 differentiation in mice. In indolent stage cells JAK3 expression was boosted by IL-2 treatment. Th17 conversion of MAC-1 cells by IL-2 was blocked by pharmacological inhibition of JAK3 or STAT5, implicating IL2RG - JAK3 - STAT5 signaling in plasticity responses. Like IL-2 treatment, SOCS1 knockdown drove indolent stage cells to mimic key aggressive stage properties, notably IL17F upregulation. Co-immunoprecipitation experiments showed that SOCS1 mutations abolished JAK3 binding, revealing a key role for SOCS1 in regulating JAK3/STAT5 signaling. Collectively, our results show how JAK/STAT pathway mutations contribute to disease progression in CTCL cells by potentiating inflammatory cytokine signaling, widening the potential therapeutic target range for this intractable entity. MAC-1/2A cells also provide a candidate human Th17 laboratory model for identifying potentally actionable CTCL markers or targets and testing their druggability in vitro.
Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/613201/1/Ehrentraut%20et%20al.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/613201/2/supplementary%20information.pdf
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https://hzi.openrepository.com/bitstream/10033/613201/9/supplementary%20information.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/6159742019-08-30T11:36:33Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Möbius, Petra
author
Hölzer, Martin
author
Felder, Marius
author
Nordsiek, Gabriele
author
Groth, Marco
author
Köhler, Heike
author
Reichwald, Kathrin
author
Platzer, Matthias
author
Marz, Manja
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-07-12T08:49:25Z
2015-09-17
Comprehensive insights in the Mycobacterium avium subsp. paratuberculosis genome using new WGS data of sheep strain JIII-386 from Germany. 2015: Genome Biol Evol
1759-6653
26384038
10.1093/gbe/evv154
http://hdl.handle.net/10033/615974
Genome biology and evolution
Mycobacterium avium (M. a.) subsp. paratuberculosis (MAP) - the etiologic agent of Johne's disease - affects cattle, sheep and other ruminants worldwide. To decipher phenotypic differences among sheep and cattle strains (belonging to MAP-S [Type-I/III] respectively MAP-C [Type-II]) comparative genome analysis needs data from diverse isolates originating from different geographic regions of the world. The current study presents the so far best assembled genome of a MAP-S-strain: sheep isolate JIII-386 from Germany. One newly sequenced cattle isolate (JII-1961, Germany), four published MAP strains of MAP-C and MAP-S from U.S. and Australia and M. a. subsp. hominissuis (MAH) strain 104 were used for assembly improvement and comparisons. All genomes were annotated by BacProt and results compared with NCBI annotation. Corresponding protein-coding sequences (CDSs) were detected, but also CDSs that were exclusively determined either by NCBI or BacProt. A new Shine-Dalgarno sequence motif (5'AGCTGG3') was extracted. Novel CDSs including PE-PGRS family protein genes and about 80 non-coding RNAs exhibiting high sequence conservation are presented. Previously found genetic differences between MAP-types are partially revised. Four out of ten assumed MAP-S-specific large sequence polymorphism regions (LSP(S)s) are still present in MAP-C strains; new LSP(S)s were identified. Independently of the regional origin of the strains, the number of individual CDSs and single nucleotide variants confirm the strong similarity of MAP-C strains and show higher diversity among MAP-S strains. This study gives ambiguous results regarding the hypothesis that MAP-S is the evolutionary intermediate between MAH and MAP-C, but it clearly shows a higher similarity of MAP to MAH than to M. intracellulare.
Comprehensive insights in the Mycobacterium avium subsp. paratuberculosis genome using new WGS data of sheep strain JIII-386 from Germany.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/615974/1/M%c3%b6bius%20et%20al.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/615974/6/M%c3%b6bius%20et%20al.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/6170202019-08-30T11:37:00Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Hampel, Annegret
author
Huber, Claudia
author
Geffers, Robert
author
Spona-Friedl, Marina
author
Eisenreich, Wolfgang
author
Bange, Franz-Christoph
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-07-15T13:37:15Z
2015
Mycobacterium tuberculosis Is a Natural Ornithine Aminotransferase (rocD) Mutant and Depends on Rv2323c for Growth on Arginine. 2015, 10 (9):e0136914 PLoS ONE
1932-6203
26368558
10.1371/journal.pone.0136914
http://hdl.handle.net/10033/617020
PloS one
Mycobacterium tuberculosis (Mtb) possesses a genetic repertoire for metabolic pathways, which are specific and fit to its intracellular life style. Under in vitro conditions, Mtb is known to use arginine as a nitrogen source, but the metabolic pathways for arginine utilization have not been identified. Here we show that, in the presence of arginine, Mtb upregulates a gene cluster which includes an ornithine aminotransferase (rocD) and Rv2323c, a gene of unknown function. Isotopologue analysis by using 13C- or 15N-arginine revealed that in Mtb arginine is not only used as nitrogen source but also as carbon source for the formation of amino acids, in particular of proline. Surprisingly, rocD, which is widespread in other bacteria and is part of the classical arginase pathway turned out to be naturally deleted in Mtb, but not in non-tuberculous mycobacteria. Mtb lacking Rv2323c showed a growth defect on arginine, did not produce proline from arginine, and incorporated less nitrogen derived from arginine in its core nitrogen metabolism. We conclude that the highly induced pathway for arginine utilization in Mtb differs from that of other bacteria including non-tuberculous mycobacteria, probably reflecting a specific metabolic feature of intracellular Mtb.
en
Mycobacterium tuberculosis Is a Natural Ornithine Aminotransferase (rocD) Mutant and Depends on Rv2323c for Growth on Arginine.
Article
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oai:repository.helmholtz-hzi.de:10033/6184462019-08-30T11:32:16Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Endig, Jessica
author
Buitrago-Molina, Laura Elisa
author
Marhenke, Silke
author
Reisinger, Florian
author
Saborowski, Anna
author
Schütt, Jutta
author
Limbourg, Florian
author
Könecke, Christian
author
Schreder, Alina
author
Michael, Alina
author
Misslitz, Ana Clara
author
Healy, Marc Eammonn
author
Geffers, Robert
author
Clavel, Thomas
author
Haller, Dirk
author
Unger, Kristian
author
Finegold, Milton
author
Weber, Achim
author
Manns, Michael P
author
Longerich, Thomas
author
Heikenwälder, Mathias
author
Vogel, Arndt
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-08-16T14:40:20Z
2016-08-08
Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development. 2016, 30 (2):308-23 Cancer Cell
1878-3686
27478039
10.1016/j.ccell.2016.06.009
http://hdl.handle.net/10033/618446
Cancer cell
Hepatocellular carcinoma (HCC) represents a classic example of inflammation-linked cancer. To characterize the role of the immune system in hepatic injury and tumor development, we comparatively studied the extent of liver disease and hepatocarcinogenesis in immunocompromised versus immunocompetent Fah-deficient mice. Strikingly, chronic liver injury and tumor development were markedly suppressed in alymphoid Fah(-/-) mice despite an overall increased mortality. Mechanistically, we show that CD8(+) T cells and lymphotoxin β are central mediators of HCC formation. Antibody-mediated depletion of CD8(+) T cells as well as pharmacological inhibition of the lymphotoxin-β receptor markedly delays tumor development in mice with chronic liver injury. Thus, our study unveils distinct functions of the immune system, which are required for liver regeneration, survival, and hepatocarcinogenesis.
en
Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/618446/1/Endig%20et%20al.pdf
File
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oai:repository.helmholtz-hzi.de:10033/6185202019-08-30T11:37:00Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Koeppen, Katja
author
Hampton, Thomas H
author
Jarek, Michael
author
Scharfe, Maren
author
Gerber, Scott A
author
Mielcarz, Daniel W
author
Demers, Elora G
author
Dolben, Emily L
author
Hammond, John H
author
Hogan, Deborah A
author
Stanton, Bruce A
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-08-18T09:35:46Z
2016-06
A Novel Mechanism of Host-Pathogen Interaction through sRNA in Bacterial Outer Membrane Vesicles. 2016, 12 (6):e1005672 PLoS Pathog.
1553-7374
27295279
10.1371/journal.ppat.1005672
http://hdl.handle.net/10033/618520
PLoS pathogens
Bacterial outer membrane vesicle (OMV)-mediated delivery of proteins to host cells is an important mechanism of host-pathogen communication. Emerging evidence suggests that OMVs contain differentially packaged short RNAs (sRNAs) with the potential to target host mRNA function and/or stability. In this study, we used RNA-Seq to characterize differentially packaged sRNAs in Pseudomonas aeruginosa OMVs, and to show transfer of OMV sRNAs to human airway cells. We selected one sRNA for further study based on its stable secondary structure and predicted mRNA targets. Our candidate sRNA (sRNA52320), a fragment of a P. aeruginosa methionine tRNA, was abundant in OMVs and reduced LPS-induced as well as OMV-induced IL-8 secretion by cultured primary human airway epithelial cells. We also showed that sRNA52320 attenuated OMV-induced KC cytokine secretion and neutrophil infiltration in mouse lung. Collectively, these findings are consistent with the hypothesis that sRNA52320 in OMVs is a novel mechanism of host-pathogen interaction whereby P. aeruginosa reduces the host immune response.
en
A Novel Mechanism of Host-Pathogen Interaction through sRNA in Bacterial Outer Membrane Vesicles.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6190792019-08-30T11:37:00Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Vences, Miguel
author
Lyra, Mariana L
author
Kueneman, Jordan G
author
Bletz, Molly C
author
Archer, Holly M
author
Canitz, Julia
author
Handreck, Svenja
author
Randrianiaina, Roger-Daniel
author
Struck, Ulrich
author
Bhuju, Sabin
author
Jarek, Michael
author
Geffers, Robert
author
McKenzie, Valerie J
author
Tebbe, Christoph C
author
Haddad, Célio F B
author
Glos, Julian
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-08-31T09:01:35Z
2016-04
Gut bacterial communities across tadpole ecomorphs in two diverse tropical anuran faunas. 2016, 103 (3-4):25 Naturwissenschaften
1432-1904
26924012
10.1007/s00114-016-1348-1
http://hdl.handle.net/10033/619079
Die Naturwissenschaften
Animal-associated microbial communities can play major roles in the physiology, development, ecology, and evolution of their hosts, but the study of their diversity has yet focused on a limited number of host species. In this study, we used high-throughput sequencing of partial sequences of the bacterial 16S rRNA gene to assess the diversity of the gut-inhabiting bacterial communities of 212 specimens of tropical anuran amphibians from Brazil and Madagascar. The core gut-associated bacterial communities among tadpoles from two different continents strongly overlapped, with eight highly represented operational taxonomic units (OTUs) in common. In contrast, the core communities of adults and tadpoles from Brazil were less similar with only one shared OTU. This suggests a community turnover at metamorphosis. Bacterial diversity was higher in tadpoles compared to adults. Distinct differences in composition and diversity occurred among gut bacterial communities of conspecific tadpoles from different water bodies and after experimental fasting for 8 days, demonstrating the influence of both environmental factors and food on the community structure. Communities from syntopic tadpoles clustered by host species both in Madagascar and Brazil, and the Malagasy tadpoles also had species-specific isotope signatures. We recommend future studies to analyze the turnover of anuran gut bacterial communities at metamorphosis, compare the tadpole core communities with those of other aquatic organisms, and assess the possible function of the gut microbiota as a reservoir for protective bacteria on the amphibian skin.
en
Gut bacterial communities across tadpole ecomorphs in two diverse tropical anuran faunas.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/619079/1/Vences_et_al.pdf
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oai:repository.helmholtz-hzi.de:10033/6201372019-08-30T11:37:00Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Quentmeier, Hilmar
author
Pommerenke, Claudia
author
Ammerpohl, Ole
author
Geffers, Robert
author
Hauer, Vivien
author
MacLeod, Roderick Af
author
Nagel, Stefan
author
Romani, Julia
author
Rosati, Emanuela
author
Rosén, Anders
author
Uphoff, Cord C
author
Zaborski, Margarete
author
Drexler, Hans G
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig.
2016-09-14T13:01:59Z
2016-08-23
Subclones in B-lymphoma cell lines: isogenic models for the study of gene regulation. 2016: Oncotarget
1949-2553
27566572
10.18632/oncotarget.11524
http://hdl.handle.net/10033/620137
Oncotarget
Genetic heterogeneity though common in tumors has been rarely documented in cell lines. To examine how often B-lymphoma cell lines are comprised of subclones, we performed immunoglobulin (IG) heavy chain hypermutation analysis. Revealing that subclones are not rare in B-cell lymphoma cell lines, 6/49 IG hypermutated cell lines (12%) consisted of subclones with individual IG mutations. Subclones were also identified in 2/284 leukemia/lymphoma cell lines exhibiting bimodal CD marker expression. We successfully isolated 10 subclones from four cell lines (HG3, SU-DHL-5, TMD-8, U-2932). Whole exome sequencing was performed to molecularly characterize these subclones. We describe in detail the clonal structure of cell line HG3, derived from chronic lymphocytic leukemia. HG3 consists of three subclones each bearing clone-specific aberrations, gene expression and DNA methylation patterns. While donor patient leukemic cells were CD5+, two of three HG3 subclones had independently lost this marker. CD5 on HG3 cells was regulated by epigenetic/transcriptional mechanisms rather than by alternative splicing as reported hitherto. In conclusion, we show that the presence of subclones in cell lines carrying individual mutations and characterized by sets of differentially expressed genes is not uncommon. We show also that these subclones can be useful isogenic models for regulatory and functional studies.
Subclones in B-lymphoma cell lines: isogenic models for the study of gene regulation.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620137/1/Quentmeier%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6206872019-08-30T11:33:57Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Ali, Tamer
author
Krüger, Marcus
author
Bhuju, Sabin
author
Jarek, Michael
author
Bartkuhn, Marek
author
Renkawitz, Rainer
department
Hel,holtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-01-09T15:20:01Z
2016-11-29
Chromatin binding of Gcn5 in Drosophila is largely mediated by CP190. 2016 Nucleic Acids Res.
1362-4962
27903907
10.1093/nar/gkw1178
http://hdl.handle.net/10033/620687
Nucleic acids research
Centrosomal 190 kDa protein (CP190) is a promoter binding factor, mediates long-range interactions in the context of enhancer-promoter contacts and in chromosomal domain formation. All Drosophila insulator proteins bind CP190 suggesting a crucial role in insulator function. CP190 has major effects on chromatin, such as depletion of nucleosomes, high nucleosomal turnover and prevention of heterochromatin expansion. Here, we searched for enzymes, which might be involved in CP190 mediated chromatin changes. Eighty percent of the genomic binding sites of the histone acetyltransferase Gcn5 are colocalizing with CP190 binding. Depletion of CP190 reduces Gcn5 binding to chromatin. Binding dependency was further supported by Gcn5 mediated co-precipitation of CP190. Gcn5 is known to activate transcription by histone acetylation. We used the dCas9 system to target CP190 or Gcn5 to a Polycomb repressed and H3K27me3 marked gene locus. Both, CP190 as well as Gcn5, activate this locus, thus supporting the model that CP190 recruits Gcn5 and thereby activates chromatin.
en
Chromatin binding of Gcn5 in Drosophila is largely mediated by CP190.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620687/1/Ali%20et%20al.pdf
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https://hzi.openrepository.com/bitstream/10033/620687/6/Ali%20et%20al.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/6207982019-08-30T11:37:24Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Bletz, Molly C
author
Goedbloed, Daniel J
author
Sanchez, Eugenia
author
Reinhardt, Timm
author
Tebbe, Christoph C
author
Bhuju, Sabin
author
Geffers, Robert
author
Jarek, Michael
author
Vences, Miguel
author
Steinfartz, Sebastian
department
Helmholtz Centre for infection research. Inhoffenstr. 7. 38124 Braunschweig, Germany.
2017-01-31T12:24:38Z
2016-12-15
Amphibian gut microbiota shifts differentially in community structure but converges on habitat-specific predicted functions. 2016, 7:13699 Nat Commun
2041-1723
27976718
10.1038/ncomms13699
http://hdl.handle.net/10033/620798
Nature communications
Complex microbial communities inhabit vertebrate digestive systems but thorough understanding of the ecological dynamics and functions of host-associated microbiota within natural habitats is limited. We investigate the role of environmental conditions in shaping gut and skin microbiota under natural conditions by performing a field survey and reciprocal transfer experiments with salamander larvae inhabiting two distinct habitats (ponds and streams). We show that gut and skin microbiota are habitat-specific, demonstrating environmental factors mediate community structure. Reciprocal transfer reveals that gut microbiota, but not skin microbiota, responds differentially to environmental change. Stream-to-pond larvae shift their gut microbiota to that of pond-to-pond larvae, whereas pond-to-stream larvae change to a community structure distinct from both habitat controls. Predicted functions, however, match that of larvae from the destination habitats in both cases. Thus, microbial function can be matched without taxonomic coherence and gut microbiota appears to exhibit metagenomic plasticity.
en
Amphibian gut microbiota shifts differentially in community structure but converges on habitat-specific predicted functions.
Article
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oai:repository.helmholtz-hzi.de:10033/6208642019-08-30T11:29:17Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Koczula, Anna
author
Jarek, Michael
author
Visscher, Christian
author
Valentin-Weigand, Peter
author
Goethe, Ralph
author
Willenborg, Jörg
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-03-17T09:57:52Z
2017-02-15
Transcriptomic Analysis Reveals Selective Metabolic Adaptation of Streptococcus suis to Porcine Blood and Cerebrospinal Fluid. 2017, 6 (1) Pathogens
28212285
10.3390/pathogens6010007
http://hdl.handle.net/10033/620864
Pathogens (Basel, Switzerland)
Streptococcus suis is a zoonotic pathogen that can cause severe pathologies such as septicemia and meningitis in its natural porcine host as well as in humans. Establishment of disease requires not only virulence of the infecting strain but also an appropriate metabolic activity of the pathogen in its host environment. However, it is yet largely unknown how the streptococcal metabolism adapts to the different host niches encountered during infection. Our previous isotopologue profiling studies on S. suis grown in porcine blood and cerebrospinal fluid (CSF) revealed conserved activities of central carbon metabolism in both body fluids. On the other hand, they suggested differences in the de novo amino acid biosynthesis. This prompted us to further dissect S. suis adaptation to porcine blood and CSF by RNA deep sequencing (RNA-seq). In blood, the majority of differentially expressed genes were associated with transport of alternative carbohydrate sources and the carbohydrate metabolism (pentose phosphate pathway, glycogen metabolism). In CSF, predominantly genes involved in the biosynthesis of branched-chain and aromatic amino acids were differentially expressed. Especially, isoleucine biosynthesis seems to be of major importance for S. suis in CSF because several related biosynthetic genes were more highly expressed. In conclusion, our data revealed niche-specific metabolic gene activity which emphasizes a selective adaptation of S. suis to host environments.
en
Transcriptomic Analysis Reveals Selective Metabolic Adaptation of Streptococcus suis to Porcine Blood and Cerebrospinal Fluid.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620864/1/Koczula%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6208652019-08-30T11:29:17Zcom_10033_620636com_10033_620644col_10033_620638col_10033_620647
Helmholtz Zentrum für Infektionsforschung Repository
author
Donner, Jannik
author
Bunk, Boyke
author
Schober, Isabel
author
Spröer, Cathrin
author
Bergmann, Simone
author
Jarek, Michael
author
Overmann, Jörg
author
Wagner-Döbler, Irene
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-03-17T11:26:10Z
2017-02-16
Complete Genome Sequences of Three Multidrug-Resistant Clinical Isolates of Streptococcus pneumoniae Serotype 19A with Different Susceptibilities to the Myxobacterial Metabolite Carolacton. 2017, 5 (7) Genome Announc
28209832
10.1128/genomeA.01641-16
http://hdl.handle.net/10033/620865
Genome announcements
The full-genome sequences of three drug- and multidrug-resistant Streptococcus pneumoniae clinical isolates of serotype 19A were determined by PacBio single-molecule real-time sequencing, in combination with Illumina MiSeq sequencing. A comparison to the genomes of other pneumococci indicates a high nucleotide sequence identity to strains Hungary19A-6 and TCH8431/19A.
en
Complete Genome Sequences of Three Multidrug-Resistant Clinical Isolates of Streptococcus pneumoniae Serotype 19A with Different Susceptibilities to the Myxobacterial Metabolite Carolacton.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6208882019-08-30T11:29:47Zcom_10033_620636com_10033_620644col_10033_620638col_10033_620647
Helmholtz Zentrum für Infektionsforschung Repository
author
Szafrański, Szymon P
author
Deng, Zhi-Luo
author
Tomasch, Jürgen
author
Jarek, Michael
author
Bhuju, Sabin
author
Rohde, Manfred
author
Sztajer, Helena
author
Wagner-Döbler, Irene
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-04-07T08:11:34Z
2017-03-20
Quorum sensing of Streptococcus mutans is activated by Aggregatibacter actinomycetemcomitans and by the periodontal microbiome. 2017, 18 (1):238 BMC Genomics
1471-2164
28320314
10.1186/s12864-017-3618-5
http://hdl.handle.net/10033/620888
BMC genomics
The oral cavity is inhabited by complex microbial communities forming biofilms that can cause caries and periodontitis. Cell-cell communication might play an important role in modulating the physiologies of individual species, but evidence so far is limited.
en
Quorum sensing of Streptococcus mutans is activated by Aggregatibacter actinomycetemcomitans and by the periodontal microbiome.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620888/1/Szafra%c5%84ski%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6209152019-08-30T11:37:44Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Chachage, Mkunde
author
Pollakis, Georgios
author
Kuffour, Edmund Osei
author
Haase, Kerstin
author
Bauer, Asli
author
Nadai, Yuka
author
Podola, Lilli
author
Clowes, Petra
author
Schiemann, Matthias
author
Henkel, Lynette
author
Hoffmann, Dieter
author
Joseph, Sarah
author
Bhuju, Sabin
author
Maboko, Leonard
author
Sarfo, Fred Stephen
author
Eberhardt, Kirsten
author
Hoelscher, Michael
author
Feldt, Torsten
author
Saathoff, Elmar
author
Geldmacher, Christof
department
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-05-10T10:49:31Z
2016-10-15
CD25+ FoxP3+ Memory CD4 T Cells Are Frequent Targets of HIV Infection In Vivo. 2016, 90 (20):8954-67 J. Virol.
1098-5514
27384654
10.1128/JVI.00612-16
http://hdl.handle.net/10033/620915
Journal of virology
Interleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replication in vitro and facilitates homeostatic proliferation of CD25(+) FoxP3(+) CD4(+) T cells. CD25(+) FoxP3(+) CD4(+) T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25(+) FoxP3(+) CD4(+) T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV(+) and HIV(-) study volunteers. Different memory CD4(+) T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV(+) subjects, 51% (median) of CD25(+) FoxP3(+) CD4(+) T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67(+) cells were detected in CD25(+) FoxP3(+) memory CD4(+) T cells (median, 27.6%) in comparison to CD25(-) FoxP3(-) memory CD4(+) T cells (median, 4.1%; P < 0.0001). HIV DNA content was 15-fold higher in CD25(+) FoxP3(+) memory CD4(+) T cells than in CD25(-) FoxP3(-) T cells (P = 0.003). EnvV1V3 sequences derived from CD25(+) FoxP3(+) memory CD4(+) T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells might facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear.
en
CD25+ FoxP3+ Memory CD4 T Cells Are Frequent Targets of HIV Infection In Vivo.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620915/1/Chachage%20et%20al.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/620915/6/Chachage%20et%20al.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/6209622019-08-30T11:28:51Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Radmanesh, Hoda
author
Spethmann, Tessa
author
Enßen, Julia
author
Schürmann, Peter
author
Bhuju, Sabin
author
Geffers, Robert
author
Antonenkova, Natalia
author
Khusnutdinova, Elza
author
Sadr-Nabavi, Ariane
author
Shandiz, Fatemeh Homaei
author
Park-Simon, Tjoung-Won
author
Hillemanns, Peter
author
Christiansen, Hans
author
Bogdanova, Natalia
author
Dörk, Thilo
department
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-06-20T11:43:15Z
2017-02
Assessment of an APOBEC3B truncating mutation, c.783delG, in patients with breast cancer. 2017, 162 (1):31-37 Breast Cancer Res. Treat.
1573-7217
28062980
10.1007/s10549-016-4100-9
http://hdl.handle.net/10033/620962
Breast cancer research and treatment
APOBEC3B belongs to the family of DNA-editing enzymes. A copy number variant targeting the genomic APOBEC3A-APOBEC3B locus has a significant impact on breast cancer risk, but the relative contribution of APOBEC3B is uncertain. In this study, we investigate a loss-of-function mutation that selectively targets APOBEC3B, for its association with breast cancer risk.
en
Assessment of an APOBEC3B truncating mutation, c.783delG, in patients with breast cancer.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620962/1/Manuscript%20APOBEC3B%20revised.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/620962/2/Table%201%20revised.pdf
File
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Table 1 revised.pdf
URL
https://hzi.openrepository.com/bitstream/10033/620962/7/Manuscript%20APOBEC3B%20revised.pdf.txt
File
MD5
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URL
https://hzi.openrepository.com/bitstream/10033/620962/9/Table%201%20revised.pdf.txt
File
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Table 1 revised.pdf.txt
oai:repository.helmholtz-hzi.de:10033/6209882019-08-30T11:31:49Zcom_10033_620636com_10033_620644col_10033_620638col_10033_620647
Helmholtz Zentrum für Infektionsforschung Repository
author
Deng, Zhi-Luo
author
Szafrański, Szymon P
author
Jarek, Michael
author
Bhuju, Sabin
author
Wagner-Döbler, Irene
department
Helmholtz Centre for infection research, Inhoffenstr. 7., 38124 Braunschweig, Germany.
2017-07-05T07:43:44Z
2017-06-16
Dysbiosis in chronic periodontitis: Key microbial players and interactions with the human host. 2017, 7 (1):3703 Sci Rep
2045-2322
28623321
10.1038/s41598-017-03804-8
http://hdl.handle.net/10033/620988
Scientific reports
Periodontitis is an extremely prevalent disease worldwide and is driven by complex dysbiotic microbiota. Here we analyzed the transcriptional activity of the periodontal pocket microbiota from all domains of life as well as the human host in health and chronic periodontitis. Bacteria showed strong enrichment of 18 KEGG functional modules in chronic periodontitis, including bacterial chemotaxis, flagellar assembly, type III secretion system, type III CRISPR-Cas system, and two component system proteins. Upregulation of these functions was driven by the red-complex pathogens and candidate pathogens, e.g. Filifactor alocis, Prevotella intermedia, Fretibacterium fastidiosum and Selenomonas sputigena. Nine virulence factors were strongly up-regulated, among them the arginine deiminase arcA from Porphyromonas gingivalis and Mycoplasma arginini. Viruses and archaea accounted for about 0.1% and 0.22% of total putative mRNA reads, respectively, and a protozoan, Entamoeba gingivalis, was highly enriched in periodontitis. Fourteen human transcripts were enriched in periodontitis, including a gene for a ferric iron binding protein, indicating competition with the microbiota for iron, and genes associated with cancer, namely nucleolar phosphoprotein B23, ankyrin-repeat domain 30B-like protein and beta-enolase. The data provide evidence on the level of gene expression in vivo for the potentially severe impact of the dysbiotic microbiota on human health.
en
Dysbiosis in chronic periodontitis: Key microbial players and interactions with the human host.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6210012019-08-30T11:26:42Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Westendorf, Astrid M
author
Skibbe, Kathrin
author
Adamczyk, Alexandra
author
Buer, Jan
author
Geffers, Robert
author
Hansen, Wiebke
author
Pastille, Eva
author
Jendrossek, Verena
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-07-10T12:52:15Z
2017
Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity. 2017, 41 (4):1271-1284 Cell. Physiol. Biochem.
1421-9778
28278498
10.1159/000464429
http://hdl.handle.net/10033/621001
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment.
en
Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621001/1/Westendorf%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6210092019-08-30T11:28:51Zcom_10033_620589com_10033_620636col_10033_620590col_10033_620596col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Khera, Tanvi
author
Todt, Daniel
author
Vercauteren, Koen
author
McClure, C Patrick
author
Verhoye, Lieven
author
Farhoudi, Ali
author
Bhuju, Sabin
author
Geffers, Robert
author
Baumert, Thomas F
author
Steinmann, Eike
author
Meuleman, Philip
author
Pietschmann, Thomas
author
Brown, Richard J P
department
Helmholtz Centre for infection research, Inhoffenstr. 7., 38124 Braunschweig, Germany.
2017-07-12T14:20:02Z
2017-03
Tracking HCV protease population diversity during transmission and susceptibility of founder populations to antiviral therapy. 2017, 139:129-137 Antiviral Res.
1872-9096
28062191
10.1016/j.antiviral.2017.01.001
http://hdl.handle.net/10033/621009
Antiviral research
Due to the highly restricted species-tropism of Hepatitis C virus (HCV) a limited number of animal models exist for pre-clinical evaluation of vaccines and antiviral compounds. The human-liver chimeric mouse model allows heterologous challenge with clinically relevant strains derived from patients. However, to date, the transmission and longitudinal evolution of founder viral populations in this model have not been characterized in-depth using state-of-the-art sequencing technologies. Focusing on NS3 protease encoding region of the viral genome, mutant spectra in a donor inoculum and individual recipient mice were determined via Illumina sequencing and compared, to determine the effects of transmission on founder viral population complexity. In all transmissions, a genetic bottleneck was observed, although diverse viral populations were transmitted in each case. A low frequency cloud of mutations (<1%) was detectable in the donor inoculum and recipient mice, with single nucleotide variants (SNVs) > 1% restricted to a subset of nucleotides. The population of SNVs >1% was reduced upon transmission while the low frequency SNV cloud remained stable. Fixation of multiple identical synonymous substitutions was apparent in independent transmissions, and no evidence for reversion of T-cell epitopes was observed. In addition, susceptibility of founder populations to antiviral therapy was assessed. Animals were treated with protease inhibitor (PI) monotherapy to track resistance associated substitution (RAS) emergence. Longitudinal analyses revealed a decline in population diversity under therapy, with no detectable RAS >1% prior to therapy commencement. Despite inoculation from a common source and identical therapeutic regimens, unique RAS emergence profiles were identified in different hosts prior to and during therapeutic failure, with complex mutational signatures at protease residues 155, 156 and 168 detected. Together these analyses track viral population complexity at high-resolution in the human-liver chimeric mouse model post-transmission and under therapeutic intervention, revealing novel insights into the evolutionary processes which shape viral protease population composition at various critical stages of the viral life-cycle.
en
openAccess
Tracking HCV protease population diversity during transmission and susceptibility of founder populations to antiviral therapy.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621009/1/Khera%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6210182019-08-30T11:33:30Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Kleist, Sarah
author
Ulbrich, Marcus
author
Bill, Nelli
author
Schmidt-Hohagen, Kerstin
author
Geffers, Robert
author
Schomburg, Dietmar
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-07-25T10:47:08Z
2017-03
Dealing with salinity extremes and nitrogen limitation - an unexpected strategy of the marine bacterium Dinoroseobacter shibae. 2017, 19 (3):894-908 Environ. Microbiol.
1462-2920
26914854
10.1111/1462-2920.13266
http://hdl.handle.net/10033/621018
Environmental microbiology
Having the right coping strategy for changes in osmolarity or desiccation is essential for the survival of every cell. So far, nothing is known about compatible solutes and the salt adaptation of the marine Rhodobacteraceae. The family member Dinoroseobacter shibae DFL12(T) is shown here to form the compatible solutes α-glucosylglycerol (GG) and α-glucosylglycerate (GGA). To our knowledge, this is the first experimental evidence for GGA formation within the α-proteobacteria. Together with glutamate and putrescine, these substances enable good growth in salinity ranging from 0.3% to 5%. A salinity of 5% leads to a biomass share of 7.6% of compatible solutes and the very low salt level of 0.3% results in an 18-fold increased putrescine concentration compared with environmental conditions. Additionally, the substitution of glutamate by GGA has been shown during exposure to nitrogen limitation and in the stationary growth phase of the organism. Salt shock transcriptome analysis of D. shibae has revealed the essential role of its 153 kb chromid, which carries the genes for GG biosynthesis and several transport and exchange systems. Within the family of Rhodobacteraceae, the genomic capability of forming GG and GGA is strictly restricted to marine family members.
en
Dealing with salinity extremes and nitrogen limitation - an unexpected strategy of the marine bacterium Dinoroseobacter shibae.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621018/1/Kleist%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6210632019-08-30T11:36:05Zcom_10033_311624com_10033_6839com_10033_620636col_10033_311625col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Swierzy, Izabela J
author
Händel, Ulrike
author
Kaever, Alexander
author
Jarek, Michael
author
Scharfe, Maren
author
Schlüter, Dirk
author
Lüder, Carsten G K
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-17T13:17:32Z
2017-08-03
Divergent co-transcriptomes of different host cells infected with Toxoplasma gondii reveal cell type-specific host-parasite interactions. 2017, 7 (1):7229 Sci Rep
2045-2322
28775382
10.1038/s41598-017-07838-w
http://hdl.handle.net/10033/621063
Scientific reports
The apicomplexan parasite Toxoplasma gondii infects various cell types in avian and mammalian hosts including humans. Infection of immunocompetent hosts is mostly asymptomatic or benign, but leads to development of largely dormant bradyzoites that persist predominantly within neurons and muscle cells. Here we have analyzed the impact of the host cell type on the co-transcriptomes of host and parasite using high-throughput RNA sequencing. Murine cortical neurons and astrocytes, skeletal muscle cells (SkMCs) and fibroblasts differed by more than 16,200 differentially expressed genes (DEGs) before and after infection with T. gondii. However, only a few hundred of them were regulated by infection and these largely diverged in neurons, SkMCs, astrocytes and fibroblasts indicating host cell type-specific transcriptional responses after infection. The heterogeneous transcriptomes of host cells before and during infection coincided with ~5,400 DEGs in T. gondii residing in different cell types. Finally, we identified gene clusters in both T. gondii and its host, which correlated with the predominant parasite persistence in neurons or SkMCs as compared to astrocytes or fibroblasts. Thus, heterogeneous expression profiles of different host cell types and the parasites' ability to adapting to them may govern the parasite-host cell interaction during toxoplasmosis.
en
Divergent co-transcriptomes of different host cells infected with Toxoplasma gondii reveal cell type-specific host-parasite interactions.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621063/1/Swierzy%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6210702019-08-30T11:32:17Zcom_10033_128109com_10033_620636col_10033_128110col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Nikolouli, Eirini
author
Hardtke-Wolenski, Matthias
author
Hapke, Martin
author
Beckstette, Michael
author
Geffers, Robert
author
Floess, Stefan
author
Jaeckel, Elmar
author
Huehn, Jochen
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-22T13:53:21Z
2017
Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance. 2017, 8:748 Front Immunol
1664-3224
28702031
10.3389/fimmu.2017.00748
http://hdl.handle.net/10033/621070
Frontiers in immunology
Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self-tolerance and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by expression of the transcription factor Foxp3, and recent work suggests that epigenetic imprinting of Foxp3 and other Treg-specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, vitamin C was reported to enhance the activity of enzymes of the ten-eleven translocation family, thereby fostering the demethylation of Foxp3 and other Treg-specific epigenetic signatures genes in developing Tregs. Here, we in vitro generated alloantigen-induced Foxp3(+) Tregs (allo-iTregs) in presence of vitamin C. Although vitamin C hardly influenced the transcriptome of allo-iTregs as revealed by RNA-seq, those vitamin C-treated allo-iTregs showed a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signatures genes accompanied with an enhanced stability of Foxp3 expression. Accordingly, when being tested in vivo in an allogeneic skin transplantation model, vitamin C-treated allo-iTregs showed a superior suppressive capacity. Together, our results pave the way for the establishment of novel protocols for the in vitro generation of alloantigen-induced Foxp3(+) Tregs for therapeutic use in transplantation medicine.
en
Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621070/1/Nikolouli%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6210872019-08-30T11:36:33Zcom_10033_620636col_10033_620638
Helmholtz Zentrum für Infektionsforschung Repository
author
Möbius, Petra
author
Nordsiek, Gabriele
author
Hölzer, Martin
author
Jarek, Michael
author
Marz, Manja
author
Köhler, Heike
department
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-09-04T10:59:13Z
2017-08-24
Complete Genome Sequence of JII-1961, a Bovine Mycobacterium avium subsp. paratuberculosis Field Isolate from Germany. 2017, 5 (34) Genome Announc
2169-8287
28839035
10.1128/genomeA.00870-17
http://hdl.handle.net/10033/621087
Genome announcements
Mycobacterium avium subsp. paratuberculosis causes Johne's disease in ruminants and was also detected in nonruminant species, including human beings, and in milk products. We announce here the 4.829-Mb complete genome sequence of the cattle-type strain JII-1961 from Germany, which is very similar to cattle-type strains recovered from different continents.
en
Complete Genome Sequence of JII-1961, a Bovine Mycobacterium avium subsp. paratuberculosis Field Isolate from Germany.
Article
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https://hzi.openrepository.com/bitstream/10033/621087/1/M%c3%b6bius%20et%20al.pdf
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Möbius et al.pdf
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Möbius et al.pdf.txt
mets///col_10033_620638/100