TY  - JOUR
A1  - Adam, W.
A1  - Ahrweiler, M.
A1  - Saha-Möller, C. R.
A1  - Sauter, M.
A1  - Schönberger, A.
A1  - Epe, B.
A1  - Müller, E.
A1  - Schiffmann, D.
A1  - Stopper, Helga
A1  - Wild, D.
T1  - Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells
N2  - 1.2-Dioxetanes, very reactive and high energy molecules. are involved as labile intermediates in dioxygenase- activated aerobic metabolism and in physiological processes. Various toxico1ogica1 tests reveal that dioxetanes are indeed genotoxic. In supercoiled DNA of bacteriophage PM2 they induce endonucleasesensitive sites, most of them are FPG protein-sensitive base modifications (8-hydroxyguanine, fonnamidopyrimidines). Pyrimidinedimersand sites ofbase loss (AP sites) which were probed by UV endonuclease and exonuclease 111 are minor lesions in this system. While the alky1-substituted dioxetanes do not show any significant mutagenic activity in different Salmonella typhimurium strains, heteroarene dioxetanes such as benzofuran and furocoumarin dioxetanes are strongly mutagenic in S. typhimurium strain TA I 00. DNA adducts formed with an intermediary alkyJating agent appear to be responsible for the mutagenic activity of benzofuran dioxetane. We assume that the benzofuran epoxides, generated in situ from benzofuran dioxetanes by deoxygenation are the ultimate mutagens of the latter. since benzofuran epoxides are highly mutagenic in the S. typhimurium strain TAIOO and they form DNA adducts. as detected by the 212Ppostlabelling technique. Our results imply that the type of D NA darnage promoted by dioxetanes is dependent on the structural feature of dioxetanes. Furthermore, the direct photochemical DNA darnage by energy transfer. i.e., pyrimidine dimers, plays a minor role in the genotoxicity of dioxetanes. Instead, photooxidation dominates in isolated DNA. while radical darnage and alkylation prevail in the cellular system.
KW  - Toxikologie
KW  - 1
KW  - 2-Dioxetane
KW  - Benzefuran dioxetane
KW  - Benzefuran epoxide
KW  - DNA damage
KW  - Mutagenicity
KW  - DNA adduct . Repair endonuclease
KW  - FPG protein
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63420
ER  - 
TY  - JOUR
A1  - Hennig, Thomas
A1  - Djakovic, Lara
A1  - Dölken, Lars
A1  - Whisnant, Adam W.
T1  - A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery
JF  - Viruses
N2  - During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional control. This review summarizes the array of impacts that HSV has on RNA Polymerase (Pol) II, which transcribes all mRNA in infected cells. We discuss alterations in Pol II holoenzymes, post-translational modifications, and how viral proteins regulate specific activities such as promoter-proximal pausing, splicing, histone repositioning, and termination with respect to host genes. Recent technological innovations that have reshaped our understanding of previous observations are summarized in detail, along with specific research directions and technical considerations for future studies.
KW  - herpes simplex virus
KW  - RNA polymerase II
KW  - transcription
KW  - host shutoff
KW  - promoter-proximal pausing
KW  - C-terminal domain
KW  - polyadenylation
KW  - splicing
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246165
SN  - 1999-4915
VL  - 13
IS  - 9
ER  - 
TY  - JOUR
A1  - Manchia, Mirko
A1  - Adli, Mazda
A1  - Akula, Nirmala
A1  - Arda, Raffaella
A1  - Aubry, Jean-Michel
A1  - Backlund, Lena
A1  - Banzato, Claudio E. M.
A1  - Baune, Bernhard T.
A1  - Bellivier, Frank
A1  - Bengesser, Susanne
A1  - Biernacka, Joanna M.
A1  - Brichant-Petitjean, Clara
A1  - Bui, Elise
A1  - Calkin, Cynthia V.
A1  - Cheng, Andrew Tai Ann
A1  - Chillotti, Caterina
A1  - Cichon, Sven
A1  - Clark, Scott
A1  - Czerski, Piotr M.
A1  - Dantas, Clarissa
A1  - Del Zompo, Maria
A1  - DePaulo, J. Raymond
A1  - Detera-Wadleigh, Sevilla D.
A1  - Etain, Bruno
A1  - Falkai, Peter
A1  - Frisén, Louise
A1  - Frye, Mark A.
A1  - Fullerton, Jan
A1  - Gard, Sébastien
A1  - Garnham, Julie
A1  - Goes, Fernando S.
A1  - Grof, Paul
A1  - Gruber, Oliver
A1  - Hashimoto, Ryota
A1  - Hauser, Joanna
A1  - Heilbronner, Urs
A1  - Hoban, Rebecca
A1  - Hou, Liping
A1  - Jamain, Stéphane
A1  - Kahn, Jean-Pierre
A1  - Kassem, Layla
A1  - Kato, Tadafumi
A1  - Kelsoe, John R.
A1  - Kittel-Schneider, Sarah
A1  - Kliwicki, Sebastian
A1  - Kuo, Po-Hsiu
A1  - Kusumi, Ichiro
A1  - Laje, Gonzalo
A1  - Lavebratt, Catharina
A1  - Leboyer, Marion
A1  - Leckband, Susan G.
A1  - López Jaramillo, Carlos A.
A1  - Maj, Mario
A1  - Malafosse, Alain
A1  - Martinsson, Lina
A1  - Masui, Takuya
A1  - Mitchell, Philip B.
A1  - Mondimore, Frank
A1  - Monteleone, Palmiero
A1  - Nallet, Audrey
A1  - Neuner, Maria
A1  - Novák, Tomás
A1  - O'Donovan, Claire
A1  - Ösby, Urban
A1  - Ozaki, Norio
A1  - Perlis, Roy H.
A1  - Pfennig, Andrea
A1  - Potash, James B.
A1  - Reich-Erkelenz, Daniela
A1  - Reif, Andreas
A1  - Reininghaus, Eva
A1  - Richardson, Sara
A1  - Rouleau, Guy A.
A1  - Rybakowski, Janusz K.
A1  - Schalling, Martin
A1  - Schofield, Peter R.
A1  - Schubert, Oliver K.
A1  - Schweizer, Barbara
A1  - Seemüller, Florian
A1  - Grigoroiu-Serbanescu, Maria
A1  - Severino, Giovanni
A1  - Seymour, Lisa R.
A1  - Slaney, Claire
A1  - Smoller, Jordan W.
A1  - Squassina, Alessio
A1  - Stamm, Thomas
A1  - Steele, Jo
A1  - Stopkova, Pavla
A1  - Tighe, Sarah K.
A1  - Tortorella, Alfonso
A1  - Turecki, Gustavo
A1  - Wray, Naomi R.
A1  - Wright, Adam
A1  - Zandi, Peter P.
A1  - Zilles, David
A1  - Bauer, Michael
A1  - Rietschel, Marcella
A1  - McMahon, Francis J.
A1  - Schulze, Thomas G.
A1  - Alda, Martin
T1  - Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report
JF  - PLoS ONE
N2  - Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. 
Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. 
Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). 
Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
KW  - age
KW  - observer agreement
KW  - prophylactic lithium
KW  - mapping susceptibility genes
KW  - mood disorders
KW  - onset
KW  - association
KW  - reliability
KW  - morality
KW  - illness
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130938
VL  - 8
IS  - 6
ER  - 
TY  - JOUR
A1  - Schartl, Manfred
A1  - Wittbrodt, J.
A1  - Mäueler, W.
A1  - Raulf, F.
A1  - Adam, D.
A1  - Hannig, G.
A1  - Telling, A.
A1  - Storch, F.
A1  - Andexinger, S.
A1  - Robertson, S. M.
T1  - Oncogenes and melanoma formation in Xiphoporus (Teleostei: Poeciliidae)
N2  - In Xiphophorus melanoma formation has been attributed by classical genetic findings to the overexpression of a cellular oncogene (Tu) due to elimination of the corresponding regulatory gene locus in hybrids. We have attempted to elucidate this phenomenon on the molecular biological level. Studies on the structure and expression of known proto-oncogenes revealed that several of these genes, especially the c-src gene of Xiphophorus, may act as effectors in establishing the neoplastic phenotype of the melanoma cells . However, these genes appear more to participate in secondary steps of tumorigenesis. Another gene, being termed Xmrk, which represents obviously a so far unknown proto-oncogene but with a cons iderably high similarity to the epidermal growth-factorreceptor gene, was mapped to the Tu-containing region of the chromosome. This gene shows features with respect to its structure and expression that seem to justify it to be regarded as a candidate for a gene involved in the primary processes leading to neoplastic transformation of pigment cells in Xiphophorus.
KW  - Schwertkärpfling
KW  - Onkogen
KW  - Melanom
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-87149
ER  - 
TY  - JOUR
A1  - Akshat, Puri
A1  - Aaboud, M.
A1  - Aad, G.
A1  - Abbott, B.
A1  - Abdinov, O.
A1  - Abeloos, B.
A1  - Abhayasinghe, D. K.
A1  - Abidi, S. H.
A1  - Abou Zeid, O. S.
A1  - Abraham, N. L.
A1  - Abramowicz, H.
A1  - Abreu, H.
A1  - Abulaiti, Y.
A1  - Acharya, B. S.
A1  - Adachi, S.
A1  - Adam, L.
A1  - Adamczyk, L.
A1  - Adelman, J.
A1  - Adersberger, M.
A1  - Adiguzel, A.
A1  - Adye, T.
A1  - Affolder, A. A.
A1  - Afik, Y.
A1  - Agheorghiesei, C.
A1  - Aguilar-Saavedra, J. A.
A1  - Ahmadov, F.
A1  - Aiellil, G.
A1  - Akatsuka, S.
A1  - Akesson, T. P. A.
A1  - Akilli, E.
A1  - Akimov, A. V.
A1  - Alberghi, G. L.
A1  - Albert, J.
A1  - Albicocco, P.
A1  - Alconada Verzini, M. J.
A1  - Alderweireld, S.
A1  - Aleksa, M.
A1  - Aleksandrov, I. N.
A1  - Alexa, C.
A1  - Alexopoulos, T.
A1  - Alhroob, M.
A1  - Ali, B.
A1  - Alimonti, G.
A1  - Alison, J.
A1  - Andre, S. P.
A1  - Allaire, C.
A1  - Allbrooke, B. M. M.
A1  - Allen, B. W.
A1  - Allport, P. P.
A1  - Aloisio, A.
A1  - Alonso, A.
A1  - Alonso, F.
A1  - Alpigiani, C.
A1  - Alshehri, A. A.
A1  - Alstaty, M. I.
A1  - Alvarez, Gonzalez B.
A1  - Alvarez Piqueras, D.
A1  - Alviggi, M. G.
A1  - Amadio, B. T.
A1  - Amaral, Coutinho, Y.
A1  - Ambler, A.
A1  - Ambroz, L.
A1  - Amelung, C.
A1  - Amidei, D.
A1  - Amor Dos Santos, S. P.
A1  - Amoroso, S.
A1  - Amrouche, C. S.
A1  - Anastopoulos, C.
A1  - Ancu, L. S.
A1  - Andari, N.
A1  - Andeen, T.
A1  - Anders, C. F.
A1  - Anders, J. K.
A1  - Anderson, K. J.
A1  - Andreazza, A.
A1  - Andrei, V.
A1  - et al, 
T1  - Measurement of angular and momentum distributions of charged particles within and around jets in Pb plus Pb and pp collisions at root s(NN)=5.02 TeV with ATLAS at the LHC : XXVIIth International Conference on Ultrarelativistic Nucleus-Nucleus Collisions
(Quark Matter 2018)
JF  - Nuclear Physics A
N2  - Studies of the fragmentation of jets into charged particles in heavy-ion collisions can help in understanding the mechanism of jet quenching by the hot and dense QCD matter created in such collisions, the quark-gluon plasma. These proceedings present a measurement of the angular distribution of charged particles around the jet axis in root s(NN) = 5.02 TeV Pb+Pb and pp collisions, done using the ATLAS detector at the LHC. The measurement is performed inside jets reconstructed with the anti-k(t) algorithm with radius parameter R = 0.4, and is extended to regions outside the jet cone. Results are presented as a function of Pb+Pb collision centrality, and both jet and charged-particle transverse momenta.
KW  - jets
KW  - fragmentation functions
KW  - jet shapes
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224703
VL  - 982
IS  - 2
ER  - 
TY  - JOUR
A1  - Djakovic, Lara
A1  - Hennig, Thomas
A1  - Reinisch, Katharina
A1  - Milić, Andrea
A1  - Whisnant, Adam W.
A1  - Wolf, Katharina
A1  - Weiß, Elena
A1  - Haas, Tobias
A1  - Grothey, Arnhild
A1  - Jürges, Christopher S.
A1  - Kluge, Michael
A1  - Wolf, Elmar
A1  - Erhard, Florian
A1  - Friedel, Caroline C.
A1  - Dölken, Lars
T1  - The HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes
JF  - Nature Communications
N2  - Herpes simplex virus 1 (HSV-1) infection and stress responses disrupt transcription termination by RNA Polymerase II (Pol II). In HSV-1 infection, but not upon salt or heat stress, this is accompanied by a dramatic increase in chromatin accessibility downstream of genes. Here, we show that the HSV-1 immediate-early protein ICP22 is both necessary and sufficient to induce downstream open chromatin regions (dOCRs) when transcription termination is disrupted by the viral ICP27 protein. This is accompanied by a marked ICP22-dependent loss of histones downstream of affected genes consistent with impaired histone repositioning in the wake of Pol II. Efficient knock-down of the ICP22-interacting histone chaperone FACT is not sufficient to induce dOCRs in ΔICP22 infection but increases dOCR induction in wild-type HSV-1 infection. Interestingly, this is accompanied by a marked increase in chromatin accessibility within gene bodies. We propose a model in which allosteric changes in Pol II composition downstream of genes and ICP22-mediated interference with FACT activity explain the differential impairment of histone repositioning downstream of genes in the wake of Pol II in HSV-1 infection.
KW  - herpes virus
KW  - transcription
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358161
VL  - 14
ER  - 
TY  - JOUR
A1  - Hennig, Thomas
A1  - Michalski, Marco
A1  - Rutkowski, Andrzej J.
A1  - Djakovic, Lara
A1  - Whisnant, Adam W.
A1  - Friedl, Marie-Sophie
A1  - Jha, Bhaskar Anand
A1  - Baptista, Marisa A. P.
A1  - L'Hernault, Anne
A1  - Erhard, Florian
A1  - Dölken, Lars
A1  - Friedel, Caroline C.
T1  - HSV-1-induced disruption of transcription termination resembles a cellular stress response but selectively increases chromatin accessibility downstream of genes
JF  - PLoS Pathogens
N2  - Lytic herpes simplex virus 1 (HSV-1) infection triggers disruption of transcription termination (DoTT) of most cellular genes, resulting in extensive intergenic transcription. Similarly, cellular stress responses lead to gene-specific transcription downstream of genes (DoG). In this study, we performed a detailed comparison of DoTT/DoG transcription between HSV-1 infection, salt and heat stress in primary human fibroblasts using 4sU-seq and ATAC-seq. Although DoTT at late times of HSV-1 infection was substantially more prominent than DoG transcription in salt and heat stress, poly(A) read-through due to DoTT/DoG transcription and affected genes were significantly correlated between all three conditions, in particular at earlier times of infection. We speculate that HSV-1 either directly usurps a cellular stress response or disrupts the transcription termination machinery in other ways but with similar consequences. In contrast to previous reports, we found that inhibition of Ca\(^{2+}\) signaling by BAPTA-AM did not specifically inhibit DoG transcription but globally impaired transcription. Most importantly, HSV-1-induced DoTT, but not stress-induced DoG transcription, was accompanied by a strong increase in open chromatin downstream of the affected poly(A) sites. In its extent and kinetics, downstream open chromatin essentially matched the poly(A) read-through transcription. We show that this does not cause but rather requires DoTT as well as high levels of transcription into the genomic regions downstream of genes. This raises intriguing new questions regarding the role of histone repositioning in the wake of RNA Polymerase II passage downstream of impaired poly(A) site recognition.
KW  - DNA transcription
KW  - dogs
KW  - thermal stresses
KW  - chromatin
KW  - histones
KW  - gene expression
KW  - cellular stress responses
KW  - transcriptional termination
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176350
VL  - 14
IS  - 3
ER  - 
TY  - INPR
A1  - Hennig, Thomas
A1  - Prusty, Archana B.
A1  - Kaufer, Benedikt
A1  - Whisnant, Adam W.
A1  - Lodha, Manivel
A1  - Enders, Antje
A1  - Thomas, Julius
A1  - Kasimir, Francesca
A1  - Grothey, Arnhild
A1  - Herb, Stefanie
A1  - Jürges, Christopher
A1  - Meister, Gunter
A1  - Erhard, Florian
A1  - Dölken, Lars
A1  - Prusty, Bhupesh K.
T1  - Selective inhibition of miRNA 1 processing by a herpesvirus encoded miRNA
N2  - Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily drugable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.
KW  - Herpesvirus
KW  - HHV-6A
KW  - miRNA processing
KW  - miR-30
KW  - mitochondria
KW  - fusion and fission
KW  - type I interferon
KW  - latency
KW  - virus reactivation
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267862
ET  - accepted version
ER  - 
TY  - INPR
A1  - Hennig, Thomas
A1  - Prusty, Archana B.
A1  - Kaufer, Benedikt
A1  - Whisnant, Adam W.
A1  - Lodha, Manivel
A1  - Enders, Antje
A1  - Thomas, Julius
A1  - Kasimir, Francesca
A1  - Grothey, Arnhild
A1  - Herb, Stefanie
A1  - Jürges, Christopher
A1  - Meister, Gunter
A1  - Erhard, Florian
A1  - Dölken, Lars
A1  - Prusty, Bhupesh K.
T1  - Selective inhibition of microRNA processing by a herpesvirus-encoded microRNA triggers virus reactivation from latency
N2  - Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture, which impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 was sufficient to trigger virus reactivation from latency thereby identifying it as a readily drugable master regulator of the herpesvirus latent-lytic switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders like myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and Long-COVID.
KW  - Herpesvirus
KW  - HHV-6
KW  - miRNA processing
KW  - miR-30
KW  - mitochondria
KW  - fusion and fission
KW  - type I interferon
KW  - latency
KW  - virus reactivation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267858
UR  - https://doi.org/10.21203/rs.3.rs-820696/v1
ET  - submitted version
ER  -