TY  - JOUR
A1  - Ullrich, M
A1  - Weber, M
A1  - Post, A M
A1  - Popp, S
A1  - Grein, J
A1  - Zechner, M
A1  - González, H Guerrero
A1  - Kreis, A
A1  - Schmitt, A G
A1  - Üҫeyler, N
A1  - Lesch, K-P
A1  - Schuh, K
T1  - OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency
JF  - Molecular Psychiatry
N2  - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.
KW  - molecular biology
KW  - neuroscience
KW  - physiology
KW  - psychiatric disorders
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232096
VL  - 23
ER  - 
TY  - JOUR
A1  - Trautz, Florian
A1  - Franke, Heike
A1  - Bohnert, Simone
A1  - Hammer, Niels
A1  - Müller, Wolf
A1  - Stassart, Ruth
A1  - Tse, Rexson
A1  - Zwirner, Johann
A1  - Dreßler, Jan
A1  - Ondruschka, Benjamin
T1  - Survival-time dependent increase in neuronal IL-6 and astroglial GFAP expression in fatally injured human brain tissue
JF  - Scientific Reports
N2  - Knowledge on trauma survival time prior to death following a lethal traumatic brain injury (TBI) may be essential for legal purposes. Immunohistochemistry studies might allow to narrow down this survival interval. The biomarkers interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) are well known in the clinical setting for their usability in TBI prediction. Here, both proteins were chosen in forensics to determine whether neuronal or glial expression in various brain regions may be associated with the cause of death and the survival time prior to death following TBI. IL-6 positive neurons, glial cells and GFAP positive astrocytes all concordantly increase with longer trauma survival time, with statistically significant changes being evident from three days post-TBI (p < 0.05) in the pericontusional zone, irrespective of its definite cortical localization. IL-6 staining in neurons increases significantly in the cerebellum after trauma, whereas increasing GFAP positivity is also detected in the cortex contralateral to the focal lesion. These systematic chronological changes in biomarkers of pericontusional neurons and glial cells allow for an estimation of trauma survival time. Higher numbers of IL-6 and GFAP-stained cells above threshold values in the pericontusional zone substantiate the existence of fatal traumatic changes in the brain with reasonable certainty.
KW  - cell death in the nervous system
KW  - diagnostic markers
KW  - outcomes research
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229037
VL  - 9
ER  - 
TY  - JOUR
A1  - Tylek, Tina
A1  - Schilling, Tatjana
A1  - Schlegelmilch, Katrin
A1  - Ries, Maximilian
A1  - Rudert, Maximilian
A1  - Jakob, Franz
A1  - Groll, Jürgen
T1  - Platelet lysate outperforms FCS and human serum for co-culture of primary human macrophages and hMSCs
JF  - Scientific Reports
N2  - In vitro co-cultures of different primary human cell types are pivotal for the testing and evaluation of biomaterials under conditions that are closer to the human in vivo situation. Especially co-cultures of macrophages and mesenchymal stem cells (MSCs) are of interest, as they are both present and involved in tissue regeneration and inflammatory reactions and play crucial roles in the immediate inflammatory reactions and the onset of regenerative processes, thus reflecting the decisive early phase of biomaterial contact with the host. A co-culture system of these cell types might thus allow for the assessment of the biocompatibility of biomaterials. The establishment of such a co-culture is challenging due to the different in vitro cell culture conditions. For human macrophages, medium is usually supplemented with human serum (hS), whereas hMSC culture is mostly performed using fetal calf serum (FCS), and these conditions are disadvantageous for the respective other cell type. We demonstrate that human platelet lysate (hPL) can replace hS in macrophage cultivation and appears to be the best option for co-cultivation of human macrophages with hMSCs. In contrast to FCS and hS, hPL maintained the phenotype of both cell types, comparable to that of their respective standard culture serum, as well as the percentage of each cell population. Moreover, the expression profile and phagocytosis activity of macrophages was similar to hS.
KW  - biomaterials – cells
KW  - tissue engineering
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229174
VL  - 9
ER  - 
TY  - JOUR
A1  - Straub, Tobias
A1  - Freudenberg, Marina A.
A1  - Schleicher, Ulrike
A1  - Bogdan, Christian
A1  - Gasteiger, Georg
A1  - Pircher, Hanspeter
T1  - Bacterial coinfection restrains antiviral CD8 T-cell response via LPS-induced inhibitory NK cells
JF  - Nature Communications
N2  - Infection of specific pathogen-free mice with lymphocytic choriomeningitis virus (LCMV) is a widely used model to study antiviral T-cell immunity. Infections in the real world, however, are often accompanied by coinfections with unrelated pathogens. Here we show that in mice, systemic coinfection with E. coli suppresses the LCMV-specific cytotoxic T-lymphocyte (CTL) response and virus elimination in a NK cell- and TLR2/4-dependent manner. Soluble TLR4 ligand LPS also induces NK cell-mediated negative CTL regulation during LCMV infection. NK cells in LPS-treated mice suppress clonal expansion of LCMV-specific CTLs by a NKG2D- or NCR1-independent but perforin-dependent mechanism. These results suggest a TLR4-mediated immunoregulatory role of NK cells during viral-bacterial coinfections.
KW  - Bacterial infection
KW  - infection
KW  - lymphocyte activation
KW  - viral infection
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240075
VL  - 9
ER  - 
TY  - JOUR
A1  - Vujanić, Gordan M.
A1  - Gessler, Manfred
A1  - Ooms, Ariadne H. A. G.
A1  - Collini, Paola
A1  - Coulomb-l'Hermine, Aurore
A1  - D'Hooghe, Ellen
A1  - de Krijger, Ronald R.
A1  - Perotti, Daniela
A1  - Pritchard-Jones, Kathy
A1  - Vokuhl, Christian
A1  - van den Heuvel-Eibrink, Marry M.
A1  - Graf, Norbert
T1  - The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol
JF  - Nature Reviews Urology
N2  - On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel.
KW  - molecular biology
KW  - paediatric cancer
KW  - pathology
KW  - renal cancer
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233265
VL  - 15
ER  - 
TY  - JOUR
A1  - Tan, Z. B.
A1  - Elo, T.
A1  - Puska, A.
A1  - Sarkar, J.
A1  - Lähteenmäki, P.
A1  - Duerr, F.
A1  - Gould, C.
A1  - Molenkamp, L. W.
A1  - Nagaev, K. E.
A1  - Hakonen, P. J.
T1  - Hanbury-Brown and Twiss exchange and non-equilibrium-induced correlations in disordered, four-terminal graphene-ribbon conductor
JF  - Scientific Reports
N2  - We have investigated current-current correlations in a cross-shaped conductor made of graphene. The mean free path of charge carriers is on the order of the ribbon width which leads to a hybrid conductor where there is diffusive transport in the device arms while the central connection region displays near ballistic transport. Our data on auto and cross correlations deviate from the predictions of Landauer-Büttiker theory, and agreement can be obtained only by taking into account contributions from non-thermal electron distributions at the inlets to the semiballistic center, in which the partition noise becomes strongly modified. The experimental results display distinct Hanbury – Brown and Twiss (HBT) exchange correlations, the strength of which is boosted by the non-equilibrium occupation-number fluctuations internal to this hybrid conductor. Our work demonstrates that variation in electron coherence along atomically-thin, two-dimensional conductors has significant implications on their noise and cross correlation properties.
KW  - conductive hybrid
KW  - partition noise
KW  - occupation number fluctuations
KW  - current-current correlation
KW  - device arm
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240348
VL  - 8
ER  - 
TY  - JOUR
A1  - Woodcock, B. A.
A1  - Garratt, M. P. D.
A1  - Powney, G. D.
A1  - Shaw, R. F.
A1  - Osborne, J. L.
A1  - Soroka, J.
A1  - Lindström, S. A. M.
A1  - Stanley, D.
A1  - Ouvrard, P.
A1  - Edwards, M. E.
A1  - Jauker, F.
A1  - McCracken, M. E.
A1  - Zou, Y.
A1  - Potts, S. G.
A1  - Rundlöf, M.
A1  - Noriega, J. A.
A1  - Greenop, A.
A1  - Smith, H. G.
A1  - Bommarco, R.
A1  - van der Werf, W.
A1  - Stout, J. C.
A1  - Steffan-Dewenter, I.
A1  - Morandin, L.
A1  - Bullock, J. M.
A1  - Pywell, R. F.
T1  - Meta-analysis reveals that pollinator functional diversity and abundance enhance crop pollination and yield
JF  - Nature Communications
N2  - How insects promote crop pollination remains poorly understood in terms of the contribution of functional trait differences between species. We used meta-analyses to test for correlations between community abundance, species richness and functional trait metrics with oilseed rape yield, a globally important crop. While overall abundance is consistently important in predicting yield, functional divergence between species traits also showed a positive correlation. This result supports the complementarity hypothesis that pollination function is maintained by non-overlapping trait distributions. In artificially constructed communities (mesocosms), species richness is positively correlated with yield, although this effect is not seen under field conditions. As traits of the dominant species do not predict yield above that attributed to the effect of abundance alone, we find no evidence in support of the mass ratio hypothesis. Management practices increasing not just pollinator abundance, but also functional divergence, could benefit oilseed rape agriculture.
KW  - agroecology
KW  - agriculture
KW  - ecosystem services
KW  - environmental sciences
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233787
VL  - 10
ER  - 
TY  - JOUR
A1  - Went, Molly
A1  - Sud, Amit
A1  - Speedy, Helen
A1  - Sunter, Nicola J.
A1  - Försti, Asta
A1  - Law, Philip J.
A1  - Johnson, David C.
A1  - Mirabella, Fabio
A1  - Holroyd, Amy
A1  - Li, Ni
A1  - Orlando, Giulia
A1  - Weinhold, Niels
A1  - van Duin, Mark
A1  - Chen, Bowang
A1  - Mitchell, Jonathan S.
A1  - Mansouri, Larry
A1  - Juliusson, Gunnar
A1  - Smedby, Karin E
A1  - Jayne, Sandrine
A1  - Majid, Aneela
A1  - Dearden, Claire
A1  - Allsup, David J.
A1  - Bailey, James R.
A1  - Pratt, Guy
A1  - Pepper, Chris
A1  - Fegan, Chris
A1  - Rosenquist, Richard
A1  - Kuiper, Rowan
A1  - Stephens, Owen W.
A1  - Bertsch, Uta
A1  - Broderick, Peter
A1  - Einsele, Hermann
A1  - Gregory, Walter M.
A1  - Hillengass, Jens
A1  - Hoffmann, Per
A1  - Jackson, Graham H.
A1  - Jöckel, Karl-Heinz
A1  - Nickel, Jolanta
A1  - Nöthen, Markus M.
A1  - da Silva Filho, Miguel Inacio
A1  - Thomsen, Hauke
A1  - Walker, Brian A.
A1  - Broyl, Annemiek
A1  - Davies, Faith E.
A1  - Hansson, Markus
A1  - Goldschmidt, Hartmut
A1  - Dyer, Martin J. S.
A1  - Kaiser, Martin
A1  - Sonneveld, Pieter
A1  - Morgan, Gareth J.
A1  - Hemminki, Kari
A1  - Nilsson, Björn
A1  - Catovsky, Daniel
A1  - Allan, James M.
A1  - Houlston, Richard S.
T1  - Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
JF  - Blood Cancer Journal
N2  - The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
KW  - cancer genetics
KW  - myeloma
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233627
VL  - 9
ER  - 
TY  - JOUR
A1  - Wen, Lai
A1  - Feil, Susanne
A1  - Wolters, Markus
A1  - Thunemann, Martin
A1  - Regler, Frank
A1  - Schmidt, Kjestine
A1  - Friebe, Andreas
A1  - Olbrich, Marcus
A1  - Langer, Harald
A1  - Gawaz, Meinrad
A1  - de Wit, Cor
A1  - Feil, Robert
T1  - A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis
JF  - Nature Communications
N2  - Mechanisms that limit thrombosis are poorly defined. One of the few known endogenous platelet inhibitors is nitric oxide (NO). NO activates NO sensitive guanylyl cyclase (NO-GC) in platelets, resulting in an increase of cyclic guanosine monophosphate (cGMP). Here we show, using cGMP sensor mice to study spatiotemporal dynamics of platelet cGMP, that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent. We delineate a new mode of platelet-inhibitory mechanotransduction via shear-activated NO-GC followed by cGMP synthesis, activation of cGMP-dependent protein kinase I (cGKI), and suppression of Ca2+ signaling. Correlative profiling of cGMP dynamics and thrombus formation in vivo indicates that high cGMP concentrations in shear-exposed platelets at the thrombus periphery limit thrombosis, primarily through facilitation of thrombus dissolution. We propose that an increase in shear stress during thrombus growth activates the NO-cGMP-cGKI pathway, which acts as an auto-regulatory brake to prevent vessel occlusion, while preserving wound closure under low shear.
KW  - calcium signalling
KW  - fluorescence imaging
KW  - platelets
KW  - thrombosis
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233616
VL  - 9
ER  - 
TY  - JOUR
A1  - Welz, M.
A1  - Eickhoff, S.
A1  - Abdullah, Z.
A1  - Trebicka, J.
A1  - Gartlan, K. H.
A1  - Spicer, J. A.
A1  - Demetris, A. J.
A1  - Akhlaghi, H.
A1  - Anton, M.
A1  - Manske, K.
A1  - Zehn, D.
A1  - Nieswandt, B.
A1  - Kurts, C.
A1  - Trapani, J. A.
A1  - Knolle, P.
A1  - Wohlleber, D.
A1  - Kastenmüller, W.
T1  - Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis
JF  - Nature Communications
N2  - CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.
KW  - cytotoxic T cells
KW  - hepatology
KW  - imaging the immune system
KW  - viral infection
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233593
VL  - 9
ER  - 
TY  - JOUR
A1  - Walker, Brian A.
A1  - Mavrommatis, Konstantinos
A1  - Wardell, Christopher P.
A1  - Ashby, T. Cody
A1  - Bauer, Michael
A1  - Davies, Faith
A1  - Rosenthal, Adam
A1  - Wang, Hongwei
A1  - Qu, Pingping
A1  - Hoering, Antje
A1  - Samur, Mehmet
A1  - Towfic, Fadi
A1  - Ortiz, Maria
A1  - Flynt, Erin
A1  - Yu, Zhinuan
A1  - Yang, Zhihong
A1  - Rozelle, Dan
A1  - Obenauer, John
A1  - Trotter, Matthew
A1  - Auclair, Daniel
A1  - Keats, Jonathan
A1  - Bolli, Niccolo
A1  - Fulciniti, Mariateresa
A1  - Szalat, Raphael
A1  - Moreau, Phillipe
A1  - Durie, Brian
A1  - Stewart, A. Keith
A1  - Goldschmidt, Hartmut
A1  - Raab, Marc S.
A1  - Einsele, Hermann
A1  - Sonneveld, Pieter
A1  - San Miguel, Jesus
A1  - Lonial, Sagar
A1  - Jackson, Graham H.
A1  - Anderson, Kenneth C.
A1  - Avet-Loiseau, Herve
A1  - Munshi, Nikhil
A1  - Thakurta, Anjan
A1  - Morgan, Gareth
T1  - A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis
JF  - Leukemia
N2  - Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
KW  - cancer genomics
KW  - risk factors
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233299
VL  - 33
ER  - 
TY  - JOUR
A1  - Wegert, Jenny
A1  - Vokuhl, Christian
A1  - Collord, Grace
A1  - Del Castillo Velasco-Herrera, Martin
A1  - Farndon, Sarah J.
A1  - Guzzo, Charlotte
A1  - Jorgensen, Mette
A1  - Anderson, John
A1  - Slater, Olga
A1  - Duncan, Catriona
A1  - Bausenwein, Sabrina
A1  - Streitenberger, Heike
A1  - Ziegler, Barbara
A1  - Furtwängler, Rhoikos
A1  - Graf, Norbert
A1  - Stratton, Michael R.
A1  - Campbell, Peter J.
A1  - Jones, David TW
A1  - Koelsche, Christian
A1  - Pfister, Stefan M.
A1  - Mifsud, William
A1  - Sebire, Neil
A1  - Sparber-Sauer, Monika
A1  - Koscielniak, Ewa
A1  - Rosenwald, Andreas
A1  - Gessler, Manfred
A1  - Behjati, Sam
T1  - Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants
JF  - Nature Communications
N2  - Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.
KW  - cancer
KW  - genetics
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233446
VL  - 9
ER  - 
TY  - JOUR
A1  - Waldherr, Max
A1  - Lundt, Nils
A1  - Klaas, Martin
A1  - Betzold, Simon
A1  - Wurdack, Matthias
A1  - Baumann, Vasilij
A1  - Estrecho, Eliezer
A1  - Nalitov, Anton
A1  - Cherotchenko, Evgenia
A1  - Cai, Hui
A1  - Ostrovskaya, Elena A.
A1  - Kavokin, Alexey V.
A1  - Tongay, Sefaattin
A1  - Klembt, Sebastian
A1  - Höfling, Sven
A1  - Schneider, Christian
T1  - Observation of bosonic condensation in a hybrid monolayer MoSe2-GaAs microcavity
JF  - Nature Communications
N2  - Bosonic condensation belongs to the most intriguing phenomena in physics, and was mostly reserved for experiments with ultra-cold quantum gases. More recently, it became accessible in exciton-based solid-state systems at elevated temperatures. Here, we demonstrate bosonic condensation driven by excitons hosted in an atomically thin layer of MoSe2, strongly coupled to light in a solid-state resonator. The structure is operated in the regime of collective strong coupling between a Tamm-plasmon resonance, GaAs quantum well excitons, and two-dimensional excitons confined in the monolayer crystal. Polariton condensation in a monolayer crystal manifests by a superlinear increase of emission intensity from the hybrid polariton mode, its density-dependent blueshift, and a dramatic collapse of the emission linewidth, a hallmark of temporal coherence. Importantly, we observe a significant spin-polarization in the injected polariton condensate, a fingerprint for spin-valley locking in monolayer excitons. Our results pave the way towards highly nonlinear, coherent valleytronic devices and light sources.
KW  - polaritons
KW  - two-dimensional materials
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233280
VL  - 9
ER  - 
TY  - JOUR
A1  - Annunziata, Ida
A1  - van de Vlekkert, Diantha
A1  - Wolf, Elmar
A1  - Finkelstein, David
A1  - Neale, Geoffrey
A1  - Machado, Eda
A1  - Mosca, Rosario
A1  - Campos, Yvan
A1  - Tillman, Heather
A1  - Roussel, Martine F.
A1  - Weesner, Jason Andrew
A1  - Fremuth, Leigh Ellen
A1  - Qiu, Xiaohui
A1  - Han, Min-Joon
A1  - Grosveld, Gerard C.
A1  - d'Azzo, Alessandra
T1  - MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat
JF  - Nature Communications
N2  - Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.
KW  - autophagy
KW  - cancer
KW  - cancer metabolism
KW  - cell biology
KW  - mechanisms of disease
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221189
VL  - 10
ER  - 
TY  - JOUR
A1  - Anany, Mohamed A.
A1  - Kreckel, Jennifer
A1  - Füllsack, Simone
A1  - Rosenthal, Alevtina
A1  - Otto, Christoph
A1  - Siegmund, Daniela
A1  - Wajant, Harald
T1  - Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis
JF  - Cell Death & Disease
N2  - TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants.
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221104
VL  - 9
ER  - 
TY  - JOUR
A1  - Lee, Hong-Jen
A1  - Li, Chien-Feng
A1  - Ruan, Diane
A1  - He, Jiabei
A1  - Montal, Emily D.
A1  - Lorenz, Sonja
A1  - Girnun, Geoffrey D.
A1  - Chan, Chia-Hsin
T1  - Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion
JF  - Nature Communications
N2  - Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.
KW  - cancer
KW  - cancer metabolism
KW  - molecular biology
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236445
VL  - 10
ER  - 
TY  - JOUR
A1  - Langhauser, Friederike
A1  - Casas, Ana I.
A1  - Dao, Vu-Thao-Vi
A1  - Guney, Emre
A1  - Menche, Jörg
A1  - Geuss, Eva
A1  - Kleikers, Pamela W. M.
A1  - López, Manuela G.
A1  - Barabási, Albert-L.
A1  - Kleinschnitz, Christoph
A1  - Schmidt, Harald H. H. W.
T1  - A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection
JF  - npj Systems Biology and Applications
N2  - Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.
KW  - neurology
KW  - pharmacology
KW  - systems biology
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236381
VL  - 4
ER  - 
TY  - JOUR
A1  - Liao, Chunyu
A1  - Ttofali, Fani
A1  - Slotkowski, Rebecca A.
A1  - Denny, Steven R.
A1  - Cecil, Taylor D.
A1  - Leenay, Ryan T.
A1  - Keung, Albert J.
A1  - Beisel, Chase L.
T1  - Modular one-pot assembly of CRISPR arrays enables library generation and reveals factors influencing crRNA biogenesis
JF  - Nature Communications
N2  - CRISPR-Cas systems inherently multiplex through CRISPR arrays—whether to defend against different invaders or mediate multi-target editing, regulation, imaging, or sensing. However, arrays remain difficult to generate due to their reoccurring repeat sequences. Here, we report a modular, one-pot scheme called CRATES to construct CRISPR arrays and array libraries. CRATES allows assembly of repeat-spacer subunits using defined assembly junctions within the trimmed portion of spacers. Using CRATES, we construct arrays for the single-effector nucleases Cas9, Cas12a, and Cas13a that mediated multiplexed DNA/RNA cleavage and gene regulation in cell-free systems, bacteria, and yeast. CRATES further allows the one-pot construction of array libraries and composite arrays utilized by multiple Cas nucleases. Finally, array characterization reveals processing of extraneous CRISPR RNAs from Cas12a terminal repeats and sequence- and context-dependent loss of RNA-directed nuclease activity via global RNA structure formation. CRATES thus can facilitate diverse multiplexing applications and help identify factors impacting crRNA biogenesis.
KW  - biotechnology
KW  - CRISPR-Cas systems
KW  - microbiology
KW  - small RNAs
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236843
VL  - 10
ER  - 
TY  - JOUR
A1  - Levy, Marion J. F.
A1  - Boulle, Fabien
A1  - Emerit, Michel Boris
A1  - Poilbout, Corinne
A1  - Steinbusch, Harry W. M.
A1  - Van den Hove, Daniel L. A.
A1  - Kenis, Gunter
A1  - Lanfumey, Laurence
T1  - 5-HTT independent effects of fluoxetine on neuroplasticity
JF  - Scientific Reports
N2  - Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB.
KW  - depression
KW  - neurotrophic factors
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236759
VL  - 9
ER  - 
TY  - JOUR
A1  - Lee, Ching Hua
A1  - Imhof, Stefan
A1  - Berger, Christian
A1  - Bayer, Florian
A1  - Brehm, Johannes
A1  - Molenkamp, Laurens W.
A1  - Kiessling, Tobias
A1  - Thomale, Ronny
T1  - Topolectrical Circuits
JF  - Communications Physics
N2  - Invented by Alessandro Volta and Félix Savary in the early 19th century, circuits consisting of resistor, inductor and capacitor (RLC) components are omnipresent in modern technology. The behavior of an RLC circuit is governed by its circuit Laplacian, which is analogous to the Hamiltonian describing the energetics of a physical system. Here we show that topological insulating and semimetallic states can be realized in a periodic RLC circuit. Topological boundary resonances (TBRs) appear in the impedance read-out of a topolectrical circuit, providing a robust signal for the presence of topological admittance bands. For experimental illustration, we build the Su-Schrieffer–Heeger circuit, where our impedance measurement detects the TBR midgap state. Topolectrical circuits establish a bridge between electrical engineering and topological states of matter, where the accessibility, scalability, and operability of electronics synergizes with the intricate boundary properties of topological phases.
KW  - electronics, photonics and device physics
KW  - topological insulators
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236422
VL  - 1
ER  -