@article{HernandezJoseRamirezMinguillonetal.2018, author = {Hern{\´a}ndez, Gonzalo and Jos{\´e} Ram{\´i}rez, Mar{\´i}a and Minguill{\´o}n, Jordi and Quiles, Paco and Ruiz de Garibay, Gorka and Aza-Carmona, Miriam and Bogliolo, Massimo and Pujol, Roser and Prados-Carvajal, Rosario and Fern{\´a}ndez, Juana and Garc{\´i}a, Nadia and L{\´o}pez, Adri{\`a} and Guti{\´e}rrez-Enr{\´i}quez, Sara and Diez, Orland and Ben{\´i}tez, Javier and Salinas, M{\´o}nica and Teul{\´e}, Alex and Brunet, Joan and Radice, Paolo and Peterlongo, Paolo and Schindler, Detlev and Huertas, Pablo and Puente, Xose S. and L{\´a}zaro, Conxi and {\`A}ngel Pujana, Miquel and Surrall{\´e}s, Jordi}, title = {Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-03433-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319929}, year = {2018}, abstract = {BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.}, language = {en} } @article{GroebnerWorstWeischenfeldtetal.2018, author = {Gr{\"o}bner, Susanne N. and Worst, Barbara C. and Weischenfeldt, Joachim and Buchhalter, Ivo and Kleinheinz, Kortine and Rudneva, Vasilisa A. and Johann, Pascal D. and Balasubramanian, Gnana Prakash and Segura-Wang, Maia and Brabetz, Sebastian and Bender, Sebastian and Hutter, Barbara and Sturm, Dominik and Pfaff, Elke and H{\"u}bschmann, Daniel and Zipprich, Gideon and Heinold, Michael and Eils, J{\"u}rgen and Lawerenz, Christian and Erkek, Serap and Lambo, Sander and Waszak, Sebastian and Blattmann, Claudia and Borkhardt, Arndt and Kuhlen, Michaela and Eggert, Angelika and Fulda, Simone and Gessler, Manfred and Wegert, Jenny and Kappler, Roland and Baumhoer, Daniel and Stefan, Burdach and Kirschner-Schwabe, Renate and Kontny, Udo and Kulozik, Andreas E. and Lohmann, Dietmar and Hettmer, Simone and Eckert, Cornelia and Bielack, Stefan and Nathrath, Michaela and Niemeyer, Charlotte and Richter, G{\"u}nther H. and Schulte, Johannes and Siebert, Reiner and Westermann, Frank and Molenaar, Jan J. and Vassal, Gilles and Witt, Hendrik and Burkhardt, Birgit and Kratz, Christian P. and Witt, Olaf and van Tilburg, Cornelis M. and Kramm, Christof M. and Fleischhack, Gudrun and Dirksen, Uta and Rutkowski, Stefan and Fr{\"u}hwald, Michael and Hoff, Katja von and Wolf, Stephan and Klingebeil, Thomas and Koscielniak, Ewa and Landgraf, Pablo and Koster, Jan and Resnick, Adam C. and Zhang, Jinghui and Liu, Yanling and Zhou, Xin and Waanders, Angela J. and Zwijnenburg, Danny A. and Raman, Pichai and Brors, Benedikt and Weber, Ursula D. and Northcott, Paul A. and Pajtler, Kristian W. and Kool, Marcel and Piro, Rosario M. and Korbel, Jan O. and Schlesner, Matthias and Eils, Roland and Jones, David T. W. and Lichter, Peter and Chavez, Lukas and Zapatka, Marc and Pfister, Stefan M.}, title = {The landscape of genomic alterations across childhood cancers}, series = {Nature}, volume = {555}, journal = {Nature}, organization = {ICGC PedBrain-Seq Project, ICGC MMML-Seq Project,}, doi = {10.1038/nature25480}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229579}, pages = {321-327}, year = {2018}, abstract = {Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8\% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50\% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.}, language = {en} } @article{HarnošCanizalJuraseketal.2019, author = {Harnoš, Jakub and Ca{\~n}izal, Maria Consuelo Alonso and Jur{\´a}sek, Miroslav and Kumar, Jitender and Holler, Cornelia and Schambony, Alexandra and Han{\´a}kov{\´a}, Kateřina and Bernat{\´i}k, Ondřej and Zdr{\´a}hal, Zbyn{\^e}k and G{\"o}m{\"o}ryov{\´a}, Krist{\´i}na and Gybeľ, Tom{\´a}š and Radaszkiewicz, Tomasz Witold and Kravec, Marek and Trant{\´i}rek, Luk{\´a}š and Ryneš, Jan and Dave, Zankruti and Fern{\´a}ndez-Llamazares, Ana Iris and V{\´a}cha, Robert and Tripsianes, Konstantinos and Hoffmann, Carsten and Bryja, V{\´i}tězslav}, title = {Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09651-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227837}, year = {2019}, abstract = {Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.}, language = {en} } @article{GottschalkRichterZiegleretal.2019, author = {Gottschalk, Michael G. and Richter, Jan and Ziegler, Christiane and Schiele, Miriam A. and Mann, Julia and Geiger, Maximilian J. and Schartner, Christoph and Homola, Gy{\"o}rgy A. and Alpers, Georg W. and B{\"u}chel, Christian and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Gloster, Andrew T. and Helbig-Lang, Sylvia and Kalisch, Raffael and Kircher, Tilo and Lang, Thomas and Lonsdorf, Tina B. and Pan{\´e}-Farr{\´e}, Christiane A. and Str{\"o}hle, Andreas and Weber, Heike and Zwanzger, Peter and Arolt, Volker and Romanos, Marcel and Wittchen, Hans-Ulrich and Hamm, Alfons and Pauli, Paul and Reif, Andreas and Deckert, J{\"u}rgen and Neufang, Susanne and H{\"o}fler, Michael and Domschke, Katharina}, title = {Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-019-0415-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227479}, year = {2019}, abstract = {Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.}, language = {en} } @article{GiampaoloWojcikKleinHesslingetal.2019, author = {Giampaolo, Sabrina and W{\´o}jcik, Gabriela and Klein-Hessling, Stefan and Serfling, Edgar and Patra, Amiya K.}, title = {B cell development is critically dependent on NFATc1 activity}, series = {Cellular \& Molecular Immunology}, volume = {16}, journal = {Cellular \& Molecular Immunology}, doi = {10.1038/s41423-018-0052-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233006}, pages = {508-520}, year = {2019}, abstract = {B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.}, language = {en} } @article{LetunicKhedkarBork2021, author = {Letunic, Ivica and Khedkar, Supriya and Bork, Peer}, title = {SMART: recent updates, new developments and status in 2020}, series = {Nucleic Acids Research}, volume = {49}, journal = {Nucleic Acids Research}, number = {D1}, doi = {10.1093/nar/gkaa937}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363816}, pages = {D458-D460}, year = {2021}, abstract = {SMART (Simple Modular Architecture Research Tool) is a web resource (https://smart.embl.de) for the identification and annotation of protein domains and the analysis of protein domain architectures. SMART version 9 contains manually curatedmodels formore than 1300 protein domains, with a topical set of 68 new models added since our last update article (1). All the new models are for diverse recombinase families and subfamilies and as a set they provide a comprehensive overview of mobile element recombinases namely transposase, integrase, relaxase, resolvase, cas1 casposase and Xer like cellular recombinase. Further updates include the synchronization of the underlying protein databases with UniProt (2), Ensembl (3) and STRING (4), greatly increasing the total number of annotated domains and other protein features available in architecture analysis mode. Furthermore, SMART's vector-based protein display engine has been extended and updated to use the latest web technologies and the domain architecture analysis components have been optimized to handle the increased number of protein features available.}, language = {en} } @article{SchwabMeeuwsenEhlickeetal.2017, author = {Schwab, Andrea and Meeuwsen, Annick and Ehlicke, Franziska and Hansmann, Jan and Mulder, Lars and Smits, Anthal and Walles, Heike and Kock, Linda}, title = {Ex vivo culture platform for assessment of cartilage repair treatment strategies}, series = {ALTEX - Alternatives to animal experimentation}, volume = {34}, journal = {ALTEX - Alternatives to animal experimentation}, number = {2}, doi = {10.14573/altex.1607111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181665}, pages = {267-277}, year = {2017}, abstract = {There is a great need for valuable ex vivo models that allow for assessment of cartilage repair strategies to reduce the high number of animal experiments. In this paper we present three studies with our novel ex vivo osteochondral culture platform. It consists of two separated media compartments for cartilage and bone, which better represents the in vivo situation and enables supply of factors pecific to the different needs of bone and cartilage. We investigated whether separation of the cartilage and bone compartments and/or culture media results in the maintenance of viability, structural and functional properties of cartilage tissue. Next, we valuated for how long we can preserve cartilage matrix stability of osteochondral explants during long-term culture over 84 days. Finally, we determined the optimal defect size that does not show spontaneous self-healing in this culture system. It was demonstrated that separated compartments for cartilage and bone in combination with tissue-specific medium allow for long-term culture of osteochondral explants while maintaining cartilage viability, atrix tissue content, structure and mechanical properties for at least 56 days. Furthermore, we could create critical size cartilage defects of different sizes in the model. The osteochondral model represents a valuable preclinical ex vivo tool for studying clinically relevant cartilage therapies, such as cartilage biomaterials, for their regenerative potential, for evaluation of drug and cell therapies, or to study mechanisms of cartilage regeneration. It will undoubtedly reduce the number of animals needed for in vivotesting.}, language = {en} } @article{BelicPageLazariotouetal.2019, author = {Belic, Stanislav and Page, Lukas and Lazariotou, Maria and Waaga-Gasser, Ana Maria and Dragan, Mariola and Springer, Jan and Loeffler, Juergen and Morton, Charles Oliver and Einsele, Hermann and Ullmann, Andrew J. and Wurster, Sebastian}, title = {Comparative Analysis of Inflammatory Cytokine Release and Alveolar Epithelial Barrier Invasion in a Transwell® Bilayer Model of Mucormycosis}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.03204}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252477}, year = {2019}, abstract = {Understanding the mechanisms of early invasion and epithelial defense in opportunistic mold infections is crucial for the evaluation of diagnostic biomarkers and novel treatment strategies. Recent studies revealed unique characteristics of the immunopathology of mucormycoses. We therefore adapted an alveolar Transwell® A549/HPAEC bilayer model for the assessment of epithelial barrier integrity and cytokine response to Rhizopus arrhizus, Rhizomucor pusillus, and Cunninghamella bertholletiae. Hyphal penetration of the alveolar barrier was validated by 18S ribosomal DNA detection in the endothelial compartment. Addition of dendritic cells (moDCs) to the alveolar compartment led to reduced fungal invasion and strongly enhanced pro-inflammatory cytokine response, whereas epithelial CCL2 and CCL5 release was reduced. Despite their phenotypic heterogeneity, the studied Mucorales species elicited the release of similar cytokine patterns by epithelial and dendritic cells. There were significantly elevated lactate dehydrogenase concentrations in the alveolar compartment and epithelial barrier permeability for dextran blue of different molecular weights in Mucorales-infected samples compared to Aspergillus fumigatus infection. Addition of monocyte-derived dendritic cells further aggravated LDH release and epithelial barrier permeability, highlighting the influence of the inflammatory response in mucormycosis-associated tissue damage. An important focus of this study was the evaluation of the reproducibility of readout parameters in independent experimental runs. Our results revealed consistently low coefficients of variation for cytokine concentrations and transcriptional levels of cytokine genes and cell integrity markers. As additional means of model validation, we confirmed that our bilayer model captures key principles of Mucorales biology such as accelerated growth in a hyperglycemic or ketoacidotic environment or reduced epithelial barrier invasion upon epithelial growth factor receptor blockade by gefitinib. Our findings indicate that the Transwell® bilayer model provides a reliable and reproducible tool for assessing host response in mucormycosis.}, language = {en} } @article{BalasubramanianSkafHolzgrabeetal.2018, author = {Balasubramanian, Srikkanth and Skaf, Joseph and Holzgrabe, Ulrike and Bharti, Richa and F{\"o}rstner, Konrad U. and Ziebuhr, Wilma and Humeida, Ute H. and Abdelmohsen, Usama R. and Oelschlaeger, Tobias A.}, title = {A new bioactive compound from the marine sponge-derived Streptomyces sp. SBT348 inhibits staphylococcal growth and biofilm formation}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.01473}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221408}, year = {2018}, abstract = {Staphylococcus epidermidis, the common inhabitant of human skin and mucosal surfaces has emerged as an important pathogen in patients carrying surgical implants and medical devices. Entering the body via surgical sites and colonizing the medical devices through formation of multi-layered biofilms leads to refractory and persistent device-related infections (DRIs). Staphylococci organized in biofilms are more tolerant to antibiotics and immune responses, and thus are difficult-to-treat. The consequent morbidity and mortality, and economic losses in health care systems has strongly necessitated the need for development of new anti-bacterial and anti-biofilm-based therapeutics. In this study, we describe the biological activity of a marine sponge-derived Streptomyces sp. SBT348 extract in restraining staphylococcal growth and biofilm formation on polystyrene, glass, medically relevant titan metal, and silicone surfaces. A bioassay-guided fractionation was performed to isolate the active compound (SKC3) from the crude SBT348 extract. Our results demonstrated that SKC3 effectively inhibits the growth (MIC: 31.25 \(\mu\)g/ml) and biofilm formation (sub-MIC range: 1.95-<31.25 \(\mu\)g/ml) of S. epidermidis RP62A in vitro. Chemical characterization of SKC3 by heat and enzyme treatments, and mass spectrometry (HRMS) revealed its heat-stable and non-proteinaceous nature, and high molecular weight (1258.3 Da). Cytotoxicity profiling of SKC3 in vitro on mouse fibroblast (NIH/3T3) and macrophage (J774.1) cell lines, and in vivo on the greater wax moth larvae Galleria mellonella revealed its non-toxic nature at the effective dose. Transcriptome analysis of SKC3 treated S. epidermidis RP62A has further unmasked its negative effect on central metabolism such as carbon flux as well as, amino acid, lipid, and energy metabolism. Taken together, these findings suggest a potential of SKC3 as a putative drug to prevent staphylococcal DRIs.}, language = {en} } @article{BaurOttoStegeretal.2018, author = {Baur, Johannes and Otto, Christoph and Steger, Ulrich and Klein-Hessling, Stefan and Muhammad, Khalid and Pusch, Tobias and Murti, Krisna and Wismer, Rhoda and Germer, Christoph-Thomas and Klein, Ingo and M{\"u}ller, Nora and Serfling, Edgar and Avots, Andris}, title = {The transcription factor NFaTc1 supports the rejection of heterotopic heart allografts}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2018.01338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221530}, year = {2018}, abstract = {The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8\(^+\) T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation.}, language = {en} } @article{JoosSaadatmandSchnabeletal.2018, author = {Joos, J. P. and Saadatmand, A. R. and Schnabel, C. and Viktorinov{\´a}, I. and Brand, T. and Kramer, M. and Nattel, S. and Dobrev, D. and Tomancak, P. and Backs, J. and Kleinbongard, P. and Heusch, G. and Lorenz, K. and Koch, E. and Weber, S. and El-Armouche, A.}, title = {Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-21372-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323637}, year = {2018}, abstract = {Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.}, language = {en} } @article{KnopSpilgiesRuflietal.2019, author = {Knop, Janin and Spilgies, Lisanne M. and Rufli, Stefanie and Reinhart, Ramona and Vasilikos, Lazaros and Yabal, Monica and Owsley, Erika and Jost, Philipp J. and Marsh, Rebecca A. and Wajant, Harald and Robinson, Mark D. and Kaufmann, Thomas and W. Wei-Lynn, Wong}, title = {TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1938-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325946}, year = {2019}, abstract = {The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap-/- macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap-/- myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.}, language = {en} } @article{KrausBrinkSiegel2019, author = {Kraus, Amelie J. and Brink, Benedikt G. and Siegel, T. Nicolai}, title = {Efficient and specific oligo-based depletion of rRNA}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-48692-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224829}, year = {2019}, abstract = {In most organisms, ribosomal RNA (rRNA) contributes to >85\% of total RNA. Thus, to obtain useful information from RNA-sequencing (RNA-seq) analyses at reasonable sequencing depth, typically, mature polyadenylated transcripts are enriched or rRNA molecules are depleted. Targeted depletion of rRNA is particularly useful when studying transcripts lacking a poly(A) tail, such as some non-coding RNAs (ncRNAs), most bacterial RNAs and partially degraded or immature transcripts. While several commercially available kits allow effective rRNA depletion, their efficiency relies on a high degree of sequence homology between oligonucleotide probes and the target RNA. This restricts the use of such kits to a limited number of organisms with conserved rRNA sequences. In this study we describe the use of biotinylated oligos and streptavidin-coated paramagnetic beads for the efficient and specific depletion of trypanosomal rRNA. Our approach reduces the levels of the most abundant rRNA transcripts to less than 5\% with minimal off-target effects. By adjusting the sequence of the oligonucleotide probes, our approach can be used to deplete rRNAs or other abundant transcripts independent of species. Thus, our protocol provides a useful alternative for rRNA removal where enrichment of polyadenylated transcripts is not an option and commercial kits for rRNA are not available.}, language = {en} } @article{KotzRischArnoldetal.2019, author = {Kotz, Frederik and Risch, Patrick and Arnold, Karl and Sevim, Semih and Puigmart{\´i}-Luis, Josep and Quick, Alexander and Thiel, Michael and Hrynevich, Andrei and Dalton, Paul D. and Helmer, Dorothea and Rapp, Bastian E.}, title = {Fabrication of arbitrary three-dimensional suspended hollow microstructures in transparent fused silica glass}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09497-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224787}, year = {2019}, abstract = {Fused silica glass is the preferred material for applications which require long-term chemical and mechanical stability as well as excellent optical properties. The manufacturing of complex hollow microstructures within transparent fused silica glass is of particular interest for, among others, the miniaturization of chemical synthesis towards more versatile, configurable and environmentally friendly flow-through chemistry as well as high-quality optical waveguides or capillaries. However, microstructuring of such complex three-dimensional structures in glass has proven evasive due to its high thermal and chemical stability as well as mechanical hardness. Here we present an approach for the generation of hollow microstructures in fused silica glass with high precision and freedom of three-dimensional designs. The process combines the concept of sacrificial template replication with a room-temperature molding process for fused silica glass. The fabricated glass chips are versatile tools for, among other, the advance of miniaturization in chemical synthesis on chip.}, language = {en} } @article{KimAmoresKangetal.2019, author = {Kim, Bo-Mi and Amores, Angel and Kang, Seunghyun and Ahn, Do-Hwan and Kim, Jin-Hyoung and Kim, Il-Chan and Lee, Jun Hyuck and Lee, Sung Gu and Lee, Hyoungseok and Lee, Jungeun and Kim, Han-Woo and Desvignes, Thomas and Batzel, Peter and Sydes, Jason and Titus, Tom and Wilson, Catherine A. and Catchen, Julian M. and Warren, Wesley C. and Schartl, Manfred and Detrich, H. William III and Postlethwait, John H. and Park, Hyun}, title = {Antarctic blackfin icefish genome reveals adaptations to extreme environments}, series = {Nature Ecology \& Evolution}, volume = {3}, journal = {Nature Ecology \& Evolution}, doi = {10.1038/s41559-019-0812-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325811}, pages = {469-478}, year = {2019}, abstract = {Icefishes (suborder Notothenioidei; family Channichthyidae) are the only vertebrates that lack functional haemoglobin genes and red blood cells. Here, we report a high-quality genome assembly and linkage map for the Antarctic blackfin icefish Chaenocephalus aceratus, highlighting evolved genomic features for its unique physiology. Phylogenomic analysis revealed that Antarctic fish of the teleost suborder Notothenioidei, including icefishes, diverged from the stickleback lineage about 77 million years ago and subsequently evolved cold-adapted phenotypes as the Southern Ocean cooled to sub-zero temperatures. Our results show that genes involved in protection from ice damage, including genes encoding antifreeze glycoprotein and zona pellucida proteins, are highly expanded in the icefish genome. Furthermore, genes that encode enzymes that help to control cellular redox state, including members of the sod3 and nqo1 gene families, are expanded, probably as evolutionary adaptations to the relatively high concentration of oxygen dissolved in cold Antarctic waters. In contrast, some crucial regulators of circadian homeostasis (cry and per genes) are absent from the icefish genome, suggesting compromised control of biological rhythms in the polar light environment. The availability of the icefish genome sequence will accelerate our understanding of adaptation to extreme Antarctic environments.}, language = {en} } @article{HoernesFaserlJuenetal.2018, author = {Hoernes, Thomas Philipp and Faserl, Klaus and Juen, Michael Andreas and Kremser, Johannes and Gasser, Catherina and Fuchs, Elisabeth and Shi, Xinying and Siewert, Aaron and Lindner, Herbert and Kreutz, Christoph and Micura, Ronald and Joseph, Simpson and H{\"o}bartner, Claudia and Westhof, Eric and H{\"u}ttenhofer, Alexander and Erlacher, Matthias David}, title = {Translation of non-standard codon nucleotides reveals minimal requirements for codon-anticodon interactions}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-07321-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321067}, year = {2018}, abstract = {The precise interplay between the mRNA codon and the tRNA anticodon is crucial for ensuring efficient and accurate translation by the ribosome. The insertion of RNA nucleobase derivatives in the mRNA allowed us to modulate the stability of the codon-anticodon interaction in the decoding site of bacterial and eukaryotic ribosomes, allowing an in-depth analysis of codon recognition. We found the hydrogen bond between the N1 of purines and the N3 of pyrimidines to be sufficient for decoding of the first two codon nucleotides, whereas adequate stacking between the RNA bases is critical at the wobble position. Inosine, found in eukaryotic mRNAs, is an important example of destabilization of the codon-anticodon interaction. Whereas single inosines are efficiently translated, multiple inosines, e.g., in the serotonin receptor 5-HT2C mRNA, inhibit translation. Thus, our results indicate that despite the robustness of the decoding process, its tolerance toward the weakening of codon-anticodon interactions is limited.}, language = {en} } @article{HommersRichterYangetal.2018, author = {Hommers, L. G. and Richter, J. and Yang, Y. and Raab, A. and Baumann, C. and Lang, K. and Schiele, M. A. and Weber, H. and Wittmann, A. and Wolf, C. and Alpers, G. W. and Arolt, V. and Domschke, K. and Fehm, L. and Fydrich, T. and Gerlach, A. and Gloster, A. T. and Hamm, A. O. and Helbig-Lang, S. and Kircher, T. and Lang, T. and Pan{\´e}-Farr{\´e}, C. A. and Pauli, P. and Pfleiderer, B. and Reif, A. and Romanos, M. and Straube, B. and Str{\"o}hle, A. and Wittchen, H.-U. and Frantz, S. and Ertl, G. and Lohse, M. J. and Lueken, U. and Deckert, J.}, title = {A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety}, series = {Translational Psychiatry}, volume = {8}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-018-0278-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322497}, year = {2018}, abstract = {Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.}, language = {en} } @article{BurySoundararajanBhartietal.2018, author = {Bury, Susanne and Soundararajan, Manonmani and Bharti, Richa and von B{\"u}nau, Rudolf and F{\"o}rstner, Konrad U. and Oelschlaeger, Tobias A.}, title = {The probiotic escherichia coli strain Nissle 1917 combats lambdoid bacteriophages stx and lambda}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.00929}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221960}, year = {2018}, abstract = {Shiga toxin (Stx) producing E. coli (STEC) such as Enterohemorrhagic E. coli (EHEC) are the major cause of foodborne illness in humans. In vitro studies showed the probiotic Escherichia coil strain Nissle 1917 (EcN) to efficiently inhibit the production of Stx. Life threatening EHEC strains as for example the serotype 0104:H4, responsible for the great outbreak in 2011 in Germany, evolutionary developed from certain E. coll strains which got infected by stx2-encoding lambdoid phages turning the E. coil into lysogenic and subsequently Stx producing strains. Since antibiotics induce stx genes and Stx production, EHEC infected persons are not recommended to be treated with antibiotics. Therefore, EcN might be an alternative medication. However, because even commensal E. coli strains might be converted into Stx-producers after becoming host to a stx encoding prophage, we tested EcN for stx-phage genome integration. Our experiments revealed the resistance of EcN toward not only stx-phages but also against lambda-phages. This resistance was not based on the lack of or by mutated phage receptors. Rather it involved the expression of a phage repressor (pr) gene of a defective prophage in EcN which was able to partially protect E. coli K-12 strain MG1655 against stx and lambda phage infection. Furthermore, we observed EcN to inactivate phages and thereby to protect E. coli K-12 strains against infection by stx- as well as lambda-phages. Inactivation of lambda-phages was due to binding of lambda-phages to LamB of EcN whereas inactivation of stx-phages was caused by a thermostable protein of EcN. These properties together with its ability to inhibit Stx production make EcN a good candidate for the prevention of illness caused by EHEC and probably for the treatment of already infected people.}, language = {en} } @article{BreitingerBahnassawyJanzenetal.2018, author = {Breitinger, Ulrike and Bahnassawy, Lamiaa M. and Janzen, Dieter and R{\"o}mer, Vera and Becker, Cord-Michael and Villmann, Carmen and Breitinger, Hans-Georg}, title = {PKA and PKC modulators affect ion channel function and internalization of recombinant alpha1 and alpha1-beta glycine receptors}, series = {Frontiers in Molecular Neurosience}, volume = {11}, journal = {Frontiers in Molecular Neurosience}, doi = {10.3389/fnmol.2018.00154}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220401}, year = {2018}, abstract = {Glycine receptors (GlyRs) are important mediators of fast inhibitory neurotransmission in the mammalian central nervous system. Their function is controlled by multiple cellular mechanisms, including intracellular regulatory processes. Modulation of GlyR function by protein kinases has been reported for many cell types, involving different techniques, and often yielding contradictory results. Here, we studied the effects of protein kinase C (PKC) and cAMP-dependent protein kinase A (PKA) on glycine induced currents in HEK293 cells expressing human homomeric \(\alpha\)1 and heteromeric \(\alpha\)1-\(\beta\) GlyRs using whole-cell patch clamp techniques as well as internalization assays. In whole-cell patch-clamp measurements, modulators were applied in the intracellular buffer at concentrations between 0.1 \(\mu\)M and 0.5 \(\mu\)M. EC50 of glycine increased upon application of the protein kinase activators Forskolin and phorbol-12-myristate-13-acetate (PMA) but decreased in the presence of the PKC inhibitor Staurosporine aglycon and the PKA inhibitor H-89. Desensitization of recombinant \(\alpha\)1 receptors was significantly increased in the presence of Forskolin. Staurosporine aglycon, on the other hand decreased desensitization of heteromeric \(\alpha\)1-\(\beta\) GlyRs. The time course of receptor activation was determined for homomeric \(\alpha\)1 receptors and revealed two simultaneous effects: cells showed a decrease of EC50 after 3-6 min of establishing whole-cell configuration. This effect was independent of protein kinase modulators. All modulators of PKA and PKC, however, produced an additional shift of EC50, which overlay and eventually exceeded the cells intrinsic variation of EC50. The effect of kinase activators was abolished if the corresponding inhibitors were co-applied, consistent with PKA and PKC directly mediating the modulation of GlyR function. Direct effects of PKA-and PKC-modulators on receptor expression on transfected HEK cells were monitored within 15 min of drug application, showing a significant increase of receptor internalization with PKA and PKC activators, while the corresponding inhibitors had no significant effect on receptor surface expression or internalization. Our results confirm the observation that phosphorylation via PKA and PKC has a direct effect on the GlyR ion channel complex and plays an important role in the fine-tuning of glycinergic signaling.}, language = {en} } @article{BohmannKurkaduMesnildeRochemontetal.2019, author = {Bohmann, Ferdinand O. and Kurka, Natalia and du Mesnil de Rochemont, Richard and Gruber, Katharina and Guenther, Joachim and Rostek, Peter and Rai, Heike and Zickler, Philipp and Ertl, Michael and Berlis, Ansgar and Poli, Sven and Mengel, Annerose and Ringleb, Peter and Nagel, Simon and Pfaff, Johannes and Wollenweber, Frank A. and Kellert, Lars and Herzberg, Moriz and Koehler, Luzie and Haeusler, Karl Georg and Alegiani, Anna and Schubert, Charlotte and Brekenfeld, Caspar and Doppler, Christopher E. J. and Onur, Oezguer A. and Kabbasch, Christoph and Manser, Tanja and Pfeilschifter, Waltraud}, title = {Simulation-based training of the rapid evaluation and management of acute stroke (STREAM) — a prospective single-arm multicenter trial}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00969}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369239}, year = {2019}, abstract = {Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2-3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period. Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the "door-to-needle" time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire. Interventions: We are applying a multi-level intervention in cooperation with three "STREAM multipliers" from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2-3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings. Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.}, language = {en} } @article{BolzoniEspostiMarcheseetal.2018, author = {Bolzoni, Francesco and Esposti, Roberto and Marchese, Silvia M. and Pozzi, Nicol{\´o} G. and Ramirez-Pasos, Uri E. and Isaias, Ioannis U. and Cavallari, Paolo}, title = {Disrupt of intra-limb APA pattern in parkinsonian patients performing index-finger flexion}, series = {Frontiers in Physiology}, volume = {9}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2018.01745}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369245}, year = {2018}, abstract = {Voluntary movements induce postural perturbations which are counteracted by anticipatory postural adjustments (APAs). These actions are known to build up long fixation chains toward available support points (inter-limb APAs), so as to grant whole body equilibrium. Moreover, recent studies highlighted that APAs also build-up short fixation chains, within the same limb where a distal segment is moved (intra-limb APAs), aimed at stabilizing the proximal segments. The neural structures generating intra-limb APAs still need investigations; the present study aims to compare focal movement kinematics and intra-limb APA latencies and pattern between healthy subjects and parkinsonian patients, assuming the latter as a model of basal ganglia dysfunction. Intra-limb APAs that stabilize the arm when the index-finger is briskly flexed were recorded in 13 parkinsonian patients and in 10 age-matched healthy subjects. Index-finger movement was smaller in parkinsonian patients vs. healthy subjects (p = 0.01) and more delayed with respect to the onset of the prime mover flexor digitorum superficialis (FDS, p < 0.0001). In agreement with the literature, in all healthy subjects the FDS activation was preceded by an inhibitory intra-limb APA in biceps brachii (BB) and anterior deltoid (AD), and almost simultaneous to an excitatory intra-limb APA in triceps brachii (TB). In parkinsonian patients, no significant differences were found for TB and AD intra-limb APA timings, however only four patients showed an inhibitory intra-limb APA in BB, while other four did not show any BB intra-limb APAs and five actually developed a BB excitation. The frequency of occurrence of normal sign, lacking, and inverted BB APAs was different in healthy vs. parkinsonian participants (p = 0.0016). The observed alterations in index-finger kinematics and intra-limb APA pattern in parkinsonian patients suggest that basal ganglia, in addition to shaping the focal movement, may also contribute to intra-limb APA control.}, language = {en} } @article{HobbsJaskaniecMcCarthyetal.2018, author = {Hobbs, Christopher and Jaskaniec, Sonia and McCarthy, Eoin K. and Downing, Clive and Opelt, Konrad and G{\"u}th, Konrad and Shmeliov, Aleksey and Mourad, Maurice C. D. and Mandel, Karl and Nicolosi, Valeria}, title = {Structural transformation of layered double hydroxides: an in situ TEM analysis}, series = {npj 2D Materials and Applications}, volume = {2}, journal = {npj 2D Materials and Applications}, doi = {10.1038/s41699-018-0048-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320752}, year = {2018}, abstract = {A comprehensive nanoscale understanding of layered double hydroxide (LDH) thermal evolution is critical for their current and future applications as catalysts, flame retardants and oxygen evolution performers. In this report, we applied in situ transmission electron microscopy (TEM) to extensively characterise the thermal progressions of nickel-iron containing (Ni-Fe) LDH nanomaterials. The combinative approach of TEM and selected area electron diffraction (SAED) yielded both a morphological and crystallographic understanding of such processes. As the Ni-Fe LDH nanomaterials are heated in situ, an amorphization occurred at 250 °C, followed by a transition to a heterogeneous structure of NiO particles embedded throughout a NiFe2O4 matrix at 850 °C, confirmed by high-resolution TEM and scanning TEM. Further electron microscopy characterisation methodologies of energy-filtered TEM were utilised to directly observe these mechanistic behaviours in real time, showing an evolution and nucleation to an array of spherical NiO nanoparticles on the platelet surfaces. The versatility of this characterisation approach was verified by the analogous behaviours of Ni-Fe LDH materials heated ex situ as well as parallel in situ TEM and SAED comparisons to that of an akin magnesium-aluminium containing (Mg-Al) LDH structure. The in situ TEM work hereby discussed allows for a state-of-the-art understanding of the Ni-Fe material thermal evolution. This is an important first, which reveals pivotal information, especially when considering LDH applications as catalysts and flame retardants.}, language = {en} } @article{HerbstSoberatsLeowanawatetal.2018, author = {Herbst, Stefanie and Soberats, Bartolome and Leowanawat, Pawaret and Stolte, Matthias and Lehmann, Matthias and W{\"u}rthner, Frank}, title = {Self-assembly of multi-stranded perylene dye J-aggregates in columnar liquid-crystalline phases}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-05018-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319914}, year = {2018}, abstract = {Many discoid dyes self-assemble into columnar liquid-crystalline (LC) phases with packing arrangements that are undesired for photonic applications due to H-type exciton coupling. Here, we report a series of crystalline and LC perylene bisimides (PBIs) self-assembling into single or multi-stranded (two, three, and four strands) aggregates with predominant J-type exciton coupling. These differences in the supramolecular packing and optical properties are achieved by molecular design variations of tetra-bay phenoxy-dendronized PBIs with two N-H groups at the imide positions. The self-assembly is driven by hydrogen bonding, slipped π-π stacking, nanosegregation, and steric requirements of the peripheral building blocks. We could determine the impact of the packing motifs on the spectroscopic properties and demonstrate different J- and H-type coupling contributions between the chromophores. Our findings on structure-property relationships and strong J-couplings in bulk LC materials open a new avenue in the molecular engineering of PBI J-aggregates with prospective applications in photonics.}, language = {en} } @article{IzquierdoKarolakPrabhakaranetal.2019, author = {Izquierdo, Manuel and Karolak, Michael and Prabhakaran, Dharmalingam and Boothroyd, Andrew T. and Scherz, Andreas O. and Lichtenstein, Alexander and Molodtsov, Serguei L.}, title = {Monitoring ultrafast metallization in LaCoO3 with femtosecond soft x-ray spectroscopy}, series = {Communications Physics}, volume = {2}, journal = {Communications Physics}, doi = {10.1038/s42005-019-0109-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323265}, year = {2019}, abstract = {The study of ultrafast dynamics is a new tool to understand and control the properties of correlated oxides. By enhancing some properties and realizing new dynamically excited phrases, this tool has opened new routes for technological applications. LaCoO3 is one paradigmatic example where the strong electron, spin, and lattice coupling induced by electronic correlations results in a low-temperature spin transition and a high-temperature semiconductor-to-metal transition that is still not completely understood. Here, we monitor ultrafast metallization in LaCoO3 using time-resolved soft x-ray reflectivity experiments. While the process is entangled at the Co L3 edge, the time information of the different channels is decrypted at different resonant energies of the O K edge. Metallization is shown to occur via transient electronic, spin, and lattice separation. Our results agree with the thermodynamical model and demonstrate the potential of femtosecond soft x-ray experiments at the O K edge to understand correlated oxides.}, language = {en} } @article{HoltfrerichPfisterElGammaletal.2018, author = {Holtfrerich, Sarah K. C. and Pfister, Roland and El Gammal, Alexander T. and Bellon, Eugen and Diekhof, Esther K.}, title = {Endogenous testosterone and exogenous oxytocin influence the response to baby schema in the female brain}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-26020-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322285}, year = {2018}, abstract = {Nurturing behavior may be critically influenced by the interplay of different hormones. The neuropeptide oxytocin is known to promote maternal behavior and its reduction has been associated with postpartum depression risk and child neglect. Contrariwise, the observed decrease in testosterone level during early parenthood may benefit caretaking behavior, whereas increased testosterone may reduce attention to infants. Here we used functional magnetic resonance imaging to investigate the interactive influence of testosterone and oxytocin on selective attention to and neural processing of the baby schema (BS). 57 nulliparous women performed a target detection task with human faces with varying degree of BS following double-blinded placebo-controlled oxytocin administration in a between-subjects design. Our results support the idea that oxytocin enhances attention to the BS. Oxytocin had a positive effect on activation of the inferior frontal junction during identification of infant targets with a high degree of BS that were presented among adult distractors. Further, activation of the putamen was positively correlated with selective attention to the BS, but only in women with high endogenous testosterone who received oxytocin. These findings provide initial evidence for the neural mechanism by which oxytocin may counteract the negative effects of testosterone in the modulation of nurturing behavior.}, language = {en} } @article{KesslerFroemblingGrossetal.2018, author = {Kessler, Almuth F. and Fr{\"o}mbling, Greta E. and Gross, Franziska and Hahn, Mirja and Dzokou, Wilfrid and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten}, title = {Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition}, series = {Cell Death Discovery}, volume = {4}, journal = {Cell Death Discovery}, doi = {10.1038/s41420-018-0079-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325744}, year = {2018}, abstract = {Tumor treating fields (TTFields) are approved for glioblastoma (GBM) therapy. TTFields disrupt cell division by inhibiting spindle fiber formation. Spindle assembly checkpoint (SAC) inhibition combined with antimitotic drugs synergistically decreases glioma cell growth in cell culture and mice. We hypothesized that SAC inhibition will increase TTFields efficacy. Human GBM cells (U-87 MG, GaMG) were treated with TTFields (200 kHz, 1.7 V/cm) and/or the SAC inhibitor MPS1-IN-3 (IN-3, 4 µM). Cells were counted after 24, 48, and 72 h of treatment and at 24 and 72 h after end of treatment (EOT). Flow cytometry, immunofluorescence microscopy, Annexin-V staining and TUNEL assay were used to detect alterations in cell cycle and apoptosis after 72 h of treatment. The TTFields/IN-3 combination decreased cell proliferation after 72 h compared to either treatment alone (-78.6\% vs. TTFields, P = 0.0337; -52.6\% vs. IN-3, P = 0.0205), and reduced the number of viable cells (62\% less than seeded). There was a significant cell cycle shift from G1 to G2/M phase (P < 0.0001). The apoptotic rate increased to 44\% (TTFields 14\%, P = 0.0002; IN-3 4\%, P < 0.0001). Cell growth recovered 24 h after EOT with TTFields and IN-3 alone, but the combination led to further decrease by 92\% at 72 h EOT if IN-3 treatment was continued (P = 0.0288). The combination of TTFields and SAC inhibition led to earlier and prolonged effects that significantly augmented the efficacy of TTFields and highlights a potential new targeted multimodal treatment for GBM.}, language = {en} } @article{KaestnerRichterUrbaniketal.2019, author = {K{\"a}stner, Niklas and Richter, S. Helene and Urbanik, Sarah and Kunert, Joachim and Waider, Jonas and Lesch, Klaus-Peter and Kaiser, Sylvia and Sachser, Norbert}, title = {Brain serotonin deficiency affects female aggression}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-37613-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325386}, year = {2019}, abstract = {The neurotransmitter serotonin plays a key role in the control of aggressive behaviour. While so far most studies have investigated variation in serotonin levels, a recently created tryptophan hydroxylase 2 (Tph2) knockout mouse model allows studying effects of complete brain serotonin deficiency. First studies revealed increased aggressiveness in homozygous Tph2 knockout mice in the context of a resident-intruder paradigm. Focussing on females, this study aimed to elucidate effects of serotonin deficiency on aggressive and non-aggressive social behaviours not in a test situation but a natural setting. For this purpose, female Tph2 wildtype (n = 40) and homozygous knockout mice (n = 40) were housed with a same-sex conspecific of either the same or the other genotype in large terraria. The main findings were: knockout females displayed untypically high levels of aggressive behaviour even after several days of co-housing. Notably, in response to aggressive knockout partners, they showed increased levels of defensive behaviours. While most studies on aggression in rodents have focussed on males, this study suggests a significant involvement of serotonin also in the control of female aggression. Future research will show, whether the observed behavioural effects are directly caused by the lack of serotonin or by potential compensatory mechanisms.}, language = {en} } @article{HechtMeierZimmeretal.2018, author = {Hecht, Markus and Meier, Friedegund and Zimmer, Lisa and Polat, B{\"u}lent and Loquai, Carmen and Weishaupt, Carsten and Forschner, Andrea and Gutzmer, Ralf and Utikal, Jochen S. and Goldinger, Simone M. and Geier, Michael and Hassel, Jessica C. and Balermpas, Panagiotis and Kiecker, Felix and Rauschenberg, Ricarda and Dietrich, Ursula and Clemens, Patrick and Berking, Carola and Grabenbauer, Gerhard and Schadendorf, Dirk and Grabbe, Stephan and Schuler, Gerold and Fietkau, Rainer and Distel, Luitpold V. and Heinzerling, Lucie}, title = {Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients}, series = {British Journal of Cancer}, volume = {118}, journal = {British Journal of Cancer}, doi = {10.1038/bjc.2017.489}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227970}, pages = {785-792}, year = {2018}, abstract = {Background: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients. Methods: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi). Results: The median duration of BRAFi treatment interruption prior to radiotherapy was 4 days and lasted for 17 days. Median OSRT and OSBRAFi in the entire cohort were 9.8 and 12.6 months in the interrupted group and 7.3 and 11.5 months in the concomitant group (P=0.075/P=0.217), respectively. Interrupted vemurafenib treatment with a median OSRT and OSBRAFi of 10.1 and 13.1 months, respectively, was superior to concomitant vemurafenib treatment with a median OSRT and OSBRAFi of 6.6 and 10.9 months (P=0.004/P=0.067). Interrupted dabrafenib treatment with a median OSRT and OSBRAFi of 7.7 and 9.8 months, respectively, did not differ from concomitant dabrafenib treatment with a median OSRT and OSBRAFi of 9.9 and 11.6 months (P=0.132/P=0.404). Median local control of the irradiated area did not differ in the interrupted and concomitant BRAFi treatment groups (P=0.619). Skin toxicity of grade ≥2 (CTCAE) was significantly increased in patients with concomitant vemurafenib compared to the group with treatment interruption (P=0.002). Conclusions: Interruption of vemurafenib treatment during radiation was associated with better survival and less toxicity compared to concomitant treatment. Due to lower number of patients, the relevance of treatment interruption in dabrafenib treated patients should be further investigated. The results of this analysis indicate that treatment with the BRAFi vemurafenib should be interrupted during radiotherapy. Prospective studies are desperately needed.}, language = {en} } @article{HolzingerSchneiderHoeflingetal.2019, author = {Holzinger, Steffen and Schneider, Christian and H{\"o}fling, Sven and Porte, Xavier and Reitzenstein, Stephan}, title = {Quantum-dot micropillar lasers subject to coherent time-delayed optical feedback from a short external cavity}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-36599-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322485}, year = {2019}, abstract = {We investigate the mode-switching dynamics of an electrically driven bimodal quantum-dot micropillar laser when subject to delayed coherent optical feedback from a short external cavity. We experimentally characterize how the external cavity length, being on the same order than the microlaser's coherence length, influences the spectral and dynamical properties of the micropillar laser. Moreover, we determine the relaxation oscillation frequency of the micropillar by superimposing optical pulse injection to a dc current. It is found that the optical pulse can be used to disturb the feedback-coupled laser within one roundtrip time in such a way that it reaches the same output power as if no feedback was present. Our results do not only expand the understanding of microlasers when subject to optical feedback from short external cavities, but pave the way towards tailoring the properties of this key nanophotonic system for studies in the quantum regime of self-feedback and its implementation to integrated photonic circuits.}, language = {en} } @article{KnoedlerKoerferKunzmannetal.2018, author = {Kn{\"o}dler, Maren and K{\"o}rfer, Justus and Kunzmann, Volker and Trojan, J{\"o}rg and Daum, Severin and Schenk, Michael and Kullmann, Frank and Schroll, Sebastian and Behringer, Dirk and Stahl, Michael and Al-Batran, Salah-Eddin and Hacker, Ulrich and Ibach, Stefan and Lindhofer, Horst and Lordick, Florian}, title = {Randomised phase II trial to investigate catumaxomab (anti-EpCAM × anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer}, series = {British Journal of Cancer}, volume = {119}, journal = {British Journal of Cancer}, doi = {10.1038/s41416-018-0150-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325938}, pages = {296-302}, year = {2018}, abstract = {Background Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC. Methods This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery. Results Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27\% in arm A and 19\% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms. Conclusions Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.}, language = {en} } @article{HeilSchreiberGoetzetal.2018, author = {Heil, Hannah S. and Schreiber, Benjamin and G{\"o}tz, Ralph and Emmerling, Monika and Dabauvalle, Marie-Christine and Krohne, Georg and H{\"o}fling, Sven and Kamp, Martin and Sauer, Markus and Heinze, Katrin G.}, title = {Sharpening emitter localization in front of a tuned mirror}, series = {Light: Science \& Applications}, volume = {7}, journal = {Light: Science \& Applications}, doi = {10.1038/s41377-018-0104-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228080}, year = {2018}, abstract = {Single-molecule localization microscopy (SMLM) aims for maximized precision and a high signal-to-noise ratio1. Both features can be provided by placing the emitter in front of a metal-dielectric nanocoating that acts as a tuned mirror2,3,4. Here, we demonstrate that a higher photon yield at a lower background on biocompatible metal-dielectric nanocoatings substantially improves SMLM performance and increases the localization precision by up to a factor of two. The resolution improvement relies solely on easy-to-fabricate nanocoatings on standard glass coverslips and is spectrally and spatially tunable by the layer design and wavelength, as experimentally demonstrated for dual-color SMLM in cells.}, language = {en} } @article{AltieriDiDatoMartinietal.2019, author = {Altieri, Barbara and Di Dato, Carla and Martini, Chiara and Sciammarella, Concetta and Di Sarno, Antonella and Colao, Annamaria and Faggiano, Antongiulio}, title = {Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management}, series = {Cancers}, volume = {11}, journal = {Cancers}, doi = {10.3390/cancers11091332}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221079}, pages = {1-20}, year = {2019}, abstract = {Bone represents a common site of metastases for several solid tumors. However, the ability of neuroendocrine neoplasms (NENs) to localize to bone has always been considered a rare and late event. Thanks to the improvement of therapeutic options, which results in longer survival, and of imaging techniques, particularly after the introduction of positron emission tomography (PET) with gallium peptides, the diagnosis of bone metastases (BMs) in NENs is increasing. The onset of BMs can be associated with severe skeletal complications that impair the patient's quality of life. Moreover, BMs negatively affect the prognosis of NEN patients, bringing out the lack of curative treatment options for advanced NENs. The current knowledge on BMs in gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) NENs is still scant and is derived from a few retrospective studies and case reports. This review aims to perform a critical analysis of the evidence regarding the role of BMs in GEP- and BP-NENs, focusing on the molecular mechanisms underlining the development of BMs, as well as clinical presentation, diagnosis, and treatment of BMs, in an attempt to provide suggestions that can be used in clinical practice.}, language = {en} } @article{ButtRaman2018, author = {Butt, Elke and Raman, Dayanidhi}, title = {New frontiers for the cytoskeletal protein LASP1}, series = {Frontiers in Oncology}, volume = {8}, journal = {Frontiers in Oncology}, doi = {10.3389/fonc.2018.00391}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221975}, year = {2018}, abstract = {In the recent two decades, LIM and SH3 protein 1 (LASP1) has been developed from a simple actin-binding structural protein to a tumor biomarker and subsequently to a complex, nuclear transcriptional regulator. Starting with a brief historical perspective, this review will mainly compare and contrast LASP1 and LASP2 from the angle of the newest data and importantly, examine their role in transcriptional regulation. We will summarize the current knowledge through pictorial models and tables including the roles of different microRNAs in the differential regulation of LASP1 levels and patient outcome rather than specify in detail all tumor entities. Finally, the novel functional roles of LASP1 in secretion of vesicles, expression of matrix metalloproteinases and transcriptional regulation as well as the activation of survival and proliferation pathways in different cancer types are described.}, language = {en} } @article{CookGeierSchmidetal.2019, author = {Cook, Nigel and Geier, Andreas and Schmid, Andreas and Hirschfeld, Gideon and Kautz, Achim and Schattenberg, J{\"o}rn M. and Balp, Maria-Magdalena}, title = {The patient perspectives on future therapeutic options in NASH and patient needs}, series = {Frontiers in Medicine}, volume = {6}, journal = {Frontiers in Medicine}, doi = {10.3389/fmed.2019.00061}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223268}, year = {2019}, abstract = {Background: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with severe complications and without approved therapies. Currently, there is limited data on the overall burden of the disease for patients or on patient needs and preferences. This study investigates patient preferences in relation to potential future therapies for NASH. In addition, the factors that are relevant to patients and their importance in relation to future treatment options are explored. Method: Telephone in-depth interviews (TDIs) preceded an online 30-min quantitative survey. The online survey included (1) multiple choice questions (MCQs) on NASH diagnosis and disease background. (2) An exercise to determine patients' satisfaction levels with information provided at diagnosis, and to explore symptomatology in detail. (3) Exercises to evaluate potential new products and product attributes, including a "drag and drop" ranking exercise, and an adaptive choice-based conjoint exercise (ACBC). (4) The EQ-5D-5L questionnaire and the Visual Analog Scale (VAS), which measures patients' health status. (5) Collection of socio-demographic data, and (6) Questions to measure patient satisfaction with the survey. Results: There were 166 patients included in this study from Canada [n = 36], Germany [n = 50], the UK [n = 30], and USA [n = 50]. Fifty seven percent of patients [n = 94] had had a liver biopsy for confirmation of NASH. Patients were often unable to link their symptoms to NASH or other conditions. ACBC results showed that efficacy, defined as "impact on liver status" was the single most important attribute of a potential future NASH therapy. Other attributes considered to have secondary importance included impact on weight, symptom control and the presence of side effects. The EQ-5D utility score was 0.81 and VAS = 67.2. Conclusion: "Impact on liver status" is the primary outcome sought. Patients demonstrate a general lack of understanding of their disease and appeared to be unfamiliar with longer-term consequences of NASH. It is necessary to improve patient understanding of NASH and its progressive nature, and there is a need for improving confirmatory diagnosis and monitoring.}, language = {en} } @article{DopplerMeyerDovernetal.2019, author = {Doppler, Christopher E. J. and Meyer, Linda and Dovern, Anna and St{\"u}hmer-Beckh, Jaro and Weiss, Peter H. and Fink, Gereon R.}, title = {Differential impact of social and monetary reward on procedural learning and consolidation in aging and its structural correlates}, series = {Frontiers in Aging Neuroscience}, volume = {11}, journal = {Frontiers in Aging Neuroscience}, doi = {10.3389/fnagi.2019.00188}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222394}, year = {2019}, abstract = {In young (n = 36, mean +/- SD: 24.8 +/- 4.5 years) and older (n = 34, mean +/- SD: 65.1 +/- 6.5 years) healthy participants, we employed a modified version of the Serial Reaction Time task to measure procedural learning (PL) and consolidation while providing monetary and social reward. Using voxel-based morphometry (VBM), we additionally determined the structural correlates of reward-related motor performance (RMP) and PL. Monetary reward had a beneficial effect on PL in the older subjects only. In contrast, social reward significantly enhanced PL in the older and consolidation in the young participants. VBM analyses revealed that motor performance related to monetary reward was associated with larger grey matter volume (GMV) of the left striatum in the young, and motor performance related to social reward with larger GMV of the medial orbitofrontal cortex in the older group. The differential effects of social reward in young (improved consolidation) and both social and monetary rewards in older (enhanced PL) healthy subjects point to the potential of rewards for interventions targeting aging-associated motor decline or stroke-induced motor deficits.}, language = {en} } @article{DopplerBrockmannSedghietal.2018, author = {Doppler, Kathrin and Brockmann, Kathrin and Sedghi, Annahita and Wurster, Isabel and Volkmann, Jens and Oertel, Wolfgang H. and Sommer, Claudia}, title = {Dermal phospho-alpha-synuclein deposition in patients with Parkinson's disease and mutation of the glucocerebrosidase gene}, series = {Frontiers in Neurology}, volume = {9}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2018.01094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222828}, year = {2018}, abstract = {Heterozygous mutations in the glucocerebrosidase gene (GBA1) represent the most common genetic risk factor for Parkinson's disease (PD) and are histopathologically associated with a widespread load of alpha-synuclein in the brain. Therefore, PD patients with GBA1 mutations are a cohort of high interest for clinical trials on disease-modifying therapies targeting alpha-synuclein. There is evidence that detection of phospho-alpha-synuclein (p-syn) in dermal nerve fibers might be a biomarker for the histopathological identification of PD patients even at premotor or very early stages of disease. It is so far unknown whether dermal p-syn deposition can also be found in PD patients with GBA1 mutations and may serve as a biomarker for PD in these patients. Skin biopsies of 10 PD patients with different GBA1 mutations (six N3705, three E326K, one L444P) were analyzed by double-immunofluorescence labeling with anti-p-syn and anti-protein gene product 9.5 (PGP9.5, axonal marker) to detect intraaxonal p-syn deposition. Four biopsy sites (distal, proximal leg, paravertebral Th10, and C7) per patient were studied. P-syn was found in six patients (three N370S, three E326K). P-syn deposition was mainly detected in autonomic nerve fibers, but also in somatosensory fibers and was not restricted to a certain GBA1 mutation. In summary, dermal p-syn in PD patients with GBA1 mutations seems to offer a similar distribution and frequency as observed in patients without a known mutation. Skin biopsy may be suitable to study p-syn deposition in these patients or even to identify premotor patients with GBA1 mutations.}, language = {en} } @article{ElHelouBiegnerBodeetal.2019, author = {El-Helou, Sabine M. and Biegner, Anika-Kerstin and Bode, Sebastian and Ehl, Stephan R. and Heeg, Maximilian and Maccari, Maria E. and Ritterbusch, Henrike and Speckmann, Carsten and Rusch, Stephan and Scheible, Raphael and Warnatz, Klaus and Atschekzei, Faranaz and Beider, Renata and Ernst, Diana and Gerschmann, Stev and Jablonka, Alexandra and Mielke, Gudrun and Schmidt, Reinhold E. and Sch{\"u}rmann, Gesine and Sogkas, Georgios and Baumann, Ulrich H. and Klemann, Christian and Viemann, Dorothee and Bernuth, Horst von and Kr{\"u}ger, Renate and Hanitsch, Leif G. and Scheibenbogen, Carmen M. and Wittke, Kirsten and Albert, Michael H. and Eichinger, Anna and Hauck, Fabian and Klein, Christoph and Rack-Hoch, Anita and Sollinger, Franz M. and Avila, Anne and Borte, Michael and Borte, Stephan and Fasshauer, Maria and Hauenherm, Anja and Kellner, Nils and M{\"u}ller, Anna H. and {\"U}lzen, Anett and Bader, Peter and Bakhtiar, Shahrzad and Lee, Jae-Yun and Heß, Ursula and Schubert, Ralf and W{\"o}lke, Sandra and Zielen, Stefan and Ghosh, Sujal and Laws, Hans-Juergen and Neubert, Jennifer and Oommen, Prasad T. and H{\"o}nig, Manfred and Schulz, Ansgar and Steinmann, Sandra and Klaus, Schwarz and D{\"u}ckers, Gregor and Lamers, Beate and Langemeyer, Vanessa and Niehues, Tim and Shai, Sonu and Graf, Dagmar and M{\"u}glich, Carmen and Schmalzing, Marc T. and Schwaneck, Eva C. and Tony, Hans-Peter and Dirks, Johannes and Haase, Gabriele and Liese, Johannes G. and Morbach, Henner and Foell, Dirk and Hellige, Antje and Wittkowski, Helmut and Masjosthusmann, Katja and Mohr, Michael and Geberzahn, Linda and Hedrich, Christian M. and M{\"u}ller, Christiane and R{\"o}sen-Wolff, Angela and Roesler, Joachim and Zimmermann, Antje and Behrends, Uta and Rieber, Nikolaus and Schauer, Uwe and Handgretinger, Rupert and Holzer, Ursula and Henes, J{\"o}rg and Kanz, Lothar and Boesecke, Christoph and Rockstroh, J{\"u}rgen K. and Schwarze-Zander, Carolynne and Wasmuth, Jan-Christian and Dilloo, Dagmar and H{\"u}lsmann, Brigitte and Sch{\"o}nberger, Stefan and Schreiber, Stefan and Zeuner, Rainald and Ankermann, Tobias and Bismarck, Philipp von and Huppertz, Hans-Iko and Kaiser-Labusch, Petra and Greil, Johann and Jakoby, Donate and Kulozik, Andreas E. and Metzler, Markus and Naumann-Bartsch, Nora and Sobik, Bettina and Graf, Norbert and Heine, Sabine and Kobbe, Robin and Lehmberg, Kai and M{\"u}ller, Ingo and Herrmann, Friedrich and Horneff, Gerd and Klein, Ariane and Peitz, Joachim and Schmidt, Nadine and Bielack, Stefan and Groß-Wieltsch, Ute and Classen, Carl F. and Klasen, Jessica and Deutz, Peter and Kamitz, Dirk and Lassy, Lisa and Tenbrock, Klaus and Wagner, Norbert and Bernbeck, Benedikt and Brummel, Bastian and Lara-Villacanas, Eusebia and M{\"u}nstermann, Esther and Schneider, Dominik T. and Tietsch, Nadine and Westkemper, Marco and Weiß, Michael and Kramm, Christof and K{\"u}hnle, Ingrid and Kullmann, Silke and Girschick, Hermann and Specker, Christof and Vinnemeier-Laubenthal, Elisabeth and Haenicke, Henriette and Schulz, Claudia and Schweigerer, Lothar and M{\"u}ller, Thomas G. and Stiefel, Martina and Belohradsky, Bernd H. and Soetedjo, Veronika and Kindle, Gerhard and Grimbacher, Bodo}, title = {The German national registry of primary immunodeficiencies (2012-2017)}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.01272}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226629}, year = {2019}, abstract = {Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57\% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36\% of patients. Familial cases were observed in 21\% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74\%) and immune dysregulation (22\%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49\% of all patients received immunoglobulin G (IgG) substitution (70\%-subcutaneous; 29\%-intravenous; 1\%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.}, language = {en} }