@article{WalkerMavrommatisWardelletal.2019, author = {Walker, Brian A. and Mavrommatis, Konstantinos and Wardell, Christopher P. and Ashby, T. Cody and Bauer, Michael and Davies, Faith and Rosenthal, Adam and Wang, Hongwei and Qu, Pingping and Hoering, Antje and Samur, Mehmet and Towfic, Fadi and Ortiz, Maria and Flynt, Erin and Yu, Zhinuan and Yang, Zhihong and Rozelle, Dan and Obenauer, John and Trotter, Matthew and Auclair, Daniel and Keats, Jonathan and Bolli, Niccolo and Fulciniti, Mariateresa and Szalat, Raphael and Moreau, Phillipe and Durie, Brian and Stewart, A. Keith and Goldschmidt, Hartmut and Raab, Marc S. and Einsele, Hermann and Sonneveld, Pieter and San Miguel, Jesus and Lonial, Sagar and Jackson, Graham H. and Anderson, Kenneth C. and Avet-Loiseau, Herve and Munshi, Nikhil and Thakurta, Anjan and Morgan, Gareth}, title = {A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis}, series = {Leukemia}, volume = {33}, journal = {Leukemia}, doi = {10.1038/s41375-018-0196-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233299}, pages = {159-170}, year = {2019}, abstract = {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.}, language = {en} } @article{WegertVokuhlCollordetal.2018, author = {Wegert, Jenny and Vokuhl, Christian and Collord, Grace and Del Castillo Velasco-Herrera, Martin and Farndon, Sarah J. and Guzzo, Charlotte and Jorgensen, Mette and Anderson, John and Slater, Olga and Duncan, Catriona and Bausenwein, Sabrina and Streitenberger, Heike and Ziegler, Barbara and Furtw{\"a}ngler, Rhoikos and Graf, Norbert and Stratton, Michael R. and Campbell, Peter J. and Jones, David TW and Koelsche, Christian and Pfister, Stefan M. and Mifsud, William and Sebire, Neil and Sparber-Sauer, Monika and Koscielniak, Ewa and Rosenwald, Andreas and Gessler, Manfred and Behjati, Sam}, title = {Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-04650-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233446}, year = {2018}, abstract = {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.}, language = {en} } @article{WaldherrLundtKlaasetal.2018, author = {Waldherr, Max and Lundt, Nils and Klaas, Martin and Betzold, Simon and Wurdack, Matthias and Baumann, Vasilij and Estrecho, Eliezer and Nalitov, Anton and Cherotchenko, Evgenia and Cai, Hui and Ostrovskaya, Elena A. and Kavokin, Alexey V. and Tongay, Sefaattin and Klembt, Sebastian and H{\"o}fling, Sven and Schneider, Christian}, title = {Observation of bosonic condensation in a hybrid monolayer MoSe2-GaAs microcavity}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-05532-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233280}, year = {2018}, abstract = {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.}, language = {en} } @article{AnnunziatavandeVlekkertWolfetal.2019, author = {Annunziata, Ida and van de Vlekkert, Diantha and Wolf, Elmar and Finkelstein, David and Neale, Geoffrey and Machado, Eda and Mosca, Rosario and Campos, Yvan and Tillman, Heather and Roussel, Martine F. and Weesner, Jason Andrew and Fremuth, Leigh Ellen and Qiu, Xiaohui and Han, Min-Joon and Grosveld, Gerard C. and d'Azzo, Alessandra}, title = {MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-11568-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221189}, year = {2019}, abstract = {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.}, language = {en} } @article{AnanyKreckelFuellsacketal.2018, author = {Anany, Mohamed A. and Kreckel, Jennifer and F{\"u}llsack, Simone and Rosenthal, Alevtina and Otto, Christoph and Siegmund, Daniela and Wajant, Harald}, title = {Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis}, series = {Cell Death \& Disease}, volume = {9}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-018-1137-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221104}, year = {2018}, abstract = {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.}, language = {en} } @article{LeeLiRuanetal.2019, author = {Lee, Hong-Jen and Li, Chien-Feng and Ruan, Diane and He, Jiabei and Montal, Emily D. and Lorenz, Sonja and Girnun, Geoffrey D. and Chan, Chia-Hsin}, title = {Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10374-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236445}, year = {2019}, abstract = {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.}, language = {en} } @article{LanghauserCasasDaoetal.2018, author = {Langhauser, Friederike and Casas, Ana I. and Dao, Vu-Thao-Vi and Guney, Emre and Menche, J{\"o}rg and Geuss, Eva and Kleikers, Pamela W. M. and L{\´o}pez, Manuela G. and Barab{\´a}si, Albert-L. and Kleinschnitz, Christoph and Schmidt, Harald H. H. W.}, title = {A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection}, series = {npj Systems Biology and Applications}, volume = {4}, journal = {npj Systems Biology and Applications}, doi = {10.1038/s41540-017-0039-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236381}, year = {2018}, abstract = {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.}, language = {en} } @article{LiaoTtofaliSlotkowskietal.2019, author = {Liao, Chunyu and Ttofali, Fani and Slotkowski, Rebecca A. and Denny, Steven R. and Cecil, Taylor D. and Leenay, Ryan T. and Keung, Albert J. and Beisel, Chase L.}, title = {Modular one-pot assembly of CRISPR arrays enables library generation and reveals factors influencing crRNA biogenesis}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10747-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236843}, year = {2019}, abstract = {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.}, language = {en} } @article{LevyBoulleEmeritetal.2019, author = {Levy, Marion J. F. and Boulle, Fabien and Emerit, Michel Boris and Poilbout, Corinne and Steinbusch, Harry W. M. and Van den Hove, Daniel L. A. and Kenis, Gunter and Lanfumey, Laurence}, title = {5-HTT independent effects of fluoxetine on neuroplasticity}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-42775-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236759}, year = {2019}, abstract = {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.}, language = {en} } @article{LeeImhofBergeretal.2018, author = {Lee, Ching Hua and Imhof, Stefan and Berger, Christian and Bayer, Florian and Brehm, Johannes and Molenkamp, Laurens W. and Kiessling, Tobias and Thomale, Ronny}, title = {Topolectrical Circuits}, series = {Communications Physics}, volume = {1}, journal = {Communications Physics}, doi = {10.1038/s42005-018-0035-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236422}, year = {2018}, abstract = {Invented by Alessandro Volta and F{\´e}lix 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.}, language = {en} } @article{KuegelKarolakKroenleinetal.2018, author = {K{\"u}gel, Jens and Karolak, Michael and Kr{\"o}nlein, Andreas and Serrate, David and Bode, Matthias and Sangiovanni, Giorgio}, title = {Reversible magnetic switching of high-spin molecules on a giant Rashba surface}, series = {npj Quantum Materials}, volume = {3}, journal = {npj Quantum Materials}, doi = {10.1038/s41535-018-0126-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230866}, year = {2018}, abstract = {The quantum mechanical screening of a spin via conduction electrons depends sensitively on the environment seen by the magnetic impurity. A high degree of responsiveness can be obtained with metal complexes, as the embedding of a metal ion into an organic molecule prevents intercalation or alloying and allows for a good control by an appropriate choice of the ligands. There are therefore hopes to reach an "on demand" control of the spin state of single molecules adsorbed on substrates. Hitherto one route was to rely on "switchable" molecules with intrinsic bistabilities triggered by external stimuli, such as temperature or light, or on the controlled dosing of chemicals to form reversible bonds. However, these methods constrain the functionality to switchable molecules or depend on access to atoms or molecules. Here, we present a way to induce bistability also in a planar molecule by making use of the environment. We found that the particular "habitat" offered by an antiphase boundary of the Rashba system BiAg2 stabilizes a second structure for manganese phthalocyanine molecules, in which the central Mn ion moves out of the molecular plane. This corresponds to the formation of a large magnetic moment and a concomitant change of the ground state with respect to the conventional adsorption site. The reversible spin switch found here shows how we can not only rearrange electronic levels or lift orbital degeneracies via the substrate, but even sway the effects of many-body interactions in single molecules by acting on their surrounding.}, language = {en} } @article{KurabiSchaererNoacketal.2018, author = {Kurabi, Arwa and Schaerer, Daniel and Noack, Volker and Bernhardt, Marlen and Pak, Kwang and Alexander, Thomas and Husseman, Jacob and Nguyen, Quyen and Harris, Jeffrey P. and Ryan, Allen F.}, title = {Active Transport of Peptides Across the Intact Human Tympanic Membrane}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-30031-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230929}, year = {2018}, abstract = {We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.}, language = {en} } @article{LiuWangSatoetal.2019, author = {Liu, Yuhai and Wang, Zhenjiu and Sato, Toshihiro and Hohenadler, Martin and Wang, Chong and Guo, Wenan and Assaad, Fakher F.}, title = {Superconductivity from the condensation of topological defects in a quantum spin-Hall insulator}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10372-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237024}, year = {2019}, abstract = {The discovery of quantum spin-Hall (QSH) insulators has brought topology to the forefront of condensed matter physics. While a QSH state from spin-orbit coupling can be fully understood in terms of band theory, fascinating many-body effects are expected if it instead results from spontaneous symmetry breaking. Here, we introduce a model of interacting Dirac fermions where a QSH state is dynamically generated. Our tuning parameter further allows us to destabilize the QSH state in favour of a superconducting state through proliferation of charge-2e topological defects. This route to superconductivity put forward by Grover and Senthil is an instance of a deconfined quantum critical point (DQCP). Our model offers the possibility to study DQCPs without a second length scale associated with the reduced symmetry between field theory and lattice realization and, by construction, is amenable to large-scale fermion quantum Monte Carlo simulations.}, language = {en} } @phdthesis{Starz2024, author = {Starz, Katharina Theresa}, title = {Das Sharenting in der Zivilrechtsdogmatik : zu den Grenzen elterlicher Dispositionsbefugnis {\"u}ber das Pers{\"o}nlichkeitsrecht des Kindes}, publisher = {Mohr Siebeck}, address = {T{\"u}bingen}, doi = {10.25972/OPUS-36966}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369667}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {256}, year = {2024}, abstract = {Im Zeitalter der sozialen Medien ist es f{\"u}r viele Eltern zur Gewohnheit geworden, nicht nur sich selbst, sondern auch das eigene Kind der Internetgemeinschaft zu pr{\"a}sentieren. Diese Praxis wird als "Sharenting" ("to share" + "parenting") bezeichnet. So kommt es, dass mittlerweile ein Großteil der Kinder bereits in sehr jungen Jahren einen - unfreiwilligen - digitalen Fußabdruck hinterl{\"a}sst. Der freiz{\"u}gige Umgang mit den Daten des Kindes bringt zahlreiche rechtliche Probleme mit sich, welche an den Schnittstellen des Rechts zum Schutz der Pers{\"o}nlichkeit, des Datenschutzrechts und des Familienrechts zu verorten sind. Am Beispiel der Plattformen Facebook, Instagram und WhatsApp lotet Katharina Theresa Starz die Grenzen des rechtlich Zul{\"a}ssigen aus und zeigt auf, welche Konsequenzen sich ergeben k{\"o}nnen, wenn ebendiese Grenzen von den Eltern {\"u}berschritten werden.}, language = {de} } @article{LopezKleinheinzAukemaetal.2019, author = {L{\´o}pez, Cristina and Kleinheinz, Kortine and Aukema, Sietse M. and Rohde, Marius and Bernhart, Stephan H. and H{\"u}bschmann, Daniel and Wagener, Rabea and Toprak, Umut H. and Raimondi, Francesco and Kreuz, Markus and Waszak, Sebastian M. and Huang, Zhiqin and Sieverling, Lina and Paramasivam, Nagarajan and Seufert, Julian and Sungalee, Stephanie and Russell, Robert B. and Bausinger, Julia and Kretzmer, Helene and Ammerpohl, Ole and Bergmann, Anke K. and Binder, Hans and Borkhardt, Arndt and Brors, Benedikt and Claviez, Alexander and Doose, Gero and Feuerbach, Lars and Haake, Andrea and Hansmann, Martin-Leo and Hoell, Jessica and Hummel, Michael and Korbel, Jan O. and Lawerenz, Chris and Lenze, Dido and Radlwimmer, Bernhard and Richter, Julia and Rosenstiel, Philip and Rosenwald, Andreas and Schilhabel, Markus B. and Stein, Harald and Stilgenbauer, Stephan and Stadler, Peter F. and Szczepanowski, Monika and Weniger, Marc A. and Zapatka, Marc and Eils, Roland and Lichter, Peter and Loeffler, Markus and M{\"o}ller, Peter and Tr{\"u}mper, Lorenz and Klapper, Wolfram and Hoffmann, Steve and K{\"u}ppers, Ralf and Burkhardt, Birgit and Schlesner, Matthias and Siebert, Reiner}, title = {Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, organization = {ICGC MMML-Seq Consortium}, doi = {10.1038/s41467-019-08578-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237281}, year = {2019}, abstract = {Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.}, language = {en} } @article{LuBoswellBoswelletal.2019, author = {Lu, Yuan and Boswell, Wiliam and Boswell, Mikki and Klotz, Barbara and Kneitz, Susanne and Regneri, Janine and Savage, Markita and Mendoza, Cristina and Postlethwait, John and Warren, Wesley C. and Schartl, Manfred and Walter, Ronald B.}, title = {Application of the Transcriptional Disease Signature (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-36656-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237322}, year = {2019}, abstract = {Cell culture and protein target-based compound screening strategies, though broadly utilized in selecting candidate compounds, often fail to eliminate candidate compounds with non-target effects and/or safety concerns until late in the drug developmental process. Phenotype screening using intact research animals is attractive because it can help identify small molecule candidate compounds that have a high probability of proceeding to clinical use. Most FDA approved, first-in-class small molecules were identified from phenotypic screening. However, phenotypic screening using rodent models is labor intensive, low-throughput, and very expensive. As a novel alternative for small molecule screening, we have been developing gene expression disease profiles, termed the Transcriptional Disease Signature (TDS), as readout of small molecule screens for therapeutic molecules. In this concept, compounds that can reverse, or otherwise affect known disease-associated gene expression patterns in whole animals may be rapidly identified for more detailed downstream direct testing of their efficacy and mode of action. To establish proof of concept for this screening strategy, we employed a transgenic strain of a small aquarium fish, medaka (Oryzias latipes), that overexpresses the malignant melanoma driver gene xmrk, a mutant egfr gene, that is driven by a pigment cell-specific mitf promoter. In this model, melanoma develops with 100\% penetrance. Using the transgenic medaka malignant melanoma model, we established a screening system that employs the NanoString nCounter platform to quantify gene expression within custom sets of TDS gene targets that we had previously shown to exhibit differential transcription among xmrk-transgenic and wild-type medaka. Compound-modulated gene expression was identified using an internet-accessible custom-built data processing pipeline. The effect of a given drug on the entire TDS profile was estimated by comparing compound-modulated genes in the TDS using an activation Z-score and Kolmogorov-Smirnov statistics. TDS gene probes were designed that target common signaling pathways that include proliferation, development, toxicity, immune function, metabolism and detoxification. These pathways may be utilized to evaluate candidate compounds for potential favorable, or unfavorable, effects on melanoma-associated gene expression. Here we present the logistics of using medaka to screen compounds, as well as, the development of a user-friendly NanoString data analysis pipeline to support feasibility of this novel TDS drug-screening strategy.}, language = {en} } @article{MercierWolmaransSchubertetal.2019, author = {Mercier, Rebecca and Wolmarans, Annemarie and Schubert, Jonathan and Neuweiler, Hannes and Johnson, Jill L. and LaPointe, Paul}, title = {The conserved NxNNWHW motif in Aha-type co-chaperones modulates the kinetics of Hsp90 ATPase stimulation}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09299-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224007}, year = {2019}, abstract = {Hsp90 is a dimeric molecular chaperone that is essential for the folding and activation of hundreds of client proteins. Co-chaperone proteins regulate the ATP-driven Hsp90 client activation cycle. Aha-type co-chaperones are the most potent stimulators of the Hsp90 ATPase activity but the relationship between ATPase regulation and in vivo activity is poorly understood. We report here that the most strongly conserved region of Aha-type co-chaperones, the N terminal NxNNWHW motif, modulates the apparent affinity of Hsp90 for nucleotide substrates. The ability of yeast Aha-type co-chaperones to act in vivo is ablated when the N terminal NxNNWHW motif is removed. This work suggests that nucleotide exchange during the Hsp90 functional cycle may be more important than rate of catalysis.}, language = {en} } @article{MeralProvasiPradaGraciaetal.2018, author = {Meral, Derya and Provasi, Davide and Prada-Gracia, Diego and M{\"o}ller, Jan and Marino, Kristen and Lohse, Martin J. and Filizola, Marta}, title = {Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-26070-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223995}, year = {2018}, abstract = {Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer. Analysis of these computations identifies kinetically distinct macrostates comprising several different short-lived dimeric configurations of either inactive or activated MOR. Calculated kinetic rates and fractions of dimers at different MOR concentrations suggest a negligible population of MOR homodimers at physiological concentrations, which is supported by acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments. This study provides a rigorous, quantitative explanation for some conflicting experimental data on GPCR oligomerization.}, language = {en} } @article{MedlerNelkeWeisenbergeretal.2019, author = {Medler, Juliane and Nelke, Johannes and Weisenberger, Daniela and Steinfatt, Tim and Rothaug, Moritz and Berr, Susanne and H{\"u}nig, Thomas and Beilhack, Andreas and Wajant, Harald}, title = {TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1456-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223948}, year = {2019}, abstract = {Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed.}, language = {en} } @article{LuebckeEbbersVolzkeetal.2019, author = {L{\"u}bcke, Paul M. and Ebbers, Meinolf N. B. and Volzke, Johann and Bull, Jana and Kneitz, Susanne and Engelmann, Robby and Lang, Hermann and Kreikemeyer, Bernd and M{\"u}ller-Hilke, Brigitte}, title = {Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-44512-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237355}, year = {2019}, abstract = {Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.}, language = {en} }