@article{LudwigDelforgeFaconetal.2018, author = {Ludwig, Heinz and Delforge, Michel and Facon, Thierry and Einsele, Hermann and Gay, Francesca and Moreau, Philippe and Avet-Loiseau, Herv{\´e} and Boccadoro, Mario and Hajek, Roman and Mohty, Mohamad and Cavo, Michele and Dimopoulos, Meletios A and San-Miguel, Jes{\´u}s F and Terpos, Evangelos and Zweegman, Sonja and Garderet, Laurent and Mateos, Mar{\´i}a-Victoria and Cook, Gordon and Leleu, Xavier and Goldschmidt, Hartmut and Jackson, Graham and Kaiser, Martin and Weisel, Katja and van de Donk, Niels W. C. J. and Waage, Anders and Beksac, Meral and Mellqvist, Ulf H. and Engelhardt, Monika and Caers, Jo and Driessen, Christoph and Blad{\´e}, Joan and Sonneveld, Pieter}, title = {Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network}, series = {Leukemia}, volume = {32}, journal = {Leukemia}, doi = {10.1038/s41375-018-0040-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237338}, pages = {1542-1560}, year = {2018}, abstract = {During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.}, language = {en} } @article{MilaneseMendePaolietal.2019, author = {Milanese, Alessio and Mende, Daniel R and Paoli, Lucas and Salazar, Guillem and Ruscheweyh, Hans-Joachim and Cuenca, Miguelangel and Hingamp, Pascal and Alves, Renato and Costea, Paul I and Coelho, Luis Pedro and Schmidt, Thomas S. B. and Almeida, Alexandre and Mitchell, Alex L and Finn, Robert D. and Huerta-Cepas, Jaime and Bork, Peer and Zeller, Georg and Sunagawa, Shinichi}, title = {Microbial abundance, activity and population genomic profiling with mOTUs2}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-08844-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224089}, year = {2019}, abstract = {Metagenomic sequencing has greatly improved our ability to profile the composition of environmental and host-associated microbial communities. However, the dependency of most methods on reference genomes, which are currently unavailable for a substantial fraction of microbial species, introduces estimation biases. We present an updated and functionally extended tool based on universal (i.e., reference-independent), phylogenetic marker gene (MG)-based operational taxonomic units (mOTUs) enabling the profiling of >7700 microbial species. As more than 30\% of them could not previously be quantified at this taxonomic resolution, relative abundance estimates based on mOTUs are more accurate compared to other methods. As a new feature, we show that mOTUs, which are based on essential housekeeping genes, are demonstrably well-suited for quantification of basal transcriptional activity of community members. Furthermore, single nucleotide variation profiles estimated using mOTUs reflect those from whole genomes, which allows for comparing microbial strain populations (e.g., across different human body sites).}, 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} }