@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} } @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} } @phdthesis{Hahn2024, author = {Hahn, Sarah}, title = {Investigating non-canonical, 5' UTR-dependent translation of MYC and its impact on colorectal cancer development}, doi = {10.25972/OPUS-36420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364202}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Colorectal cancer (CRC) is the second most common tumour disease in Germany, with the sequential accumulation of certain mutations playing a decisive role in the transition from adenoma to carcinoma. In particular, deregulation of the Wnt signalling pathway and the associated deregulated expression of the MYC oncoprotein play a crucial role. Targeting MYC thus represents an important therapeutic approach in the treatment of tumours. Since direct inhibition of MYC is challenging, various approaches have been pursued to date to target MYC indirectly. The MYC 5' UTR contains an internal ribosomal entry site (IRES), which has a particular role in the initiation of MYC translation, especially in multiple myeloma. As basis for this work, it was hypothesised on the basis of previous data that translation of MYC potentially occurs via its IRES in CRC as well. Based on this, two IRES inhibitors were tested for their potential to regulate MYC expression in CRC cells. In addition, alternative, 5' UTR-dependent translation of MYC and interacting factors were investigated. EIF3D was identified as a MYC 5' UTR binding protein which has the potential to regulate MYC expression in CRC. The results of this work suggest that there is a link between eIF3D and MYC expression/translation, rendering eIF3D a potential therapeutic target for MYC-driven CRCs.}, subject = {Myc}, language = {en} } @phdthesis{Diehl2024, author = {Diehl, Janina Marie Christin}, title = {Ecology and evolution of symbiont management in ambrosia beetles}, doi = {10.25972/OPUS-32121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321213}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The relationship between a farmer and their cultivated crops in agriculture is multifaceted, with pathogens affecting both the farmer and crop, and weeds that take advantage of resources provided by farmers. For my doctoral thesis, I aimed to gain a comprehensive understanding of the ecology and symbiosis of fungus farming ambrosia beetles. Through my research, I discovered that the microbial composition of fungus gardens, particularly the mutualists, is significantly influenced by the presence of both adults and larvae. The recognition of both beneficial and harmful symbionts is crucial for the success of ambrosia beetles, who respond differently depending on their life stage and the microbial species they encounter, which can contribute to the division of labour among family groups. The presence of antagonists and pathogens in the fungus garden depends on habitat and substrate quality, and beetle response to their introduction results in behavioural and developmental changes. Individual and social immunity measures, as well as changes in bacterial and fungal communities, were detected as a result of pathogen introduction. Additionally, the ability of ambrosia beetles to establish two nutritional fungal species depends on several factors. These insects must strike a balance between their essential functions and adapt to the constantly changing ecological and social conditions, which demonstrates their adaptive flexibility. However, interpreting data from laboratory studies should be approached with caution, as the natural environment allows for more flexibility and the potential for other beneficial symbionts to become more prominent if required. To aid in my research, I designed primers that use the 'fungal large subunit' (LSU) as genetic marker to identify and differentiate mutualistic and antagonistic fungi in X. saxesenii. The primers were able to distinguish closely related species of the Ophiostomataceae and other fungal symbionts. This allowed me to associate the abundance of key fungal taxa with factors such as the presence of beetles, the nest's age and condition, and the various developmental stages present. My primers are a valuable tool for understanding fungal communities, including their composition and the identification of previously unknown functional symbionts. However, some aspects should be approached with caution due to the exclusion of non-amplified taxa in the relative fungal community compositions.}, subject = {{\"O}kologie}, language = {en} } @phdthesis{Merscher2024, author = {Merscher, Alma-Sophia}, title = {To Fear or not to Fear: Unraveling the (Oculo)motor and Autonomic Components of Defensive States in Humans}, doi = {10.25972/OPUS-32791}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-327913}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Defensive behaviors in response to threats are key factors in maintaining mental and physical health, but their phenomenology remains poorly understood. Prior work reported an inhibition of oculomotor activity in response to avoidable threat in humans that reminded of freezing behaviors in rodents. This notion of a homology between defensive responding in rodents and humans was seconded by concomitant heart rate decrease and skin conductance increase. However, several aspects of this presumed defense state remained ambiguous. For example, it was unclear whether the observed oculomotor inhibition would 1) robustly occur during preparation for threat-avoidance irrespective of task demands, 2) reflect a threat-specific defensive state, 3) be related to an inhibition of somatomotor activity as both motion metrics have been discussed as indicators for freezing behaviors in humans, and 4) manifest in unconstrained settings. We thus embarked on a series of experiments to unravel the robustness, threat-specificity, and validity of previously observed (oculo)motor and autonomic dynamics upon avoidable threat in humans. We provided robust evidence for reduced gaze dispersion, significantly predicting the speed of subsequent motor reactions across a wide range of stimulus contexts. Along this gaze pattern, we found reductions in body movement and showed that the temporal profiles between gaze and body activity were positively related within individuals, suggesting that both metrics reflect the same construct. A simultaneous activation of the parasympathetic (i.e., heart rate deceleration) and sympathetic (i.e., increased skin conductance and pupil dilation) nervous system was present in both defensive and appetitive contexts, suggesting that these autonomic dynamics are not only sensitive to threat but reflecting a more general action-preparatory mechanism. We further gathered evidence for two previously proposed defensive states involving a decrease of (oculo)motor activity in a naturalistic, unconstrained virtual reality environment. Specifically, we observed a state consisting of a cessation of ongoing behaviors and orienting upon relatively distal, ambiguous threat (Attentive Immobility) while an entire immobilization and presumed allocation of attention to the threat stimulus became apparent upon approaching potential threat (Immobility under Attack). Taken together, we provided evidence for specific oculomotor and autonomic dynamics upon increasing levels of threat that may inspire future translational work in rodents and humans on shared mechanisms of threat processing, ultimately supporting the development of novel therapeutic approaches.}, subject = {Furcht}, language = {en} } @phdthesis{KanmegneTamga2024, author = {Kanmegne Tamga, Dan Emmanuel}, title = {Modelling Carbon Sequestration of Agroforestry Systems in West Africa using Remote Sensing}, doi = {10.25972/OPUS-36926}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369269}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The production of commodities such as cocoa, rubber, oil palm and cashew, is the main driver of deforestation in West Africa (WA). The practiced production systems correspond to a land managment approach referred to as agroforestry systems (AFS), which consist of managing trees and crops on the same unit of land.Because of the ubiquity of trees, AFS reported as viable solution for climate mitigation; the carbon sequestrated by the trees could be estimated with remote sensing (RS) data and methods and reported as emission reduction efforts. However, the diversity in AFS in relation to their composition, structure and spatial distribution makes it challenging for an accurate monitoring of carbon stocks using RS. Therefore, the aim of this research is to propose a RS-based approach for the estimation of carbon sequestration in AFS across the climatic regions of WA. The main objectives were to (i) provide an accurate classification map of AFS by modelling the spatial distribution of the classification error; (ii) estimate the carbon stock of AFS in the main climatic regions of WA using RS data; (iii) evaluate the dynamic of carbon stocks within AFS across WA. Three regions of interest (ROI) were defined in Cote d'Ivoire and Burkina Faso, one in each climatic region of WA namely the Guineo-Congolian, Guinean and Sudanian, and three field campaigns were carried out for data collection. The collected data consisted of reference points for image classification, biometric tree measurements (diameter, height, species) for biomass estimation. A total of 261 samples were collected in 12 AFS across WA. For the RS data, yearly composite images from Sentinel-1 and -2 (S1 and S2), ALOS-PALSAR and GEDI data were used. A supervised classification using random forest (RF) was implemented and the classification error was assessed using the Shannon entropy generated from the class probabilities. For carbon estimation, different RS data, machine learning algorithms and carbon reference sources were compared for the prediction of the aboveground biomass in AFS. The assessment of the carbon dynamic was carried between 2017 and 2021. An average carbon map was genrated and use as reference for the comparison of annual carbon estimations, using the standard deviation as threshold. As far as the results are concerned, the classification accuracy was higher than 0.9 in all the ROIs, and AFS were mainly represented by rubber (38.9\%), cocoa (36.4\%), palm (10.8\%) in the ROI-1, mango (15.2\%) and cashew (13.4\%) in ROI-2, shea tree (55.7\%) and African locust bean (28.1\%) in ROI-3. However, evidence of misclassification was found in cocoa, mango, and shea butter. The assessment of the classification error suggested that the error level was higher in the ROI-3 and ROI-1. The error generated from the entropy was able to reduced the level of misclassification by 63\% with 11\% of loss of information. Moreover, the approach was able to accuretely detect encroachement in protected areas. On carbon estimation, the highest prediction accuracy (R²>0.8) was obtained for a RF model using the combination of S1 and S2 and AGB derived from field measurements. Predictions from GEDI could only be used as reference in the ROI-1 but resulted in a prediction error was higher in cashew, mango, rubber and cocoa plantations, and the carbon stock level was higher in African locust bean (43.9 t/ha), shea butter (15 t/ha), cashew (13.8 t/ha), mango (12.8 t/ha), cocoa (7.51 t/ha) and rubber (7.33 t/ha). The analysis showed that carbon stock is determined mainly by the diameter (R²=0.45) and height (R²=0.13) of trees. It was found that crop plantations had the lowest biodiversity level, and no significant relationship was found between the considered biodiversity indices and carbon stock levels. The assessment of the spatial distribution of carbon sources and sinks showed that cashew plantations are carbon emitters due to firewood collection, while cocoa plantations showed the highest potential for carbon sequestration. The study revealed that Sentinel data could be used to support a RS-based approach for modelling carbon sequestration in AFS. Entropy could be used to map crop plantations and to monitor encroachment in protected areas. Moreover, field measurements with appropriate allometric models could ensure an accurate estimation of carbon stocks in AFS. Even though AFS in the Sudanian region had the highest carbon stocks level, there is a high potential to increase the carbon level in cocoa plantations by integrating and/or maintaining forest trees.}, subject = {Sequestrierung}, language = {en} } @phdthesis{Laqua2024, author = {Laqua, Caroline}, title = {Association of myocardial tissue characteristics and functional outcome in biopsy-verified myocarditis assessed by cardiac magnetic resonance imaging}, doi = {10.25972/OPUS-36390}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363903}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The relation between LV function and cardiac MRI tissue characteristics in separate myocardial segments and their change over time has yet to be explored in myocarditis. Thus, our research aimed to investigate possible associations between global and regional myocardial T1 and T2 times and peak strain in patients with suspected myocarditis. From 2012 to 2015, 129 patients with clinically suspected myocarditis of the prospective, observational MyoRacer-Trial underwent systematic biventricular EMB at baseline and cardiac MRI at baseline and after three months as a follow-up. We divided the LV myocardium into 17 segments and estimated the segmental myocardial strain using FT. We registered T1 and T2 maps to the cine sequences and transferred the segmentations used for FT to ensure conformity of the myocardial segments. Multi-level multivariable linear mixed effects regression was applied to investigate the relation of segmental myocardial strain to relaxation times and their respective change from baseline to follow-up. We found a significant improvement in myocardial peak strain from baseline to follow-up (p < 0.001; all p-values given for likelihood ratio tests) and significant associations between higher T1 and T2 times and lower segmental myocardial peak strain (p ranging from < 0.001 to 0.049). E.g., regression coefficient (Reg. coef.) for segmental radial peak strain in short axis view (SRPS_SAX) and T1 time: -1.9, 95\% CI (-2.6;-1.2) \%/100 ms, p < 0.001. A decrease in T1 and T2 times from baseline to follow-up was also significantly related to a recovery of segmental peak strains (p ranging from < 0.001 to 0.050). E.g., Reg. coef. for SRPS_SAX per ΔT1: -1.8, 95\% CI (-2.5;-1.0) \%/100 ms, p < 0.001. Moreover, the higher the baseline T1 time, the more substantial the functional recovery from baseline to follow-up (p ranging from 0.004 to 0.042, e.g., for SRPS_SAX: Reg. coef. 1.3, 95\% CI (0.4;2.1) \%/100 ms, p 0.004). We did not find an effect modification by the presence of myocarditis in the EMB (p > 0.1). Our cross-sectional and longitudinal analyses provide evidence of dose-dependent correlations between T1 and T2 relaxation times and myocardial peak strain in patients with clinical presentation of myocarditis, regardless of the EMB result. Thus, assessing strain values and mapping relaxation times helps estimate the functional prognosis in patients with clinically suspected myocarditis.}, subject = {Myokarditis}, language = {en} }