TY  - JOUR
A1  - Kügel, Jens
A1  - Karolak, Michael
A1  - Krönlein, Andreas
A1  - Serrate, David
A1  - Bode, Matthias
A1  - Sangiovanni, Giorgio
T1  - Reversible magnetic switching of high-spin molecules on a giant Rashba surface
JF  - npj Quantum Materials
N2  - 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.
KW  - electronic structure of atoms and molecules
KW  - magnetic properties and materials
KW  - surfaces, interfaces and thin films
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230866
VL  - 3
ER  - 
TY  - JOUR
A1  - Kurabi, Arwa
A1  - Schaerer, Daniel
A1  - Noack, Volker
A1  - Bernhardt, Marlen
A1  - Pak, Kwang
A1  - Alexander, Thomas
A1  - Husseman, Jacob
A1  - Nguyen, Quyen
A1  - Harris, Jeffrey P.
A1  - Ryan, Allen F.
T1  - Active Transport of Peptides Across the Intact Human Tympanic Membrane
JF  - Scientific Reports
N2  - 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.
KW  - assay systems
KW  - biological models
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230929
VL  - 8
ER  - 
TY  - JOUR
A1  - Liu, Yuhai
A1  - Wang, Zhenjiu
A1  - Sato, Toshihiro
A1  - Hohenadler, Martin
A1  - Wang, Chong
A1  - Guo, Wenan
A1  - Assaad, Fakher F.
T1  - Superconductivity from the condensation of topological defects in a quantum spin-Hall insulator
JF  - Nature Communications
N2  - 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.
KW  - computational science
KW  - phase transitions and critical phenomena
KW  - topological insulators
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237024
VL  - 10
ER  - 
TY  - THES
A1  - Starz, Katharina Theresa
T1  - Das Sharenting in der Zivilrechtsdogmatik : zu den Grenzen elterlicher Dispositionsbefugnis über das Persönlichkeitsrecht des Kindes
T1  - Sharenting in Civil Law Dogmatics : On the Limits of Parental Power of Disposition over the Personal Rights of the Child
N2  - Im Zeitalter der sozialen Medien ist es für viele Eltern zur Gewohnheit geworden, nicht nur sich selbst, sondern auch das eigene Kind der Internetgemeinschaft zu präsentieren. 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 hinterlässt. Der freizügige Umgang mit den Daten des Kindes bringt zahlreiche rechtliche Probleme mit sich, welche an den Schnittstellen des Rechts zum Schutz der Persönlichkeit, des Datenschutzrechts und des Familienrechts zu verorten sind. Am Beispiel der Plattformen Facebook, Instagram und WhatsApp lotet Katharina Theresa Starz die Grenzen des rechtlich Zulässigen aus und zeigt auf, welche Konsequenzen sich ergeben können, wenn ebendiese Grenzen von den Eltern überschritten werden.
Y1  - 2024
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369667
PB  - Mohr Siebeck
CY  - Tübingen
ER  - 
TY  - JOUR
A1  - López, Cristina
A1  - Kleinheinz, Kortine
A1  - Aukema, Sietse M.
A1  - Rohde, Marius
A1  - Bernhart, Stephan H.
A1  - Hübschmann, Daniel
A1  - Wagener, Rabea
A1  - Toprak, Umut H.
A1  - Raimondi, Francesco
A1  - Kreuz, Markus
A1  - Waszak, Sebastian M.
A1  - Huang, Zhiqin
A1  - Sieverling, Lina
A1  - Paramasivam, Nagarajan
A1  - Seufert, Julian
A1  - Sungalee, Stephanie
A1  - Russell, Robert B.
A1  - Bausinger, Julia
A1  - Kretzmer, Helene
A1  - Ammerpohl, Ole
A1  - Bergmann, Anke K.
A1  - Binder, Hans
A1  - Borkhardt, Arndt
A1  - Brors, Benedikt
A1  - Claviez, Alexander
A1  - Doose, Gero
A1  - Feuerbach, Lars
A1  - Haake, Andrea
A1  - Hansmann, Martin-Leo
A1  - Hoell, Jessica
A1  - Hummel, Michael
A1  - Korbel, Jan O.
A1  - Lawerenz, Chris
A1  - Lenze, Dido
A1  - Radlwimmer, Bernhard
A1  - Richter, Julia
A1  - Rosenstiel, Philip
A1  - Rosenwald, Andreas
A1  - Schilhabel, Markus B.
A1  - Stein, Harald
A1  - Stilgenbauer, Stephan
A1  - Stadler, Peter F.
A1  - Szczepanowski, Monika
A1  - Weniger, Marc A.
A1  - Zapatka, Marc
A1  - Eils, Roland
A1  - Lichter, Peter
A1  - Loeffler, Markus
A1  - Möller, Peter
A1  - Trümper, Lorenz
A1  - Klapper, Wolfram
A1  - Hoffmann, Steve
A1  - Küppers, Ralf
A1  - Burkhardt, Birgit
A1  - Schlesner, Matthias
A1  - Siebert, Reiner
T1  - Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma
JF  - Nature Communications
N2  - 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.
KW  - cancer genomics
KW  - lymphocytes
KW  - lymphoid tissues
KW  - oncology
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237281
VL  - 10
ER  - 
TY  - JOUR
A1  - Lu, Yuan
A1  - Boswell, Wiliam
A1  - Boswell, Mikki
A1  - Klotz, Barbara
A1  - Kneitz, Susanne
A1  - Regneri, Janine
A1  - Savage, Markita
A1  - Mendoza, Cristina
A1  - Postlethwait, John
A1  - Warren, Wesley C.
A1  - Schartl, Manfred
A1  - Walter, Ronald B.
T1  - Application of the Transcriptional Disease Signature (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model
JF  - Scientific Reports
N2  - 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.
KW  - bioinformatics
KW  - phenotypic screening
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237322
VL  - 9
ER  - 
TY  - JOUR
A1  - Mercier, Rebecca
A1  - Wolmarans, Annemarie
A1  - Schubert, Jonathan
A1  - Neuweiler, Hannes
A1  - Johnson, Jill L.
A1  - LaPointe, Paul
T1  - The conserved NxNNWHW motif in Aha-type co-chaperones modulates the kinetics of Hsp90 ATPase stimulation
JF  - Nature Communications
N2  - 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.
KW  - biophysics
KW  - cell growth
KW  - chaperones
KW  - enzymes
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224007
VL  - 10
ER  - 
TY  - JOUR
A1  - Meral, Derya
A1  - Provasi, Davide
A1  - Prada-Gracia, Diego
A1  - Möller, Jan
A1  - Marino, Kristen
A1  - Lohse, Martin J.
A1  - Filizola, Marta
T1  - Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations
JF  - Scientific Reports
N2  - 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.
KW  - computational biophysics
KW  - fluorescence resonance energy transfer
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223995
VL  - 8
ER  - 
TY  - JOUR
A1  - Medler, Juliane
A1  - Nelke, Johannes
A1  - Weisenberger, Daniela
A1  - Steinfatt, Tim
A1  - Rothaug, Moritz
A1  - Berr, Susanne
A1  - Hünig, Thomas
A1  - Beilhack, Andreas
A1  - Wajant, Harald
T1  - TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity
JF  - Cell Death & Disease
N2  - 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.
KW  - biologics
KW  - proteins
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223948
VL  - 10
ER  - 
TY  - JOUR
A1  - Lübcke, Paul M.
A1  - Ebbers, Meinolf N. B.
A1  - Volzke, Johann
A1  - Bull, Jana
A1  - Kneitz, Susanne
A1  - Engelmann, Robby
A1  - Lang, Hermann
A1  - Kreikemeyer, Bernd
A1  - Müller-Hilke, Brigitte
T1  - Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss
JF  - Scientific Reports
N2  - 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.
KW  - rheumatic diseases
KW  - rheumatology
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237355
VL  - 9
ER  -