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  - 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  - 
TY  - JOUR
A1  - Snaebjornsson, Marteinn T
A1  - Schulze, Almut
T1  - Non-canonical functions of enzymes facilitate cross-talk between cell metabolic and regulatory pathways
JF  - Experimental & Molecular Medicine
N2  - The metabolic rewiring that occurs during cell transformation is a hallmark of cancer. It is diverse in different cancers as it reflects different combinations of oncogenic drivers, tumor suppressors, and the microenvironment. Metabolic rewiring is essential to cancer as it enables uncontrolled proliferation and adaptation to the fluctuating availability of nutrients and oxygen caused by poor access to the vasculature due to tumor growth and a foreign microenvironment encountered during metastasis. Increasing evidence now indicates that the metabolic state in cancer cells also plays a causal role in tumor growth and metastasis, for example through the action of oncometabolites, which modulate cell signaling and epigenetic pathways to promote malignancy. In addition to altering the metabolic state in cancer cells, some multifunctional enzymes possess non-metabolic functions that also contribute to cell transformation. Some multifunctional enzymes that are highly expressed in cancer, such as pyruvate kinase M2 (PKM2), have non-canonical functions that are co-opted by oncogenic signaling to drive proliferation and inhibit apoptosis. Other multifunctional enzymes that are frequently downregulated in cancer, such as fructose-bisphosphatase 1 (FBP1), are tumor suppressors, directly opposing mitogenic signaling via their non-canonical functions. In some cases, the enzymatic and non-canonical roles of these enzymes are functionally linked, making the modulation of non-metabolic cellular processes dependent on the metabolic state of the cell.
KW  - cancer metabolism
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238763
VL  - 50
ER  - 
TY  - JOUR
A1  - Sirtl, Simon
A1  - Knoll, Gertrud
A1  - Dieu Thuy, Trinh
A1  - Lang, Isabell
A1  - Siegmund, Daniela
A1  - Gross, Stefanie
A1  - Schuler-Thurner, Beatrice
A1  - Neubert, Patrick
A1  - Jantsch, Jonathan
A1  - Wajant, Harald
A1  - Ehrenschwender, Martin
T1  - Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors
JF  - Oncogene
N2  - Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.
KW  - apoptosis
KW  - cancer microenvironment
KW  - cytokines
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238327
VL  - 37
ER  - 
TY  - JOUR
A1  - Stegmann, Yannik
A1  - Reicherts, Philipp
A1  - Andreatta, Marta
A1  - Pauli, Paul
A1  - Wieser, Matthias J.
T1  - The effect of trait anxiety on attentional mechanisms in combined context and cue conditioning and extinction learning
JF  - Scientific Reports
N2  - Sensory processing and attention allocation are shaped by threat, but the role of trait-anxiety in sensory processing as a function of threat predictability remains incompletely understood. Therefore, we measured steady-state visual evoked potentials (ssVEPs) as an index of sensory processing of predictable and unpredictable threat cues in 29 low (LA) and 29 high (HA) trait-anxious participants during a modified NPU-paradigm followed by an extinction phase. Three different contextual cues indicated safety (N), predictable (P) or unpredictable threat (U), while foreground cues signalled shocks in the P-condition only. All participants allocated increased attentional resources to the central P-threat cue, replicating previous findings. Importantly, LA individuals exhibited larger ssVEP amplitudes to contextual threat (U and P) than to contextual safety cues, while HA individuals did not differentiate among contextual cues in general. Further, HA exhibited higher aversive ratings of all contexts compared to LA. These results suggest that high trait-anxious individuals might be worse at discriminating contextual threat stimuli and accordingly overestimate the probability and aversiveness of unpredictable threat. These findings support the notion of aberrant sensory processing of unpredictable threat in anxiety disorders, as this processing pattern is already evident in individuals at risk of these disorders.
KW  - attention
KW  - fear conditioning
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239394
VL  - 9
ER  - 
TY  - JOUR
A1  - Sommerfeld, Andreas
A1  - Senf, Cornelius
A1  - Buma, Brian
A1  - D'Amato, Anthony W.
A1  - Després, Tiphaine
A1  - Díaz-Hormazábal, Ignacio
A1  - Fraver, Shawn
A1  - Frelich, Lee E.
A1  - Gutiérrez, Álvaro G.
A1  - Hart, Sarah J.
A1  - Harvey, Brian J.
A1  - He, Hong S.
A1  - Hlásny, Tomáš
A1  - Holz, Andrés
A1  - Kitzberger, Thomas
A1  - Kulakowski, Dominik
A1  - Lindenmayer, David
A1  - Mori, Akira S.
A1  - Müller, Jörg
A1  - Paritsis, Juan
A1  - Perry, George L. W.
A1  - Stephens, Scott L.
A1  - Svoboda, Miroslav
A1  - Turner, Monica G.
A1  - Veblen, Thomas T.
A1  - Seidl, Rupert
T1  - Patterns and drivers of recent disturbances across the temperate forest biome
JF  - Nature Communications
N2  - Increasing evidence indicates that forest disturbances are changing in response to global change, yet local variability in disturbance remains high. We quantified this considerable variability and analyzed whether recent disturbance episodes around the globe were consistently driven by climate, and if human influence modulates patterns of forest disturbance. We combined remote sensing data on recent (2001–2014) disturbances with in-depth local information for 50 protected landscapes and their surroundings across the temperate biome. Disturbance patterns are highly variable, and shaped by variation in disturbance agents and traits of prevailing tree species. However, high disturbance activity is consistently linked to warmer and drier than average conditions across the globe. Disturbances in protected areas are smaller and more complex in shape compared to their surroundings affected by human land use. This signal disappears in areas with high recent natural disturbance activity, underlining the potential of climate-mediated disturbance to transform forest landscapes.
KW  - forest ecology
KW  - forestry
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239157
VL  - 9
ER  - 
TY  - JOUR
A1  - Shumilova, T. G.
A1  - Lutoev, V. P.
A1  - Isaenko, S. I.
A1  - Kovalchuk, N. S.
A1  - Makeev, B. A.
A1  - Lysiuk, A. Yu.
A1  - Zubov, A. A.
A1  - Ernstson, K.
T1  - Spectroscopic features of ultrahigh-pressure impact glasses of the Kara astrobleme
JF  - Scientific Reports
N2  - The state of substances under ultrahigh pressures and temperatures (UHPHT) now raises a special interest as a matter existing under extreme conditions and as potential new material. Under laboratory conditions only small amounts of micrometer-sized matter are produced at a pressure up to 100 GPa and at room temperature. Simultaneous combination of ultrahigh pressures and temperatures in a lab still requires serious technological effort. Here we describe the composition and structure of the UHPHT vein-like impact glass discovered by us in 2015 on the territory of the Kara astrobleme (Russia) and compare its properties with impact glass from the Ries crater (Germany). A complex of structural and spectroscopic methods presents unusual high pressure marks of structural elements in 8-fold co-ordination that had been described earlier neither in synthetic nor natural glasses. The Kara natural UHPHT glasses being about 70 Ma old have well preserved initial structure, presenting some heterogeneity as a result of partial liquation and crystallization differentiation where an amorphous component is proposed to originate from low level polymerization. Homogeneous parts of the UHPHT glasses can be used to deepened fundamental investigation of a substance under extreme PT conditions and to technological studies for novel material creations.
KW  - glasses
KW  - mineralogy
KW  - phase transitions and critical phenomena
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237983
VL  - 8
ER  - 
TY  - JOUR
A1  - Solimando, A G
A1  - Brandl, A
A1  - Mattenheimer, K
A1  - Graf, C
A1  - Ritz, M
A1  - Ruckdeschel, A
A1  - Stühmer, T
A1  - Mokhtari, Z
A1  - Rudelius, M
A1  - Dotterweich, J
A1  - Bittrich, M
A1  - Desantis, V
A1  - Ebert, R
A1  - Trerotoli, P
A1  - Frassanito, M A
A1  - Rosenwald, A
A1  - Vacca, A
A1  - Einsele, H
A1  - Jakob, F
A1  - Beilhack, A
T1  - JAM-A as a prognostic factor and new therapeutic target in multiple myeloma
JF  - Leukemia
N2  - Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.
KW  - haematological cancer
KW  - myeloma
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239069
VL  - 32
ER  - 
TY  - JOUR
A1  - Soltamov, V. A.
A1  - Kasper, C.
A1  - Poshakinskiy, A. V.
A1  - Anisimov, A. N.
A1  - Mokhov, E. N.
A1  - Sperlich, A.
A1  - Tarasenko, S. A.
A1  - Baranov, P. G.
A1  - Astakhov, G. V.
A1  - Dyakonov, V.
T1  - Excitation and coherent control of spin qudit modes in silicon carbide at room temperature
JF  - Nature Communications
N2  - One of the challenges in the field of quantum sensing and information processing is to selectively address and coherently manipulate highly homogeneous qubits subject to external perturbations. Here, we present room-temperature coherent control of high-dimensional quantum bits, the so-called qudits, associated with vacancy-related spins in silicon carbide enriched with nuclear spin-free isotopes. In addition to the excitation of a spectrally narrow qudit mode at the pump frequency, several other modes are excited in the electron spin resonance spectra whose relative positions depend on the external magnetic field. We develop a theory of multipole spin dynamics and demonstrate selective quantum control of homogeneous spin packets with sub-MHz spectral resolution. Furthermore, we perform two-frequency Ramsey interferometry to demonstrate absolute dc magnetometry, which is immune to thermal noise and strain inhomogeneity.
KW  - quantum information
KW  - qubits
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239149
VL  - 10
ER  - 
TY  - JOUR
A1  - Siegmund, Daniela
A1  - Ehrenschwender, Martin
A1  - Wajant, Harald
T1  - TNFR2 unlocks a RIPK1 kinase activity-dependent mode of proinflammatory TNFR1 signaling
JF  - Cell Death & Disease
N2  - TNF is not only a major effector molecule of PAMP/DAMP-activated macrophages, but also regulates macrophage function and viability. We recently demonstrated that TNFR2 triggers necroptosis in macrophages with compromised caspase activity by two cooperating mechanisms: induction of endogenous TNF with subsequent stimulation of TNFR1 and depletion of cytosolic TRAF2-cIAP complexes. Here we show that TNFR2 activation in caspase-inhibited macrophages results in the production of endogenous TNF and TNFR1 stimulation followed by upregulation of A20, TRAF1, IL-6, and IL-1β. Surprisingly, TNFR1-mediated induction of IL-6 and IL-1β was clearly evident in response to TNFR2 stimulation but occurred not or only weakly in macrophages selectively and directly stimulated via TNFR1. Moreover, TNFR2-induced TNFR1-mediated gene induction was largely inhibited by necrostatin-1, whereas upregulation of A20 and TRAF1 by direct and exclusive stimulation of TNFR1 remained unaffected by this compound. Thus, treatment with TNFR2/ZVAD enables TNFR1 in macrophages to stimulate gene induction via a pathway requiring RIPK1 kinase activity. TNFR2/ZVAD-induced production of IL-6 and IL-1β was largely blocked in necroptosis-resistant MLKL- and RIPK3-deficient macrophages, whereas induction of A20 and TRAF1 remained unaffected. In sum, our results show that in caspase-inhibited macrophages TNFR2 not only triggers TNF/TNFR1-mediated necroptosis but also TNF/TNFR1-mediated RIPK3/MLKL-dependent and -independent gene induction.
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238034
VL  - 9
ER  - 
TY  - JOUR
A1  - Vaeth, Martin
A1  - Wang, Yin-Hu
A1  - Eckstein, Miriam
A1  - Yang, Jun
A1  - Silverman, Gregg J.
A1  - Lacruz, Rodrigo S.
A1  - Kannan, Kasthuri
A1  - Feske, Stefan
T1  - Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels
JF  - Nature Communications
N2  - T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells.
KW  - gene regulation in immune cells
KW  - lymphocytes
KW  - regulatory T cells
KW  - signal transduction
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232148
VL  - 10
ER  - 
TY  - JOUR
A1  - Sulzer, David
A1  - Cassidy, Clifford
A1  - Horga, Guillermo
A1  - Kang, Un Jung
A1  - Fahn, Stanley
A1  - Casella, Luigi
A1  - Pezzoli, Gianni
A1  - Langley, Jason
A1  - Hu, Xiaoping P.
A1  - Zucca, Fabio A.
A1  - Isaias, Ioannis U.
A1  - Zecca, Luigi
T1  - Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease
JF  - npj Parkinson's Disease
N2  - The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD.
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240207
VL  - 4
ER  - 
TY  - JOUR
A1  - Ullrich, M
A1  - Weber, M
A1  - Post, A M
A1  - Popp, S
A1  - Grein, J
A1  - Zechner, M
A1  - González, H Guerrero
A1  - Kreis, A
A1  - Schmitt, A G
A1  - Üҫeyler, N
A1  - Lesch, K-P
A1  - Schuh, K
T1  - OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency
JF  - Molecular Psychiatry
N2  - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.
KW  - molecular biology
KW  - neuroscience
KW  - physiology
KW  - psychiatric disorders
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232096
VL  - 23
ER  -