TY - JOUR T1 - Search for new high-mass phenomena in the dilepton final state using 36 fb\(^{−1}\) of proton-proton collision data at \(\sqrt{s}=13\) TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - A search is conducted for new resonant and non-resonant high-mass phenomena in dielectron and dimuon final states. The search uses 36.1 fb\(^{−1}\) of proton-proton collision data, collected at \(\sqrt{s}=13\) TeV by the ATLAS experiment at the LHC in 2015 and 2016. No significant deviation from the Standard Model prediction is observed. Upper limits at 95% credibility level are set on the cross-section times branching ratio for resonances decaying into dileptons, which are converted to lower limits on the resonance mass, up to 4.1 TeV for the E\(_6\)-motivated \(Z^′_χ\). Lower limits on the \({qqℓℓ}\) contact interaction scale are set between 2.4 TeV and 40 TeV, depending on the model. KW - High energy physics KW - Beyond Standard Model KW - Hadron-Hadron scattering (experiments) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172462 VL - 2017 IS - 182 ER - TY - JOUR A1 - Kaireit, Till F. A1 - Sorrentino, Sajoscha A. A1 - Renne, Julius A1 - Schoenfeld, Christian A1 - Voskrebenzev, Andreas A1 - Gutberlet, Marcel A1 - Schulz, Angela A1 - Jakob, Peter M. A1 - Hansen, Gesine A1 - Wacker, Frank A1 - Welte, Tobias A1 - Tümmler, Burkhard A1 - Vogel-Claussen, Jens T1 - Functional lung MRI for regional monitoring of patients with cystic fibrosis JF - PLoS ONE N2 - Purpose To test quantitative functional lung MRI techniques in young adults with cystic fibrosis (CF) compared to healthy volunteers and to monitor immediate treatment effects of a single inhalation of hypertonic saline in comparison to clinical routine pulmonary function tests. Materials and methods Sixteen clinically stable CF patients and 12 healthy volunteers prospectively underwent two functional lung MRI scans and pulmonary function tests before and 2h after a single treatment of inhaled hypertonic saline or without any treatment. MRI-derived oxygen enhanced T1 relaxation measurements, fractional ventilation, first-pass perfusion parameters and a morpho-functional CF-MRI score were acquired. Results Compared to healthy controls functional lung MRI detected and quantified significantly increased ventilation heterogeneity in CF patients. Regional functional lung MRI measures of ventilation and perfusion as well as the CF-MRI score and pulmonary function tests could not detect a significant treatment effect two hours after a single treatment with hypertonic saline in young adults with CF (p>0.05). Conclusion This study shows the feasibility of functional lung MRI as a non-invasive, radiation-free tool for monitoring patients with CF. KW - Physics KW - Magnetic resonance imaging KW - Functional magnetic resonance imaging KW - Cystic fibrosis KW - Oxygen KW - Pulmonary imaging KW - Hypertonic KW - Pulmonary function KW - Quantum chronodynamics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172457 VL - 12 IS - 12 ER - TY - JOUR A1 - Eisele, Marion A1 - Boczor, Sigrid A1 - Rakebrandt, Anja A1 - Blozik, Eva A1 - Trader, Jens-Martin A1 - Stork, Stefan A1 - Herrmann-Lingen, Christoph A1 - Scherer, Martin T1 - General practitioners' awareness of depressive symptomatology is not associated with quality of life in heart failure patients - cross-sectional results of the observational RECODE-HF Study JF - BMC Family Practice N2 - Background Depression is a common comorbidity in patients with chronic heart failure (HF) and linked to a wider range of symptoms which, in turn, are linked to a decreased health-related quality of life (HRQOL). Treatment of depression might improve HRQOL but detecting depression is difficult due to the symptom overlap between HF and depression. Therefore, clinical guidelines recommend to routinely screen for depression in HF patients. No studies have so far investigated the treatment after getting aware of a depressive symptomatology and its correlation with HRQOL in primary care HF patients. Therefore, we examined the factors linked to depression treatment and those linked to HRQOL in HF patients. We hypothesized that GPs’ awareness of depressive symptomatology was associated with depression treatment and HRQOL in HF patients. Methods For this observational study, HF patients were recruited in primary care practices and filled out a questionnaire including PHQ-9 and HADS. A total of 574 patients screened positive for depressive symptomatology. Their GPs were interviewed by phone regarding the patients’ comorbidities and potential depression treatment. Descriptive and regression analysis were performed. Results GPs reported various types of depression treatments (including dialogue/counselling by the GP him/herself in 31.8% of the patients). The reported rates differed considerably between GP-reported initiated treatment and patient-reported utilised treatment regarding psychotherapy (16.4% vs. 9.5%) and pharmacotherapy (61.2% vs. 30.3%). The GPs' awareness of depressive symptomatology was significantly associated with the likelihood of receiving pharmacotherapy (OR 2.8; p < 0.001) but not psychotherapy. The patient’s HRQOL was not significantly associated with the GPs' awareness of depression. Conclusion GPs should be aware of the gap between GP-initiated and patient-utilised depression treatments in patients with chronic HF, which might lead to an undersupply of depression treatment. It remains to be investigated why GPs’ awareness of depressive symptomatology is not linked to patients’ HRQOL. We hypothesize that GPs are aware of cases with reduced HRQOL (which improves under depression treatment) and unaware of cases whose depression do not significantly impair HRQOL, resulting in comparable levels of HRQOL in both groups. This hypothesis needs to be further investigated. KW - Medicine KW - Depression KW - Heart failure KW - Recognition of depression KW - Quality of life KW - Depression treatment KW - Observational study KW - Primary care KW - Healthcare research KW - Depressive symptomatology Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172445 VL - 18 ER - TY - JOUR T1 - Measurement of the \(t\overline{t}γ\) production cross section in proton-proton collisions at \(\sqrt{s} = 8\) TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - The cross section of a top-quark pair produced in association with a photon is measured in proton-proton collisions at a centre-of-mass energy of \(\sqrt{s} = 8\) TeV with 20.2 fb\(^{−1}\) of data collected by the ATLAS detector at the Large Hadron Collider in 2012. The measurement is performed by selecting events that contain a photon with transverse momentum \(p_T\) > 15 GeV, an isolated lepton with large transverse momentum, large missing transverse momentum, and at least four jets, where at least one is identified as originating from a \(b\)-quark. The production cross section is measured in a fiducial region close to the selection requirements. It is found to be 139 ± 7 (stat.) ± 17 (syst.) fb, in good agreement with the theoretical prediction at next-to-leading order of 151 ± 24 fb. In addition, differential cross sections in the fiducial region are measured as a function of the transverse momentum and pseudorapidity of the photon. KW - High energy physics KW - Hadron-Hadron scattering (experiments) KW - Top physics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172399 VL - 2017 IS - 86 ER - TY - JOUR T1 - Measurements of top-quark pair differential cross-sections in the lepton+jets channel in pp collisions at \( \sqrt{s}=13 \) TeV using the ATLAS detector JF - Journal of High Energy Physics N2 - Measurements of differential cross-sections of top-quark pair production in fiducial phase-spaces are presented as a function of top-quark and \(t\overline{t}\) system kinematic observables in proton-proton collisions at a centre-of-mass energy of \(\sqrt{s}\) = 13 TeV. The data set corresponds to an integrated luminosity of 3.2 fb\(^{−1}\), recorded in 2015 with the ATLAS detector at the CERN Large Hadron Collider. Events with exactly one electron or muon and at least two jets in the final state are used for the measurement. Two separate selections are applied that each focus on different top-quark momentum regions, referred to as resolved and boosted topologies of the \(t\overline{t}\) final state. The measured spectra are corrected for detector effects and are compared to several Monte Carlo simulations by means of calculated \(χ^2\) and \(p\)-values. KW - High energy physics KW - Hadron-Hadron scattering (experiments) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172386 VL - 2017 IS - 191 ER - TY - JOUR A1 - Hassan, Musa A. A1 - Vasquez, Juan J. A1 - Guo-Liang, Chew A1 - Meissner, Markus A1 - Siegel, T. Nicolai T1 - Comparative ribosome profiling uncovers a dominant role for translational control in \(Toxoplasma\) \(gondii\) JF - BMC Genomics N2 - Background The lytic cycle of the protozoan parasite \(Toxoplasma\) \(gondii\), which involves a brief sojourn in the extracellular space, is characterized by defined transcriptional profiles. For an obligate intracellular parasite that is shielded from the cytosolic host immune factors by a parasitophorous vacuole, the brief entry into the extracellular space is likely to exert enormous stress. Due to its role in cellular stress response, we hypothesize that translational control plays an important role in regulating gene expression in \(Toxoplasma\) during the lytic cycle. Unlike transcriptional profiles, insights into genome-wide translational profiles of \(Toxoplasma\) \(gondii\) are lacking. Methods We have performed genome-wide ribosome profiling, coupled with high throughput RNA sequencing, in intracellular and extracellular \(Toxoplasma\) \(gondii\) parasites to investigate translational control during the lytic cycle. Results Although differences in transcript abundance were mostly mirrored at the translational level, we observed significant differences in the abundance of ribosome footprints between the two parasite stages. Furthermore, our data suggest that mRNA translation in the parasite is potentially regulated by mRNA secondary structure and upstream open reading frames. Conclusion We show that most of the \(Toxoplasma\) genes that are dysregulated during the lytic cycle are translationally regulated. KW - Biology KW - Ribosome profiling KW - RNA-sequencing KW - Translation efficiency KW - Toxoplasma gondii KW - Apicomplexan Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172376 VL - 18 ER - TY - JOUR T1 - Search for supersymmetry in events with \(b\)-tagged jets and missing transverse momentum in \(pp\) collisions at \(\sqrt{s}\) = 13 TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - A search for the supersymmetric partners of the Standard Model bottom and top quarks is presented. The search uses 36.1 fb\(^{−1}\) of \(pp\) collision data at \(\sqrt{s}\) = 13 TeV collected by the ATLAS experiment at the Large Hadron Collider. Direct production of pairs of bottom and top squarks (\(\overline{b}_1\) and \(\overline{t}_1\)) is searched for in final states with \(b\)-tagged jets and missing transverse momentum. Distinctive selections are defined with either no charged leptons (electrons or muons) in the final state, or one charged lepton. The zero-lepton selection targets models in which the \(\overline{b}_1\) is the lightest squark and decays via \(\overline{b}_1\) → \(b\overline{χ}^0_1\), where \(\overline{χ}^0_1\) is the lightest neutralino. The one-lepton final state targets models where bottom or top squarks are produced and can decay into multiple channels, \(\overline{b}_1\) → \(b\overline{χ}^0_1\) and \(\overline{b}_1\) → \(t\overline{χ}^±_1\), or \(\overline{t}_1\) → \(t\overline{χ}^0_1\) and \(\overline{t}_1\) → \(b\overline{χ}^±_1\), where \(\overline{χ}^±_1\) is the lightest chargino and the mass difference \(m_{\overline{χ}^±_1}\) − \(m_{\overline{χ}^0_1}\) is set to 1 GeV. No excess above the expected Standard Model background is observed. Exclusion limits at 95% confidence level on the mass of third-generation squarks are derived in various supersymmetry-inspired simplified models. KW - High energy physics KW - Hadron-Hadron scattering (experiments) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172320 VL - 2017 IS - 195 ER - TY - JOUR A1 - Jodeleit, Henrika A1 - Palamides, Pia A1 - Beigel, Florian A1 - Mueller, Thomas A1 - Wolf, Eckhard A1 - Siebeck, Matthias A1 - Gropp, Roswitha T1 - Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model JF - Journal of Translational Medicine N2 - Background: Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγ\(^{null}\) (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Methods: Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Results: Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. Conclusions: The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects. KW - Autoimmunity KW - Disease network KW - Inflammatory bowel disease KW - NSG KW - NSG-UC KW - Ulcerative colitis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225516 VL - 15 ER - TY - JOUR T1 - Search for new phenomena with large jet multiplicities and missing transverse momentum using large-radius jets and flavour-tagging at ATLAS in 13 TeV \(pp\) collisions JF - Journal of High Energy Physics N2 - A search is presented for particles that decay producing a large jet multiplicity and invisible particles. The event selection applies a veto on the presence of isolated electrons or muons and additional requirements on the number of \(b\)-tagged jets and the scalar sum of masses of large-radius jets. Having explored the full ATLAS 2015-2016 dataset of LHC proton-proton collisions at \(\sqrt{s}\) = 13 TeV, which corresponds to 36.1 fb\(^{−1}\) of integrated luminosity, no evidence is found for physics beyond the Standard Model. The results are interpreted in the context of simplified models inspired by R-parity-conserving and R-parity-violating supersymmetry, where gluinos are pair-produced. More generic models within the phenomenological minimal supersymmetric Standard Model are also considered. KW - High energy physics KW - Beyond Standard Model KW - Hadron-Hadron scattering (experiments) KW - Supersymmetry Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172302 VL - 34 ER - TY - JOUR A1 - Maurer, Jana A1 - Hupp, Sabrina A1 - Bischoff, Carolin A1 - Foertsch, Christina A1 - Mitchell, Timothy J. A1 - Chakraborty, Trinad A1 - Iliev, Asparouh I. T1 - Distinct neurotoxicity profile of listeriolysin O from \(Listeria\) \(monocytogenes\) JF - Toxins N2 - Cholesterol-dependent cytolysins (CDCs) are protein toxins that originate from Gram-positive bacteria and contribute substantially to their pathogenicity. CDCs bind membrane cholesterol and build prepores and lytic pores. Some effects of the toxins are observed in non-lytic concentrations. Two pathogens, \(Streptococcus\) \(pneumoniae\) and \(Listeria\) \(monocytogenes\), cause fatal bacterial meningitis, and both produce toxins of the CDC family—pneumolysin and listeriolysin O, respectively. It has been demonstrated that pneumolysin produces dendritic varicosities (dendrite swellings) and dendritic spine collapse in the mouse neocortex, followed by synaptic loss and astrocyte cell shape remodeling without elevated cell death. We utilized primary glial cultures and acute mouse brain slices to examine the neuropathological effects of listeriolysin O and to compare it to pneumolysin with identical hemolytic activity. In cultures, listeriolysin O permeabilized cells slower than pneumolysin did but still initiated non-lytic astrocytic cell shape changes, just as pneumolysin did. In an acute brain slice culture system, listeriolysin O produced dendritic varicosities in an NMDA-dependent manner but failed to cause dendritic spine collapse and cortical astrocyte reorganization. Thus, listeriolysin O demonstrated slower cell permeabilization and milder glial cell remodeling ability than did pneumolysin and lacked dendritic spine collapse capacity but exhibited equivalent dendritic pathology. KW - medicine KW - listeriolysin O KW - meningitis KW - acute slices KW - variocosities KW - dendritic spines Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172130 VL - 9 IS - 1 ER - TY - JOUR T1 - Search for a scalar partner of the top quark in the jets plus missing transverse momentum final state at \(\sqrt{s}\) = 13 TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - A search for pair production of a scalar partner of the top quark in events with four or more jets plus missing transverse momentum is presented. An analysis of 36.1 fb\(^{−1}\) of \(\sqrt{s}\) = 13 TeV proton-proton collisions collected using the ATLAS detector at the LHC yields no significant excess over the expected Standard Model background. To interpret the results a simplified supersymmetric model is used where the top squark is assumed to decay via \(\tilde{t}_1\) → \(t^{(∗)}\)\(\tilde{χ}^0_1\) and \(\tilde{t}_1\) → \(b\tilde{χ}^±_1\) → \({bW}^{(∗)}\tilde{χ}^0_1\), where \(\tilde{χ}^0_1\) (\(\tilde{χ}^±_1\)) denotes the lightest neutralino (chargino). Exclusion limits are placed in terms of the top-squark and neutralino masses. Assuming a branching ratio of 100% to \(t\tilde{χ}^0_1\), top-squark masses in the range 450–1000 GeV are excluded for \(\tilde{χ}^0_1\) masses below 160 GeV. In the case where \(m_{\tilde{t}_1}\) ∼ \(m_t\) + \(m_{\tilde{χ}^0_1}\), top-squark masses in the range 235–590 GeV are excluded. KW - high energy physics KW - Hadron-Hadron scattering (experiments) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172161 VL - 12 ER - TY - JOUR T1 - All-sky search for high-energy neutrinos from gravitational wave event GW170104 with the ANTARES neutrino telescope JF - European Physical Journal C N2 - Advanced LIGO detected a significant gravitational wave signal (GW170104) originating from the coalescence of two black holes during the second observation run on January 4th, 2017. An all-sky high-energy neutrino follow-up search has been made using data from the Antares neutrino telescope, including both upgoing and downgoing events in two separate analyses. No neutrino candidates were found within ±500 s around the GW event time nor any time clustering of events over an extended time window of ±3 months. The non-detection is used to constrain isotropic-equivalent high-energy neutrino emission from GW170104 to less than ∼ 1.2 × \(10^{55}\) erg for a \(E^{−2}\) spectrum. This constraint is valid in the energy range corresponding to the 5–95% quantiles of the neutrino flux [3.2 TeV; 3.6 PeV], if the GW emitter was below the Antares horizon at the alert time. KW - high energy physics KW - high energy neutrinos KW - neutrino telescope KW - neutrino emission KW - neutrino flux Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172174 VL - 77 ER - TY - JOUR T1 - Measurement of the Drell-Yan triple-differential cross section in \(pp\) collisions at \(\sqrt{s}\) = 8 TeV JF - Journal of High Energy Physics N2 - This paper presents a measurement of the triple-differential cross section for the Drell-Yan process \({Z/γ^*}\) → ℓ\(^+\)ℓ\(^-\) where ℓ is an electron or a muon. The measurement is performed for invariant masses of the lepton pairs, \(m_{ℓℓ}\) , between 46 and 200 GeV using a sample of 20.2 fb\(^{−1}\) of \(pp\) collisions data at a centre-of-mass energy of \(\sqrt{s}\) = 8 TeV collected by the ATLAS detector at the LHC in 2012. The data are presented in bins of invariant mass, absolute dilepton rapidity, |\(y_{ℓℓ}\)|, and the angular variable cos \(θ^*\) between the outgoing lepton and the incoming quark in the Collins-Soper frame. The measurements are performed in the range |\(y_{ℓℓ}\)| < 2.4 in the muon channel, and extended to |\(y_{ℓℓ}\)| < 3.6 in the electron channel. The cross sections are used to determine the \(Z\) boson forward-backward asymmetry as a function of |\(y_{ℓℓ}\)| and \(m_{ℓℓ}\) . The measurements achieve high-precision, below the percent level in the pole region, excluding the uncertainty in the integrated luminosity, and are in agreement with predictions. These precision data are sensitive to the parton distribution functions and the effective weak mixing angle. KW - high energy physics KW - Hadron-Hadron scattering (experiments) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172204 VL - 59 ER - TY - JOUR T1 - Evidence for the \(H\) → \({b\overline{b}}\) decay with the ATLAS detector JF - Journal of High Energy Physics N2 - A search for the decay of the Standard Model Higgs boson into a \({b\overline{b}}\) pair when produced in association with a \(W\) or \(Z\) boson is performed with the ATLAS detector. The analysed data, corresponding to an integrated luminosity of 36.1 fb\(^{−1}\), were collected in proton-proton collisions in Run 2 of the Large Hadron Collider at a centre-of-mass energy of 13 TeV. Final states containing zero, one and two charged leptons (electrons or muons) are considered, targeting the decays \(Z\) → \({νν}\), \(W\) → \({ℓν}\) and \(Z\) → \({ℓℓ}\). For a Higgs boson mass of 125 GeV, an excess of events over the expected background from other Standard Model processes is found with an observed significance of 3.5 standard deviations, compared to an expectation of 3.0 standard deviations. This excess provides evidence for the Higgs boson decay into b-quarks and for its production in association with a vector boson. The combination of this result with that of the Run 1 analysis yields a ratio of the measured signal events to the Standard Model expectation equal to 0.90 ± 0.18(stat.)\(^{+0.21}_{−0.19}\)(syst.). Assuming the Standard Model production cross-section, the results are consistent with the value of the Yukawa coupling to \(b\)-quarks in the Standard Model. KW - High energy physics KW - Hadron-Hadron scattering (experiments) KW - Higgs physics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172216 VL - 24 ER - TY - JOUR A1 - Schönegge, Anne-Marie A1 - Gallion, Jonathan A1 - Picard, Louis-Philippe A1 - Wilkins, Angela D. A1 - Le Gouill, Christian A1 - Audet, Martin A1 - Stallaert, Wayne A1 - Lohse, Martin J. A1 - Kimmel, Marek A1 - Lichtarge, Olivier A1 - Bouvier, Michel T1 - Evolutionary action and structural basis of the allosteric switch controlling β\(_2\)AR functional selectivity JF - Nature Communications N2 - Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non-negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the β\(_2\)-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or βarrestin/endocytosis pathways with no effect on Gs activation. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro-switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity. KW - toxicology KW - functional clustering KW - molecular modelling KW - protein design KW - receptor pharmacology Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172268 VL - 8 ER - TY - JOUR T1 - Analysis of the Wtb vertex from the measurement of triple-differential angular decay rates of single top quarks produced in the \(t\)-channel at \(\sqrt{s}\) = 8 TeV with the ATLAS detector JF - Journal or High Energy Physics N2 - The electroweak production and subsequent decay of single top quarks in the \(t\)-channel is determined by the properties of the \({Wtb}\) vertex, which can be described by the complex parameters of an effective Lagrangian. An analysis of a triple-differential decay rate in \(t\)-channel production is used to simultaneously determine five generalised helicity fractions and phases, as well as the polarisation of the produced top quark. The complex parameters are then constrained. This analysis is based on 20.2 fb\(^{−1}\) of proton-proton collision data at a centre-of-mass energy of 8 TeV collected with the ATLAS detector at the LHC. The fraction of decays containing transversely polarised \(W\) bosons is measured to be \(f_1\) = 0.30 ± 0.05. The phase between amplitudes for transversely and longitudinally polarised \(W\) bosons recoiling against left-handed \(b\)-quarks is measured to be \(\delta\)_ = 0.002\(\pi^{+0.016\pi}_{+0.017\pi}\), giving no indication of CP violation. The fractions of longitudinal or transverse \(W\) bosons accompanied by right-handed \(b\)-quarks are also constrained. Based on these measurements, limits are placed at 95% CL on the ratio of the complex coupling parameters Re [\({g_R/V_L}\) \(\in\) [−0.12, 0.17] and Im [\({g_R/V_L}\) \(\in\) [−0.07, 0.06]. Constraints are also placed on the ratios |\({V_R}/{V_L}\)| and |\({g_L}/{V_L}\)|. In addition, the polarisation of single top quarks in the \(t\)-channel is constrained to be \(P\) > 0.72 (95% CL). None of the above measurements make assumptions about the value of any of the other parameters or couplings and all of them are in agreement with the Standard Model. KW - High energy physics KW - Electroweak interaction KW - Hadron-Hadron scattering (experiments) KW - Top physics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172310 VL - 2017 IS - 17 ER - TY - JOUR A1 - Mende, Daniel R. A1 - Letunic, Ivica A1 - Huerta-Cepas, Jaime A1 - Li, Simone S. A1 - Forslund, Kristoffer A1 - Sunagawa, Shinichi A1 - Bork, Peer T1 - proGenomes: a resource for consistent functional and taxonomic annotations of prokaryotic genomes JF - Nucleic Acids Research N2 - The availability of microbial genomes has opened many new avenues of research within microbiology. This has been driven primarily by comparative genomics approaches, which rely on accurate and consistent characterization of genomic sequences. It is nevertheless difficult to obtain consistent taxonomic and integrated functional annotations for defined prokaryotic clades. Thus, we developed proGenomes, a resource that provides user-friendly access to currently 25 038 high-quality genomes whose sequences and consistent annotations can be retrieved individually or by taxonomic clade. These genomes are assigned to 5306 consistent and accurate taxonomic species clusters based on previously established methodology. proGenomes also contains functional information for almost 80 million protein-coding genes, including a comprehensive set of general annotations and more focused annotations for carbohydrate-active enzymes and antibiotic resistance genes. Additionally, broad habitat information is provided for many genomes. All genomes and associated information can be downloaded by user-selected clade or multiple habitat-specific sets of representative genomes. We expect that the availability of high-quality genomes with comprehensive functional annotations will promote advances in clinical microbial genomics, functional evolution and other subfields of microbiology. proGenomes is available at http://progenomes.embl.de. KW - biology KW - genomic sequence KW - prokaryotic clade KW - proGenomes KW - habitat information KW - taxonomic description KW - genome collection KW - comparative genomics KW - genomics research Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171987 VL - 45 IS - D1 ER - TY - JOUR A1 - Elsässer, S. A1 - Schiebl, M. A1 - Mukhin, A. A. A1 - Balbashov, A. M. A1 - Pimenov, A. A1 - Geurts, J. T1 - Impact of temperature-dependent local and global spin order in \(R\)MnO\(_3\) compounds for spin-phonon coupling and electromagnon activity JF - New Journal of Physics N2 - The orthorhombic rare-earth manganite compounds \(R\)MnO\(_3\) show a global magnetic order for \(T\) < \(T\)\(_N\), and several representatives are multiferroic with a cycloidal spin ground state order for \(T\) < \(T\)\(_c\)\(_y\)\(_c\)\(_l\) < \(T\)\(_N\) \(\approx\) 40 K. We deduce from the temperature dependence of spin–phonon coupling in Raman spectroscopy for a series of \(R\)MnO\(_3\) compounds that their spin order locally persists up to about twice \(T\)\(_N\). Along the same line, our observation of the persistence of the electromagnon in GdMnO\(_3\) up to \(T\) \(\approx\) 100 K is attributed to a local cycloidal spin order for \(T\) > \(T\)\(_c\)\(_y\)\(_c\)\(_l\), in contrast to the hitherto assumed incommensurate sinusoidal phase in the intermediate temperature range. The development of the magnetization pattern can be described in terms of an order–disorder transition at \(T\)\(_c\)\(_y\)\(_c\)\(_l\) within a pseudospin model of localized spin cycloids with opposite chirality. KW - physics KW - RMnO3 KW - multiferroics KW - electromagnon KW - Raman spectroscopy KW - spin-phonon coupling Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171978 VL - 19 ER - TY - JOUR A1 - Jannasch, Maren A1 - Weigel, Tobias A1 - Engelhardt, Lisa A1 - Wiezoreck, Judith A1 - Gaetzner, Sabine A1 - Walles, Heike A1 - Schmitz, Tobias A1 - Hansmann, Jan T1 - \({In}\) \({vitro}\) chemotaxis and tissue remodeling assays quantitatively characterize foreign body reaction JF - ALTEX - Alternatives to Animal Experimentation N2 - Surgical implantation of a biomaterial triggers foreign-body-induced fibrous encapsulation. Two major mechanisms of this complex physiological process are (I) chemotaxis of fibroblasts from surrounding tissue to the implant region, followed by (II) tissue remodeling. As an alternative to animal studies, we here propose a process-aligned \({in}\) \({vitro}\) test platform to investigate the material dependency of fibroblast chemotaxis and tissue remodeling mediated by material-resident macrophages. Embedded in a biomimetic three-dimensional collagen hydrogel, chemotaxis of fibroblasts in the direction of macrophage-material-conditioned cell culture supernatant was analyzed by live cell imaging. A combination of statistical analysis with a complementary parameterized random walk model allowed quantitative and qualitative characterization of the cellular walk process. We thereby identified an increasing macrophage-mediated chemotactic potential ranking of biomaterials from glass over polytetrafluorethylene to titanium. To address long-term effects of biomaterial-resident macrophages on fibroblasts in a three-dimensional microenvironment, we further studied tissue remodeling by applying macrophage-material-conditioned medium on fibrous \({in}\) \({vitro}\) tissue models. A high correlation of the \({in}\) \({vitro}\) tissue model to state of the art \({in}\) \({vivo}\) study data was found. Titanium exhibited a significantly lower tissue remodeling capacity compared to polytetrafluorethylene. With this approach, we identified a material dependency of both chemotaxis and tissue remodeling processes, strengthening knowledge on their specific contribution to the foreign body reaction. KW - medicine KW - foreign body reaction KW - fibroblast chemotaxis KW - tissue remodeling KW - in vitro KW - quanititative characterization Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172080 VL - 34 IS - 2 ER - TY - JOUR A1 - Lapa, Constantin A1 - Schreder, Martin A1 - Schirbel, Andreas A1 - Samnick, Samuel A1 - Kortüm, Klaus Martin A1 - Herrmann, Ken A1 - Kropf, Saskia A1 - Einsele, Herrmann A1 - Buck, Andreas K. A1 - Wester, Hans-Jürgen A1 - Knop, Stefan A1 - Lückerath, Katharina T1 - [\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values JF - Theranostics N2 - Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018). [\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma. KW - medicine KW - multiple myeloma KW - FDG KW - molecular imaging KW - CXCR4 KW - PET KW - radionuclide therapy KW - theranostics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172106 VL - 7 IS - 1 ER -