TY - JOUR A1 - Steinmetzger, Christian A1 - Bessi, Irene A1 - Lenz, Ann-Kathrin A1 - Höbartner, Claudia T1 - Structure-fluorescence activation relationships of a large Stokes shift fluorogenic RNA aptamer JF - Nucleic Acids Research N2 - The Chili RNA aptamer is a 52 nt long fluorogen-activating RNA aptamer (FLAP) that confers fluorescence to structurally diverse derivatives of fluorescent protein chromophores. A key feature of Chili is the formation of highly stable complexes with different ligands, which exhibit bright, highly Stokes-shifted fluorescence emission. In this work, we have analyzed the interactions between the Chili RNA and a family of conditionally fluorescent ligands using a variety of spectroscopic, calorimetric and biochemical techniques to reveal key structure - fluorescence activation relationships (SFARs). The ligands under investigation form two categories with emission maxima of ~540 nm or ~590 nm, respectively, and bind with affinities in the nanomolar to low-micromolar range. Isothermal titration calorimetry was used to elucidate the enthalpic and entropic contributions to binding affinity for a cationic ligand that is unique to the Chili aptamer. In addition to fluorescence activation, ligand binding was also observed by NMR spectroscopy, revealing characteristic signals for the formation of a G-quadruplex only upon ligand binding. These data shed light on the molecular features required and responsible for the large Stokes shift and the strong fluorescence enhancement of red and green emitting RNA-chromophore complexes. KW - Chili RNA Aptamer KW - fluorogen-activating RNA aptamer (FLAP) KW - Stokes-shifted fluorescence emission KW - key structure - fluorescence activation relationships (SFARs) KW - ligand binding Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-192340 ER - TY - JOUR A1 - Kasaragod, Vikram Babu A1 - Schindelin, Hermann T1 - Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin JF - Frontiers in Molecular Neuroscience N2 - γ-Aminobutyric acid type A receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABAARs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABAARs are key drug targets. The majority of synaptic GABAARs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3–M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABAAR provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABAARs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABAARs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission. KW - GABAA KW - gephyrin KW - diazepam KW - GABA KW - PIP2 KW - artemisinin KW - Cryo-EM KW - inhibitory neurotransmission Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189308 SN - 1662-5099 VL - 12 ER - TY - JOUR A1 - Kasaragod, Vikram Babu A1 - Schindelin, Hermann T1 - Structure of heteropentameric GABA\(_A\) receptors and receptor-anchoring properties of gephyrin JF - Frontiers in Molecular Neuroscience N2 - γ-Aminobutyric acid type A receptors (GABA\(_A\)Rs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABA\(_A\)Rs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABA\(_A\)Rs are key drug targets. The majority of synaptic GABA\(_A\)Rs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3–M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABA\(_A\)R provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABA\(_A\)Rs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABA\(_A\)Rs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission. KW - GABAA receptors KW - gephyrin KW - diazepam KW - GABA KW - PIP2 KW - artemisinin KW - Cryo-EM KW - inhibitory neurotransmission Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201886 VL - 12 IS - 191 ER - TY - JOUR A1 - Wutzler, Alexander A1 - Krogias, Christos A1 - Grau, Anna A1 - Veltkamp, Roland A1 - Heuschmann, Peter U. A1 - Haeusler, Karl Georg T1 - Stroke prevention in patients with acute ischemic stroke and atrial fibrillation in Germany - a cross sectional survey JF - BMC Neurology N2 - Background Atrial fibrillation (AF) is present in 15–20% of patients with acute ischemic stroke. Oral anticoagulation reduces the risk of AF-related recurrent stroke but clinical guideline recommendations are rather vague regarding its use in the acute phase of stroke. We aimed to assess the current clinical practice of medical stroke prevention in AF patients during the acute phase of ischemic stroke. Methods In April 2017, a standardized anonymous questionnaire was sent to clinical leads of all 298 certified stroke units in Germany. Results Overall, 154 stroke unit leads participated (response rate 52%). Anticoagulation in the acute phase of stroke is considered feasible in more than 90% of AF patients with ischemic stroke. Clinicians assume that about two thirds of all AF patients (range 20–100%) are discharged on oral anticoagulation. According to local preferences, acetylsalicylic acid is given orally in the majority of patients with delayed initiation of oral anticoagulation. A non-vitamin K-dependent oral anticoagulant (NOAC) is more often prescribed than a vitamin K-dependent oral anticoagulant (VKA). VKA is more often chosen in patients with previous VKA intake than in VKA naive patients. In the minority of patients, stroke unit leads discuss the prescription of a specific oral anticoagulant with the treating general practitioner. Adherence to medical stroke prevention after hospital discharge is not assessed on a regular basis in any patient by the majority of participating stroke centers. Conclusions Early secondary stroke prevention in AF patients in German stroke units is based on OAC use but prescription modalities vary in clinical practice. KW - Ischemic stroke KW - Secondary stroke prevention KW - Atrial fibrillation KW - Survey KW - Oral anticoagulation KW - Stroke unit Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201078 VL - 19 ER - TY - JOUR A1 - Kim, Brandon J. A1 - McDonagh, Maura A. A1 - Deng, Liwen A1 - Gastfriend, Benjamin D. A1 - Schubert-Unkmeir, Alexandra A1 - Doran, Kelly S. A1 - Shusta, Eric V. T1 - Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells JF - Fluids and Barriers of the CNS N2 - Bacterial meningitis is a serious life threatening infection of the CNS. To cause meningitis, blood–borne bacteria need to interact with and penetrate brain endothelial cells (BECs) that comprise the blood–brain barrier. BECs help maintain brain homeostasis and they possess an array of efflux transporters, such as P-glycoprotein (P-gp), that function to efflux potentially harmful compounds from the CNS back into the circulation. Oftentimes, efflux also serves to limit the brain uptake of therapeutic drugs, representing a major hurdle for CNS drug delivery. During meningitis, BEC barrier integrity is compromised; however, little is known about efflux transport perturbations during infection. Thus, understanding the impact of bacterial infection on P-gp function would be important for potential routes of therapeutic intervention. To this end, the meningeal bacterial pathogen, Streptococcus agalactiae, was found to inhibit P-gp activity in human induced pluripotent stem cell-derived BECs, and live bacteria were required for the observed inhibition. This observation was correlated to decreased P-gp expression both in vitro and during infection in vivo using a mouse model of bacterial meningitis. Given the impact of bacterial interactions on P-gp function, it will be important to incorporate these findings into analyses of drug delivery paradigms for bacterial infections of the CNS. KW - Group B Streptococcus KW - Streptococcus agalactiae KW - Brain endothelial cells KW - P-glycoprotein KW - Efflux transport KW - Meningitis KW - Stem cells KW - P-gp Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201895 VL - 16 ER - TY - JOUR A1 - Schlottmann, Elisabeth A1 - Schicke, David A1 - Krüger, Felix A1 - Lingnau, Benjamin A1 - Schneider, Christian A1 - Höfling, Sven A1 - Lüdge, Kathy A1 - Porte, Xavier A1 - Reitzenstein, Stephan T1 - Stochastic polarization switching induced by optical injection in bimodal quantum-dot micropillar lasers JF - Optics Express N2 - Mutual coupling and injection locking of semiconductor lasers is of great interest in non-linear dynamics and its applications for instance in secure data communication and photonic reservoir computing. Despite its importance, it has hardly been studied in microlasers operating at mu W light levels. In this context, vertically emitting quantum dot micropillar lasers are of high interest. Usually, their light emission is bimodal, and the gain competition of the associated linearly polarized fundamental emission modes results in complex switching dynamics. We report on selective optical injection into either one of the two fundamental mode components of a bimodal micropillar laser. Both modes can lock to the master laser and influence the non-injected mode by reducing the available gain. We demonstrate that the switching dynamics can be tailored externally via optical injection in very good agreement with our theory based on semi-classical rate equations. (C) 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement KW - Nonlinear Dynamics KW - Bistability KW - Generation KW - Subject KW - Regimes KW - Physics KW - Vcsels Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228603 VL - 27 IS - 20 ER - TY - JOUR A1 - Lenczyk, Carsten A1 - Roy, Dipak Kumar A1 - Nitsch, Jörn A1 - Radacki, Krzysztof A1 - Rauch, Florian A1 - Dewhurst, Rian D. A1 - Bickelhaupt, F. Matthias A1 - Marder, Todd B. A1 - Braunschweig, Holger T1 - Steric Effects Dictate the Formation of Terminal Arylborylene Complexes of Ruthenium from Dihydroboranes JF - Chemistry - A European Journal N2 - The steric and electronic properties of aryl substituents in monoaryl borohydrides (Li[ArBH\(_3\)]) and dihydroboranes were systematically varied and their reactions with [Ru(PCy\(_3\))\(_2\)HCl(H\(_2\))] (Cy: cyclohexyl) were studied, resulting in bis(σ)‐borane or terminal borylene complexes of ruthenium. These variations allowed for the investigation of the factors involved in the activation of dihydroboranes in the synthesis of terminal borylene complexes. The complexes were studied by multinuclear NMR spectroscopy, mass spectrometry, X‐ray diffraction analysis, and density functional theory (DFT) calculations. The experimental and computational results suggest that the ortho‐substitution of the aryl groups is necessary for the formation of terminal borylene complexes. KW - Arylborylene Complexes KW - Ruthenium KW - Dihydroboranes KW - boranes KW - borohydrides KW - borylenes KW - steric effects KW - sigma boranes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219537 SN - 1521-3765 VL - 25 IS - 59 ER - TY - JOUR A1 - Zhang, Fangyuan A1 - Michail, Evripidis A1 - Saal, Fridolin A1 - Krause, Ana-Maria A1 - Ravat, Prince T1 - Stereospecific Synthesis and Photophysical Properties of Propeller-Shaped C\(_{90}\)H\(_{48}\) PAH JF - Chemistry - A European Journal N2 - Herein, we have synthesized an enantiomerically pure propeller‐shaped PAH, C\(_{90}\)H\(_{48}\), possessing three [7]helicene and three [5]helicene subunits. This compound can be obtained in gram quantities in a straightforward manner. The photophysical and chiroptical properties were investigated using UV/Vis absorption and emission, optical rotation and circular dichroism spectroscopy, supported by DFT calculations. The nonlinear optical properties were investigated by two‐photon absorption measurements using linearly and circularly polarized light. The extremely twisted structure and packing of the homochiral compound were investigated by single‐crystal X‐ray diffraction analysis. KW - chirality KW - enantiomers KW - helicenes KW - polycyclic aromatic hydrocarbons KW - stereospecific sythesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208682 VL - 25 IS - 71 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Heuschmann, Peter U. A1 - Pham, Mirko A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis JF - Frontiers in Neurology N2 - Background and Purpose: Internal carotid artery stenosis (ICAS)≥70% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for sICAS<70% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for sICAS<90% and sICAS 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with ICAS <70%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70% to be longer than that of sICAS≥70%. Moreover, the ultrasound-measured length of sICAS<90% was significantly longer than that of sICAS 90%. Among patients with sICAS≥70%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results. KW - ischemic stroke KW - carotid stenosis KW - carotid atherosclerosis KW - length of stenosis KW - degree of stenosis KW - carotid ultrasound KW - outcome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196225 SN - 1664-2295 VL - 10 IS - 317 ER - TY - JOUR A1 - Bratengeier, Klaus A1 - Holubyev, Kostyantyn A1 - Wegener, Sonja T1 - Steeper dose gradients resulting from reduced source to target distance—a planning system independent study JF - Journal of Applied Clinical Medical Physics N2 - Purpose: To quantify the contribution of penumbra in the improvement of healthy tissue sparing at reduced source‐to‐axis distance (SAD) for simple spherical target and different prescription isodoses (PI). Method: A TPS‐independent method was used to estimate three‐dimensional (3D) dose distribution for stereotactic treatment of spherical targets of 0.5 cm radius based on single beam two‐dimensional (2D) film dosimetry measurements. 1 cm target constitutes the worst case for the conformation with standard Multi‐Leaf Collimator (MLC) with 0.5 cm leaf width. The measured 2D transverse dose cross‐sections and the profiles in leaf and jaw directions were used to calculate radial dose distribution from isotropic beam arrangement, for both quadratic and circular beam openings, respectively. The results were compared for standard (100 cm) and reduced SAD 70 and 55 cm for different PI. Results: For practical reduction of SAD using quadratic openings, the improvement of healthy tissue sparing (HTS) at distances up to 3 times the PTV radius was at least 6%–12%; gradient indices (GI) were reduced by 3–39% for PI between 40% and 90%. Except for PI of 80% and 90%, quadratic apertures at SAD 70 cm improved the HTS by up to 20% compared to circular openings at 100 cm or were at least equivalent; GI were 3%–33% lower for reduced SAD in the PI range 40%–70%. For PI = 80% and 90% the results depend on the circular collimator model. Conclusion: Stereotactic treatments of spherical targets delivered at reduced SAD of 70 or 55 cm using MLC spare healthy tissue around the target at least as good as treatments at SAD 100 cm using circular collimators. The steeper beam penumbra at reduced SAD seems to be as important as perfect target conformity. The authors argue therefore that the beam penumbra width should be addressed in the stereotactic studies. KW - radiotherapy KW - stereotactic irradiation KW - penumbra KW - leaf width KW - virtual isocenter Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177424 VL - 20 IS - 1 ER - TY - JOUR A1 - Wick, Christoph A1 - Hartelt, Alexander A1 - Puppe, Frank T1 - Staff, symbol and melody detection of Medieval manuscripts written in square notation using deep Fully Convolutional Networks JF - Applied Sciences N2 - Even today, the automatic digitisation of scanned documents in general, but especially the automatic optical music recognition (OMR) of historical manuscripts, still remains an enormous challenge, since both handwritten musical symbols and text have to be identified. This paper focuses on the Medieval so-called square notation developed in the 11th–12th century, which is already composed of staff lines, staves, clefs, accidentals, and neumes that are roughly spoken connected single notes. The aim is to develop an algorithm that captures both the neumes, and in particular its melody, which can be used to reconstruct the original writing. Our pipeline is similar to the standard OMR approach and comprises a novel staff line and symbol detection algorithm based on deep Fully Convolutional Networks (FCN), which perform pixel-based predictions for either staff lines or symbols and their respective types. Then, the staff line detection combines the extracted lines to staves and yields an F\(_1\) -score of over 99% for both detecting lines and complete staves. For the music symbol detection, we choose a novel approach that skips the step to identify neumes and instead directly predicts note components (NCs) and their respective affiliation to a neume. Furthermore, the algorithm detects clefs and accidentals. Our algorithm predicts the symbol sequence of a staff with a diplomatic symbol accuracy rate (dSAR) of about 87%, which includes symbol type and location. If only the NCs without their respective connection to a neume, all clefs and accidentals are of interest, the algorithm reaches an harmonic symbol accuracy rate (hSAR) of approximately 90%. In general, the algorithm recognises a symbol in the manuscript with an F\(_1\) -score of over 96%. KW - optical music recognition KW - historical document analysis KW - medieval manuscripts KW - neume notation KW - fully convolutional neural networks Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197248 SN - 2076-3417 VL - 9 IS - 13 ER - TY - JOUR A1 - Radeva, Mariya Y. A1 - Walter, Elias A1 - Stach, Ramona Alexandra A1 - Yazdi, Amir S. A1 - Schlegel, Nicolas A1 - Sarig, Ofer A1 - Sprecher, Eli A1 - Waschke, Jens T1 - ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation JF - Frontiers in Immunology N2 - Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1 alpha, IL-6, TNF alpha, and IFN-gamma was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1 alpha and IL-6 was enhanced in some experiments but not in others whereas release of TNF-alpha dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling. KW - pemphigus KW - desmosome KW - desmoglein KW - ST18 KW - ERK KW - cytokines Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224910 VL - 10 ER - TY - JOUR A1 - Streng, Andrea A1 - Goettler, David A1 - Haerlein, Miriam A1 - Lehmann, Lisa A1 - Ulrich, Kristina A1 - Prifert, Christiane A1 - Krempl, Christine A1 - Weißbrich, Benedikt A1 - Liese, Johannes G. T1 - Spread and clinical severity of respiratory syncytial virus A genotype ON1 in Germany, 2011–2017 JF - BMC Infectious Diseases N2 - Background The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings. Methods During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes. Results A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6%) were infected with RSV-A, 235 (39.0%) with RSV-B, and one child (0.2%) with both RSV-A and RSV-B; in 26 (4.3%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4%), NA1 in 92 (26.9%), and GA5 in 2 children (0.6%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7–12 vs. 7 days, IQR 5–9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4–9 vs. 4 days, IQR 2–6; p = 0.03) for children infected with RSV-A ON1. Conclusions In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar. KW - Children KW - Respiratory tract infection KW - RSV-A ON1 KW - Epidemiology KW - Disease severity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201516 VL - 19 ER - TY - JOUR A1 - Sierra, Miguel A. A1 - Sánchez, David A1 - Gutierrez, Rafael A1 - Cuniberti, Gianaurelio A1 - Domínguez-Adame, Francisco A1 - Díaz, Elena T1 - Spin-polarized electron transmission in DNA-like systems JF - Biomolecules N2 - The helical distribution of the electronic density in chiral molecules, such as DNA and bacteriorhodopsin, has been suggested to induce a spin–orbit coupling interaction that may lead to the so-called chirality-induced spin selectivity (CISS) effect. Key ingredients for the theoretical modelling are, in this context, the helically shaped potential of the molecule and, concomitantly, a Rashba-like spin–orbit coupling due to the appearance of a magnetic field in the electron reference frame. Symmetries of these models clearly play a crucial role in explaining the observed effect, but a thorough analysis has been largely ignored in the literature. In this work, we present a study of these symmetries and how they can be exploited to enhance chiral-induced spin selectivity in helical molecular systems. KW - chirality-induced spin selectivity KW - helical molecules KW - spin transport KW - spin polarization KW - DNA electronic transport Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193813 SN - 2218-273X VL - 10 IS - 1 ER - TY - JOUR A1 - Lohr, David A1 - Terekhov, Maxim A1 - Weng, Andreas Max A1 - Schroeder, Anja A1 - Walles, Heike A1 - Schreiber, Laura Maria T1 - Spin echo based cardiac diffusion imaging at 7T: An ex vivo study of the porcine heart at 7T and 3T JF - PLoS ONE N2 - Purpose of this work was to assess feasibility of cardiac diffusion tensor imaging (cDTI) at 7 T in a set of healthy, unfixed, porcine hearts using various parallel imaging acceleration factors and to compare SNR and derived cDTI metrics to a reference measured at 3 T. Magnetic resonance imaging was performed on 7T and 3T whole body systems using a spin echo diffusion encoding sequence with echo planar imaging readout. Five reference (b = 0 s/mm\(^2\)) images and 30 diffusion directions (b = 700 s/mm\(^2\)) were acquired at both 7 T and 3 T using a GRAPPA acceleration factor R = 1. Scans at 7 T were repeated using R = 2, R = 3, and R = 4. SNR evaluation was based on 30 reference (b = 0 s/mm\(^2\)) images of 30 slices of the left ventricle and cardiac DTI metrics were compared within AHA segmentation. The number of hearts scanned at 7 T and 3 T was n = 11. No statistically significant differences were found for evaluated helix angle, secondary eigenvector angle, fractional anisotropy and apparent diffusion coefficient at the different field strengths, given sufficiently high SNR and geometrically undistorted images. R≥3 was needed to reduce susceptibility induced geometric distortions to an acceptable amount. On average SNR in myocardium of the left ventricle was increased from 29±3 to 44±6 in the reference image (b = 0 s/mm\(^2\)) when switching from 3 T to 7 T. Our study demonstrates that high resolution, ex vivo cDTI is feasible at 7 T using commercial hardware. KW - Heart KW - Diffusion tensor imaging KW - Eigenvectors KW - Cardiac ventricles KW - Tractography KW - Magnetic resonance imaging KW - Data acquisition KW - Swine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201376 VL - 14 IS - 3 ER - TY - JOUR A1 - Avota, Elita A1 - de Lira, Maria Nathalia A1 - Schneider-Schaulies, Sibylle T1 - Sphingomyelin breakdown in T cells: role of membrane compartmentalization in T cell signaling and interference by a pathogen JF - Frontiers in Cell and Developmental Biology N2 - Sphingolipids are major components of cellular membranes, and at steady-state level, their metabolic fluxes are tightly controlled. On challenge by external signals, they undergo rapid turnover, which substantially affects the biophysical properties of membrane lipid and protein compartments and, consequently, signaling and morphodynamics. In T cells, external cues translate into formation of membrane microdomains where proximal signaling platforms essential for metabolic reprograming and cytoskeletal reorganization are organized. This review will focus on sphingomyelinases, which mediate sphingomyelin breakdown and ensuing ceramide release that have been implicated in T-cell viability and function. Acting at the sphingomyelin pool at the extrafacial or cytosolic leaflet of cellular membranes, acid and neutral sphingomyelinases organize ceramide-enriched membrane microdomains that regulate T-cell homeostatic activity and, upon stimulation, compartmentalize receptors, membrane proximal signaling complexes, and cytoskeletal dynamics as essential for initiating T-cell motility and interaction with endothelia and antigen-presenting cells. Prominent examples to be discussed in this review include death receptor family members, integrins, CD3, and CD28 and their associated signalosomes. Progress made with regard to experimental tools has greatly aided our understanding of the role of bioactive sphingolipids in T-cell biology at a molecular level and of targets explored by a model pathogen (measles virus) to specifically interfere with their physiological activity. KW - T cell KW - sphingomyelinase KW - activation KW - motility KW - measles virus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199168 SN - 2296-634X VL - 7 IS - 152 ER - TY - JOUR A1 - Gräb, Patrick A1 - Geidel, Ekkehard T1 - Spectroscopic studies of food colorings JF - World Journal of Chemical Education N2 - In chemical education, it is often a challenge to understand the basic principles of spectroscopic techniques due to missing connections to the real world. Therefore, the present contribution offers context-based applications of UV/Vis spectroscopy for analytics of food colorings with which learners can improve their skills regarding this method. The spectroscopic determination of food colorings seems to be a promising approach due to the long tradition and omnipresence of dyes in supermarket products. The therefor-required spectral data for commonly used dyes are provided for educational usage. Qualitative and quantitative analytics of food colorings in four different lemonades and chocolate beans have been used to introduce learners to important analytical techniques like sample preparation or elimination of confounding factors. These analytics also display the limitations of the method in the visible range of light in the case of tartrazine and curcumin. By applying Lambert-Beer-Bouguer’s Law in different variations, typical calculations of concentrations can be studied in quantitative analyses. The studied food samples demonstrate the different usage of food colorings depending on the country of sale. Finally, a 3D-printable low-cost photometer suitable for the discussed quantitative analytics in educational contexts is presented. KW - UV/Vis spectroscopy KW - quantitative analysis KW - food colorings KW - context-based teaching KW - low-cost photometer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201908 VL - 7 IS - 2 ER - TY - JOUR A1 - Nickel, Joachim A1 - Mueller, Thomas D. T1 - Specification of BMP signaling JF - Cells N2 - Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties. KW - TGFβ/BMP signaling KW - ligand-receptor promiscuity KW - signal specification Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193869 SN - 2073-4409 VL - 8 IS - 12 ER - TY - JOUR A1 - Streinzer, Martin A1 - Chakravorty, Jharna A1 - Neumayer, Johann A1 - Megu, Karsing A1 - Narah, Jaya A1 - Schmitt, Thomas A1 - Bharti, Himender A1 - Spaethe, Johannes A1 - Brockmann, Axel T1 - Species composition and elevational distribution of bumble bees (Hymenoptera, Apidae, Bombus Latreille) in the East Himalaya, Arunachal Pradesh, India JF - ZooKeys N2 - The East Himalaya is one of the world’s most biodiverse ecosystems. However, very little is known about the abundance and distribution of many plant and animal taxa in this region. Bumble bees are a group of cold-adapted and high elevation insects that fulfil an important ecological and economical function as pollinators of wild and agricultural flowering plants and crops. The Himalayan mountain range provides ample suitable habitats for bumble bees. Systematic study of Himalayan bumble bees began a few decades ago and the main focus has centred on the western region, while the eastern part of the mountain range has received little attention and only a few species have been verified. During a three-year survey, more than 700 bumble bee specimens of 21 species were collected in Arunachal Pradesh, the largest of the north-eastern states of India. The material included a range of species that were previously known from a limited number of collected specimens, which highlights the unique character of the East Himalayan ecosystem. Our results are an important first step towards a future assessment of species distribution, threat, and conservation. Clear elevation patterns of species diversity were observed, which raise important questions about the functional adaptations that allow bumble bees to thrive in this particularly moist region in the East Himalaya. KW - Alpine habitats KW - Apidae KW - conservation KW - global change KW - insect collection KW - pollination Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201937 VL - 851 ER - TY - JOUR A1 - Lange, Bastian A1 - Pauli, Paul T1 - Social anxiety changes the way we move—A social approach-avoidance task in a virtual reality CAVE system JF - PLoS ONE N2 - Investigating approach-avoidance behavior regarding affective stimuli is important in broadening the understanding of one of the most common psychiatric disorders, social anxiety disorder. Many studies in this field rely on approach-avoidance tasks, which mainly assess hand movements, or interpersonal distance measures, which return inconsistent results and lack ecological validity. Therefore, the present study introduces a virtual reality task, looking at avoidance parameters (movement time and speed, distance to social stimulus, gaze behavior) during whole-body movements. These complex movements represent the most ecologically valid form of approach and avoidance behavior. These are at the core of complex and natural social behavior. With this newly developed task, the present study examined whether high socially anxious individuals differ in avoidance behavior when bypassing another person, here virtual humans with neutral and angry facial expressions. Results showed that virtual bystanders displaying angry facial expressions were generally avoided by all participants. In addition, high socially anxious participants generally displayed enhanced avoidance behavior towards virtual people, but no specifically exaggerated avoidance behavior towards virtual people with a negative facial expression. The newly developed virtual reality task proved to be an ecological valid tool for research on complex approach-avoidance behavior in social situations. The first results revealed that whole body approach-avoidance behavior relative to passive bystanders is modulated by their emotional facial expressions and that social anxiety generally amplifies such avoidance. KW - emotions KW - face KW - behavior KW - social anxiety disorder KW - anxiolytics KW - analysis of variance KW - virtual reality KW - questionnaires Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200528 VL - 14 IS - 12 ER - TY - JOUR A1 - Ruf, Katharina A1 - Beer, Meinrad A1 - Köstler, Herbert A1 - Weng, Andreas Max A1 - Neubauer, Henning A1 - Klein, Alexander A1 - Platek, Kathleen A1 - Roth, Kristina A1 - Beneke, Ralph A1 - Hebestreit, Helge T1 - Size-adjusted muscle power and muscle metabolism in patients with cystic fibrosis are equal to healthy controls – a case control study JF - BMC Pulmonary Medicine N2 - Background Skeletal muscle function dysfunction has been reported in patients with cystic fibrosis (CF). Studies so far showed inconclusive data whether reduced exercise capacity is related to intrinsic muscle dysfunction in CF. Methods Twenty patients with CF and 23 age-matched controls completed an incremental cardiopulmonary cycling test. Further, a Wingate anaerobic test to assess muscle power was performed. In addition, all participants completed an incremental knee-extension test with 31P magnetic resonance spectroscopy to assess muscle metabolism (inorganic phosphate (Pi) and phosphocreatinine (PCr) as well as intracellular pH). In the MRI, muscle cross-sectional area of the M. quadriceps (qCSA) was also measured. A subgroup of 15 participants (5 CF, 10 control) additionally completed a continuous high-intensity, high-frequency knee-extension exercise task during 31P magnetic resonance spectroscopy to assess muscle metabolism. Results Patients with CF showed a reduced exercise capacity in the incremental cardiopulmonary cycling test (VO2peak: CF 77.8 ± 16.2%predicted (36.5 ± 7.4 ml/qCSA/min), control 100.6 ± 18.8%predicted (49.1 ± 11.4 ml/qCSA/min); p < 0.001), and deficits in anaerobic capacity reflected by the Wingate test (peak power: CF 537 ± 180 W, control 727 ± 186 W; mean power: CF 378 ± 127 W, control 486 ± 126 W; power drop CF 12 ± 5 W, control 8 ± 4 W. all: p < 0.001). In the knee-extension task, patients with CF achieved a significantly lower workload (p < 0.05). However, in a linear model analysing maximal work load of the incremental knee-extension task and results of the Wingate test, respectively, only muscle size and height, but not disease status (CF or not) contributed to explaining variance. In line with this finding, no differences were found in muscle metabolism reflected by intracellular pH and the ratio of Pi/PCr at submaximal stages and peak exercise measured through MRI spectroscopy. Conclusions The lower absolute muscle power in patients with CF compared to controls is exclusively explained by the reduced muscle size in this study. No evidence was found for an intrinsic skeletal muscle dysfunction due to primary alterations of muscle metabolism. KW - Cystic fibrosis KW - Exercise capacity KW - MRI spectroscopy KW - Muscle power KW - Phosphorylation KW - Lung disease, KW - Muscle function Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200981 VL - 19 ER - TY - JOUR A1 - Bohmann, Ferdinand O. A1 - Kurka, Natalia A1 - du Mesnil de Rochemont, Richard A1 - Gruber, Katharina A1 - Guenther, Joachim A1 - Rostek, Peter A1 - Rai, Heike A1 - Zickler, Philipp A1 - Ertl, Michael A1 - Berlis, Ansgar A1 - Poli, Sven A1 - Mengel, Annerose A1 - Ringleb, Peter A1 - Nagel, Simon A1 - Pfaff, Johannes A1 - Wollenweber, Frank A. A1 - Kellert, Lars A1 - Herzberg, Moriz A1 - Koehler, Luzie A1 - Haeusler, Karl Georg A1 - Alegiani, Anna A1 - Schubert, Charlotte A1 - Brekenfeld, Caspar A1 - Doppler, Christopher E. J. A1 - Onur, Oezguer A. A1 - Kabbasch, Christoph A1 - Manser, Tanja A1 - Pfeilschifter, Waltraud T1 - Simulation-based training of the rapid evaluation and management of acute stroke (STREAM) — a prospective single-arm multicenter trial JF - Frontiers in Neurology N2 - Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period. Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire. Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings. Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251. KW - CRM KW - thrombolysis (tPA) KW - stroke KW - emergency care KW - simulation training Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369239 SN - 1664-2295 VL - 10 ER - TY - JOUR A1 - Saddique, Naeem A1 - Usman, Muhammad A1 - Bernhofer, Christian T1 - Simulating the impact of climate change on the hydrological regimes of a sparsely gauged mountainous basin, northern Pakistan JF - Water N2 - Projected climate changes for the 21st century may cause great uncertainties on the hydrology of a river basin. This study explored the impacts of climate change on the water balance and hydrological regime of the Jhelum River Basin using the Soil and Water Assessment Tool (SWAT). Two downscaling methods (SDSM, Statistical Downscaling Model and LARS-WG, Long Ashton Research Station Weather Generator), three Global Circulation Models (GCMs), and two representative concentration pathways (RCP4.5 and RCP8.5) for three future periods (2030s, 2050s, and 2090s) were used to assess the climate change impacts on flow regimes. The results exhibited that both downscaling methods suggested an increase in annual streamflow over the river basin. There is generally an increasing trend of winter and autumn discharge, whereas it is complicated for summer and spring to conclude if the trend is increasing or decreasing depending on the downscaling methods. Therefore, the uncertainty associated with the downscaling of climate simulation needs to consider, for the best estimate, the impact of climate change, with its uncertainty, on a particular basin. The study also resulted that water yield and evapotranspiration in the eastern part of the basin (sub-basins at high elevation) would be most affected by climate change. The outcomes of this study would be useful for providing guidance in water management and planning for the river basin under climate change. KW - water balance KW - hydrological regime KW - evapotranspiration KW - uncertainties KW - climate change KW - SWAT Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193175 SN - 2073-4441 VL - 11 IS - 10 ER - TY - JOUR A1 - Dechaud, Corentin A1 - Volff, Jean-Nicolas A1 - Schartl, Manfred A1 - Naville, Magali T1 - Sex and the TEs: transposable elements in sexual development and function in animals JF - Mobile DNA N2 - Transposable elements are endogenous DNA sequences able to integrate into and multiply within genomes. They constitute a major source of genetic innovations, as they can not only rearrange genomes but also spread ready-to-use regulatory sequences able to modify host gene expression, and even can give birth to new host genes. As their evolutionary success depends on their vertical transmission, transposable elements are intrinsically linked to reproduction. In organisms with sexual reproduction, this implies that transposable elements have to manifest their transpositional activity in germ cells or their progenitors. The control of sexual development and function can be very versatile, and several studies have demonstrated the implication of transposable elements in the evolution of sex. In this review, we report the functional and evolutionary relationships between transposable elements and sexual reproduction in animals. In particular, we highlight how transposable elements can influence expression of sexual development genes, and how, reciprocally, they are tightly controlled in gonads. We also review how transposable elements contribute to the organization, expression and evolution of sexual development genes and sex chromosomes. This underscores the intricate co-evolution between host functions and transposable elements, which regularly shift from a parasitic to a domesticated status useful to the host. KW - Transposable element KW - Sex determination KW - Sexual development and function KW - Germline KW - piRNA KW - Sex chromosome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202510 VL - 10 ER - TY - JOUR A1 - Waider, Jonas A1 - Popp, Sandy A1 - Mlinar, Boris A1 - Montalbano, Alberto A1 - Bonfiglio, Francesco A1 - Aboagye, Benjamin A1 - Thuy, Elisabeth A1 - Kern, Raphael A1 - Thiel, Christopher A1 - Araragi, Naozumi A1 - Svirin, Evgeniy A1 - Schmitt-Böhrer, Angelika G. A1 - Corradetti, Renato A1 - Lowry, Christopher A. A1 - Lesch, Klaus-Peter T1 - Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity JF - Frontiers in Neuroscience N2 - Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses. KW - tryptophan hydroxylase 2 KW - knockout KW - fear learning KW - extinction KW - long-term potentiation KW - hippocampus KW - immediate-early gene KW - serotonin deficiency Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196077 SN - 1662-453X VL - 13 IS - 245 ER - TY - JOUR A1 - Thölken, Clemens A1 - Thamm, Markus A1 - Erbacher, Christoph A1 - Lechner, Marcus T1 - Sequence and structural properties of circular RNAs in the brain of nurse and forager honeybees (Apis mellifera) JF - BMC Genomics N2 - Background The honeybee (Apis mellifera) represents a model organism for social insects displaying behavioral plasticity. This is reflected by an age-dependent task allocation. The most protruding tasks are performed by young nurse bees and older forager bees that take care of the brood inside the hive and collect food from outside the hive, respectively. The molecular mechanism leading to the transition from nurse bees to foragers is currently under intense research. Circular RNAs, however, were not considered in this context so far. As of today, this group of non-coding RNAs was only known to exist in two other insects, Drosophila melanogaster and Bombyx mori. Here we complement the state of circular RNA research with the first characterization in a social insect. Results We identified numerous circular RNAs in the brain of A. mellifera nurse bees and forager bees using RNA-Seq with exonuclease enrichment. Presence and circularity were verified for the most abundant representatives. Back-splicing in honeybee occurs further towards the end of transcripts and in transcripts with a high number of exons. The occurrence of circularized exons is correlated with length and CpG-content of their flanking introns. The latter coincides with increased DNA-methylation in the respective loci. For two prominent circular RNAs the abundance in worker bee brains was quantified in TaqMan assays. In line with previous findings of circular RNAs in Drosophila, circAmrsmep2 accumulates with increasing age of the insect. In contrast, the levels of circAmrad appear age-independent and correlate with the bee's task. Its parental gene is related to amnesia-resistant memory. Conclusions We provide the first characterization of circRNAs in a social insect. Many of the RNAs identified here show homologies to circular RNAs found in Drosophila and Bombyx, indicating that circular RNAs are a common feature among insects. We find that exon circularization is correlated to DNA-methylation at the flanking introns. The levels of circAmrad suggest a task-dependent abundance that is decoupled from age. Moreover, a GO term analysis shows an enrichment of task-related functions. We conclude that circular RNAs could be relevant for task allocation in honeybee and should be investigated further in this context. KW - circRNA KW - circular transcriptome sequencing KW - honeybee KW - brain KW - neuronal KW - Methylation KW - CpG KW - alternative splicing KW - behavioral plasticity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241302 VL - 20 ER - TY - JOUR T1 - Sensitivity of the KM3NeT/ARCA neutrino telescope to point-like neutrino sources JF - Astroparticle Physics N2 - KM3NeT will be a network of deep-sea neutrino telescopes in the Mediterranean Sea. The KM3NeT/ARCA detector, to be installed at the Capo Passero site (Italy), is optimised for the detection of high-energy neutrinos of cosmic origin. Thanks to its geographical location on the Northern hemisphere, KM3NeT/ARCA can observe upgoing neutrinos from most of the Galactic Plane, including the Galactic Centre. Given its effective area and excellent pointing resolution, KM3NeT/ARCA will measure or significantly constrain the neutrino flux from potential astrophysical neutrino sources. At the same time, it will test flux predictions based on gamma-ray measurements and the assumption that the gamma-ray flux is of hadronic origin. Assuming this scenario, discovery potentials and sensitivities for a selected list of Galactic sources and to generic point sources with an E-2 spectrum are presented. These spectra are assumed to be time independent. The results indicate that an observation with 3 sigma significance is possible in about six years of operation for the most intense sources, such as Supernovae Remnants RX J1713.7-3946 and Vela Jr. If no signal will be found during this time, the fraction of the gamma-ray flux coming from hadronic processes can be constrained to be below 50% for these two objects. (C) 2019 The Authors. Published by Elsevier B.V. KW - Astrophysical neutrino sources KW - Cherenkov underwater neutrino telescope KW - KM3NeT KW - Remnant RX J1713.7-3946 KW - Particle-acceleration KW - Galactic sources KW - Cosmic-rays KW - Supernova KW - Radiation KW - Icecube KW - Shell KW - TEV Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227759 VL - 111 ER - TY - JOUR A1 - Wurm, Michael A1 - Stark, Thomas A1 - Zhu, Xiao Xiang A1 - Weigand, Matthias A1 - Taubenböck, Hannes T1 - Semantic segmentation of slums in satellite images using transfer learning on fully convolutional neural networks JF - ISPRS Journal of Photogrammetry and Remote Sensing N2 - Unprecedented urbanization in particular in countries of the global south result in informal urban development processes, especially in mega cities. With an estimated 1 billion slum dwellers globally, the United Nations have made the fight against poverty the number one sustainable development goal. To provide better infrastructure and thus a better life to slum dwellers, detailed information on the spatial location and size of slums is of crucial importance. In the past, remote sensing has proven to be an extremely valuable and effective tool for mapping slums. The nature of used mapping approaches by machine learning, however, made it necessary to invest a lot of effort in training the models. Recent advances in deep learning allow for transferring trained fully convolutional networks (FCN) from one data set to another. Thus, in our study we aim at analyzing transfer learning capabilities of FCNs to slum mapping in various satellite images. A model trained on very high resolution optical satellite imagery from QuickBird is transferred to Sentinel-2 and TerraSAR-X data. While free-of-charge Sentinel-2 data is widely available, its comparably lower resolution makes slum mapping a challenging task. TerraSAR-X data on the other hand, has a higher resolution and is considered a powerful data source for intra-urban structure analysis. Due to the different image characteristics of SAR compared to optical data, however, transferring the model could not improve the performance of semantic segmentation but we observe very high accuracies for mapped slums in the optical data: QuickBird image obtains 86–88% (positive prediction value and sensitivity) and a significant increase for Sentinel-2 applying transfer learning can be observed (from 38 to 55% and from 79 to 85% for PPV and sensitivity, respectively). Using transfer learning proofs extremely valuable in retrieving information on small-scaled urban structures such as slum patches even in satellite images of decametric resolution. KW - slums KW - FCN KW - convolutional neural networks KW - deep learning KW - transfer learning Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233799 VL - 150 ER - TY - JOUR A1 - Müller-Scholden, Lara A1 - Kirchhof, Jan A1 - Morbach, Caroline A1 - Breunig, Margret A1 - Meijer, Rudy A1 - Rücker, Viktoria A1 - Tiffe, Theresa A1 - Yurdadogan, Tino A1 - Wagner, Martin A1 - Gelbrich, Götz A1 - Bots, Michiel L. A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - Segment-specific association of carotid-intima-media thickness with cardiovascular risk factors – findings from the STAAB cohort study JF - BMC Cardiovascular Disorders N2 - Background The guideline recommendation to not measure carotid intima-media thickness (CIMT) for cardiovascular risk prediction is based on the assessment of just one single carotid segment. We evaluated whether there is a segment-specific association between different measurement locations of CIMT and cardiovascular risk factors. Methods Subjects from the population-based STAAB cohort study comprising subjects aged 30 to 79 years of the general population from Würzburg, Germany, were investigated. CIMT was measured on the far wall of both sides in three different predefined locations: common carotid artery (CCA), bulb, and internal carotid artery (ICA). Diabetes, dyslipidemia, hypertension, smoking, and obesity were considered as risk factors. In multivariable logistic regression analysis, odds ratios of risk factors per location were estimated for the endpoint of individual age- and sex-adjusted 75th percentile of CIMT. Results 2492 subjects were included in the analysis. Segment-specific CIMT was highest in the bulb, followed by CCA, and lowest in the ICA. Dyslipidemia, hypertension, and smoking were associated with CIMT, but not diabetes and obesity. We observed no relevant segment-specific association between the three different locations and risk factors, except for a possible interaction between smoking and ICA. Conclusions As no segment-specific association between cardiovascular risk factors and CIMT became evident, one simple measurement of one location may suffice to assess the cardiovascular risk of an individual. KW - Carotid intima-media thickness (CIMT) KW - Carotid segment KW - Carotid ultrasound KW - Cardiovascular risk factors KW - Cardiovascular risk prediction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200720 VL - 19 IS - 84 ER - TY - JOUR A1 - Klotz, Peter A1 - Higgins, Paul G. A1 - Schaubmar, Andreas R. A1 - Failing, Klaus A1 - Leidner, Ursula A1 - Seifert, Harald A1 - Scheufen, Sandra A1 - Semmler, Torsten A1 - Ewers, Christa T1 - Seasonal Occurrence and Carbapenem Susceptibility of Bovine Acinetobacter baumannii in Germany JF - Frontiers in Microbiology N2 - Acinetobacter baumannii is one of the leading causes of nosocomial infections in humans. To investigate its prevalence, distribution of sequence types (STs), and antimicrobial resistance in cattle, we sampled 422 cattle, including 280 dairy cows, 59 beef cattle, and 83 calves over a 14-month period. Metadata, such as the previous use of antimicrobial agents and feeding, were collected to identify putative determining factors. Bacterial isolates were identified via MALDI-TOF/MS and PCR, antimicrobial susceptibility was evaluated via VITEK2 and antibiotic gradient tests, resistance genes were identified by PCR. Overall, 15.6% of the cattle harbored A. baumannii, predominantly in the nose (60.3% of the A. baumannii isolates). It was more frequent in dairy cows (21.1%) than in beef cattle (6.8%) and calves (2.4%). A seasonal occurrence was shown with a peak between May and August. The rate of occurrence of A. baumannii was correlated with a history of use of 3rd generation cephalosporins in the last 6 months prior to sampling Multilocus sequence typing (Pasteur scheme) revealed 83 STs among 126 unique isolates. Nine of the bovine STs have previously been implicated in human infections. Besides known intrinsic resistance of the species, the isolates did not show additional resistance to the antimicrobial substances tested, including carbapenems. Our data suggest that cattle are not a reservoir for nosocomial A. baumannii but carry a highly diverse population of this species. Nevertheless, some STs seem to be able to colonize both cattle and humans. KW - ESKAPE KW - Acinetobacter baumannii KW - antimicrobial susceptibility KW - MLST KW - cattle KW - epidemiology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325927 VL - 10 ER - TY - JOUR T1 - Search for Multimessenger Sources of Gravitational Waves and High-energy Neutrinos with Advanced LIGO during Its First Observing Run, ANTARES, and IceCube JF - The Astrophysical Journal N2 - Astrophysical sources of gravitational waves, such as binary neutron star and black hole mergers or core-collapse supernovae, can drive relativistic outflows, giving rise to non-thermal high-energy emission. High-energy neutrinos are signatures of such outflows. The detection of gravitational waves and high-energy neutrinos from common sources could help establish the connection between the dynamics of the progenitor and the properties of the outflow. We searched for associated emission of gravitational waves and high-energy neutrinos from astrophysical transients with minimal assumptions using data from Advanced LIGO from its first observing run O1, and data from the Antares and IceCube neutrino observatories from the same time period. We focused on candidate events whose astrophysical origins could not be determined from a single messenger. We found no significant coincident candidate, which we used to constrain the rate density of astrophysical sources dependent on their gravitational-wave and neutrino emission processes. KW - gravitational waves KW - neutrinos KW - Electromagnetic signals KW - Events GW150914 KW - ray KW - emission Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-360189 VL - 870 IS - 2 PB - The American Astronomical Society ER - TY - JOUR T1 - Search for light resonances decaying to boosted quark pairs and produced in association with a photon or a jet in proton-proton collisions at root s=13 TeV with the ATLAS detector JF - Physics Letters B N2 - This Letter presents a search for new light resonances decaying to pairs of quarks and produced in association with a high-p(T) photon or jet. The dataset consists of proton-proton collisions with an integrated luminosity of 36.1 fb(-1) at a centre-of-mass energy of root s = 13 TeV recorded by the ATLAS detector at the Large Hadron Collider. Resonance candidates are identified as massive large-radius jets with substructure consistent with a particle decaying into a quark pair. The mass spectrum of the candidates is examined for local excesses above background. No evidence of a new resonance is observed in the data, which are used to exclude the production of a lepto-phobic axial-vector Z' boson. (C) 2018 The Author(s). Published by Elsevier B.V. KW - Parton Distributions KW - Dark-matter KW - Constraints Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319552 VL - 788 ER - TY - JOUR T1 - Search for high-mass dilepton resonances using 139 fb\(^{-1}\) of \(pp\) collision data collected at root \(s\)=13 TeV with the ATLAS detector JF - Physics Letters B N2 - A search for high-mass dielectron and dimuon resonances in the mass range of 250 GeV to 6TeV is presented. The data were recorded by the ATLAS experiment in proton-proton collisions at a centre-ofmass energy of root s = 13 TeV during Run 2 of the Large Hadron Collider and correspond to an integrated luminosity of 139 fb(-1). A functional form is fitted to the dilepton invariant-mass distribution to model the contribution from background processes, and a generic signal shape is used to determine the significance of observed deviations from this background estimate. No significant deviation is observed and upper limits are placed at the 95% confidence level on the fiducial cross-section times branching ratio for various resonance width hypotheses. The derived limits are shown to be applicable to spin-0, spin-1 and spin-2 signal hypotheses. For a set of benchmark models, the limits are converted into lower limits on the resonance mass and reach 4.5 TeV for the E-6-motivated Z(psi)' boson. Also presented are limits on Heavy Vector Triplet model couplings. (C) 2019 The Author. Published by Elsevier B.V. KW - Monte-Carlo KW - Bosons KW - Decay Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226844 VL - 796 ER - TY - JOUR T1 - Search for heavy particles decaying into a top-quark pair in the fully hadronic final state in \({pp}\) collisions at root s=13 TeV with the ATLAS detector JF - Physical Review D N2 - A search for new particles decaying into a pair of top quarks is performed using proton-proton collision data recorded with the ATLAS detector at the Large Hadron Collider at a center-of-mass energy of root s = 13 TeV corresponding to an integrated luminosity of 36.1 fb(-1). Events consistent with top-quark pair production and the fully hadronic decay mode of the top quarks are selected by requiring multiple high transverse momentum jets including those containing b-hadrons. Two analysis techniques, exploiting dedicated top-quark pair reconstruction in different kinematic regimes, are used to optimize the search sensitivity to new hypothetical particles over a wide mass range. The invariant mass distribution of the two reconstructed top-quark candidates is examined for resonant production of new particles with various spins and decay widths. No significant deviation from the Standard Model prediction is observed and limits are set on the production cross-section times branching fraction for new hypothetical Z' bosons, dark-matter mediators, Kaluza-Klein gravitons and Kaluza-Klein gluons. By comparing with the predicted production cross sections, the Z' boson in the topcolor-assisted-technicolor model is excluded for masses up to 3.1-3.6 TeV, the dark-matter mediators in a simplified framework are excluded in the mass ranges from 0.8 to 0.9 TeV and from 2.0 to 2.2 TeV, and the Kaluza-Klein gluon is excluded for masses up to 3.4 TeV, depending on the decay widths of the particles. KW - Parton distributions KW - ++ KW - Algorithm KW - Cross-section KW - Physics KW - LHC KW - Gravitons KW - Hypothetical gauge bosons KW - Top quark KW - Hadron colliders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317362 VL - 99 IS - 9 ER - TY - JOUR T1 - Search for electroweak diboson production in association with a high-mass dijet system in semileptonic final states in \(pp\) collisions at √\(s\) =13 TeV with the ATLAS detector JF - Physical Review D N2 - This paper reports on a search for electroweak diboson (WW/WZ/ZZ) production in association with a high-mass dijet system, using data from proton-proton collisions at a center-of-mass energy of N root s = 13 TeV. The data, corresponding to an integrated luminosity of 35.5 fb(-1), were recorded with the ATLAS detector in 2015 and 2016 at the Large Hadron Collider. The search is performed in final states in which one boson decays leptonically, and the other boson decays hadronically. The hadronically decaying W/Z boson is reconstructed as either two small-radius jets or one large-radius jet using jet substructure techniques. The electroweak production of WW/WZ/ZZ in association with two jets is measured with an observed (expected) significance of 2.7 (2.5) standard deviations, and the fiducial cross section is measured to be 45.1 +/- 8.6(stat.)(-14.6)(+15.9)(syst.) fb. KW - Proton-Proton Collisions KW - 2 Jets KW - Parton Distributions KW - Weak-Interactions KW - Cross-Section KW - High-Energies KW - Boson KW - Constraints KW - Scattering KW - Couplings KW - Particle accelerators KW - Hadron colliders KW - W & Z bosons KW - Gauge bosons KW - Quantum electrodynamics KW - Electroweak interaction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226877 VL - 100 ER - TY - JOUR T1 - Search for diboson resonances in hadronic final states in 139 fb\(^{-1}\) of \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - Narrow resonances decaying into WW, WZ or ZZ boson pairs are searched for in 139 fb(-1) of proton-proton collision data at a centre-of-mass energy of root s = 13TeV recorded with the ATLAS detector at the Large Hadron Collider from 2015 to 2018. The diboson system is reconstructed using pairs of high transverse momentum, large-radius jets. These jets are built from a combination of calorimeter- and tracker-inputs compatible with the hadronic decay of a boosted W or Z boson, using jet mass and substructure properties. The search is performed for diboson resonances with masses greater than 1.3TeV. No significant deviations from the background expectations are observed. Exclusion limits at the 95% confidence level are set on the production cross-section times branching ratio into dibosons for resonances in a range of theories beyond the Standard Model, with the highest excluded mass of a new gauge boson at 3.8TeV in the context of mass-degenerate resonances that couple predominantly to gauge bosons. KW - Hadron-Hadron scattering (experiments) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226905 VL - 09 IS - 91 ER - TY - JOUR T1 - Search for a heavy charged boson in events with a charged lepton and missing transverse momentum from \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - Physical Review D N2 - A search for a heavy charged-boson resonance decaying into a charged lepton (electron or muon) and a neutrino is reported. A data sample of 139 fb(-1) of proton-proton collisions at root s = 13 TeV collected with the ATLAS detector at the LHC during 2015-2018 is used in the search. The observed transverse mass distribution computed from the lepton and missing transverse momenta is consistent with the distribution expected from the Standard Model, and upper limits on the cross section for pp -> W'-> lv are extracted (l = e or mu). These vary between 1.3 pb and 0.05 tb depending on the resonance mass in the range between 0.15 and 7.0 TeV at 95% confidence level for the electron and muon channels combined. Gauge bosons with a mass below 6.0 and 5.1 TeV are excluded in the electron and muon channels, respectively, in a model with a resonance that has couplings to fermions identical to those of the Standard Model W boson. Cross-section limits are also provided for resonances with several fixed Gamma/m values in the range between 1% and 15%. Model-independent limits are derived in single-bin signal regions defined by a varying minimum transverse mass threshold. The resulting visible cross-section upper limits range between 4.6 (15) ph and 22 (22) ab as the threshold increases from 130 (110) GeV to 5.1 (5.1) TeV in the electron (muon) channel. KW - Pair Production KW - Symmetry KW - Decay KW - Monte-Carlo KW - semileptonic & radiative decays KW - Leptonic KW - Hadron-hadron interactions KW - Extensions of gauge sector Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226835 VL - 100 ER - TY - JOUR A1 - Dirimanov, Stoyan A1 - Högger, Petra T1 - Screening of inhibitory effects of polyphenols on Akt-phosphorylation in endothelial cells and determination of structure-activity features JF - Biomolecules N2 - Polyphenols exert beneficial effects in type 2 diabetes mellitus (T2DM). However, their mechanism of action remains largely unknown. Endothelial Akt-kinase plays a key role in the pathogenesis of cardiovascular complications in T2DM and therefore the modulation of its activity is of interest. This work aimed to characterize effects of structurally different polyphenols on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926) and to describe structure-activity features. A comprehensive screening via ELISA quantified the effects of 44 polyphenols (10 µM) on pAkt Ser473. The most pronounced inhibitors were luteolin (44 ± 18%), quercetin (36 ± 8%), urolithin A (35 ± 12%), apigenin, fisetin, and resveratrol; (p < 0.01). The results were confirmed by Western blotting and complemented with corresponding experiments in HUVEC cells. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested polyphenols on both Akt-residues Ser473 and Thr308 (r = 0.9478, p = 0.0003) was determined by immunoblotting. Interestingly, the structural characteristics favoring pAkt inhibition partially differed from structural features enhancing the compounds’ antioxidant activity. The present study is the first to quantitatively compare the influence of polyphenols from nine different structural subclasses on pAkt in endothelial cells. These effects might be advantageous in certain T2DM-complications involving over-activation of the Akt-pathway. The suggested molecular mode of action of polyphenols involving Akt-inhibition contributes to understanding their effects on the cellular level. KW - Akt/PKB KW - endothelium KW - diabetes KW - polyphenols KW - in vitro KW - structure-activity relationships KW - screening Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197333 SN - 2218-273X VL - 9 IS - 6 ER - TY - JOUR A1 - Rager, Sabrina A1 - Jakowetz, Andreas C. A1 - Gole, Bappaditya A1 - Beuerle, Florian A1 - Medina, Dana D. A1 - Bein, Thomas T1 - Scaffold-Induced Diketopyrrolopyrrole Molecular Stacks in a Covalent Organic Framework JF - Chemistry of Materials N2 - In recent years, covalent organic frameworks (COFs) have attracted considerable attention due to their crystalline and porous nature, which positions them as intriguing candidates for diverse applications such as catalysis, sensing, or optoelectronics. The incorporation of dyes or semiconducting moieties into a rigid two-dimensional COF can offer emergent features such as enhanced light harvesting or charge transport. However, this approach can be challenging when dealing with dye molecules that exhibit a large aromatic backbone, since the steric demand of solubilizing side chains also needs to be integrated into the framework. Here, we report the successful synthesis of DPP2-HHTP-COF consisting of diketopyrrolopyrrole (DPP) diboronic acid and hexahydroxytriphenylene (HHTP) building blocks. The well-known boronate ester coupling motif guides the formation of a planar and rigid backbone and long-range molecular DPP stacks, resulting in a highly crystalline and porous material. DPP2-HHTP-COF exhibits excellent optical properties including strong absorption over the visible spectral range, broad emission into the NIR and a singlet lifetime of over 5 ns attributed to the formation of molecular stacks with J-type interactions between the DPP subcomponents in the COF. Electrical measurements of crystalline DPP2-HHTP-COF pellets revealed conductivity values of up to 10(-6) S cm(-1). KW - Polymers KW - Electron KW - Design Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224927 VL - 31 IS - 8 ER - TY - JOUR A1 - Hickl, Oskar A1 - Heintz-Buschart, Anna A1 - Trautwein-Schult, Anke A1 - Hercog, Rajna A1 - Bork, Peer A1 - Wilmes, Paul A1 - Becher, Dörte T1 - Sample preservation and storage significantly impact taxonomic and functional profiles in metaproteomics studies of the human gut microbiome JF - Microorganisms N2 - With the technological advances of the last decade, it is now feasible to analyze microbiome samples, such as human stool specimens, using multi-omic techniques. Given the inherent sample complexity, there exists a need for sample methods which preserve as much information as possible about the biological system at the time of sampling. Here, we analyzed human stool samples preserved and stored using different methods, applying metagenomics as well as metaproteomics. Our results demonstrate that sample preservation and storage have a significant effect on the taxonomic composition of identified proteins. The overall identification rates, as well as the proportion of proteins from Actinobacteria were much higher when samples were flash frozen. Preservation in RNAlater overall led to fewer protein identifications and a considerable increase in the share of Bacteroidetes, as well as Proteobacteria. Additionally, a decrease in the share of metabolism-related proteins and an increase of the relative amount of proteins involved in the processing of genetic information was observed for RNAlater-stored samples. This suggests that great care should be taken in choosing methods for the preservation and storage of microbiome samples, as well as in comparing the results of analyses using different sampling and storage methods. Flash freezing and subsequent storage at −80 °C should be chosen wherever possible. KW - proteomics KW - metaproteomics KW - metagenomics KW - microbiome KW - microbiota KW - flash freezing KW - RNAlater KW - sample storage Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195976 SN - 2076-2607 VL - 7 IS - 9 ER - TY - JOUR A1 - Zhou, Xiang A1 - Wuchter, Patrick A1 - Egerer, Gerlinde A1 - Kriegsmann, Mark A1 - Mataityte, Aiste A1 - Koelsche, Christian A1 - Witzens-Harig, Mathias A1 - Kriegsmann, Katharina T1 - Role of virological serum markers in patients with both hepatitis B virus infection and diffuse large B-cell lymphoma JF - European Journal of Haematology N2 - Background Causality between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) was reported in various studies. However, the implication of different virological serum markers of HBV infection in patients with both HBV infection and DLBCL is not fully understood. The aim of this study was to investigate the impact of HBV markers on overall survival (OS) and progression-free survival (PFS) in patients with both HBV infection and DLBCL. Methods In this study, patients (n = 40) diagnosed with both HBV infection and DLBCL were identified between 2000 and 2017. Six patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) co-infection were excluded from this study. We retrospectively analyzed patients’ demographic characteristics, treatment, and the prognostic impact of different HBV markers at first diagnosis of DLBCL (HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV-DNA) on OS and PFS. Results The majority of patients (n = 21, 62%) had advanced disease stage (III/IV) at diagnosis. In the first-line therapy, 24 patients (70%) were treated with R-CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone). HBeAg positive patients had a trend toward inferior OS and PFS compared with HBeAg negative patients. Anti-HBe positive patients had a statistically significant better OS and PFS compared with anti-HBe negative group (both P < .0001). Viremia with HBV-DNA ≥ 2 × 107 IU/L had a significant negative impact on OS and PFS (both P < .0001). Conclusion High activity of viral replication is associated with a poor survival outcome of patients with both HBV infection and DLBCL. KW - hepatitis B virus KW - diffuse large B-cell lymphoma KW - prognosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258442 VL - 103 IS - 4 ER - TY - JOUR A1 - Börtlein, Charlene A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Dölken, Lars A1 - Avota, Elita T1 - Role of neutral sphingomyelinase-2 (NSM 2) in the control of T cell plasma membrane lipid composition and cholesterol homeostasis JF - Frontiers in Cell and Developmental Biology N2 - The activity of neutral sphingomyelinase-2 (NSM2) to catalyze the conversion of sphingomyelin (SM) to ceramide and phosphocholine at the cytosolic leaflet of plasma membrane (PM) is important in T cell receptor (TCR) signaling. We recently identified PKCζ as a major NSM2 downstream effector which regulates microtubular polarization. It remained, however, unclear to what extent NSM2 activity affected overall composition of PM lipids and downstream effector lipids in antigen stimulated T cells. Here, we provide a detailed lipidomics analyses on PM fractions isolated from TCR stimulated wild type and NSM2 deficient (ΔNSM) Jurkat T cells. This revealed that in addition to that of sphingolipids, NSM2 depletion also affected concentrations of many other lipids. In particular, NSM2 ablation resulted in increase of lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) which both govern PM biophysical properties. Crucially, TCR dependent upregulation of the important T cell signaling lipid diacylglycerol (DAG), which is fundamental for activation of conventional and novel PKCs, was abolished in ΔNSM cells. Moreover, NSM2 activity was found to play an important role in PM cholesterol transport to the endoplasmic reticulum (ER) and production of cholesteryl esters (CE) there. Most importantly, CE accumulation was essential to sustain human T cell proliferation. Accordingly, inhibition of CE generating enzymes, the cholesterol acetyltransferases ACAT1/SOAT1 and ACAT2/SOAT2, impaired TCR driven expansion of both CD4\(^+\) and CD8\(^+\) T cells. In summary, our study reveals an important role of NSM2 in regulating T cell functions by its multiple effects on PM lipids and cholesterol homeostasis. KW - neutral sphingomyelinase-2 KW - T cell receptor KW - plasma membrane KW - lyso-phospholipids KW - diacylglycerol KW - cholesteryl ester Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190596 SN - 2296-634X VL - 7 IS - 226 ER - TY - JOUR A1 - Gehrke, Thomas A1 - Scherzad, Agmal A1 - Hagen, Rudolf A1 - Hackenberg, Stephan T1 - Risk factors for children requiring adenotonsillectomy and their impact on postoperative complications: a retrospective analysis of 2000 patients JF - Anaesthesia N2 - Adenotonsillectomies are commonly performed procedures and sleep‐disordered breathing is becoming increasingly important as an indication for surgery. Because of the higher risks in patients with obstructive sleep apnoea, the required level of postoperative care for these patients is currently under discussion, and better identification of patients at risk may reduce unnecessary postoperative monitoring. To evaluate the influence of obstructive sleep apnoea, and other risk factors, on peri‐operative complications in children requiring adenotonsillectomy, we performed a retrospective case‐control study that included 1995 patients treated between January 2009 and June 2017. In our analysis, young age (OR 3.8, 95%CI 2.1–7.1), low body weight (OR 2.6, 95%CI 1.5–4.4), obstructive sleep apnoea (OR 2.4, 95%CI 1.5–3.8), pre‐existing craniofacial or syndromal disorders (OR 2.3, 95%CI 1.4–3.8) and adenotonsillectomy, compared with adenoidectomy alone, (OR 7.9, 95%CI 4.7–13.1) were identified as risk factors for complications during or after surgery, p < 0.001. All 13 patients suffering from complications more than 3 h postoperatively had obstructive sleep apnoea plus at least one more of these risk factors. Patients at risk of postoperative complications can therefore be identified by several criteria pre‐operatively, and should be monitored postoperatively using pulse oximetry overnight. For all other patients, postoperative observation on a surgical ward without extra monitoring is sufficient. Admission to paediatric intensive care should be reserved for patients suffering serious intra‐operative complications. KW - adenotonsillectromy KW - monotoring KW - obstructive sleep apnoea KW - paediatrics KW - retrospective KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204787 VL - 74 IS - 12 ER - TY - JOUR A1 - Lyutova, Radostina A1 - Selcho, Mareike A1 - Pfeuffer, Maximilian A1 - Segebarth, Dennis A1 - Habenstein, Jens A1 - Rohwedder, Astrid A1 - Frantzmann, Felix A1 - Wegener, Christian A1 - Thum, Andreas S. A1 - Pauls, Dennis T1 - Reward signaling in a recurrent circuit of dopaminergic neurons and peptidergic Kenyon cells JF - Nature Communications N2 - Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that recurrent signaling exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. Optogenetic activation of Kenyon cells paired with odor stimulation is sufficient to induce appetitive memory. Simultaneous impairment of the dopaminergic pPAM neurons abolishes appetitive memory expression. Thus, we argue that dopaminergic pPAM neurons mediate reward information to the Kenyon cells, and in turn receive feedback from Kenyon cells. We further show that this feedback signaling is dependent on short neuropeptide F, but not on acetylcholine known to be important for odor-shock memories in adult flies. Our data suggest that recurrent signaling routes within the larval mushroom body circuitry may represent a mechanism subserving memory stabilization. KW - Learning and memory KW - Neural circuits Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202161 VL - 10 ER - TY - JOUR A1 - Brodehl, Andreas A1 - Pour Hakimi, Seyed Ahmad A1 - Stanasiuk, Caroline A1 - Ratnavadivel, Sandra A1 - Hendig, Doris A1 - Gaertner, Anna A1 - Gerull, Brenda A1 - Gummert, Jan A1 - Paluszkiewicz, Lech A1 - Milting, Hendrik T1 - Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect JF - Genes N2 - Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations. KW - cardiovascular genetics KW - restrictive cardiomyopathy KW - desmin KW - intermediate filaments KW - desmin-related myopathy KW - cardiomyopathy KW - desminopathy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193121 SN - 2073-4425 VL - 10 IS - 11 ER - TY - JOUR A1 - Dietrich, Thomas A1 - Krug, Ralf A1 - Krastl, Gabriel A1 - Tomson, Philip L. T1 - Restoring the unrestorable! Developing coronal tooth tissue with a minimally invasive surgical extrusion technique JF - British Dental Journal N2 - Surgical extrusion is a recognised treatment option for teeth that have insufficient coronal tooth structure remaining due to deep caries, resorption or traumatic injury. However, the technique has not been widely adopted, arguably because extraction of a severely compromised tooth may be difficult to achieve in a gentle and predictable way. In this paper, we present our novel approach to surgical extrusion and subsequent management of teeth using a vertical extraction system (Benex), which has become the method of choice in the authors' practice for many teeth that would otherwise be deemed unrestorable. We describe the clinical procedure in detail and discuss the advantages and disadvantages compared to alternative approaches, including surgical crown lengthening and orthodontic extrusion. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225333 VL - 226 ER - TY - JOUR A1 - Müntze, Jonas A1 - Nordbeck, Peter T1 - Response to “Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real-World Data” JF - Clinical Pharmacology & Therapeutics N2 - No abstract available Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231600 VL - 106 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Grän, Franziska A1 - Weber, Judith A1 - Gesierich, Anja A1 - Goebeler, Matthias A1 - Schilling, Bastian T1 - Response to combined ipilimumab and nivolumab after development of a nephrotic syndrome related to PD-1 monotherapy JF - Journal for ImmunoTherapy of Cancer N2 - Background High response rates of metastatic melanoma have been reported upon immune checkpoint inhibition by PD-1 blockade alone or in combination with CTLA-4 inhibitors. However, the majority of patients with a primary resistance to anti-PD-1 monotherapy is also refractory to a subsequent combined checkpoint inhibition. In BRAF wildtype patients with a primary resistance to PD-1 inhibitors, therapeutic options are therefore limited and immune-related adverse events (irAE) have to be taken into consideration when discussing a subsequent immunotherapy. Case presentation We report the case of a 68-year-old male patient with metastatic melanoma who experienced an acute renal failure with nephrotic syndrome due to a minimal change disease developing after a single dose of the anti-PD-1 antibody pembrolizumab. A kidney biopsy revealed a podocytopathy without signs of interstitial nephritis. Renal function recovered to almost normal creatinine and total urine protein levels upon treatment with oral steroids and diuretics. Unfortunately, a disease progression (PD, RECIST 1.1) was observed in a CT scan after resolution of the irAE. In a grand round, re-exposure to a PD-1-containing regime was recommended. Consensually, a combined immunotherapy with ipilimumab and nivolumab was initiated. Nephrotoxicity was tolerable during combined immunotherapy and a CT scan of chest and abdomen showed a deep partial remission (RECIST 1.1) after three doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Conclusion This case illustrates that a fulminant response to combined checkpoint inhibition is possible after progression after anti-PD-1 monotherapy and a severe irAE. KW - PD-1 KW - Immune-related adverse event KW - Minimal change disease KW - Ipilimumab KW - Nivolumab Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201214 VL - 7 ER - TY - JOUR T1 - Resolution of the ATLAS muon spectrometer monitored drift tubes in LHC Run 2 JF - Journal of Instrumentation N2 - The momentum measurement capability of the ATLAS muon spectrometer relies fundamentally on the intrinsic single-hit spatial resolution of the monitored drift tube precision tracking chambers. Optimal resolution is achieved with a dedicated calibration program that addresses the specific operating conditions of the 354 000 high-pressure drift tubes in the spectrometer. The calibrations consist of a set of timing offsets and drift time to drift distance transfer relations, and result in chamber resolution functions. This paper describes novel algorithms to obtain precision calibrations from data collected by ATLAS in LHC Run 2 and from a gas monitoring chamber, deployed in a dedicated gas facility. The algorithm output consists of a pair of correction constants per chamber which are applied to baseline calibrations, and determined to be valid for the entire ATLAS Run 2. The final single-hit spatial resolution, averaged over 1172 monitored drift tube chambers, is 81.7 +/- 2.2 mu m. KW - Gaseous detectors KW - Chambers KW - Muon spectrometers KW - Particle tracking detectors (Gaseous detectors) KW - Wire chambers (MWPC, Thin-gap chambers, drift chambers, drift tubes, proportional chambers etc) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226869 VL - 14 ER - TY - JOUR A1 - König, Kerstin A1 - Zundel, Petra A1 - Krimmer, Elena A1 - König, Christian A1 - Pollmann, Marie A1 - Gottlieb, Yuval A1 - Steidle, Johannes L. M. T1 - Reproductive isolation due to prezygotic isolation and postzygotic cytoplasmic incompatibility in parasitoid wasps JF - Ecology and Evolution N2 - The reproductive barriers that prevent gene flow between closely related species are a major topic in evolutionary research. Insect clades with parasitoid lifestyle are among the most species-rich insects and new species are constantly described, indicating that speciation occurs frequently in this group. However, there are only very few studies on speciation in parasitoids. We studied reproductive barriers in two lineages of Lariophagus distinguendus (Chalcidoidea: Hymenoptera), a parasitoid wasp of pest beetle larvae that occur in human environments. One of the two lineages occurs in households preferably attacking larvae of the drugstore beetle Stegobium paniceum (“DB-lineage”), the other in grain stores with larvae of the granary weevil Sitophilus granarius as main host (“GW-lineage”). Between two populations of the DB-lineage, we identified slight sexual isolation as intraspecific barrier. Between populations from both lineages, we found almost complete sexual isolation caused by female mate choice, and postzygotic isolation, which is partially caused by cytoplasmic incompatibility induced by so far undescribed endosymbionts which are not Wolbachia or Cardinium. Because separation between the two lineages is almost complete, they should be considered as separate species according to the biological species concept. This demonstrates that cryptic species within parasitoid Hymenoptera also occur in Central Europe in close contact to humans. KW - cytoplasmic incompatibility KW - endosymbiotic bacteria KW - Lariophagus distinguendus KW - parasitoid wasps KW - sexual isolation KW - speciation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222796 VL - 9 ER -