TY - JOUR A1 - Tshitenge Tshitenge, Dieudonné A1 - Bruhn, Torsten A1 - Feineis, Doris A1 - Mudogo, Virima A1 - Kaiser, Marcel A1 - Brun, Reto A1 - Bringmann, Gerhard T1 - An unusually broad series of seven cyclombandakamines, bridged dimeric naphthylisoquinoline alkaloids from the Congolese liana Ancistrocladus ealaensis JF - Scientific Reports N2 - A series of seven unusual dimeric naphthylisoquinoline alkaloids was isolated from the leaves of the tropical liana Ancistrocladus ealaensis J. Léonard, named cyclombandakamine A (1), 1-epi-cyclombandakamine A (2), and cyclombandakamines A3–7 (3–7). These alkaloids have a chemically thrilling structural array consisting of a twisted dihydrofuran-cyclohexenone-isochromene system. The 1′″-epimer of 4, cyclombandakamine A1 (8), had previously been discovered in an unidentified Ancistrocladus species related to A. ealaensis. Both lianas produce the potential parent precursor, mbandakamine A (9), but only A. ealaensis synthesizes the corresponding cyclized form, along with a broad series of slightly modified analogs. The challenging isolation required, besides multi-dimensional chromatography, the use of a pentafluorophenyl stationary phase. Featuring up to six stereocenters and two types of chiral axes, their structures were elucidated by means of 1D and 2D NMR, HRESIMS, in combination with oxidative chemical degradation experiments as well as chiroptical (electronic circular dichroism spectroscopy) and quantum chemical calculations. Compared to the ‘open-chain’ parent compound 9, these dimers displayed rather moderate antiplasmodial activities. KW - Screening KW - Solution-state NMR KW - Stereochemistry KW - Structure elucidation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200759 VL - 9 ER - TY - JOUR A1 - Bauer, Maria A1 - Opitz, Anne A1 - Filser, Jörg A1 - Jansen, Hendrik A1 - Meffert, Rainer H. A1 - Germer, Christoph T. A1 - Roewer, Norbert A1 - Muellenbach, Ralf M. A1 - Kredel, Markus T1 - Perioperative redistribution of regional ventilation and pulmonary function: a prospective observational study in two cohorts of patients at risk for postoperative pulmonary complications JF - BMC Anesthesiology N2 - Background Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients, duration of hospital stay and costs. Postoperative atelectasis of dorsal lung regions as a common PPC has been described before, but its clinical relevance is insufficiently examined. Pulmonary electrical impedance tomography (EIT) enables the bedside visualization of regional ventilation in real-time within a transversal section of the lung. Dorsal atelectasis or effusions might cause a ventral redistribution of ventilation. We hypothesized the existence of ventral redistribution in spontaneously breathing patients during their recovery from abdominal and peripheral surgery and that vital capacity is reduced if regional ventilation shifts to ventral lung regions. Methods This prospective observational study included 69 adult patients undergoing elective surgery with an expected intermediate or high risk for PPCs. Patients undergoing abdominal and peripheral surgery were recruited to obtain groups of equal size. Patients received general anesthesia with and without additional regional anesthesia. On the preoperative, the first and the third postoperative day, EIT was performed at rest and during spirometry (forced breathing). The center of ventilation in dorso-ventral direction (COVy) was calculated. Results Both groups received intraoperative low tidal volume ventilation. Postoperative ventral redistribution of ventilation (forced breathing COVy; preoperative: 16.5 (16.0–17.3); first day: 17.8 (16.9–18.2), p < 0.004; third day: 17.4 (16.2–18.2), p = 0.020) and decreased forced vital capacity in percentage of predicted values (FVC%predicted) (median: 93, 58, 64%, respectively) persisted after abdominal surgery. In addition, dorsal to ventral shift was associated with a decrease of the FVC%predicted on the third postoperative day (r = − 0.66; p < 0.001). A redistribution of pulmonary ventilation was not observed after peripheral surgery. FVC%predicted was only decreased on the first postoperative day (median FVC%predicted on the preoperative, first and third day: 85, 81 and 88%, respectively). In ten patients occurred pulmonary complications after abdominal surgery also in two patients after peripheral surgery. Conclusions After abdominal surgery ventral redistribution of ventilation persisted up to the third postoperative day and was associated with decreased vital capacity. The peripheral surgery group showed only minor changes in vital capacity, suggesting a role of the location of surgery for postoperative redistribution of pulmonary ventilation. KW - Electrical impedance tomography KW - General anaesthesia KW - Postoperative complications KW - Pulmonary function tests Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200730 VL - 19 ER - TY - JOUR A1 - Wobser, Marion A1 - Weber, Alexandra A1 - Glunz, Amelie A1 - Tauch, Saskia A1 - Seitz, Kristina A1 - Butelmann, Tobias A1 - Hesbacher, Sonja A1 - Goebeler, Matthias A1 - Bartz, René A1 - Kohlhof, Hella A1 - Schrama, David A1 - Houben, Roland T1 - Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells JF - Journal of Hematology & Oncology N2 - Background Targeting epigenetic modifiers is effective in cutaneous T cell lymphoma (CTCL). However, there is a need for further improvement of this therapeutic approach. Here, we compared the mode of action of romidepsin (FK228), an established class I histone deacetylase inhibitor, and domatinostat (4SC-202), a novel inhibitor of class I HDACs, which has been reported to also target the lysine-specific histone demethylase 1A (LSD1). Methods We performed MTS assays and flow cytometric analyses of propidium iodide or annexin V-stained cells to assess drug impact on cellular proliferation, cell cycle distribution, and survival. Histone acetylation and methylation as well as caspase activation was analyzed by immunoblot. Gene expression analysis was performed using NanosString technology. Knockdown and knockout of LSD1 was achieved with shRNA and CRISPR/Cas9, respectively, while the CRISPR/Cas9 synergistic activation mediator system was used to induce expression of endogenous HDACs and LSD1. Furthermore, time-lapse fluorescence microscopy and an in vitro tubulin polymerization assay were applied. Results While FK228 as well as 4SC-202 potently induced cell death in six different CTCL cell lines, only in the case of 4SC-202 death was preceded by an accumulation of cells in the G2/M phase of the cell cycle. Surprisingly, apoptosis and accumulation of cells with double DNA content occurred already at 4SC-202 concentrations hardly affecting histone acetylation and methylation, and provoking significantly less changes in gene expression compared to biologically equivalent doses of FK228. Indeed, we provide evidence that the 4SC-202-induced G2/M arrest in CTCL cells is independent of de novo transcription. Furthermore, neither enforced expression of HDAC1 nor knockdown or knockout of LSD1 affected the 4SC-202-induced effects. Since time-lapse microscopy revealed that 4SC-202 could affect mitotic spindle formation, we performed an in vitro tubulin polymerization assay revealing that 4SC-202 can directly inhibit microtubule formation. Conclusions We demonstrate that 4SC-202, a drug currently tested in clinical trials, effectively inhibits growth of CTCL cells. The anti-cancer cell activity of 4SC-202 is however not limited to LSD1-inhibition, modulation of histone modifications, and consecutive alteration of gene expression. Indeed, the compound is also a potent microtubule-destabilizing agent. KW - Cutaneous lymphoma KW - Epigenetic regulation KW - Histone deacetylase KW - HDAC KW - Lysine-specific methylase KW - LSD1 KW - Tubulin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200703 VL - 12 ER - TY - JOUR A1 - Karl, Franziska A1 - Nandini Colaço, Maria B. A1 - Schulte, Annemarie A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Affective and cognitive behavior is not altered by chronic constriction injury in B7-H1 deficient and wildtype mice JF - BMC Neuroscience N2 - Background Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response. Results Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light–dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI. Conclusions Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion. KW - B7-H1 KW - Immune system KW - CCI KW - Anxiety KW - Cognitive behavior Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200540 VL - 20 ER - TY - JOUR A1 - Rueckl, Kilian A1 - Runer, Armin A1 - Bechler, Ulrich A1 - Faschingbauer, Martin A1 - Boelch, Sebastian Philipp A1 - Keyes Sculco, Peter A1 - Boettner, Friedrich T1 - The posterior-anterior-flexed view is essential for the evaluation of valgus osteoarthritis. A prospective study on 134 valgus knees JF - BMC Muscoskeletal Disorders N2 - Background Radiographic imaging is an important tool to assess osteoarthritis (OA). Lateral compartment osteoarthritis (valgus OA) usually starts with cartilage degeneration along the posterior aspect of the lateral femoral condyle. There is evidence that the posterior-anterior (PA)-flexed view is more sensitive when diagnosing early stages of valgus OA compared to the anterior-posterior (AP) view. The current paper analyzes the value of the PA-flexed view for patients scheduled for total knee arthroplasty (TKA). Methods Radiographs of 134 valgus knees were assessed prior to TKA. The minimal joint space width (minJSW) was measured on AP and PA-flexed views. The extent of mechanical deformity was measured on hip to ankle standing films. Results 49 (36.6%) AP views showed Kellgren and Lawrence (K/L)-grade 4 osteoarthritis in the lateral compartment, 82 (63.4%) showed grade 3 or less. The PA-flexed view resulted in an increased K/L-grading to grade 4 for 53 knees (62.4%) that were considered grade 3 or less on standard AP-radiographs. There was a significant differences between lateral minJSW on AP and PA-flexed view for patients with up to 10 degrees of mechanical valgus deformity (p < 0.001), as well as 11 to 15 degrees of mechanical deformity (p = 0.021). Only knees with severe deformity of more than 15 degrees did not show a difference in minJSW between PA-flexed view and AP view (p = 0.345). Conclusions The PA-flexed view is superior to the standard AP view in quantifying the extent of valgus OA in patients with zero to fifteen degrees of valgus deformity. It is recommended for the initial assessment of patients with valgus osteoarthritis and better documents the extent of osteoarthritis prior to TKA. KW - Valgus osteoarthritis KW - Knee KW - PA-flexed view KW - View KW - Radiographs Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200536 VL - 20 ER - TY - INPR A1 - Breitenbach, Tim A1 - Borzì, Alfio T1 - On the SQH scheme to solve non-smooth PDE optimal control problems T2 - Numerical Functional Analysis and Optimization N2 - A sequential quadratic Hamiltonian (SQH) scheme for solving different classes of non-smooth and non-convex PDE optimal control problems is investigated considering seven different benchmark problems with increasing difficulty. These problems include linear and nonlinear PDEs with linear and bilinear control mechanisms, non-convex and discontinuous costs of the controls, L\(^1\) tracking terms, and the case of state constraints. The SQH method is based on the characterisation of optimality of PDE optimal control problems by the Pontryagin's maximum principle (PMP). For each problem, a theoretical discussion of the PMP optimality condition is given and results of numerical experiments are presented that demonstrate the large range of applicability of the SQH scheme. KW - SQH method KW - non-smooth optimization KW - Pontryagin maximum principle KW - nonconvex optimization Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180936 N1 - This is an Accepted Manuscript of an article published by Taylor & Francis in Numerical Functional Analysis and Optimization on 27.04.2019, available online: http://www.tandfonline.com/10.1080/01630563.2019.1599911. ER - TY - JOUR A1 - Uereyen, Soner A1 - Kuenzer, Claudia T1 - A review of earth observation-based analyses for major river basins JF - Remote Sensing N2 - Regardless of political boundaries, river basins are a functional unit of the Earth’s land surface and provide an abundance of resources for the environment and humans. They supply livelihoods supported by the typical characteristics of large river basins, such as the provision of freshwater, irrigation water, and transport opportunities. At the same time, they are impacted i.e., by human-induced environmental changes, boundary conflicts, and upstream–downstream inequalities. In the framework of water resource management, monitoring of river basins is therefore of high importance, in particular for researchers, stake-holders and decision-makers. However, land surface and surface water properties of many major river basins remain largely unmonitored at basin scale. Several inventories exist, yet consistent spatial databases describing the status of major river basins at global scale are lacking. Here, Earth observation (EO) is a potential source of spatial information providing large-scale data on the status of land surface properties. This review provides a comprehensive overview of existing research articles analyzing major river basins primarily using EO. Furthermore, this review proposes to exploit EO data together with relevant open global-scale geodata to establish a database and to enable consistent spatial analyses and evaluate past and current states of major river basins. KW - major river basins KW - catchment KW - watershed KW - Earth observation KW - remote sensing KW - spatial analyses KW - land surface KW - surface water Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193849 SN - 2072-4292 VL - 11 IS - 24 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 - Cecil, Alexander A1 - Gentschev, Ivaylo A1 - Adelfinger, Marion A1 - Dandekar, Thomas A1 - Szalay, Aladar A. T1 - Vaccinia virus injected human tumors: oncolytic virus efficiency predicted by antigen profiling analysis fitted boolean models JF - Bioengineered N2 - Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a promising approach for cancer therapy. Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a therapeutic potential in treating human prostate and hepatocellular carcinomas in xenografted mice. In this study, we describe the use of dynamic boolean modeling for tumor growth prediction of vaccinia virus-injected human tumors. Antigen profiling data of vaccinia virus GLV-1h68-injected human xenografted mice were obtained, analyzed and used to calculate differences in the tumor growth signaling network by tumor type and gender. Our model combines networks for apoptosis, MAPK, p53, WNT, Hedgehog, the T-killer cell mediated cell death, Interferon and Interleukin signaling networks. The in silico findings conform very well with in vivo findings of tumor growth. Similar to a previously published analysis of vaccinia virus-injected canine tumors, we were able to confirm the suitability of our boolean modeling for prediction of human tumor growth after virus infection in the current study as well. In summary, these findings indicate that our boolean models could be a useful tool for testing of the efficacy of VACV-mediated cancer therapy already before its use in human patients. KW - boolean modeling KW - oncolytic virus KW - human xenografted mouse models KW - cancer therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200507 VL - 10 IS - 1 ER - TY - JOUR A1 - Wajant, Harald T1 - Molecular mode of action of TRAIL receptor agonists—common principles and their translational exploitation JF - Cancers N2 - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application. KW - antibody KW - antibody fusion proteins KW - apoptosis KW - cancer therapy KW - cell death KW - death receptors KW - TNF superfamily KW - TNF receptor superfamily KW - TRAIL Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202416 VL - 11 IS - 7 ER - TY - JOUR A1 - Muenstermann, Marcel A1 - Strobel, Lea A1 - Klos, Andreas A1 - Wetsel, Rick A. A1 - Woodruff, Trent M. A1 - Köhl, Jörg A1 - Johswich, Kay O. T1 - Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections JF - Virulence N2 - The complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar\(^{-/-}\) mice, whereas C5ar1\(^{-/-}\) and C5ar2\(^{-/-}\) mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1\(^{-/-}\) mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8\(^{Δ71−73}\)) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a “super-agonist” peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis. KW - inflammation KW - C3a KW - C5a KW - C3aR KW - C5aR1 KW - C5aR2 KW - meningococcal disease KW - sepsis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200496 VL - 10 IS - 1 ER - TY - JOUR A1 - Lenhard, Alexandra A1 - Lenhard, Wolfgang A1 - Gary, Sebastian T1 - Continuous norming of psychometric tests: A simulation study of parametric and semi-parametric approaches JF - PLoS ONE N2 - Continuous norming methods have seldom been subjected to scientific review. In this simulation study, we compared parametric with semi-parametric continuous norming methods in psychometric tests by constructing a fictitious population model within which a latent ability increases with age across seven age groups. We drew samples of different sizes (n = 50, 75, 100, 150, 250, 500 and 1,000 per age group) and simulated the results of an easy, medium, and difficult test scale based on Item Response Theory (IRT). We subjected the resulting data to different continuous norming methods and compared the data fit under the different test conditions with a representative cross-validation dataset of n = 10,000 per age group. The most significant differences were found in suboptimal (i.e., too easy or too difficult) test scales and in ability levels that were far from the population mean. We discuss the results with regard to the selection of the appropriate modeling techniques in psychometric test construction, the required sample sizes, and the requirement to report appropriate quantitative and qualitative test quality criteria for continuous norming methods in test manuals. KW - statistical models KW - simulation and modeling KW - psychometrics KW - age groups KW - skewness KW - normal distribution KW - polynomials KW - statistical distributions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200480 VL - 14 IS - 9 ER - TY - JOUR A1 - Doppler, Kathrin A1 - Schuster, Yasmin A1 - Appeltshauser, Luise A1 - Biko, Lydia A1 - Villmann, Carmen A1 - Weishaupt, Andreas A1 - Werner, Christian A1 - Sommer, Claudia T1 - Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model JF - Journal of Neuroinflammation N2 - Background: Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods: In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results: Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions: Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis. KW - complement deposition KW - paranodopathy KW - anti-contactin-1 KW - CIDP KW - passive transfer KW - autoantibody Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200476 VL - 16 IS - 73 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 - Khayenko, Vladimir A1 - Maric, Hans Michael T1 - Targeting GABA\(_A\)R-associated proteins: new modulators, labels and concepts JF - Frontiers in Molecular Neuroscience N2 - γ-aminobutyric acid type A receptors (GABA\(_A\)Rs) are the major mediators of synaptic inhibition in the brain. Aberrant GABA\(_A\)R activity or regulation is observed in various neurodevelopmental disorders, neurodegenerative diseases and mental illnesses, including epilepsy, Alzheimer’s and schizophrenia. Benzodiazepines, anesthetics and other pharmaceutics targeting these receptors find broad clinical use, but their inherent lack of receptor subtype specificity causes unavoidable side effects, raising a need for new or adjuvant medications. In this review article, we introduce a new strategy to modulate GABAeric signaling: targeting the intracellular protein interactors of GABA\(_A\)Rs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABA\(_A\)R subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABA\(_A\)R-associated proteins can be successfully targeted through diverse molecules, including recombinant proteins, intrabodies, peptide-based probes and small molecules. Small-molecule artemisinins and peptides derived from endogenous interactors, that specifically target the universal receptor binding site of gephyrin, acutely affect synaptic GABA\(_A\)R numbers and clustering, modifying neuronal transmission. Interference with GABA\(_A\)R trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABA\(_A\)R to AP2 increase the surface concentration of GABA\(_A\)R clusters and enhance GABAergic signaling. Engineering of gephyrin binding peptides delivered superior means to interrogate neuronal structure and function. Fluorescent peptides, designed from gephyrin binders, enable live neuronal staining and visualization of gephyrin in the post synaptic sites with submicron resolution. We anticipate that in the future, novel fluorescent probes, with improved size and binding efficiency, may find wide application in super resolution microscopy studies, enlightening the nanoscale architecture of the inhibitory synapse. Broader studies on GABA\(_A\)R accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABA\(_A\)R modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs. KW - GABAA receptors KW - gephyrin KW - collybistin KW - protein-protein interaction (PPI) KW - super resolution microscopy KW - fluorescent probes KW - dimeric peptide KW - peptide inhibitor design Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201876 VL - 12 IS - 162 ER - TY - JOUR A1 - Breun, Maria A1 - Monoranu, Camelia M. A1 - Kessler, Almuth F. A1 - Matthies, Cordula A1 - Löhr, Mario A1 - Hagemann, Carsten A1 - Schirbel, Andreas A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Buck, Andreas K. A1 - Wester, Hans-Jürgen A1 - Ernestus, Ralf-Ingo A1 - Lapa, Constantin T1 - [\(^{68}\)Ga]-Pentixafor PET/CT for CXCR4-mediated imaging of vestibular schwannomas JF - Frontiers in Oncology N2 - We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor. Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients. Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors. Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression. KW - vestibular schwannoma KW - CXCR4 KW - PET/CT KW - molecular imaging KW - Pentixafor Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201863 VL - 9 IS - 503 ER - TY - JOUR A1 - Gromer, Daniel A1 - Reinke, Max A1 - Christner, Isabel A1 - Pauli, Paul T1 - Causal interactive links between presence and fear in virtual reality height exposure JF - Frontiers in Psychology N2 - Virtual reality plays an increasingly important role in research and therapy of pathological fear. However, the mechanisms how virtual environments elicit and modify fear responses are not yet fully understood. Presence, a psychological construct referring to the ‘sense of being there’ in a virtual environment, is widely assumed to crucially influence the strength of the elicited fear responses, however, causality is still under debate. The present study is the first that experimentally manipulated both variables to unravel the causal link between presence and fear responses. Height-fearful participants (N = 49) were immersed into a virtual height situation and a neutral control situation (fear manipulation) with either high versus low sensory realism (presence manipulation). Ratings of presence and verbal and physiological (skin conductance, heart rate) fear responses were recorded. Results revealed an effect of the fear manipulation on presence, i.e., higher presence ratings in the height situation compared to the neutral control situation, but no effect of the presence manipulation on fear responses. However, the presence ratings during the first exposure to the high quality neutral environment were predictive of later fear responses in the height situation. Our findings support the hypothesis that experiencing emotional responses in a virtual environment leads to a stronger feeling of being there, i.e., increase presence. In contrast, the effects of presence on fear seem to be more complex: on the one hand, increased presence due to the quality of the virtual environment did not influence fear; on the other hand, presence variability that likely stemmed from differences in user characteristics did predict later fear responses. These findings underscore the importance of user characteristics in the emergence of presence. KW - presence KW - fear KW - virtual reality KW - visual realism KW - acrophobia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201855 VL - 10 IS - 141 ER - TY - JOUR A1 - Silwedel, Christine A1 - Speer, Christian P. A1 - Haarmann, Axel A1 - Fehrholz, Markus A1 - Claus, Heike A1 - Schlegel, Nicolas A1 - Glaser, Kirsten T1 - Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells JF - International Journal of Molecular Science N2 - Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation. KW - Ureaplasma urealyticum KW - Ureaplasma parvum KW - neuroinflammation KW - meningitis KW - blood–brain barrier KW - HBMEC Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201848 SN - 1422-0067 VL - 20 IS - 14 ER - TY - JOUR A1 - Wajant, Harald T1 - Molecular mode of action of TRAIL receptor agonists—common principles and their translational exploitation JF - Cancers N2 - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application. KW - antibody KW - antibody fusion proteins KW - apoptosis KW - cancer therapy KW - cell death KW - death receptors KW - TNF superfamily KW - TNF receptor superfamily KW - TRAIL Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201833 N1 - Zugriff gesperrt. Zugriff auf den Volltext erhalten Sie unter https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-202416 VL - 11 IS - 7 ER - TY - JOUR A1 - Kreckel, Jennifer A1 - Anany, Mohammed A. A1 - Siegmund, Daniela A1 - Wajant, Harald T1 - TRAF2 controls death receptor-induced caspase-8 processing and facilitates proinflammatory signaling JF - Frontiers in Immunology N2 - Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity. KW - caspase-8 KW - death receptors KW - CD95 KW - TNFR1 KW - TRAF1 KW - TRAF2 KW - TRAILR1 KW - TRAILR2 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201822 VL - 10 IS - 2024 ER - TY - JOUR A1 - Derakhshani, Shaghayegh A1 - Kurz, Andreas A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Pilgram, Lisa A1 - Steinke, Maria A1 - Kleuser, Burkhard A1 - Sauer, Markus A1 - Schneider-Schaulies, Sibylle A1 - Avota, Elita T1 - Measles virus infection fosters dendritic cell motility in a 3D environment to enhance transmission to target cells in the respiratory epithelium JF - Frontiers in Immunology N2 - Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit. KW - dendritic cell KW - cell migration KW - measles virus KW - 3D tissue model KW - sphingosine-1-phosphate Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201818 VL - 10 IS - 1294 ER - TY - JOUR A1 - Rau-Bredow, Hans T1 - Bigger is not always safer: a critical analysis of the subadditivity assumption for coherent risk measures JF - Risks N2 - This paper provides a critical analysis of the subadditivity axiom, which is the key condition for coherent risk measures. Contrary to the subadditivity assumption, bank mergers can create extra risk. We begin with an analysis how a merger affects depositors, junior or senior bank creditors, and bank owners. Next it is shown that bank mergers can result in higher payouts having to be made by the deposit insurance scheme. Finally, we demonstrate that if banks are interconnected via interbank loans, a bank merger could lead to additional contagion risks. We conclude that the subadditivity assumption should be rejected, since a subadditive risk measure, by definition, cannot account for such increased risks. KW - coherent risk measures KW - subadditivity KW - bank mergers KW - regulatory capital Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201808 VL - 7 IS - 3 ER - TY - JOUR A1 - Lechermeier, Carina G. A1 - Zimmer, Frederic A1 - Lüffe, Teresa M. A1 - Lesch, Klaus-Peter A1 - Romanos, Marcel A1 - Lillesaar, Christina A1 - Drepper, Carsten T1 - Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, define overlapping as well as distinct expression domains in the zebrafish (Danio rerio) central nervous system JF - Frontiers in Molecular Neuroscience N2 - The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders. KW - glucose transporter KW - nervous system KW - brain disorders KW - psychiatric disorders KW - brain development KW - GABA KW - GAD1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201797 VL - 12 IS - 199 ER - TY - JOUR A1 - Tarau, Ioana-Sandra A1 - Berlin, Andreas A1 - Curcio, Christine A. A1 - Ach, Thomas T1 - The cytoskeleton of the retinal pigment epithelium: from normal aging to age-related macular degeneration JF - International Journal of Molecular Science N2 - The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, adjacent to the fenestrated capillaries of the choriocapillaris. It shows strong apical (towards photoreceptors) to basal/basolateral (towards Bruch membrane) polarization. Multiple functions are bound to a complex structure of highly organized and polarized intracellular components: the cytoskeleton. A strong connection between the intracellular cytoskeleton and extracellular matrix is indispensable to maintaining the function of the RPE and thus, the photoreceptors. Impairments of these intracellular structures and the regular architecture they maintain often result in a disrupted cytoskeleton, which can be found in many retinal diseases, including age-related macular degeneration (AMD). This review article will give an overview of current knowledge on the molecules and proteins involved in cytoskeleton formation in cells, including RPE and how the cytoskeleton is affected under stress conditions — especially in AMD. KW - retinal pigment epithelium KW - cytoskeleton KW - aging KW - age-related macular degeneration KW - actin KW - microfilament KW - microtubules KW - stress fiber Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201781 SN - 1422-0067 VL - 20 IS - 14 ER - TY - JOUR A1 - Krieter, Detlef H. A1 - Kerwagen, Simon A1 - Rüth, Marieke A1 - Lemke, Horst-Dieter A1 - Wanner, Christoph T1 - Differences in dialysis efficacy have limited effects on protein-bound uremic toxins plasma levels over time JF - Toxins N2 - The protein-bound uremic toxins para-cresyl sulfate (pCS) and indoxyl sulfate (IS) are associated with cardiovascular disease in chronic renal failure, but the effect of different dialysis procedures on their plasma levels over time is poorly studied. The present prospective, randomized, cross-over trial tested dialysis efficacy and monitored pre-treatment pCS and IS concentrations in 15 patients on low-flux and high-flux hemodialysis and high-convective volume postdilution hemodiafiltration over six weeks each. Although hemodiafiltration achieved by far the highest toxin removal, only the mean total IS level was decreased at week three (16.6 ± 12.1 mg/L) compared to baseline (18.9 ± 13.0 mg/L, p = 0.027) and to low-flux dialysis (20.0 ± 12.7 mg/L, p = 0.021). At week six, the total IS concentration in hemodiafiltration reached the initial values again. Concentrations of free IS and free and total pCS remained unaltered. Highest beta2-microglobulin elimination in hemodiafiltration (p < 0.001) led to a persistent decrease of the plasma levels at week three and six (each p < 0.001). In contrast, absent removal in low-flux dialysis resulted in rising beta2-microglobulin concentrations (p < 0.001). In conclusion, this trial demonstrated that even large differences in instantaneous protein-bound toxin removal by current extracorporeal dialysis techniques may have only limited impact on IS and pCS plasma levels in the longer term. KW - protein-bound uremic toxins KW - end-stage renal disease KW - hemodialysis KW - hemodiafiltration KW - dialysis adequacy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201770 VL - 11 IS - 4 ER - TY - JOUR A1 - Kim, Brandon J. A1 - Shusta, Eric V. A1 - Doran, Kelly S. T1 - Past and current perspectives in modeling bacteria and blood–brain barrier interactions JF - Frontiers in Microbiology N2 - The central nervous system (CNS) barriers are highly specialized cellular barriers that promote brain homeostasis while restricting pathogen and toxin entry. The primary cellular constituent regulating pathogen entry in most of these brain barriers is the brain endothelial cell (BEC) that exhibits properties that allow for tight regulation of CNS entry. Bacterial meningoencephalitis is a serious infection of the CNS and occurs when bacteria can cross specialized brain barriers and cause inflammation. Models have been developed to understand the bacterial – BEC interaction that lead to pathogen crossing into the CNS, however, these have been met with challenges due to these highly specialized BEC phenotypes. This perspective provides a brief overview and outlook of the in vivo and in vitro models currently being used to study bacterial brain penetration, and opinion on improved models for the future. KW - bacteria KW - blood–brain barrier KW - meningitis KW - stem cells KW - brain endothelial cell Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201766 VL - 10 IS - 1336 ER - TY - JOUR A1 - Kunz, Tobias C. A1 - Kozjak-Pavlovic, Vera T1 - Diverse facets of sphingolipid involvement in bacterial infections JF - Frontiers in Cell and Developmental Biology N2 - Sphingolipids are constituents of the cell membrane that perform various tasks as structural elements and signaling molecules, in addition to regulating many important cellular processes, such as apoptosis and autophagy. In recent years, it has become increasingly clear that sphingolipids and sphingolipid signaling play a vital role in infection processes. In many cases the attachment and uptake of pathogenic bacteria, as well as bacterial development and survival within the host cell depend on sphingolipids. In addition, sphingolipids can serve as antimicrobials, inhibiting bacterial growth and formation of biofilms. This review will give an overview of our current information about these various aspects of sphingolipid involvement in bacterial infections. KW - infection KW - pathogenic bacteria KW - sphingolipids KW - ceramide KW - autophagy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201757 VL - 7 IS - 203 ER - TY - JOUR A1 - Voulgari‐Kokota, Anna A1 - Ankenbrand, Markus J. A1 - Grimmer, Gudrun A1 - Steffan‐Dewenter, Ingolf A1 - Keller, Alexander T1 - Linking pollen foraging of megachilid bees to their nest bacterial microbiota JF - Ecology and Evolution N2 - Solitary bees build their nests by modifying the interior of natural cavities, and they provision them with food by importing collected pollen. As a result, the microbiota of the solitary bee nests may be highly dependent on introduced materials. In order to investigate how the collected pollen is associated with the nest microbiota, we used metabarcoding of the ITS2 rDNA and the 16S rDNA to simultaneously characterize the pollen composition and the bacterial communities of 100 solitary bee nest chambers belonging to seven megachilid species. We found a weak correlation between bacterial and pollen alpha diversity and significant associations between the composition of pollen and that of the nest microbiota, contributing to the understanding of the link between foraging and bacteria acquisition for solitary bees. Since solitary bees cannot establish bacterial transmission routes through eusociality, this link could be essential for obtaining bacterial symbionts for this group of valuable pollinators. KW - foraging patterns KW - nest microbiota KW - plant–microbe–pollinator triangle KW - pollination network KW - solitary bees KW - wild bees Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201749 SN - 00 VL - 2019 IS - 9 ER - TY - JOUR A1 - Deol, Kirandeep K. A1 - Lorenz, Sonja A1 - Strieter, Eric R. T1 - Enzymatic logic of ubiquitin chain assembly JF - Frontiers in Physiology N2 - Protein ubiquitination impacts virtually every biochemical pathway in eukaryotic cells. The fate of a ubiquitinated protein is largely dictated by the type of ubiquitin modification with which it is decorated, including a large variety of polymeric chains. As a result, there have been intense efforts over the last two decades to dissect the molecular details underlying the synthesis of ubiquitin chains by ubiquitin-conjugating (E2) enzymes and ubiquitin ligases (E3s). In this review, we highlight these advances. We discuss the evidence in support of the alternative models of transferring one ubiquitin at a time to a growing substrate-linked chain (sequential addition model) versus transferring a pre-assembled ubiquitin chain (en bloc model) to a substrate. Against this backdrop, we outline emerging principles of chain assembly: multisite interactions, distinct mechanisms of chain initiation and elongation, optimal positioning of ubiquitin molecules that are ultimately conjugated to each other, and substrate-assisted catalysis. Understanding the enzymatic logic of ubiquitin chain assembly has important biomedical implications, as the misregulation of many E2s and E3s and associated perturbations in ubiquitin chain formation contribute to human disease. The resurgent interest in bifunctional small molecules targeting pathogenic proteins to specific E3s for polyubiquitination and subsequent degradation provides an additional incentive to define the mechanisms responsible for efficient and specific chain synthesis and harness them for therapeutic benefit. KW - ubiquitin KW - E2 conjugating enzyme KW - E3 ligating enzyme KW - sequential addition KW - en bloc transfer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201731 VL - 10 IS - 835 ER - TY - JOUR A1 - Huestegge, Sujata M. T1 - Matching unfamiliar voices to static and dynamic faces: no evidence for a dynamic face advantage in a simultaneous presentation paradigm JF - Frontiers in Psychology N2 - Previous research has demonstrated that humans are able to match unfamiliar voices to corresponding faces and vice versa. It has been suggested that this matching ability might be based on common underlying factors that have a characteristic impact on both faces and voices. Some researchers have additionally assumed that dynamic facial information might be especially relevant to successfully match faces to voices. In the present study, static and dynamic face-voice matching ability was compared in a simultaneous presentation paradigm. Additionally, a procedure (matching additionally supported by incidental association learning) was implemented which allowed for reliably excluding participants that did not pay sufficient attention to the task. A comparison of performance between static and dynamic face-voice matching suggested a lack of substantial differences in matching ability, suggesting that dynamic (as opposed to mere static) facial information does not contribute meaningfully to face-voice matching performance. Importantly, this conclusion was not merely derived from the lack of a statistically significant group difference in matching performance (which could principally be explained by assuming low statistical power), but from a Bayesian analysis as well as from an analysis of the 95% confidence interval (CI) of the actual effect size. The extreme border of this CI suggested a maximally plausible dynamic face advantage of less than four percentage points, which was considered way too low to indicate any theoretically meaningful dynamic face advantage. Implications regarding the underlying mechanisms of face-voice matching are discussed. KW - voice-face matching KW - static vs. dynamic faces KW - face-voice integration KW - simultaneous presentation paradigm KW - person identity processing Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201714 VL - 10 IS - 1957 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Kraft, Peter A1 - Bieber, Michael A1 - Kollikowski, Alexander M. A1 - Schulze, Harald A1 - Nieswandt, Bernhard A1 - Pham, Mirko A1 - Stegner, David A1 - Stoll, Guido T1 - Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice JF - International Journal of Molecular Science N2 - Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{−/−}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke. KW - ischemic stroke KW - integrin α2 KW - glycoprotein VI KW - recombinant tissue-type plasminogen activator KW - intracranial bleeding KW - transient middle cerebral artery occlusion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201700 SN - 1422-0067 VL - 20 IS - 8 ER - TY - JOUR A1 - Trappe, Julian A1 - Kneisel, Christof T1 - Geophysical and sedimentological investigations of Peatlands for the assessment of lithology and subsurface water pathways JF - Geosciences N2 - Peatlands located on slopes (herein called slope bogs) are typical landscape units in the Hunsrueck, a low mountain range in Southwestern Germany. The pathways of the water feeding the slope bogs have not yet been documented and analyzed. The identification of the different mechanisms allowing these peatlands to originate and survive requires a better understanding of the subsurface lithology and hydrogeology. Hence, we applied a multi-method approach to two case study sites in order to characterize the subsurface lithology and to image the variable spatio-temporal hydrological conditions. The combination of Electrical Resistivity Tomography (ERT) and an ERT-Monitoring and Ground Penetrating Radar (GPR), in conjunction with direct methods and data (borehole drilling and meteorological data), allowed us to gain deeper insights into the subsurface characteristics and dynamics of the peatlands and their catchment area. The precipitation influences the hydrology of the peatlands as well as the interflow in the subsurface. Especially, the geoelectrical monitoring data, in combination with the precipitation and temperature data, indicate that there are several forces driving the hydrology and hydrogeology of the peatlands. While the water content of the uppermost layers changes with the weather conditions, the bottom layer seems to be more stable and changes to a lesser extent. At the selected case study sites, small differences in subsurface properties can have a huge impact on the subsurface hydrogeology and the water paths. Based on the collected data, conceptual models have been deduced for the two case study sites. KW - peatland KW - slope bogs KW - geomorphology KW - subsurface hydrology KW - electrical resistivity tomography KW - ground penetrating radar KW - boreholes KW - Hunsrueck Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201699 VL - 9 IS - 3 ER - TY - JOUR A1 - Lange, Benjamin P. A1 - Andrian-Werburg, Maximilian T. P. von A1 - Adler, Dorothea C. A1 - Zaretsky, Eugen T1 - The name is the game: nicknames as predictors of personality and mating strategy in online dating JF - Frontiers in Communication N2 - Objective: We investigated the communicative function of online dating nicknames. Our aim was to assess if it is possible to correctly guess personality traits of a user simply by reading his/her nickname. Method: We had 69 nickname users (average age: 33.59 years, 36 female) complete questionnaires assessing their personality (Big 5 + narcissism) and mating strategy (short- vs. long-term). We then checked (using a total of 638 participants, average age: 26.83 years, 355 female), whether personality and mating strategy of the nickname users could be assessed correctly based only on the nickname. We also captured the motivation to contact the user behind a nickname and looked at linguistic features of the nicknames. Results: We found that personality and mating strategy could be inferred from a nickname. Furthermore, going by trends, women were better at intersexual personality judgments, whereas men were better in intrasexual judgements. We also found several correlates of the motivation to contact the person behind the nickname. Among other factors, long nicknames seemed to deter people from contacting the nickname user. Conclusions: Findings display that humans are capable of making accurate personality judgements in computer-mediated communication by means of even small cues like nicknames. KW - computer-mediated communication KW - linguistic cues KW - nicknames KW - online dating KW - personality judgments KW - hyperpersonal communication Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201659 VL - 4 IS - 3 ER - TY - JOUR A1 - Karl, Franziska A1 - Wußmann, Maximiliane A1 - Kreß, Luisa A1 - Malzacher, Tobias A1 - Fey, Phillip A1 - Groeber‐Becker, Florian A1 - Üçeyler, Nurcan T1 - Patient‐derived in vitro skin models for investigation of small fiber pathology JF - Annals of Clinical and Translational Neurology N2 - Objective To establish individually expandable primary fibroblast and keratinocyte cultures from 3‐mm skin punch biopsies for patient‐derived in vitro skin models to investigate of small fiber pathology. Methods We obtained 6‐mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient‐derived full‐thickness three‐dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto‐ and ‐histochemically (vimentin, cytokeratin (CK)‐10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance. Results Distal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two‐dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell‐specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject‐derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell‐specific markers and showed a homogenous expression of extracellular matrix proteins. Interpretation Our protocol allows the generation of disease‐specific 2D and 3D skin models, which can be used to investigate the cross‐talk between skin cells and sensory neurons in small fiber pathology. KW - neurology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201649 VL - 6 IS - 9 ER - TY - JOUR A1 - Schlegel, Jan A1 - Peters, Simon A1 - Doose, Sören A1 - Schubert-Unkmeir, Alexandra A1 - Sauer, Markus T1 - Super-resolution microscopy reveals local accumulation of plasma membrane gangliosides at Neisseria meningitidis Invasion Sites JF - Frontiers in Cell and Developmental Biology N2 - Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for epidemic meningitis and sepsis worldwide. A critical step in the development of meningitis is the interaction of bacteria with cells forming the blood-cerebrospinal fluid barrier, which requires tight adhesion of the pathogen to highly specialized brain endothelial cells. Two endothelial receptors, CD147 and the β2-adrenergic receptor, have been found to be sequentially recruited by meningococci involving the interaction with type IV pilus. Despite the identification of cellular key players in bacterial adhesion the detailed mechanism of invasion is still poorly understood. Here, we investigated cellular dynamics and mobility of the type IV pilus receptor CD147 upon treatment with pili enriched fractions and specific antibodies directed against two extracellular Ig-like domains in living human brain microvascular endothelial cells. Modulation of CD147 mobility after ligand binding revealed by single-molecule tracking experiments demonstrates receptor activation and indicates plasma membrane rearrangements. Exploiting the binding of Shiga (STxB) and Cholera toxin B (CTxB) subunits to the two native plasma membrane sphingolipids globotriaosylceramide (Gb3) and raft-associated monosialotetrahexosylganglioside GM1, respectively, we investigated their involvement in bacterial invasion by super-resolution microscopy. Structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM) unraveled accumulation and coating of meningococci with GM1 upon cellular uptake. Blocking of CTxB binding sites did not impair bacterial adhesion but dramatically reduced bacterial invasion efficiency. In addition, cell cycle arrest in G1 phase induced by serum starvation led to an overall increase of GM1 molecules in the plasma membrane and consequently also in bacterial invasion efficiency. Our results will help to understand downstream signaling events after initial type IV pilus-host cell interactions and thus have general impact on the development of new therapeutics targeting key molecules involved in infection. KW - Neisseria meningitidis KW - sphingolipids KW - gangliosides and lipid rafts KW - super-resolution microscopy KW - single-molecule tracking Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201639 VL - 7 IS - 194 ER - TY - JOUR A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - Targeting regulatory T cells by addressing tumor necrosis factor and its receptors in allogeneic hematopoietic cell transplantation and cancer JF - Frontiers in Immunology N2 - An intricate network of molecular and cellular actors orchestrates the delicate balance between effector immune responses and immune tolerance. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) proves as a pivotal protagonist promoting but also suppressing immune responses. These opposite actions are accomplished through specialist cell types responding to TNF via TNF receptors TNFR1 and TNFR2. Recent findings highlight the importance of TNFR2 as a key regulator of activated natural FoxP3+ regulatory T cells (Tregs) in inflammatory conditions, such as acute graft-vs.-host disease (GvHD) and the tumor microenvironment. Here we review recent advances in our understanding of TNFR2 signaling in T cells and discuss how these can reconcile seemingly conflicting observations when manipulating TNF and TNFRs. As TNFR2 emerges as a new and attractive target we furthermore pinpoint strategies and potential pitfalls for therapeutic targeting of TNFR2 for cancer treatment and immune tolerance after allogeneic hematopoietic cell transplantation. KW - GVHD KW - graft vs. host disease KW - cancer KW - Tregs (regulatory T cells) KW - TNFR family costimulatory receptors KW - TNFR2 agonists KW - TNFR2 antagonism Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201578 VL - 10 IS - 2040 ER - TY - JOUR A1 - Gomes, Sara F. Martins A1 - Westermann, Alexander J. A1 - Sauerwein, Till A1 - Hertlein, Tobias A1 - Förstner, Konrad U. A1 - Ohlsen, Knut A1 - Metzger, Marco A1 - Shusta, Eric V. A1 - Kim, Brandon J. A1 - Appelt-Menzel, Antje A1 - Schubert-Unkmeir, Alexandra T1 - Induced pluripotent stem cell-derived brain endothelial cells as a cellular model to study Neisseria meningitidis infection JF - Frontiers in Microbiology N2 - Meningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs. KW - Neisseria meningitidis KW - meningococcus KW - bacteria KW - stem cells KW - blood-cerebrospinal fluid barrier KW - blood-brain barrier KW - brain endothelial cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201562 VL - 10 IS - 1181 ER - TY - JOUR A1 - Wajant, Harald A1 - Siegmund, Daniela T1 - TNFR1 and TNFR2 in the control of the life and death balance of macrophages JF - Frontiers in Cell and Developmental Biology N2 - Macrophages stand in the first line of defense against a variety of pathogens but are also involved in the maintenance of tissue homeostasis. To fulfill their functions macrophages sense a broad range of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) by plasma membrane and intracellular pattern recognition receptors (PRRs). Intriguingly, the overwhelming majority of PPRs trigger the production of the pleiotropic cytokine tumor necrosis factor-alpha (TNF). TNF affects almost any type of cell including macrophages themselves. TNF promotes the inflammatory activity of macrophages but also controls macrophage survival and death. TNF exerts its activities by stimulation of two different types of receptors, TNF receptor-1 (TNFR1) and TNFR2, which are both expressed by macrophages. The two TNF receptor types trigger distinct and common signaling pathways that can work in an interconnected manner. Based on a brief general description of major TNF receptor-associated signaling pathways, we focus in this review on research of recent years that revealed insights into the molecular mechanisms how the TNFR1-TNFR2 signaling network controls the life and death balance of macrophages. In particular, we discuss how the TNFR1-TNFR2 signaling network is integrated into PRR signaling. KW - apoptosis KW - necroptosis KW - TNF KW - TNFR1 KW - TNFR2 KW - ripk1 KW - ripk3 KW - caspase-8 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201551 VL - 7 IS - 91 ER - TY - JOUR A1 - Pasos, Uri E. Ramirez A1 - Steigerwald, Frank A1 - Reich, Martin M. A1 - Matthies, Cordula A1 - Volkmann, Jens A1 - Reese, René T1 - Levodopa modulates functional connectivity in the upper beta band between bubthalamic nucleus and muscle activity in tonic and phasic motor activity patterns in Parkinson’s disease JF - Frontiers in Human Neuroscience N2 - Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson’s disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons. Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI). Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50–150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300–500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF. Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus’ functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy. KW - Parkinson’s disease KW - subthalamic nucleus KW - deep brain stimulation KW - local field potentials KW - dopamine KW - movement Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201540 VL - 13 IS - 223 ER - TY - JOUR A1 - Krakow, Sören A1 - Crescimone, Marie L. A1 - Bartels, Charlotte A1 - Wiegering, Verena A1 - Eyrich, Matthias A1 - Schlegel, Paul G. A1 - Wölfl, Matthias T1 - Re-expression of CD14 in response to a combined IL-10/TLR stimulus defines monocyte-derived cells with an immunoregulatory phenotype JF - Frontiers in Immunology N2 - Interleukin 10 is a central regulator of the antigen-presenting function of myeloid cells. It exerts immunomodulatory effects in vivo and induces a regulatory phenotype in monocyte-derived cells in vitro. We analyzed phenotype and function of monocytic cells in vitro in relation to the cytokine milieu and the timing of TLR-based activation. In GM-CSF/IL-4 cultured human monocytic cells, we identified two, mutually exclusive cell populations arising from undifferentiated cells: CD83\(^+\) fully activated dendritic cells and CD14\(^+\) macrophage like cells. Re-expression of CD14 occurs primarily after a sequential trigger with a TLR signal following IL-10 preincubation. This cell population with re-expressed CD14 greatly differs in phenotype and function from the CD83+ cells. Detailed analysis of individual subpopulations reveals that exogenous IL-10 is critical for inducing the shift toward the CD14\(^+\) population, but does not affect individual changes in marker expression or cell function in most cases. Thus, plasticity of CD14 expression, defining a subset of immunoregulatory cells, is highly relevant for the composition of cellular products (such as DC vaccines) as it affects the function of the total product. KW - regulatory dendritic cells KW - MDSC KW - monocyte-derived DC KW - IL-10 KW - macrophages Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201537 VL - 10 IS - 1484 ER - TY - JOUR A1 - Scheurer, Mario Joachim Johannes A1 - Brands, Roman Camillus A1 - El-Mesery, Mohamed A1 - Hartmann, Stefan A1 - Müller-Richter, Urs Dietmar Achim A1 - Kübler, Alexander Christian A1 - Seher, Axel T1 - The selection of NFκB inhibitors to block inflammation and induce sensitisation to FasL-induced apoptosis in HNSCC cell lines is critical for their use as a prospective cancer therapy JF - International Journal of Molecular Science N2 - Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors — Cortisol, MLN4924, QNZ and TPCA1 — on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted. KW - HNSCC KW - NFκB KW - inhibitor KW - TPCA1 KW - apoptosis KW - inflammation KW - TNFα KW - FasL Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201524 SN - 1422-0067 VL - 20 IS - 6 ER - TY - JOUR A1 - El-Hawary, Seham S. A1 - Sayed, Ahmed M. A1 - Mohammed, Rabab A1 - Hassan, Hossam M. A1 - Rateb, Mostafa E. A1 - Amin, Elham A1 - Mohammed, Tarek A. A1 - El-Mesery, Mohamed A1 - Bin Muhsinah, Abdullatif A1 - Alsayari, Abdulrhman A1 - Wajant, Harald A1 - Anany, Mohamed A. A1 - Abdelmohsen, Usama Ramadan T1 - Bioactive brominated oxindole alkaloids from the Red Sea sponge Callyspongia siphonella JF - Marine Drugs N2 - In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents. KW - Callyspongia siphonella KW - LC-HRESIMS KW - metabolomic profiling KW - oxindole alkaloids KW - tisindoline KW - antibacterial KW - antibiofilm KW - antitrypanosomal KW - anticancer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201485 VL - 17 IS - 8 ER - TY - JOUR A1 - Liu, Ruiqi A1 - Kinoshita, Masato A1 - Adolfi, Mateus C. A1 - Schartl, Manfred T1 - Analysis of the role of the Mc4r system in development, growth, and puberty of medaka JF - Frontiers in Endocrinology N2 - In mammals the melanocortin 4 receptor (Mc4r) signaling system has been mainly associated with the regulation of appetite and energy homeostasis. In fish of the genus Xiphophorus (platyfish and swordtails) puberty onset is genetically determined by a single locus, which encodes the mc4r. Wild populations of Xiphophorus are polymorphic for early and late-maturing individuals. Copy number variation of different mc4r alleles is responsible for the difference in puberty onset. To answer whether this is a special adaptation of the Mc4r signaling system in the lineage of Xiphophorus or a more widely conserved mechanism in teleosts, we studied the role of Mc4r in reproductive biology of medaka (Oryzias latipes), a close relative to Xiphophorus and a well-established model to study gonadal development. To understand the potential role of Mc4r in medaka, we characterized the major features of the Mc4r signaling system (mc4r, mrap2, pomc, agrp1). In medaka, all these genes are expressed before hatching. In adults, they are mainly expressed in the brain. The transcript of the receptor accessory protein mrap2 co-localizes with mc4r in the hypothalamus in adult brains indicating a conserved function of modulating Mc4r signaling. Comparing growth and puberty between wild-type and mc4r knockout medaka revealed that absence of Mc4r does not change puberty timing but significantly delays hatching. Embryonic development of knockout animals is retarded compared to wild-types. In conclusion, the Mc4r system in medaka is involved in regulation of growth rather than puberty. KW - medaka KW - Mc4r KW - knockout KW - puberty KW - growth Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201472 VL - 10 ER - TY - JOUR A1 - Panzer, Sabine A1 - Brych, Annika A1 - Batschauer, Alfred A1 - Terpitz, Ulrich T1 - Opsin 1 and Opsin 2 of the corn smut fungus ustilago maydis are green light-driven proton pumps JF - Frontiers in Microbiology N2 - In fungi, green light is absorbed by rhodopsins, opsin proteins carrying a retinal molecule as chromophore. The basidiomycete Ustilago maydis, a fungal pathogen that infects corn plants, encodes three putative photoactive opsins, called ops1 (UMAG_02629), ops2 (UMAG_00371), and ops3 (UMAG_04125). UmOps1 and UmOps2 are expressed during the whole life cycle, in axenic cultures as well as in planta, whereas UmOps3 was recently shown to be absent in axenic cultures but highly expressed during plant infection. Here we show that expression of UmOps1 and UmOps2 is induced by blue light under control of white collar 1 (Wco1). UmOps1 is mainly localized in the plasma membrane, both when expressed in HEK cells and U. maydis sporidia. In contrast, UmOps2 was mostly found intracellularly in the membranes of vacuoles. Patch-clamp studies demonstrated that both rhodopsins are green light-driven outward rectifying proton pumps. UmOps1 revealed an extraordinary pH dependency with increased activity in more acidic environment. Also, UmOps1 showed a pronounced, concentration-dependent enhancement of pump current caused by weak organic acids (WOAs), especially by acetic acid and indole-3-acetic acid (IAA). In contrast, UmOps2 showed the typical behavior of light-driven, outwardly directed proton pumps, whereas UmOps3 did not exhibit any electrogenity. With this work, insights were gained into the localization and molecular function of two U. maydis rhodopsins, paving the way for further studies on the biological role of these rhodopsins in the life cycle of U. maydis. KW - Ustilago maydis KW - patch-clamp KW - fungal rhodopsins KW - microbial rhodopsins KW - acetate KW - indole-3-acetic acid KW - structured illumination microscopy KW - sporidia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201453 VL - 10 ER - TY - JOUR A1 - Nothhaft, Matthias A1 - Klepper, Joerg A1 - Kneitz, Hermann A1 - Meyer, Thomas A1 - Hamm, Henning A1 - Morbach, Henner T1 - Hemorrhagic bullous Henoch-Schönlein Purpura: case report and review of the literature JF - Frontiers in Pediatrics N2 - Henoch-Schönlein Purpura (HSP) or IgA vasculitis is the most common systemic vasculitis of childhood and may affect skin, joints, gastrointestinal tract, and kidneys. Skin manifestations of HSP are characteristic and include a non-thrombocytopenic palpable purpura of the lower extremities and buttocks. Rarely, HSP may initially present as or evolve into hemorrhagic vesicles and bullae. We present an otherwise healthy 5-year-old boy with an acute papulovesicular rash of both legs and intermittent abdominal pain. After a few days the skin lesions rapidly evolved into palpable purpura and hemorrhagic bullous lesions of variable size and severe hemorrhagic HSP was suspected. A histological examination of a skin biopsy showed signs of a small vessel leukocytoclastic vasculitis limited to the upper dermis and direct immunofluorescence analysis revealed IgA deposits in vessel walls, compatible with HSP. To further characterize the clinical picture and treatment options of bullous HSP we performed an extensive literature research and identified 41 additional pediatric patients with bullous HSP. Two thirds of the reported patients were treated with systemic corticosteroids, however, up to 25% of the reported patients developed skin sequelae such as hyperpigmentation and/or scarring. The early use of systemic corticosteroids has been discussed controversially and suggested in some case series to be beneficial by reducing the extent of lesions and minimizing sequelae of disease. Our patient was treated with systemic corticosteroids tapered over 5 weeks. Fading of inflammation resulted in healing of most erosions, however, a deep necrosis developing from a large blister at the dorsum of the right foot persisted so that autologous skin transplantation was performed. Re-examination 11 months after disease onset showed complete clinical remission with re-epithelialization but also scarring of some affected areas. KW - henoch-schönlein purpura KW - vasculitis KW - hemorrhagic KW - bullae KW - children Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201435 VL - 6 ER - TY - JOUR A1 - Brill, Michael A1 - Schwab, Frank T1 - A mixed-methods approach using self-report, observational time series data, and content analysis for process analysis of a media reception phenomenon JF - Frontiers in Psychology N2 - Due to the complexityof research objects, theoretical concepts, and stimuli in media research, researchers in psychology and communications presumably need sophisticated measures beyond self-report scales to answer research questions on media use processes. The present study evaluates stimulus-dependent structure in spontaneous eye-blink behavior as an objective, corroborative measure for the media use phenomenon of spatial presence. To this end, a mixed methods approach is used in an experimental setting to collect, combine, analyze, and interpret data from standardized participant self-report, observation of participant behavior, and content analysis of the media stimulus. T-pattern detection is used to analyze stimulus-dependent blinking behavior, and this structural data is then contrasted with self-report data. The combined results show that behavioral indicators yield the predicted results, while self-report data shows unpredicted results that are not predicted by the underlying theory. The use of a mixed methods approach offered insights that support further theory development and theory testing beyond a traditional, mono-method experimental approach. KW - presence KW - measurement KW - blinking KW - structure KW - mixed methods Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201380 VL - 10 ER - TY - JOUR A1 - Srivastava, Mugdha A1 - Bencurova, Elena A1 - Gupta, Shishir K. A1 - Weiss, Esther A1 - Löffler, Jürgen A1 - Dandekar, Thomas T1 - Aspergillus fumigatus challenged by human dendritic cells: metabolic and regulatory pathway responses testify a tight battle JF - Frontiers in Cellular and Infection Microbiology N2 - Dendritic cells (DCs) are antigen presenting cells which serve as a passage between the innate and the acquired immunity. Aspergillosis is a major lethal condition in immunocompromised patients caused by the adaptable saprophytic fungus Aspergillus fumigatus. The healthy human immune system is capable to ward off A. fumigatus infections however immune-deficient patients are highly vulnerable to invasive aspergillosis. A. fumigatus can persist during infection due to its ability to survive the immune response of human DCs. Therefore, the study of the metabolism specific to the context of infection may allow us to gain insight into the adaptation strategies of both the pathogen and the immune cells. We established a metabolic model of A. fumigatus central metabolism during infection of DCs and calculated the metabolic pathway (elementary modes; EMs). Transcriptome data were used to identify pathways activated when A. fumigatus is challenged with DCs. In particular, amino acid metabolic pathways, alternative carbon metabolic pathways and stress regulating enzymes were found to be active. Metabolic flux modeling identified further active enzymes such as alcohol dehydrogenase, inositol oxygenase and GTP cyclohydrolase participating in different stress responses in A. fumigatus. These were further validated by qRT-PCR from RNA extracted under these different conditions. For DCs, we outlined the activation of metabolic pathways in response to the confrontation with A. fumigatus. We found the fatty acid metabolism plays a crucial role, along with other metabolic changes. The gene expression data and their analysis illuminate additional regulatory pathways activated in the DCs apart from interleukin regulation. In particular, Toll-like receptor signaling, NOD-like receptor signaling and RIG-I-like receptor signaling were active pathways. Moreover, we identified subnetworks and several novel key regulators such as UBC, EGFR, and CUL3 of DCs to be activated in response to A. fumigatus. In conclusion, we analyze the metabolic and regulatory responses of A. fumigatus and DCs when confronted with each other. KW - infection KW - dendritic cells KW - Aspergillus fumigalus KW - metabolic modelling KW - signalling Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201368 VL - 9 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Stoll, Guido A1 - Bohr, Arne A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats JF - International Journal of Molecular Science N2 - Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level. KW - photothrombotic stroke KW - deep brain stimulation KW - mesencephalic locomotor region KW - neuroprotection KW - neuronal apoptosis KW - neuroinflammation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201355 SN - 1422-0067 VL - 20 IS - 9 ER - TY - JOUR A1 - Weidner, Magdalena T. A1 - Lardenoije, Roy A1 - Eijssen, Lars A1 - Mogavero, Floriana A1 - De Groodt, Lilian P. M. T. A1 - Popp, Sandy A1 - Palme, Rupert A1 - Förstner, Konrad U. A1 - Strekalova, Tatyana A1 - Steinbusch, Harry W. M. A1 - Schmitt-Böhrer, Angelika G. A1 - Glennon, Jeffrey C. A1 - Waider, Jonas A1 - van den Hove, Daniel L. A. A1 - Lesch, Klaus-Peter T1 - Identification of cholecystokinin by genome-wide profiling as potential mediator of serotonin-dependent behavioral effects of maternal separation in the amygdala JF - Frontiers in Neuroscience N2 - Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability. KW - serotonin KW - maternal separation KW - mouse KW - emotional behavior KW - DNA methylation KW - RNA expression Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201340 VL - 13 ER - TY - JOUR A1 - Neueder, Dorothea A1 - Andreatta, Marta A1 - Pauli, Paul T1 - Contextual fear conditioning and fear generalization in individuals with panic attacks JF - Frontiers in Behavioral Neuroscience N2 - Context conditioning is characterized by unpredictable threat and its generalization may constitute risk factors for panic disorder (PD). Therefore, we examined differences between individuals with panic attacks (PA; N = 21) and healthy controls (HC, N = 22) in contextual learning and context generalization using a virtual reality (VR) paradigm. Successful context conditioning was indicated in both groups by higher arousal, anxiety and contingency ratings, and increased startle responses and skin conductance levels (SCLs) in an anxiety context (CTX+) where an aversive unconditioned stimulus (US) occurred unpredictably vs. a safety context (CTX−). PA compared to HC exhibited increased differential responding to CTX+ vs. CTX− and overgeneralization of contextual anxiety on an evaluative verbal level, but not on a physiological level. We conclude that increased contextual conditioning and contextual generalization may constitute risk factors for PD or agoraphobia contributing to the characteristic avoidance of anxiety contexts and withdrawal to safety contexts and that evaluative cognitive process may play a major role. KW - contextual fear conditioning KW - anxiety generalization KW - startle response KW - panic disorder KW - virtual reality Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201318 VL - 13 ER -