@article{GronwaldHoosHottenrott2019, author = {Gronwald, Thomas and Hoos, Olaf and Hottenrott, Kuno}, title = {Effects of Acute Normobaric Hypoxia on Non-linear Dynamics of Cardiac Autonomic Activity During Constant Workload Cycling Exercise}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, doi = {10.3389/fphys.2019.00999}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369199}, year = {2019}, abstract = {Aim: Measurements of Non-linear dynamics of heart rate variability (HRV) provide new possibilities to monitor cardiac autonomic activity during exercise under different environmental conditions. Using detrended fluctuation analysis (DFA) technique to assess correlation properties of heart rate (HR) dynamics, the present study examines the influence of normobaric hypoxic conditions (HC) in comparison to normoxic conditions (NC) during a constant workload exercise. Materials and Methods: Nine well trained cyclists performed a continuous workload exercise on a cycle ergometer with an intensity corresponding to the individual anaerobic threshold until voluntary exhaustion under both NC and HC (15\% O2). The individual exercise duration was normalized to 10\% sections (10-100\%). During exercise HR and RR-intervals were continuously-recorded. Besides HRV time-domain measurements (meanRR, SDNN), fractal correlation properties using short-term scaling exponent alpha1 of DFA were calculated. Additionally, blood lactate (La), oxygen saturation of the blood (SpO2), and rating of perceived exertion (RPE) were recorded in regular time intervals. Results: We observed significant changes under NC and HC for all parameters from the beginning to the end of the exercise (10\% vs. 100\%) except for SpO2 and SDNN during NC: increases for HR, La, and RPE in both conditions; decreases for SpO2 and SDNN during HC, meanRR and DFA-alpha1 during both conditions. Under HC HR (40-70\%), La (10-90\%), and RPE (50-90\%) were significantly-higher, SpO2 (10-100\%), meanRR (40-70\%), and DFA-alpha1 (20-60\%) were significantly-lower than under NC. Conclusion: Under both conditions, prolonged exercise until voluntary exhaustion provokes a lower total variability combined with a reduction in the amplitude and correlation properties of RR fluctuations which may be attributed to increased organismic demands. Additionally, HC provoked higher demands and loss of correlation properties at an earlier stage during the exercise regime, implying an accelerated alteration of cardiac autonomic regulation.}, language = {en} } @article{FahmyGarciaFarrellWitteBoumaetal.2019, author = {Fahmy-Garcia, Shorouk and Farrell, Eric and Witte-Bouma, Janneke and Robbesom-van den Berge, Iris and Suarez, Melva and Mumcuoglu, Didem and Walles, Heike and Kluijtmans, Sebastiaan G. J. M. and van der Eerden, Bram C. J. and van Osch, Gerjo J. V. M. and van Leeuwen, Johannes P. T. M. and van Driel, Marjolein}, title = {Follistatin Effects in Migration, Vascularization, and Osteogenesis in vitro and Bone Repair in vivo}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {7}, journal = {Frontiers in Bioengineering and Biotechnology}, doi = {10.3389/fbioe.2019.00038}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227617}, year = {2019}, abstract = {The use of biomaterials and signaling molecules to induce bone formation is a promising approach in the field of bone tissue engineering. Follistatin (FST) is a glycoprotein able to bind irreversibly to activin A, a protein that has been reported to inhibit bone formation. We investigated the effect of FST in critical processes for bone repair, such as cell recruitment, osteogenesis and vascularization, and ultimately its use for bone tissue engineering. In vitro, FST promoted mesenchymal stem cell (MSC) and endothelial cell (EC) migration as well as essential steps in the formation and expansion of the vasculature such as EC tube-formation and sprouting. FST did not enhance osteogenic differentiation of MSCs, but increased committed osteoblast mineralization. In vivo, FST was loaded in an in situ gelling formulation made by alginate and recombinant collagen-based peptide microspheres and implanted in a rat calvarial defect model. Two FST variants (FST288 and FST315) with major differences in their affinity to cell-surface proteoglycans, which may influence their effect upon in vivo bone repair, were tested. In vitro, most of the loaded FST315 was released over 4 weeks, contrary to FST288, which was mostly retained in the biomaterial. However, none of the FST variants improved in vivo bone healing compared to control. These results demonstrate that FST enhances crucial processes needed for bone repair. Further studies need to investigate the optimal FST carrier for bone regeneration.}, language = {en} } @article{GalKilenczAlbertetal.2019, author = {G{\´a}l, Bernadett I. and Kilencz, T{\"u}nde and Albert, Anita and Demeter, Ildik{\´o} and Hegedűs, Kl{\´a}ra M{\´a}ria and Janka, Zolt{\´a}n and Csifcs{\´a}k, G{\´a}bor and {\´A}lmos, P{\´e}ter Z.}, title = {Mild Effect of Nalmefene on Alcoholic Cue-Induced Response Invigoration in Alcohol Use Disorder Without Accompanying Changes in Electrophysiological Signatures of Early Visual Processing and Executive Control}, series = {Frontiers in Pharmacology}, volume = {10}, journal = {Frontiers in Pharmacology}, doi = {10.3389/fphar.2019.01087}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369182}, year = {2019}, abstract = {Nalmefene is approved for as-needed pharmacological treatment in alcohol use disorder (AUD) by the European Medicines Agency. While the cellular effects of nalmefene have been thoroughly investigated, data are very limited on how this agent influences neural signals associated with inhibitory control and the visual analysis of environmental cues. This double-blind crossover study assessed the behavioral and neural effects of acute nalmefene administration in patients diagnosed with AUD. In experiment 1, we validated our experimental paradigm (electroencephalography combined with a modified Go/NoGo task using images of alcoholic and nonalcoholic drinks as prime stimuli) in 20 healthy adults to ensure that our protocol is suitable for assessing the behavioral and neural aspects of executive control. In experiment 2, we recruited 19 patients with AUD, and in a double-blind crossover design, we investigated the effects of nalmefene versus placebo on task performance (response accuracy, the sensitivity index, and reaction times), visual responses to appetitive cues (occipital P1, N1, and P2 components), and electrophysiological markers of conflict detection and response inhibition (frontal N2 and P3 waveforms). Under placebo, patients produced faster reaction times to alcohol-primed Go stimuli, an effect that was weak despite being statistically significant. However, the effect of alcoholic cues on the speed of response initiation disappeared after receiving nalmefene. We found no placebo versus nalmefene difference regarding our patients' ability to accurately inhibit responses to NoGo stimuli or for occipital and frontal event-related potentials. Our results suggest that nalmefene might be potent in reducing the vigor to act upon alcoholic cues in AUD patients, but this effect is most probably mediated via subcortical (rather than cortical) neural circuits.}, language = {en} } @article{FrankeConzelmannGruenblattetal.2019, author = {Franke, Maximilian and Conzelmann, Annette and Gr{\"u}nblatt, Edna and Werling, Anna M. and Spieles, Helen and Wewetzer, Christoph and Warnke, Andreas and Romanos, Marcel and Walitza, Susanne and Renner, Tobias J.}, title = {No Association of Variants of the NPY-System With Obsessive-Compulsive Disorder in Children and Adolescents}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2019.00112}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229051}, year = {2019}, abstract = {Obsessive-compulsive disorder (OCD) causes severe distress and is therefore counted by the World Health Organisation (WHO) as one of the 10 most impairing illnesses. There is evidence for a strong genetic underpinning especially in early onset OCD (eoOCD). Though several genes involved in neurotransmission have been reported as candidates, there is still a need to identify new pathways. In this study, we focussed on genetic variants of the Neuropeptide Y (NPY) system. NPY is one of the most abundant neuropeptides in the human brain with emerging evidence of capacity to modulate stress response, which is of high relevance in OCD. We focussed on tag-SNPs of NPY and its receptor gene NPY1R in a family-based approach. The sample comprised 86 patients (children and adolescents) with eoOCD with both their biological parents. However, this first study on genetic variants of the NPY-system could not confirm the association between the investigated SNPs and eoOCD. Based on the small sample size results have to be interpreted as preliminary and should be replicated in larger samples. However, also in an additional GWAS analysis in a large sample, we could not observe an associations between NPY and OCD. Overall, these preliminary results point to a minor role of NPY on the stress response of OCD.}, language = {en} } @article{GeranUeckerPruessetal.2019, author = {Geran, Rohat and Uecker, Florian C. and Pr{\"u}ss, Harald and Haeusler, Karl Georg and Paul, Friedemann and Ruprecht, Klemens and Harms, Lutz and Schmidt, Felix A.}, title = {Olfactory and Gustatory Dysfunction in Patients With Autoimmune Encephalitis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2019.00480}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232921}, year = {2019}, abstract = {Objective: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE). Methods: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST). Results: Overall, 24/32 (75\%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3\%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; rs = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score. Conclusions: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results.}, language = {en} } @article{JarickMokhtariSchelleretal.2018, author = {Jarick, Katja J. and Mokhtari, Zeinab and Scheller, Lukas and Hartweg, Julia and Thusek, Sina and Le, Duc-Dung and Ranecky, Maria and Shaikh, Haroon and Qureischi, Musga and Heinze, Katrin G. and Beilhack, Andreas}, title = {Photoconversion of Alloreactive T Cells in Murine Peyer's Patches During Acute Graft-Versus-Host Disease: Tracking the Homing Route of Highly Proliferative Cells In Vivo}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2018.01468}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323309}, year = {2018}, abstract = {The regulation of immune cell migration throughout the body is essential to warrant immunosurveillance and to maintain immune homeostasis. Marking and tracking of these cells has proven important to study mechanisms of immune cell trafficking and cell interaction in vivo. Photoconversion is a well-suited technique for intravital application because it enables contactless time- and location-specific marking of cells in the tissue without surgically manipulating the microenvironment of the cells in question. However, in dividing cells the converted fluorescent protein may decline quickly. Here, we provide a detailed description of the photoconversion technique and its applicability to tracking highly proliferating T cells from the priming site of T cell activation to peripheral target organs of effector function in a preclinical model. Dendra2+ T cells were photoconverted in the Peyer's patches during the initiation phase of acute graft-versus-host disease (GvHD) and tracked through the mesenteric lymph nodes and the peripheral blood to the small intestine with flow cytometry and intravital two-photon microscopy. Photoconverted alloreactive T cells preserved the full proliferative capacity, homing, and migration of alloreactive T cells in the intestinal lamina propria. We conclusively proved that photoconversion of highly proliferative alloreactive T cells in the Peyer's patches is an effective tool to study trafficking of alloreactive T cells under physiologic conditions and to GvHD target tissues. This technique can also be applied to the study of immune cell tracking under inflammatory and non-inflammatory conditions.}, language = {en} } @article{HersterBittnerCodreaetal.2019, author = {Herster, Franziska and Bittner, Zsofia and Codrea, Marius Cosmin and Archer, Nathan K. and Heister, Martin and L{\"o}ffler, Markus W. and Heumos, Simon and Wegner, Joanna and Businger, Ramona and Schindler, Michael and Stegner, David and Sch{\"a}kel, Knut and Grabbe, Stephan and Ghoreschi, Kamran and Miller, Lloyd S. and Weber, Alexander N. R.}, title = {Platelets Aggregate With Neutrophils and Promote Skin Pathology in Psoriasis}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.01867}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320175}, year = {2019}, abstract = {Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes, but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well-defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental in vivo mouse model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease incidence directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in mice in vivo ameliorated disease severity significantly, indicating that both PMNs and platelets may be relevant for psoriasis pathology and disease severity.}, language = {en} } @article{KasaragodSchindelin2018, author = {Kasaragod, Vikram B. and Schindelin, Hermann}, title = {Structure-Function Relationships of Glycine and GABAA Receptors and Their Interplay With the Scaffolding Protein Gephyrin}, series = {Frontiers in Molecular Neuroscience}, volume = {11}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2018.00317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325607}, year = {2018}, abstract = {Glycine and γ-aminobutyric acid (GABA) are the major determinants of inhibition in the central nervous system (CNS). These neurotransmitters target glycine and GABAA receptors, respectively, which both belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGICs). Interactions of the neurotransmitters with the cognate receptors result in receptor opening and a subsequent influx of chloride ions, which, in turn, leads to hyperpolarization of the membrane potential, thus counteracting excitatory stimuli. The majority of glycine receptors and a significant fraction of GABAA receptors (GABAARs) are recruited and anchored to the post-synaptic membrane by the central scaffolding protein gephyrin. This ∼93 kDa moonlighting protein is structurally organized into an N-terminal G-domain (GephG) connected to a C-terminal E-domain (GephE) via a long unstructured linker. Both inhibitory neurotransmitter receptors interact via a short peptide motif located in the large cytoplasmic loop located in between transmembrane helices 3 and 4 (TM3-TM4) of the receptors with a universal receptor-binding epitope residing in GephE. Gephyrin engages in nearly identical interactions with the receptors at the N-terminal end of the peptide motif, and receptor-specific interaction toward the C-terminal region of the peptide. In addition to its receptor-anchoring function, gephyrin also interacts with a rather large collection of macromolecules including different cytoskeletal elements, thus acting as central scaffold at inhibitory post-synaptic specializations. Dysfunctions in receptor-mediated or gephyrin-mediated neurotransmission have been identified in various severe neurodevelopmental disorders. Although biochemical, cellular and electrophysiological studies have helped to understand the physiological and pharmacological roles of the receptors, recent high resolution structures of the receptors have strengthened our understanding of the receptors and their gating mechanisms. Besides that, multiple crystal structures of GephE in complex with receptor-derived peptides have shed light into receptor clustering by gephyrin at inhibitory post-synapses. This review will highlight recent biochemical and structural insights into gephyrin and the GlyRs as well as GABAA receptors, which provide a deeper understanding of the molecular machinery mediating inhibitory neurotransmission.}, language = {en} } @article{KervarrecSamimiGuyetantetal.2019, author = {Kervarrec, Thibault and Samimi, Mahtab and Guy{\´e}tant, Serge and Sarma, Bhavishya and Ch{\´e}ret, J{\´e}r{\´e}my and Blanchard, Emmanuelle and Berthon, Patricia and Schrama, David and Houben, Roland and Touz{\´e}, Antoine}, title = {Histogenesis of Merkel Cell Carcinoma: A Comprehensive Review}, series = {Frontiers in Oncology}, volume = {9}, journal = {Frontiers in Oncology}, doi = {10.3389/fonc.2019.00451}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325733}, year = {2019}, abstract = {Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin. This neoplasia features aggressive behavior, resulting in a 5-year overall survival rate of 40\%. In 2008, Feng et al. identified Merkel cell polyomavirus (MCPyV) integration into the host genome as the main event leading to MCC oncogenesis. However, despite identification of this crucial viral oncogenic trigger, the nature of the cell in which MCC oncogenesis occurs is actually unknown. In fact, several hypotheses have been proposed. Despite the large similarity in phenotype features between MCC tumor cells and physiological Merkel cells (MCs), a specialized subpopulation of the epidermis acting as mechanoreceptor of the skin, several points argue against the hypothesis that MCC derives directly from MCs. Alternatively, MCPyV integration could occur in another cell type and induce acquisition of an MC-like phenotype. Accordingly, an epithelial as well as a fibroblastic or B-cell origin of MCC has been proposed mainly based on phenotype similarities shared by MCC and these potential ancestries. The aim of this present review is to provide a comprehensive review of the current knowledge of the histogenesis of MCC.}, language = {en} } @article{NagyvanGeffenStegneretal.2019, author = {Nagy, Magdolna and van Geffen, Johanna P. and Stegner, David and Adams, David J. and Braun, Attila and de Witt, Susanne M. and Elvers, Margitta and Geer, Mitchell J. and Kuijpers, Marijke J. E. and Kunzelmann, Karl and Mori, Jun and Oury, C{\´e}cile and Pircher, Joachim and Pleines, Irina and Poole, Alastair W. and Senis, Yotis A. and Verdoold, Remco and Weber, Christian and Nieswandt, Bernhard and Heemskerk, Johan W. M. and Baaten, Constance C. F. M. J.}, title = {Comparative Analysis of Microfluidics Thrombus Formation in Multiple Genetically Modified Mice: Link to Thrombosis and Hemostasis}, series = {Frontiers in Cardiovascular Medicine}, volume = {6}, journal = {Frontiers in Cardiovascular Medicine}, doi = {10.3389/fcvm.2019.00099}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232194}, year = {2019}, abstract = {Genetically modified mice are indispensable for establishing the roles of platelets in arterial thrombosis and hemostasis. Microfluidics assays using anticoagulated whole blood are commonly used as integrative proxy tests for platelet function in mice. In the present study, we quantified the changes in collagen-dependent thrombus formation for 38 different strains of (genetically) modified mice, all measured with the same microfluidics chamber. The mice included were deficient in platelet receptors, protein kinases or phosphatases, small GTPases or other signaling or scaffold proteins. By standardized re-analysis of high-resolution microscopic images, detailed information was obtained on altered platelet adhesion, aggregation and/or activation. For a subset of 11 mouse strains, these platelet functions were further evaluated in rhodocytin- and laminin-dependent thrombus formation, thus allowing a comparison of glycoprotein VI (GPVI), C-type lectin-like receptor 2 (CLEC2) and integrin α6β1 pathways. High homogeneity was found between wild-type mice datasets concerning adhesion and aggregation parameters. Quantitative comparison for the 38 modified mouse strains resulted in a matrix visualizing the impact of the respective (genetic) deficiency on thrombus formation with detailed insight into the type and extent of altered thrombus signatures. Network analysis revealed strong clusters of genes involved in GPVI signaling and Ca2+ homeostasis. The majority of mice demonstrating an antithrombotic phenotype in vivo displayed with a larger or smaller reduction in multi-parameter analysis of collagen-dependent thrombus formation in vitro. Remarkably, in only approximately half of the mouse strains that displayed reduced arterial thrombosis in vivo, this was accompanied by impaired hemostasis. This was also reflected by comparing in vitro thrombus formation (by microfluidics) with alterations in in vivo bleeding time. In conclusion, the presently developed multi-parameter analysis of thrombus formation using microfluidics can be used to: (i) determine the severity of platelet abnormalities; (ii) distinguish between altered platelet adhesion, aggregation and activation; and (iii) elucidate both collagen and non-collagen dependent alterations of thrombus formation. This approach may thereby aid in the better understanding and better assessment of genetic variation that affect in vivo arterial thrombosis and hemostasis.}, language = {en} }