TY - JOUR A1 - Vaahtoranta, Enni A1 - Lenhart, Jan A1 - Suggate, Sebastian A1 - Lenhard, Wolfgang T1 - Interactive Elaborative Storytelling: Engaging Children as Storytellers to Foster Vocabulary JF - Frontiers in Psychology N2 - Positive effects of shared reading for children’s language development are boosted by including instruction of word meanings and by increasing interactivity. The effects of engaging children as storytellers on vocabulary development have been less well studied. We developed an approach termed Interactive Elaborative Storytelling (IES), which employs both word-learning techniques and children’s storytelling in a shared-reading setting. To systematically investigate potential benefits of children as storytellers, we contrasted this approach to two experimental groups, an Elaborative Storytelling group employing word-learning techniques but no storytelling by children and a Read-Aloud group, excluding any additional techniques. The study was a 3 × 2 pre-posttest randomized design with 126 preschoolers spanning 1 week. Measured outcomes were receptive and expressive target vocabulary, story memory, and children’s behavior during story sessions. All three experimental groups made comparable gains on target words from pre- to posttest and there was no difference between groups in story memory. However, in the Elaborative Storytelling group, children were the least restless. Findings are discussed in terms of their contribution to optimizing shared reading as a method of fostering language. KW - storytelling KW - shared reading KW - language intervention KW - preschool KW - language development Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232136 VL - 10 ER - TY - JOUR A1 - Treff, Gunnar A1 - Winkert, Kay A1 - Sareban, Mahdi A1 - Steinacker, Jürgen M. A1 - Sperlich, Billy T1 - The Polarization-Index: A Simple Calculation to Distinguish Polarized From Non-polarized Training Intensity Distributions JF - Frontiers in Physiology N2 - The training intensity distribution (TID) of endurance athletes has retrieved substantial scientific interest since it reflects a vital component of training prescription: (i) the intensity of exercise and its distribution over time are essential components for adaptation to endurance training and (ii) the training volume (at least for most endurance disciplines) is already near or at maximum, so optimization of training procedures including TID have become paramount for success. This paper aims to elaborate the polarization-index (PI) which is calculated as log10(Zone 1/Zone 2∗Zone 3∗100), where Zones 1–3 refer to aggregated volume (time or distance) spent with low, mid, or high intensity training. PI allows to distinguish between non-polarized and polarized TID using a cut-off > 2.00 a.U. and to quantify the level of a polarized TID. Within this hypothesis paper, examples from the literature illustrating the usefulness of PI-calculation are discussed as well as its limitations. Further it is elucidated how the PI may contribute to a more precise definition of TID descriptors. KW - high-intensity training KW - high-performance sports KW - lactate threshold training KW - endurance training KW - elite Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229040 VL - 10 ER - TY - JOUR A1 - Siebert, Claudia A1 - Ciato, Denis A1 - Murakami, Masanori A1 - Frei-Stuber, Ludwig A1 - Perez-Rivas, Luis Gustavo A1 - Monteserin-Garcia, José Luis A1 - Nölting, Svenja A1 - Maurer, Julian A1 - Feuchtinger, Annette A1 - Walch, Axel K. A1 - Haak, Harm R. A1 - Bertherat, Jérôme A1 - Mannelli, Massimo A1 - Fassnacht, Martin A1 - Korpershoek, Esther A1 - Reincke, Martin A1 - Stalla, Günter K. A1 - Hantel, Constanze A1 - Beuschlein, Felix T1 - Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma JF - Frontiers in Endocrinology N2 - Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC. Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines. Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment. Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC. KW - adrenal gland KW - cortisol KW - N-terminal HSP90 inhibitors KW - C-terminal HSP90 inhibitors KW - prognostic marker Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238029 VL - 10 ER - TY - JOUR A1 - Schurig, Johannes A1 - Haeusler, Karl Georg A1 - Grittner, Ulrike A1 - Nolte, Christian H. A1 - Fiebach, Jochen B. A1 - Audebert, Heinrich J. A1 - Endres, Matthias A1 - Rocco, Andrea T1 - Frequency of Hemorrhage on Follow Up Imaging in Stroke Patients Treated With rt-PA Depending on Clinical Course JF - Frontiers in Neurology N2 - Background: According to current guidelines, stroke patients treated with rt-PA should undergo brain imaging to exclude intracerebral bleeding 24 h after thrombolysis, before the start of medical secondary prevention. However, the usefulness of routine follow-up imaging with regard to changes in therapeutic management in patients without neurological deterioration is unclear. We hypothesized that follow up brain imaging solely to exclude bleeding in patients who clinically improved after rt-PA application may not be necessary. Methods: Retrospective single-center analysis including stroke patients treated with rt-PA. Records were reviewed for hemorrhagic transformation one day after systemic thrombolysis and brain imaging-based changes in therapeutic management. Twenty-four hour after thrombolysis patients were divided into four groups: (1) increased NIHSS score; (2) unchanged NIHSS score; (3) improved NIHSS score and; (4) NIHSS score = 0. Results: Out of 188 patients (mean age 73 years, 100 female) receiving rt-PA, 32 (17%) had imaging-proven hemorrhagic transformation including 11 (6%) patients with parenchymal hemorrhage. Patients in group (1, 2) more often had hypertension (p = 0.015) and more often had parenchymal hemorrhage (9 vs. 4%; p < 0.206) compared to group (3, 4) and imaging-based changes in therapeutic management were more frequent (19% vs. 6%; p = 0.007). Patients of group (3, 4) had no changes in therapeutic management in 94% of the cases. Patients in group (4) had no hemorrhagic transformation in routine follow-up brain imaging. Conclusions: Frequency of hemorrhagic transformation in Routine follow-up brain imaging and consecutive changes in therapeutic management were different depending on clinical course measured by NHISS score. KW - thrombolysis KW - stroke KW - stroke management KW - magnetic resonance imaging KW - computerized tomography KW - intracerebral hemorrhage Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234947 VL - 10 ER - TY - JOUR A1 - Schneider, Christoph A1 - Wiewelhove, Thimo A1 - Raeder, Christian A1 - Flatt, Andrew A. A1 - Hoos, Olaf A1 - Hottenrott, Laura A1 - Schumbera, Oliver A1 - Kellmann, Michael A1 - Meyer, Tim A1 - Pfeiffer, Mark A1 - Ferrauti, Alexander T1 - Heart Rate Variability Monitoring During Strength and High-Intensity Interval Training Overload Microcycles JF - Frontiers in Physiology N2 - Objective: In two independent study arms, we determine the effects of strength training (ST) and high-intensity interval training (HIIT) overload on cardiac autonomic modulation by measuring heart rate (HR) and vagal heart rate variability (HRV). Methods: In the study, 37 well-trained athletes (ST: 7 female, 12 male; HIIT: 9 female, 9 male) were subjected to orthostatic tests (HR and HRV recordings) each day during a 4-day baseline period, a 6-day overload microcycle, and a 4-day recovery period. Discipline-specific performance was assessed before and 1 and 4 days after training. Results: Following ST overload, supine HR, and vagal HRV (Ln RMSSD) were clearly increased and decreased (small effects), respectively, and the standing recordings remained unchanged. In contrast, HIIT overload resulted in decreased HR and increased Ln RMSSD in the standing position (small effects), whereas supine recordings remained unaltered. During the recovery period, these responses were reversed (ST: small effects, HIIT: trivial to small effects). The correlations between changes in HR, vagal HRV measures, and performance were weak or inconsistent. At the group and individual levels, moderate to strong negative correlations were found between HR and Ln RMSSD when analyzing changes between testing days (ST: supine and standing position, HIIT: standing position) and individual time series, respectively. Use of rolling 2–4-day averages enabled more precise estimation of mean changes with smaller confidence intervals compared to single-day values of HR or Ln RMSSD. However, the use of averaged values displayed unclear effects for evaluating associations between HR, vagal HRV measures, and performance changes, and have the potential to be detrimental for classification of individual short-term responses. Conclusion: Measures of HR and Ln RMSSD during an orthostatic test could reveal different autonomic responses following ST or HIIT which may not be discovered by supine or standing measures alone. However, these autonomic changes were not consistently related to short-term changes in performance and the use of rolling averages may alter these relationships differently on group and individual level. KW - orthostatic test KW - cardiac autonomic nervous system KW - fatigue KW - recovery KW - individual response KW - multivariate analysis KW - resistance training KW - overreaching Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231515 VL - 10 ER - TY - JOUR A1 - Nagy, Magdolna A1 - van Geffen, Johanna P. A1 - Stegner, David A1 - Adams, David J. A1 - Braun, Attila A1 - de Witt, Susanne M. A1 - Elvers, Margitta A1 - Geer, Mitchell J. A1 - Kuijpers, Marijke J. E. A1 - Kunzelmann, Karl A1 - Mori, Jun A1 - Oury, Cécile A1 - Pircher, Joachim A1 - Pleines, Irina A1 - Poole, Alastair W. A1 - Senis, Yotis A. A1 - Verdoold, Remco A1 - Weber, Christian A1 - Nieswandt, Bernhard A1 - Heemskerk, Johan W. M. A1 - Baaten, Constance C. F. M. J. T1 - Comparative Analysis of Microfluidics Thrombus Formation in Multiple Genetically Modified Mice: Link to Thrombosis and Hemostasis JF - Frontiers in Cardiovascular Medicine N2 - 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. KW - arterial thrombus formation KW - bleeding KW - collagen KW - glycoprotein VI KW - platelets KW - microfluidics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232194 VL - 6 ER - TY - JOUR A1 - Nguyen, Minh-Thu A1 - Saising, Jongkon A1 - Tribelli, Paula Maria A1 - Nega, Mulugeta A1 - Diene, Seydina M. A1 - François, Patrice A1 - Schrenzel, Jacques A1 - Spröer, Cathrin A1 - Bunk, Boyke A1 - Ebner, Patrick A1 - Hertlein, Tobias A1 - Kumari, Nimerta A1 - Härtner, Thomas A1 - Wistuba, Dorothee A1 - Voravuthikunchai, Supayang P. A1 - Mäder, Ulrike A1 - Ohlsen, Knut A1 - Götz, Friedrich T1 - Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus JF - Frontiers in Microbiology N2 - Rhodomyrtone (Rom) is an acylphloroglucinol antibiotic originally isolated from leaves of Rhodomyrtus tomentosa. Rom targets the bacterial membrane and is active against a wide range of Gram-positive bacteria but the exact mode of action remains obscure. Here we isolated and characterized a spontaneous Rom-resistant mutant from the model strain Staphylococcus aureus HG001 (RomR) to learn more about the resistance mechanism. We showed that Rom-resistance is based on a single point mutation in the coding region of farR [regulator of fatty acid (FA) resistance] that causes an amino acid change from Cys to Arg at position 116 in FarR, that affects FarR activity. Comparative transcriptome analysis revealed that mutated farR affects transcription of many genes in distinct pathways. FarR represses for example the expression of its own gene (farR), its flanking gene farE (effector of FA resistance), and other global regulators such as agr and sarA. All these genes were consequently upregulated in the RomR clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the RomR clone more cytotoxic and more pathogenic in a mouse infection model. The Rom-resistance is largely due to the de-repression of farE. FarE is described as an efflux pump for linoleic and arachidonic acids. We observed an increased release of lipids in the RomR clone compared to its parental strain HG001. If farE is deleted in the RomR clone, or, if native farR is expressed in the RomR strain, the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the RomR clone, that FarR is an important regulator, and that the point mutation in farR (RomR clone) makes the clone hyper-virulent. KW - antibiotic KW - Gram-positive bacteria KW - rhodomyrtone KW - Staphylococcus KW - membrane active Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224117 VL - 10 ER - TY - JOUR A1 - Klotz, Peter A1 - Higgins, Paul G. A1 - Schaubmar, Andreas R. A1 - Failing, Klaus A1 - Leidner, Ursula A1 - Seifert, Harald A1 - Scheufen, Sandra A1 - Semmler, Torsten A1 - Ewers, Christa T1 - Seasonal Occurrence and Carbapenem Susceptibility of Bovine Acinetobacter baumannii in Germany JF - Frontiers in Microbiology N2 - Acinetobacter baumannii is one of the leading causes of nosocomial infections in humans. To investigate its prevalence, distribution of sequence types (STs), and antimicrobial resistance in cattle, we sampled 422 cattle, including 280 dairy cows, 59 beef cattle, and 83 calves over a 14-month period. Metadata, such as the previous use of antimicrobial agents and feeding, were collected to identify putative determining factors. Bacterial isolates were identified via MALDI-TOF/MS and PCR, antimicrobial susceptibility was evaluated via VITEK2 and antibiotic gradient tests, resistance genes were identified by PCR. Overall, 15.6% of the cattle harbored A. baumannii, predominantly in the nose (60.3% of the A. baumannii isolates). It was more frequent in dairy cows (21.1%) than in beef cattle (6.8%) and calves (2.4%). A seasonal occurrence was shown with a peak between May and August. The rate of occurrence of A. baumannii was correlated with a history of use of 3rd generation cephalosporins in the last 6 months prior to sampling Multilocus sequence typing (Pasteur scheme) revealed 83 STs among 126 unique isolates. Nine of the bovine STs have previously been implicated in human infections. Besides known intrinsic resistance of the species, the isolates did not show additional resistance to the antimicrobial substances tested, including carbapenems. Our data suggest that cattle are not a reservoir for nosocomial A. baumannii but carry a highly diverse population of this species. Nevertheless, some STs seem to be able to colonize both cattle and humans. KW - ESKAPE KW - Acinetobacter baumannii KW - antimicrobial susceptibility KW - MLST KW - cattle KW - epidemiology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325927 VL - 10 ER - TY - JOUR A1 - Kervarrec, Thibault A1 - Samimi, Mahtab A1 - Guyétant, Serge A1 - Sarma, Bhavishya A1 - Chéret, Jérémy A1 - Blanchard, Emmanuelle A1 - Berthon, Patricia A1 - Schrama, David A1 - Houben, Roland A1 - Touzé, Antoine T1 - Histogenesis of Merkel Cell Carcinoma: A Comprehensive Review JF - Frontiers in Oncology N2 - 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. KW - merkel cell polyomavirus (MCPyV) KW - epithelial KW - fibroblast KW - B cell KW - Merkel cell carcinoma (MCC) KW - histogenesis KW - origin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325733 VL - 9 ER - TY - JOUR A1 - John, Cathy N. A1 - Abrantes, Pedro M. D. S. A1 - Prusty, Bhupesh K. A1 - Ablashi, Dharam V. A1 - Africa, Charlene W. J. T1 - K21 Compound, a Potent Antifungal Agent: Implications for the Treatment of Fluconazole-Resistant HIV-Associated Candida Species JF - Frontiers in Microbiology N2 - Background/Objectives: With mucocutaneous candidiasis being highly prevalent in HIV patients, the emergence of fluconazole-resistant Candida species forms a major challenge in treating and eradicating these infections. The objective of this study was to establish the antifungal activity of K21, a membrane-rupturing antimicrobial compound derived from a silica quaternary ammonium compound (SiQAC) with tetraethoxysilane (TEOS). Methods: The study sample included 81 Candida species of which 9 were type strains and 72 were clinical isolates. Minimum inhibitory concentrations, synergy, fractional inhibitory concentration index (FICI), and time kill assays were determined by broth microdilution. Electron microscopy (EM) was used to determine the qualitative changes brought about after treatment with K21. Results: K21 inhibited the growth of all fluconazole-resistant and susceptible Candida strains with only 2 h of exposure required to effectively kill 99.9% of the inoculum, and a definite synergistic effect was observed with a combination of K21 and fluconazole. EM demonstrated the presence of two forms of extracellular vesicles indicative of biofilm formation and cell lysis. Conclusion: The study established the efficacy of K21 as an antifungal agent and with fluconazole-resistant candidiasis on the increase, the development of K21 can provide a promising alternative to combat acquired drug resistance. KW - HIV-associated candidiasis KW - antimicrobial compounds KW - Candida KW - fluconazole KW - antifungal susceptibility KW - broth microdilution Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323505 VL - 10 ER - TY - JOUR A1 - Herster, Franziska A1 - Bittner, Zsofia A1 - Codrea, Marius Cosmin A1 - Archer, Nathan K. A1 - Heister, Martin A1 - Löffler, Markus W. A1 - Heumos, Simon A1 - Wegner, Joanna A1 - Businger, Ramona A1 - Schindler, Michael A1 - Stegner, David A1 - Schäkel, Knut A1 - Grabbe, Stephan A1 - Ghoreschi, Kamran A1 - Miller, Lloyd S. A1 - Weber, Alexander N. R. T1 - Platelets Aggregate With Neutrophils and Promote Skin Pathology in Psoriasis JF - Frontiers in Immunology N2 - 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. KW - psoriasis KW - neutrophil KW - platelet KW - platelet-neutrophil complexes (PNCs) KW - imiquimod Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320175 VL - 10 ER - TY - JOUR A1 - Gronwald, Thomas A1 - Hoos, Olaf A1 - Hottenrott, Kuno T1 - Effects of Acute Normobaric Hypoxia on Non-linear Dynamics of Cardiac Autonomic Activity During Constant Workload Cycling Exercise JF - Frontiers in Physiology N2 - 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. KW - autonomic nervous system KW - heart rate variability KW - detrended fluctuation analysis KW - endurance exercise KW - voluntary exhaustion KW - hypoxia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369199 VL - 10 ER - TY - JOUR A1 - Geran, Rohat A1 - Uecker, Florian C. A1 - Prüss, Harald A1 - Haeusler, Karl Georg A1 - Paul, Friedemann A1 - Ruprecht, Klemens A1 - Harms, Lutz A1 - Schmidt, Felix A. T1 - Olfactory and Gustatory Dysfunction in Patients With Autoimmune Encephalitis JF - Frontiers in Neurology N2 - 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. KW - autoimmune encephalitis KW - olfactory dysfunction KW - gustatory dysfunction KW - olfactory testing KW - threshold discrimination identification test Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232921 VL - 10 ER - TY - JOUR A1 - Gál, Bernadett I. A1 - Kilencz, Tünde A1 - Albert, Anita A1 - Demeter, Ildikó A1 - Hegedűs, Klára Mária A1 - Janka, Zoltán A1 - Csifcsák, Gábor A1 - Álmos, Péter Z. T1 - 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 JF - Frontiers in Pharmacology N2 - 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. KW - nalmefene KW - alcohol use disorder KW - response inhibition KW - incentive salience KW - event-related potentials KW - Go/NoGo task Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369182 VL - 10 ER - TY - JOUR A1 - Franke, Maximilian A1 - Conzelmann, Annette A1 - Grünblatt, Edna A1 - Werling, Anna M. A1 - Spieles, Helen A1 - Wewetzer, Christoph A1 - Warnke, Andreas A1 - Romanos, Marcel A1 - Walitza, Susanne A1 - Renner, Tobias J. T1 - No Association of Variants of the NPY-System With Obsessive-Compulsive Disorder in Children and Adolescents JF - Frontiers in Molecular Neuroscience N2 - 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. KW - NPY KW - obsessive-compulsive KW - children KW - anxiety KW - neuropeptide Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229051 VL - 12 ER - TY - JOUR A1 - Fahmy-Garcia, Shorouk A1 - Farrell, Eric A1 - Witte-Bouma, Janneke A1 - Robbesom-van den Berge, Iris A1 - Suarez, Melva A1 - Mumcuoglu, Didem A1 - Walles, Heike A1 - Kluijtmans, Sebastiaan G. J. M. A1 - van der Eerden, Bram C. J. A1 - van Osch, Gerjo J. V. M. A1 - van Leeuwen, Johannes P. T. M. A1 - van Driel, Marjolein T1 - Follistatin Effects in Migration, Vascularization, and Osteogenesis in vitro and Bone Repair in vivo JF - Frontiers in Bioengineering and Biotechnology N2 - 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. KW - follistatin 315 (FST315) KW - follistatin 288 (FST288) KW - migration KW - vascularization KW - osteogenesis KW - injectable in situ gelling slow release system KW - bone tissue engineering KW - regenerative medicine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227617 VL - 7 ER - TY - JOUR A1 - Milanese, Alessio A1 - Mende, Daniel R A1 - Paoli, Lucas A1 - Salazar, Guillem A1 - Ruscheweyh, Hans-Joachim A1 - Cuenca, Miguelangel A1 - Hingamp, Pascal A1 - Alves, Renato A1 - Costea, Paul I A1 - Coelho, Luis Pedro A1 - Schmidt, Thomas S. B. A1 - Almeida, Alexandre A1 - Mitchell, Alex L A1 - Finn, Robert D. A1 - Huerta-Cepas, Jaime A1 - Bork, Peer A1 - Zeller, Georg A1 - Sunagawa, Shinichi T1 - Microbial abundance, activity and population genomic profiling with mOTUs2 JF - Nature Communications N2 - Metagenomic sequencing has greatly improved our ability to profile the composition of environmental and host-associated microbial communities. However, the dependency of most methods on reference genomes, which are currently unavailable for a substantial fraction of microbial species, introduces estimation biases. We present an updated and functionally extended tool based on universal (i.e., reference-independent), phylogenetic marker gene (MG)-based operational taxonomic units (mOTUs) enabling the profiling of >7700 microbial species. As more than 30% of them could not previously be quantified at this taxonomic resolution, relative abundance estimates based on mOTUs are more accurate compared to other methods. As a new feature, we show that mOTUs, which are based on essential housekeeping genes, are demonstrably well-suited for quantification of basal transcriptional activity of community members. Furthermore, single nucleotide variation profiles estimated using mOTUs reflect those from whole genomes, which allows for comparing microbial strain populations (e.g., across different human body sites). KW - microbiome KW - software Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224089 VL - 10 ER - TY - JOUR A1 - Krah, Franz-Sebastian A1 - Büntgen, Ulf A1 - Schaefer, Hanno A1 - Müller, Jörg A1 - Andrew, Carrie A1 - Boddy, Lynne A1 - Diez, Jeffrey A1 - Egli, Simon A1 - Freckleton, Robert A1 - Gange, Alan C. A1 - Halvorsen, Rune A1 - Heegaard, Einar A1 - Heideroth, Antje A1 - Heibl, Christoph A1 - Heilmann-Clausen, Jacob A1 - Høiland, Klaus A1 - Kar, Ritwika A1 - Kauserud, Håvard A1 - Kirk, Paul M. A1 - Kuyper, Thomas W. A1 - Krisai-Greilhuber, Irmgard A1 - Norden, Jenni A1 - Papastefanou, Phillip A1 - Senn-Irlet, Beatrice A1 - Bässler, Claus T1 - European mushroom assemblages are darker in cold climates JF - Nature Communications N2 - Thermal melanism theory states that dark-colored ectotherm organisms are at an advantage at low temperature due to increased warming. This theory is generally supported for ectotherm animals, however, the function of colors in the fungal kingdom is largely unknown. Here, we test whether the color lightness of mushroom assemblages is related to climate using a dataset of 3.2 million observations of 3,054 species across Europe. Consistent with the thermal melanism theory, mushroom assemblages are significantly darker in areas with cold climates. We further show differences in color phenotype between fungal lifestyles and a lifestyle differentiated response to seasonality. These results indicate a more complex ecological role of mushroom colors and suggest functions beyond thermal adaption. Because fungi play a crucial role in terrestrial carbon and nutrient cycles, understanding the links between the thermal environment, functional coloration and species’ geographical distributions will be critical in predicting ecosystem responses to global warming. KW - evolutionary ecology KW - fungal ecology KW - fungal evolution KW - macroecology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224815 VL - 10 ER - TY - JOUR A1 - Woodcock, B. A. A1 - Garratt, M. P. D. A1 - Powney, G. D. A1 - Shaw, R. F. A1 - Osborne, J. L. A1 - Soroka, J. A1 - Lindström, S. A. M. A1 - Stanley, D. A1 - Ouvrard, P. A1 - Edwards, M. E. A1 - Jauker, F. A1 - McCracken, M. E. A1 - Zou, Y. A1 - Potts, S. G. A1 - Rundlöf, M. A1 - Noriega, J. A. A1 - Greenop, A. A1 - Smith, H. G. A1 - Bommarco, R. A1 - van der Werf, W. A1 - Stout, J. C. A1 - Steffan-Dewenter, I. A1 - Morandin, L. A1 - Bullock, J. M. A1 - Pywell, R. F. T1 - Meta-analysis reveals that pollinator functional diversity and abundance enhance crop pollination and yield JF - Nature Communications N2 - How insects promote crop pollination remains poorly understood in terms of the contribution of functional trait differences between species. We used meta-analyses to test for correlations between community abundance, species richness and functional trait metrics with oilseed rape yield, a globally important crop. While overall abundance is consistently important in predicting yield, functional divergence between species traits also showed a positive correlation. This result supports the complementarity hypothesis that pollination function is maintained by non-overlapping trait distributions. In artificially constructed communities (mesocosms), species richness is positively correlated with yield, although this effect is not seen under field conditions. As traits of the dominant species do not predict yield above that attributed to the effect of abundance alone, we find no evidence in support of the mass ratio hypothesis. Management practices increasing not just pollinator abundance, but also functional divergence, could benefit oilseed rape agriculture. KW - agroecology KW - agriculture KW - ecosystem services KW - environmental sciences Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233787 VL - 10 ER - TY - JOUR A1 - Walker, Brian A. A1 - Mavrommatis, Konstantinos A1 - Wardell, Christopher P. A1 - Ashby, T. Cody A1 - Bauer, Michael A1 - Davies, Faith A1 - Rosenthal, Adam A1 - Wang, Hongwei A1 - Qu, Pingping A1 - Hoering, Antje A1 - Samur, Mehmet A1 - Towfic, Fadi A1 - Ortiz, Maria A1 - Flynt, Erin A1 - Yu, Zhinuan A1 - Yang, Zhihong A1 - Rozelle, Dan A1 - Obenauer, John A1 - Trotter, Matthew A1 - Auclair, Daniel A1 - Keats, Jonathan A1 - Bolli, Niccolo A1 - Fulciniti, Mariateresa A1 - Szalat, Raphael A1 - Moreau, Phillipe A1 - Durie, Brian A1 - Stewart, A. Keith A1 - Goldschmidt, Hartmut A1 - Raab, Marc S. A1 - Einsele, Hermann A1 - Sonneveld, Pieter A1 - San Miguel, Jesus A1 - Lonial, Sagar A1 - Jackson, Graham H. A1 - Anderson, Kenneth C. A1 - Avet-Loiseau, Herve A1 - Munshi, Nikhil A1 - Thakurta, Anjan A1 - Morgan, Gareth T1 - A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis JF - Leukemia N2 - Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches. KW - cancer genomics KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233299 VL - 33 ER -