@article{ElhfnawyVolkmannSchliesseretal.2019, author = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix}, title = {Symptomatic vs. asymptomatic 20-40\% internal carotid artery stenosis: Does the plaque size matter?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {960}, doi = {10.3389/fneur.2019.00960}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201262}, year = {2019}, abstract = {Background: Around 9-15\% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50\%. However, the extent to which ICA-stenosis <50\% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20-40\%. Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of W{\"u}rzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20-40\%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans. Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20-40\%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21-0.69) cm2 and 0.27 (0.21-0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71\% and a specificity of 76\% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95\% CI) of 5.54 (1.2-25.6), p = 0.028 and 1.78 (0.36-8.73), p = 0.48, respectively, for symptomatic ICA-stenosis. Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20-40\%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment.}, language = {en} } @article{ElhfnawyVolkmannSchliesseretal.2019, author = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix}, title = {Are cerebral white matter lesions related to the presence of bilateral internal carotid artery stenosis or to the length of stenosis among patients with ischemic cerebrovascular events?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {919}, doi = {10.3389/fneur.2019.00919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201241}, year = {2019}, abstract = {Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL). Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values. Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95\% CI 1.12-11.18, p = 0.03), female sex (OR 3.11, 95\% CI 1.19-8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95\% CI 1.16-6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95\% CI 0.93-5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs. Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML.}, language = {en} } @article{KleefeldtBoemmelBroedeetal.2019, author = {Kleefeldt, Florian and B{\"o}mmel, Heike and Broede, Britta and Thomsen, Michael and Pfeiffer, Verena and W{\"o}rsd{\"o}rfer, Philipp and Karnati, Srikanth and Wagner, Nicole and Rueckschloss, Uwe and Erg{\"u}n, S{\"u}leyman}, title = {Aging-related carcinoembryonic antigen-related cell adhesion molecule 1 signaling promotes vascular dysfunction}, series = {Aging Cell}, volume = {2019}, journal = {Aging Cell}, number = {18}, doi = {10.1111/acel.13025}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201231}, pages = {e13025}, year = {2019}, abstract = {Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF-α is CEACAM1-dependently upregulated in the aging vasculature. Vice versa, TNF-α induces CEACAM1 expression. This results in a feed-forward loop in the aging vasculature that maintains a chronic pro-inflammatory milieu. Furthermore, we demonstrate that age-associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age-dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR-2 signaling. Consequently, aging-related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.}, language = {en} } @article{ReichertsPauliMoesleretal.2019, author = {Reicherts, Philipp and Pauli, Paul and M{\"o}sler, Camilla and Wieser, Matthias J.}, title = {Placebo manipulations reverse pain potentiation by unpleasant affective stimuli}, series = {Frontiers in Psychiatry}, volume = {10}, journal = {Frontiers in Psychiatry}, number = {663}, doi = {10.3389/fpsyt.2019.00663}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201200}, year = {2019}, abstract = {According to the motivational priming hypothesis, unpleasant stimuli activate the motivational defense system, which in turn promotes congruent affective states such as negative emotions and pain. The question arises to what degree this bottom-up impact of emotions on pain is susceptible to a manipulation of top-down-driven expectations. To this end, we investigated whether verbal instructions implying pain potentiation vs. reduction (placebo or nocebo expectations)—later on confirmed by corresponding experiences (placebo or nocebo conditioning)—might alter behavioral and neurophysiological correlates of pain modulation by unpleasant pictures. We compared two groups, which underwent three experimental phases: first, participants were either instructed that watching unpleasant affective pictures would increase pain (nocebo group) or that watching unpleasant pictures would decrease pain (placebo group) relative to neutral pictures. During the following placebo/nocebo-conditioning phase, pictures were presented together with electrical pain stimuli of different intensities, reinforcing the instructions. In the subsequent test phase, all pictures were presented again combined with identical pain stimuli. Electroencephalogram was recorded in order to analyze neurophysiological responses of pain (somatosensory evoked potential) and picture processing [visually evoked late positive potential (LPP)], in addition to pain ratings. In the test phase, ratings of pain stimuli administered while watching unpleasant relative to neutral pictures were significantly higher in the nocebo group, thus confirming the motivational priming effect for pain perception. In the placebo group, this effect was reversed such that unpleasant compared with neutral pictures led to significantly lower pain ratings. Similarly, somatosensory evoked potentials were decreased during unpleasant compared with neutral pictures, in the placebo group only. LPPs of the placebo group failed to discriminate between unpleasant and neutral pictures, while the LPPs of the nocebo group showed a clear differentiation. We conclude that the placebo manipulation already affected the processing of the emotional stimuli and, in consequence, the processing of the pain stimuli. In summary, the study revealed that the modulation of pain by emotions, albeit a reliable and well-established finding, is further tuned by reinforced expectations—known to induce placebo/nocebo effects—which should be addressed in future research and considered in clinical applications.}, language = {en} } @article{SuessWehnerDostaletal.2019, author = {S{\"u}ß, Jasmin and Wehner, Johannes G. and Dost{\´a}l, Jakub and Engel, Volker and Brixner, Tobias}, title = {Mapping of exciton-exciton annihilation in a molecular dimer via fifth-order femtosecond two-dimensional spectroscopy}, series = {Journal of Physical Chemistry Letters}, volume = {150}, journal = {Journal of Physical Chemistry Letters}, number = {10}, doi = {10.1063/1.5086151}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178420}, pages = {104304}, year = {2019}, abstract = {We present a theoretical study on exciton-exciton annihilation (EEA) in a molecular dimer. This process is monitored using a fifth-order coherent two-dimensional (2D) spectroscopy as was recently proposed by Dost{\´a}l et al. [Nat. Commun. 9, 2466 (2018)]. Using an electronic three-level system for each monomer, we analyze the different paths which contribute to the 2D spectrum. The spectrum is determined by two entangled relaxation processes, namely, the EEA and the direct relaxation of higher lying excited states. It is shown that the change of the spectrum as a function of a pulse delay can be linked directly to the presence of the EEA process.}, subject = {Exziton}, language = {en} } @article{LekszasNandaVonaetal.2019, author = {Lekszas, Caroline and Nanda, Indrajit and Vona, Barbara and B{\"o}ck, Julia and Ashrafzadeh, Farah and Donyadideh, Nahid and Ebrahimzadeh, Farnoosh and Ahangari, Najmeh and Maroofian, Reza and Karimiani, Ehsan Ghayoor and Haaf, Thomas}, title = {Unbalanced segregation of a paternal t(9;11)(p24.3;p15.4) translocation causing familial Beckwith-Wiedemann syndrome: a case report}, series = {BMC Medical Genomics}, volume = {12}, journal = {BMC Medical Genomics}, doi = {10.1186/s12920-019-0539-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200422}, pages = {83}, year = {2019}, abstract = {Background The vast majority of cases with Beckwith-Wiedemann syndrome (BWS) are caused by a molecular defect in the imprinted chromosome region 11p15.5. The underlying mechanisms include epimutations, uniparental disomy, copy number variations, and structural rearrangements. In addition, maternal loss-of-function mutations in CDKN1C are found. Despite growing knowledge on BWS pathogenesis, up to 20\% of patients with BWS phenotype remain without molecular diagnosis. Case presentation Herein, we report an Iranian family with two females affected with BWS in different generations. Bisulfite pyrosequencing revealed hypermethylation of the H19/IGF2: intergenic differentially methylated region (IG DMR), also known as imprinting center 1 (IC1) and hypomethylation of the KCNQ1OT1: transcriptional start site (TSS) DMR (IC2). Array CGH demonstrated an 8 Mb duplication on chromosome 11p15.5p15.4 (205,827-8,150,933) and a 1 Mb deletion on chromosome 9p24.3 (209,020-1,288,114). Chromosome painting revealed that this duplication-deficiency in both patients is due to unbalanced segregation of a paternal reciprocal t(9;11)(p24.3;p15.4) translocation. Conclusions This is the first report of a paternally inherited unbalanced translocation between the chromosome 9 and 11 short arms underlying familial BWS. Copy number variations involving the 11p15.5 region are detected by the consensus diagnostic algorithm. However, in complex cases which do not only affect the BWS region itself, characterization of submicroscopic chromosome rearrangements can assist to estimate the recurrence risk and possible phenotypic outcomes.}, language = {en} } @article{SchneiderHuestegge2019, author = {Schneider, Norbert and Huestegge, Lynn}, title = {Interaction of oculomotor and manual behavior: evidence from simulated driving in an approach-avoidance steering task}, series = {Cognitive Research: Principles and Implications}, volume = {4}, journal = {Cognitive Research: Principles and Implications}, doi = {10.1186/s41235-019-0170-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200419}, pages = {19}, year = {2019}, abstract = {Background While the coordination of oculomotor and manual behavior is essential for driving a car, surprisingly little is known about this interaction, especially in situations requiring a quick steering reaction. In the present study, we analyzed oculomotor gaze and manual steering behavior in approach and avoidance tasks. Three task blocks were implemented within a dynamic simulated driving environment requiring the driver either to steer away from/toward a visual stimulus or to switch between both tasks. Results Task blocks requiring task switches were associated with higher manual response times and increased error rates. Manual response times did not significantly differ depending on whether drivers had to steer away from vs toward a stimulus, whereas oculomotor response times and gaze pattern variability were increased when drivers had to steer away from a stimulus compared to steering toward a stimulus. Conclusion The increased manual response times and error rates in mixed tasks indicate performance costs associated with cognitive flexibility, while the increased oculomotor response times and gaze pattern variability indicate a parsimonious cross-modal action control strategy (avoiding stimulus fixation prior to steering away from it) for the avoidance scenario. Several discrepancies between these results and typical eye-hand interaction patterns in basic laboratory research suggest that the specific goals and complex perceptual affordances associated with driving a vehicle strongly shape cross-modal control of behavior.}, language = {en} } @article{SchmalzlPlumhoffGilbertetal.2019, author = {Schmalzl, Jonas and Plumhoff, Piet and Gilbert, Fabian and Gohlke, Frank and Konrads, Christian and Brunner, Ulrich and Jakob, Franz and Ebert, Regina and Steinert, Andre F.}, title = {Tendon-derived stem cells from the long head of the biceps tendon}, series = {Bone \& Joint Research}, volume = {8}, journal = {Bone \& Joint Research}, number = {9}, doi = {10.1302/2046-3758.89.BJR-2018-0214.R2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200370}, pages = {414-424}, year = {2019}, abstract = {Objectives The long head of the biceps (LHB) is often resected in shoulder surgery and could therefore serve as a cell source for tissue engineering approaches in the shoulder. However, whether it represents a suitable cell source for regenerative approaches, both in the inflamed and non-inflamed states, remains unclear. In the present study, inflamed and native human LHBs were comparatively characterized for features of regeneration. Methods In total, 22 resected LHB tendons were classified into inflamed samples (n = 11) and non-inflamed samples (n = 11). Proliferation potential and specific marker gene expression of primary LHB-derived cell cultures were analyzed. Multipotentiality, including osteogenic, adipogenic, chondrogenic, and tenogenic differentiation potential of both groups were compared under respective lineage-specific culture conditions. Results Inflammation does not seem to affect the proliferation rate of the isolated tendon-derived stem cells (TDSCs) and the tenogenic marker gene expression. Cells from both groups showed an equivalent osteogenic, adipogenic, chondrogenic and tenogenic differentiation potential in histology and real-time polymerase chain reaction (RT-PCR) analysis. Conclusion These results suggest that the LHB tendon might be a suitable cell source for regenerative approaches, both in inflamed and non-inflamed states. The LHB with and without tendinitis has been characterized as a novel source of TDSCs, which might facilitate treatment of degeneration and induction of regeneration in shoulder surgery.}, language = {en} } @article{LoehrKesslerMonoranuetal.2019, author = {L{\"o}hr, Mario and Kessler, Almuth F. and Monoranu, Camelia-Maria and Grosche, Jens and Linsenmann, Thomas and Ernestus, Ralf-Ingo and H{\"a}rtig, Wolfgang}, title = {Primary brain amyloidoma, both a neoplastic and a neurodegenerative disease: a case report}, series = {BMC Neurology}, volume = {19}, journal = {BMC Neurology}, doi = {10.1186/s12883-019-1274-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200341}, pages = {59}, year = {2019}, abstract = {Background Scattered extracellular deposits of amyloid within the brain parenchyma can be found in a heterogeneous group of diseases. Its condensed accumulation in the white matter without evidence for systemic amyloidosis is known as primary brain amyloidoma (PBA). Although originally considered as a tumor-like lesion by its space-occupying effect, this condition displays also common hallmarks of a neurodegenerative disorder. Case presentation A 50-year-old woman presented with a mild cognitive decline and seizures with a right temporal, irregular and contrast-enhancing mass on magnetic resonance imaging. Suspecting a high-grade glioma, the firm tumor was subtotally resected. Neuropathological examination showed no glioma, but distinct features of a neurodegenerative disorder. The lesion was composed of amyloid AL λ aggregating within the brain parenchyma as well as the adjacent vessels, partially obstructing the vascular lumina. Immunostaining confirmed a distinct perivascular inflammatory reaction. After removal of the PBA, mnestic impairments improved considerably, the clinical course and MRI-results are stable in the 8-year follow-up. Conclusion Based on our histopathological findings, we propose to regard the clinicopathological entity of PBA as an overlap between a neoplastic and neurodegenerative disorder. Since the lesions are locally restricted, they might be amenable to surgery with the prospect of a definite cure.}, language = {en} } @article{KunzAzadEngelHolmbergetal.2019, author = {Kunz, Philipp and Azad Engel, Florian and Holmberg, Hans-Christer and Sperlich, Billy}, title = {A meta-comparison of the effects of high-intensity interval training to those of small-sided games and other training protocols on parameters related to the physiology and performance of youth soccer players}, series = {Sports Medicine - Open}, volume = {5}, journal = {Sports Medicine - Open}, doi = {10.1186/s40798-019-0180-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200332}, pages = {7}, year = {2019}, abstract = {Background High-intensity interval training (HIIT) is frequently employed to improve the endurance of various types of athletes. To determine whether youth soccer players may benefit from the intermittent load and time efficiency of HIIT, we performed a meta-analysis of the relevant scientific literature. Objectives Our primary objective was to compare changes in various physiological parameters related to the performance of youth soccer players in response to running-based HIIT to the effects of other common training protocols (i.e., small-sided games, technical training and soccer-specific training, or high-volume endurance training). A secondary objective was to compare specifically running-based HIIT to a soccer-specific form of HIIT known as small-sided games (SSG) in this same respect, since this latter type of training is being discussed extensively by coaches. Method A systematic search of the PubMed, SPORTDiscus, and Web of Science databases was performed in August of 2017 and updated during the review process in December of 2018. The criteria for inclusion of articles for analysis were as follows: (1) comparison of HIIT to SSG or some other training protocol employing a pre-post design, (2) involvement of healthy young athletes (≤ 18 years old), and (3) assessment of variables related to endurance or soccer performance. Hedges' g effect size (dppc2) and associated 95\% confidence intervals for the comparison of the responses to HIIT and other interventions were calculated. Results Nine studies, involving 232 young soccer players (mean age 16.2 ± 1.6 years), were examined. Endurance training in the form of HIIT or SSG produced similar positive effects on most parameters assessed, including peak oxygen uptake and maximal running performance during incremental running (expressed as Vmax or maximal aerobic speed (MAS)), shuttle runs (expressed as the distance covered or time to exhaustion), and time-trials, as well as submaximal variables such as running economy and running velocity at the lactate threshold. HIIT induced a moderate improvement in soccer-related tests involving technical exercises with the soccer ball and other game-specific parameters (i.e., total distance covered, number of sprints, and number of involvements with the ball). Neuromuscular parameters were largely unaffected by HIIT or SSG. Conclusion The present meta-analysis indicates that HIIT and SSG have equally beneficial impacts on variables related to the endurance and soccer-specific performance of youth soccer players, but little influence on neuromuscular performance.}, language = {en} } @article{RichterExnerBratengeieretal.2019, author = {Richter, Anne and Exner, Florian and Bratengeier, Klaus and Polat, B{\"u}lent and Flentje, Michael and Weick, Stefan}, title = {Impact of beam configuration on VMAT plan quality for Pinnacle\(^3\)Auto-Planning for head and neck cases}, series = {Radiation Oncology}, volume = {14}, journal = {Radiation Oncology}, doi = {10.1186/s13014-019-1211-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200301}, pages = {12}, year = {2019}, abstract = {Background The purpose of this study was to compare automatically generated VMAT plans to find the superior beam configurations for Pinnacle3 Auto-Planning and share "best practices". Methods VMAT plans for 20 patients with head and neck cancer were generated using Pinnacle3 Auto-Planning Module (Pinnacle3 Version 9.10) with different beam setup parameters. VMAT plans for single (V1) or double arc (V2) and partial or full gantry rotation were optimized. Beam configurations with different collimator positions were defined. Target coverage and sparing of organs at risk were evaluated based on scoring of an evaluation parameter set. Furthermore, dosimetric evaluation was performed based on the composite objective value (COV) and a new cross comparison method was applied using the COVs. Results The evaluation showed a superior plan quality for double arcs compared to one single arc or two single arcs for all cases. Plan quality was superior if a full gantry rotation was allowed during optimization for unilateral target volumes. A double arc technique with collimator setting of 15° was superior to a double arc with collimator 60° and a two single arcs with collimator setting of 15° and 345°. Conclusion The evaluation showed that double and full arcs are superior to single and partial arcs in terms of organs at risk sparing even for unilateral target volumes. The collimator position was found as an additional setup parameter, which can further improve the target coverage and sparing of organs at risk.}, language = {en} } @article{DjuzenovaFiedlerMemmeletal.2019, author = {Djuzenova, Cholpon S. and Fiedler, Vanessa and Memmel, Simon and Katzer, Astrid and Sisario, Dmitri and Brosch, Philippa K. and G{\"o}hrung, Alexander and Frister, Svenja and Zimmermann, Heiko and Flentje, Michael and Sukhorukov, Vladimir L.}, title = {Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells}, series = {BMC Cancer}, volume = {19}, journal = {BMC Cancer}, doi = {10.1186/s12885-019-5517-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200290}, pages = {299}, year = {2019}, abstract = {Background Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. Methods Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition. Results We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy. Conclusions Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.}, language = {en} } @article{StrahlGerlichAlpersetal.2019, author = {Strahl, Andr{\´e} and Gerlich, Christian and Alpers, Georg W. and Gehrke, J{\"o}rg and M{\"u}ller-Garnn, Annette and Vogel, Heiner}, title = {An instrument for quality assurance in work capacity evaluation: development, evaluation, and inter-rater reliability}, series = {BMC Health Services Research}, volume = {19}, journal = {BMC Health Services Research}, doi = {10.1186/s12913-019-4387-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200289}, pages = {556}, year = {2019}, abstract = {Background: Employees insured in pension insurance, who are incapable of working due to ill health, are entitled to a disability pension. To assess whether an individual meets the medical requirements to be considered as disabled, a work capacity evaluation is conducted. However, there are no official guidelines on how to perform an external quality assurance for this evaluation process. Furthermore, the quality of medical reports in the field of insurance medicine can vary substantially, and systematic evaluations are scarce. Reliability studies using peer review have repeatedly shown insufficient ability to distinguish between high, moderate and low quality. Considering literature recommendations, we developed an instrument to examine the quality of medical experts'reports. Methods: The peer review manual developed contains six quality domains (formal structure, clarity, transparency, completeness, medical-scientific principles, and efficiency) comprising 22 items. In addition, a superordinate criterion (survey confirmability) rank the overall quality and usefulness of a report. This criterion evaluates problems of innerlogic and reasoning. Development of the manual was assisted by experienced physicians in a pre-test. We examined the observable variance in peer judgements and reliability as the most important outcome criteria. To evaluate inter-rater reliability, 20 anonymous experts' reports detailing the work capacity evaluation were reviewed by 19 trained raters (peers). Percentage agreement and Kendall's W, a reliability measure of concordance between two or more peers, were calculated. A total of 325 reviews were conducted. Results: Agreement of peer judgements with respect to the superordinate criterion ranged from 29.2 to 87.5\%. Kendall's W for the quality domain items varied greatly, ranging from 0.09 to 0.88. With respect to the superordinate criterion, Kendall's W was 0.39, which indicates fair agreement. The results of the percentage agreement revealed systemic peer preferences for certain deficit scale categories. Conclusion: The superordinate criterion was not sufficiently reliable. However, in comparison to other reliability studies, this criterion showed an equivalent reliability value. This report aims to encourage further efforts to improve evaluation instruments. To reduce disagreement between peer judgments, we propose the revision of the peer review instrumentand the development and implementation of a standardized rater training to improve reliability.}, language = {en} } @article{FuchsYoussefSeheretal.2019, author = {Fuchs, A. and Youssef, A. and Seher, A. and Hochleitner, G. and Dalton, P. D. and Hartmann, S. and Brands, R. C. and M{\"u}ller-Richter, U. D. A. and Linz, C,}, title = {Medical-grade polycaprolactone scaffolds made by melt electrospinning writing for oral bone regeneration - a pilot study in vitro}, series = {BMC Oral Health}, volume = {19}, journal = {BMC Oral Health}, doi = {10.1186/s12903-019-0717-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200274}, pages = {28}, year = {2019}, abstract = {Background The spectrum of indications for the use of membranes and scaffolds in the field of oral and maxillofacial surgery includes, amongst others, guided bone regeneration (GBR). Currently available membrane systems face certain disadvantages such as difficult clinical handling, inconsistent degradation, undirected cell growth and a lack of stability that often complicate their application. Therefore, new membranes which can overcome these issues are of great interest in this field. Methods In this pilot study, we investigated polycaprolactone (PCL) scaffolds intended to enhance oral wound healing by means of melt electrospinning writing (MEW), which allowed for three-dimensional (3D) printing of micron scale fibers and very exact fiber placement. A singular set of box-shaped scaffolds of different sizes consisting of medical-grade PCL was examined and the scaffolds' morphology was evaluated via scanning electron microscopy (SEM). Each prototype sample with box sizes of 225 μm, 300 μm, 375 μm, 450 μm and 500 μm was assessed for cytotoxicity and cell growth by seeding each scaffold with human osteoblast-like cell line MG63. Results All scaffolds demonstrated good cytocompatibility according to cell viability, protein concentration, and cell number. SEM analysis revealed an exact fiber placement of the MEW scaffolds and the growth of viable MG63 cells on them. For the examined box-shaped scaffolds with pore sizes between 225 μm and 500 μm, a preferred box size for initial osteoblast attachment could not be found. Conclusions These well-defined 3D scaffolds consisting of medical-grade materials optimized for cell attachment and cell growth hold the key to a promising new approach in GBR in oral and maxillofacial surgery.}, language = {en} } @article{PfisterFringsMoeller2019, author = {Pfister, Roland and Frings, Christian and Moeller, Birte}, title = {The Role of Congruency for Distractor-Response Binding: A Caveat}, series = {Advances in Cognitive Psychologe}, volume = {15}, journal = {Advances in Cognitive Psychologe}, number = {2}, doi = {10.5709/acp-0262-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200265}, pages = {127-132}, year = {2019}, abstract = {Responding in the presence of stimuli leads to an integration of stimulus features and response features into event fles, which can later be retrieved to assist action control. This integration mechanism is not limited to target stimuli, but can also include distractors (distractor-response binding). A recurring research question is which factors determine whether or not distractors are integrated. One suggested candidate factor is target-distractor congruency: Distractor-response binding effects were reported to be stronger for congruent than for incongruent target-distractor pairs. Here, we discuss a general problem with including the factor of congruency in typical analyses used to study distractor-based binding effects. Integrating this factor leads to a confound that may explain any differences between distractor-response binding effects of congruent and incongruent distractors with a simple congruency effect. Simulation data confrmed this argument. We propose to interpret previous data cautiously and discuss potential avenues to circumvent this problem in the future.}, language = {en} } @article{NickelMueller2019, author = {Nickel, Joachim and Mueller, Thomas D.}, title = {Specification of BMP signaling}, series = {Cells}, volume = {8}, journal = {Cells}, number = {12}, issn = {2073-4409}, doi = {10.3390/cells8121579}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193869}, pages = {1579}, year = {2019}, abstract = {Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.}, language = {en} } @article{HollmannWieseDennstaedtetal.2019, author = {Hollmann, Claudia and Wiese, Teresa and Dennst{\"a}dt, Fabio and Fink, Julian and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Translational approaches targeting ceramide generation from sphingomyelin in T cells to modulate immunity in humans}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {2363}, issn = {1664-3224}, doi = {10.3389/fimmu.2019.02363}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198806}, year = {2019}, abstract = {In T cells, as in all other cells of the body, sphingolipids form important structural components of membranes. Due to metabolic modifications, sphingolipids additionally play an active part in the signaling of cell surface receptors of T cells like the T cell receptor or the co-stimulatory molecule CD28. Moreover, the sphingolipid composition of their membranes crucially affects the integrity and function of subcellular compartments such as the lysosome. Previously, studying sphingolipid metabolism has been severely hampered by the limited number of analytical methods/model systems available. Besides well-established high resolution mass spectrometry new tools are now available like novel minimally modified sphingolipid subspecies for click chemistry as well as recently generated mouse mutants with deficiencies/overexpression of sphingolipid-modifying enzymes. Making use of these tools we and others discovered that the sphingolipid sphingomyelin is metabolized to ceramide to different degrees in distinct T cell subpopulations of mice and humans. This knowledge has already been translated into novel immunomodulatory approaches in mice and will in the future hopefully also be applicable to humans. In this paper we are, thus, summarizing the most recent findings on the impact of sphingolipid metabolism on T cell activation, differentiation, and effector functions. Moreover, we are discussing the therapeutic concepts arising from these insights and drugs or drug candidates which are already in clinical use or could be developed for clinical use in patients with diseases as distant as major depression and chronic viral infection.}, language = {en} } @article{KunzZinnerHolmbergetal.2019, author = {Kunz, Philipp and Zinner, Christoph and Holmberg, Hans-Christer and Sperlich, Billy}, title = {Intra- and post-match time-course of indicators related to perceived and performance fatigability and recovery in elite youth soccer players}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, number = {1383}, issn = {1664-042X}, doi = {10.3389/fphys.2019.01383}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195657}, year = {2019}, abstract = {PurposeOur aims were to examine (i) the internal load during simulated soccer match-play by elite youth players; and (ii) the time-course of subsequent recovery from perceived and performance fatigability. MethodsEleven male youth players (16 ± 1 years, 178 ± 7 cm, 67 ± 7 kg) participated in a 2 × 40-min simulated soccer match, completing 30 rounds (160 s each) with every round including multidirectional and linear sprinting (LS20m), jumping (CMJ) and running at different intensities. During each round, LS20m, CMJ, agility, heart rate (HR), oxygen uptake (VO2), energy expenditure (EE), substrate utilization and perceived exertion RPE were assessed. In addition, the blood level of lactate (Lac) was obtained after each of the five rounds. Creatine kinase (CK) concentration, maximal voluntary isometric knee extension and flexion, CMJ, number of skippings in 30 s, and subjective ratings on the Acute Recovery and Stress Scale (ARSS) were examined before and immediately, 24 and 48 h after the simulation. Results: During the game \%HR\(_{peak}\) (p < 0.05, d = 1.08), \%VO2\(_{peak}\) (p < 0.05; d = 0.68), Lac (p < 0.05, d = 2.59), RPE\(_{total}\) (p < 0.05, d = 4.59), and RPE\(_{legs}\) (p < 0.05, d = 4.45) all increased with time during both halves (all p < 0.05). Agility improved (p < 0.05, d = 0.70) over the time-course of the game, with no changes in LS20m (p ≥ 0.05, d = 0.34) or CMJ (p ≥ 0.05, d = 0.27). EE was similar during both halves (528 ± 58 vs. 514 ± 61 kcal; p = 0.60; d = 0.23), with 62\% (second half: 65\%) carbohydrate, 9\% (9\%) protein and 26\% (27\%) fat utilization. With respect to recovery, maximal voluntary knee extension (p ≥ 0.05, d = 0.50) and flexion force (p ≥ 0.05, d = 0.19), CMJ (p ≥ 0.05, d = 0.13), number of ground contacts (p ≥ 0.05, d = 0.57) and average contact time (p ≥ 0.05, d = 0.39) during 30-s of skipping remained unaltered 24 and 48 h after the game. Most ARSS dimensions of load (p < 0.05, d = 3.79) and recovery (p < 0.05, d = 3.22) returned to baseline levels after 24 h of recovery. Relative to baseline values, CK was elevated immediately and 24 h after (p < 0.05, d = 2.03) and normalized 48 h later. ConclusionIn youth soccer players the simulated match evoked considerable circulatory, metabolic and perceptual load, with an EE of 1042 ± 118 kcal. Among the indicators of perceived and performance fatigability examined, the level of CK and certain subjective ratings differed considerably immediately following or 24-48 h after a 2 × 40-min simulated soccer match in comparison to baseline. Accordingly, monitoring these variables may assist coaches in assessing a U17 player's perceived and performance fatigability in connection with scheduling training following a soccer match.}, language = {en} } @article{SeidlmayerMagesBerbneretal.2019, author = {Seidlmayer, Lea K. and Mages, Christine and Berbner, Annette and Eder-Negrin, Petra and Arias-Loza, Paula Anahi and Kaspar, Mathias and Song, Moshi and Dorn, Gerald W. and Kohlhaas, Michael and Frantz, Stefan and Maack, Christoph and Gerull, Brenda and Dedkova, Elena N.}, title = {Mitofusin 2 is essential for IP3-mediated SR/Mitochondria metabolic feedback in ventricular myocytes}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, number = {733}, issn = {1664-042X}, doi = {10.3389/fphys.2019.00733}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199141}, year = {2019}, abstract = {Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP\(_3\)) by activating their membrane-bound receptors. We have previously demonstrated that IP\(_3\)-mediated sarcoplasmic reticulum (SR) Ca\(^{2+}\) release results in mitochondrial Ca\(^{2+}\) uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP\(_3\)-mediated SR/mitochondrial feedback in ventricular myocytes. Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca\(^{2+}\) uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates. Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca\(^{2+}\) uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca\(^{2+}\) uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca\(^{2+}\) uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca\(^{2+}\) uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca\(^{2+}\) uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions. Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP\(_3\)-mediated SR Ca\(^{2+}\) release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP\(_3\)R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter).}, language = {en} } @article{GrafenSchumacherChithelenetal.2019, author = {Grafen, Anika and Schumacher, Fabian and Chithelen, Janice and Kleuser, Burkhard and Beyersdorf, Niklas and Schneider-Schaulies, J{\"u}rgen}, title = {Use of acid ceramidase and sphingosine kinase inhibitors as antiviral compounds against measles virus infection of lymphocytes in vitro}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {218}, issn = {2296-634X}, doi = {10.3389/fcell.2019.00218}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196099}, year = {2019}, abstract = {As structural membrane components and signaling effector molecules sphingolipids influence a plethora of host cell functions, and by doing so also the replication of viruses. Investigating the effects of various inhibitors of sphingolipid metabolism in primary human peripheral blood lymphocytes (PBL) and the human B cell line BJAB we found that not only the sphingosine kinase (SphK) inhibitor SKI-II, but also the acid ceramidase inhibitor ceranib-2 efficiently inhibited measles virus (MV) replication. Virus uptake into the target cells was not grossly altered by the two inhibitors, while titers of newly synthesized MV were reduced by approximately 1 log (90\%) in PBL and 70-80\% in BJAB cells. Lipidomic analyses revealed that in PBL SKI-II led to increased ceramide levels, whereas in BJAB cells ceranib-2 increased ceramides. SKI-II treatment decreased sphingosine-1-phosphate (S1P) levels in PBL and BJAB cells. Furthermore, we found that MV infection of lymphocytes induced a transient (0.5-6 h) increase in S1P, which was prevented by SKI-II. Investigating the effect of the inhibitors on the metabolic (mTORC1) activity we found that ceranib-2 reduced the phosphorylation of p70 S6K in PBL, and that both inhibitors, ceranib-2 and SKI-II, reduced the phosphorylation of p70 S6K in BJAB cells. As mTORC1 activity is required for efficient MV replication, this effect of the inhibitors is one possible antiviral mechanism. In addition, reduced intracellular S1P levels affect a number of signaling pathways and functions including Hsp90 activity, which was reported to be required for MV replication. Accordingly, we found that pharmacological inhibition of Hsp90 with the inhibitor 17-AAG strongly impaired MV replication in primary PBL. Thus, our data suggest that treatment of lymphocytes with both, acid ceramidase and SphK inhibitors, impair MV replication by affecting a number of cellular activities including mTORC1 and Hsp90, which alter the metabolic state of the cells causing a hostile environment for the virus.}, language = {en} }