@article{KotsevaDeBackerDeBacqueretal.2019, author = {Kotseva, Kornelia and De Backer, Guy and De Bacquer, Dirk and Ryd{\´e}n, Lars and Hoes, Arno and Grobbee, Diederick and Maggioni, Aldo and Marques-Vidal, Pedro and Jennings, Catriona and Abreu, Ana and Aguiar, Carlos and Badariene, Jolita and Bruthans, Jan and Castro Conde, Almudena and Cifkova, Renata and Crowley, Jim and Davletov, Kairat and Deckers, Jaap and De Smedt, Delphine and De Sutter, Johan and Dilic, Mirza and Dolzhenko, Marina and Dzerve, Vilnis and Erglis, Andrejs and Fras, Zlatko and Gaita, Dan and Gotcheva, Nina and Heuschmann, Peter and Hasan-Ali, Hosam and Jankowski, Piotr and Lalic, Nebojsa and Lehto, Seppo and Lovic, Dragan and Mancas, Silvia and Mellbin, Linda and Milicic, Davor and Mirrakhimov, Erkin and Oganov, Rafael and Pogosova, Nana and Reiner, Zeljko and St{\"o}erk, Stefan and Tokg{\"o}zoğlu, L{\^a}le and Tsioufis, Costas and Vulic, Dusko and Wood, David}, title = {Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry}, series = {European Journal of Preventive Cardiology}, volume = {26}, journal = {European Journal of Preventive Cardiology}, number = {8}, organization = {EUROASPIRE Investigators}, issn = {2047-4873}, doi = {10.1177/2047487318825350}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205526}, pages = {824-835}, year = {2019}, abstract = {Aims The aim of this study was to determine whether the Joint European Societies guidelines on secondary cardiovascular prevention are followed in everyday practice. Design A cross-sectional ESC-EORP survey (EUROASPIRE V) at 131 centres in 81 regions in 27 countries. Methods Patients (<80 years old) with verified coronary artery events or interventions were interviewed and examined ≥6 months later. Results A total of 8261 patients (females 26\%) were interviewed. Nineteen per cent smoked and 55\% of them were persistent smokers, 38\% were obese (body mass index ≥30 kg/m2), 59\% were centrally obese (waist circumference: men ≥102 cm; women ≥88 cm) while 66\% were physically active <30 min 5 times/week. Forty-two per cent had a blood pressure ≥140/90 mmHg (≥140/85 if diabetic), 71\% had low-density lipoprotein cholesterol ≥1.8 mmol/L (≥70 mg/dL) and 29\% reported having diabetes. Cardioprotective medication was: anti-platelets 93\%, beta-blockers 81\%, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75\% and statins 80\%. Conclusion A large majority of coronary patients have unhealthy lifestyles in terms of smoking, diet and sedentary behaviour, which adversely impacts major cardiovascular risk factors. A majority did not achieve their blood pressure, low-density lipoprotein cholesterol and glucose targets. Cardiovascular prevention requires modern preventive cardiology programmes delivered by interdisciplinary teams of healthcare professionals addressing all aspects of lifestyle and risk factor management, in order to reduce the risk of recurrent cardiovascular events.}, language = {en} } @article{FigueiredoKraussSteffanDewenteretal.2019, author = {Figueiredo, Ludmilla and Krauss, Jochen and Steffan-Dewenter, Ingolf and Cabral, Juliano Sarmento}, title = {Understanding extinction debts: spatio-temporal scales, mechanisms and a roadmap for future research}, series = {Ecography}, volume = {42}, journal = {Ecography}, number = {12}, doi = {10.1111/ecog.04740}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204859}, pages = {1973-1990}, year = {2019}, abstract = {Extinction debt refers to delayed species extinctions expected as a consequence of ecosystem perturbation. Quantifying such extinctions and investigating long-term consequences of perturbations has proven challenging, because perturbations are not isolated and occur across various spatial and temporal scales, from local habitat losses to global warming. Additionally, the relative importance of eco-evolutionary processes varies across scales, because levels of ecological organization, i.e. individuals, (meta)populations and (meta)communities, respond hierarchically to perturbations. To summarize our current knowledge of the scales and mechanisms influencing extinction debts, we reviewed recent empirical, theoretical and methodological studies addressing either the spatio-temporal scales of extinction debts or the eco-evolutionary mechanisms delaying extinctions. Extinction debts were detected across a range of ecosystems and taxonomic groups, with estimates ranging from 9 to 90\% of current species richness. The duration over which debts have been sustained varies from 5 to 570 yr, and projections of the total period required to settle a debt can extend to 1000 yr. Reported causes of delayed extinctions are 1) life-history traits that prolong individual survival, and 2) population and metapopulation dynamics that maintain populations under deteriorated conditions. Other potential factors that may extend survival time such as microevolutionary dynamics, or delayed extinctions of interaction partners, have rarely been analyzed. Therefore, we propose a roadmap for future research with three key avenues: 1) the microevolutionary dynamics of extinction processes, 2) the disjunctive loss of interacting species and 3) the impact of multiple regimes of perturbation on the payment of debts. For their ability to integrate processes occurring at different levels of ecological organization, we highlight mechanistic simulation models as tools to address these knowledge gaps and to deepen our understanding of extinction dynamics.}, language = {en} } @article{AtaeeMaghsoudiLatifietal.2019, author = {Ataee, Mohammad Sadegh and Maghsoudi, Yasser and Latifi, Hooman and Fadaie, Farhad}, title = {Improving estimation accuracy of growing stock by multi-frequency SAR and multi-spectral data over Iran's heterogeneously-structured broadleaf Hyrcanian forests}, series = {Forests}, volume = {10}, journal = {Forests}, number = {8}, issn = {1999-4907}, doi = {10.3390/f10080641}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197212}, year = {2019}, abstract = {Via providing various ecosystem services, the old-growth Hyrcanian forests play a crucial role in the environment and anthropogenic aspects of Iran and beyond. The amount of growing stock volume (GSV) is a forest biophysical parameter with great importance in issues like economy, environmental protection, and adaptation to climate change. Thus, accurate and unbiased estimation of GSV is also crucial to be pursued across the Hyrcanian. Our goal was to investigate the potential of ALOS-2 and Sentinel-1's polarimetric features in combination with Sentinel-2 multi-spectral features for the GSV estimation in a portion of heterogeneously-structured and mountainous Hyrcanian forests. We used five different kernels by the support vector regression (nu-SVR) for the GSV estimation. Because each kernel differently models the parameters, we separately selected features for each kernel by a binary genetic algorithm (GA). We simultaneously optimized R\(^2\) and RMSE in a suggested GA fitness function. We calculated R\(^2\), RMSE to evaluate the models. We additionally calculated the standard deviation of validation metrics to estimate the model's stability. Also for models over-fitting or under-fitting analysis, we used mean difference (MD) index. The results suggested the use of polynomial kernel as the final model. Despite multiple methodical challenges raised from the composition and structure of the study site, we conclude that the combined use of polarimetric features (both dual and full) with spectral bands and indices can improve the GSV estimation over mixed broadleaf forests. This was partially supported by the use of proposed evaluation criterion within the GA, which helped to avoid the curse of dimensionality for the applied SVR and lowest over estimation or under estimation.}, language = {en} } @article{JungwirthYuMoustafaetal.2019, author = {Jungwirth, Gerhard and Yu, Tao and Moustafa, Mahmoud and Rapp, Carmen and Warta, Rolf and Jungk, Christine and Sahm, Felix and Dettling, Steffen and Zweckberger, Klaus and Lamszus, Katrin and Senft, Christian and Loehr, Mario and Keßler, Almuth F. and Ketter, Ralf and Westphal, Manfred and Debus, Juergen and von Deimling, Andreas and Simon, Matthias and Unterberg, Andreas and Abdollahi, Amir and Herold-Mende, Christel}, title = {Identification of KIF11 as a Novel Target in Meningioma}, series = {Cancers}, volume = {11}, journal = {Cancers}, number = {4}, issn = {2072-6694}, doi = {10.3390/cancers11040545}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197402}, year = {2019}, abstract = {Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I n = 61, WHO°II n = 88, and WHO°III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95\% and 71\%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.}, language = {en} } @article{MayrKuenzerGessneretal.2019, author = {Mayr, Stefan and Kuenzer, Claudia and Gessner, Ursula and Klein, Igor and Rutzinger, Martin}, title = {Validation of earth observation time-series: a review for large-area and temporally dense land surface products}, series = {Remote Sensing}, volume = {11}, journal = {Remote Sensing}, number = {22}, issn = {2072-4292}, doi = {10.3390/rs11222616}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193202}, year = {2019}, abstract = {Large-area remote sensing time-series offer unique features for the extensive investigation of our environment. Since various error sources in the acquisition chain of datasets exist, only properly validated results can be of value for research and downstream decision processes. This review presents an overview of validation approaches concerning temporally dense time-series of land surface geo-information products that cover the continental to global scale. Categorization according to utilized validation data revealed that product intercomparisons and comparison to reference data are the conventional validation methods. The reviewed studies are mainly based on optical sensors and orientated towards global coverage, with vegetation-related variables as the focus. Trends indicate an increase in remote sensing-based studies that feature long-term datasets of land surface variables. The hereby corresponding validation efforts show only minor methodological diversification in the past two decades. To sustain comprehensive and standardized validation efforts, the provision of spatiotemporally dense validation data in order to estimate actual differences between measurement and the true state has to be maintained. The promotion of novel approaches can, on the other hand, prove beneficial for various downstream applications, although typically only theoretical uncertainties are provided.}, language = {en} } @article{GrebinykPrylutskaBuchelnikovetal.2019, author = {Grebinyk, Anna and Prylutska, Svitlana and Buchelnikov, Anatoliy and Tverdokhleb, Nina and Grebinyk, Sergii and Evstigneev, Maxim and Matyshevska, Olga and Cherepanov, Vsevolod and Prylutskyy, Yuriy and Yashchuk, Valeriy and Naumovets, Anton and Ritter, Uwe and Dandekar, Thomas and Frohme, Marcus}, title = {C60 fullerene as an effective nanoplatform of alkaloid Berberine delivery into leukemic cells}, series = {Pharmaceutics}, volume = {11}, journal = {Pharmaceutics}, number = {11}, issn = {1999-4923}, doi = {10.3390/pharmaceutics11110586}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193216}, pages = {586}, year = {2019}, abstract = {A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle—C60 fullerene (C60)—for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV-Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C\(_{60}\) binding in an aqueous solution. Complexation with C\(_{60}\) was found to promote Ber intracellular uptake. By increasing C\(_{60}\) concentration, the C\(_{60}\)-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C\(_{60}\)-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C\(_{60}\) improved its in vitro efficiency against cancer cells.}, language = {en} } @article{LiLiLinketal.2019, author = {Li, Shan and Li, Xin and Link, Roman and Li, Ren and Deng, Liping and Schuldt, Bernhard and Jiang, Xiaomei and Zhao, Rongjun and Zheng, Jingming and Li, Shuang and Yin, Yafang}, title = {Influence of cambial age and axial height on the spatial patterns of xylem traits in Catalpa bungei, a ring-porous tree species native to China}, series = {Forests}, volume = {10}, journal = {Forests}, number = {8}, issn = {1999-4907}, doi = {10.3390/f10080662}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196297}, year = {2019}, abstract = {Studying how cambial age and axial height affects wood anatomical traits may improve our understanding of xylem hydraulics, heartwood formation and axial growth. Radial strips were collected from six different heights (0-11.3 m) along the main trunk of three Manchurian catalpa (Catalpa bungei) trees, yielding 88 samples. In total, thirteen wood anatomical vessel and fiber traits were observed usinglight microscopy (LM) and scanning electron microscopy (SEM), and linear models were used to analyse the combined effect of axial height, cambial age and their interaction. Vessel diameter differed by about one order of magnitude between early- and latewood, and increased significantly with both cambial age and axial height in latewood, while it was positively affected by cambial age and independent of height in earlywood. Vertical position further had a positive effect on earlywood vessel density, and negative effects on fibre wall thickness, wall thickness to diameter ratio and length. Cambial age had positive effects on the pit membrane diameter and vessel element length, while the annual diameter growth decreased with both cambial age and axial position. In contrast, early- and latewood fiber diameter were unaffected by both cambial age and axial height. We further observed an increasing amount of tyloses from sapwood to heartwood, accompanied by an increase of warty layers and amorphous deposits on cell walls, bordered pit membranes and pit apertures. This study highlights the significant effects of cambial age and vertical position on xylem anatomical traits, and confirms earlier work that cautions to take into account xylem spatial position when interpreting wood anatomical structures, and thus, xylem hydraulic functioning.}, language = {en} } @article{AbdullahiWesselHuberetal.2019, author = {Abdullahi, Sahra and Wessel, Birgit and Huber, Martin and Wendleder, Anna and Roth, Achim and Kuenzer, Claudia}, title = {Estimating penetration-related X-band InSAR elevation bias: a study over the Greenland ice sheet}, series = {Remote Sensing}, volume = {11}, journal = {Remote Sensing}, number = {24}, issn = {2072-4292}, doi = {10.3390/rs11242903}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193902}, year = {2019}, abstract = {Accelerating melt on the Greenland ice sheet leads to dramatic changes at a global scale. Especially in the last decades, not only the monitoring, but also the quantification of these changes has gained considerably in importance. In this context, Interferometric Synthetic Aperture Radar (InSAR) systems complement existing data sources by their capability to acquire 3D information at high spatial resolution over large areas independent of weather conditions and illumination. However, penetration of the SAR signals into the snow and ice surface leads to a bias in measured height, which has to be corrected to obtain accurate elevation data. Therefore, this study purposes an easy transferable pixel-based approach for X-band penetration-related elevation bias estimation based on single-pass interferometric coherence and backscatter intensity which was performed at two test sites on the Northern Greenland ice sheet. In particular, the penetration bias was estimated using a multiple linear regression model based on TanDEM-X InSAR data and IceBridge laser-altimeter measurements to correct TanDEM-X Digital Elevation Model (DEM) scenes. Validation efforts yielded good agreement between observations and estimations with a coefficient of determination of R\(^2\) = 68\% and an RMSE of 0.68 m. Furthermore, the study demonstrates the benefits of X-band penetration bias estimation within the application context of ice sheet elevation change detection.}, language = {en} } @article{BeerSchenkHelfrichFoersteretal.2019, author = {Beer, Katharina and Schenk, Mariela and Helfrich-F{\"o}rster, Charlotte and Holzschuh, Andrea}, title = {The circadian clock uses different environmental time cues to synchronize emergence and locomotion of the solitary bee Osmia bicornis}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-54111-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202721}, pages = {17748}, year = {2019}, abstract = {Life on earth adapted to the daily reoccurring changes in environment by evolving an endogenous circadian clock. Although the circadian clock has a crucial impact on survival and behavior of solitary bees, many aspects of solitary bee clock mechanisms remain unknown. Our study is the first to show that the circadian clock governs emergence in Osmia bicornis, a bee species which overwinters as adult inside its cocoon. Therefore, its eclosion from the pupal case is separated by an interjacent diapause from its emergence in spring. We show that this bee species synchronizes its emergence to the morning. The daily rhythms of emergence are triggered by temperature cycles but not by light cycles. In contrast to this, the bee's daily rhythms in locomotion are synchronized by light cycles. Thus, we show that the circadian clock of O. bicornis is set by either temperature or light, depending on what activity is timed. Light is a valuable cue for setting the circadian clock when bees have left the nest. However, for pre-emerged bees, temperature is the most important cue, which may represent an evolutionary adaptation of the circadian system to the cavity-nesting life style of O. bicornis.}, language = {en} } @article{MaierhoferFlunkertOshimaetal.2019, author = {Maierhofer, Anna and Flunkert, Julia and Oshima, Junko and Martin, George M. and Poot, Martin and Nanda, Indrajit and Dittrich, Marcus and M{\"u}ller, Tobias and Haaf, Thomas}, title = {Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes}, series = {Aging Cell}, volume = {18}, journal = {Aging Cell}, doi = {10.1111/acel.12995}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202733}, pages = {e12995}, year = {2019}, abstract = {Werner Syndrome (WS) is an adult-onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 WRN-mutant) or atypical WS (3 LMNA-mutant and 3 POLD1-mutant) patients and age- and sex-matched controls. WS was not associated with either age-related accelerated global losses of ALU, LINE1, and α-satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the HOXA4 promoter. Additional DMR genes included LMNA, POLD1, and 132 genes which have been reported to be differentially expressed in WRN-mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence-specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of WRN protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS- and age-related methylation changes exhibited a constant offset of methylation between WRN-mutant patients and controls across the entire analyzed age range. WS-specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes.}, language = {en} } @article{FayezFeineisAkeAssietal.2019, author = {Fayez, Shaimaa and Feineis, Doris and Ak{\´e} Assi, Laurent and Seo, Ean-Jeong and Efferth, Thomas and Bringmann, Gerhard}, title = {Ancistrobreveines A-D and related dehydrogenated naphthylisoquinoline alkaloids with antiproliferative activities against leukemia cells, from the West African liana Ancistrocladus abbreviatus}, series = {RSC Advances}, volume = {9}, journal = {RSC Advances}, number = {28}, doi = {10.1039/C9RA03105G}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201686}, pages = {15738-15748}, year = {2019}, abstract = {A unique series of six biaryl natural products displaying four different coupling types (5,10 , 7,10 , 7,80 , and 5,80) were isolated from the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African Ancistrocladus species, A. abbreviatus is so far only the second one that was found to produce compounds with such a molecular entity. Here, we report on four new representatives, named ancistrobreveines A-D (12-14, and 6). They were identified along with the two known alkaloids 6-O-methylhamateine (4) and entdioncophylleine A (10). The two latter naphthylisoquinolines had so far only been detected in Ancistrocladus species from Southeast Asia. All of these fully dehydrogenated alkaloids have in common being optically active despite the absence of stereogenic centers, due to the presence of the rotationally hindered biaryl axis as the only element of chirality. Except for ent-dioncophylleine A (10), which lacks an oxygen function at C-6, the ancistrobreveines A-D (12-14, and 6) and 6-O-methylhamateine (4) are 6-oxygenated alkaloids, and are, thus, typical 'Ancistrocladaceae-type' compounds. Ancistrobreveine C (14), is the first - and so far only - example of a 7,80-linked fully dehydrogenated naphthylisoquinoline discovered in nature that is configurationally stable at the biaryl axis. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR) and chiroptical (electronic circular dichroism) methods. Ancistrobreveine C (14) and 6-O-methylhamateine (4) exhibited strong antiproliferative activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrugresistant subline, CEM/ADR5000.}, language = {en} } @article{TrappeKneisel2019, author = {Trappe, Julian and Kneisel, Christof}, title = {Geophysical and sedimentological investigations of Peatlands for the assessment of lithology and subsurface water pathways}, series = {Geosciences}, volume = {9}, journal = {Geosciences}, number = {3}, doi = {10.3390/geosciences9030118}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201699}, pages = {118}, year = {2019}, abstract = {Peatlands located on slopes (herein called slope bogs) are typical landscape units in the Hunsrueck, a low mountain range in Southwestern Germany. The pathways of the water feeding the slope bogs have not yet been documented and analyzed. The identification of the different mechanisms allowing these peatlands to originate and survive requires a better understanding of the subsurface lithology and hydrogeology. Hence, we applied a multi-method approach to two case study sites in order to characterize the subsurface lithology and to image the variable spatio-temporal hydrological conditions. The combination of Electrical Resistivity Tomography (ERT) and an ERT-Monitoring and Ground Penetrating Radar (GPR), in conjunction with direct methods and data (borehole drilling and meteorological data), allowed us to gain deeper insights into the subsurface characteristics and dynamics of the peatlands and their catchment area. The precipitation influences the hydrology of the peatlands as well as the interflow in the subsurface. Especially, the geoelectrical monitoring data, in combination with the precipitation and temperature data, indicate that there are several forces driving the hydrology and hydrogeology of the peatlands. While the water content of the uppermost layers changes with the weather conditions, the bottom layer seems to be more stable and changes to a lesser extent. At the selected case study sites, small differences in subsurface properties can have a huge impact on the subsurface hydrogeology and the water paths. Based on the collected data, conceptual models have been deduced for the two case study sites.}, language = {en} } @article{SchulerMurauerStangletal.2019, author = {Schuler, Michael and Murauer, Kathrin and Stangl, Stephanie and Grau, Anna and Gabriel, Katharina and Podger, Lauren and Heuschmann, Peter U. and Faller, Hermann}, title = {Pre-post changes in main outcomes of medical rehabilitation in Germany: protocol of a systematic review and meta-analysis of individual participant and aggregated data}, series = {BMJ Open}, volume = {9}, journal = {BMJ Open}, number = {5}, doi = {10.1136/bmjopen-2018-023826}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201929}, pages = {e023826}, year = {2019}, abstract = {Introduction Multidisciplinary, complex rehabilitation interventions are an important part of the treatment of chronic diseases. However, little is known about the effectiveness of routine rehabilitation interventions within the German healthcare system. Due to the nature of the social insurance system in Germany, randomised controlled trials examining the effects of rehabilitation interventions are challenging to implement and scarcely accessible. Consequently, alternative pre-post designs can be employed to assess pre-post effects of medical rehabilitation programmes. We present a protocol of systematic review and meta-analysis methods to assess the pre-post effects of rehabilitation interventions in Germany. Methods and analysis The respective study will be conducted within the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A systematic literature review will be conducted to identify studies reporting the pre-post effects (start of intervention vs end of intervention or later) in German healthcare. Studies investigating the following disease groups will be included: orthopaedics, rheumatology, oncology, pulmonology, cardiology, endocrinology, gastroenterology and psychosomatics. The primary outcomes of interest are physical/mental quality of life, physical functioning and social participation for all disease groups as well as pain (orthopaedic and rheumatologic patients only), blood pressure (cardiac patients only), asthma control (patients with asthma only), dyspnoea (patients with chronic obstructive pulmonary disease only) and depression/anxiety (psychosomatic patients only). We will invite the principal investigators of the identified studies to provide additional individual patient data. We aim to perform the meta-analyses using individual patient data as well as aggregate data. We will examine the effects of both study-level and patient-level moderators by using a meta-regression method. Ethics and dissemination Only studies that have received institutional approval from an ethics committee and present anonymised individual patient data will be included in the meta-analysis. The results will be presented in a peer-reviewed publication and at research conferences. A declaration of no objection by the ethics committee of the University of W{\"u}rzburg is available (number 20180411 01).}, language = {en} } @article{MufusamaFeineisMudogoetal.2019, author = {Mufusama, Jean-Pierre and Feineis, Doris and Mudogo, Virima and Kaiser, Marcel and Brun, Reto and Bringmann, Gerhard}, title = {Antiprotozoal dimeric naphthylisoquinolines, mbandakamines B\(_3\) and B\(_4\), and related 5,8′-coupled monomeric alkaloids, ikelacongolines A-D, from a Congolese Ancistrocladus liana}, series = {RSC Advances}, volume = {9}, journal = {RSC Advances}, number = {21}, doi = {10.1039/C9RA01784D}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201141}, pages = {12034-12046}, year = {2019}, abstract = {From the leaves of a botanically and phytochemically as yet unexplored Ancistrocladus liana discovered in the rainforests of the Central region of the Democratic Republic of the Congo in the vicinity of the town of Ikela, six new naphthylisoquinoline alkaloids were isolated, viz., two constitutionally unsymmetric dimers, the mbandakamines B\(_3\) (3) and B\(_4\) (4), and four related 5,8′-linked monomeric alkaloids, named ikelacongolines A-D (5a, 5b, 6, and 7). The dimers 3 and 4 are structurally unusual quateraryls comprising two 5,8′-coupled monomers linked via a sterically strongly constrained 6′,1′′-connection between their naphthalene units. These compounds contain seven elements of chirality, four stereogenic centers and three consecutive chiral axes. They were identified along with two known related compounds, the mbandakamines A (1) and B\(_2\) (2), which had so far only been detected in two Ancistrocladus species indigenous to the Northwestern Congo Basin. In addition, five known monomeric alkaloids, previously found in related Central African Ancistrocladus species, were isolated from the here investigated Congolese liana, three of them belonging to the subclass of 5,8′-coupled naphthylisoquinoline alkaloids, whereas two compounds exhibited a less frequently occurring 7,8′-biaryl linkage. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR), chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods. The mbandakamines B\(_3\) (3) and B\(_4\) (4) displayed pronounced activities in vitro against the malaria parasite Plasmodium falciparum and the pathogen of African sleeping sickness, Trypanosoma brucei rhodesiense.}, language = {en} } @article{KarlNandiniColacoSchulteetal.2019, author = {Karl, Franziska and Nandini Cola{\c{c}}o, Maria B. and Schulte, Annemarie and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Affective and cognitive behavior is not altered by chronic constriction injury in B7-H1 deficient and wildtype mice}, series = {BMC Neuroscience}, volume = {20}, journal = {BMC Neuroscience}, doi = {10.1186/s12868-019-0498-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200540}, pages = {16}, year = {2019}, abstract = {Background Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response. Results Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light-dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI. Conclusions Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.}, language = {en} } @article{MietrachSchlosserGeibel2019, author = {Mietrach, Nicole and Schlosser, Andreas and Geibel, Sebastian}, title = {An extracellular domain of the EsaA membrane component of the type VIIb secretion system: expression, purification and crystallization}, series = {Acta Crystallographica Section F}, volume = {75}, journal = {Acta Crystallographica Section F}, number = {12}, doi = {10.1107/S2053230X1901495X}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213681}, pages = {725-730}, year = {2019}, abstract = {The membrane protein EsaA is a conserved component of the type VIIb secretion system. Limited proteolysis of purified EsaA from Staphylococcus aureus USA300 identified a stable 48 kDa fragment, which was mapped by fingerprint mass spectrometry to an uncharacterized extracellular segment of EsaA. Analysis by circular dichroism spectroscopy showed that this fragment folds into a single stable domain made of mostly α-helices with a melting point of 34.5°C. Size-exclusion chromatography combined with multi-angle light scattering indicated the formation of a dimer of the purified extracellular domain. Octahedral crystals were grown in 0.2 M ammonium citrate tribasic pH 7.0, 16\% PEG 3350 using the hanging-drop vapor-diffusion method. Diffraction data were analyzed to 4.0 {\AA} resolution, showing that the crystals belonged to the enantiomorphic tetragonal space groups P41212 or P43212, with unit-cell parameters a = 197.5, b = 197.5, c = 368.3 {\AA}, α = β = γ = 90°.}, language = {en} } @article{Schlenkrich2019, author = {Schlenkrich, Oliver}, title = {Identifying Profiles of Democracies: A Cluster Analysis Based on the Democracy Matrix Dataset from 1900 to 2017}, series = {Politics and Governance}, volume = {7}, journal = {Politics and Governance}, number = {4}, issn = {2183-2463}, doi = {10.17645/pag.v7i4.2244}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150882}, pages = {315-330}, year = {2019}, abstract = {This study examines types of democracies that result from trade-offs within the democratic quality. Recently, the existence and relevance of trade-offs has been widely discussed. The idea is that the functions associated with the quality of democracy cannot all be maximized simultaneously. Thus, trade-offs are expressed in distinct profiles of democracy. Different profiles of democracy favour certain democracy dimensions over others due to their institutional design. Conceptually, we differentiate between four different democracy profiles: a libertarian-majoritarian (high political freedom, lower political equality, and lower political and legal control values), an egalitarian-majoritarian (high equality combined with lower freedom and control values), as well as two control-focused democracy profiles (high control values either with high degrees of freedom or high degrees of equality). We apply a cluster analysis with a focus on cluster validation on the Democracy Matrix dataset—a customized version of the Varieties-of-Democracy dataset. To increase the robustness of the cluster results, this study uses several different cluster algorithms, multiple fit indices as well as data resampling techniques. Based on all democracies between 1900 and 2017, we find strong empirical evidence for these democracy profiles. Finally, we discuss the temporal development and spatial distribution of the democracy profiles globally across the three waves of democracy, as well as for individual countries.}, language = {en} } @article{RamlerPoaterHirschetal.2019, author = {Ramler, Jacqueline and Poater, Jordi and Hirsch, Florian and Ritschel, Benedikt and Fischer, Ingo and Bickelhaupt, F. Matthias and Lichtenberg, Crispin}, title = {Carbon monoxide insertion at a heavy p-block element: unprecedented formation of a cationic bismuth carbamoyl}, series = {Chemical Science}, volume = {10}, journal = {Chemical Science}, doi = {10.1039/C9SC00278B}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181627}, pages = {4169 - 4176}, year = {2019}, abstract = {Major advances in the chemistry of 5th and 6th row heavy p-block element compounds have recently uncovered intriguing reactivity patterns towards small molecules such as H\(_2\), CO\(_2\), and ethylene. However, well-defined, homogeneous insertion reactions with carbon monoxide, one of the benchmark substrates in this field, have not been reported to date. We demonstrate here, that a cationic bismuth amide undergoes facile insertion of CO into the Bi-N bond under mild conditions. This approach grants direct access to the first cationic bismuth carbamoyl species. Its characterization by NMR, IR, and UV/vis spectroscopy, elemental analysis, single-crystal X-ray analysis, cyclic voltammetry, and DFT calculations revealed intriguing properties, such as a reversible electron transfer at the bismuth center and an absorption feature at 353 nm ascribed to a transition involving σ- and π-type orbitals of the bismuth-carbamoyl functionality. A combined experimental and theoretical approach provided insight into the mechanism of CO insertion. The substrate scope could be extended to isonitriles.}, 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{MagyarWagnerThomasetal.2019, author = {Magyar, Attila and Wagner, Martin and Thomas, Phillip and Malsch, Carolin and Schneider, Reinhard and St{\"o}rk, Stefan and Heuschmann, Peter U and Leyh, Rainer G and Oezkur, Mehmet}, title = {HO-1 concentrations 24 hours after cardiac surgery are associated with the incidence of acute kidney injury: a prospective cohort study}, series = {International Journal of Nephrology and Renovascular Disease}, volume = {12}, journal = {International Journal of Nephrology and Renovascular Disease}, doi = {10.2147/IJNRD.S165308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177250}, pages = {9-18}, year = {2019}, abstract = {Background: Acute kidney injury (AKI) is a serious complication after cardiac surgery that is associated with increased mortality and morbidity. Heme oxygenase-1 (HO-1) is an enzyme synthesized in renal tubular cells as one of the most intense responses to oxidant stress linked with protective, anti-inflammatory properties. Yet, it is unknown if serum HO-1 induction following cardiac surgical procedure involving cardiopulmonary bypass (CPB) is associated with incidence and severity of AKI. Patients and methods: In the present study, we used data from a prospective cohort study of 150 adult cardiac surgical patients. HO-1 measurements were performed before, immediately after and 24 hours post-CPB. In univariate and multivariate analyses, the association between HO-1 and AKI was investigated. Results: AKI with an incidence of 23.3\% (35 patients) was not associated with an early elevation of HO-1 after CPB in all patients (P=0.88), whereas patients suffering from AKI developed a second burst of HO-1 24 hours after CBP. In patients without AKI, the HO-1 concentrations dropped to baseline values (P=0.031). Furthermore, early HO-1 induction was associated with CPB time (P=0.046), while the ones 24 hours later lost this association (P=0.219). Conclusion: The association of the second HO-1 burst 24 hours after CBP might help to distinguish between the causality of AKI in patients undergoing CBP, thus helping to adapt patient stratification and management.}, language = {en} } @article{Zonneveld2019, author = {Zonneveld, Ben J. M.}, title = {The DNA weights per nucleus (genome size) of more than 2350 species of the Flora of The Netherlands, of which 1370 are new to science, including the pattern of their DNA peaks}, series = {Forum Geobotanicum}, volume = {8}, journal = {Forum Geobotanicum}, issn = {1867-9315}, doi = {10.3264/FG.2019.1022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189724}, pages = {24-78}, year = {2019}, abstract = {Besides external characteristics and reading a piece of DNA (barcode), the DNA weight per nucleus (genome size) via flow cytometry is a key value to detect species and hybrids and determine ploidy. In addition, the DNA weight appears to be related to various properties, such as the size of the cell and the nucleus, the duration of mitosis and meiosis and the generation time. Sometimes it is even possible to distinguish between groups or sections, which can lead to new classification of the genera. The variation in DNA weight is also useful to analyze biodiversity, genome evolution and relationships between related taxa. Moreover, it is important to know how large a genome is before one determines the base sequence of the DNA of a plant. Flow cytometry is also important for understanding fundamental processes in plants such as growth and development and recognizing chimeras. In the literature, DNA weight measurements are usually limited to one genus and often only locally (Siljak et al. 2010; Bai et al. 2012). In this study, however, it was decided to investigate all vascular plants from one country. This can also contribute to the protection of rare plants. This study is the first flora in the world whose weight of DNA per nucleus and peak patterns has been determined. More than 6400 plants, representing more than 2350 (sub)species (more than 90\%) have been collected, thanks to the help of almost 100 volunteers of Floristisch Onderzoek Nederland (Floron). Multiple specimens of many species have therefore been measured, preferably from different populations, in some cases more than fifty. For 1370 species, these values were not previously published. Moreover, a good number of the remaining 45\% are new for The Netherlands. In principle, each species has a fixed weight of DNA per nucleus. It has also been found that, especially between the genera, there are strong differences in the number of peaks that determine the DNA weight, from one to five peaks. This indicates that in a plant or organ there are sometimes nuclei with multiples of its standard DNA weight (multiple ploidy levels). It is impossible to show graphs of more than 2350 species. Therefore, we have chosen to show the peak pattern in a new way in a short formula. Within most genera there are clear differences in the DNA weights per nucleus between the species, in some other genera the DNA weight is hardly variable. Based on about twenty genera that were previously measured completely in most cases ('t Hart et al. 2003: Veldkamp and Zonneveld 2011; Soes et al. 2012; Dirkse et al. 2014, 2015; Verloove et al. 2017; Zonneveld [et al.] 2000-2018), it can be noted that even if all species of a genus have the same number of chromosomes, there can still be a difference of up to three times in the weight of the DNA. Therefore, a twice larger DNA weight does not have to indicate four sets of chromosomes. Finally, this research has also found clues to examine further the current taxonomy of a number of species or genera.}, subject = {Pflanzen}, language = {en} } @article{BruecknerDewhurstDellermannetal.2019, author = {Br{\"u}ckner, Tobias and Dewhurst, Rian D. and Dellermann, Theresa and M{\"u}ller, Marcel and Braunschweig, Holger}, title = {Mild synthesis of diboryldiborenes by diboration of B-B triple bonds}, series = {Chemical Science}, volume = {10}, journal = {Chemical Science}, doi = {10.1039/C9SC02544H}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186306}, pages = {7375-7378}, year = {2019}, abstract = {A set of diboryldiborenes are prepared by the mild, catalyst-free, room-temperature diboration of the B-B triple bonds of doubly base-stabilized diborynes. Two of the product diboryldiborenes are found to be air- and water-stable in the solid state, an effect that is attributed to their high crystallinity and extreme insolubility in a wide range of solvents.}, language = {en} } @article{HocheSchulzDietrichetal.2019, author = {Hoche, Joscha and Schulz, Alexander and Dietrich, Lysanne Monika and Humeniuk, Alexander and Stolte, Matthias and Schmidt, David and Brixner, Tobias and W{\"u}rthner, Frank and Mitric, Roland}, title = {The origin of the solvent dependence of fluorescence quantum yields in dipolar merocyanine dyes}, series = {Chemical Science}, volume = {10}, journal = {Chemical Science}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198707}, pages = {11013}, year = {2019}, abstract = {Fluorophores with high quantum yields are desired for a variety of applications. Optimization of promising chromophores requires an understanding of the non-radiative decay channels that compete with the emission of photons. We synthesized a new derivative of the famous laser dye 4-dicyanomethylen-2-methyl-6-p-dimethylaminostyryl-4H-pyran (DCM),i.e., merocyanine 4-(dicyanomethylene)-2-tert-butyl-6-[3-(3-butyl-benzothiazol-2-ylidene)1-propenyl]-4H-pyran (DCBT). We measured fluorescence lifetimes and quantum yields in a variety of solvents and found a trend opposite to the energy gap law.This motivated a theoretical investigation into the possible non-radiative decay channels. We propose that a barrier to a conical intersection exists that is very sensitive to the solvent polarity. The conical intersection is characterized by a twisted geometry which allows a subsequent photoisomerization. Transient absorption measurements confirmed the formation of a photoisomer in unpolar solvents, while the measurements of fluorescence quantum yields at low temperature demonstrated the existence of an activation energy barrier.}, language = {en} } @article{FarrellGrandeSchmidtetal.2019, author = {Farrell, Jeffrey M. and Grande, Vincenzo and Schmidt, David and W{\"u}rthner, Frank}, title = {A Highly Warped Heptagon-Containing sp\(^2\) Carbon Scaffold via Vinylnaphthyl π-Extension}, series = {Angewandte Chemie International Edition}, volume = {58}, journal = {Angewandte Chemie International Edition}, number = {46}, doi = {10.1002/anie.201909975}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206682}, pages = {16504-16507}, year = {2019}, abstract = {A new strategy is demonstrated for the synthesis of warped, negatively curved, all-sp\(^2\)-carbon π-scaffolds. Multifold C-C coupling reactions are used to transform a polyaromatic borinic acid into a saddle-shaped polyaromatic hydrocarbon (2 ) bearing two heptagonal rings. Notably, this Schwarzite substructure is synthesized in only two steps from an unfunctionalized alkene. A highly warped structure of 2 was revealed by X-ray crystallographic studies and pronounced flexibility of this π-scaffold was ascertained by experimental and computational studies. Compound 2 exhibits excellent solubility, visible range absorption and fluorescence, and readily undergoes two reversible one-electron oxidations at mild potentials.}, language = {en} } @article{ThoelkenThammErbacheretal.2019, author = {Th{\"o}lken, Clemens and Thamm, Markus and Erbacher, Christoph and Lechner, Marcus}, title = {Sequence and structural properties of circular RNAs in the brain of nurse and forager honeybees (Apis mellifera)}, series = {BMC Genomics}, volume = {20}, journal = {BMC Genomics}, doi = {10.1186/s12864-018-5402-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241302}, year = {2019}, abstract = {Background The honeybee (Apis mellifera) represents a model organism for social insects displaying behavioral plasticity. This is reflected by an age-dependent task allocation. The most protruding tasks are performed by young nurse bees and older forager bees that take care of the brood inside the hive and collect food from outside the hive, respectively. The molecular mechanism leading to the transition from nurse bees to foragers is currently under intense research. Circular RNAs, however, were not considered in this context so far. As of today, this group of non-coding RNAs was only known to exist in two other insects, Drosophila melanogaster and Bombyx mori. Here we complement the state of circular RNA research with the first characterization in a social insect. Results We identified numerous circular RNAs in the brain of A. mellifera nurse bees and forager bees using RNA-Seq with exonuclease enrichment. Presence and circularity were verified for the most abundant representatives. Back-splicing in honeybee occurs further towards the end of transcripts and in transcripts with a high number of exons. The occurrence of circularized exons is correlated with length and CpG-content of their flanking introns. The latter coincides with increased DNA-methylation in the respective loci. For two prominent circular RNAs the abundance in worker bee brains was quantified in TaqMan assays. In line with previous findings of circular RNAs in Drosophila, circAmrsmep2 accumulates with increasing age of the insect. In contrast, the levels of circAmrad appear age-independent and correlate with the bee's task. Its parental gene is related to amnesia-resistant memory. Conclusions We provide the first characterization of circRNAs in a social insect. Many of the RNAs identified here show homologies to circular RNAs found in Drosophila and Bombyx, indicating that circular RNAs are a common feature among insects. We find that exon circularization is correlated to DNA-methylation at the flanking introns. The levels of circAmrad suggest a task-dependent abundance that is decoupled from age. Moreover, a GO term analysis shows an enrichment of task-related functions. We conclude that circular RNAs could be relevant for task allocation in honeybee and should be investigated further in this context.}, language = {en} } @article{MayerLoefflerLozaValdesetal.2019, author = {Mayer, Alexander E. and L{\"o}ffler, Mona C. and Loza Vald{\´e}s, Angel E. and Schmitz, Werner and El-Merahbi, Rabih and Trujillo-Viera, Jonathan and Erk, Manuela and Zhang, Thianzhou and Braun, Ursula and Heikenwalder, Mathias and Leitges, Michael and Schulze, Almut and Sumara, Grzegorz}, title = {The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling}, series = {Science Signaling}, journal = {Science Signaling}, edition = {accepted manuscript}, doi = {10.1126/scisignal.aav9150}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250025}, year = {2019}, abstract = {Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.}, language = {en} } @article{SchlottmannSchickeKruegeretal.2019, author = {Schlottmann, Elisabeth and Schicke, David and Kr{\"u}ger, Felix and Lingnau, Benjamin and Schneider, Christian and H{\"o}fling, Sven and L{\"u}dge, Kathy and Porte, Xavier and Reitzenstein, Stephan}, title = {Stochastic polarization switching induced by optical injection in bimodal quantum-dot micropillar lasers}, series = {Optics Express}, volume = {27}, journal = {Optics Express}, number = {20}, doi = {10.1364/OE.27.028816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228603}, pages = {28816-28831}, year = {2019}, abstract = {Mutual coupling and injection locking of semiconductor lasers is of great interest in non-linear dynamics and its applications for instance in secure data communication and photonic reservoir computing. Despite its importance, it has hardly been studied in microlasers operating at mu W light levels. In this context, vertically emitting quantum dot micropillar lasers are of high interest. Usually, their light emission is bimodal, and the gain competition of the associated linearly polarized fundamental emission modes results in complex switching dynamics. We report on selective optical injection into either one of the two fundamental mode components of a bimodal micropillar laser. Both modes can lock to the master laser and influence the non-injected mode by reducing the available gain. We demonstrate that the switching dynamics can be tailored externally via optical injection in very good agreement with our theory based on semi-classical rate equations. (C) 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement}, language = {en} } @article{ScherzadHagenHackenberg2019, author = {Scherzad, Agmal and Hagen, Rudolf and Hackenberg, Stephan}, title = {Current Understanding of Nasal Epithelial Cell Mis-Differentiation}, series = {Journal of Inflammation Research}, volume = {12}, journal = {Journal of Inflammation Research}, doi = {10.2147/JIR.S180853}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228562}, pages = {309-317}, year = {2019}, abstract = {The functional role of the respiratory epithelium is to generate a physical barrier. In addition, the epithelium supports the innate and acquired immune system through various cytokines and chemokines. However, epithelial cells are also involved in the pathogenesis of various respiratory diseases, some of which are mediated by increased permeability of the mucosal membrane or disturbed mucociliary transport. In addition, it has been shown that epithelial cells are involved in the development of inflammatory respiratory diseases. The following review article focuses on the aspects of epithelial mis-differentiation, in particular with respect to nasal mucosal barrier function, epithelial immunogenicity, nasal epithelial-mesenchymal transition and nasal microbiome.}, language = {en} } @article{RascheKumarGershneretal.2019, author = {Rasche, Leo and Kumar, Manoj and Gershner, Grant and Samant, Rohan and Van Hemert, Rudy and Heidemeier, Anke and Lapa, Constantin and Bley, Thorsten and Buck, Andreas and McDonald, James and Hillengass, Jens and Epstein, Joshua and Thanendrarajan, Sharmilan and Schinke, Carolina and van Rhee, Frits and Zangari, Maurizio and Barlogie, Bart and Davies, Faith E. and Morgan, Gareth J. and Weinhold, Niels}, title = {Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis?}, series = {Theranostics}, volume = {9}, journal = {Theranostics}, number = {16}, doi = {10.7150/thno.33289}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224982}, pages = {4756-4763}, year = {2019}, abstract = {Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24\%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10(-10)) and International Staging System 3 (P=0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions: The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM.}, language = {en} } @article{RoyLachanceCohenetal.2019, author = {Roy, Denis Claude and Lachance, Sylvie and Cohen, Sandra and Delisle, Jean-S{\´e}bastien and Kiss, Thomas and Sauvageau, Guy and Busque, Lambert and Ahmad, Imran and Bernard, Lea and Bambace, Nadia and Boum{\´e}dine, Radia S. and Guertin, Marie-Claude and Rezvani, Katayoun and Mielke, Stephan and Perreault, Claude and Roy, Jean}, title = {Allodepleted T-cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft-versus-host disease (GVHD) in the absence of GVHD prophylaxis}, series = {British Journal of Haematology}, volume = {186}, journal = {British Journal of Haematology}, number = {5}, doi = {10.1111/bjh.15970}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227075}, pages = {754-766}, year = {2019}, abstract = {Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 x 10(4)-5 x 10(6) CD3(+) cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0 center dot 3-2 x 10(6) CD3(+) cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0\%, relapse-related mortality was 33\% and overall survival was 67\% in these patients.}, language = {en} } @article{GrollBurdickChoetal.2019, author = {Groll, J and Burdick, J A and Cho, D-W and Derby, B and Gelinsky, M and Heilshorn, S C and J{\"u}ngst, T and Malda, J and Mironov, V A and Nakayama, K and Ovsianikov, A and Sun, W and Takeuchi, S and Yoo, J J and Woodfield, T B F}, title = {A definition of bioinks and their distinction from biomaterial inks}, series = {Biofabrication}, volume = {11}, journal = {Biofabrication}, number = {1}, doi = {10.1088/1758-5090/aaec52}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-253993}, year = {2019}, abstract = {Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384-402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.}, language = {en} } @article{SierraSanchezGutierrezetal.2019, author = {Sierra, Miguel A. and S{\´a}nchez, David and Gutierrez, Rafael and Cuniberti, Gianaurelio and Dom{\´i}nguez-Adame, Francisco and D{\´i}az, Elena}, title = {Spin-polarized electron transmission in DNA-like systems}, series = {Biomolecules}, volume = {10}, journal = {Biomolecules}, number = {1}, issn = {2218-273X}, doi = {10.3390/biom10010049}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193813}, year = {2019}, abstract = {The helical distribution of the electronic density in chiral molecules, such as DNA and bacteriorhodopsin, has been suggested to induce a spin-orbit coupling interaction that may lead to the so-called chirality-induced spin selectivity (CISS) effect. Key ingredients for the theoretical modelling are, in this context, the helically shaped potential of the molecule and, concomitantly, a Rashba-like spin-orbit coupling due to the appearance of a magnetic field in the electron reference frame. Symmetries of these models clearly play a crucial role in explaining the observed effect, but a thorough analysis has been largely ignored in the literature. In this work, we present a study of these symmetries and how they can be exploited to enhance chiral-induced spin selectivity in helical molecular systems.}, language = {en} } @article{SchleicherArbetEngelsBaacketal.2019, author = {Schleicher, Bernd and Arbet-Engels, Axel and Baack, Dominik and Balbo, Matteo and Biland, Adrian and Blank, Michael and Bretz, Thomas and Bruegge, Kai and Bulinski, Michael and Buss, Jens and Doerr, Manuel and Dorner, Daniela and Elsaesser, Dominik and Grischagin, Sergej and Hildebrand, Dorothee and Linhoff, Lena and Mannheim, Karl and Mueller, Sebastian Achim and Neise, Dominik and Neronov, Andrii and Noethe, Maximilian and Paravac, Aleksander and Rhode, Wolfgang and Schulz, Florian and Sedlaczek, Kevin and Shukla, Amit and Sliusar, Vitalii and Willert, Elan and Walter, Roland}, title = {Fractional Variability—A Tool to Study Blazar Variability}, series = {Galaxies}, volume = {7}, journal = {Galaxies}, number = {2}, issn = {2075-4434}, doi = {10.3390/galaxies7020062}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197348}, year = {2019}, abstract = {Active Galactic Nuclei emit radiation over the whole electromagnetic spectrum up to TeV energies. Blazars are one subtype with their jets pointing towards the observer. One of their typical features is extreme variability on timescales, from minutes to years. The fractional variability is an often used parameter for investigating the degree of variability of a light curve. Different detection methods and sensitivities of the instruments result in differently binned data and light curves with gaps. As they can influence the physics interpretation of the broadband variability, the effects of these differences on the fractional variability need to be studied. In this paper, we study the systematic effects of completeness in time coverage and the sampling rate. Using public data from instruments monitoring blazars in various energy ranges, we study the variability of the bright TeV blazars Mrk 421 and Mrk 501 over the electromagnetic spectrum, taking into account the systematic effects, and compare our findings with previous results. Especially in the TeV range, the fractional variability is higher than in previous studies, which can be explained by the much longer (seven years compared to few weeks) and more complete data sample.}, language = {en} } @article{RoedelTessmarGrolletal.2019, author = {R{\"o}del, Michaela and Teßmar, J{\"o}rg and Groll, J{\"u}rgen and Gbureck, Uwe}, title = {Tough and Elastic alpha-Tricalcium Phosphate Cement Composites with Degradable PEG-Based Cross-Linker}, series = {Materials}, volume = {12}, journal = {Materials}, number = {53}, doi = {10.3390/ma12010053}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226437}, pages = {1-20}, year = {2019}, abstract = {Dual setting cements composed of an in situ forming hydrogel and a reactive mineral phase combine high compressive strength of the cement with sufficient ductility and bending strength of the polymeric network. Previous studies were focused on the modification with non-degradable hydrogels based on 2-hydroxyethyl methacrylate (HEMA). Here, we describe the synthesis of suitable triblock degradable poly(ethylene glycol)-poly(lactide) (PEG-PLLA) cross-linker to improve the resorption capacity of such composites. A study with four different formulations was established. As reference, pure hydroxyapatite (HA) cements and composites with 40 wt\% HEMA in the liquid cement phase were produced. Furthermore, HEMA was modified with 10 wt\% of PEG-PLLA cross-linker or a test series containing only 25\% cross-linker was chosen for composites with a fully degradable polymeric phase. Hence, we developed suitable systems with increased elasticity and 5-6 times higher toughn ess values in comparison to pure inorganic cement matrix. Furthermore, conversion rate from alpha-tricalcium phosphate (alpha-TCP) to HA was still about 90\% for all composite formulations, whereas crystal size decreased. Based on this material development and advancement for a dual setting system, we managed to overcome the drawback of brittleness for pure calcium phosphate cements.}, language = {en} } @article{AkshatAaboudAadetal.2019, author = {Akshat, Puri and Aaboud, M. and Aad, G. and Abbott, B. and Abdinov, O. and Abeloos, B. and Abhayasinghe, D. K. and Abidi, S. H. and Abou Zeid, O. S. and Abraham, N. L. and Abramowicz, H. and Abreu, H. and Abulaiti, Y. and Acharya, B. S. and Adachi, S. and Adam, L. and Adamczyk, L. and Adelman, J. and Adersberger, M. and Adiguzel, A. and Adye, T. and Affolder, A. A. and Afik, Y. and Agheorghiesei, C. and Aguilar-Saavedra, J. A. and Ahmadov, F. and Aiellil, G. and Akatsuka, S. and Akesson, T. P. A. and Akilli, E. and Akimov, A. V. and Alberghi, G. L. and Albert, J. and Albicocco, P. and Alconada Verzini, M. J. and Alderweireld, S. and Aleksa, M. and Aleksandrov, I. N. and Alexa, C. and Alexopoulos, T. and Alhroob, M. and Ali, B. and Alimonti, G. and Alison, J. and Andre, S. P. and Allaire, C. and Allbrooke, B. M. M. and Allen, B. W. and Allport, P. P. and Aloisio, A. and Alonso, A. and Alonso, F. and Alpigiani, C. and Alshehri, A. A. and Alstaty, M. I. and Alvarez, Gonzalez B. and Alvarez Piqueras, D. and Alviggi, M. G. and Amadio, B. T. and Amaral, Coutinho, Y. and Ambler, A. and Ambroz, L. and Amelung, C. and Amidei, D. and Amor Dos Santos, S. P. and Amoroso, S. and Amrouche, C. S. and Anastopoulos, C. and Ancu, L. S. and Andari, N. and Andeen, T. and Anders, C. F. and Anders, J. K. and Anderson, K. J. and Andreazza, A. and Andrei, V. and et al,}, title = {Measurement of angular and momentum distributions of charged particles within and around jets in Pb plus Pb and pp collisions at root s(NN)=5.02 TeV with ATLAS at the LHC : XXVIIth International Conference on Ultrarelativistic Nucleus-Nucleus Collisions (Quark Matter 2018)}, series = {Nuclear Physics A}, volume = {982}, journal = {Nuclear Physics A}, number = {2}, doi = {10.1016/j.nuclphysa.2018.09.021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224703}, pages = {177-179}, year = {2019}, abstract = {Studies of the fragmentation of jets into charged particles in heavy-ion collisions can help in understanding the mechanism of jet quenching by the hot and dense QCD matter created in such collisions, the quark-gluon plasma. These proceedings present a measurement of the angular distribution of charged particles around the jet axis in root s(NN) = 5.02 TeV Pb+Pb and pp collisions, done using the ATLAS detector at the LHC. The measurement is performed inside jets reconstructed with the anti-k(t) algorithm with radius parameter R = 0.4, and is extended to regions outside the jet cone. Results are presented as a function of Pb+Pb collision centrality, and both jet and charged-particle transverse momenta.}, language = {en} } @article{SchwedhelmZdziebloAppeltMenzeletal.2019, author = {Schwedhelm, Ivo and Zdzieblo, Daniela and Appelt-Menzel, Antje and Berger, Constantin and Schmitz, Tobias and Schuldt, Bernhard and Franke, Andre and M{\"u}ller, Franz-Josef and Pless, Ole and Schwarz, Thomas and Wiedemann, Philipp and Walles, Heike and Hansmann, Jan}, title = {Automated real-time monitoring of human pluripotent stem cell aggregation in stirred tank reactors}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-48814-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202649}, pages = {12297}, year = {2019}, abstract = {The culture of human induced pluripotent stem cells (hiPSCs) at large scale becomes feasible with the aid of scalable suspension setups in continuously stirred tank reactors (CSTRs). Innovative monitoring options and emerging automated process control strategies allow for the necessary highly defined culture conditions. Next to standard process characteristics such as oxygen consumption, pH, and metabolite turnover, a reproducible and steady formation of hiPSC aggregates is vital for process scalability. In this regard, we developed a hiPSC-specific suspension culture unit consisting of a fully monitored CSTR system integrated into a custom-designed and fully automated incubator. As a step towards cost-effective hiPSC suspension culture and to pave the way for flexibility at a large scale, we constructed and utilized tailored miniature CSTRs that are largely made from three-dimensional (3D) printed polylactic acid (PLA) filament, which is a low-cost material used in fused deposition modelling. Further, the monitoring tool for hiPSC suspension cultures utilizes in situ microscopic imaging to visualize hiPSC aggregation in real-time to a statistically significant degree while omitting the need for time-intensive sampling. Suitability of our culture unit, especially concerning the developed hiPSC-specific CSTR system, was proven by demonstrating pluripotency of CSTR-cultured hiPSCs at RNA (including PluriTest) and protein level.}, 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{ElmaidomyMohammedHassanetal.2019, author = {Elmaidomy, Abeer H. and Mohammed, Rabab and Hassan, Hossam M. and Owis, Asmaa I. and Rateb, Mostafa E. and Khanfar, Mohammad A. and Krischke, Markus and Mueller, Martin J. and Abdelmohsen, Usama Ramadan}, title = {Metabolomic profiling and cytotoxic tetrahydrofurofuran lignans investigations from Premna odorata Blanco}, series = {Metabolites}, volume = {9}, journal = {Metabolites}, number = {10}, issn = {2218-1989}, doi = {10.3390/metabo9100223}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193187}, pages = {223}, year = {2019}, abstract = {Metabolomic profiling of different Premna odorata Blanco (Lamiaceae) organs, bark, wood, young stems, flowers, and fruits dereplicated 20, 20, 10, 20, and 20 compounds, respectively, using LC-HRESIMS. The identified metabolites (1-34) belonged to different chemical classes, including iridoids, flavones, phenyl ethanoids, and lignans. A phytochemical investigation of P. odorata bark afforded one new tetrahydrofurofuran lignan, 4β-hydroxyasarinin 35, along with fourteen known compounds. The structure of the new compound was confirmed using extensive 1D and 2D NMR, and HRESIMS analyses. A cytotoxic investigation of compounds 35-38 against the HL-60, HT-29, and MCF-7 cancer cell lines, using the MTT assay showed that compound 35 had cytotoxic effects against HL-60 and MCF-7 with IC50 values of 2.7 and 4.2 µg/mL, respectively. A pharmacophore map of compounds 35 showed two hydrogen bond acceptor (HBA) aligning the phenoxy oxygen atoms of benzodioxole moieties, two aromatic ring features vectored on the two phenyl rings, one hydrogen bond donor (HBD) feature aligning the central hydroxyl group and thirteen exclusion spheres which limit the boundaries of sterically inaccessible regions of the target's active site.}, language = {en} } @article{DraganovSantidrianMinevetal.2019, author = {Draganov, Dobrin D. and Santidrian, Antonio F. and Minev, Ivelina and Duong, Nguyen and Kilinc, Mehmet Okyay and Petrov, Ivan and Vyalkova, Anna and Lander, Elliot and Berman, Mark and Minev, Boris and Szalay, Aladar A.}, title = {Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers}, series = {Journal of Translational Medicine}, volume = {17}, journal = {Journal of Translational Medicine}, issn = {100}, doi = {10.1186/s12967-019-1829-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226312}, year = {2019}, abstract = {Background Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties. Methods To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations. Results Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor. Conclusions Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach.}, language = {en} } @article{DuanNagelGao2019, author = {Duan, Xiaodong and Nagel, Georg and Gao, Shiqiang}, title = {Mutated channelrhodopsins with increased sodium and calcium permeability}, series = {Applied Sciences}, volume = {9}, journal = {Applied Sciences}, number = {4}, issn = {2076-3417}, doi = {10.3390/app9040664}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197435}, pages = {664}, year = {2019}, abstract = {(1) Background: After the discovery and application of Chlamydomonas reinhardtii channelrhodopsins, the optogenetic toolbox has been greatly expanded with engineered and newly discovered natural channelrhodopsins. However, channelrhodopsins of higher Ca\(^{2+}\) conductance or more specific ion permeability are in demand. (2) Methods: In this study, we mutated the conserved aspartate of the transmembrane helix 4 (TM4) within Chronos and PsChR and compared them with published ChR2 aspartate mutants. (3) Results: We found that the ChR2 D156H mutant (XXM) showed enhanced Na\(^+\) and Ca\(^{2+}\) conductance, which was not noticed before, while the D156C mutation (XXL) influenced the Na\(^+\) and Ca\(^{2+}\) conductance only slightly. The aspartate to histidine and cysteine mutations of Chronos and PsChR also influenced their photocurrent, ion permeability, kinetics, and light sensitivity. Most interestingly, PsChR D139H showed a much-improved photocurrent, compared to wild type, and even higher Na+ selectivity to H\(^+\) than XXM. PsChR D139H also showed a strongly enhanced Ca\(^{2+}\) conductance, more than two-fold that of the CatCh. (4) Conclusions: We found that mutating the aspartate of the TM4 influences the ion selectivity of channelrhodopsins. With the large photocurrent and enhanced Na\(^+\) selectivity and Ca\(^{2+}\) conductance, XXM and PsChR D139H are promising powerful optogenetic tools, especially for Ca\(^{2+}\) manipulation.}, language = {en} } @article{MinevLanderFelleretal.2019, author = {Minev, Boris R. and Lander, Elliot and Feller, John F. and Berman, Mark and Greenwood, Bernadette M. and Minev, Ivelina and Santidrian, Antonio F. and Nguyen, Duong and Draganov, Dobrin and Killinc, Mehmet O. and Vyalkova, Anna and Kesari, Santosh and McClay, Edward and Carabulea, Gabriel and Marincola, Francesco M. and Butterfield, Lisa H. and Szalay, Aladar A.}, title = {First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells}, series = {Journal of Translational Medicine}, volume = {17}, journal = {Journal of Translational Medicine}, doi = {10.1186/s12967-019-2011-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224105}, year = {2019}, abstract = {Background ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML). Methods Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 106 plaque-forming units (PFU) to 1.8 × 107 PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment. Results No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days—an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients' blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition. Conclusions Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility. Trial registration Retrospectively registered (ISRCTN\#10201650) on October 22, 2018.}, language = {en} } @article{DopplerSchusterAppeltshauseretal.2019, author = {Doppler, Kathrin and Schuster, Yasmin and Appeltshauser, Luise and Biko, Lydia and Villmann, Carmen and Weishaupt, Andreas and Werner, Christian and Sommer, Claudia}, title = {Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model}, series = {Journal of Neuroinflammation}, volume = {16}, journal = {Journal of Neuroinflammation}, number = {73}, doi = {10.1186/s12974-019-1462-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200476}, year = {2019}, abstract = {Background: Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods: In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results: Conduction blocks were measured in rats injected with the "acute" IgG more often than after injection of "chronic" IgG (83.3\% versus 35\%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the "acute" IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the "acute IgG". We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions: Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis.}, language = {en} } @article{SchuhmannStollPappetal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Papp, Lena and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region has no impact on blood-brain barrier alterations after cerebral photothrombosis in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms20164036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201284}, year = {2019}, abstract = {Blood-brain barrier (BBB) disruption is a critical event after ischemic stroke, which results in edema formation and hemorrhagic transformation of infarcted tissue. BBB dysfunction following stroke is partly mediated by proinflammatory agents. We recently have shown that high frequency stimulation of the mesencephalic locomotor region (MLR-HFS) exerts an antiapoptotic and anti-inflammatory effect in the border zone of cerebral photothrombotic stroke in rats. Whether MLR-HFS also has an impact on BBB dysfunction in the early stage of stroke is unknown. In this study, rats were subjected to photothrombotic stroke of the sensorimotor cortex and implantation of a stimulating microelectrode into the ipsilesional MLR. Thereafter, either HFS or sham stimulation of the MLR was applied for 24 h. After scarifying the rats, BBB disruption was assessed by determining albumin extravasation and tight junction integrity (claudin 3, claudin 5, and occludin) using Western blot analyses and immunohistochemistry. In addition, by applying zymography, expression of pro-metalloproteinase-9 (pro-MMP-9) was analyzed. No differences were found regarding infarct size and BBB dysfunction between stimulated and unstimulated animals 24 h after induction of stroke. Our results indicate that MLR-HFS neither improves nor worsens the damaged BBB after stroke. Attenuating cytokines/chemokines in the perilesional area, as mediated by MLR-HFS, tend to play a less significant role in preventing the BBB integrity.}, language = {en} } @article{Voulgari‐KokotaAnkenbrandGrimmeretal.2019, author = {Voulgari-Kokota, Anna and Ankenbrand, Markus J. and Grimmer, Gudrun and Steffan-Dewenter, Ingolf and Keller, Alexander}, title = {Linking pollen foraging of megachilid bees to their nest bacterial microbiota}, series = {Ecology and Evolution}, volume = {2019}, journal = {Ecology and Evolution}, number = {9}, issn = {00}, doi = {10.1002/ece3.5599}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201749}, pages = {10788-10800}, year = {2019}, abstract = {Solitary bees build their nests by modifying the interior of natural cavities, and they provision them with food by importing collected pollen. As a result, the microbiota of the solitary bee nests may be highly dependent on introduced materials. In order to investigate how the collected pollen is associated with the nest microbiota, we used metabarcoding of the ITS2 rDNA and the 16S rDNA to simultaneously characterize the pollen composition and the bacterial communities of 100 solitary bee nest chambers belonging to seven megachilid species. We found a weak correlation between bacterial and pollen alpha diversity and significant associations between the composition of pollen and that of the nest microbiota, contributing to the understanding of the link between foraging and bacteria acquisition for solitary bees. Since solitary bees cannot establish bacterial transmission routes through eusociality, this link could be essential for obtaining bacterial symbionts for this group of valuable pollinators.}, language = {en} } @article{HeRauchFriedrichetal.2019, author = {He, Jiang and Rauch, Florian and Friedrich, Alexandra and Sieh, Daniel and Ribbeck, Tatjana and Krummenacher, Ivo and Braunschweig, Holger and Finze, Maik and Marder, Todd B.}, title = {N-Heterocyclic Olefins as Electron Donors in Combination with Triarylborane Acceptors: Synthesis, Optical and Electronic Properties of D-π-A Compounds}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, doi = {10.1002/chem.201903118}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204690}, pages = {13777-13784}, year = {2019}, abstract = {N-heterocyclic olefins (NHOs), relatives of N-heterocyclic carbenes (NHCs), exhibit high nucleophilicity and soft Lewis basic character. To investigate their π-electron donating ability, NHOs were attached to triarylborane π-acceptors (A) giving donor (D)-π-A compounds 1-3. In addition, an enamine π-donor analogue (4) was synthesized for comparison. UV-visible absorption studies show a larger red shift for the NHO-containing boranes than for the enamine analogue, a relative of cyclic (alkyl)(amino) carbenes (CAACs). Solvent-dependent emission studies indicate that 1-4 have moderate intramolecular charge-transfer (ICT) behavior. Electrochemical investigations reveal that the NHO-containing boranes have extremely low reversible oxidation potentials (e.g., for 3, \(E^{ox}_{1/2}\) =-0.40 V vs. ferrocene/ferrocenium, Fc/Fc\(^+\), in THF). Time-dependent (TD) DFT calculations show that the HOMOs of 1-3 are much more destabilized than that of the enamine-containing 4, which confirms the stronger donating ability of NHOs.}, language = {en} } @article{SalmanHaiderSchreinerKendletal.2019, author = {Salman Haider, Malik and Schreiner, Jochen and Kendl, Sabine and Kroiss, Matthias and Luxenhofer, Robert}, title = {A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models}, series = {Macromolecular Bioscience}, volume = {20}, journal = {Macromolecular Bioscience}, number = {1}, doi = {10.1002/mabi.201900178}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206224}, pages = {1900178}, year = {2019}, abstract = {Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14-20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT-loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.}, language = {en} } @article{GonzalezDornerBretzetal.2019, author = {Gonz{\´a}lez, Mar{\´i}a Magdalena and Dorner, Daniela and Bretz, Thomas and Garc{\´i}a-Gonz{\´a}lez, Jos{\´e} Andr{\´e}s}, title = {Unbiased long-term monitoring at TeV energies}, series = {Galaxies}, volume = {7}, journal = {Galaxies}, number = {2}, issn = {2075-4434}, doi = {10.3390/galaxies7020051}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197389}, year = {2019}, abstract = {For the understanding of the variable, transient and non-thermal universe, unbiased long-term monitoring is crucial. To constrain the emission mechanisms at the highest energies, it is important to characterize the very high energy emission and its correlation with observations at other wavelengths. At very high energies, only a limited number of instruments is available. This article reviews the current status of monitoring of the extra-galactic sky at TeV energies.}, language = {en} } @article{WaiderPoppMlinaretal.2019, author = {Waider, Jonas and Popp, Sandy and Mlinar, Boris and Montalbano, Alberto and Bonfiglio, Francesco and Aboagye, Benjamin and Thuy, Elisabeth and Kern, Raphael and Thiel, Christopher and Araragi, Naozumi and Svirin, Evgeniy and Schmitt-B{\"o}hrer, Angelika G. and Corradetti, Renato and Lowry, Christopher A. and Lesch, Klaus-Peter}, title = {Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {245}, issn = {1662-453X}, doi = {10.3389/fnins.2019.00245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196077}, year = {2019}, abstract = {Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.}, language = {en} } @article{BreitenbachLorenzDandekar2019, author = {Breitenbach, Tim and Lorenz, Kristina and Dandekar, Thomas}, title = {How to steer and control ERK and the ERK signaling cascade exemplified by looking at cardiac insufficiency}, series = {International Journal of Molecular Sciences}, volume = {20}, journal = {International Journal of Molecular Sciences}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms20092179}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285164}, year = {2019}, abstract = {Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK\(^{Thr188}\) phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.}, language = {en} } @article{JaiteBuehrenDahmenetal.2019, author = {Jaite, Charlotte and B{\"u}hren, Katharina and Dahmen, Brigitte and Dempfle, Astrid and Becker, Katja and Correll, Christoph U. and Egberts, Karin M. and Ehrlich, Stefan and Fleischhaker, Christian and von Gontard, Alexander and Hahn, Freia and Kolar, David and Kaess, Michael and Legenbauer, Tanja and Renner, Tobias J. and Schulze, Ulrike and Sinzig, Judith and Thomae, Ellen and Weber, Linda and Wessing, Ida and Antony, Gisela and Hebebrand, Johannes and F{\"o}cker, Manuel and Herpertz-Dahlmann, Beate}, title = {Clinical Characteristics of Inpatients with Childhood vs. Adolescent Anorexia Nervosa}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {11}, issn = {2072-6643}, doi = {10.3390/nu11112593}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193160}, pages = {2593}, year = {2019}, abstract = {We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children: n = 72; adolescents: n = 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months, p = 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2, p = 0.004) as well as at discharge (median: 19.3 vs. 15.1, p = 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children.}, language = {en} } @article{ThiessMellerupBraunschweig2019, author = {Thiess, Torsten and Mellerup, Soren K. and Braunschweig, Holger}, title = {B-B Cleavage and Ring-Expansion of a 1,4,2,3-Diazadiborinine with N-Heterocyclic Carbenes}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, number = {59}, doi = {10.1002/chem.201903259}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206173}, pages = {13572-13578}, year = {2019}, abstract = {A 1,4,2,3-diazadiborinine derivative was found to form Lewis adducts with strong two-electron donors such as N-heterocyclic and cyclic (alkyl)(amino)carbenes. Depending on the donor, some of these Lewis pairs are thermally unstable, converting to sole B,N-embedded products upon gentle heating. The products of these reactions, which have been fully characterized by NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction, were identified as B,N-heterocycles with fused 1,5,2,4-diazadiborepine and 1,4,2-diazaborinine rings. Computational modelling of the reaction mechanism provides insight into the formation of these unique structures, suggesting that a series of B-H, C-N, and B-B bond activation steps are responsible for these "intercalation" reactions between the 1,4,2,3-diazadiborinine and NHCs.}, language = {en} } @article{OPUS4-31955, title = {Search for light resonances decaying to boosted quark pairs and produced in association with a photon or a jet in proton-proton collisions at root s=13 TeV with the ATLAS detector}, series = {Physics Letters B}, volume = {788}, journal = {Physics Letters B}, organization = {The ATLAS Collaboration}, doi = {10.1016/j.physletb.2018.09.062}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319552}, pages = {316-335}, year = {2019}, abstract = {This Letter presents a search for new light resonances decaying to pairs of quarks and produced in association with a high-p(T) photon or jet. The dataset consists of proton-proton collisions with an integrated luminosity of 36.1 fb(-1) at a centre-of-mass energy of root s = 13 TeV recorded by the ATLAS detector at the Large Hadron Collider. Resonance candidates are identified as massive large-radius jets with substructure consistent with a particle decaying into a quark pair. The mass spectrum of the candidates is examined for local excesses above background. No evidence of a new resonance is observed in the data, which are used to exclude the production of a lepto-phobic axial-vector Z' boson. (C) 2018 The Author(s). Published by Elsevier B.V.}, language = {en} } @article{LewitzkiKlementKosmalaetal.2019, author = {Lewitzki, Victor and Klement, Rainer J. and Kosmala, Rebekka and Lisowski, Dominik and Flentje, Michael and Polat, B{\"u}lent}, title = {Accelerated hyperfractionated radiochemotherapy with temozolomide is equivalent to normofractionated radiochemotherapy in a retrospective analysis of patients with glioblastoma}, series = {Radiation Oncology}, volume = {14}, journal = {Radiation Oncology}, doi = {10.1186/s13014-019-1427-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202614}, pages = {227}, year = {2019}, abstract = {Background Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ. Methods Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method. Results Median overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95\% CI 1.47-3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95\% CI 1.21-3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504). Conclusions Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.}, 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{LandmanLauth2019, author = {Landman, Todd and Lauth, Hans-Joachim}, title = {Political Trade-Offs: Democracy and Governance in a Changing World}, series = {Politics and Governance}, volume = {7}, journal = {Politics and Governance}, number = {4}, issn = {2183-2463}, doi = {10.17645/pag.v7i4.2642}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144308}, pages = {237-242}, year = {2019}, abstract = {The investigation of trade-offs in political science receives only limited attention, although many scholars acknowledge the importance of trade-offs across a variety of different areas. A systematic and comprehensive examination of the topic is missing. This thematic issue of Politics and Governance sheds light on this research deficit by providing a holistic but also an integrative view on trade-offs in the political realm for the first time. Researchers of trade-offs from different political areas present and discuss their findings, and promote a fruitful exchange, which overcomes the current isolation of the approaches. They consider the theoretical and methodological questions as well as the identification of empirical tradeoffs. Furthermore, they provide insights into the possibility to balance trade-offs and strategies, which could help actors to find such compromises.}, language = {en} } @article{SchuhmannStollBohretal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms20092341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201355}, year = {2019}, abstract = {Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson's disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.}, language = {en} } @article{RadchukRajivPotokinaetal.2019, author = {Radchuk, Volodymyr and Rajiv, Sharma and Potokina, Elena and Radchuk, Ruslana and Weier, Diana and Munz, Eberhard and Schreiber, Miriam and Mascher, Martin and Stein, Nils and Wicker, Thomas and Kilian, Benjamin and Borisjuk, Ljudmilla}, title = {The highly divergent \(Jekyll\) genes, required for sexual reproduction, are lineage specific for the related grass tribes Triticeae and Bromeae}, series = {Plant Journal}, volume = {98}, journal = {Plant Journal}, number = {6}, doi = {10.1111/tpj.14363}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224769}, pages = {961-974}, year = {2019}, abstract = {Phylogenetically related groups of species contain lineage-specific genes that exhibit no sequence similarity to any genes outside the lineage. We describe here that the Jekyll gene, required for sexual reproduction, exists in two much diverged allelic variants, Jek1 and Jek3. Despite low similarity, the Jek1 and Jek3 proteins share identical signal peptides, conserved cysteine positions and direct repeats. The Jek1/Jek3 sequences are located at the same chromosomal locus and inherited in a monogenic Mendelian fashion. Jek3 has a similar expression as Jek1 and complements the Jek1 function in Jek1-deficient plants. Jek1 and Jek3 allelic variants were almost equally distributed in a collection of 485 wild and domesticated barley accessions. All domesticated barleys harboring the Jek1 allele belong to single haplotype J1-H1 indicating a genetic bottleneck during domestication. Domesticated barleys harboring the Jek3 allele consisted of three haplotypes. Jekyll-like sequences were found only in species of the closely related tribes Bromeae and Triticeae but not in other Poaceae. Non-invasive magnetic resonance imaging revealed intrinsic grain structure in Triticeae and Bromeae, associated with the Jekyll function. The emergence of Jekyll suggests its role in the separation of the Bromeae and Triticeae lineages within the Poaceae and identifies the Jekyll genes as lineage-specific.}, language = {en} } @article{RaynerColemanPurvesetal.2019, author = {Rayner, Christopher and Coleman, Jonathan R. I. and Purves, Kirstin L. and Hodsoll, John and Goldsmith, Kimberley and Alpers, Georg W. and Andersson, Evelyn and Arolt, Volker and Boberg, Julia and B{\"o}gels, Susan and Creswell, Cathy and Cooper, Peter and Curtis, Charles and Deckert, J{\"u}rgen and Domschke, Katharina and El Alaoui, Samir and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Grocholewski, Anja and Hahlweg, Kurt and Hamm, Alfons and Hedman, Erik and Heiervang, Einar R. and Hudson, Jennifer L. and J{\"o}hren, Peter and Keers, Robert and Kircher, Tilo and Lang, Thomas and Lavebratt, Catharina and Lee, Sang-hyuck and Lester, Kathryn J. and Lindefors, Nils and Margraf, J{\"u}rgen and Nauta, Maaike and Pan{\´e}-Farr{\´e}, Christiane A. and Pauli, Paul and Rapee, Ronald M. and Reif, Andreas and Rief, Winfried and Roberts, Susanna and Schalling, Martin and Schneider, Silvia and Silverman, Wendy K. and Str{\"o}hle, Andreas and Teismann, Tobias and Thastum, Mikael and Wannem{\"u}ller, Andre and Weber, Heike and Wittchen, Hans-Ulrich and Wolf, Christiane and R{\"u}ck, Christian and Breen, Gerome and Eley, Thalia C.}, title = {A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, number = {150}, doi = {10.1038/s41398-019-0481-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225048}, pages = {1-13}, year = {2019}, abstract = {Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.}, language = {en} } @article{SchlegelPetersDooseetal.2019, author = {Schlegel, Jan and Peters, Simon and Doose, S{\"o}ren and Schubert-Unkmeir, Alexandra and Sauer, Markus}, title = {Super-resolution microscopy reveals local accumulation of plasma membrane gangliosides at Neisseria meningitidis Invasion Sites}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {194}, doi = {10.3389/fcell.2019.00194}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201639}, year = {2019}, abstract = {Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for epidemic meningitis and sepsis worldwide. A critical step in the development of meningitis is the interaction of bacteria with cells forming the blood-cerebrospinal fluid barrier, which requires tight adhesion of the pathogen to highly specialized brain endothelial cells. Two endothelial receptors, CD147 and the β2-adrenergic receptor, have been found to be sequentially recruited by meningococci involving the interaction with type IV pilus. Despite the identification of cellular key players in bacterial adhesion the detailed mechanism of invasion is still poorly understood. Here, we investigated cellular dynamics and mobility of the type IV pilus receptor CD147 upon treatment with pili enriched fractions and specific antibodies directed against two extracellular Ig-like domains in living human brain microvascular endothelial cells. Modulation of CD147 mobility after ligand binding revealed by single-molecule tracking experiments demonstrates receptor activation and indicates plasma membrane rearrangements. Exploiting the binding of Shiga (STxB) and Cholera toxin B (CTxB) subunits to the two native plasma membrane sphingolipids globotriaosylceramide (Gb3) and raft-associated monosialotetrahexosylganglioside GM1, respectively, we investigated their involvement in bacterial invasion by super-resolution microscopy. Structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM) unraveled accumulation and coating of meningococci with GM1 upon cellular uptake. Blocking of CTxB binding sites did not impair bacterial adhesion but dramatically reduced bacterial invasion efficiency. In addition, cell cycle arrest in G1 phase induced by serum starvation led to an overall increase of GM1 molecules in the plasma membrane and consequently also in bacterial invasion efficiency. Our results will help to understand downstream signaling events after initial type IV pilus-host cell interactions and thus have general impact on the development of new therapeutics targeting key molecules involved in infection.}, 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{RuboGamer2019, author = {Rubo, Marius and Gamer, Matthias}, title = {Visuo-tactile congruency influences the body schema during full body ownership illusion}, series = {Consciousness and Cognition}, volume = {73}, journal = {Consciousness and Cognition}, doi = {10.1016/j.concog.2019.05.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227095}, pages = {UNSP 102758, 1-14}, year = {2019}, abstract = {Previous research showed that full body ownership illusions in virtual reality (VR) can be robustly induced by providing congruent visual stimulation, and that congruent tactile experiences provide a dispensable extension to an already established phenomenon. Here we show that visuo-tactile congruency indeed does not add to already high measures for body ownership on explicit measures, but does modulate movement behavior when walking in the laboratory. Specifically, participants who took ownership over a more corpulent virtual body with intact visuo-tactile congruency increased safety distances towards the laboratory's walls compared to participants who experienced the same illusion with deteriorated visuo-tactile congruency. This effect is in line with the body schema more readily adapting to a more corpulent body after receiving congruent tactile information. We conclude that the action-oriented, unconscious body schema relies more heavily on tactile information compared to more explicit aspects of body ownership.}, language = {en} } @article{NeugebauerSchneiderKollmar2019, author = {Neugebauer, Hermann and Schneider, Hauke and Kollmar, Rainer}, title = {Letter by Neugebauer et al. regarding article "Hypothermia after decompressive hemicraniectomy in treatment of malignant middle cerebral artery stroke: comment on the randomized clinical trial"}, series = {Critical Care}, volume = {23}, journal = {Critical Care}, doi = {10.1186/s13054-019-2600-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232268}, year = {2019}, abstract = {No abstract available.}, language = {en} } @article{KoenigPechmannThieleetal.2019, author = {K{\"o}nig, Kirsten and Pechmann, Astrid and Thiele, Simone and Walter, Maggie C. and Schorling, David and Tassoni, Adrian and Lochm{\"u}ller, Hanns and M{\"u}ller-Reible, Clemens and Kirschner, Janbernd}, title = {De-duplicating patient records from three independent data sources reveals the incidence of rare neuromuscular disorders in Germany}, series = {Orphanet Journal of Rare Diseases}, volume = {14}, journal = {Orphanet Journal of Rare Diseases}, doi = {10.1186/s13023-019-1125-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222807}, year = {2019}, abstract = {Background Estimation of incidence in rare diseases is often challenging due to unspecific and incomplete coding and recording systems. Patient- and health care provider-driven data collections are held with different organizations behind firewalls to protect the privacy of patients. They tend to be fragmented, incomplete and their aggregation leads to further inaccuracies, as the duplicated records cannot easily be identified. We here report about a novel approach to evaluate the incidences of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) in Germany. Methods We performed a retrospective epidemiological study collecting data from patients with dystrophinopathies (DMD and Becker muscular dystrophy) and SMA born between 1995 and 2018. We invited all neuromuscular centers, genetic institutes and the patient registries for DMD and SMA in Germany to participate in the data collection. A novel web-based application for data entry was developed converting patient identifying information into a hash code. Duplicate entries were reliably allocated to the distinct patient. Results We collected 5409 data entries in our web-based database representing 1955 distinct patients with dystrophinopathies and 1287 patients with SMA. 55.0\% of distinct patients were found in one of the 3 data sources only, while 32.0\% were found in 2, and 13.0\% in all 3 data sources. The highest number of SMA patients was reported by genetic testing laboratories, while for DMD the highest number was reported by the clinical specialist centers. After the removal of duplicate records, the highest yearly incidence for DMD was calculated as 2.57:10,000 in 2001 and the highest incidence for SMA as 1.36:10,000 in 2014. Conclusion With our novel approach (compliant with data protection regulations), we were able to identify unique patient records and estimate the incidence of DMD and SMA in Germany combining and de-duplicating data from patient registries, genetic institutes, and clinical care centers. Although we combined three different data sources, an unknown number of patients might not have been reported by any of these sources. Therefore, our results reflect the minimal incidence of these diseases.}, language = {en} } @article{SepahiFaustSturmetal.2019, author = {Sepahi, Ilnaz and Faust, Ulrike and Sturm, Marc and Bosse, Kristin and Kehrer, Martin and Heinrich, Tilman and Grundman-Hauser, Kathrin and Bauer, Peter and Ossowski, Stephan and Susak, Hana and Varon, Raymonda and Schr{\"o}ck, Evelin and Niederacher, Dieter and Auber, Bernd and Sutter, Christian and Arnold, Norbert and Hahnen, Eric and Dworniczak, Bernd and Wang-Gorke, Shan and Gehrig, Andrea and Weber, Bernhard H. F. and Engel, Christoph and Lemke, Johannes R. and Hartkopf, Andreas and Huu Phuc, Nguyen and Riess, Olaf and Schroeder, Christopher}, title = {Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women}, series = {BMC Cancer}, volume = {19}, journal = {BMC Cancer}, doi = {10.1186/s12885-019-5946-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237676}, year = {2019}, abstract = {Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72\%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00-27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2\%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6\%; 95\%-CI 24.7 - 47.7\%) compared to 16 women of controls (26.7\%; 95\%-CI 16.1 to 39.7\%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95\%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.}, language = {en} } @article{WiechmannRoehSaueretal.2019, author = {Wiechmann, Tobias and R{\"o}h, Simone and Sauer, Susann and Czamara, Darina and Arloth, Janine and K{\"o}del, Maik and Beintner, Madita and Knop, Lisanne and Menke, Andreas and Binder, Elisabeth B. and Proven{\c{c}}al, Nadine}, title = {Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus}, series = {Clinical Epigenetics}, volume = {11}, journal = {Clinical Epigenetics}, doi = {10.1186/s13148-019-0682-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233673}, year = {2019}, abstract = {Background Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported. Results We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS. Conclusion Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.}, language = {en} } @article{KolbMaeurerSunderkoetterKukowskietal.2019, author = {Kolb-M{\"a}urer, Annette and Sunderk{\"o}tter, Cord and Kukowski, Borries and Meuth, Sven G.}, title = {An update on Peginterferon beta-1a Management in Multiple Sclerosis: results from an interdisciplinary Board of German and Austrian Neurologists and dermatologists}, series = {BMC Neurology}, volume = {19}, journal = {BMC Neurology}, doi = {10.1186/s12883-019-1354-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224646}, year = {2019}, abstract = {Background: Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125g dosed every 2weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6years was shown. Main text In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted. Conclusions This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience.}, language = {en} } @article{BartelPeinPopperetal.2019, author = {Bartel, Karin and Pein, Helmut and Popper, Bastian and Schmitt, Sabine and Janaki-Raman, Sudha and Schulze, Almut and Lengauer, Florian and Koeberle, Andreas and Werz, Oliver and Zischka, Hans and M{\"u}ller, Rolf and Vollmar, Angelika M. and Schwarzenberg, Karin von}, title = {Connecting lysosomes and mitochondria - a novel role for lipid metabolism in cancer cell death}, series = {Cell Communication and Signaling}, volume = {17}, journal = {Cell Communication and Signaling}, doi = {10.1186/s12964-019-0399-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221524}, year = {2019}, abstract = {Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors.}, language = {en} } @article{ReinermannGessnerAsametal.2019, author = {Reinermann, Sophie and Gessner, Ursula and Asam, Sarah and Kuenzer, Claudia and Dech, Stefan}, title = {The Effect of Droughts on Vegetation Condition in Germany: An Analysis Based on Two Decades of Satellite Earth Observation Time Series and Crop Yield Statistics}, series = {Remote Sensing}, volume = {11}, journal = {Remote Sensing}, number = {15}, doi = {10.3390/rs11151783}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225165}, pages = {1783, 1-21}, year = {2019}, abstract = {Central Europe experienced several droughts in the recent past, such as in the year 2018, which was characterized by extremely low rainfall rates and high temperatures, resulting in substantial agricultural yield losses. Time series of satellite earth observation data enable the characterization of past drought events over large temporal and spatial scales. Within this study, Moderate Resolution Spectroradiometer (MODIS) Enhanced Vegetation Index (EVI) (MOD13Q1) 250 m time series were investigated for the vegetation periods of 2000 to 2018. The spatial and temporal development of vegetation in 2018 was compared to other dry and hot years in Europe, like the drought year 2003. Temporal and spatial inter- and intra-annual patterns of EVI anomalies were analyzed for all of Germany and for its cropland, forest, and grassland areas individually. While vegetation development in spring 2018 was above average, the summer months of 2018 showed negative anomalies in a similar magnitude as in 2003, which was particularly apparent within grassland and cropland areas in Germany. In contrast, the year 2003 showed negative anomalies during the entire growing season. The spatial pattern of vegetation status in 2018 showed high regional variation, with north-eastern Germany mainly affected in June, north-western parts in July, and western Germany in August. The temporal pattern of satellite-derived EVI deviances within the study period 2000-2018 were in good agreement with crop yield statistics for Germany. The study shows that the EVI deviation of the summer months of 2018 were among the most extreme in the study period compared to other years. The spatial pattern and temporal development of vegetation condition between the drought years differ.}, language = {en} } @article{GrebinykPrylutskaGrebinyketal.2019, author = {Grebinyk, Anna and Prylutska, Svitlana and Grebinyk, Sergii and Prylutskyy, Yuriy and Ritter, Uwe and Matyshevska, Olga and Dandekar, Thomas and Frohme, Marcus}, title = {Complexation with C\(_{60}\) fullerene increases doxorubicin efficiency against leukemic cells in vitro}, series = {Nanoscale Research Letters}, volume = {14}, journal = {Nanoscale Research Letters}, number = {61}, doi = {10.1186/s11671-019-2894-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228257}, year = {2019}, abstract = {Conventional anticancer chemotherapy is limited because of severe side effects as well as a quickly evolving multidrug resistance of the tumor cells. To address this problem, we have explored a C\(_{60}\) fullerene-based nanosized system as a carrier for anticancer drugs for an optimized drug delivery to leukemic cells.Here, we studied the physicochemical properties and anticancer activity of C\(_{60}\) fullerene noncovalent complexes with the commonly used anticancer drug doxorubicin. C\(_{60}\)-Doxorubicin complexes in a ratio 1:1 and 2:1 were characterized with UV/Vis spectrometry, dynamic light scattering, and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The obtained analytical data indicated that the 140-nm complexes were stable and could be used for biological applications. In leukemic cell lines (CCRF-CEM, Jurkat, THP1 and Molt-16), the nanocomplexes revealed 3.5 higher cytotoxic potential in comparison with the free drug in a range of nanomolar concentrations. Also, the intracellular drug's level evidenced C\(_{60}\) fullerene considerable nanocarrier function.The results of this study indicated that C\(_{60}\) fullerene-based delivery nanocomplexes had a potential value for optimization of doxorubicin efficiency against leukemic cells.}, language = {en} } @article{EbnerWoeckelSchwentneretal.2019, author = {Ebner, Florian and W{\"o}ckel, Achim and Schwentner, Lukas and Blettner, Maria and Janni, Wolfgang and Kreienberg, Rolf and Wischnewsky, Manfred}, title = {Does the number of removed axillary lymphnodes in high risk breast cancer patients influence the survival?}, series = {BMC Cancer}, volume = {19}, journal = {BMC Cancer}, doi = {10.1186/s12885-019-5292-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226445}, year = {2019}, abstract = {Background The decision making process for axillary dissection has changed in recent years for patients with early breast cancer and positive sentinel lymph nodes (LN). The question now arises, what is the optimal surgical treatment for patients with positive axillary LN (pN+). This article tries to answer the following questions: (1) Is there a survival benefit for breast cancer patients with 3 or more positive LN (pN3+) and with more than 10 removed LN? (2) Is there a survival benefit for high risk breast cancer patients (triple negative or Her2 + breast cancer) and with 3 or more positive LN (pN3+) with more than 10 removed LN? (3) In pN + patients is the prognostic value of the lymph node ratio (LNR) of pN+/pN removed impaired if 10 or less LN are removed? Methods A retrospective database analysis of the multi center cohort database BRENDA (breast cancer under evidence based guidelines) with data from 9625 patients from 17 breast centers was carried out. Guideline adherence was defined by the 2008 German National consensus guidelines. Results 2992 out of 9625 patients had histological confirmed positive lymph nodes. The most important factors for survival were intrinsic sub types, tumor size and guideline adherent chemo- and hormonal treatment (and age at diagnosis for overall survival (OAS)). Uni-and multivariable analyses for recurrence free survival (RFS) and OAS showed no significant survival benefit when removing more than 10 lymph nodes even for high-risk patients. The mean and median of LNR were significantly higher in the pN+ patients with ≤10 excised LN compared to patients with > 10 excised LN. LNR was in both, uni-and multivariable, analysis a highly significant prognostic factor for RFS and OAS in both subgroups of pN + patients with less respective more than 10 excised LN. Multivariable COX regression analysis was adjusted by age, tumor size, intrinsic sub types and guideline adherent adjuvant systemic therapy. Conclusion The removal of more than 10 LN did not result in a significant survival benefit even in high risk pN + breast cancer patients.}, language = {en} } @article{RadevaWalterStachetal.2019, author = {Radeva, Mariya Y. and Walter, Elias and Stach, Ramona Alexandra and Yazdi, Amir S. and Schlegel, Nicolas and Sarig, Ofer and Sprecher, Eli and Waschke, Jens}, title = {ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.00770}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224910}, pages = {770, 1-11}, year = {2019}, abstract = {Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1 alpha, IL-6, TNF alpha, and IFN-gamma was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1 alpha and IL-6 was enhanced in some experiments but not in others whereas release of TNF-alpha dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling.}, language = {en} } @article{LeistnerSommerKanofskyetal.2019, author = {Leistner, Marcus and Sommer, Stefanie and Kanofsky, Peer and Leyh, Rainer and Sommer, Sebastian-Patrick}, title = {Ischemia time impacts on respiratory chain functions and Ca\(^{2+}\)-handling of cardiac subsarcolemmal mitochondria subjected to ischemia reperfusion injury}, series = {Journal of Cardiothoracic Surgery}, volume = {14}, journal = {Journal of Cardiothoracic Surgery}, doi = {10.1186/s13019-019-0911-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236455}, year = {2019}, abstract = {Background Mitochondrial impairment can result from myocardial ischemia reperfusion injury (IR). Despite cardioplegic arrest, IR-associated cardiodepression is a major problem in heart surgery. We determined the effect of increasing ischemia time on the respiratory chain (RC) function, the inner membrane polarization and Ca\(^{2+}\) homeostasis of rat cardiac subsarcolemmal mitochondria (SSM). Methods Wistar rat hearts were divided into 4 groups of stop-flow induced warm global IR using a pressure-controlled Langendorff system: 0, 15, 30 and 40 min of ischemia with 30 min of reperfusion, respectively. Myocardial contractility was determined from left ventricular pressure records (dP/dt, dPmax) with an intraventricular balloon. Following reperfusion, SSM were isolated and analyzed regarding electron transport chain (ETC) coupling by polarography (Clark-Type electrode), membrane polarization (JC1 fluorescence) and Ca2+-handling in terms of Ca\(^{2+}\)-induced swelling and Ca\(^{2+}\)-uptake/release (Calcium Green-5 N® fluorescence). Results LV contractility and systolic pressure during reperfusion were impaired by increasing ischemic times. Ischemia reduced ETC oxygen consumption in IR40/30 compared to IR0/30 at complex I-V (8.1 ± 1.2 vs. 18.2 ± 2.0 nmol/min) and II-IV/V (16.4 ± 2.6/14.8 ± 2.3 vs. 2.3 ± 0.6 nmol/min) in state 3 respiration (p < 0.01). Relative membrane potential revealed a distinct hyperpolarization in IR30/30 and IR40/30 (171.5 ± 17.4\% and 170.9 ± 13.5\%) compared to IR0/30 (p < 0.01), wearing off swiftly after CCCP-induced uncoupling. Excess mitochondrial permeability transition pore (mPTP)-gated Ca\(^{2+}\)-induced swelling was recorded in all groups and was most pronounced in IR40/30. Pyruvate addition for mPTP blocking strongly reduced SSM swelling in IR40/30 (relative AUC, ± pyruvate; IR0/30: 1.00 vs. 0.61, IR15/30: 1.68 vs. 1.00, IR30/30: 1.42 vs. 0.75, IR40/30: 1.97 vs. 0.85; p < 0.01). Ca2+-uptake remained unaffected by previous IR. Though Ca\(^{2+}\)-release was delayed for ≥30 min of ischemia (p < 0.01), Ca\(^{2+}\) retention was highest in IR15/30 (RFU; IR0/30: 6.3 ± 3.6, IR 15/30 42.9 ± 5.0, IR30/30 15.9 ± 3.8, IR40/30 11.5 ± 6.6; p ≤ 0.01 for IR15/30 against all other groups). Conclusions Ischemia prolongation in IR injury gradually impaired SSM in terms of respiratory chain function and Ca\(^{2+}\)-homeostasis. Membrane hyperpolarization appears to be responsible for impaired Ca2+-cycling and ETC function. Ischemia time should be considered an important factor influencing IR experimental data on subsarcolemmal mitochondria. Periods of warm global ischemia should be minimized during cardiac surgery to avoid excessive damage to SSMs.}, language = {en} } @article{ScharnaglKempfSchilling2019, author = {Scharnagl, Julian and Kempf, Florian and Schilling, Klaus}, title = {Combining Distributed Consensus with Robust H-infinity-Control for Satellite Formation Flying}, series = {Electronics}, volume = {8}, journal = {Electronics}, number = {319}, doi = {10.3390/electronics8030319}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228431}, pages = {1-27}, year = {2019}, abstract = {Control methods that guarantee stability in the presence of uncertainties are mandatory in space applications. Further, distributed control approaches are beneficial in terms of scalability and to achieve common goals, especially in multi-agent setups like formation control. This paper presents a combination of robust H-infinity control and distributed control using the consensus approach by deriving a distributed consensus-based generalized plant description that can be used in H-infinity synthesis. Special focus was set towards space applications, namely satellite formation flying. The presented results show the applicability of the developed distributed robust control method to a simple, though realistic space scenario, namely a spaceborne distributed telescope. By using this approach, an arbitrary number of satellites/agents can be controlled towards an arbitrary formation geometry. Because of the combination with robust H-infinity control, the presented method satisfies the high stability and robustness demands as found e.g., in space applications.}, language = {en} } @article{LoefflerWirthKreuzHoppetal.2019, author = {Loeffler-Wirth, Henry and Kreuz, Markus and Hopp, Lydia and Arakelyan, Arsen and Haake, Andrea and Cogliatti, Sergio B. and Feller, Alfred C. and Hansmann, Martin-Leo and Lenze, Dido and M{\"o}ller, Peter and M{\"u}ller-Hermelink, Hans Konrad and Fortenbacher, Erik and Willscher, Edith and Ott, German and Rosenwald, Andreas and Pott, Christiane and Schwaenen, Carsten and Trautmann, Heiko and Wessendorf, Swen and Stein, Harald and Szczepanowski, Monika and Tr{\"u}mper, Lorenz and Hummel, Michael and Klapper, Wolfram and Siebert, Reiner and Loeffler, Markus and Binder, Hans}, title = {A modular transcriptome map of mature B cell lymphomas}, series = {Genome Medicine}, volume = {11}, journal = {Genome Medicine}, doi = {10.1186/s13073-019-0637-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237262}, year = {2019}, abstract = {Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.}, language = {en} } @article{GrubisicHaimBhusaletal.2019, author = {Grubisic, Maja and Haim, Abraham and Bhusal, Pramod and Dominoni, Davide M. and Gabriel, Katharina M. A. and Jechow, Andreas and Kupprat, Franziska and Lerner, Amit and Marchant, Paul and Riley, William and Stebelova, Katarina and van Grunsven, Roy H. A. and Zeman, Michal and Zubidat, Abed E. and H{\"o}lker, Franz}, title = {Light Pollution, Circadian Photoreception, and Melatonin in Vertebrates}, series = {Sustainability}, volume = {11}, journal = {Sustainability}, number = {22}, issn = {2071-1050}, doi = {10.3390/su11226400}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193095}, year = {2019}, abstract = {Artificial light at night (ALAN) is increasing exponentially worldwide, accelerated by the transition to new efficient lighting technologies. However, ALAN and resulting light pollution can cause unintended physiological consequences. In vertebrates, production of melatonin—the "hormone of darkness" and a key player in circadian regulation—can be suppressed by ALAN. In this paper, we provide an overview of research on melatonin and ALAN in vertebrates. We discuss how ALAN disrupts natural photic environments, its effect on melatonin and circadian rhythms, and different photoreceptor systems across vertebrate taxa. We then present the results of a systematic review in which we identified studies on melatonin under typical light-polluted conditions in fishes, amphibians, reptiles, birds, and mammals, including humans. Melatonin is suppressed by extremely low light intensities in many vertebrates, ranging from 0.01-0.03 lx for fishes and rodents to 6 lx for sensitive humans. Even lower, wavelength-dependent intensities are implied by some studies and require rigorous testing in ecological contexts. In many studies, melatonin suppression occurs at the minimum light levels tested, and, in better-studied groups, melatonin suppression is reported to occur at lower light levels. We identify major research gaps and conclude that, for most groups, crucial information is lacking. No studies were identified for amphibians and reptiles and long-term impacts of low-level ALAN exposure are unknown. Given the high sensitivity of vertebrate melatonin production to ALAN and the paucity of available information, it is crucial to research impacts of ALAN further in order to inform effective mitigation strategies for human health and the wellbeing and fitness of vertebrates in natural ecosystems.}, language = {en} } @article{HeydarianYangSchweinlinetal.2019, author = {Heydarian, Motaharehsadat and Yang, Tao and Schweinlin, Matthias and Steinke, Maria and Walles, Heike and Rudel, Thomas and Kozjak-Pavlovic, Vera}, title = {Biomimetic human tissue model for long-term study of Neisseria gonorrhoeae infection}, series = {Frontiers in Microbiology}, volume = {10}, journal = {Frontiers in Microbiology}, number = {1740}, issn = {1664-302X}, doi = {10.3389/fmicb.2019.01740}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197912}, year = {2019}, abstract = {Gonorrhea is the second most common sexually transmitted infection in the world and is caused by Gram-negative diplococcus Neisseria gonorrhoeae. Since N. gonorrhoeae is a human-specific pathogen, animal infection models are only of limited use. Therefore, a suitable in vitro cell culture model for studying the complete infection including adhesion, transmigration and transport to deeper tissue layers is required. In the present study, we generated three independent 3D tissue models based on porcine small intestinal submucosa (SIS) scaffold by co-culturing human dermal fibroblasts with human colorectal carcinoma, endometrial epithelial, and male uroepithelial cells. Functional analyses such as transepithelial electrical resistance (TEER) and FITC-dextran assay indicated the high barrier integrity of the created monolayer. The histological, immunohistochemical, and ultra-structural analyses showed that the 3D SIS scaffold-based models closely mimic the main characteristics of the site of gonococcal infection in human host including the epithelial monolayer, the underlying connective tissue, mucus production, tight junction, and microvilli formation. We infected the established 3D tissue models with different N. gonorrhoeae strains and derivatives presenting various phenotypes regarding adhesion and invasion. The results indicated that the disruption of tight junctions and increase in interleukin production in response to the infection is strain and cell type-dependent. In addition, the models supported bacterial survival and proved to be better suitable for studying infection over the course of several days in comparison to commonly used Transwell® models. This was primarily due to increased resilience of the SIS scaffold models to infection in terms of changes in permeability, cell destruction and bacterial transmigration. In summary, the SIS scaffold-based 3D tissue models of human mucosal tissues represent promising tools for investigating N. gonorrhoeae infections under close-to-natural conditions.}, language = {en} } @article{WeigandWurmDechetal.2019, author = {Weigand, Matthias and Wurm, Michael and Dech, Stefan and Taubenb{\"o}ck, Hannes}, title = {Remote sensing in environmental justice research—a review}, series = {ISPRS International Journal of Geo-Information}, volume = {8}, journal = {ISPRS International Journal of Geo-Information}, number = {1}, issn = {2220-9964}, doi = {10.3390/ijgi8010020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196950}, year = {2019}, abstract = {Human health is known to be affected by the physical environment. Various environmental influences have been identified to benefit or challenge people's physical condition. Their heterogeneous distribution in space results in unequal burdens depending on the place of living. In addition, since societal groups tend to also show patterns of segregation, this leads to unequal exposures depending on social status. In this context, environmental justice research examines how certain social groups are more affected by such exposures. Yet, analyses of this per se spatial phenomenon are oftentimes criticized for using "essentially aspatial" data or methods which neglect local spatial patterns by aggregating environmental conditions over large areas. Recent technological and methodological developments in satellite remote sensing have proven to provide highly detailed information on environmental conditions. This narrative review therefore discusses known influences of the urban environment on human health and presents spatial data and applications for analyzing these influences. Furthermore, it is discussed how geographic data are used in general and in the interdisciplinary research field of environmental justice in particular. These considerations include the modifiable areal unit problem and ecological fallacy. In this review we argue that modern earth observation data can represent an important data source for research on environmental justice and health. Especially due to their high level of spatial detail and the provided large-area coverage, they allow for spatially continuous description of environmental characteristics. As a future perspective, ongoing earth observation missions, as well as processing architectures, ensure data availability and applicability of 'big earth data' for future environmental justice analyses.}, language = {en} } @article{GrebinykPrylutskaChepurnaetal.2019, author = {Grebinyk, Anna and Prylutska, Svitlana and Chepurna, Oksana and Grebinyk, Sergii and Prylutskyy, Yuriy and Ritter, Uwe and Ohulchanskyy, Tymish Y. and Matyshevska, Olga and Dandekar, Thomas and Frohme, Marcus}, title = {Synergy of chemo- and photodynamic therapies with C\(_{60}\) Fullerene-Doxorubicin nanocomplex}, series = {Nanomaterials}, volume = {9}, journal = {Nanomaterials}, number = {11}, issn = {2079-4991}, doi = {10.3390/nano9111540}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193140}, year = {2019}, abstract = {A nanosized drug complex was explored to improve the efficiency of cancer chemotherapy, complementing it with nanodelivery and photodynamic therapy. For this, nanomolar amounts of a non-covalent nanocomplex of Doxorubicin (Dox) with carbon nanoparticle C\(_{60}\) fullerene (C\(_{60}\)) were applied in 1:1 and 2:1 molar ratio, exploiting C\(_{60}\) both as a drug-carrier and as a photosensitizer. The fluorescence microscopy analysis of human leukemic CCRF-CEM cells, in vitro cancer model, treated with nanocomplexes showed Dox's nuclear and C\(_{60}\)'s extranuclear localization. It gave an opportunity to realize a double hit strategy against cancer cells based on Dox's antiproliferative activity and C\(_{60}\)'s photoinduced pro-oxidant activity. When cells were treated with 2:1 C\(_{60}\)-Dox and irradiated at 405 nm the high cytotoxicity of photo-irradiated C\(_{60}\)-Dox enabled a nanomolar concentration of Dox and C\(_{60}\) to efficiently kill cancer cells in vitro. The high pro-oxidant and pro-apoptotic efficiency decreased IC\(_{50}\) 16, 9 and 7 × 10\(^3\)-fold, if compared with the action of Dox, non-irradiated nanocomplex, and C\(_{60}\)'s photodynamic effect, correspondingly. Hereafter, a strong synergy of therapy arising from the combination of C\(_{60}\)-mediated Dox delivery and C\(_{60}\) photoexcitation was revealed. Our data indicate that a combination of chemo- and photodynamic therapies with C\(_{60}\)-Dox nanoformulation provides a promising synergetic approach for cancer treatment.}, language = {en} } @article{HomburgWeissAlwanetal.2019, author = {Homburg, Annika and Weiß, Christian H. and Alwan, Layth C. and Frahm, Gabriel and G{\"o}b, Rainer}, title = {Evaluating approximate point forecasting of count processes}, series = {Econometrics}, volume = {7}, journal = {Econometrics}, number = {3}, issn = {2225-1146}, doi = {10.3390/econometrics7030030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196929}, year = {2019}, abstract = {In forecasting count processes, practitioners often ignore the discreteness of counts and compute forecasts based on Gaussian approximations instead. For both central and non-central point forecasts, and for various types of count processes, the performance of such approximate point forecasts is analyzed. The considered data-generating processes include different autoregressive schemes with varying model orders, count models with overdispersion or zero inflation, counts with a bounded range, and counts exhibiting trend or seasonality. We conclude that Gaussian forecast approximations should be avoided.}, language = {en} } @article{ShahBulittaKinzigetal.2019, author = {Shah, Nirav R. and Bulitta, J{\"u}rgen B. and Kinzig, Martina and Landersdorfer, Cornelia B. and Jiao, Yuanyuan and Sutaria, Dhruvitkumar S. and Tao, Xun and H{\"o}hl, Rainer and Holzgrabe, Ulrike and Kees, Frieder and Stephan, Ulrich and S{\"o}rgel, Fritz}, title = {Novel population pharmacokinetic approach to explain the differences between cystic fibrosis patients and healthy volunteers via protein binding}, series = {Pharmaceutics}, volume = {11}, journal = {Pharmaceutics}, number = {6}, issn = {1999-4923}, doi = {10.3390/pharmaceutics11060286}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196934}, year = {2019}, abstract = {The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3\% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50\% in male and estimated as 54.5\% in female healthy volunteers as well as 56.3\% in male and 74.4\% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.}, language = {en} } @article{KhareLatifiRossietal.2019, author = {Khare, Siddhartha and Latifi, Hooman and Rossi, Sergio and Ghosh, Sanjay Kumar}, title = {Fractional cover mapping of invasive plant species by combining very high-resolution stereo and multi-sensor multispectral imageries}, series = {Forests}, volume = {10}, journal = {Forests}, number = {7}, issn = {1999-4907}, doi = {10.3390/f10070540}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197250}, year = {2019}, abstract = {Invasive plant species are major threats to biodiversity. They can be identified and monitored by means of high spatial resolution remote sensing imagery. This study aimed to test the potential of multiple very high-resolution (VHR) optical multispectral and stereo imageries (VHRSI) at spatial resolutions of 1.5 and 5 m to quantify the presence of the invasive lantana (Lantana camara L.) and predict its distribution at large spatial scale using medium-resolution fractional cover analysis. We created initial training data for fractional cover analysis by classifying smaller extent VHR data (SPOT-6 and RapidEye) along with three dimensional (3D) VHRSI derived digital surface model (DSM) datasets. We modelled the statistical relationship between fractional cover and spectral reflectance for a VHR subset of the study area located in the Himalayan region of India, and finally predicted the fractional cover of lantana based on the spectral reflectance of Landsat-8 imagery of a larger spatial extent. We classified SPOT-6 and RapidEye data and used the outputs as training data to create continuous field layers of Landsat-8 imagery. The area outside the overlapping region was predicted by fractional cover analysis due to the larger extent of Landsat-8 imagery compared with VHR datasets. Results showed clear discrimination of understory lantana from upperstory vegetation with 87.38\% (for SPOT-6), and 85.27\% (for RapidEye) overall accuracy due to the presence of additional VHRSI derived DSM information. Independent validation for lantana fractional cover estimated root-mean-square errors (RMSE) of 11.8\% (for RapidEye) and 7.22\% (for SPOT-6), and R\(^2\) values of 0.85 and 0.92 for RapidEye (5 m) and SPOT-6 (1.5 m), respectively. Results suggested an increase in predictive accuracy of lantana within forest areas along with increase in the spatial resolution for the same Landsat-8 imagery. The variance explained at 1.5 m spatial resolution to predict lantana was 64.37\%, whereas it decreased by up to 37.96\% in the case of 5 m spatial resolution data. This study revealed the high potential of combining small extent VHR and VHRSI- derived 3D optical data with larger extent, freely available satellite data for identification and mapping of invasive species in mountainous forests and remote regions.}, language = {en} } @article{VillalobosWieseImhoffetal.2019, author = {Villalobos, Alvaro S. and Wiese, Jutta and Imhoff, Johannes F. and Dorador, Cristina and Keller, Alexander and Hentschel, Ute}, title = {Systematic affiliation and genome analysis of Subtercola vilae DB165T with particular emphasis on cold adaptation of an isolate from a high-altitude cold volcano lake}, series = {Microorganisms}, volume = {7}, journal = {Microorganisms}, number = {4}, issn = {2076-2607}, doi = {10.3390/microorganisms7040107}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197394}, year = {2019}, abstract = {Among the Microbacteriaceae the species of Subtercola and Agreia form closely associated clusters. Phylogenetic analysis demonstrated three major phylogenetic branches of these species. One of these branches contains the two psychrophilic species Subtercola frigoramans and Subtercola vilae, together with a larger number of isolates from various cold environments. Genomic evidence supports the separation of Agreia and Subtercola species. In order to gain insight into the ability of S. vilae to adapt to life in this extreme environment, we analyzed the genome with a particular focus on properties related to possible adaptation to a cold environment. General properties of the genome are presented, including carbon and energy metabolism, as well as secondary metabolite production. The repertoire of genes in the genome of S. vilae DB165\(^T\) linked to adaptations to the harsh conditions found in Llullaillaco Volcano Lake includes several mechanisms to transcribe proteins under low temperatures, such as a high number of tRNAs and cold shock proteins. In addition, S. vilae DB165\(^T\) is capable of producing a number of proteins to cope with oxidative stress, which is of particular relevance at low temperature environments, in which reactive oxygen species are more abundant. Most important, it obtains capacities to produce cryo-protectants, and to combat against ice crystal formation, it produces ice-binding proteins. Two new ice-binding proteins were identified which are unique to S. vilae DB165\(^T\). These results indicate that S. vilae has the capacity to employ different mechanisms to live under the extreme and cold conditions prevalent in Llullaillaco Volcano Lake.}, language = {en} } @article{LiuKinoshitaAdolfietal.2019, author = {Liu, Ruiqi and Kinoshita, Masato and Adolfi, Mateus C. and Schartl, Manfred}, title = {Analysis of the role of the Mc4r system in development, growth, and puberty of medaka}, series = {Frontiers in Endocrinology}, volume = {10}, journal = {Frontiers in Endocrinology}, doi = {10.3389/fendo.2019.00213}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201472}, pages = {213}, year = {2019}, abstract = {In mammals the melanocortin 4 receptor (Mc4r) signaling system has been mainly associated with the regulation of appetite and energy homeostasis. In fish of the genus Xiphophorus (platyfish and swordtails) puberty onset is genetically determined by a single locus, which encodes the mc4r. Wild populations of Xiphophorus are polymorphic for early and late-maturing individuals. Copy number variation of different mc4r alleles is responsible for the difference in puberty onset. To answer whether this is a special adaptation of the Mc4r signaling system in the lineage of Xiphophorus or a more widely conserved mechanism in teleosts, we studied the role of Mc4r in reproductive biology of medaka (Oryzias latipes), a close relative to Xiphophorus and a well-established model to study gonadal development. To understand the potential role of Mc4r in medaka, we characterized the major features of the Mc4r signaling system (mc4r, mrap2, pomc, agrp1). In medaka, all these genes are expressed before hatching. In adults, they are mainly expressed in the brain. The transcript of the receptor accessory protein mrap2 co-localizes with mc4r in the hypothalamus in adult brains indicating a conserved function of modulating Mc4r signaling. Comparing growth and puberty between wild-type and mc4r knockout medaka revealed that absence of Mc4r does not change puberty timing but significantly delays hatching. Embryonic development of knockout animals is retarded compared to wild-types. In conclusion, the Mc4r system in medaka is involved in regulation of growth rather than puberty.}, 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{WallmannSperlichHoffmannSaldittetal.2019, author = {Wallmann-Sperlich, Birgit and Hoffmann, Sophie and Salditt, Anne and Bipp, Tanja and Froboese, Ingo}, title = {Moving to an "active" biophilic designed office workplace: a pilot study about the effects on sitting time and sitting habits of office-based workers}, series = {International Journal of Environmental Research and Public Health}, volume = {16}, journal = {International Journal of Environmental Research and Public Health}, number = {9}, issn = {1660-4601}, doi = {10.3390/ijerph16091559}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197371}, pages = {1559}, year = {2019}, abstract = {Promising initial insights show that offices designed to permit physical activity (PA) may reduce workplace sitting time. Biophilic approaches are intended to introduce natural surroundings into the workplace, and preliminary data show positive effects on stress reduction and elevated productivity within the workplace. The primary aim of this pilot study was to analyze changes in workplace sitting time and self-reported habit strength concerning uninterrupted sitting and PA during work, when relocating from a traditional office setting to "active" biophilic-designed surroundings. The secondary aim was to assess possible changes in work-associated factors such as satisfaction with the office environment, work engagement, and work performance, among office staff. In a pre-post designed field study, we collected data through an online survey on health behavior at work. Twelve participants completed the survey before (one-month pre-relocation, T1) and twice after the office relocation (three months (T2) and seven months post-relocation (T3)). Standing time per day during office hours increased from T1 to T3 by about 40 min per day (p < 0.01). Other outcomes remained unaltered. The results suggest that changing office surroundings to an active-permissive biophilic design increased standing time during working hours. Future larger-scale controlled studies are warranted to investigate the influence of office design on sitting time and work-associated factors during working hours in depth.}, 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{Gonzalez‐EscamillaMuthuramanReichetal.2019, author = {Gonzalez-Escamilla, Gabriel and Muthuraman, Muthuraman and Reich, Martin M. and Koirala, Nabin and Riedel, Christian and Glaser, Martin and Lange, Florian and Deuschl, G{\"u}nther and Volkmann, Jens and Groppa, Sergiu}, title = {Cortical network fingerprints predict deep brain stimulation outcome in dystonia}, series = {Movement Disorders}, volume = {34}, journal = {Movement Disorders}, number = {10}, doi = {10.1002/mds.27808}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213532}, pages = {1536 -- 1545}, year = {2019}, abstract = {Background Deep brain stimulation (DBS) is an effective evidence-based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns. Methods From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior-outcome group or moderate-outcome group, depending on whether they had above or below 70\% motor improvement, respectively. Fifty-one patients met MRI-quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray-matter fingerprints. Results The moderate-outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45\% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88\% of accuracy using individual gray-matter atrophy patterns to predict DBS outcomes. Conclusions The analysis of cortical integrity, informed by group-level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS.}, language = {en} } @article{EngelWagnerSchelhornetal.2019, author = {Engel, Florian A. and Wagner, Matthias Oliver and Schelhorn, Franziska and Deubert, Felix and Leutzsch, Sascha and Stolz, Alexander and Sperlich, Billy}, title = {Classroom-Based Micro-Sessions of Functional High-Intensity Circuit Training Enhances Functional Strength but Not Cardiorespiratory Fitness in School Children — A Feasibility Study}, series = {Frontiers in Public Health}, volume = {7}, journal = {Frontiers in Public Health}, number = {291}, issn = {2296-2565}, doi = {10.3389/fpubh.2019.00291}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195669}, year = {2019}, abstract = {The present study assessed the short-term effect of 6 min classroom-based micro-sessions of multi-joint functional high-intensity circuit training (FunctionalHIIT) performed by students during regular classes on parameters related to functional strength and cardiorespiratory fitness. In this randomized controlled 4-week study, 17 students (11 male; 6 female; age: 11.6 ± 0.2 years) performed 6 min of FunctionalHIIT (targeting >17 on the Borg scale) 4 days per week during regular school classes and 18 students (11 male; 7 female; age: 11.7 ± 0.3 years) served as control group (CG) without any additional in-class physical activity. The FunctionalHIIT group completed 86\% of all planned sessions (mean duration: 6.0 ± 1.5 min) with a mean RPE of 17.3 ± 2.1. Body height, mass and BMI did not differ between the groups at baseline or between pre- and post-testing (p > 0.05; eta2 ≤ 0.218). The performances in lateral jumping (p < 0.000; part eta2 = 0.382; Δ\% 4.6 ± 8.6), sit-ups (p < 0.000; part eta2 = 0.485; Δ\% 3.1 ± 8.6) and 20-m sprints (p < 0.000; part eta2 = 0.691; Δ\% 15.8 ± 5.4) improved in both groups with greater increase following FunctionalHIIT. No baseline differences and no interaction effects occurred in performance of 6 min run, flexibility, push-ups, balance, and long jump. Classroom-based FunctionalHIIT sessions, performed 4 days per week during 4 weeks did not improve variables related to aerobic endurance performance but enhanced certain parameters of functional strength in schoolchildren. As time is limited in the educational system of schools, FunctionalHIIT during regular school classes could offer a new perspective for increasing functional strength in schoolchildren.}, language = {en} } @article{RadeloffRadeloffTiradoetal.2019, author = {Radeloff, Katrin and Radeloff, Andreas and Tirado, Mario Ramos and Scherzad, Agmal and Hagen, Rudolf and Kleinsasser, Norbert H. and Hackenberg, Stephan}, title = {Long-Term Impact of Zinc Oxide Nanoparticles on Differentiation and Cytokine Secretion of Human Adipose-Derived Stromal Cells}, series = {Materials}, volume = {12}, journal = {Materials}, number = {1823}, doi = {10.3390/ma12111823}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224779}, pages = {1-14}, year = {2019}, abstract = {Zinc oxide nanoparticles (ZnO-NPs) are widely utilized, for example in manufacturing paints and in the cosmetic industry. In addition, there is raising interest in the application of NPs in stem cell research. However, cytotoxic, genotoxic and pro-inflammatory effects were shown for NPs. The aim of this study was to evaluate the impact of ZnO-NPs on cytokine secretion and differentiation properties of human adipose tissue-derived stromal cells (ASCs). Human ASCs were exposed to the subtoxic concentration of 0.2 mu g/mL ZnO-NPs for 24 h. After four weeks of cultivation, adipogenic and osteogenic differentiation procedures were performed. The multi-differentiation potential was confirmed histologically and using polymerase chain reaction (PCR). In addition, the gene expression of IL-6, IL-8, vascular endothelial growth factor (VEGF) and caspase 3 was analyzed. Over the course of four weeks after ZnO-NPs exposure, no significant differences were detected in the gene expression of IL-6, IL-8, VEGF and caspase 3 compared to non-exposed cells. The differentiation was also not affected by the ZnO-NPs. These findings underline the fact, that functionality of ASCs is likely to be unaffected by ZnO-NPs, despite a long-term disposition of NPs in the cells, supposing that the starting concentration was safely in the non-toxic range. This might provide important information for single-use nanomedical applications of ZnO-NPs.}, language = {en} } @article{RauschenbergerSchmittAzeemetal.2019, author = {Rauschenberger, Tabea and Schmitt, Viola and Azeem, Muhammad and Klein-Hessling, Stefan and Murti, Krisna and Gr{\"a}n, Franziska and Goebeler, Matthias and Kerstan, Andreas and Klein, Matthias and Bopp, Tobias and Serfling, Edgar and Muhammad, Khalid}, title = {T cells control chemokine secretion by keratinocytes}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {1917}, issn = {1664-3224}, doi = {10.3389/fimmu.2019.01917}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195695}, year = {2019}, abstract = {The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8\(^+\)T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8\(^+\)T cells. One key molecule is IFN-γ that is synthesized by CD8\(^+\)T cells under the control of NFATc1 and NFATc2. CD8\(^+\)T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8\(^+\)T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.}, language = {en} } @article{RiceEikemaMarshetal.2019, author = {Rice, Carmel and Eikema, Dirk-Jan and Marsh, Judith C. W. and Knol, Cora and Hebert, Kyle and Putter, Hein and Peterson, Eefke and Deeg, H. Joachim and Halkes, Stijn and Pidala, Joseph and Anderlini, Paolo and Tischer, Johanna and Kroger, Nicolaus and McDonald, Andrew and Antin, Joseph H. and Schaap, Nicolaas P. and Hallek, Michael and Einsele, Herman and Mathews, Vikram and Kapoor, Neena and Boelens, Jaap-Jan and Mufti, Ghulam J. and Potter, Victoria and de la Tour, R{\´e}gis Pefault and Eapen, Mary and Dufour, Carlo}, title = {Allogeneic Hematopoietic Cell Transplantation in Patients Aged 50 Years or Older with Severe Aplastic Anemia}, series = {Biology of Blood and Marrow Transplantation}, volume = {25}, journal = {Biology of Blood and Marrow Transplantation}, number = {3}, doi = {10.1016/j.bbmt.2018.08.029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225229}, pages = {488-495}, year = {2019}, abstract = {We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55\%) or HLA-matched (8/8) unrelated donors (n =187, 37\%) between 2005 and 2016. The median age at HCT was 57.8 years; 16\% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90\% (hazard ratio HR], 1.41; 95\% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95\% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66\% (range, 57\% to 75\%) and 57\% (range, 47\% to 76\%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57\% (range, 48\% to 67\%) and 48\% (range, 36\% to 59\%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95\% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95\% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95\% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.}, language = {en} } @article{RagerJakowetzGoleetal.2019, author = {Rager, Sabrina and Jakowetz, Andreas C. and Gole, Bappaditya and Beuerle, Florian and Medina, Dana D. and Bein, Thomas}, title = {Scaffold-Induced Diketopyrrolopyrrole Molecular Stacks in a Covalent Organic Framework}, series = {Chemistry of Materials}, volume = {31}, journal = {Chemistry of Materials}, number = {8}, doi = {10.1021/acs.chemmater.8b02882}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224927}, pages = {2707-2712}, year = {2019}, abstract = {In recent years, covalent organic frameworks (COFs) have attracted considerable attention due to their crystalline and porous nature, which positions them as intriguing candidates for diverse applications such as catalysis, sensing, or optoelectronics. The incorporation of dyes or semiconducting moieties into a rigid two-dimensional COF can offer emergent features such as enhanced light harvesting or charge transport. However, this approach can be challenging when dealing with dye molecules that exhibit a large aromatic backbone, since the steric demand of solubilizing side chains also needs to be integrated into the framework. Here, we report the successful synthesis of DPP2-HHTP-COF consisting of diketopyrrolopyrrole (DPP) diboronic acid and hexahydroxytriphenylene (HHTP) building blocks. The well-known boronate ester coupling motif guides the formation of a planar and rigid backbone and long-range molecular DPP stacks, resulting in a highly crystalline and porous material. DPP2-HHTP-COF exhibits excellent optical properties including strong absorption over the visible spectral range, broad emission into the NIR and a singlet lifetime of over 5 ns attributed to the formation of molecular stacks with J-type interactions between the DPP subcomponents in the COF. Electrical measurements of crystalline DPP2-HHTP-COF pellets revealed conductivity values of up to 10(-6) S cm(-1).}, language = {en} } @article{SilwedelHaarmannFehrholzetal.2019, author = {Silwedel, Christine and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Speer, Christian P. and Glaser, Kirsten}, title = {More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells}, series = {Journal of Neuroinflammation}, volume = {16}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-019-1413-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200711}, pages = {38}, year = {2019}, abstract = {Background Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma-driven cell death, concentrating on apoptosis as well as inflammatory cell death. Methods Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma (U.) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties. Results Both Ureaplasma isolates induced cell death (p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 (p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure (p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 (p < 0.05). Conclusions By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp.}, language = {en} } @article{RobindeWreedeWolschkeetal.2019, author = {Robin, Marie and de Wreede, Liesbeth C. and Wolschke, Christine and Schetelig, Johannes and Eikema, Diderik-Jan and Van Lint, Maria Teresa and Knelange, Nina Simone and Beelen, Dietrich and Brecht, Arne and Niederwieser, Dietger and Vitek, Antonin and Bethge, Wolfgang and Arnold, Renate and Finke, J{\"u}rgen and Volin, Liisa and Yakoub-Agha, Ibrahim and Nagler, Arnon and Poir{\´e}, Xavier and Einsele, Hermann and Chevallier, Patrice and Holler, Ernst and Ljungman, Per and Robinson, Stephen and Radujkovic, Alekxandar and McLornan, Donal and Chalandon, Yves and Kr{\"o}ger, Nicolaus}, title = {Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis}, series = {Haematologica}, volume = {104}, journal = {Haematologica}, number = {9}, doi = {10.3324/haematol.2018.205211}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226386}, pages = {1782-1788}, year = {2019}, abstract = {Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events Aoccur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64\% (60-68\%) and overall survival was 74\% (71-78\%) at ten years; results were better in younger individuals and in women. Excess mortality was 14\% (8-21\%) in patients aged <45 years and 33\% (13-53\%) in patients aged >= 65 years. The main cause of death was relapse of the primary disease. Graft-versus-host disease (GvHD) before two years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GvHD disease prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at two years. However, the occurrence of late complications, including late relapses, infectious complications and secondary malignancies, highlights the importance of screening and monitoring of long-term survivors.}, subject = {Midollo-Osseo}, language = {en} } @article{YoussifHaggagElshamyetal.2019, author = {Youssif, Khayrya A. and Haggag, Eman G. and Elshamy, Ali M. and Rabeh, Mohamed A. and Gabr, Nagwan M. and Seleem, Amany and Salem, M. Alaraby and Hussein, Ahmed S. and Krischke, Markus and Mueller, Martin J. and Ramadan Abdelmohsen, Usama}, title = {Anti-Alzheimer potential, metabolomic profiling and molecular docking of green synthesized silver nanoparticles of Lampranthus coccineus and Malephora lutea aqueous extracts}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0223781}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202696}, pages = {e0223781}, year = {2019}, abstract = {The green synthesis of silver nanoparticles (SNPs) using plant extracts is an eco-friendly method. It is a single step and offers several advantages such as time reducing, cost-effective and environmental non-toxic. Silver nanoparticles are a type of Noble metal nanoparticles and it has tremendous applications in the field of diagnostics, therapeutics, antimicrobial activity, anticancer and neurodegenerative diseases. In the present work, the aqueous extracts of aerial parts of Lampranthus coccineus and Malephora lutea F. Aizoaceae were successfully used for the synthesis of silver nanoparticles. The formation of silver nanoparticles was early detected by a color change from pale yellow to reddish-brown color and was further confirmed by transmission electron microscope (TEM), UV-visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), and energy-dispersive X-ray diffraction (EDX). The TEM analysis of showed spherical nanoparticles with a mean size between 12.86 nm and 28.19 nm and the UV- visible spectroscopy showed λ\(_{max}\) of 417 nm, which confirms the presence of nanoparticles. The neuroprotective potential of SNPs was evaluated by assessing the antioxidant and cholinesterase inhibitory activity. Metabolomic profiling was performed on methanolic extracts of L. coccineus and M. lutea and resulted in the identification of 12 compounds, then docking was performed to investigate the possible interaction between the identified compounds and human acetylcholinesterase, butyrylcholinesterase, and glutathione transferase receptor, which are associated with the progress of Alzheimer's disease. Overall our SNPs highlighted its promising potential in terms of anticholinesterase and antioxidant activity as plant-based anti-Alzheimer drug and against oxidative stress.}, language = {en} } @article{SchmalzlPlumhoffGilbertetal.2019, author = {Schmalzl, J. and Plumhoff, P. and Gilbert, F. and Gohlke, F. and Konrads, C. and Brunner, U. and Jakob, F. and Ebert, R. and Steinert, AF}, title = {The inflamed biceps tendon as a pain generator in the shoulder: A histological and biomolecular analysis}, series = {Journal of Orthopaedic Surgery}, volume = {27}, journal = {Journal of Orthopaedic Surgery}, number = {1}, doi = {10.1177/2309499018820349}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228611}, pages = {1-10}, year = {2019}, abstract = {Introduction: The long head of the biceps (LHB) is often resected in shoulder surgery. However, its contribution to inflammatory processes in the shoulder remains unclear. In the present study, inflamed and noninflamed human LHBs were comparatively characterized for features of inflammation. Materials and methods: Twenty-two resected LHB tendons were classified into inflamed (n = 11) and noninflamed (n = 11) samples. For histological examination, samples were stained with hematoxylin eosin, Azan, van Gieson, and Masson Goldner trichrome. Neuronal tissue was immunohistochemically visualized. In addition, specific inflammatory marker gene expression of primary LHB-derived cell cultures were analyzed. Results: Features of tendinopathy, such as collagen disorganization, infiltration by inflammatory cells, neovascularization, and extensive neuronal innervation were found in the tendinitis group. Compared to noninflamed samples, inflamed LHBs showed a significantly increased inflammatory marker gene expression Conclusion: Structural and biomolecular differences of both groups suggest that the LHB tendon acts as an important pain generator in the shoulder joint. These findings can, on the one hand, contribute to the understanding of the biomolecular genesis of LHB tendinitis and, on the other hand, provide possibilities for new therapeutic approaches.}, language = {en} } @article{BauerOpitzFilseretal.2019, author = {Bauer, Maria and Opitz, Anne and Filser, J{\"o}rg and Jansen, Hendrik and Meffert, Rainer H. and Germer, Christoph T. and Roewer, Norbert and Muellenbach, Ralf M. and Kredel, Markus}, title = {Perioperative redistribution of regional ventilation and pulmonary function: a prospective observational study in two cohorts of patients at risk for postoperative pulmonary complications}, series = {BMC Anesthesiology}, volume = {19}, journal = {BMC Anesthesiology}, doi = {10.1186/s12871-019-0805-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200730}, pages = {132}, year = {2019}, abstract = {Background Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients, duration of hospital stay and costs. Postoperative atelectasis of dorsal lung regions as a common PPC has been described before, but its clinical relevance is insufficiently examined. Pulmonary electrical impedance tomography (EIT) enables the bedside visualization of regional ventilation in real-time within a transversal section of the lung. Dorsal atelectasis or effusions might cause a ventral redistribution of ventilation. We hypothesized the existence of ventral redistribution in spontaneously breathing patients during their recovery from abdominal and peripheral surgery and that vital capacity is reduced if regional ventilation shifts to ventral lung regions. Methods This prospective observational study included 69 adult patients undergoing elective surgery with an expected intermediate or high risk for PPCs. Patients undergoing abdominal and peripheral surgery were recruited to obtain groups of equal size. Patients received general anesthesia with and without additional regional anesthesia. On the preoperative, the first and the third postoperative day, EIT was performed at rest and during spirometry (forced breathing). The center of ventilation in dorso-ventral direction (COVy) was calculated. Results Both groups received intraoperative low tidal volume ventilation. Postoperative ventral redistribution of ventilation (forced breathing COVy; preoperative: 16.5 (16.0-17.3); first day: 17.8 (16.9-18.2), p < 0.004; third day: 17.4 (16.2-18.2), p = 0.020) and decreased forced vital capacity in percentage of predicted values (FVC\%predicted) (median: 93, 58, 64\%, respectively) persisted after abdominal surgery. In addition, dorsal to ventral shift was associated with a decrease of the FVC\%predicted on the third postoperative day (r = - 0.66; p < 0.001). A redistribution of pulmonary ventilation was not observed after peripheral surgery. FVC\%predicted was only decreased on the first postoperative day (median FVC\%predicted on the preoperative, first and third day: 85, 81 and 88\%, respectively). In ten patients occurred pulmonary complications after abdominal surgery also in two patients after peripheral surgery. Conclusions After abdominal surgery ventral redistribution of ventilation persisted up to the third postoperative day and was associated with decreased vital capacity. The peripheral surgery group showed only minor changes in vital capacity, suggesting a role of the location of surgery for postoperative redistribution of pulmonary ventilation.}, language = {en} } @article{ReichelMitnachtFenwicketal.2019, author = {Reichel, Thomas and Mitnacht, Martin and Fenwick, Annabel and Meffert, Rainer and Hoos, Olaf and Fehske, Kai}, title = {Incidence and characteristics of acute andoveruse injuries in elite powerlifters}, series = {Cogent Medicine}, volume = {6}, journal = {Cogent Medicine}, doi = {10.1080/2331205X.2019.1588192}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204005}, pages = {1588192}, year = {2019}, abstract = {Abstract: The aim of this study was the analysis of incidence and type of injury in German elite powerlifters. A total of n = 57 competitive athletes of the German powerlifting federation completed a retrospective survey regarding acute andoveruse injuries. With 224 total injuries, a mean incidence of 1.51 per 1.000 h or 0.49 per year was calculated. Most injuries affected the lower back (20.5\%), elbow (11.2\%), pelvic region (10.3) and the shoulder (9.8\%). Regarding the type of injury acute inflammation (25.9\%), muscle strains/sprains (20.5\%) and skin lesions (13\%) dominated. The mean incidence significantly declined with increasing age and training experience of the athlete. Athletes using a bench press shirt and various regenerative methods like sauna or swimming also showed decreased injury rates. There was no significant correlation between body weight, height or gender and injury incidence. Compared to other sports, the incidence of injuries and overuse syndromes is still low in powerlifting. Nonetheless, appropriate strategies in training, equipment, prevention and regeneration should be employed to protect the athlete from injury.}, language = {en} } @article{SchmidtJakubietzGilbertetal.2019, author = {Schmidt, Karsten and Jakubietz, Michael Gregor and Gilbert, Fabian and Hausknecht, Franca and Meffert, Rainer Heribert and Jakubietz, Rafael Gregor}, title = {Quality of life after flap reconstruction of the distal lower extremity: is there a difference between a pedicled suralis flap and a free anterior lateral thigh flap?}, series = {Plastic and Reconstructive Surgery - Global Open}, volume = {7}, journal = {Plastic and Reconstructive Surgery - Global Open}, number = {4}, doi = {10.1097/GOX.0000000000002114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203940}, pages = {e2114}, year = {2019}, abstract = {Background: Flap reconstruction of the distal lower extremity is challenging. Especially, the concept of perforator surgery has increased available surgical options. Although results are generally judged in terms of objective facts, patients-perceived quality of life has largely remained unexamined. The aim of the study was to compare quality of life after lower extremity reconstruction with pedicled and free flaps. Methods: Patients were evaluated retrospectively after reconstruction of defects of the distal lower extremity either with distally based adipofascial sural flap (pedicled reverse sural flap) or an anterior lateral thigh (ALT) flap. A specific questionnaire was developed to measure the patient's quality of life, based on short form health survey-12, Dresden Body Image Score-35, Patient Health Questionnaire-4, and XSMFA questionnaires with additional specific questions. Furthermore, results, secondary surgeries, and complications were analyzed. Results: Thirty-seven patients with reconstruction of lower limb defects treated with a pedicled reverse sural flap and 34 patients treated with an ALT flap were included in the study. There was no statistical significant difference in the overall satisfaction with the procedure in the long-term follow-up between both groups, but patients with ALT showed a higher satisfaction with the treatment in the initial postoperative period. Both groups demonstrated approximately similar results in the long term for self-acceptance and vitality. Conclusions: Although anatomic situation may dictate flap choice coverage with free flaps, a less-complicated flap is by no means regarded as an inferior treatment option in patient's estimation. Despite the intuitive speculation that patients with more advanced reconstruction methods should have better function and subsequently higher quality of life, this assumption was clearly not supported by data in this study.}, language = {en} } @article{JakubietzJakubietzHorchetal.2019, author = {Jakubietz, Rafael G. and Jakubietz, Danni F. and Horch, Raymund E. and Gruenert, Joerg G. and Meffert, Rainer H. and Jakubietz, Michael G.}, title = {The microvascular peroneal artery perforator flap as a "lifeboat" for pedicled flaps}, series = {Plastic and Reconstructive Surgery - Global Open}, volume = {7}, journal = {Plastic and Reconstructive Surgery - Global Open}, number = {9}, doi = {10.1097/GOX.0000000000002396}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202233}, pages = {e2396}, year = {2019}, abstract = {Background: Pedicled perforator flaps have expanded reconstructive options in extremity reconstruction. Despite preoperative mapping, intraoperative findings may require microvascular tissue transfer when no adequate perforators can be found. The free peroneal artery perforator flap may serve as a reliable back-up plan in small defects. Methods: In 16 patients with small soft tissue defects on the upper and lower extremities, perforator-based propeller flaps were planned. The handheld Doppler device was used to localize potential perforators for a propeller flap in close proximity to the defect. Perforators of the proximal peroneal artery were also marked to allow conversion to microvascular tissue transfer. Results: In 6 cases, no adequate perforators were found intraoperatively. In 4 patients, the peroneal artery perforator flap was harvested and transferred. The pedicle length did not exceed 4 cm. No flap loss occurred. Conclusions: When no adequate perforator capable of nourishing a propeller flap can be found intraoperatively, the free peroneal artery flap is a good option to reconstruct small soft tissue defects in the distal extremities. The short vascular pedicle is less ideal in cases with a large zone of injury requiring a more distant site of anastomosis or when recipient vessels are located in deeper tissue planes.}, language = {en} }