TY - JOUR A1 - Kotseva, Kornelia A1 - De Backer, Guy A1 - De Bacquer, Dirk A1 - Rydén, Lars A1 - Hoes, Arno A1 - Grobbee, Diederick A1 - Maggioni, Aldo A1 - Marques-Vidal, Pedro A1 - Jennings, Catriona A1 - Abreu, Ana A1 - Aguiar, Carlos A1 - Badariene, Jolita A1 - Bruthans, Jan A1 - Castro Conde, Almudena A1 - Cifkova, Renata A1 - Crowley, Jim A1 - Davletov, Kairat A1 - Deckers, Jaap A1 - De Smedt, Delphine A1 - De Sutter, Johan A1 - Dilic, Mirza A1 - Dolzhenko, Marina A1 - Dzerve, Vilnis A1 - Erglis, Andrejs A1 - Fras, Zlatko A1 - Gaita, Dan A1 - Gotcheva, Nina A1 - Heuschmann, Peter A1 - Hasan-Ali, Hosam A1 - Jankowski, Piotr A1 - Lalic, Nebojsa A1 - Lehto, Seppo A1 - Lovic, Dragan A1 - Mancas, Silvia A1 - Mellbin, Linda A1 - Milicic, Davor A1 - Mirrakhimov, Erkin A1 - Oganov, Rafael A1 - Pogosova, Nana A1 - Reiner, Zeljko A1 - Stöerk, Stefan A1 - Tokgözoğlu, Lâle A1 - Tsioufis, Costas A1 - Vulic, Dusko A1 - Wood, David T1 - 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 JF - European Journal of Preventive Cardiology N2 - 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. KW - EUROASPIRE KW - lifestyle KW - cardiovascular risk factors KW - secondary prevention KW - guidelines Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205526 SN - 2047-4873 SN - 2047-4881 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 26 IS - 8 ER - TY - JOUR A1 - Figueiredo, Ludmilla A1 - Krauss, Jochen A1 - Steffan-Dewenter, Ingolf A1 - Cabral, Juliano Sarmento T1 - Understanding extinction debts: spatio-temporal scales, mechanisms and a roadmap for future research JF - Ecography N2 - 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. KW - Anthropocene KW - biotic interaction KW - extinction dynamics KW - mechanistic modelling KW - time lag KW - transient dynamics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204859 VL - 42 IS - 12 ER - TY - JOUR A1 - Ataee, Mohammad Sadegh A1 - Maghsoudi, Yasser A1 - Latifi, Hooman A1 - Fadaie, Farhad T1 - Improving estimation accuracy of growing stock by multi-frequency SAR and multi-spectral data over Iran's heterogeneously-structured broadleaf Hyrcanian forests JF - Forests N2 - 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. KW - GSV KW - nu SVR KW - uneven-aged mountainous KW - polarimetery KW - multi-spectral KW - optimization Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197212 SN - 1999-4907 VL - 10 IS - 8 ER - TY - JOUR A1 - Jungwirth, Gerhard A1 - Yu, Tao A1 - Moustafa, Mahmoud A1 - Rapp, Carmen A1 - Warta, Rolf A1 - Jungk, Christine A1 - Sahm, Felix A1 - Dettling, Steffen A1 - Zweckberger, Klaus A1 - Lamszus, Katrin A1 - Senft, Christian A1 - Loehr, Mario A1 - Keßler, Almuth F. A1 - Ketter, Ralf A1 - Westphal, Manfred A1 - Debus, Juergen A1 - von Deimling, Andreas A1 - Simon, Matthias A1 - Unterberg, Andreas A1 - Abdollahi, Amir A1 - Herold-Mende, Christel T1 - Identification of KIF11 as a Novel Target in Meningioma JF - Cancers N2 - 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. KW - meningioma KW - KIF KW - kinesin KW - KIF11 KW - NCH93 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197402 SN - 2072-6694 VL - 11 IS - 4 ER - TY - JOUR A1 - Mayr, Stefan A1 - Kuenzer, Claudia A1 - Gessner, Ursula A1 - Klein, Igor A1 - Rutzinger, Martin T1 - Validation of earth observation time-series: a review for large-area and temporally dense land surface products JF - Remote Sensing N2 - 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. KW - accuracy KW - error estimation KW - global KW - intercomparison KW - remote sensing KW - uncertainty Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193202 SN - 2072-4292 VL - 11 IS - 22 ER - TY - JOUR A1 - Grebinyk, Anna A1 - Prylutska, Svitlana A1 - Buchelnikov, Anatoliy A1 - Tverdokhleb, Nina A1 - Grebinyk, Sergii A1 - Evstigneev, Maxim A1 - Matyshevska, Olga A1 - Cherepanov, Vsevolod A1 - Prylutskyy, Yuriy A1 - Yashchuk, Valeriy A1 - Naumovets, Anton A1 - Ritter, Uwe A1 - Dandekar, Thomas A1 - Frohme, Marcus T1 - C60 fullerene as an effective nanoplatform of alkaloid Berberine delivery into leukemic cells JF - Pharmaceutics N2 - 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. KW - C60 fullerene KW - Berberine KW - noncovalent nanocomplex KW - UV–Vis KW - DLS and AFM measurements KW - drug release KW - leukemic cells KW - uptake KW - cytotoxicity KW - apoptosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193216 SN - 1999-4923 VL - 11 IS - 11 ER - TY - JOUR A1 - Li, Shan A1 - Li, Xin A1 - Link, Roman A1 - Li, Ren A1 - Deng, Liping A1 - Schuldt, Bernhard A1 - Jiang, Xiaomei A1 - Zhao, Rongjun A1 - Zheng, Jingming A1 - Li, Shuang A1 - Yin, Yafang T1 - 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 JF - Forests N2 - 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. KW - wood anatomy KW - vertical and radial variation KW - earlywood KW - latewood KW - growth ring width KW - tyloses KW - pit membrane diameter KW - vessel lumen diameter KW - fibre length Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196297 SN - 1999-4907 VL - 10 IS - 8 ER - TY - JOUR A1 - Abdullahi, Sahra A1 - Wessel, Birgit A1 - Huber, Martin A1 - Wendleder, Anna A1 - Roth, Achim A1 - Kuenzer, Claudia T1 - Estimating penetration-related X-band InSAR elevation bias: a study over the Greenland ice sheet JF - Remote Sensing N2 - 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. KW - InSAR height KW - penetration bias KW - cryosphere KW - TanDEM-X KW - Greenland ice sheet KW - DEM Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193902 SN - 2072-4292 VL - 11 IS - 24 ER - TY - JOUR A1 - Beer, Katharina A1 - Schenk, Mariela A1 - Helfrich-Förster, Charlotte A1 - Holzschuh, Andrea T1 - The circadian clock uses different environmental time cues to synchronize emergence and locomotion of the solitary bee Osmia bicornis JF - Scientific Reports N2 - 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. KW - Behavioural ecology KW - Evolutionary developmental biology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202721 VL - 9 ER - TY - JOUR A1 - Maierhofer, Anna A1 - Flunkert, Julia A1 - Oshima, Junko A1 - Martin, George M. A1 - Poot, Martin A1 - Nanda, Indrajit A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Haaf, Thomas T1 - Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes JF - Aging Cell N2 - 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. KW - (classical and atypical) Werner syndrome KW - bisulfite pyrosequencing KW - methylation array KW - premature aging KW - segmental progeria KW - transcription deficiency Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202733 VL - 18 ER - TY - JOUR A1 - Fayez, Shaimaa A1 - Feineis, Doris A1 - Aké Assi, Laurent A1 - Seo, Ean-Jeong A1 - Efferth, Thomas A1 - Bringmann, Gerhard T1 - Ancistrobreveines A–D and related dehydrogenated naphthylisoquinoline alkaloids with antiproliferative activities against leukemia cells, from the West African liana Ancistrocladus abbreviatus JF - RSC Advances N2 - 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. KW - chemistry Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201686 VL - 9 IS - 28 ER - TY - JOUR A1 - Trappe, Julian A1 - Kneisel, Christof T1 - Geophysical and sedimentological investigations of Peatlands for the assessment of lithology and subsurface water pathways JF - Geosciences N2 - Peatlands located on slopes (herein called slope bogs) are typical landscape units in the Hunsrueck, a low mountain range in Southwestern Germany. The pathways of the water feeding the slope bogs have not yet been documented and analyzed. The identification of the different mechanisms allowing these peatlands to originate and survive requires a better understanding of the subsurface lithology and hydrogeology. Hence, we applied a multi-method approach to two case study sites in order to characterize the subsurface lithology and to image the variable spatio-temporal hydrological conditions. The combination of Electrical Resistivity Tomography (ERT) and an ERT-Monitoring and Ground Penetrating Radar (GPR), in conjunction with direct methods and data (borehole drilling and meteorological data), allowed us to gain deeper insights into the subsurface characteristics and dynamics of the peatlands and their catchment area. The precipitation influences the hydrology of the peatlands as well as the interflow in the subsurface. Especially, the geoelectrical monitoring data, in combination with the precipitation and temperature data, indicate that there are several forces driving the hydrology and hydrogeology of the peatlands. While the water content of the uppermost layers changes with the weather conditions, the bottom layer seems to be more stable and changes to a lesser extent. At the selected case study sites, small differences in subsurface properties can have a huge impact on the subsurface hydrogeology and the water paths. Based on the collected data, conceptual models have been deduced for the two case study sites. KW - peatland KW - slope bogs KW - geomorphology KW - subsurface hydrology KW - electrical resistivity tomography KW - ground penetrating radar KW - boreholes KW - Hunsrueck Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201699 VL - 9 IS - 3 ER - TY - JOUR A1 - Schuler, Michael A1 - Murauer, Kathrin A1 - Stangl, Stephanie A1 - Grau, Anna A1 - Gabriel, Katharina A1 - Podger, Lauren A1 - Heuschmann, Peter U. A1 - Faller, Hermann T1 - 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 JF - BMJ Open N2 - 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 Würzburg is available (number 20180411 01). KW - medical rehabilitation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201929 VL - 9 IS - 5 ER - TY - JOUR A1 - Mufusama, Jean-Pierre A1 - Feineis, Doris A1 - Mudogo, Virima A1 - Kaiser, Marcel A1 - Brun, Reto A1 - Bringmann, Gerhard T1 - Antiprotozoal dimeric naphthylisoquinolines, mbandakamines B\(_3\) and B\(_4\), and related 5,8′-coupled monomeric alkaloids, ikelacongolines A–D, from a Congolese Ancistrocladus liana JF - RSC Advances N2 - 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. KW - chemistry Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201141 VL - 9 IS - 21 ER - TY - JOUR A1 - Karl, Franziska A1 - Nandini Colaço, Maria B. A1 - Schulte, Annemarie A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Affective and cognitive behavior is not altered by chronic constriction injury in B7-H1 deficient and wildtype mice JF - BMC Neuroscience N2 - Background Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response. Results Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light–dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI. Conclusions Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion. KW - B7-H1 KW - Immune system KW - CCI KW - Anxiety KW - Cognitive behavior Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200540 VL - 20 ER - TY - JOUR A1 - Mietrach, Nicole A1 - Schlosser, Andreas A1 - Geibel, Sebastian T1 - An extracellular domain of the EsaA membrane component of the type VIIb secretion system: expression, purification and crystallization JF - Acta Crystallographica Section F N2 - 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 Å 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 Å, α = β = γ = 90°. KW - ESAT‐6‐like secretion system KW - ESS KW - type VII secretion system KW - EsaA KW - extracellular domain KW - Staphylococcus aureus USA300 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213681 VL - 75 IS - 12 ER - TY - JOUR A1 - Schlenkrich, Oliver T1 - Identifying Profiles of Democracies: A Cluster Analysis Based on the Democracy Matrix Dataset from 1900 to 2017 JF - Politics and Governance N2 - 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. KW - cluster analysis KW - democracy KW - democracy profiles KW - quality of democracy KW - trade-offs Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150882 SN - 2183-2463 VL - 7 IS - 4 ER - TY - JOUR A1 - Ramler, Jacqueline A1 - Poater, Jordi A1 - Hirsch, Florian A1 - Ritschel, Benedikt A1 - Fischer, Ingo A1 - Bickelhaupt, F. Matthias A1 - Lichtenberg, Crispin T1 - Carbon monoxide insertion at a heavy p-block element: unprecedented formation of a cationic bismuth carbamoyl JF - Chemical Science N2 - 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. KW - carbon monoxide KW - p-block element Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181627 VL - 10 ER - TY - JOUR A1 - Süß, Jasmin A1 - Wehner, Johannes G. A1 - Dostál, Jakub A1 - Engel, Volker A1 - Brixner, Tobias T1 - Mapping of exciton-exciton annihilation in a molecular dimer via fifth-order femtosecond two-dimensional spectroscopy JF - Journal of Physical Chemistry Letters N2 - 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 Dostál 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. KW - exciton-exciton KW - Exziton KW - Spektroskopie KW - EEA KW - 2Dimensionale Spektroskopie KW - exciton Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178420 UR - https://aip.scitation.org/doi/full/10.1063/1.5086151 N1 - This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in J. Süß et al., J. Chem. Phys. 150, 104304 (2019); https://doi.org/10.1063/1.5086151 and may be found at https://doi.org/10.1063/1.5086151. VL - 150 IS - 10 ER - TY - JOUR A1 - Magyar, Attila A1 - Wagner, Martin A1 - Thomas, Phillip A1 - Malsch, Carolin A1 - Schneider, Reinhard A1 - Störk, Stefan A1 - Heuschmann, Peter U A1 - Leyh, Rainer G A1 - Oezkur, Mehmet T1 - HO-1 concentrations 24 hours after cardiac surgery are associated with the incidence of acute kidney injury: a prospective cohort study JF - International Journal of Nephrology and Renovascular Disease N2 - 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. KW - acute kidney injury KW - cardiac surgery KW - heme oxygenase-1 KW - cardiopulmonary bypass Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177250 VL - 12 ER - TY - JOUR A1 - Zonneveld, Ben J. M. T1 - 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 JF - Forum Geobotanicum N2 - 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. KW - DNA weight KW - Pflanzen KW - genome KW - flora KW - Netherlands Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189724 UR - http://www.forum-geobotanicum.net/articles/vol_8-2018/zonneveld_flora-of-the-netherlands/zonneveld_flora-of-the-netherlands.pdf SN - 1867-9315 VL - 8 ER - TY - JOUR A1 - Brückner, Tobias A1 - Dewhurst, Rian D. A1 - Dellermann, Theresa A1 - Müller, Marcel A1 - Braunschweig, Holger T1 - Mild synthesis of diboryldiborenes by diboration of B–B triple bonds JF - Chemical Science N2 - 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. KW - boron KW - diborenes KW - diboration KW - triple bonds KW - diborynes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186306 VL - 10 ER - TY - JOUR A1 - Hoche, Joscha A1 - Schulz, Alexander A1 - Dietrich, Lysanne Monika A1 - Humeniuk, Alexander A1 - Stolte, Matthias A1 - Schmidt, David A1 - Brixner, Tobias A1 - Würthner, Frank A1 - Mitric, Roland T1 - The origin of the solvent dependence of fluorescence quantum yields in dipolar merocyanine dyes JF - Chemical Science N2 - 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. KW - solvent-dependent fluorescence yield Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198707 UR - https://doi.org/10.1039/C9SC05012D VL - 10 ER - TY - JOUR A1 - Farrell, Jeffrey M. A1 - Grande, Vincenzo A1 - Schmidt, David A1 - Würthner, Frank T1 - A Highly Warped Heptagon-Containing sp\(^2\) Carbon Scaffold via Vinylnaphthyl π-Extension JF - Angewandte Chemie International Edition N2 - 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. KW - arenes KW - carbon KW - C-C coupling KW - curvature KW - polycyclic aromatic hydrocarbons Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206682 VL - 58 IS - 46 ER - TY - JOUR A1 - Thölken, Clemens A1 - Thamm, Markus A1 - Erbacher, Christoph A1 - Lechner, Marcus T1 - Sequence and structural properties of circular RNAs in the brain of nurse and forager honeybees (Apis mellifera) JF - BMC Genomics N2 - 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. KW - circRNA KW - circular transcriptome sequencing KW - honeybee KW - brain KW - neuronal KW - Methylation KW - CpG KW - alternative splicing KW - behavioral plasticity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241302 VL - 20 ER - TY - JOUR A1 - Mayer, Alexander E. A1 - Löffler, Mona C. A1 - Loza Valdés, Angel E. A1 - Schmitz, Werner A1 - El-Merahbi, Rabih A1 - Trujillo-Viera, Jonathan A1 - Erk, Manuela A1 - Zhang, Thianzhou A1 - Braun, Ursula A1 - Heikenwalder, Mathias A1 - Leitges, Michael A1 - Schulze, Almut A1 - Sumara, Grzegorz T1 - The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling JF - Science Signaling N2 - 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. KW - Protein kinase D3 (PKD3) KW - cholesterol KW - diacylglycerol (DAG) KW - liver KW - metabolism Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250025 ET - accepted manuscript ER - TY - JOUR A1 - Schlottmann, Elisabeth A1 - Schicke, David A1 - Krüger, Felix A1 - Lingnau, Benjamin A1 - Schneider, Christian A1 - Höfling, Sven A1 - Lüdge, Kathy A1 - Porte, Xavier A1 - Reitzenstein, Stephan T1 - Stochastic polarization switching induced by optical injection in bimodal quantum-dot micropillar lasers JF - Optics Express N2 - 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 KW - Nonlinear Dynamics KW - Bistability KW - Generation KW - Subject KW - Regimes KW - Physics KW - Vcsels Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228603 VL - 27 IS - 20 ER - TY - JOUR A1 - Scherzad, Agmal A1 - Hagen, Rudolf A1 - Hackenberg, Stephan T1 - Current Understanding of Nasal Epithelial Cell Mis-Differentiation JF - Journal of Inflammation Research N2 - 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. KW - nasal mucosal barrier function KW - tight junction KW - epithelial-mesenchymal transition KW - microbiome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228562 VL - 12 ER - TY - JOUR A1 - Rasche, Leo A1 - Kumar, Manoj A1 - Gershner, Grant A1 - Samant, Rohan A1 - Van Hemert, Rudy A1 - Heidemeier, Anke A1 - Lapa, Constantin A1 - Bley, Thorsten A1 - Buck, Andreas A1 - McDonald, James A1 - Hillengass, Jens A1 - Epstein, Joshua A1 - Thanendrarajan, Sharmilan A1 - Schinke, Carolina A1 - van Rhee, Frits A1 - Zangari, Maurizio A1 - Barlogie, Bart A1 - Davies, Faith E. A1 - Morgan, Gareth J. A1 - Weinhold, Niels T1 - 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? JF - Theranostics N2 - 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. KW - multiple myeloma KW - diffusion weighted mri KW - spleen KW - tumor burden KW - high risk KW - extramedullary hematopoiesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224982 VL - 9 IS - 16 ER - TY - JOUR A1 - Roy, Denis Claude A1 - Lachance, Sylvie A1 - Cohen, Sandra A1 - Delisle, Jean-Sébastien A1 - Kiss, Thomas A1 - Sauvageau, Guy A1 - Busque, Lambert A1 - Ahmad, Imran A1 - Bernard, Lea A1 - Bambace, Nadia A1 - Boumédine, Radia S. A1 - Guertin, Marie-Claude A1 - Rezvani, Katayoun A1 - Mielke, Stephan A1 - Perreault, Claude A1 - Roy, Jean T1 - Allodepleted T-cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft-versus-host disease (GVHD) in the absence of GVHD prophylaxis JF - British Journal of Haematology N2 - 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. KW - haematopoietic stem cell KW - stem cell transplantation KW - graft-versus-host-disease KW - cell therapy and immunotherapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227075 VL - 186 IS - 5 ER - TY - JOUR A1 - Groll, J A1 - Burdick, J A A1 - Cho, D-W A1 - Derby, B A1 - Gelinsky, M A1 - Heilshorn, S C A1 - Jüngst, T A1 - Malda, J A1 - Mironov, V A A1 - Nakayama, K A1 - Ovsianikov, A A1 - Sun, W A1 - Takeuchi, S A1 - Yoo, J J A1 - Woodfield, T B F T1 - A definition of bioinks and their distinction from biomaterial inks JF - Biofabrication N2 - 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. KW - bioink KW - biomaterial ink KW - definition Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-253993 VL - 11 IS - 1 ER - TY - JOUR A1 - Sierra, Miguel A. A1 - Sánchez, David A1 - Gutierrez, Rafael A1 - Cuniberti, Gianaurelio A1 - Domínguez-Adame, Francisco A1 - Díaz, Elena T1 - Spin-polarized electron transmission in DNA-like systems JF - Biomolecules N2 - 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. KW - chirality-induced spin selectivity KW - helical molecules KW - spin transport KW - spin polarization KW - DNA electronic transport Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193813 SN - 2218-273X VL - 10 IS - 1 ER - TY - JOUR A1 - Schleicher, Bernd A1 - Arbet-Engels, Axel A1 - Baack, Dominik A1 - Balbo, Matteo A1 - Biland, Adrian A1 - Blank, Michael A1 - Bretz, Thomas A1 - Bruegge, Kai A1 - Bulinski, Michael A1 - Buss, Jens A1 - Doerr, Manuel A1 - Dorner, Daniela A1 - Elsaesser, Dominik A1 - Grischagin, Sergej A1 - Hildebrand, Dorothee A1 - Linhoff, Lena A1 - Mannheim, Karl A1 - Mueller, Sebastian Achim A1 - Neise, Dominik A1 - Neronov, Andrii A1 - Noethe, Maximilian A1 - Paravac, Aleksander A1 - Rhode, Wolfgang A1 - Schulz, Florian A1 - Sedlaczek, Kevin A1 - Shukla, Amit A1 - Sliusar, Vitalii A1 - Willert, Elan A1 - Walter, Roland T1 - Fractional Variability—A Tool to Study Blazar Variability JF - Galaxies N2 - 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. KW - blazars KW - variability KW - fractional variability KW - active galactic nuclei Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197348 SN - 2075-4434 VL - 7 IS - 2 ER - TY - JOUR A1 - Rödel, Michaela A1 - Teßmar, Jörg A1 - Groll, Jürgen A1 - Gbureck, Uwe T1 - Tough and Elastic alpha-Tricalcium Phosphate Cement Composites with Degradable PEG-Based Cross-Linker JF - Materials N2 - 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. KW - dual setting system KW - bending strength KW - calcium phosphate cement KW - composite material KW - HEMA KW - hydroxyapatite KW - free radical polymerization Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226437 VL - 12 IS - 53 ER - TY - JOUR A1 - Akshat, Puri A1 - Aaboud, M. A1 - Aad, G. A1 - Abbott, B. A1 - Abdinov, O. A1 - Abeloos, B. A1 - Abhayasinghe, D. K. A1 - Abidi, S. H. A1 - Abou Zeid, O. S. A1 - Abraham, N. L. A1 - Abramowicz, H. A1 - Abreu, H. A1 - Abulaiti, Y. A1 - Acharya, B. S. A1 - Adachi, S. A1 - Adam, L. A1 - Adamczyk, L. A1 - Adelman, J. A1 - Adersberger, M. A1 - Adiguzel, A. A1 - Adye, T. A1 - Affolder, A. A. A1 - Afik, Y. A1 - Agheorghiesei, C. A1 - Aguilar-Saavedra, J. A. A1 - Ahmadov, F. A1 - Aiellil, G. A1 - Akatsuka, S. A1 - Akesson, T. P. A. A1 - Akilli, E. A1 - Akimov, A. V. A1 - Alberghi, G. L. A1 - Albert, J. A1 - Albicocco, P. A1 - Alconada Verzini, M. J. A1 - Alderweireld, S. A1 - Aleksa, M. A1 - Aleksandrov, I. N. A1 - Alexa, C. A1 - Alexopoulos, T. A1 - Alhroob, M. A1 - Ali, B. A1 - Alimonti, G. A1 - Alison, J. A1 - Andre, S. P. A1 - Allaire, C. A1 - Allbrooke, B. M. M. A1 - Allen, B. W. A1 - Allport, P. P. A1 - Aloisio, A. A1 - Alonso, A. A1 - Alonso, F. A1 - Alpigiani, C. A1 - Alshehri, A. A. A1 - Alstaty, M. I. A1 - Alvarez, Gonzalez B. A1 - Alvarez Piqueras, D. A1 - Alviggi, M. G. A1 - Amadio, B. T. A1 - Amaral, Coutinho, Y. A1 - Ambler, A. A1 - Ambroz, L. A1 - Amelung, C. A1 - Amidei, D. A1 - Amor Dos Santos, S. P. A1 - Amoroso, S. A1 - Amrouche, C. S. A1 - Anastopoulos, C. A1 - Ancu, L. S. A1 - Andari, N. A1 - Andeen, T. A1 - Anders, C. F. A1 - Anders, J. K. A1 - Anderson, K. J. A1 - Andreazza, A. A1 - Andrei, V. A1 - et al, T1 - 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) JF - Nuclear Physics A N2 - 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. KW - jets KW - fragmentation functions KW - jet shapes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224703 VL - 982 IS - 2 ER - TY - JOUR A1 - Schwedhelm, Ivo A1 - Zdzieblo, Daniela A1 - Appelt-Menzel, Antje A1 - Berger, Constantin A1 - Schmitz, Tobias A1 - Schuldt, Bernhard A1 - Franke, Andre A1 - Müller, Franz-Josef A1 - Pless, Ole A1 - Schwarz, Thomas A1 - Wiedemann, Philipp A1 - Walles, Heike A1 - Hansmann, Jan T1 - Automated real-time monitoring of human pluripotent stem cell aggregation in stirred tank reactors JF - Scientific Reports N2 - 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. KW - Biomedical engineering KW - Stem-cell biotechnology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202649 VL - 9 ER - TY - JOUR A1 - Nickel, Joachim A1 - Mueller, Thomas D. T1 - Specification of BMP signaling JF - Cells N2 - 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. KW - TGFβ/BMP signaling KW - ligand-receptor promiscuity KW - signal specification Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193869 SN - 2073-4409 VL - 8 IS - 12 ER - TY - JOUR A1 - Elmaidomy, Abeer H. A1 - Mohammed, Rabab A1 - Hassan, Hossam M. A1 - Owis, Asmaa I. A1 - Rateb, Mostafa E. A1 - Khanfar, Mohammad A. A1 - Krischke, Markus A1 - Mueller, Martin J. A1 - Abdelmohsen, Usama Ramadan T1 - Metabolomic profiling and cytotoxic tetrahydrofurofuran lignans investigations from Premna odorata Blanco JF - Metabolites N2 - 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. KW - Premna KW - lignan KW - metabolomic KW - cytotoxic KW - pharmacophore map Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193187 SN - 2218-1989 VL - 9 IS - 10 ER - TY - JOUR A1 - Draganov, Dobrin D. A1 - Santidrian, Antonio F. A1 - Minev, Ivelina A1 - Duong, Nguyen A1 - Kilinc, Mehmet Okyay A1 - Petrov, Ivan A1 - Vyalkova, Anna A1 - Lander, Elliot A1 - Berman, Mark A1 - Minev, Boris A1 - Szalay, Aladar A. T1 - Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers JF - Journal of Translational Medicine N2 - 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. KW - vaccinia KW - cancer KW - stem Cells KW - oncolysis KW - oncolytic virus KW - virotherapy KW - immunity KW - immunotherapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226312 SN - 100 VL - 17 ER - TY - JOUR A1 - Duan, Xiaodong A1 - Nagel, Georg A1 - Gao, Shiqiang T1 - Mutated channelrhodopsins with increased sodium and calcium permeability JF - Applied Sciences N2 - (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. KW - optogenetics KW - channelrhodopsins KW - sodium KW - calcium KW - DC gate Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197435 SN - 2076-3417 VL - 9 IS - 4 ER - TY - JOUR A1 - Minev, Boris R. A1 - Lander, Elliot A1 - Feller, John F. A1 - Berman, Mark A1 - Greenwood, Bernadette M. A1 - Minev, Ivelina A1 - Santidrian, Antonio F. A1 - Nguyen, Duong A1 - Draganov, Dobrin A1 - Killinc, Mehmet O. A1 - Vyalkova, Anna A1 - Kesari, Santosh A1 - McClay, Edward A1 - Carabulea, Gabriel A1 - Marincola, Francesco M. A1 - Butterfield, Lisa H. A1 - Szalay, Aladar A. T1 - First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells JF - Journal of Translational Medicine N2 - 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. KW - clinical trial KW - oncolytic vaccinia virus KW - stromal vascular fraction KW - immunotherapy of cancer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224105 VL - 17 ER - TY - JOUR A1 - Doppler, Kathrin A1 - Schuster, Yasmin A1 - Appeltshauser, Luise A1 - Biko, Lydia A1 - Villmann, Carmen A1 - Weishaupt, Andreas A1 - Werner, Christian A1 - Sommer, Claudia T1 - Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model JF - Journal of Neuroinflammation N2 - Background: Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods: In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results: Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions: Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis. KW - complement deposition KW - paranodopathy KW - anti-contactin-1 KW - CIDP KW - passive transfer KW - autoantibody Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200476 VL - 16 IS - 73 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Stoll, Guido A1 - Papp, Lena A1 - Bohr, Arne A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Electrical stimulation of the mesencephalic locomotor region has no impact on blood–brain barrier alterations after cerebral photothrombosis in rats JF - International Journal of Molecular Science N2 - 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. KW - photothrombotic stroke KW - deep brain stimulation KW - mesencephalic locomotor region KW - blood-brain barrier KW - tight junctions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201284 SN - 1422-0067 VL - 20 IS - 16 ER - TY - JOUR A1 - Voulgari‐Kokota, Anna A1 - Ankenbrand, Markus J. A1 - Grimmer, Gudrun A1 - Steffan‐Dewenter, Ingolf A1 - Keller, Alexander T1 - Linking pollen foraging of megachilid bees to their nest bacterial microbiota JF - Ecology and Evolution N2 - Solitary bees build their nests by modifying the interior of natural cavities, and they provision them with food by importing collected pollen. As a result, the microbiota of the solitary bee nests may be highly dependent on introduced materials. In order to investigate how the collected pollen is associated with the nest microbiota, we used metabarcoding of the ITS2 rDNA and the 16S rDNA to simultaneously characterize the pollen composition and the bacterial communities of 100 solitary bee nest chambers belonging to seven megachilid species. We found a weak correlation between bacterial and pollen alpha diversity and significant associations between the composition of pollen and that of the nest microbiota, contributing to the understanding of the link between foraging and bacteria acquisition for solitary bees. Since solitary bees cannot establish bacterial transmission routes through eusociality, this link could be essential for obtaining bacterial symbionts for this group of valuable pollinators. KW - foraging patterns KW - nest microbiota KW - plant–microbe–pollinator triangle KW - pollination network KW - solitary bees KW - wild bees Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201749 SN - 00 VL - 2019 IS - 9 ER - TY - JOUR A1 - He, Jiang A1 - Rauch, Florian A1 - Friedrich, Alexandra A1 - Sieh, Daniel A1 - Ribbeck, Tatjana A1 - Krummenacher, Ivo A1 - Braunschweig, Holger A1 - Finze, Maik A1 - Marder, Todd B. T1 - N-Heterocyclic Olefins as Electron Donors in Combination with Triarylborane Acceptors: Synthesis, Optical and Electronic Properties of D-π-A Compounds JF - Chemistry - A European Journal N2 - 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. KW - donor-acceptor systems KW - electrochemistry KW - photophysical prosperties KW - N-heterocyclic olefins KW - triarylboranes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204690 VL - 25 ER - TY - JOUR A1 - Salman Haider, Malik A1 - Schreiner, Jochen A1 - Kendl, Sabine A1 - Kroiss, Matthias A1 - Luxenhofer, Robert T1 - A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models JF - Macromolecular Bioscience N2 - 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. KW - adrenocortical carcinoma KW - amphiphilic block copolymer KW - NCI-H295R KW - poly(2-oxazoline) KW - solubility enhancement Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206224 VL - 20 IS - 1 ER - TY - JOUR A1 - González, María Magdalena A1 - Dorner, Daniela A1 - Bretz, Thomas A1 - García-González, José Andrés T1 - Unbiased long-term monitoring at TeV energies JF - Galaxies N2 - 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. KW - monitoring KW - very high energies (VHE) KW - TeV energies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197389 SN - 2075-4434 VL - 7 IS - 2 ER - TY - JOUR A1 - Waider, Jonas A1 - Popp, Sandy A1 - Mlinar, Boris A1 - Montalbano, Alberto A1 - Bonfiglio, Francesco A1 - Aboagye, Benjamin A1 - Thuy, Elisabeth A1 - Kern, Raphael A1 - Thiel, Christopher A1 - Araragi, Naozumi A1 - Svirin, Evgeniy A1 - Schmitt-Böhrer, Angelika G. A1 - Corradetti, Renato A1 - Lowry, Christopher A. A1 - Lesch, Klaus-Peter T1 - Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity JF - Frontiers in Neuroscience N2 - 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. KW - tryptophan hydroxylase 2 KW - knockout KW - fear learning KW - extinction KW - long-term potentiation KW - hippocampus KW - immediate-early gene KW - serotonin deficiency Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196077 SN - 1662-453X VL - 13 IS - 245 ER - TY - JOUR A1 - Breitenbach, Tim A1 - Lorenz, Kristina A1 - Dandekar, Thomas T1 - How to steer and control ERK and the ERK signaling cascade exemplified by looking at cardiac insufficiency JF - International Journal of Molecular Sciences N2 - 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. KW - optimal pharmacological modulation KW - efficient intervention points KW - ERK signaling KW - optimal treatment strategies KW - optimal drug targeting KW - optimal drug combination Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285164 SN - 1422-0067 VL - 20 IS - 9 ER - TY - JOUR A1 - Jaite, Charlotte A1 - Bühren, Katharina A1 - Dahmen, Brigitte A1 - Dempfle, Astrid A1 - Becker, Katja A1 - Correll, Christoph U. A1 - Egberts, Karin M. A1 - Ehrlich, Stefan A1 - Fleischhaker, Christian A1 - von Gontard, Alexander A1 - Hahn, Freia A1 - Kolar, David A1 - Kaess, Michael A1 - Legenbauer, Tanja A1 - Renner, Tobias J. A1 - Schulze, Ulrike A1 - Sinzig, Judith A1 - Thomae, Ellen A1 - Weber, Linda A1 - Wessing, Ida A1 - Antony, Gisela A1 - Hebebrand, Johannes A1 - Föcker, Manuel A1 - Herpertz-Dahlmann, Beate T1 - Clinical Characteristics of Inpatients with Childhood vs. Adolescent Anorexia Nervosa JF - Nutrients N2 - 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. KW - anorexia nervosa KW - children KW - adolescents KW - clinical characteristics KW - BMI KW - outcome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193160 SN - 2072-6643 VL - 11 IS - 11 ER - TY - JOUR A1 - Thiess, Torsten A1 - Mellerup, Soren K. A1 - Braunschweig, Holger T1 - B–B Cleavage and Ring-Expansion of a 1,4,2,3-Diazadiborinine with N-Heterocyclic Carbenes JF - Chemistry - A European Journal N2 - 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. KW - B,N-heterocylcles KW - B-B bond activation KW - diazadiborinines KW - NHCs KW - ring-expansion reactions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206173 VL - 25 IS - 59 ER - TY - JOUR T1 - 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 JF - Physics Letters B N2 - 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. KW - Parton Distributions KW - Dark-matter KW - Constraints Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319552 VL - 788 ER - TY - JOUR A1 - Lewitzki, Victor A1 - Klement, Rainer J. A1 - Kosmala, Rebekka A1 - Lisowski, Dominik A1 - Flentje, Michael A1 - Polat, Bülent T1 - Accelerated hyperfractionated radiochemotherapy with temozolomide is equivalent to normofractionated radiochemotherapy in a retrospective analysis of patients with glioblastoma JF - Radiation Oncology N2 - 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. KW - Brain cancer KW - Glioblastoma KW - High grade glioma KW - Radiotherapy KW - Temozolomide KW - Corticosteroids Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202614 VL - 14 ER - TY - JOUR A1 - Seidlmayer, Lea K. A1 - Mages, Christine A1 - Berbner, Annette A1 - Eder-Negrin, Petra A1 - Arias-Loza, Paula Anahi A1 - Kaspar, Mathias A1 - Song, Moshi A1 - Dorn, Gerald W. A1 - Kohlhaas, Michael A1 - Frantz, Stefan A1 - Maack, Christoph A1 - Gerull, Brenda A1 - Dedkova, Elena N. T1 - Mitofusin 2 is essential for IP3-mediated SR/Mitochondria metabolic feedback in ventricular myocytes JF - Frontiers in Physiology N2 - 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). KW - mitofusin 2 KW - IP3 KW - SR/mitochondria metabolic feedback KW - mitochondrial mRyR1 KW - ATP generation KW - endothelin-1 KW - Mfn2 KO mice Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199141 SN - 1664-042X VL - 10 IS - 733 ER - TY - JOUR A1 - Landman, Todd A1 - Lauth, Hans-Joachim T1 - Political Trade-Offs: Democracy and Governance in a Changing World JF - Politics and Governance N2 - 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. KW - balancing trade-offs KW - constructed trade-offs KW - logical trade-offs KW - trade-offs Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144308 SN - 2183-2463 VL - 7 IS - 4 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Stoll, Guido A1 - Bohr, Arne A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats JF - International Journal of Molecular Science N2 - Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level. KW - photothrombotic stroke KW - deep brain stimulation KW - mesencephalic locomotor region KW - neuroprotection KW - neuronal apoptosis KW - neuroinflammation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201355 SN - 1422-0067 VL - 20 IS - 9 ER - TY - JOUR A1 - Radchuk, Volodymyr A1 - Rajiv, Sharma A1 - Potokina, Elena A1 - Radchuk, Ruslana A1 - Weier, Diana A1 - Munz, Eberhard A1 - Schreiber, Miriam A1 - Mascher, Martin A1 - Stein, Nils A1 - Wicker, Thomas A1 - Kilian, Benjamin A1 - Borisjuk, Ljudmilla T1 - The highly divergent \(Jekyll\) genes, required for sexual reproduction, are lineage specific for the related grass tribes Triticeae and Bromeae JF - Plant Journal N2 - 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. KW - gene alleles KW - lineage-specific genes KW - Triticeae KW - Hordeum vulgare KW - Triticum aestivum KW - gene family evolution KW - plant reproduction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224769 VL - 98 IS - 6 ER - TY - JOUR A1 - Rayner, Christopher A1 - Coleman, Jonathan R. I. A1 - Purves, Kirstin L. A1 - Hodsoll, John A1 - Goldsmith, Kimberley A1 - Alpers, Georg W. A1 - Andersson, Evelyn A1 - Arolt, Volker A1 - Boberg, Julia A1 - Bögels, Susan A1 - Creswell, Cathy A1 - Cooper, Peter A1 - Curtis, Charles A1 - Deckert, Jürgen A1 - Domschke, Katharina A1 - El Alaoui, Samir A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Grocholewski, Anja A1 - Hahlweg, Kurt A1 - Hamm, Alfons A1 - Hedman, Erik A1 - Heiervang, Einar R. A1 - Hudson, Jennifer L. A1 - Jöhren, Peter A1 - Keers, Robert A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lavebratt, Catharina A1 - Lee, Sang-hyuck A1 - Lester, Kathryn J. A1 - Lindefors, Nils A1 - Margraf, Jürgen A1 - Nauta, Maaike A1 - Pané-Farré, Christiane A. A1 - Pauli, Paul A1 - Rapee, Ronald M. A1 - Reif, Andreas A1 - Rief, Winfried A1 - Roberts, Susanna A1 - Schalling, Martin A1 - Schneider, Silvia A1 - Silverman, Wendy K. A1 - Ströhle, Andreas A1 - Teismann, Tobias A1 - Thastum, Mikael A1 - Wannemüller, Andre A1 - Weber, Heike A1 - Wittchen, Hans-Ulrich A1 - Wolf, Christiane A1 - Rück, Christian A1 - Breen, Gerome A1 - Eley, Thalia C. T1 - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders JF - Translational Psychiatry N2 - 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. KW - Human behaviour KW - Personalized medicine KW - Prognostic markers KW - Psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048 VL - 9 IS - 150 ER - TY - JOUR A1 - Schlegel, Jan A1 - Peters, Simon A1 - Doose, Sören A1 - Schubert-Unkmeir, Alexandra A1 - Sauer, Markus T1 - Super-resolution microscopy reveals local accumulation of plasma membrane gangliosides at Neisseria meningitidis Invasion Sites JF - Frontiers in Cell and Developmental Biology N2 - Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for epidemic meningitis and sepsis worldwide. A critical step in the development of meningitis is the interaction of bacteria with cells forming the blood-cerebrospinal fluid barrier, which requires tight adhesion of the pathogen to highly specialized brain endothelial cells. Two endothelial receptors, CD147 and the β2-adrenergic receptor, have been found to be sequentially recruited by meningococci involving the interaction with type IV pilus. Despite the identification of cellular key players in bacterial adhesion the detailed mechanism of invasion is still poorly understood. Here, we investigated cellular dynamics and mobility of the type IV pilus receptor CD147 upon treatment with pili enriched fractions and specific antibodies directed against two extracellular Ig-like domains in living human brain microvascular endothelial cells. Modulation of CD147 mobility after ligand binding revealed by single-molecule tracking experiments demonstrates receptor activation and indicates plasma membrane rearrangements. Exploiting the binding of Shiga (STxB) and Cholera toxin B (CTxB) subunits to the two native plasma membrane sphingolipids globotriaosylceramide (Gb3) and raft-associated monosialotetrahexosylganglioside GM1, respectively, we investigated their involvement in bacterial invasion by super-resolution microscopy. Structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM) unraveled accumulation and coating of meningococci with GM1 upon cellular uptake. Blocking of CTxB binding sites did not impair bacterial adhesion but dramatically reduced bacterial invasion efficiency. In addition, cell cycle arrest in G1 phase induced by serum starvation led to an overall increase of GM1 molecules in the plasma membrane and consequently also in bacterial invasion efficiency. Our results will help to understand downstream signaling events after initial type IV pilus-host cell interactions and thus have general impact on the development of new therapeutics targeting key molecules involved in infection. KW - Neisseria meningitidis KW - sphingolipids KW - gangliosides and lipid rafts KW - super-resolution microscopy KW - single-molecule tracking Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201639 VL - 7 IS - 194 ER - TY - JOUR A1 - Kleefeldt, Florian A1 - Bömmel, Heike A1 - Broede, Britta A1 - Thomsen, Michael A1 - Pfeiffer, Verena A1 - Wörsdörfer, Philipp A1 - Karnati, Srikanth A1 - Wagner, Nicole A1 - Rueckschloss, Uwe A1 - Ergün, Süleyman T1 - Aging‐related carcinoembryonic antigen‐related cell adhesion molecule 1 signaling promotes vascular dysfunction JF - Aging Cell N2 - 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. KW - aging KW - anti‐aging KW - cytokines KW - inflammation KW - mouse KW - reactive oxygen species Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201231 VL - 2019 IS - 18 ER - TY - JOUR A1 - Rubo, Marius A1 - Gamer, Matthias T1 - Visuo-tactile congruency influences the body schema during full body ownership illusion JF - Consciousness and Cognition N2 - 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. KW - Full body ownership illusion KW - Visuo-tactile congruency KW - Body schema KW - Movement behavior Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227095 VL - 73 ER - TY - JOUR A1 - Neugebauer, Hermann A1 - Schneider, Hauke A1 - Kollmar, Rainer T1 - 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” JF - Critical Care N2 - No abstract available. KW - stroke KW - hypothermia KW - hemicraniectomy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232268 VL - 23 ER - TY - JOUR A1 - König, Kirsten A1 - Pechmann, Astrid A1 - Thiele, Simone A1 - Walter, Maggie C. A1 - Schorling, David A1 - Tassoni, Adrian A1 - Lochmüller, Hanns A1 - Müller-Reible, Clemens A1 - Kirschner, Janbernd T1 - De-duplicating patient records from three independent data sources reveals the incidence of rare neuromuscular disorders in Germany JF - Orphanet Journal of Rare Diseases N2 - 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. KW - incidence KW - neuromuscular disease KW - spinal muscular atrophy KW - duchenne muscular dystrophy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222807 VL - 14 ER - TY - JOUR A1 - Sepahi, Ilnaz A1 - Faust, Ulrike A1 - Sturm, Marc A1 - Bosse, Kristin A1 - Kehrer, Martin A1 - Heinrich, Tilman A1 - Grundman-Hauser, Kathrin A1 - Bauer, Peter A1 - Ossowski, Stephan A1 - Susak, Hana A1 - Varon, Raymonda A1 - Schröck, Evelin A1 - Niederacher, Dieter A1 - Auber, Bernd A1 - Sutter, Christian A1 - Arnold, Norbert A1 - Hahnen, Eric A1 - Dworniczak, Bernd A1 - Wang-Gorke, Shan A1 - Gehrig, Andrea A1 - Weber, Bernhard H. F. A1 - Engel, Christoph A1 - Lemke, Johannes R. A1 - Hartkopf, Andreas A1 - Huu Phuc, Nguyen A1 - Riess, Olaf A1 - Schroeder, Christopher T1 - Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women JF - BMC Cancer N2 - 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. KW - breast cancer KW - age at onset KW - DNA-repair genes KW - next-generation-sequencing KW - panel sequencing KW - extreme phenotypes KW - hereditary breast and ovarian cancer KW - BRCA1 KW - DNA-repair Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237676 VL - 19 ER - TY - JOUR A1 - Wiechmann, Tobias A1 - Röh, Simone A1 - Sauer, Susann A1 - Czamara, Darina A1 - Arloth, Janine A1 - Ködel, Maik A1 - Beintner, Madita A1 - Knop, Lisanne A1 - Menke, Andreas A1 - Binder, Elisabeth B. A1 - Provençal, Nadine T1 - Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus JF - Clinical Epigenetics N2 - 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. KW - DNA methylation KW - FKBP5 KW - glucocorticoid receptor KW - early-life stress KW - targeted bisulfite sequencing KW - dexamethasone Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233673 VL - 11 ER - TY - JOUR T1 - Resolution of the ATLAS muon spectrometer monitored drift tubes in LHC Run 2 JF - Journal of Instrumentation N2 - The momentum measurement capability of the ATLAS muon spectrometer relies fundamentally on the intrinsic single-hit spatial resolution of the monitored drift tube precision tracking chambers. Optimal resolution is achieved with a dedicated calibration program that addresses the specific operating conditions of the 354 000 high-pressure drift tubes in the spectrometer. The calibrations consist of a set of timing offsets and drift time to drift distance transfer relations, and result in chamber resolution functions. This paper describes novel algorithms to obtain precision calibrations from data collected by ATLAS in LHC Run 2 and from a gas monitoring chamber, deployed in a dedicated gas facility. The algorithm output consists of a pair of correction constants per chamber which are applied to baseline calibrations, and determined to be valid for the entire ATLAS Run 2. The final single-hit spatial resolution, averaged over 1172 monitored drift tube chambers, is 81.7 +/- 2.2 mu m. KW - Gaseous detectors KW - Chambers KW - Muon spectrometers KW - Particle tracking detectors (Gaseous detectors) KW - Wire chambers (MWPC, Thin-gap chambers, drift chambers, drift tubes, proportional chambers etc) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226869 VL - 14 ER - TY - JOUR T1 - Search for high-mass dilepton resonances using 139 fb\(^{-1}\) of \(pp\) collision data collected at root \(s\)=13 TeV with the ATLAS detector JF - Physics Letters B N2 - A search for high-mass dielectron and dimuon resonances in the mass range of 250 GeV to 6TeV is presented. The data were recorded by the ATLAS experiment in proton-proton collisions at a centre-ofmass energy of root s = 13 TeV during Run 2 of the Large Hadron Collider and correspond to an integrated luminosity of 139 fb(-1). A functional form is fitted to the dilepton invariant-mass distribution to model the contribution from background processes, and a generic signal shape is used to determine the significance of observed deviations from this background estimate. No significant deviation is observed and upper limits are placed at the 95% confidence level on the fiducial cross-section times branching ratio for various resonance width hypotheses. The derived limits are shown to be applicable to spin-0, spin-1 and spin-2 signal hypotheses. For a set of benchmark models, the limits are converted into lower limits on the resonance mass and reach 4.5 TeV for the E-6-motivated Z(psi)' boson. Also presented are limits on Heavy Vector Triplet model couplings. (C) 2019 The Author. Published by Elsevier B.V. KW - Monte-Carlo KW - Bosons KW - Decay Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226844 VL - 796 ER - TY - JOUR T1 - Search for electroweak diboson production in association with a high-mass dijet system in semileptonic final states in \(pp\) collisions at √\(s\) =13 TeV with the ATLAS detector JF - Physical Review D N2 - This paper reports on a search for electroweak diboson (WW/WZ/ZZ) production in association with a high-mass dijet system, using data from proton-proton collisions at a center-of-mass energy of N root s = 13 TeV. The data, corresponding to an integrated luminosity of 35.5 fb(-1), were recorded with the ATLAS detector in 2015 and 2016 at the Large Hadron Collider. The search is performed in final states in which one boson decays leptonically, and the other boson decays hadronically. The hadronically decaying W/Z boson is reconstructed as either two small-radius jets or one large-radius jet using jet substructure techniques. The electroweak production of WW/WZ/ZZ in association with two jets is measured with an observed (expected) significance of 2.7 (2.5) standard deviations, and the fiducial cross section is measured to be 45.1 +/- 8.6(stat.)(-14.6)(+15.9)(syst.) fb. KW - Proton-Proton Collisions KW - 2 Jets KW - Parton Distributions KW - Weak-Interactions KW - Cross-Section KW - High-Energies KW - Boson KW - Constraints KW - Scattering KW - Couplings KW - Particle accelerators KW - Hadron colliders KW - W & Z bosons KW - Gauge bosons KW - Quantum electrodynamics KW - Electroweak interaction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226877 VL - 100 ER - TY - JOUR T1 - Search for a heavy charged boson in events with a charged lepton and missing transverse momentum from \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - Physical Review D N2 - A search for a heavy charged-boson resonance decaying into a charged lepton (electron or muon) and a neutrino is reported. A data sample of 139 fb(-1) of proton-proton collisions at root s = 13 TeV collected with the ATLAS detector at the LHC during 2015-2018 is used in the search. The observed transverse mass distribution computed from the lepton and missing transverse momenta is consistent with the distribution expected from the Standard Model, and upper limits on the cross section for pp -> W'-> lv are extracted (l = e or mu). These vary between 1.3 pb and 0.05 tb depending on the resonance mass in the range between 0.15 and 7.0 TeV at 95% confidence level for the electron and muon channels combined. Gauge bosons with a mass below 6.0 and 5.1 TeV are excluded in the electron and muon channels, respectively, in a model with a resonance that has couplings to fermions identical to those of the Standard Model W boson. Cross-section limits are also provided for resonances with several fixed Gamma/m values in the range between 1% and 15%. Model-independent limits are derived in single-bin signal regions defined by a varying minimum transverse mass threshold. The resulting visible cross-section upper limits range between 4.6 (15) ph and 22 (22) ab as the threshold increases from 130 (110) GeV to 5.1 (5.1) TeV in the electron (muon) channel. KW - Pair Production KW - Symmetry KW - Decay KW - Monte-Carlo KW - semileptonic & radiative decays KW - Leptonic KW - Hadron-hadron interactions KW - Extensions of gauge sector Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226835 VL - 100 ER - TY - JOUR T1 - Measurement of distributions sensitive to the underlying event in inclusive Z boson production in \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - European Physical Journal C N2 - This paper presents measurements of charged-particle distributions sensitive to the properties of the underlying event in events containing a Z boson decaying into a muon pair. The data were obtained using the ATLAS detector at the LHC in proton-proton collisions at a centre-of-mass energy of 13 TeV with an integrated luminosity of 3.2 fb(-1). Distributions of the charged-particle multiplicity and of the charged-particle transverse momentum are measured in regions of the azimuth defined relative to the Z boson direction. The measured distributions are compared with the predictions of various Monte Carlo generators which implement different underyling event models. The Monte Carlo model predictions qualitatively describe the data well, but with some significant discrepancies. KW - Cross-Section Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226883 VL - 79 IS - 666 ER - TY - JOUR T1 - Measurement of the cross-section and charge asymmetry of W bosons produced in proton-proton collisions at √\(s\)=8 TeV with the ATLAS detector JF - European Physical Journal C N2 - This paper presents measurements of the W+->mu+nu and W-->mu-nu cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton-proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2fb(-1). The precision of the cross-section measurements varies between 0.8 and 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them. KW - Pair Production KW - Monte-Carlo Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226850 VL - 79 IS - 760 ER - TY - JOUR T1 - Observation of Light-by-Light Scattering in Ultraperipheral Pb + Pb Collisions with the ATLAS Detector JF - Physical Review Letters N2 - This Letter describes the observation of the light-by-light scattering process, gamma gamma -> gamma gamma, in Pb + Pb collisions at root S-NN = 5.02 TeV. The analysis is conducted using a data sample corresponding to an integrated luminosity of 1.73 nb(-1), collected in November 2018 by the ATLAS experiment at the LHC. Light-by-light scattering candidates are selected in events with two photons produced exclusively, each with transverse energy E-T(gamma) > 3 GeV and pseudorapidity vertical bar eta(gamma)vertical bar < 2.4, diphoton invariant mass above 6 GeV, and small diphoton transverse momentum and acoplanarity. After applying all selection criteria, 59 candidate events are observed for a background expectation of 12 +/- 3 events. The observed excess of events over the expected background has a significance of 8.2 standard deviations. The measured fiducial cross section is 78 +/- 13(stat) +/- 7(syst) +/- 3(lumi) nb. KW - Ultrarelativistic Heavy-Ion KW - Delbruck Scattering KW - Physics KW - Relativistic heavy-ion collisions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226892 VL - 123 ER - TY - JOUR T1 - Identification of boosted Higgs bosons decaying into \(b\)-quark pairs with the ATLAS detector at 13 TeV JF - European Physical Journal C N2 - This paper describes a study of techniques for identifying Higgs bosons at high transverse momenta decaying into bottom-quark pairs, H -> b (b) over bar, for proton-proton collision data collected by the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy root s = 13 TeV. These decays are reconstructed from calorimeter jets found with the anti-k(t) R = 1.0 jet algorithm. To tag Higgs bosons, a combination of requirements is used: b-tagging of R = 0.2 track-jets matched to the large-R calorimeter jet, and requirements on the jet mass and other jet substructure variables. The Higgs boson tagging efficiency and corresponding multijet and hadronic top-quark background rejections are evaluated using Monte Carlo simulation. Several benchmark tagging selections are defined for different signal efficiency targets. The modelling of the relevant input distributions used to tag Higgs bosons is studied in 36 fb(-1) of data collected in 2015 and 2016 using g -> b (b) over bar and Z(-> b (b) over bar)gamma event selections in data. Both processes are found to be well modelled within the statistical and systematic uncertainties. KW - Parton distributions KW - PP collisions KW - search KW - MASS Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226812 VL - 79 IS - 836 ER - TY - JOUR T1 - Measurement of the inclusive cross-section for the production of jets in association with a \(Z\) boson in proton-proton collisions at 8 TeV using the ATLAS detector JF - European Physical Journal C N2 - The inclusive cross-section for jet production in association with a Z boson decaying into an electronpositron pair is measured as a function of the transverse momentum and the absolute rapidity of jets using 19.9 fb(-1) of root s = 8 TeV proton-proton collision data collected with the ATLAS detector at the Large Hadron Collider. The measured Z + jets cross-section is unfolded to the particle level. The cross-section is compared with state-of-the-art Standard Model calculations, including the next-to-leading-order and next-to-next-to-leading-order perturbative QCD calculations, corrected for non-perturbative and QED radiation effects. The results of the measurements cover final-state jets with transverse momenta up to 1 TeV, and show good agreement with fixed-order calculations. KW - P(P) over-bar collisions KW - + KW - distributions KW - decay Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226821 VL - 79 IS - 847 ER - TY - JOUR T1 - Search for diboson resonances in hadronic final states in 139 fb\(^{-1}\) of \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - Narrow resonances decaying into WW, WZ or ZZ boson pairs are searched for in 139 fb(-1) of proton-proton collision data at a centre-of-mass energy of root s = 13TeV recorded with the ATLAS detector at the Large Hadron Collider from 2015 to 2018. The diboson system is reconstructed using pairs of high transverse momentum, large-radius jets. These jets are built from a combination of calorimeter- and tracker-inputs compatible with the hadronic decay of a boosted W or Z boson, using jet mass and substructure properties. The search is performed for diboson resonances with masses greater than 1.3TeV. No significant deviations from the background expectations are observed. Exclusion limits at the 95% confidence level are set on the production cross-section times branching ratio into dibosons for resonances in a range of theories beyond the Standard Model, with the highest excluded mass of a new gauge boson at 3.8TeV in the context of mass-degenerate resonances that couple predominantly to gauge bosons. KW - Hadron-Hadron scattering (experiments) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226905 VL - 09 IS - 91 ER - TY - JOUR T1 - FCC-hh: The Hadron Collider: Future Circular Collider Conceptual Design Report Volume 3 JF - European Physical Journal - Special Topics N2 - In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries. KW - Multiple-Scattering KW - Top-Quark KW - CERN KW - Energy KW - Reduction KW - Impact Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226917 VL - 228 ER - TY - JOUR T1 - HE-LHC: The High-Energy Large Hadron Collider : Future Circular Collider Conceptual Design Report Volume 4 JF - European Physical Journal - Special Topics N2 - In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries. KW - Event builder KW - Impact Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226928 VL - 228 IS - 5 ER - TY - JOUR T1 - FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1 JF - European Physical Journal C N2 - We review the physics opportunities of the Future Circular Collider, covering its e(+)e(-), pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics. KW - Electroweak Phase-Transition KW - By-Light Scattering KW - Deep Inelastic-scattering KW - Strange Baryon Production KW - Dark-Matter KW - Radiative-corrections KW - E(+)E(-) collicions KW - Transverse-Momentum KW - Top-Quark KW - Branching fractions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226938 VL - 79 IS - 474 ER - TY - JOUR A1 - Nentwich, Julia A1 - Ruf, Katharina A1 - Girschick, Hermann A1 - Holl-Wieden, Annette A1 - Morbach, Henner A1 - Hebestreit, Helge A1 - Hofmann, Christine T1 - Physical activity and health-related quality of life in chronic non-bacterial osteomyelitis JF - Pediatric Rheumatology N2 - Background Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disorder of the skeletal system of yet unknown etiology. Patients present with local bone pain and inflammation and - to our experience - often suffer from functional impairment with significant disabilities of daily life. The objective of this study was to assess physical activity, fitness and health-related quality of life (HRQOL) in adolescents with established diagnosis of CNO versus healthy controls (HC). Methods 15 patients with CNO and 15 age and gender matched HC aged 13–18 years, completed questionnaires, performed an incremental exercise test with gas exchange measures up to voluntary fatigue and wore an accelerometer over 7 days at home to assess physical activity behavior. Results At the time of assessment, 5 CNO patients were in clinical, one in radiological and 5 in clinical and radiological remission. 7 did not receive any therapy at the time of assessment. The results of the exercise test and of the accelerometry did not show any significant difference between CNO and HC. However, reported sports participation was lower in patients with CNO and PedsQL3.0 and 4.0 showed significant lower values in most of the scores indicating reduced HRQOL. Conclusion Although most CNO patients showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, questionnaires revealed perceived limitations. Further studies are needed to measure HRQOL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity. KW - chronic non-bacterial osteomyelitis KW - CRMO KW - HRQOL KW - physical activity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323710 VL - 17 ER - TY - JOUR A1 - Kleinert, Evelyn A1 - Müller, Frank A1 - Furaijat, Ghefar A1 - Hillermann, Nele A1 - Jablonka, Alexandra A1 - Happle, Christine A1 - Simmenroth, Anne T1 - Does refugee status matter? Medical needs of newly arrived asylum seekers and resettlement refugees - a retrospective observational study of diagnoses in a primary care setting JF - Conflict and Health N2 - Background Providing adequate healthcare to newly arrived refugees is considered one of the significant challenges for the German healthcare system. These refugees can be classified mainly into two groups: asylum seekers (who have applied for asylum after arrival in Germany and are waiting for the refugee-status decision) and resettlement refugees (who have already been granted asylum status before arriving in Germany). Whereas earlier studies have explored the health status of asylum seekers especially in terms of mental and behavioural disorders and infectious diseases without distinguishing between these two groups, our study aims to evaluate possible relationships of asylum status and medical needs of these two groups with a special focus on mental and behavioural disorders and infectious diseases. Methods In this retrospective observational study, collected data on all asylum-seeker and resettlement-refugee patients (N = 2252) of a German reception centre (August 2017 to August 2018) is analysed by absolute and relative frequencies and medians. Patient data, collected by chart review, include age, gender, country of origin, asylum status, and diagnoses (ICD-10). To describe the relationship between sociodemographic factors (including asylum status) and diagnoses, we used tests of significance and bivariate correlations with Spearman correlation coefficients. All collected data are pseudonymised. Results Of all 2252 patients, 43% were resettlement refugees. In almost all ICD-10 categories, asylum seekers received significantly more diagnoses than resettlement refugees. According to our data, asylum seekers presented with mental and behavioural disorders nine times more often (9%) than resettlement refugees (1%). In the case of infectious diseases, the results are mixed: asylum seekers were twice as frequently (11%) diagnosed with certain infectious and parasitic diseases than resettlement refugees (5%), but resettlement refugees were treated twice as often (22% of the asylum seekers and 41% of the resettlement refugees) for diseases of the respiratory system, of which 84% were acute respiratory infections (in both groups). Conclusion This study indicates that patients with unregulated migration more frequently present symptoms of psychiatric diseases and somatoform symptoms than resettlement refugees. A health policy approach within migration policy should aim to enable persecuted persons to migrate under regulated and safe conditions. Trial registration German Clinical Trials Register: DRKS00013076, retrospectively registered on 29.09.2017. KW - primary healthcare KW - resettlement refugees KW - asylum seekers KW - asylum status KW - common diseases KW - migrant KW - infections KW - mental health Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325869 VL - 13 ER - TY - JOUR A1 - Hinkelbein, Jochen A1 - Iovino, Ivan A1 - De Robertis, Edoardo A1 - Kranke, Peter T1 - Outcomes in video laryngoscopy studies from 2007 to 2017: systematic review and analysis of primary and secondary endpoints for a core set of outcomes in video laryngoscopy research JF - BMC Anesthesiology N2 - Background Airway management is crucial and, probably, even the most important key competence in anaesthesiology, which directly influences patient safety and outcome. However, high-quality research is rarely published and studies usually have different primary or secondary endpoints which impedes clear unbiased comparisons between studies. The aim of the present study was to gather and analyse primary and secondary endpoints in video laryngoscopy studies being published over the last ten years and to create a core set of uniform or homogeneous outcomes (COS). Methods Retrospective analysis. Data were identified by using MEDLINE® database and the terms “video laryngoscopy” and “video laryngoscope” limited to the years 2007 to 2017. A total of 3351 studies were identified by the applied search strategy in PubMed. Papers were screened by two anaesthesiologists independently to identify study endpoints. The DELPHI method was used for consensus finding. Results In the 372 studies analysed and included, 49 different outcome categories/columns were reported. The items “time to intubation” (65.86%), “laryngeal view grade” (44.89%), “successful intubation rate” (36.56%), “number of intubation attempts” (23.39%), “complications” (21.24%), and “successful first-pass intubation rate” (19.09%) were reported most frequently. A total of 19 specific parameters is recommended. Conclusions In recent video laryngoscopy studies, many different and inhomogeneous parameters were used as outcome descriptors/endpoints. Based on these findings, we recommend that 19 specific parameters (e.g., “time to intubation” (inserting the laryngoscope to first ventilation), “laryngeal view grade” (C&L and POGO), “successful intubation rate”, etc.) should be used in coming research to facilitate future comparisons of video laryngoscopy studies. KW - airway management KW - video laryngoscopy KW - primary outcome KW - primary endpoint Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320747 VL - 19 ER - TY - JOUR A1 - Hrudka, Jan A1 - Eis, Václav A1 - Heřman, Josef A1 - Prouzová, Zuzana A1 - Rosenwald, Andreas A1 - František, Duška T1 - Panniculitis-like T-cell-lymphoma in the mesentery associated with hemophagocytic syndrome: autopsy case report JF - Diagnostic Pathology N2 - Background Panniculitis-like T-cell lymphoma is an uncommon type of non-Hodgkin lymphoma, occurring usually in the form of nodules within the subcutaneous fat tissue of the extremities or trunk. In the literature, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is described as a distinct type of T-cell lymphoma with a variable clinical behavior, depending on molecular phenotype of T-cell receptor (TCR) and on the presence or absence of hemophagocytic syndrome. Case presentation We present a bioptic and autoptic case of a 65-years old Caucasian man with panniculitic T-cell lymphoma with morphological and immunohistochemical features of SPTCL, limited to the retroperitoneal and mesenteric mass, i.e. without any cutaneous involvement, and associated with severe hemophagocytic lymphohistiocytosis. Conclusion A panniculitic T-cell lymphoma with morphological and molecular features of SPTCL, which is limited to mesentery, i.e. does not involve subcutaneous fat, seems to be exceedingly rare. KW - panniculitis KW - T-cell lymphoma KW - mesentery KW - hemophagocytosis KW - lymphohistiocytosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322665 VL - 14 ER - TY - JOUR A1 - Coelho, Luis Pedro A1 - Alves, Renato A1 - Monteiro, Paulo A1 - Huerta-Cepas, Jaime A1 - Freitas, Ana Teresa A1 - Bork, Peer T1 - NG-meta-profiler: fast processing of metagenomes using NGLess, a domain-specific language JF - Microbiome N2 - Background Shotgun metagenomes contain a sample of all the genomic material in an environment, allowing for the characterization of a microbial community. In order to understand these communities, bioinformatics methods are crucial. A common first step in processing metagenomes is to compute abundance estimates of different taxonomic or functional groups from the raw sequencing data. Given the breadth of the field, computational solutions need to be flexible and extensible, enabling the combination of different tools into a larger pipeline. Results We present NGLess and NG-meta-profiler. NGLess is a domain specific language for describing next-generation sequence processing pipelines. It was developed with the goal of enabling user-friendly computational reproducibility. It provides built-in support for many common operations on sequencing data and is extensible with external tools with configuration files. Using this framework, we developed NG-meta-profiler, a fast profiler for metagenomes which performs sequence preprocessing, mapping to bundled databases, filtering of the mapping results, and profiling (taxonomic and functional). It is significantly faster than either MOCAT2 or htseq-count and (as it builds on NGLess) its results are perfectly reproducible. Conclusions NG-meta-profiler is a high-performance solution for metagenomics processing built on NGLess. It can be used as-is to execute standard analyses or serve as the starting point for customization in a perfectly reproducible fashion. NGLess and NG-meta-profiler are open source software (under the liberal MIT license) and can be downloaded from https://ngless.embl.de or installed through bioconda. KW - metagenomics KW - next-generation sequencing KW - domain-specific language Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223161 VL - 7 IS - 84 ER - TY - JOUR A1 - de Nijs, Laurence A1 - Choe, Kyonghwan A1 - Steinbusch, Hellen A1 - Schijns, Olaf E. M. G. A1 - Dings, Jim A1 - van den Hove, Daniel L. A. A1 - Rutten, Bart P. F. A1 - Hoogland, Govert T1 - DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures JF - Clinical Epigenetics N2 - Background Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS. Results We found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls. Conclusion Together, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted. KW - febrile seizures KW - temporal lobe epilepsy KW - epigenetics KW - DNA methylation KW - DNA methyltransferases Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223636 VL - 11 ER - TY - JOUR A1 - Abimannan, Nagarajan A1 - Sumathi, G. A1 - Krishnarajasekhar, O. R. A1 - Sinha, Bhanu A1 - Krishnan, Padma T1 - Clonal Clusters and Virulence Factors of Methicillin-Resistant \(Staphylococcus\) \(Aureus\): Evidence for Community-Acquired Methicillin-Resistant \(Staphylococcus\) \(Aureus\) Infiltration into Hospital Settings in Chennai, South India JF - Indian Journal of Medical Microbiology N2 - Background and Objective: Staphylococcus aureus is one of the major pathogens of nosocomial infections as wells as community-acquired (CA) infections worldwide. So far, large-scale comprehensive molecular and epidemiological characterisation of S. aureus from very diverse settings has not been carried out in India. The objective of this study is to evaluate the molecular, epidemiological and virulence characteristics of S. aureus in both community and hospital settings in Chennai, southern India. Methods: S. aureus isolates were obtained from four different groups (a) healthy individuals from closed community settings, (b) inpatients from hospitals, (c) outpatients from hospitals, representing isolates of hospital-community interface and (d) HIV-infected patients to define isolates associated with the immunocompromised. Antibiotic susceptibility testing, multiplex polymerase chain reactions for detection of virulence and resistance determinants, molecular typing including Staphylococcal cassette chromosome mec (SCCmec) and agr typing, were carried out. Sequencing-based typing was done using spa and multilocus sequence typing (MLST) methods. Clonal complexes (CC) of hospital and CA methicillin-resistant S. aureus (MRSA) were identified and compared for virulence and resistance. Results and Conclusion: A total of 769 isolates of S. aureus isolates were studied. The prevalence of MRSA was found to be 7.17%, 81.67%, 58.33% and 22.85% for groups a, b, c and d, respectively. Of the four SCCmec types (I, III, IV and V) detected, SCCmec V was found to be predominant. Panton-Valentine leucocidin toxin genes were detected among MRSA isolates harbouring SCCmec IV and V. A total of 78 spa types were detected, t657 being the most prevalent. 13 MLST types belonging to 9 CC were detected. CC1 (ST-772, ST-1) and CC8 (ST238, ST368 and ST1208) were found to be predominant among MRSA. CA-MRSA isolates with SCCmec IV and V were isolated from all study groups including hospitalised patients and were found to be similar by molecular tools. This shows that CA MRSA has probably infiltrated into the hospital settings. KW - Community-acquired methicillin-resistant Staphylococcus aureus KW - HIV KW - hospital-acquired methicillin-resistant Staphylococcus aureus KW - innate immune evasions KW - MLST KW - microbial surface component recognising adhesive matrix molecules KW - spa typing KW - ST 772 KW - Inducible Clindamycin Resistance KW - Valentine Leukocidin Genes KW - Multiplex PCR KW - Nasal Carriage KW - Colonization KW - Prevalence KW - Emergence KW - Skin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226963 VL - 37 IS - 3 ER - TY - JOUR T1 - FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2 JF - European Physical Journal - Special Topics N2 - In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today's technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics. KW - Large Hadron Collider KW - Double-Beta Decay KW - e(+)e(-) Collisions KW - Flavor Violation KW - Electroweak Measurements KW - Bhabha Scattering KW - Missing Energy KW - Single-Photon KW - Neutrino Mass KW - Higgy-Boson Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226947 VL - 228 IS - 2 ER - TY - JOUR A1 - Hetzer, Benjamin A1 - Orth-Höller, Dorothea A1 - Würzner, Reinhard A1 - Kreidl, Peter A1 - Lackner, Michaela A1 - Müller, Thomas A1 - Knabl, Ludwig A1 - Geisler-Moroder, Daniel Rudolf A1 - Mellmann, Alexander A1 - Sesli, Özcan A1 - Holzknecht, Jeanett A1 - Noce, Damia A1 - Akarathum, Noppadon A1 - Chotinaruemol, Somporn A1 - Prelog, Martina A1 - Oberdorfer, Peninnah T1 - “Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study” JF - Antimicrobial Resistance & Infection Control N2 - Background Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance. KW - Escherichia coli KW - antibiotic resistance KW - multiresistance KW - transmission KW - persistence KW - children KW - neonates Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320284 VL - 8 ER - TY - JOUR A1 - Moremi, Nyambura A1 - Claus, Heike A1 - Vogel, Ulrich A1 - Mshana, Stephen E. T1 - The role of patients and healthcare workers Staphylococcus aureus nasal colonization in occurrence of surgical site infection among patients admitted in two centers in Tanzania JF - Antimicrobial Resistance & Infection Control N2 - Background Colonization with Staphylococcus aureus has been identified as a risk for subsequent occurrence of infection. This study investigated the relationship between S. aureus colonization of patients and healthcare workers (HCWs), and subsequent surgical site infections (SSI). Methods Between December 2014 and September 2015, a total of 930 patients and 143 HCWs were enrolled from the Bugando Medical Centre and Sekou Toure hospital in Mwanza, Tanzania. On admission and discharge nasal swabs, with an additional of wound swab for those who developed SSI were collected from patients whereas HCWs were swabbed once. Identification and antimicrobial susceptibility testing were done by VITEK-MS and VITEK-2, respectively. Detection of Panton Valentine leukocidin (PVL) and mecA genes was done by PCR. S. aureus isolates were further characterized by spa typing and Multi-Locus Sequence Typing (MLST). Results Among 930 patients screened for S. aureus on admission, 129 (13.9%) were positive of which 5.4% (7/129) were methicillin-resistant S. aureus (MRSA). Amongst 363 patients rescreened on discharge, 301 patients had been tested negative on admission of whom 29 (9.6%) turned positive after their hospital stay. Three (10.3%) of the 29 acquired S. aureus were MRSA. Inducible Clindamycin resistance occurred more often among acquired S. aureus isolates than among isolates from admission [34.5% (10/29) vs. 17.1% (22/129), P = 0.018]. S. aureus contributed to 21.1% (n = 12) of the 57 cases of investigated SSIs among 536 patients followed. Seven out of eight S. aureus carriage/infection pairs had the same spa and sequence types. The previously reported dominant PVL-positive ST88 MRSA strain with spa type t690 was detected in patients and HCW. Conclusion A significant proportion of patients acquired S. aureus during hospitalization. The finding of more than 90% of S. aureus SSI to be of endogenous source underscores the need of improving infection prevention and control measures including screening and decolonization of high risk patients. KW - S. aureus KW - colonization KW - surgical site infection KW - Tanzania Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224185 VL - 8 ER - TY - JOUR A1 - Brumberg, Joachim A1 - Blazhenets, Ganna A1 - Schröter, Nils A1 - Frings, Lars A1 - Jost, Wolfgang H. A1 - Lapa, Constantin A1 - Meyer, Philipp T. T1 - Imaging cardiac sympathetic innervation with MIBG: linear conversion of the heart-to-mediastinum ratio between different collimators JF - EJNMMI Physics N2 - Background The heart-to-mediastinum (H/M) ratio is a commonly used parameter to measure cardiac I-123 metaiodobenzylguanidine (MIBG) uptake. Since the H/M ratio is substantially influenced by the collimator type, we investigated whether an empirical linear conversion of H/M ratios between camera systems with low-energy (LE) and medium-energy (ME) collimator is possible. Methods We included 18 patients with parkinsonism who were referred to one of the two participating molecular imaging facilities for the evaluation of cardiac sympathetic innervation by MIBG scintigraphy. Two consecutive planar image datasets were acquired with LE and ME collimators at 4 h after MIBG administration. Linear regression analyses were performed to describe the association between the H/M ratios gained with both collimator settings, and the accuracy of a linear transfer of the H/M ratio between collimators and across centers was assessed using a leave-one-out procedure. Results H/M ratios acquired with LE and ME collimators showed a strong linear relationship both within each imaging facility (R\(^2\) = 0.99, p < 0.001 and R\(^2\) = 0.90, p < 0.001) and across centers (H/M-LE = 0.41 × H/M-ME + 0.63, R\(^2\) = 0.97, p < 0.001). A linear conversion of H/M ratios between collimators and across centers was estimated to be very accurate (mean absolute error 0.05 ± 0.04; mean relative absolute error 3.2 ± 2.6%). Conclusions The present study demonstrates that a simple linear conversion of H/M ratios acquired with different collimators is possible with high accuracy. This should greatly facilitate the exchange of normative data between settings and pooling of data from different institutions. KW - MIBG KW - collimator KW - heart-to-mediastinum ratio KW - linear conversion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221675 VL - 6 ER - TY - JOUR A1 - Kiener, Mirjam A1 - Chen, Lanpeng A1 - Krebs, Markus A1 - Grosjean, Joȅl A1 - Klima, Irena A1 - Kalogirou, Charis A1 - Riedmiller, Hubertus A1 - Kneitz, Burkhard A1 - Thalmann, George N. A1 - Snaar-Jagalska, Ewa A1 - Spahn, Martin A1 - Kruithof-de Julio, Marianna A1 - Zoni, Eugenio T1 - miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo JF - BMC Cancer N2 - Background Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa. Methods miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4–2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth. Results Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa. Conclusions Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target. KW - prostate cancer KW - miR-221-5p KW - proliferation KW - migration KW - tumor suppressor miRNA Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325762 VL - 19 ER - TY - JOUR A1 - Klement, Rainer J. A1 - Abbasi-Senger, N. A1 - Adebahr, S. A1 - Alheid, H. A1 - Allgaeuer, M. A1 - Becker, G. A1 - Blanck, O. A1 - Boda-Heggemann, J. A1 - Brunner, T. A1 - Duma, M. A1 - Eble, M. J. A1 - Ernst, I. A1 - Gerum, S. A1 - Habermehl, D. A1 - Hass, P. A1 - Henkenberens, C. A1 - Hildebrandt, G. A1 - Imhoff, D. A1 - Kahl, H. A1 - Klass, N. D. A1 - Krempien, R. A1 - Lewitzki, V. A1 - Lohaus, F. A1 - Ostheimer, C. A1 - Papachristofilou, A. A1 - Petersen, C. A1 - Rieber, J. A1 - Schneider, T. A1 - Schrade, E. A1 - Semrau, R. A1 - Wachter, S. A1 - Wittig, A. A1 - Guckenberger, M. A1 - Andratschke, N. T1 - The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases JF - BMC Cancer N2 - Background The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. Methods The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. Results Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. Conclusion In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months. KW - colorectal cancer KW - illness-death model KW - liver metastases KW - lung metastases KW - tumor control probability KW - stereotactic body radiation therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325877 VL - 19 ER - TY - JOUR A1 - Hörterer, Hubert A1 - Baumbach, Sebastian Felix A1 - Lemperle, Stefan A1 - Altenberger, Sebastian A1 - Gottschalk, Oliver A1 - Mehlhorn, Alexander Tobias A1 - Röser, Anke A1 - Walther, Markus T1 - Clinical outcome and concomitant injuries in operatively treated fractures of the lateral process of the talus JF - BMC Musculoskeletal Disorders N2 - Background The aim of this study was to review the patient rated outcome (PROM) of surgically treated fractures to the lateral process of the talus (LPTF) and identify factors influencing the outcome. Methods Retrospective study with a current follow-up. Eligible were all patients treated surgically for a LPTF (n = 23) with a minimum follow-up of one year. Demographics, medical history, trauma mechanism, fracture characteristics, concomitant injuries, treatment details, complications, return to work and sports were assessed retrospectively. The current follow-up included the VAS FA, Karlsson Score, and SF-12. The primary outcome was the VAS FA. Secondary aim was the identification of parameters influencing the PROMs. Results 22 patients (96% follow-up) with a mean age of 32 ± 9 (18 to 49) years were included. 73% suffered a Hawkins Type 1, 23% a Type 2, and one patient a Type 3 fracture. 82% suffered concomitant injuries. 9% suffered minor surgical side infections, 50% developed symptomatic subtalar osteoarthritis. At final follow-up (44 ± 2 (12 to 97) months), the mean VAS FA Overall was 77 ± 21 (20 to 100), the Karlsson Score 72 ± 21 (34 to 97), and for the SF 12 the PCS 53 ± 8 (36 to 64) and the MCS 53 ± 7 (32 to 63). 50% of patients returned to their previous level of sports. Hawkins Type 1 fractures resulted in better VAS FA Overall score than Type 2 fractures. Posttraumatic subtalar osteoarthritis was the independent factor associated to a poor patient rated outcome (VAS FA, Karlsson Score). Conclusion After a follow-up of over 3.5 years, surgically treated LPTF resulted in only moderate results. 50% suffered posttraumatic symptomatic subtalar osteoarthritis, which was the primary independent parameter for a poor outcome following LPTF. Level of evidence Level III. KW - fracture KW - snowboarder's ankle KW - snowboarder's fracture KW - lateral process of the talus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321207 VL - 20 ER - TY - JOUR A1 - Richter, Gesa M. A1 - Kruppa, Jochen A1 - Munz, Matthias A1 - Wiehe, Ricarda A1 - Häsler, Robert A1 - Franke, Andre A1 - Martins, Orlando A1 - Jockel-Schneider, Yvonne A1 - Bruckmann, Corinna A1 - Dommisch, Henrik A1 - Schaefer, Arne S. T1 - A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers JF - Clinical Epigenetics N2 - Background The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. Results Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1. Conclusion This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa. KW - EWAS KW - Methylation KW - Expression KW - Masticatory mucosa KW - CYP1B1 KW - AHRR KW - Cytochrome P 450 pathway KW - OSCC KW - Smoking Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226175 VL - 11 ER - TY - JOUR A1 - Wagner, Fabienne A1 - Kunz, Tobias C. A1 - Chowdhury, Suvagata R. A1 - Thiede, Bernd A1 - Fraunholz, Martin A1 - Eger, Debora A1 - Kozjak-Pavlovic, Vera T1 - Armadillo repeat-containing protein 1 is a dual localization protein associated with mitochondrial intermembrane space bridging complex JF - PLoS ONE N2 - Cristae architecture is important for the function of mitochondria, the organelles that play the central role in many cellular processes. The mitochondrial contact site and cristae organizing system (MICOS) together with the sorting and assembly machinery (SAM) forms the mitochondrial intermembrane space bridging complex (MIB), a large protein complex present in mammalian mitochondria that partakes in the formation and maintenance of cristae. We report here a new subunit of the mammalian MICOS/MIB complex, an armadillo repeat-containing protein 1 (ArmC1). ArmC1 localizes both to cytosol and mitochondria, where it associates with the outer mitochondrial membrane through its carboxy-terminus. ArmC1 interacts with other constituents of the MICOS/MIB complex and its amounts are reduced upon MICOS/MIB complex depletion. Mitochondria lacking ArmC1 do not show defects in cristae structure, respiration or protein content, but appear fragmented and with reduced motility. ArmC1 represents therefore a peripheral MICOS/MIB component that appears to play a role in mitochondrial distribution in the cell. KW - Mitochondria KW - Outer membrane proteins KW - HeLa cells KW - Immunoprecipitation KW - Cytosol KW - Small interfering RNAs KW - Confocal microscopy KW - Cell stainin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202670 VL - 14 IS - 10 ER - TY - JOUR A1 - Belka, Janina A1 - Nickel, Joachim A1 - Kurth, Dirk G. T1 - Growth on metallo-supramolecular coordination polyelectrolyte (MEPE) stimulates osteogenic differentiation of human osteosarcoma cells (MG63) and human bone marrow derived mesenchymal stem cells JF - Polymers N2 - Background: Culturing of cells is typically performed on standard tissue culture plates generating growth conditions, which in general do not reflect the native three-dimensional cellular environment. Recent investigations provide insights in parameters, which strongly affect the general cellular behavior triggering essential processes such as cell differentiation. The physical properties of the used material, such as stiffness, roughness, or topology, as well as the chemical composition of the cell-surface interface are shown to play a key role in the initiation of particular cellular responses. Methods: We extended our previous research, which identified thin films of metallo-supramolecular coordination polyelectrolytes (MEPEs) as substrate to trigger the differentiation of muscular precursor cells. Results: Here, we show that the same MEPEs similarly stimulate the osteogenic differentiation of pre-osteoblasts. Remarkably, MEPE modified surfaces also trigger the differentiation of primary bone derived mesenchymal stem cells (BMSCs) towards the osteogenic lineage. Conclusion: This result leads to the conclusion that these surfaces individually support the specification of cell differentiation toward lineages that correspond to the natural commitment of the particular cell types. We, therefore, propose that Fe-MEPEs may be used as scaffold for the treatment of defects at least in muscular or bone tissue. KW - cell differentiation KW - metallo-supramolecular polymer KW - interface KW - iron metabolism Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197264 SN - 2073-4360 VL - 11 IS - 7 ER - TY - JOUR A1 - Reusch, Engelbert A1 - Holzmeier, Fabian A1 - Gerlach, Marius A1 - Fischer, Ingo A1 - Hemberger, Patrick T1 - Decomposition of Picolyl Radicals at High Temperature: A Mass Selective Threshold Photoelectron Spectroscopy Study JF - Chemistry - A European Journal N2 - The reaction products of the picolyl radicals at high temperature were characterized by mass‐selective threshold photoelectron spectroscopy in the gas phase. Aminomethylpyridines were pyrolyzed to initially produce picolyl radicals (m /z =92). At higher temperatures further thermal reaction products are generated in the pyrolysis reactor. All compounds were identified by mass‐selected threshold photoelectron spectroscopy and several hitherto unexplored reactive molecules were characterized. The mechanism for several dissociation pathways was outlined in computations. The spectrum of m /z =91, resulting from hydrogen loss of picolyl, shows four isomers, two ethynyl pyrroles with adiabatic ionization energies (IE\(_{ad}\)) of 7.99 eV (2‐ethynyl‐1H ‐pyrrole) and 8.12 eV (3‐ethynyl‐1H ‐pyrrole), and two cyclopentadiene carbonitriles with IE′s of 9.14 eV (cyclopenta‐1,3‐diene‐1‐carbonitrile) and 9.25 eV (cyclopenta‐1,4‐diene‐1‐carbonitrile). A second consecutive hydrogen loss forms the cyanocyclopentadienyl radical with IE′s of 9.07 eV (T\(_0\)) and 9.21 eV (S\(_1\)). This compound dissociates further to acetylene and the cyanopropynyl radical (IE=9.35 eV). Furthermore, the cyclopentadienyl radical, penta‐1,3‐diyne, cyclopentadiene and propargyl were identified in the spectra. Computations indicate that dissociation of picolyl proceeds initially via a resonance‐stabilized seven‐membered ring. KW - ionization energy KW - photoelectron spectroscopy KW - pyrolysis KW - radicals KW - synchrotron radiation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208132 VL - 25 IS - 72 ER - TY - JOUR A1 - Ruiz, E. Josue A1 - Diefenbacher, Markus E. A1 - Nelson, Jessica K. A1 - Sancho, Rocio A1 - Pucci, Fabio A1 - Chakraborty, Atanu A1 - Moreno, Paula A1 - Annibaldi, Alessandro A1 - Liccardi, Gianmaria A1 - Encheva, Vesela A1 - Mitter, Richard A1 - Rosenfeldt, Mathias A1 - Snijders, Ambrosius P. A1 - Meier, Pascal A1 - Calzado, Marco A. A1 - Behrens, Axel T1 - LUBAC determines chemotherapy resistance in squamous cell lung cancer JF - Journal of Experimental Medicine N2 - Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10(+), but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-kappa B signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-kappa B activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment. KW - Solid tumors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227146 VL - 216 IS - 2 ER - TY - JOUR A1 - Wörsdörfer, Philipp A1 - Dalda, Nahide A1 - Kern, Anna A1 - Krüger, Sarah A1 - Wagner, Nicole A1 - Kwok, Chee Keong A1 - Henke, Erik A1 - Ergün, Süleyman T1 - Generation of complex human organoid models including vascular networks by incorporation of mesodermal progenitor cells JF - Scientific Reports N2 - Organoids derived from human pluripotent stem cells are interesting models to study mechanisms of morphogenesis and promising platforms for disease modeling and drug screening. However, they mostly remain incomplete as they lack stroma, tissue resident immune cells and in particular vasculature, which create important niches during development and disease. We propose, that the directed incorporation of mesodermal progenitor cells (MPCs) into organoids will overcome the aforementioned limitations. In order to demonstrate the feasibility of the method, we generated complex human tumor as well as neural organoids. We show that the formed blood vessels display a hierarchic organization and mural cells are assembled into the vessel wall. Moreover, we demonstrate a typical blood vessel ultrastructure including endothelial cell-cell junctions, a basement membrane as well as luminal caveolae and microvesicles. We observe a high plasticity in the endothelial network, which expands, while the organoids grow and is responsive to anti-angiogenic compounds and pro-angiogenic conditions such as hypoxia. We show that vessels within tumor organoids connect to host vessels following transplantation. Remarkably, MPCs also deliver Iba1\(^+\) cells that infiltrate the neural tissue in a microglia-like manner. KW - Developmental biology KW - Stem cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202681 VL - 9 ER - TY - JOUR A1 - Dietrich, Laura A1 - Meister, Julia A1 - Dietrich, Oliver A1 - Notroff, Jens A1 - Kiep, Janika A1 - Heeb, Julia A1 - Beuger, André A1 - Schütt, Brigitta T1 - Cereal processing at Early Neolithic Göbekli Tepe, southeastern Turkey JF - PLoS ONE N2 - We analyze the processing of cereals and its role at Early Neolithic Göbekli Tepe, southeastern Anatolia (10th / 9th millennium BC), a site that has aroused much debate in archaeological discourse. To date, only zooarchaeological evidence has been discussed in regard to the subsistence of its builders. Göbekli Tepe consists of monumental round to oval buildings, erected in an earlier phase, and smaller rectangular buildings, built around them in a partially contemporaneous and later phase. The monumental buildings are best known as they were in the focus of research. They are around 20 m in diameter and have stone pillars that are up to 5.5 m high and often richly decorated. The rectangular buildings are smaller and–in some cases–have up to 2 m high, mostly undecorated, pillars. Especially striking is the number of tools related to food processing, including grinding slabs/bowls, handstones, pestles, and mortars, which have not been studied before. We analyzed more than 7000 artifacts for the present contribution. The high frequency of artifacts is unusual for contemporary sites in the region. Using an integrated approach of formal, experimental, and macro- / microscopical use-wear analyses we show that Neolithic people at Göbekli Tepe have produced standardized and efficient grinding tools, most of which have been used for the processing of cereals. Additional phytolith analysis confirms the massive presence of cereals at the site, filling the gap left by the weakly preserved charred macro-rests. The organization of work and food supply has always been a central question of research into Göbekli Tepe, as the construction and maintenance of the monumental architecture would have necessitated a considerable work force. Contextual analyses of the distribution of the elements of the grinding kit on site highlight a clear link between plant food preparation and the rectangular buildings and indicate clear delimitations of working areas for food production on the terraces the structures lie on, surrounding the circular buildings. There is evidence for extensive plant food processing and archaeozoological data hint at large-scale hunting of gazelle between midsummer and autumn. As no large storage facilities have been identified, we argue for a production of food for immediate use and interpret these seasonal peaks in activity at the site as evidence for the organization of large work feasts. KW - Specimen grinding KW - Archaeology KW - Neolithic period KW - Sediment KW - Equipment KW - Stratigraphy KW - Limestone KW - Meat Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201504 VL - 14 IS - 5 ER - TY - JOUR A1 - Wegener, Sonja A1 - Sauer, Otto A. T1 - The effective point of measurement for depth-dose measurements in small MV photon beams with different detectors JF - Medical Physics N2 - Purpose: The effective point of measurement (EPOM) of cylindrical ionization chambers differs from their geometric center. The exact shift depends on chamber construction details, above all the chamber size, and to some degree on the field-size and beam quality. It generally decreases as the chamber dimensions get smaller. In this work, effective points of measurement in small photon fields of a range of cylindrical chambers of different sizes are investigated, including small chambers that have not been studied previously. Methods: In this investigation, effective points of measurement for different ionization chambers (Farmer type, scanning chambers, micro-ionization chambers) and solid state detectors were determined by measuring depth-ionization curves in a 6 MV beam in field sizes between 2 9 2 cm2 and 10 9 10 cm2 and comparing those curves with curves measured with plane-parallel chambers. Results: It was possible to average the results to one shift per detector, as the results were sufficiently independent of the studied field sizes. For cylindrical ion chambers, shifts of the EPOM were determined to be between 0.49 and 0.30 times the inner chamber radius from the reference point. Conclusions: We experimentally confirmed the previously reported decrease of the EPOM shift with decreasing detector size. Highly accurate data for a large range of detectors, including new very small ones, were determined. Thus, small chambers noticeably differ from the 0.5-times to 0.6-times the inner chamber radius recommendations in current dosimetry protocols. The detector-individual EPOMs need to be considered for measurements of depth-dose curves. KW - depth dose curves KW - effective point of measurement KW - ionization chambers KW - micro-chambers Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206148 VL - 46 IS - 11 ER -