TY - JOUR A1 - Bekes, Inga A1 - Löb, Sanja A1 - Holzheu, Iris A1 - Janni, Wolfgang A1 - Baumann, Lisa A1 - Wöckel, Achim A1 - Wulff, Christine T1 - Nectin‐2 in ovarian cancer: how is it expressed and what might be its functional role? JF - Cancer Science N2 - Nectin‐2 is an adhesion molecule that has been reported to play a role in tumor growth, metastasis and tumor angiogenesis. Herein, we investigated Nectin‐2 in ovarian cancer patients and in cell culture. Tumor as well as peritoneal biopsies of 60 ovarian cancer patients and 22 controls were dual stained for Nectin‐2 and CD31 using immunohistochemistry. Gene expression of Nectin‐2 was quantified by real‐time PCR and differences analyzed in relation to various tumor characteristics. In the serum of patients, vascular endothelial growth factor (VEGF) was quantified by ELISA. Effect of VEGF on Nectin‐2 expression as well as permeability was investigated in HUVEC. In tumor biopsies, Nectin‐2 protein was mainly localized in tumor cells, whereas in peritoneal biopsies, clear colocalization was found in the vasculature. T3 patients had a significantly higher percentage of positive lymph nodes and this correlated with survival. Nectin‐2 was significantly upregulated in tumor biopsies in patients with lymph node metastasis and with residual tumor >1 cm after surgery. Nectin‐2 expression was significantly suppressed in the peritoneal endothelium of patients associated with significantly increased VEGF serum levels. In cell culture, VEGF stimulation led to a significant downregulation of Nectin‐2 which was reversed by VEGF‐inhibition. In addition, Nectin‐2 knockdown in endothelial cells was associated with significantly increased endothelial permeability. Nectin‐2 expression in ovarian cancer may support tumor cell adhesion, leading to growth and lymph node metastasis. In addition, VEGF‐induced Nectin‐2 suppression in peritoneal endothelium may support an increase in vascular permeability leading to ascites production. KW - metastasis KW - ovarian cancer KW - survival KW - Nectin‐2 KW - VEGF Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202748 VL - 110 IS - 6 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 - 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 - Werner, Rudolf A. A1 - Wakabayashi, Hiroshi A1 - Chen, Xinyu A1 - Hayakawa, Nobuyuki A1 - Lapa, Constantin A1 - Rowe, Steven P. A1 - Javadi, Mehrbod S. A1 - Robinson, Simon A1 - Higuchi, Takahiro T1 - Ventricular distribution pattern of the novel sympathetic nerve PET radiotracer \(^{18}\)F-LMI1195 in Rabbit Hearts JF - Scientific Reports N2 - We aimed to determine a detailed regional ventricular distribution pattern of the novel cardiac nerve PET radiotracer \(^{18}\)F-LMI1195 in healthy rabbits. Ex-vivo high resolution autoradiographic imaging was conducted to identify accurate ventricular distribution of \(^{18}\)F-LMI1195. In healthy rabbits, \(^{18}\)F-LMI1195 was administered followed by the reference perfusion marker \(^{201}\)Tl for a dual-radiotracer analysis. After 20 min of \(^{18}\)F-LMI1195 distribution time, the rabbits were euthanized, the hearts were extracted, frozen, and cut into 20-μm short axis slices. Subsequently, the short axis sections were exposed to a phosphor imaging plate to determine \(^{18}\)F-LMI1195 distribution (exposure for 3 h). After complete \(^{18}\)F decay, sections were re-exposed to determine 201Tl distribution (exposure for 7 days). For quantitative analysis, segmental regions of Interest (ROIs) were divided into four left ventricular (LV) and a right ventricular (RV) segment on mid-ventricular short axis sections. Subendocardial, mid-portion, and subepicardial ROIs were placed on the LV lateral wall. \(^{18}\)F-LMI1195 distribution was almost homogeneous throughout the LV wall without any significant differences in all four LV ROIs (anterior, posterior, septal and lateral wall, 99 ± 2, 94 ± 5, 94 ± 4 and 97 ± 3%LV, respectively, n.s.). Subepicardial \(^{201}\)Tl uptake was significantly lower compared to the subendocardial portion (subendocardial, mid-portion, and subepicardial activity: 90 ± 3, 96 ± 2 and *80 ± 5%LV, respectively, *p < 0.01 vs. mid-portion). This was in contradistinction to the transmural wall profile of \(^{18}\)F-LMI1195 (90 ± 4, 96 ± 5 and 84 ± 4%LV, n.s.). A slight but significant discrepant transmural radiotracer distribution pattern of \(^{201}\)Tl in comparison to \(^{18}\)F-LMI1195 may be a reflection of physiological sympathetic innervation and perfusion in rabbit hearts. KW - Cardiovascular diseases KW - Heart failure Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202707 VL - 9 ER - TY - JOUR A1 - Youssif, Khayrya A. A1 - Haggag, Eman G. A1 - Elshamy, Ali M. A1 - Rabeh, Mohamed A. A1 - Gabr, Nagwan M. A1 - Seleem, Amany A1 - Salem, M. Alaraby A1 - Hussein, Ahmed S. A1 - Krischke, Markus A1 - Mueller, Martin J. A1 - Ramadan Abdelmohsen, Usama T1 - Anti-Alzheimer potential, metabolomic profiling and molecular docking of green synthesized silver nanoparticles of Lampranthus coccineus and Malephora lutea aqueous extracts JF - PLoS ONE N2 - The green synthesis of silver nanoparticles (SNPs) using plant extracts is an eco-friendly method. It is a single step and offers several advantages such as time reducing, cost-effective and environmental non-toxic. Silver nanoparticles are a type of Noble metal nanoparticles and it has tremendous applications in the field of diagnostics, therapeutics, antimicrobial activity, anticancer and neurodegenerative diseases. In the present work, the aqueous extracts of aerial parts of Lampranthus coccineus and Malephora lutea F. Aizoaceae were successfully used for the synthesis of silver nanoparticles. The formation of silver nanoparticles was early detected by a color change from pale yellow to reddish-brown color and was further confirmed by transmission electron microscope (TEM), UV–visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), and energy-dispersive X-ray diffraction (EDX). The TEM analysis of showed spherical nanoparticles with a mean size between 12.86 nm and 28.19 nm and the UV- visible spectroscopy showed λ\(_{max}\) of 417 nm, which confirms the presence of nanoparticles. The neuroprotective potential of SNPs was evaluated by assessing the antioxidant and cholinesterase inhibitory activity. Metabolomic profiling was performed on methanolic extracts of L. coccineus and M. lutea and resulted in the identification of 12 compounds, then docking was performed to investigate the possible interaction between the identified compounds and human acetylcholinesterase, butyrylcholinesterase, and glutathione transferase receptor, which are associated with the progress of Alzheimer’s disease. Overall our SNPs highlighted its promising potential in terms of anticholinesterase and antioxidant activity as plant-based anti-Alzheimer drug and against oxidative stress. KW - Nanoparticles KW - Silver KW - Alzheimer's disease KW - Glutathione KW - Antioxidants KW - Serine proteases KW - Brain diseases KW - Metabolomics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202696 VL - 14 IS - 11 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 - 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 - Akhoon, Bashir A. A1 - Gupta, Shishir K. A1 - Tiwari, Sudeep A1 - Rathor, Laxmi A1 - Pant, Aakanksha A1 - Singh, Nivedita A1 - Gupta, Shailendra K. A1 - Dandekar, Thomas A1 - Pandey, Rakesh T1 - C. elegans protein interaction network analysis probes RNAi validated pro-longevity effect of nhr-6, a human homolog of tumor suppressor Nr4a1 JF - Scientific Reports N2 - Protein-protein interaction (PPI) studies are gaining momentum these days due to the plethora of various high-throughput experimental methods available for detecting PPIs. Proteins create complexes and networks by functioning in harmony with other proteins and here in silico network biology hold the promise to reveal new functionality of genes as it is very difficult and laborious to carry out experimental high-throughput genetic screens in living organisms. We demonstrate this approach by computationally screening C. elegans conserved homologs of already reported human tumor suppressor and aging associated genes. We select by this nhr-6, vab-3 and gst-23 as predicted longevity genes for RNAi screen. The RNAi results demonstrated the pro-longevity effect of these genes. Nuclear hormone receptor nhr-6 RNAi inhibition resulted in a C. elegans phenotype of 23.46% lifespan reduction. Moreover, we show that nhr-6 regulates oxidative stress resistance in worms and does not affect the feeding behavior of worms. These findings imply the potential of nhr-6 as a common therapeutic target for aging and cancer ailments, stressing the power of in silico PPI network analysis coupled with RNAi screens to describe gene function. KW - Computer modelling KW - Embryonic induction KW - RNAi Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202666 VL - 9 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 - Liu, Yi A1 - Maierhofer, Tobias A1 - Rybak, Katarzyna A1 - Sklenar, Jan A1 - Breakspear, Andy A1 - Johnston, Matthew G. A1 - Fliegmann, Judith A1 - Huang, Shouguang A1 - Roelfsema, M. Rob G. A1 - Felix, Georg A1 - Faulkner, Christine A1 - Menke, Frank L.H. A1 - Geiger, Dietmar A1 - Hedrich, Rainer A1 - Robatzek, Silke T1 - Anion channel SLAH3 is a regulatory target of chitin receptor-associated kinase PBL27 in microbial stomatal closure JF - eLife N2 - In plants, antimicrobial immune responses involve the cellular release of anions and are responsible for the closure of stomatal pores. Detection of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) induces currents mediated via slow-type (S-type) anion channels by a yet not understood mechanism. Here, we show that stomatal closure to fungal chitin is conferred by the major PRRs for chitin recognition, LYK5 and CERK1, the receptor-like cytoplasmic kinase PBL27, and the SLAH3 anion channel. PBL27 has the capacity to phosphorylate SLAH3, of which S127 and S189 are required to activate SLAH3. Full activation of the channel entails CERK1, depending on PBL27. Importantly, both S127 and S189 residues of SLAH3 are required for chitin-induced stomatal closure and anti-fungal immunity at the whole leaf level. Our results demonstrate a short signal transduction module from MAMP recognition to anion channel activation, and independent of ABA-induced SLAH3 activation. KW - plants Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202631 VL - 8 ER - TY - JOUR A1 - Jakubietz, Rafael G. A1 - Schmidt, Karsten A1 - Bernuth, Silvia A1 - Meffert, Rainer H. A1 - Jakubietz, Michael G. T1 - Evaluation of the intraoperative blood flow of pedicled perforator flaps using indocyanine green-fluorescence angiography JF - Plastic and Reconstructive Surgery – Global Open N2 - Background: Although indocyanine-green fluorescence angiography (ICG-FA) has been established as a useful tool to assess perfusion in free tissue transfer, only few studies have applied this modality to pedicled perforator flaps. As both volume and reach of pedicled perforator flaps are limited and tip necrosis often equals complete flap failure, ICG-FA may help to detect hypoperfusion in pedicled flaps. Methods: In 5 patients, soft tissue reconstruction was achieved with pedicled perforator flaps. ICG-FA was utilized intraoperatively to visualize flap perfusion. Results: Three pedicled anterolateral thigh flap flaps and 2 propeller flaps were transferred. ICG-FA detected hypoperfusion in 2 flaps. No flap loss occurred; in 2 cases, prolonged wound healing was encountered. Conclusions: ICG-FA confirmed clinical findings and reliably detected tissue areas with hypoperfusion. A clear cut-off point between nonvital tissue and such that stabilized in the following clinical course could not be found. ICG-FA is a promising technology which could also be used in pedicled perforator flaps. KW - surgery Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202625 VL - 7 IS - 9 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 - Kehrberger, Sandra A1 - Holzschuh, Andrea T1 - How does timing of flowering affect competition for pollinators, flower visitation and seed set in an early spring grassland plant? JF - Scientific Reports N2 - Knowledge on how the timing of flowering is related to plant fitness and species interactions is crucial to understand consequences of phenological shifts as they occur under climate change. Early flowering plants may face advantages of low competition for pollinators and disadvantages of low pollinator abundances and unfavourable weather conditions. However, it is unknown how this trade-off changes over the season and how the timing affects reproductive success. On eight grasslands we recorded intra-seasonal changes in pollinators, co-flowering plants, weather conditions, flower visitation rates, floral longevity and seed set of Pulsatilla vulgaris. Although bee abundances and the number of pollinator-suitable hours were low at the beginning of the season, early flowers of P. vulgaris received higher flower visitation rates and estimated total number of bee visits than later flowers, which was positively related to seed set. Flower visitation rates decreased over time and with increasing number of co-flowering plants, which competed with P. vulgaris for pollinators. Low interspecific competition for pollinators seems to be a major driver for early flowering dates. Thus, non-synchronous temporal shifts of co-flowering plants as they may occur under climate warming can be expected to strongly affect plant-pollinator interactions and the fitness of the involved plants. KW - ecology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202549 VL - 9 ER - TY - JOUR A1 - Heiby, Julia C. A1 - Goretzki, Benedikt A1 - Johnson, Christopher M. A1 - Hellmich, Ute A. A1 - Neuweiler, Hannes T1 - Methionine in a protein hydrophobic core drives tight interactions required for assembly of spider silk JF - Nature Communications N2 - Web spiders connect silk proteins, so-called spidroins, into fibers of extraordinary toughness. The spidroin N-terminal domain (NTD) plays a pivotal role in this process: it polymerizes spidroins through a complex mechanism of dimerization. Here we analyze sequences of spidroin NTDs and find an unusually high content of the amino acid methionine. We simultaneously mutate all methionines present in the hydrophobic core of a spidroin NTD from a nursery web spider’s dragline silk to leucine. The mutated NTD is strongly stabilized and folds at the theoretical speed limit. The structure of the mutant is preserved, yet its ability to dimerize is substantially impaired. We find that side chains of core methionines serve to mobilize the fold, which can thereby access various conformations and adapt the association interface for tight binding. Methionine in a hydrophobic core equips a protein with the capacity to dynamically change shape and thus to optimize its function. KW - Circular dichroism KW - Fluorescence spectroscopy KW - Protein folding KW - Solution-state NMR Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202539 VL - 10 ER - TY - JOUR A1 - Vogel, Patrick A1 - Markert, Jonathan A1 - Rückert, Martin A. A1 - Herz, Stefan A1 - Keßler, Benedikt A1 - Dremel, Kilian A1 - Althoff, Daniel A1 - Weber, Matthias A1 - Buzug, Thorsten M. A1 - Bley, Thorsten A. A1 - Kullmann, Walter H. A1 - Hanke, Randolf A1 - Zabler, Simon A1 - Behr, Volker C. T1 - Magnetic Particle Imaging meets computed tomography: first simultaneous imaging JF - Scientific Reports N2 - Magnetic Particle Imaging (MPI) is a promising new tomographic modality for fast as well as three-dimensional visualization of magnetic material. For anatomical or structural information an additional imaging modality such as computed tomography (CT) is required. In this paper, the first hybrid MPI-CT scanner for multimodal imaging providing simultaneous data acquisition is presented. KW - Applied physics KW - Biomedical engineering KW - Imaging techniques Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202501 VL - 9 ER - TY - JOUR A1 - Müller-Scholden, Lara A1 - Kirchhof, Jan A1 - Morbach, Caroline A1 - Breunig, Margret A1 - Meijer, Rudy A1 - Rücker, Viktoria A1 - Tiffe, Theresa A1 - Yurdadogan, Tino A1 - Wagner, Martin A1 - Gelbrich, Götz A1 - Bots, Michiel L. A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - Segment-specific association of carotid-intima-media thickness with cardiovascular risk factors – findings from the STAAB cohort study JF - BMC Cardiovascular Disorders N2 - Background The guideline recommendation to not measure carotid intima-media thickness (CIMT) for cardiovascular risk prediction is based on the assessment of just one single carotid segment. We evaluated whether there is a segment-specific association between different measurement locations of CIMT and cardiovascular risk factors. Methods Subjects from the population-based STAAB cohort study comprising subjects aged 30 to 79 years of the general population from Würzburg, Germany, were investigated. CIMT was measured on the far wall of both sides in three different predefined locations: common carotid artery (CCA), bulb, and internal carotid artery (ICA). Diabetes, dyslipidemia, hypertension, smoking, and obesity were considered as risk factors. In multivariable logistic regression analysis, odds ratios of risk factors per location were estimated for the endpoint of individual age- and sex-adjusted 75th percentile of CIMT. Results 2492 subjects were included in the analysis. Segment-specific CIMT was highest in the bulb, followed by CCA, and lowest in the ICA. Dyslipidemia, hypertension, and smoking were associated with CIMT, but not diabetes and obesity. We observed no relevant segment-specific association between the three different locations and risk factors, except for a possible interaction between smoking and ICA. Conclusions As no segment-specific association between cardiovascular risk factors and CIMT became evident, one simple measurement of one location may suffice to assess the cardiovascular risk of an individual. KW - Carotid intima-media thickness (CIMT) KW - Carotid segment KW - Carotid ultrasound KW - Cardiovascular risk factors KW - Cardiovascular risk prediction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200720 VL - 19 IS - 84 ER - TY - JOUR A1 - Silwedel, Christine A1 - Haarmann, Axel A1 - Fehrholz, Markus A1 - Claus, Heike A1 - Speer, Christian P. A1 - Glaser, Kirsten T1 - More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells JF - Journal of Neuroinflammation N2 - Background Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma-driven cell death, concentrating on apoptosis as well as inflammatory cell death. Methods Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma (U.) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties. Results Both Ureaplasma isolates induced cell death (p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 (p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure (p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 (p < 0.05). Conclusions By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp. KW - Ureaplasma urealyticum KW - Ureaplasma parvum KW - Neuroinflammation KW - Meningitis KW - Caspase KW - Apoptosis KW - HBMEC Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200711 VL - 16 ER - TY - JOUR A1 - Mueller, Stefan A1 - Lüttig, Julian A1 - Malý, Pavel A1 - Ji, Lei A1 - Han, Jie A1 - Moos, Michael A1 - Marder, Todd B. A1 - Bunz, Uwe H. F. A1 - Dreuw, Andreas A1 - Lambert, Christoph A1 - Brixner, Tobias T1 - Rapid multiple-quantum three-dimensional fluorescence spectroscopy disentangles quantum pathways JF - Nature Communications N2 - Coherent two-dimensional spectroscopy is a powerful tool for probing ultrafast quantum dynamics in complex systems. Several variants offer different types of information but typically require distinct beam geometries. Here we introduce population-based three-dimensional (3D) electronic spectroscopy and demonstrate the extraction of all fourth- and multiple sixth-order nonlinear signal contributions by employing 125-fold (1⨯5⨯5⨯5) phase cycling of a four-pulse sequence. Utilizing fluorescence detection and shot-to-shot pulse shaping in single-beam geometry, we obtain various 3D spectra of the dianion of TIPS-tetraazapentacene, a fluorophore with limited stability at ambient conditions. From this, we recover previously unknown characteristics of its electronic two-photon state. Rephasing and nonrephasing sixth-order contributions are measured without additional phasing that hampered previous attempts using noncollinear geometries. We systematically resolve all nonlinear signals from the same dataset that can be acquired in 8 min. The approach is generalizable to other incoherent observables such as external photoelectrons, photocurrents, or photoions. KW - Atomic and molecular interactions with photons KW - Optical spectroscopy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202529 VL - 10 ER - TY - JOUR A1 - Dechaud, Corentin A1 - Volff, Jean-Nicolas A1 - Schartl, Manfred A1 - Naville, Magali T1 - Sex and the TEs: transposable elements in sexual development and function in animals JF - Mobile DNA N2 - Transposable elements are endogenous DNA sequences able to integrate into and multiply within genomes. They constitute a major source of genetic innovations, as they can not only rearrange genomes but also spread ready-to-use regulatory sequences able to modify host gene expression, and even can give birth to new host genes. As their evolutionary success depends on their vertical transmission, transposable elements are intrinsically linked to reproduction. In organisms with sexual reproduction, this implies that transposable elements have to manifest their transpositional activity in germ cells or their progenitors. The control of sexual development and function can be very versatile, and several studies have demonstrated the implication of transposable elements in the evolution of sex. In this review, we report the functional and evolutionary relationships between transposable elements and sexual reproduction in animals. In particular, we highlight how transposable elements can influence expression of sexual development genes, and how, reciprocally, they are tightly controlled in gonads. We also review how transposable elements contribute to the organization, expression and evolution of sexual development genes and sex chromosomes. This underscores the intricate co-evolution between host functions and transposable elements, which regularly shift from a parasitic to a domesticated status useful to the host. KW - Transposable element KW - Sex determination KW - Sexual development and function KW - Germline KW - piRNA KW - Sex chromosome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202510 VL - 10 ER - TY - JOUR A1 - Lopez-Arreguin, A. J. R. A1 - Montenegro, S. T1 - Improving engineering models of terramechanics for planetary exploration JF - Results in Engineering N2 - This short letter proposes more consolidated explicit solutions for the forces and torques acting on typical rover wheels, that can be used as a method to determine their average mobility characteristics in planetary soils. The closed loop solutions stand in one of the verified methods, but at difference of the previous, observables are decoupled requiring a less amount of physical parameters to measure. As a result, we show that with knowledge of terrain properties, wheel driving performance rely in a single observable only. Because of their generality, the formulated equations established here can have further implications in autonomy and control of rovers or planetary soil characterization. KW - Wheel KW - Terramechanics KW - Forces KW - Torque KW - Robotics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202490 VL - 3 ER - TY - JOUR A1 - Krebs, Markus A1 - Behrmann, Christoph A1 - Kalogirou, Charis A1 - Sokolakis, Ioannis A1 - Kneitz, Susanne A1 - Kruithof-de Julio, Marianna A1 - Zoni, Eugenio A1 - Rech, Anne A1 - Schilling, Bastian A1 - Kübler, Hubert A1 - Spahn, Martin A1 - Kneitz, Burkhard T1 - miR-221 Augments TRAIL-mediated apoptosis in prostate cancer cells by inducing endogenous TRAIL expression and targeting the functional repressors SOCS3 and PIK3R1 JF - BioMed Research International N2 - miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent. KW - Cancer Cell Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202480 VL - 2019 ER - TY - JOUR A1 - Herz, Michaela A1 - Brehm, Klaus T1 - Evidence for densovirus integrations into tapeworm genomes JF - Parasites & Vectors N2 - Background Tapeworms lack a canonical piRNA-pathway, raising the question of how they can silence existing mobile genetic elements (MGE). Investigation towards the underlying mechanisms requires information on tapeworm transposons which is, however, presently scarce. Methods The presence of densovirus-related sequences in tapeworm genomes was studied by bioinformatic approaches. Available RNA-Seq datasets were mapped against the Echinococcus multilocularis genome to calculate expression levels of densovirus-related genes. Transcription of densovirus loci was further analyzed by sequencing and RT-qPCR. Results We herein provide evidence for the presence of densovirus-related elements in a variety of tapeworm genomes. In the high-quality genome of E. multilocularis we identified more than 20 individual densovirus integration loci which contain the information for non-structural and structural virus proteins. The majority of densovirus loci are present as head-to-tail concatemers in isolated repeat containing regions of the genome. In some cases, unique densovirus loci have integrated close to histone gene clusters. We show that some of the densovirus loci of E. multilocularis are actively transcribed, whereas the majority are transcriptionally silent. RT-qPCR data further indicate that densovirus expression mainly occurs in the E. multilocularis stem cell population, which probably forms the germline of this organism. Sequences similar to the non-structural densovirus genes present in E. multilocularis were also identified in the genomes of E. canadensis, E. granulosus, Hydatigera taeniaeformis, Hymenolepis diminuta, Hymenolepis microstoma, Hymenolepis nana, Taenia asiatica, Taenia multiceps, Taenia saginata and Taenia solium. Conclusions Our data indicate that densovirus integration has occurred in many tapeworm species. This is the first report on widespread integration of DNA viruses into cestode genomes. Since only few densovirus integration sites were transcriptionally active in E. multilocularis, our data are relevant for future studies into gene silencing mechanisms in tapeworms. Furthermore, they indicate that densovirus-based vectors might be suitable tools for genetic manipulation of cestodes. KW - Echinococcus KW - Echinococcosis KW - Densovirus KW - Parvovirus KW - Mobile genetic element KW - Gene silencing KW - Stem cell KW - Epigenetic Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202478 VL - 12 ER - TY - JOUR A1 - Stengel, Helena A1 - Vural, Atay A1 - Brunder, Anna-Michelle A1 - Heinius, Annika A1 - Appeltshauser, Luise A1 - Fiebig, Bianca A1 - Giese, Florian A1 - Dresel, Christian A1 - Papagianni, Aikaterini A1 - Birklein, Frank A1 - Weis, Joachim A1 - Huchtemann, Tessa A1 - Schmidt, Christian A1 - Körtvelyessy, Peter A1 - Villmann, Carmen A1 - Meinl, Edgar A1 - Sommer, Claudia A1 - Leypoldt, Frank A1 - Doppler, Kathrin T1 - Anti–pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy JF - Neurology: Neuroimmunology & Neuroinflammation N2 - Objective To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms. Methods Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays. Results Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti–NF-155 IgG4 were directed against the NF-155–specific Fn3Fn4 domain. The description of a second phenotype of anti–NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year. Conclusions Our results indicate that anti–pan-NF-associated neuropathy differs from anti–NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti–NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response. KW - neurology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202462 VL - 6 IS - 5 ER - TY - JOUR A1 - Otto, C. A1 - Schmidt, S. A1 - Kastner, C. A1 - Denk, S. A1 - Kettler, J. A1 - Müller, N. A1 - Germer, C.T. A1 - Wolf, E. A1 - Gallant, P. A1 - Wiegering, A. T1 - Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells JF - Neoplasia N2 - The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1. KW - Cancer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202451 VL - 21 IS - 11 ER - TY - JOUR A1 - Ruf, Katharina A1 - Thomas, Wolfgang A1 - Brunner, Maximilian A1 - Speer, Christian P. A1 - Hebestreit, Helge T1 - Diverging effects of premature birth and bronchopulmonary dysplasia on exercise capacity and physical activity – a case control study JF - Respiratory Research N2 - Background Extreme prematurity has been associated with exercise intolerance and reduced physical activity. We hypothesized that children with bronchopulmonary dysplasia (BPD) would be especially affected based on long-term lung function impairments. Therefore, the objective of this study was to compare exercise capacity and habitual physical activity between children born very and extremely preterm with and without BPD and term-born children. Methods Twenty-two school-aged children (aged 8 to 12 years) born with a gestational age < 32 weeks and a birthweight < 1500 g (9 with moderate or severe BPD (=BPD), 13 without BPD (=No-BPD)) and 15 healthy term-born children (=CONTROL) were included in the study. Physical activity was measured by accelerometry, lung function by spirometry and exercise capacity by an incremental cardiopulmonary exercise test. Results Peak oxygen uptake was reduced in the BPD-group (83 ± 11%predicted) compared to the No-BPD group (91 ± 8%predicted) and the CONTROL group (94 ± 9%predicted). In a general linear model, variance of peak oxygen uptake was significantly explained by BPD status and height but not by prematurity (p < 0.001). Compared to CONTROL, all children born preterm spent significantly more time in sedentary behaviour (BPD 478 ± 50 min, No-BPD 450 ± 52 min, CONTROL 398 ± 56 min, p < 0.05) and less time in moderate-to-vigorous-physical activity (BPD 13 ± 8 min, No-BPD 16 ± 8 min, CONTROL 33 ± 16 min, p < 0.001). Prematurity but not BPD contributed significantly to explained variance in a general linear model of sedentary behaviour and likewise moderate-to-vigorous-physical activity (p < 0.05 and p < 0.001 respectively). Conclusion In our cohort, BPD but not prematurity was associated with a reduced exercise capacity at school-age. However, prematurity regardless of BPD was related to less engagement in physical activity and more time spent in sedentary behaviour. Thus, our findings suggest diverging effects of prematurity and BPD on exercise capacity and physical activity." KW - Bronchopulmonary dysplasia KW - Physical activity KW - Exercise testing KW - Preterm birth KW - Exercise capacity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202449 VL - 20 ER - TY - JOUR A1 - Evers, Ann-Kristin A1 - Veeh, Julia A1 - McNeill, Rhiannon A1 - Reif, Andreas A1 - Kittel-Schneider, Sarah T1 - C-reactive protein concentration in bipolar disorder: association with genetic variants JF - International Journal of Bipolar Disorders N2 - Background Several recent studies have investigated the role of C-reactive protein (CRP) in bipolar disorder (BD), but few studies have directly investigated the interaction between CRP genetic variants and peripheral CRP concentration across different phases of BD. In this study, we aimed to replicate previous findings that demonstrated altered CRP levels in BD, and to investigate whether there is an association of peripheral protein expression with genetic variants in the CRP gene. Methods 221 patients were included in the study, of which 183 (all episodes, 46 not medicated, 174 medicated) were genotyped for CRP single-nucleotide polymorphisms (SNPs) shown to influence peripheral CRP protein expression (rs1800947, rs2808630, rs1417938, rs1205). Results There were no differences in CRP levels associated with the genotypes, only regarding the rs1205 SNP there were significantly different CRP protein expression between the genotypes when taking body mass index, age, BD polarity, subtype and leukocyte number into account. However, we could show significantly elevated CRP protein expression in manic patients compared to euthymic and depressed patients, independent from genotype. Medication was found to have no effect on CRP protein expression. Conclusions These results indicate that low grade inflammation might play a role in mania and might be rather a state than a trait marker of bipolar disorder. KW - Bipolar disorder KW - Genotype KW - C-reactive protein KW - Biomarke KW - Inflammatio Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202289 VL - 7 ER - TY - JOUR A1 - Petschke, Danny A1 - Staab, Torsten E.M. T1 - DDRS4PALS: a software for the acquisition and simulation of lifetime spectra using the DRS4 evaluation board JF - SoftwareX N2 - Lifetime techniques are applied to diverse fields of study including materials sciences, semiconductor physics, biology, molecular biophysics and photochemistry. Here we present DDRS4PALS, a software for the acquisition and simulation of lifetime spectra using the DRS4 evaluation board (Paul Scherrer Institute, Switzerland) for time resolved measurements and digitization of detector output pulses. Artifact afflicted pulses can be corrected or rejected prior to the lifetime calculation to provide the generation of high-quality lifetime spectra, which are crucial for a profound analysis, i.e. the decomposition of the true information. Moreover, the pulses can be streamed on an (external) hard drive during the measurement and subsequently downloaded in the offline mode without being connected to the hardware. This allows the generation of various lifetime spectra at different configurations from one single measurement and, hence, a meaningful comparison in terms of analyzability and quality. Parallel processing and an integrated JavaScript based language provide convenient options to accelerate and automate time consuming processes such as lifetime spectra simulations. KW - Lifetime spectroscopy KW - Positron annihilation spectroscopy KW - Simulation KW - Time resolved measurements Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202276 VL - 10 ER - TY - JOUR A1 - Käthner, Ivo A1 - Bader, Thomas A1 - Pauli, Paul T1 - Heat pain modulation with virtual water during a virtual hand illusion JF - Scientific Reports N2 - Immersive virtual reality is a powerful method to modify the environment and thereby influence experience. The present study used a virtual hand illusion and context manipulation in immersive virtual reality to examine top-down modulation of pain. Participants received painful heat stimuli on their forearm and placed an embodied virtual hand (co-located with their real one) under a virtual water tap, which dispensed virtual water under different experimental conditions. We aimed to induce a temperature illusion by a red, blue or white light suggesting warm, cold or no virtual water. In addition, the sense of agency was manipulated by allowing participants to have high or low control over the virtual hand’s movements. Most participants experienced a thermal sensation in response to the virtual water and associated the blue and red light with cool/cold or warm/hot temperatures, respectively. Importantly, the blue light condition reduced and the red light condition increased pain intensity and unpleasantness, both compared to the control condition. The control manipulation influenced the sense of agency, but did not influence pain ratings. The large effects revealed in our study suggest that context effects within an embodied setting in an immersive virtual environment should be considered within VR based pain therapy. KW - Cognitive neuroscience KW - Neuroscience KW - Psychology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202221 VL - 9 ER - TY - JOUR A1 - Schartl, Manfred A1 - Kneitz, Susanne A1 - Volkoff, Helene A1 - Adolfi, Mateus A1 - Schmidt, Cornelia A1 - Fischer, Petra A1 - Minx, Patrick A1 - Tomlinson, Chad A1 - Meyer, Axel A1 - Warren, Wesley C. T1 - The piranha genome provides molecular insight associated to its unique feeding behavior JF - Genome Biology and Evolution N2 - The piranha enjoys notoriety due to its infamous predatory behavior but much is still not understood about its evolutionary origins and the underlying molecular mechanisms for its unusual feeding biology. We sequenced and assembled the red-bellied piranha (Pygocentrus nattereri) genome to aid future phenotypic and genetic investigations. The assembled draft genome is similar to other related fishes in repeat composition and gene count. Our evaluation of genes under positive selection suggests candidates for adaptations of piranhas’ feeding behavior in neural functions, behavior, and regulation of energy metabolism. In the fasted brain, we find genes differentially expressed that are involved in lipid metabolism and appetite regulation as well as genes that may control the aggression/boldness behavior of hungry piranhas. Our first analysis of the piranha genome offers new insight and resources for the study of piranha biology and for feeding motivation and starvation in other organisms. KW - whole-genome sequencing KW - genome annotation KW - comparative genomics KW - RNA-seq transcriptome KW - energy homeostasis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202218 VL - 11 IS - 8 ER - TY - JOUR A1 - Jurowich, Christian A1 - Lichthardt, Sven A1 - Kastner, Caroline A1 - Haubitz, Imme A1 - Prock, Andre A1 - Filser, Jörg A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Laparoscopic versus open right hemicolectomy in colon carcinoma: A propensity score analysis of the DGAV StuDoQ|ColonCancer registry JF - PLoS ONE N2 - Objective To assess whether laparoscopy has any advantages over open resection for right-sided colon cancer. Summary background data Right hemicolectomy can be performed using either a conventional open or a minimally invasive laparoscopic technique. It is not clear whether these different access routes differ with regard to short-term postoperative outcomes. Methods Patients documented in the German Society for General and Visceral Surgery StuDoQ|ColonCancer registry who underwent right hemicolectomy were analyzed regarding early postoperative complications according to Clavien-Dindo (primary endpoint), operation (OP) time, length of postoperative hospital stay (LOS), MTL30 and number of lymph nodes retrieved (secondary endpoints). Results A total of 4.997 patients were identified as undergoing oncological right hemicolectomy without additional interventions. Of these, 4.062 (81.3%) underwent open, 935 (18.7%) laparoscopic surgery. Propensity score analysis showed a significantly shorter LOS (OR: 0.55 CI 95%0.47-.64) and a significantly longer OP time (OR2.32 CI 1.98–2.71) for the laparoscopic route. Risk factors for postoperative complications, anastomotic insufficiency, ileus, reoperation and positive MTL30 were higher ASA status, higher age and increasing BMI. The surgical access route (open / lap) had no influence on these factors, but the laparoscopic group did have markedly fewer lymph nodes retrieved. Conclusion The present registry-based analysis could detect no relevant advantages for the minimally invasive laparoscopic access route. Further oncological analyses are needed to clarify the extent to which the smaller lymph node harvest in the laparoscopic group is accompanied by a poorer oncological outcome. KW - Laparoscopy KW - Lymph nodes KW - Minimally invasive surgery KW - Surgical oncology KW - Oncology KW - Surgical and invasive medical procedures Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202184 VL - 14 IS - 6 ER - TY - JOUR A1 - Mottola, Austin A1 - Morschhäuser, Joachim T1 - An intragenic recombination event generates a Snf4-independent form of the essential protein kinase SNF1 in Candida albicans JF - mSphere N2 - The heterotrimeric protein kinase SNF1 plays a key role in the metabolic adaptation of the pathogenic yeast Candida albicans. It consists of the essential catalytic α-subunit Snf1, the γ-subunit Snf4, and one of the two β-subunits Kis1 and Kis2. Snf4 is required to release the N-terminal catalytic domain of Snf1 from autoinhibition by the C-terminal regulatory domain, and snf4Δ mutants cannot grow on carbon sources other than glucose. In a screen for suppressor mutations that restore growth of a snf4Δ mutant on alternative carbon sources, we isolated a mutant in which six amino acids between the N-terminal kinase domain and the C-terminal regulatory domain of Snf1 were deleted. The deletion was caused by an intragenic recombination event between two 8-bp direct repeats flanking six intervening codons. In contrast to truncated forms of Snf1 that contain only the kinase domain, the Snf4-independent Snf1\(^{Δ311 − 316}\) was fully functional and could replace wild-type Snf1 for normal growth, because it retained the ability to interact with the Kis1 and Kis2 β-subunits via its C-terminal domain. Indeed, the Snf4-independent Snf1\(^{Δ311 − 316}\) still required the β-subunits of the SNF1 complex to perform its functions and did not rescue the growth defects of kis1Δ mutants. Our results demonstrate that a preprogrammed in-frame deletion event within the SNF1 coding region can generate a mutated form of this essential kinase which abolishes autoinhibition and thereby overcomes growth deficiencies caused by a defect in the γ-subunit Snf4. KW - AMP-activated kinases KW - Candida albicans KW - genetic recombination KW - metabolic adaptation KW - suppressor mutation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202170 VL - 4 IS - 3 ER - TY - JOUR A1 - Pattschull, Grit A1 - Walz, Susanne A1 - Gründl, Marco A1 - Schwab, Melissa A1 - Rühl, Eva A1 - Baluapuri, Apoorva A1 - Cindric-Vranesic, Anita A1 - Kneitz, Susanne A1 - Wolf, Elmar A1 - Ade, Carsten P. A1 - Rosenwald, Andreas A1 - von Eyss, Björn A1 - Gaubatz, Stefan T1 - The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes JF - Cell Reports N2 - YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways. KW - YAP KW - B-MYB KW - Myb-MuvB KW - mitotic genes KW - enhancer KW - transcription Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202039 VL - 27 IS - 12 ER - TY - JOUR A1 - Jaślan, Dawid A1 - Dreyer, Ingo A1 - Lu, Jinping A1 - O'Malley, Ronan A1 - Dindas, Julian A1 - Marten, Irene A1 - Hedrich, Rainer T1 - Voltage-dependent gating of SV channel TPC1 confers vacuole excitability JF - Nature Communications N2 - In contrast to the plasma membrane, the vacuole membrane has not yet been associated with electrical excitation of plants. Here, we show that mesophyll vacuoles from Arabidopsis sense and control the membrane potential essentially via the K\(^+\)-permeable TPC1 and TPK channels. Electrical stimuli elicit transient depolarization of the vacuole membrane that can last for seconds. Electrical excitability is suppressed by increased vacuolar Ca\(^{2+}\) levels. In comparison to wild type, vacuoles from the fou2 mutant, harboring TPC1 channels insensitive to luminal Ca\(^{2+}\), can be excited fully by even weak electrical stimuli. The TPC1-loss-of-function mutant tpc1-2 does not respond to electrical stimulation at all, and the loss of TPK1/TPK3-mediated K\(^{+}\) transport affects the duration of TPC1-dependent membrane depolarization. In combination with mathematical modeling, these results show that the vacuolar K\(^+\)-conducting TPC1 and TPK1/TPK3 channels act in concert to provide for Ca\(^{2+}\)- and voltage-induced electrical excitability to the central organelle of plant cells. KW - Biophysics KW - Plant signalling Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202029 VL - 10 ER - TY - JOUR A1 - von Collenberg, Cora R. A1 - Schmitt, Dominique A1 - Rülicke, Thomas A1 - Sendtner, Michael A1 - Blum, Robert A1 - Buchner, Erich T1 - An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance JF - Biology Open N2 - Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice. KW - Syap1 knockout KW - Motor behaviour KW - Associative learning KW - Fear conditioning KW - Object recognition Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201986 N1 - PDF includes: Correction: An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance - February 15, 2020. Biology Open (2020) 9, bio048942. doi:10.1242/bio.048942 VL - 8 ER - TY - JOUR A1 - Petritsch, Berhard A1 - Kosmala, Aleksander A1 - Weng, Andreas Max A1 - Bley, Thorsten Alexander T1 - Tin-filtered 100kV ultra-low-dose CT of the paranasal sinus: initial clinical results JF - PLoS ONE N2 - Objectives To investigate the feasibility, diagnostic image quality and radiation dose of 3\(^{rd}\) generation dual-source computed tomography (CT) using a tin-filtered 100 kV protocol in patients with suspected acute inflammatory sinus disease. Methods We retrospectively evaluated 109 consecutive patients who underwent CT (Siemens SOMATOM Force, Erlangen, Germany) of the paranasal sinus with a new tin-filtered scanprotocol (Sn100 kV; tube current 35 mAs) using iterative reconstruction. Two readers independently assessed subjective image quality using a five-point Likert scale (1 = excellent, 5 = non-diagnostic). Inter-observer agreement was calculated and expressed as percentage of agreement. Noise was determined for calculation of signal-to-noise-ratio (SNR). Effective radiation dose (ED) was calculated from the dose-length-product (DLP). Results All examinations showed diagnostic image quality regarding evaluation of inflammatory sinus disease. On average, subjective general image quality was rated moderate (= 3) with a percentage of agreement between the observers of 81%. The mean image noise was 14.3 HU. The calculated median SNR was 6.0 for intraorbital fat, and 3.6 for the vitreous body, respectively. The median DLP was 2.1 mGy*cm, resulting in a median ED of 0.012 mSv. Conclusions Taking the study limitations into account, ultra-low-dose tin-filtered CT of the paranasal sinus at a tube voltage of 100 kV utilizing an iterative reconstruction algorithm provides for reliable exclusion of suspected acute inflammatory sinus disease in 100% of the cases. KW - Computed axial tomography KW - Inflammatory diseases KW - Radiation exposure KW - Diagnostic medicine KW - Fats KW - Mastoid process KW - X-ray radiography KW - Soft tissues Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204127 VL - 14 IS - 5 ER - TY - JOUR A1 - Zetzl, Teresa A1 - Schuler, Michael A1 - Renner, Agnes A1 - Jentschke, Elisabeth A1 - van Oorschot, Birgitt T1 - Yoga intervention and reminder e-mails for reducing cancer-related fatigue - a study protocol of a randomized controlled trial JF - BMC Psychology N2 - Background Almost 90% of cancer patients suffer from symptoms of fatigue during treatment. Supporting treatments are increasingly used to alleviate the burden of fatigue. This study examines the short-term and long-term effects of yoga on fatigue and the effect of weekly reminder e-mails on exercise frequency and fatigue symptoms. Methods The aim of the first part of the study will evaluate the effectiveness of yoga for cancer patients with mixed diagnoses reporting fatigue. We will randomly allocate 128 patients to an intervention group (N = 64) receiving yoga and a wait-list control group (N = 64) receiving yoga 9 weeks later. The yoga therapy will be performed in weekly sessions of 60 min each for 8 weeks. The primary outcome will be self-reported fatigue symptoms. In the second part of the study, the effectiveness of reminder e-mails with regard to the exercise frequency and self-reported fatigue symptoms will be evaluated. A randomized allocated group of the participants (“email”) receives weekly reminder e-mails, the other group does not. Data will be assessed using questionnaires the beginning and after yoga therapy as well as after 6  months. Discussion Support of patients suffering from fatigue is an important goal in cancer patients care. If yoga therapy will reduce fatigue, this type of therapy may be introduced into routine practice. If the reminder e-mails prove to be helpful, new offers for patients may also develop from this. KW - Cancer KW - Fatigue KW - Yoga KW - Reminder e-mails KW - Supportive therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202268 VL - 7 ER - TY - JOUR A1 - Jakubietz, Rafael G. A1 - Jakubietz, Danni F. A1 - Horch, Raymund E. A1 - Gruenert, Joerg G. A1 - Meffert, Rainer H. A1 - Jakubietz, Michael G. T1 - The microvascular peroneal artery perforator flap as a "lifeboat" for pedicled flaps JF - Plastic and Reconstructive Surgery – Global Open N2 - Background: Pedicled perforator flaps have expanded reconstructive options in extremity reconstruction. Despite preoperative mapping, intraoperative findings may require microvascular tissue transfer when no adequate perforators can be found. The free peroneal artery perforator flap may serve as a reliable back-up plan in small defects. Methods: In 16 patients with small soft tissue defects on the upper and lower extremities, perforator-based propeller flaps were planned. The handheld Doppler device was used to localize potential perforators for a propeller flap in close proximity to the defect. Perforators of the proximal peroneal artery were also marked to allow conversion to microvascular tissue transfer. Results: In 6 cases, no adequate perforators were found intraoperatively. In 4 patients, the peroneal artery perforator flap was harvested and transferred. The pedicle length did not exceed 4 cm. No flap loss occurred. Conclusions: When no adequate perforator capable of nourishing a propeller flap can be found intraoperatively, the free peroneal artery flap is a good option to reconstruct small soft tissue defects in the distal extremities. The short vascular pedicle is less ideal in cases with a large zone of injury requiring a more distant site of anastomosis or when recipient vessels are located in deeper tissue planes. KW - surgery Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202233 VL - 7 IS - 9 ER - TY - JOUR A1 - Jansen, Hendrik A1 - Heintel, Timo M. A1 - Jordan, Martin A1 - Meffert, Rainer H. A1 - Frey, Soenke P. T1 - Survived traumatic hemipelvectomy with salvage of the limb in a 14  months old toddler JF - Trauma Case Reports N2 - We report on a 14 months old toddler who sustained a traumatic hemipelvectomy by being crushed between a car and a stone wall. After stabilization in the resuscitation room he was treated operatively by laparotomy, osteosynthesis of the pelvic ring, reconstruction of the both external iliac vessels and the urethra and reposition of the testicles. After 66 days he was discharged into rehabilitation. Implants were removed after eight months. 20 months after the injury, the leg was plegic, initial radiological signs of femoral head necrosis showed up but the infant was able to walk with an orthesis and a walker. Up to our knowledge, this is the youngest patient described in the literature with a survived traumatic hemipelvectomy and salvaged limb. KW - Hemipelvectomy KW - Survival KW - Limb salvage KW - Toddler Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202207 VL - 22 ER - TY - JOUR A1 - Lyutova, Radostina A1 - Selcho, Mareike A1 - Pfeuffer, Maximilian A1 - Segebarth, Dennis A1 - Habenstein, Jens A1 - Rohwedder, Astrid A1 - Frantzmann, Felix A1 - Wegener, Christian A1 - Thum, Andreas S. A1 - Pauls, Dennis T1 - Reward signaling in a recurrent circuit of dopaminergic neurons and peptidergic Kenyon cells JF - Nature Communications N2 - Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that recurrent signaling exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. Optogenetic activation of Kenyon cells paired with odor stimulation is sufficient to induce appetitive memory. Simultaneous impairment of the dopaminergic pPAM neurons abolishes appetitive memory expression. Thus, we argue that dopaminergic pPAM neurons mediate reward information to the Kenyon cells, and in turn receive feedback from Kenyon cells. We further show that this feedback signaling is dependent on short neuropeptide F, but not on acetylcholine known to be important for odor-shock memories in adult flies. Our data suggest that recurrent signaling routes within the larval mushroom body circuitry may represent a mechanism subserving memory stabilization. KW - Learning and memory KW - Neural circuits Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202161 VL - 10 ER - TY - JOUR A1 - Liedtke, Daniel A1 - Orth, Melanie A1 - Meissler, Michelle A1 - Geuer, Sinje A1 - Knaup, Sabine A1 - Köblitz, Isabell A1 - Klopocki, Eva T1 - ECM alterations in fndc3a (fibronectin domain containing protein 3A) deficient zebrafish cause temporal fin development and regeneration defects JF - Scientific Reports N2 - Fin development and regeneration are complex biological processes that are highly relevant in teleost fish. They share genetic factors, signaling pathways and cellular properties to coordinate formation of regularly shaped extremities. Especially correct tissue structure defined by extracellular matrix (ECM) formation is essential. Gene expression and protein localization studies demonstrated expression of fndc3a (fibronectin domain containing protein 3a) in both developing and regenerating caudal fins of zebrafish (Danio rerio). We established a hypomorphic fndc3a mutant line (fndc3a\(^{wue1/wue1}\)) via CRISPR/Cas9, exhibiting phenotypic malformations and changed gene expression patterns during early stages of median fin fold development. These developmental effects are mostly temporary, but result in a fraction of adults with permanent tail fin deformations. In addition, caudal fin regeneration in adult fndc3a\(^{wue1/wue1}\) mutants is hampered by interference with actinotrichia formation and epidermal cell organization. Investigation of the ECM implies that loss of epidermal tissue structure is a common cause for both of the observed defects. Our results thereby provide a molecular link between these developmental processes and foreshadow Fndc3a as a novel temporal regulator of epidermal cell properties during extremity development and regeneration in zebrafish. KW - Extracellular matrix KW - Limb development KW - Self-renewal Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202141 VL - 9 ER - TY - JOUR A1 - Heidenreich, Julius F. A1 - Weng, Andreas M. A1 - Donhauser, Julian A1 - Greiser, Andreas A1 - Chow, Kelvin A1 - Nordbeck, Peter A1 - Bley, Thorsten A. A1 - Köstler, Herbert T1 - T1- and ECV-mapping in clinical routine at 3 T: differences between MOLLI, ShMOLLI and SASHA JF - BMC Medical Imaging N2 - Background T1 mapping sequences such as MOLLI, ShMOLLI and SASHA make use of different technical approaches, bearing strengths and weaknesses. It is well known that obtained T1 relaxation times differ between the sequence techniques as well as between different hardware. Yet, T1 quantification is a promising tool for myocardial tissue characterization, disregarding the absence of established reference values. The purpose of this study was to evaluate the feasibility of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T. Methods Native and post-contrast T1 mapping data acquired on a 3 T full-body scanner using the three pulse sequences 5(3)3 MOLLI, ShMOLLI and SASHA in 19 patients with clinical indication for contrast enhanced MRI were compared. We analyzed global and segmental T1 relaxation times as well as respective extracellular volumes and compared the emerged differences between the used pulse sequences. Results T1 times acquired with MOLLI and ShMOLLI exhibited systematic T1 deviation compared to SASHA. Myocardial MOLLI T1 times were 19% lower and ShMOLLI T1 times 25% lower compared to SASHA. Native blood T1 times from MOLLI were 13% lower than SASHA, while post-contrast MOLLI T1-times were only 5% lower. ECV values exhibited comparably biased estimation with MOLLI and ShMOLLI compared to SASHA in good agreement with results reported in literature. Pathology-suspect segments were clearly differentiated from remote myocardium with all three sequences. Conclusion Myocardial T1 mapping yields systematically biased pre- and post-contrast T1 times depending on the applied pulse sequence. Additionally calculating ECV attenuates this bias, making MOLLI, ShMOLLI and SASHA better comparable. Therefore, myocardial T1 mapping is a powerful clinical tool for classification of soft tissue abnormalities in spite of the absence of established reference values. KW - T1 mapping KW - MOLLI KW - ShMOLLI KW - SASHA KW - Extracellular volume KW - 3 T Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201999 VL - 19 ER - TY - JOUR A1 - Streinzer, Martin A1 - Chakravorty, Jharna A1 - Neumayer, Johann A1 - Megu, Karsing A1 - Narah, Jaya A1 - Schmitt, Thomas A1 - Bharti, Himender A1 - Spaethe, Johannes A1 - Brockmann, Axel T1 - Species composition and elevational distribution of bumble bees (Hymenoptera, Apidae, Bombus Latreille) in the East Himalaya, Arunachal Pradesh, India JF - ZooKeys N2 - The East Himalaya is one of the world’s most biodiverse ecosystems. However, very little is known about the abundance and distribution of many plant and animal taxa in this region. Bumble bees are a group of cold-adapted and high elevation insects that fulfil an important ecological and economical function as pollinators of wild and agricultural flowering plants and crops. The Himalayan mountain range provides ample suitable habitats for bumble bees. Systematic study of Himalayan bumble bees began a few decades ago and the main focus has centred on the western region, while the eastern part of the mountain range has received little attention and only a few species have been verified. During a three-year survey, more than 700 bumble bee specimens of 21 species were collected in Arunachal Pradesh, the largest of the north-eastern states of India. The material included a range of species that were previously known from a limited number of collected specimens, which highlights the unique character of the East Himalayan ecosystem. Our results are an important first step towards a future assessment of species distribution, threat, and conservation. Clear elevation patterns of species diversity were observed, which raise important questions about the functional adaptations that allow bumble bees to thrive in this particularly moist region in the East Himalaya. KW - Alpine habitats KW - Apidae KW - conservation KW - global change KW - insect collection KW - pollination Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201937 VL - 851 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 - Gräb, Patrick A1 - Geidel, Ekkehard T1 - Spectroscopic studies of food colorings JF - World Journal of Chemical Education N2 - In chemical education, it is often a challenge to understand the basic principles of spectroscopic techniques due to missing connections to the real world. Therefore, the present contribution offers context-based applications of UV/Vis spectroscopy for analytics of food colorings with which learners can improve their skills regarding this method. The spectroscopic determination of food colorings seems to be a promising approach due to the long tradition and omnipresence of dyes in supermarket products. The therefor-required spectral data for commonly used dyes are provided for educational usage. Qualitative and quantitative analytics of food colorings in four different lemonades and chocolate beans have been used to introduce learners to important analytical techniques like sample preparation or elimination of confounding factors. These analytics also display the limitations of the method in the visible range of light in the case of tartrazine and curcumin. By applying Lambert-Beer-Bouguer’s Law in different variations, typical calculations of concentrations can be studied in quantitative analyses. The studied food samples demonstrate the different usage of food colorings depending on the country of sale. Finally, a 3D-printable low-cost photometer suitable for the discussed quantitative analytics in educational contexts is presented. KW - UV/Vis spectroscopy KW - quantitative analysis KW - food colorings KW - context-based teaching KW - low-cost photometer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201908 VL - 7 IS - 2 ER - TY - JOUR A1 - Kim, Brandon J. A1 - McDonagh, Maura A. A1 - Deng, Liwen A1 - Gastfriend, Benjamin D. A1 - Schubert-Unkmeir, Alexandra A1 - Doran, Kelly S. A1 - Shusta, Eric V. T1 - Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells JF - Fluids and Barriers of the CNS N2 - Bacterial meningitis is a serious life threatening infection of the CNS. To cause meningitis, blood–borne bacteria need to interact with and penetrate brain endothelial cells (BECs) that comprise the blood–brain barrier. BECs help maintain brain homeostasis and they possess an array of efflux transporters, such as P-glycoprotein (P-gp), that function to efflux potentially harmful compounds from the CNS back into the circulation. Oftentimes, efflux also serves to limit the brain uptake of therapeutic drugs, representing a major hurdle for CNS drug delivery. During meningitis, BEC barrier integrity is compromised; however, little is known about efflux transport perturbations during infection. Thus, understanding the impact of bacterial infection on P-gp function would be important for potential routes of therapeutic intervention. To this end, the meningeal bacterial pathogen, Streptococcus agalactiae, was found to inhibit P-gp activity in human induced pluripotent stem cell-derived BECs, and live bacteria were required for the observed inhibition. This observation was correlated to decreased P-gp expression both in vitro and during infection in vivo using a mouse model of bacterial meningitis. Given the impact of bacterial interactions on P-gp function, it will be important to incorporate these findings into analyses of drug delivery paradigms for bacterial infections of the CNS. KW - Group B Streptococcus KW - Streptococcus agalactiae KW - Brain endothelial cells KW - P-glycoprotein KW - Efflux transport KW - Meningitis KW - Stem cells KW - P-gp Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201895 VL - 16 ER - TY - JOUR A1 - Drayß, Maria A1 - Claus, Heike A1 - Hubert, Kerstin A1 - Thiel, Katrin A1 - Berger, Anja A1 - Sing, Andreas A1 - van der Linden, Mark A1 - Vogel, Ulrich A1 - Lâm, Thiên-Trí T1 - Asymptomatic carriage of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Group A Streptococcus and Staphylococcus aureus among adults aged 65 years and older JF - PLoS ONE N2 - Objective The aim of this study was to determine the prevalence of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, group A Streptococcus (GAS), and Staphylococcus aureus in asymptomatic elderly people and to unravel risk factors leading to colonization. Methods A multi-centre cross-sectional study was conducted including 677 asymptomatic adults aged 65 years or more, living at home or in nursing homes. Study areas were Greater Aachen (North-Rhine-Westphalia) and Wuerzburg (Bavaria), both regions with medium to high population density. Nasal and oropharyngeal swabs as well as questionnaires were collected from October 2012 to May 2013. Statistical analysis included multiple logistic regression models. Results The carriage rate was 1.9% ([95%CI: 1.0–3.3%]; 13/677) for H. influenzae, 0.3% ([95%CI: 0–1.1%]; 2/677) for N. meningitidis and 0% ([95% CI: 0–0.5%]; 0/677) for S. pneumoniae and GAS. Staphylococcus aureus was harboured by 28.5% of the individuals ([95% CI: 25.1–32.1%]; 193/677) and 0.7% ([95% CI: 0.2–1.7%]; 5/677) were positive for methicillin-resistant S. aureus. Among elderly community-dwellers colonization with S. aureus was significantly associated with higher educational level (adjusted OR: 1.905 [95% CI: 1.248–2.908]; p = 0.003). Among nursing home residents colonization was associated with being married (adjusted OR: 3.367 [1.502–7.546]; p = 0.003). Conclusion The prevalence of N. meningitidis, H. influenzae, S. pneumoniae and GAS was low among older people in Germany. The S. aureus rate was expectedly high, while MRSA was found in less than 1% of the individuals. KW - Geriatric care KW - Geriatrics KW - Elderly KW - Staphylococcus aureus KW - Nursing homes KW - Haemophilus influenzae KW - Neisseria meningitidis KW - Methicillin-resistant Staphylococcus aureus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201042 VL - 14 IS - 2 ER - TY - JOUR A1 - Thiem, Alexander A1 - Hesbacher, Sonja A1 - Kneitz, Hermann A1 - di Primio, Teresa A1 - Heppt, Markus V. A1 - Hermanns, Heike M. A1 - Goebeler, Matthias A1 - Meierjohann, Svenja A1 - Houben, Roland A1 - Schrama, David T1 - IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression JF - Journal of Experimental & Clinical Cancer Research N2 - Background Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma. Methods We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway. Results For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53\(^{L22Q,W23S}\), a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53\(^{L22Q,W23S}\) in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression. Conclusions While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy. KW - Melanoma KW - PD-L1 KW - CD274 KW - p53 KW - TP53 KW - JAK2 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201016 VL - 38 ER - TY - JOUR A1 - Vadokas, Georg A1 - Koehler, Stefan A1 - Weiland, Judith A1 - Lilla, Nadine A1 - Stetter, Christian A1 - Westermaier, Thomas T1 - Early antiinflammatory therapy attenuates brain damage after SAH in rats JF - Translational Neuroscience N2 - Background Early inflammatory processes may play an important role in the development of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Experimental studies suggest that anti-inflammatory and membrane-stabilizing drugs might have beneficial effects, although the underlying mechanisms are not fully understood. The aim of this study was to investigate the effect of early treatment with methylprednisolone and minocycline on cerebral perfusion and EBI after experimental SAH. Methods Male Sprague-Dawley rats were subjected to SAH using the endovascular filament model. 30 minutes after SAH, they were randomly assigned to receive an intravenous injection of methylprednisolone (16mg/kg body weight, n=10), minocycline (45mg/kg body weight, n=10) or saline (n=11). Mean arterial blood pressure (MABP), intracranial pressure (ICP) and local cerebral blood flow (LCBF) over both hemispheres were recorded continuously for three hours following SAH. Neurological assessment was performed after 24 hours. Hippocampal damage was analyzed by immunohistochemical staining (caspase 3). Results Treatment with methylprednisolone or minocycline did not result in a significant improvement of MABP, ICP or LCBF. Animals of both treatment groups showed a non-significant trend to better neurological recovery compared to animals of the control group. Mortality was reduced and hippocampal damage significantly attenuated in both methylprednisolone and minocycline treated animals. Conclusion The results of this study suggest that inflammatory processes may play an important role in the pathophysiology of EBI after SAH. Early treatment with the anti-inflammatory drugs methylprednisolone or minocycline in the acute phase of SAH has the potential to reduce brain damage and exert a neuroprotective effect. KW - subarachnoid hemorrhage KW - early brain injury KW - methylprednisolone KW - minocycline KW - neuroprotection Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201440 VL - 10 IS - 1 ER - TY - JOUR A1 - Huestegge, Lynn A1 - Herbort, Oliver A1 - Gosch, Nora A1 - Kunde, Wilfried A1 - Pieczykolan, Aleks T1 - Free-choice saccades and their underlying determinants: explorations of high-level voluntary oculomotor control JF - Journal of Vision N2 - Models of eye-movement control distinguish between different control levels, ranging from automatic (bottom-up, stimulus-driven selection) and automatized (based on well-learned routines) to voluntary (top-down, goal-driven selection, e.g., based on instructions). However, one type of voluntary control has yet only been examined in the manual and not in the oculomotor domain, namely free-choice selection among arbitrary targets, that is, targets that are of equal interest from both a bottom-up and top-down processing perspective. Here, we ask which features of targets (identity- or location-related) are used to determine such oculomotor free-choice behavior. In two experiments, participants executed a saccade to one of four peripheral targets in three different choice conditions: unconstrained free choice, constrained free choice based on target identity (color), and constrained free choice based on target location. The analysis of choice frequencies revealed that unconstrained free-choice selection closely resembled constrained choice based on target location. The results suggest that free-choice oculomotor control is mainly guided by spatial (location-based) target characteristics. We explain these results by assuming that participants tend to avoid less parsimonious recoding of target-identity representations into spatial codes, the latter being a necessary prerequisite to configure oculomotor commands. KW - Adolescent KW - Stimulation KW - Adult KW - Eye Movements/physiology KW - Female KW - Humans KW - Learning/physiology KW - Male KW - Oculomotor Muscles/physiology KW - Photic KW - Choice Behavior/physiology KW - Psychomotor Performance/physiology KW - Saccades/physiology KW - Young Adult KW - eye movement KW - saccades KW - free choice KW - top-down processing KW - bottom-up processing KW - control levels Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201493 VL - 19 IS - 3 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 -