@article{DingemansMonsieursYuetal.2016, author = {Dingemans, Josef and Monsieurs, Pieter and Yu, Sung-Huan and Crabb{\´e}, Aur{\´e}lie and F{\"o}rstner, Konrad U. and Malfroot, Anne and Cornelis, Pierre and Van Houdt, Rob}, title = {Effect of Shear Stress on Pseudomonas aeruginosa Isolated from the Cystic Fibrosis Lung}, series = {mBio}, volume = {7}, journal = {mBio}, number = {4}, doi = {10.1128/mBio.00813-16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165821}, pages = {e00813-16}, year = {2016}, abstract = {Chronic colonization of the lungs by Pseudomonas aeruginosa is one of the major causes of morbidity and mortality in cystic fibrosis (CF) patients. To gain insights into the characteristic biofilm phenotype of P. aeruginosa in the CF lungs, mimicking the CF lung environment is critical. We previously showed that growth of the non-CF-adapted P. aeruginosa PAO1 strain in a rotating wall vessel, a device that simulates the low fluid shear (LS) conditions present in the CF lung, leads to the formation of in-suspension, self-aggregating biofilms. In the present study, we determined the phenotypic and transcriptomic changes associated with the growth of a highly adapted, transmissible P. aeruginosa CF strain in artificial sputum medium under LS conditions. Robust self-aggregating biofilms were observed only under LS conditions. Growth under LS conditions resulted in the upregulation of genes involved in stress response, alginate biosynthesis, denitrification, glycine betaine biosynthesis, glycerol metabolism, and cell shape maintenance, while genes involved in phenazine biosynthesis, type VI secretion, and multidrug efflux were downregulated. In addition, a number of small RNAs appeared to be involved in the response to shear stress. Finally, quorum sensing was found to be slightly but significantly affected by shear stress, resulting in higher production of autoinducer molecules during growth under high fluid shear (HS) conditions. In summary, our study revealed a way to modulate the behavior of a highly adapted P. aeruginosa CF strain by means of introducing shear stress, driving it from a biofilm lifestyle to a more planktonic lifestyle.}, language = {en} } @article{FecherHofmannBucketal.2016, author = {Fecher, David and Hofmann, Elisabeth and Buck, Andreas and Bundschuh, Ralph and Nietzer, Sarah and Dandekar, Gudrun and Walles, Thorsten and Walles, Heike and L{\"u}ckerath, Katharina and Steinke, Maria}, title = {Human Organotypic Lung Tumor Models: Suitable For Preclinical \(^{18}\)F-FDG PET-Imaging}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0160282}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179678}, year = {2016}, abstract = {Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and -testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[\(^{18}\)F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future.}, language = {en} } @article{FeldbauerSchlegelWeissbeckeretal.2016, author = {Feldbauer, Katrin and Schlegel, Jan and Weissbecker, Juliane and Sauer, Frank and Wood, Phillip G. and Bamberg, Ernst and Terpitz, Ulrich}, title = {Optochemokine Tandem for Light-Control of Intracellular Ca\(^{2+}\)}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {10}, doi = {10.1371/journal.pone.0165344}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178921}, year = {2016}, abstract = {An optochemokine tandem was developed to control the release of calcium from endosomes into the cytosol by light and to analyze the internalization kinetics of G-protein coupled receptors (GPCRs) by electrophysiology. A previously constructed rhodopsin tandem was re-engineered to combine the light-gated Ca\(^{2+}\)-permeable cation channel Channelrhodopsin-2(L132C), CatCh, with the chemokine receptor CXCR4 in a functional tandem protein tCXCR4/CatCh. The GPCR was used as a shuttle protein to displace CatCh from the plasma membrane into intracellular areas. As shown by patch-clamp measurements and confocal laser scanning microscopy, heterologously expressed tCXCR4/CatCh was internalized via the endocytic SDF1/CXCR4 signaling pathway. The kinetics of internalization could be followed electrophysiologically via the amplitude of the CatCh signal. The light-induced release of Ca\(^{2+}\) by tandem endosomes into the cytosol via CatCh was visualized using the Ca\(^{2+}\)-sensitive dyes rhod2 and rhod2-AM showing an increase of intracellular Ca\(^{2+}\) in response to light.}, language = {en} } @article{KirschmerBandleonvonEhrlichTreuenstaettetal.2016, author = {Kirschmer, Nadine and Bandleon, Sandra and von Ehrlich-Treuenst{\"a}tt, Viktor and Hartmann, Sonja and Schaaf, Alice and Lamprecht, Anna-Karina and Miranda-Laferte, Erick and Langsenlehner, Tanja and Ritter, Oliver and Eder, Petra}, title = {TRPC4α and TRPC4β Similarly Affect Neonatal Cardiomyocyte Survival during Chronic GPCR Stimulation}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0168446}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178539}, year = {2016}, abstract = {The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca\(^{2+}\) component in cardiomyocytes promoting structural and functional remodeling in the course of pathological cardiac hypertrophy. TRPC4 assembles as homo or hetero-tetramer in the plasma membrane, allowing a non-selective Na\(^{+}\) and Ca\(^{2+}\) influx. Gαq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca\(^{2+}\) influx which has been regarded as ideal Ca\(^{2+}\) source for calcineurin and subsequent nuclear factor of activated T-cells (NFAT) activation. Functional properties of TRPC4 are also based on the expression of the TRPC4 splice variants TRPC4α and TRPC4β. Aim of the present study was to analyze cytosolic Ca\(^{2+}\) signals, signaling, hypertrophy and vitality of cardiomyocytes in dependence on the expression level of either TRPC4α or TRPC4β. The analysis of Ca\(^{2+}\) transients in neonatal rat cardiomyocytes (NRCs) showed that TRPC4α and TRPC4β affected Ca\(^{2+}\) cycling in beating cardiomyocytes with both splice variants inducing an elevation of the Ca\(^{2+}\) transient amplitude at baseline and TRPC4β increasing the Ca\(^{2+}\) peak during angiotensin II (Ang II) stimulation. NRCs infected with TRPC4β (Ad-C4β) also responded with a sustained Ca\(^{2+}\) influx when treated with Ang II under non-pacing conditions. Consistent with the Ca\(^{2+}\) data, NRCs infected with TRPC4α (Ad-C4α) showed an elevated calcineurin/NFAT activity and a baseline hypertrophic phenotype but did not further develop hypertrophy during chronic Ang II/phenylephrine stimulation. Down-regulation of endogenous TRPC4α reversed these effects, resulting in less hypertrophy of NRCs at baseline but a markedly increased hypertrophic enlargement after chronic agonist stimulation. Ad-C4β NRCs did not exhibit baseline calcineurin/NFAT activity or hypertrophy but responded with an increased calcineurin/NFAT activity after GPCR stimulation. However, this effect was not translated into an increased propensity towards hypertrophy but rather less hypertrophy during GPCR stimulation. Further analyses revealed that, although hypertrophy was preserved in Ad-C4α NRCs and even attenuated in Ad-C4β NRCs, cardiomyocytes had an increased apoptosis rate and thus were less viable after chronic GPCR stimulation. These findings suggest that TRPC4α and TRPC4β differentially affect Ca\(^{2+}\) signals, calcineurin/NFAT signaling and hypertrophy but similarly impair cardiomyocyte viability during GPCR stimulation.}, language = {en} } @article{DiessnerWischnewskyBlettneretal.2016, author = {Diessner, Joachim and Wischnewsky, Manfred and Blettner, Maria and H{\"a}usler, Sebastian and Janni, Wolfgang and Kreienberg, Rolf and Stein, Roland and St{\"u}ber, Tanja and Schwentner, Lukas and Bartmann, Catharina and W{\"o}ckel, Achim}, title = {Do Patients with Luminal A Breast Cancer Profit from Adjuvant Systemic Therapy? A Retrospective Multicenter Study}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0168730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178217}, year = {2016}, abstract = {Background Luminal A breast cancers respond well to anti-hormonal therapy (HT), are associated with a generally favorable prognosis and constitute the majority of breast cancer subtypes. HT is the mainstay of treatment of these patients, accompanied by an acceptable profile of side effects, whereas the added benefit of chemotherapy (CHT), including anthracycline and taxane-based programs, is less clear-cut and has undergone a process of critical revision. Methods In the framework of the BRENDA collective, we analyzed the benefits of CHT compared to HT in 4570 luminal A patients (pts) with primary diagnosis between 2001 and 2008. The results were adjusted by nodal status, age, tumor size and grading. Results There has been a progressive reduction in the use of CHT in luminal A patients during the last decade. Neither univariate nor multivariate analyses showed any statistically significant differences in relapse free survival (RFS) with the addition of CHT to adjuvant HT, independent of the nodal status, age, tumor size or grading. Even for patients with more than 3 affected lymph nodes, there was no significant difference (univariate: p = 0.865; HR 0.94; 95\% CI: 0.46-1.93; multivariate: p = 0.812; HR 0.92; 95\% CI: 0.45-1.88). Conclusions The addition of CHT to HT provides minimal or no clinical benefit at all to patients with luminal A breast cancer, independent of the RFS-risk. Consequently, risk estimation cannot be the initial step in the decisional process. These findings-that are in line with several publications-should encourage the critical evaluation of applying adjuvant CHT to patients with luminal A breast cancer.}, language = {en} } @article{ChenReiherHermannLuibletal.2016, author = {Chen, Jiangtian and Reiher, Wencke and Hermann-Luibl, Christiane and Sellami, Azza and Cognigni, Paola and Kondo, Shu and Helfrich-F{\"o}rster, Charlotte and Veenstra, Jan A. and Wegener, Christian}, title = {Allatostatin A Signalling in Drosophila Regulates Feeding and Sleep and Is Modulated by PDF}, series = {PLoS Genetics}, volume = {12}, journal = {PLoS Genetics}, number = {9}, doi = {10.1371/journal.pgen.1006346}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178170}, year = {2016}, abstract = {Feeding and sleep are fundamental behaviours with significant interconnections and cross-modulations. The circadian system and peptidergic signals are important components of this modulation, but still little is known about the mechanisms and networks by which they interact to regulate feeding and sleep. We show that specific thermogenetic activation of peptidergic Allatostatin A (AstA)-expressing PLP neurons and enteroendocrine cells reduces feeding and promotes sleep in the fruit fly Drosophila. The effects of AstA cell activation are mediated by AstA peptides with receptors homolog to galanin receptors subserving similar and apparently conserved functions in vertebrates. We further identify the PLP neurons as a downstream target of the neuropeptide pigment-dispersing factor (PDF), an output factor of the circadian clock. PLP neurons are contacted by PDF-expressing clock neurons, and express a functional PDF receptor demonstrated by cAMP imaging. Silencing of AstA signalling and continuous input to AstA cells by tethered PDF changes the sleep/activity ratio in opposite directions but does not affect rhythmicity. Taken together, our results suggest that pleiotropic AstA signalling by a distinct neuronal and enteroendocrine AstA cell subset adapts the fly to a digestive energy-saving state which can be modulated by PDF.}, language = {en} } @article{SenthilanHelfrichFoerster2016, author = {Senthilan, Pingkalai R. and Helfrich-F{\"o}rster, Charlotte}, title = {Rhodopsin 7-The unusual Rhodopsin in Drosophila}, series = {PeerJ}, volume = {4}, journal = {PeerJ}, doi = {10.7717/peerj.2427}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177998}, year = {2016}, abstract = {Rhodopsins are the major photopigments in the fruit fly Drosophila melanogaster. Drosophila express six well-characterized Rhodopsins (Rh1-Rh6) with distinct absorption maxima and expression pattern. In 2000, when the Drosophila genome was published, a novel Rhodopsin gene was discovered: Rhodopsin 7 (Rh7). Rh7 is highly conserved among the Drosophila genus and is also found in other arthropods. Phylogenetic trees based on protein sequences suggest that the seven Drosophila Rhodopsins cluster in three different groups. While Rh1, Rh2 and Rh6 form a "vertebrate-melanopsin-type"-cluster, and Rh3, Rh4 and Rh5 form an "insect-type"-Rhodopsin cluster, Rh7 seem to form its own cluster. Although Rh7 has nearly all important features of a functional Rhodopsin, it differs from other Rhodopsins in its genomic and structural properties, suggesting it might have an overall different role than other known Rhodopsins.}, language = {en} } @article{BoschertFrischBacketal.2016, author = {Boschert, V. and Frisch, C. and Back, J. W. and van Pee,, K. and Weidauer, S. E. and Muth, E.-M. and Schmieder, P. and Beerbaum, M. and Knappik, A. and Timmerman, P. and Mueller, T. D.}, title = {The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6}, series = {Open Biology}, volume = {6}, journal = {Open Biology}, doi = {10.1098/rsob.160120}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177925}, year = {2016}, abstract = {The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up. Biochemical analyses have identified one Fab developed against murine sclerostin, AbD09097 that efficiently neutralizes sclerostin's Wnt inhibitory activity. In vitro interaction analysis using sclerostin variants revealed that this neutralizing Fab binds to sclerostin's flexible second loop, which has been shown to harbour the LRP5/6 binding motif. Affinity maturation was then applied to AbD09097, providing a set of improved neutralizing Fab antibodies which particularly bind human sclerostin with enhanced affinity. Determining the crystal structure of AbD09097 provides first insights into how this antibody might recognize and neutralize sclerostin. Together with the structure-function relationship derived from affinity maturation these new data will foster the rational design of new and highly efficient anti-sclerostin antibodies for the therapy of bone loss diseases such as osteoporosis.}, language = {en} } @article{HesbacherPfitzerWiedorferetal.2016, author = {Hesbacher, Sonja and Pfitzer, Lisa and Wiedorfer, Katharina and Angermeyer, Sabrina and Borst, Andreas and Haferkamp, Sebastian and Scholz, Claus-J{\"u}rgen and Wobser, Marion and Schrama, David and Houben, Roland}, title = {RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {22}, doi = {10.18632/oncotarget.8793}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177858}, pages = {32956-32968}, year = {2016}, abstract = {The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells.}, language = {en} } @article{KepplerWeissbachLangeretal.2016, author = {Keppler, Sarah and Weißbach, Susann and Langer, Christian and Knop, Stefan and Pischimarov, Jordan and Kull, Miriam and St{\"u}hmer, Thorsten and Steinbrunn, Torsten and Bargou, Ralf and Einsele, Hermann and Rosenwald, Andreas and Leich, Ellen}, title = {Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {25}, doi = {10.18632/oncotarget.9607}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177840}, pages = {38762-38774}, year = {2016}, abstract = {Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom". Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significantly lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors.}, language = {en} } @article{DjuzenovaFiedlerKatzeretal.2016, author = {Djuzenova, Cholpon S. and Fiedler, Vanessa and Katzer, Astrid and Michel, Konstanze and Deckert, Stefanie and Zimmermann, Heiko and Sukhorukov, Vladimir L. and Flentje, Michael}, title = {Dual PI3K-and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {25}, doi = {10.18632/oncotarget.9501}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177770}, pages = {38191-38209}, year = {2016}, abstract = {Inhibition of Hsp90 can increase the radiosensitivity of tumor cells. However, inhibition of Hsp90 alone induces the anti-apoptotic Hsp70 and thereby decreases radiosensitivity. Therefore, preventing Hsp70 induction can be a promising strategy for radiosensitization. PI-103, an inhibitor of PI3K and mTOR, has previously been shown to suppress the up-regulation of Hsp70. Here, we explore the impact of combining PI-103 with the Hsp90 inhibitor NVP-AUY922 in irradiated glioblastoma and colon carcinoma cells. We analyzed the cellular response to drug-irradiation treatments by colony-forming assay, expression of several marker proteins, cell cycle progression and induction/repair of DNA damage. Although PI-103, given 24 h prior to irradiation, slightly suppressed the NVP-AUY922-mediated up-regulation of Hsp70, it did not cause radiosensitization and even diminished the radiosensitizing effect of NVP-AUY922. This result can be explained by the activation of PI3K and ERK pathways along with G1-arrest at the time of irradiation. In sharp contrast, PI-103 not only exerted a radiosensitizing effect but also strongly enhanced the radiosensitization by NVP-AUY922 when both inhibitors were added 3 h before irradiation and kept in culture for 24 h. Possible reasons for the observed radiosensitization under this drug-irradiation schedule may be a down-regulation of PI3K and ERK pathways during or directly after irradiation, increased residual DNA damage and strong G2/M arrest 24 h thereafter. We conclude that duration of drug treatment before irradiation plays a key role in the concomitant targeting of PI3K/mTOR and Hsp90 in tumor cells.}, language = {en} } @article{WernerBeykanHiguchietal.2016, author = {Werner, Rudolf A. and Beykan, Seval and Higuchi, Takahiro and L{\"u}ckerath, Katharina and Weich, Alexander and Scheurlen, Michael and Bluemel, Christina and Herrmann, Ken and Buck, Andreas K. and Lassmann, Michael and Lapa, Constantin and H{\"a}nscheid, Heribert}, title = {The impact of \(^{177}\)Lu-octreotide therapy on \(^{99m}\)Tc-MAG3 clearance is not predictive for late nephropathy}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {27}, doi = {10.18632/oncotarget.9775}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177318}, pages = {41233-41241}, year = {2016}, abstract = {Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3\%, range: -27\% to +19\%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3­clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.}, language = {en} } @article{EndresKneitzOrthetal.2016, author = {Endres, Marcel and Kneitz, Susanne and Orth, Martin F. and Perera, Ruwan K. and Zernecke, Alma and Butt, Elke}, title = {Regulation of matrix metalloproteinases (MMPs) expression and secretion in MDA-MB-231 breast cancer cells by LIM and SH3 protein 1 (LASP1)}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {39}, doi = {10.18632/oncotarget.11720}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176920}, pages = {64244-64259}, year = {2016}, abstract = {The process of tumor invasion requires degradation of extracellular matrix by proteolytic enzymes. Cancer cells form protrusive invadopodia, which produce and release matrix metalloproteinases (MMPs) to degrade the basement membrane thereby enabling metastasis. We investigated the effect of LASP1, a newly identified protein in invadopodia, on expression, secretion and activation of MMPs in invasive breast tumor cell lines. By analyzing microarray data of in-house generated control and LASP1-depleted MDA-MB-231 breast cancer cells, we observed downregulation of MMP1, -3 and -9 upon LASP1 depletion. This was confirmed by Western blot analysis. Conversely, rescue experiments restored in part MMP expression and secretion. The regulatory effect of LASP1 on MMP expression was also observed in BT-20 breast cancer cells as well as in prostate and bladder cancer cell lines. In line with bioinformatic FunRich analysis of our data, which mapped a high regulation of transcription factors by LASP1, public microarray data analysis detected a correlation between high LASP1 expression and enhanced c-Fos levels, a protein that is part of the transcription factor AP-1 and known to regulate MMP expression. Compatibly, in luciferase reporter assays, AP-1 showed a decreased transcriptional activity after LASP1 knockdown. Zymography assays and Western blot analysis revealed an additional promotion of MMP secretion into the extracellular matrix by LASP1, thus, most likely, altering the microenvironment during cancer progression. The newly identified role of LASP1 in regulating matrix degradation by affecting MMP transcription and secretion elucidated the migratory potential of LASP1 overexpressing aggressive tumor cells in earlier studies.}, language = {en} } @article{MoenchGrimmigKannenetal.2016, author = {Moench, Romana and Grimmig, Tanja and Kannen, Vinicius and Tripathi, Sudipta and Faber, Marc and Moll, Eva-Maria and Chandraker, Anil and Lissner, Reinhard and Germer, Christoph-Thomas and Waaga-Gasser, Ana Maria and Gasser, Martin}, title = {Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {42}, doi = {10.18632/oncotarget.11899}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176910}, pages = {68749-68767}, year = {2016}, abstract = {Platelet-derived growth factor (PDGF) and signaling via its receptors plays a crucial role in tumor cell proliferation and thus may represent an attractive target besides VEGF/EGFR-based antibody therapies. In this study we analyzed the influence of PDGF in colorectal cancer. PDGF was expressed intensively in early and even more intensively in late stage primary CRCs. Like VEGF, PDGF enhanced human colon cancer proliferation, and increased oxidative glycolytic activity, and activated HIF1α and c-Myc in vitro. PDGF activated the PI3K/Akt/mTOR pathway while leaving MAPK signaling untouched. Further dissection showed that inhibition of Akt strongly impeded cancer cell growth while inhibition of PI3K did not. MAPK analysis suggested an inhibitory crosstalk between both pathways, thus explaining the different effects of the Akt and PI3K inhibitors on cancer cell proliferation. PDGF stimulates colon cancer cell proliferation, and prevents inhibitor induced apoptosis, resulting in tumor growth. Therefore inhibition of PDGF signaling seems to be a promising target in colorectal cancer therapy. However, due to the multifaceted nature of the intracellular PDGF signaling, careful intervention strategies are needed when looking into specific signaling pathways like PI3K/Akt/mTOR and MAPK.}, language = {en} } @article{LapaReiterKircheretal.2016, author = {Lapa, Constantin and Reiter, Theresa and Kircher, Malte and Schirbel, Andreas and Werner, Rudolf A. and Pelzer, Theo and Pizarro, Carmen and Skowasch, Dirk and Thomas, Lena and Schlesinger-Irsch, Ulrike and Thomas, Daniel and Bundschuh, Ralph A. and Bauer, Wolfgang R. and Gartner, Florian C.}, title = {Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {47}, doi = {10.18632/oncotarget.12799}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175423}, pages = {77807-77814}, year = {2016}, abstract = {Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with \(^{18}\)F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR-PET/CT for detecting cardiac sarcoidosis in comparison to CMR. 15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUV\(_{mean}\)) and maximum standardized uptake values (SUV\(_{max}\)) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity. SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25\% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up. In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1\% (245/255 segments analyzed). SUV\(_{mean}\) and SUV\(_{max}\) in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUV\(_{mean}\) and 2.0±0.3 and 1.7±0.3 for SUV\(_{max}\), respectively. Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series.}, language = {en} } @article{StrittNurdenFavieretal.2016, author = {Stritt, Simon and Nurden, Paquita and Favier, Remi and Favier, Marie and Ferioli, Silvia and Gotru, Sanjeev K. and van Eeuwijk, Judith M.M. and Schulze, Harald and Nurden, Alan T. and Lambert, Michele P. and Turro, Ernest and Burger-Stritt, Stephanie and Matsushita, Masayuki and Mittermeier, Lorenz and Ballerini, Paola and Zierler, Susanna and Laffan, Michael A. and Chubanov, Vladimir and Gudermann, Thomas and Nieswandt, Bernhard and Braun, Attila}, title = {Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg\(^{2+}\) homeostasis and cytoskeletal architecture}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms11097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173843}, year = {2016}, abstract = {Mg\(^{2+}\) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg\(^{2+}\)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7\(^{fl/fl-Pf4Cre}\)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7\(^{fl/fl-Pf4Cre}\) MKs, which is rescued by Mg\(^{2+}\) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.}, language = {en} } @article{MaassBentmannSeibeletal.2016, author = {Maaß, Henriette and Bentmann, Hendrik and Seibel, Christoph and Tusche, Christian and Eremeev, Sergey V. and Peixoto, Thiago R.F. and Tereshchenko, Oleg E. and Kokh, Konstantin A. and Chulkov, Evgueni V. and Kirschner, J{\"u}rgen and Reinert, Friedrich}, title = {Spin-texture inversion in the giant Rashba semiconductor BiTeI}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms11621}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173769}, year = {2016}, abstract = {Semiconductors with strong spin-orbit interaction as the underlying mechanism for the generation of spin-polarized electrons are showing potential for applications in spintronic devices. Unveiling the full spin texture in momentum space for such materials and its relation to the microscopic structure of the electronic wave functions is experimentally challenging and yet essential for exploiting spin-orbit effects for spin manipulation. Here we employ a state-of-the-art photoelectron momentum microscope with a multichannel spin filter to directly image the spin texture of the layered polar semiconductor BiTeI within the full two-dimensional momentum plane. Our experimental results, supported by relativistic ab initio calculations, demonstrate that the valence and conduction band electrons in BiTeI have spin textures of opposite chirality and of pronounced orbital dependence beyond the standard Rashba model, the latter giving rise to strong optical selection-rule effects on the photoelectron spin polarization. These observations open avenues for spin-texture manipulation by atomic-layer and charge carrier control in polar semiconductors.}, language = {en} } @article{DugarSvenssonBischleretal.2016, author = {Dugar, Gaurav and Svensson, Sarah L. and Bischler, Thorsten and Waldchen, Sina and Reinhardt, Richard and Sauer, Markus and Sharma, Cynthia M.}, title = {The CsrA-FliW network controls polar localization of the dual-function flagellin mRNA in Campylobacter jejuni}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms11667}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173201}, year = {2016}, abstract = {The widespread CsrA/RsmA protein regulators repress translation by binding GGA motifs in bacterial mRNAs. CsrA activity is primarily controlled through sequestration by multiple small regulatory RNAs. Here we investigate CsrA activity control in the absence of antagonizing small RNAs by examining the CsrA regulon in the human pathogen Campylobacter jejuni. We use genome-wide co-immunoprecipitation combined with RNA sequencing to show that CsrA primarily binds flagellar mRNAs and identify the major flagellin mRNA (flaA) as the main CsrA target. The flaA mRNA is translationally repressed by CsrA, but it can also titrate CsrA activity. Together with the main C. jejuni CsrA antagonist, the FliW protein, flaA mRNA controls CsrA-mediated post-transcriptional regulation of other flagellar genes. RNA-FISH reveals that flaA mRNA is expressed and localized at the poles of elongating cells. Polar flaA mRNA localization is translation dependent and is post-transcriptionally regulated by the CsrA-FliW network. Overall, our results suggest a role for CsrA-FliW in spatiotemporal control of flagella assembly and localization of a dual-function mRNA.}, language = {en} } @article{AlrefaiMuhammadRudolfetal.2016, author = {Alrefai, Hani and Muhammad, Khalid and Rudolf, Ronald and Pham, Duong Anh Thuy and Klein-Hessling, Stefan and Patra, Amiya K. and Avots, Andris and Bukur, Valesca and Sahin,, Ugur and Tenzer, Stefan and Goebeler, Matthias and Kerstan, Andreas and Serfling, Edgar}, title = {NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms11724}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173053}, year = {2016}, abstract = {Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.}, language = {en} } @article{KleinHesslingRudolfMuhammadetal.2016, author = {Klein-Hessling, Stefan and Rudolf, Ronald and Muhammad, Khalid and Knobeloch, Klaus-Peter and Maqbool, Muhammad Ahmad and Cauchy, Pierre and Andrau, Jean-Christophe and Avots, Andris and Talora, Claudio and Ellenrieder, Volker and Screpanti, Isabella and Serfling, Edgar and Patra, Amiya Kumar}, title = {A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms11841}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172974}, year = {2016}, abstract = {NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.}, language = {en} } @article{BahnikStrack2016, author = {Bahn{\´i}k, Štěp{\´a}n and Strack, Fritz}, title = {Overlap of accessible information undermines the anchoring effect}, series = {Judgment and Decision Making}, volume = {11}, journal = {Judgment and Decision Making}, number = {1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169287}, pages = {92-98}, year = {2016}, abstract = {According to the Selective Accessibility Model of anchoring, the comparison question in the standard anchoring paradigm activates information that is congruent with an anchor. As a consequence, this information will be more likely to become the basis for the absolute judgment which will therefore be assimilated toward the anchor. However, if the activated information overlaps with information that is elicited by the absolute judgment itself, the preceding comparative judgment should not exert an incremental effect and should fail to result in an anchoring effect. The present studies find this result when the comparative judgment refers to a general category and the absolute judgment refers to a subset of the general category that was activated by the anchor value. For example, participants comparing the average annual temperature in New York City to a high 102 °F judged the average winter, but not summer temperature to be higher than participants making no comparison. On the other hand, participants comparing the annual temperature to a low -4 °F judged the average summer, but not winter temperature to be lower than control participants. This pattern of results was shown also in another content domain. It is consistent with the Selective Accessibility Model but difficult to reconcile with other main explanations of the anchoring effect.}, language = {en} } @article{VermaSteinbacherSchmiedeletal.2016, author = {Verma, Pramod Kumar and Steinbacher, Andreas and Schmiedel, Alexander and Nuernberger, Patrick and Brixner, Tobias}, title = {Excited-state intramolecular proton transfer of 2-acetylindan-1,3-dione studied by ultrafast absorption and fluorescence spectroscopy}, series = {Structural Dynamics}, volume = {3}, journal = {Structural Dynamics}, doi = {10.1063/1.4937363}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181301}, year = {2016}, abstract = {We employ transient absorption from the deep-UV to the visible region and fluorescence upconversion to investigate the photoinduced excited-state intramolecular proton-transfer dynamics in a biologically relevant drug molecule, 2-acetylindan-1,3-dione. The molecule is a ß-diketone which in the electronic ground state exists as exocyclic enol with an intramolecular H-bond. Upon electronic excitation at 300 nm, the first excited state of the exocyclic enol is initially populated, followed by ultrafast proton transfer (≈160 fs) to form the vibrationally hot endocyclic enol. Subsequently, solvent-induced vibrational relaxation takes place (≈10 ps) followed by decay (≈390 ps) to the corresponding ground state.}, language = {en} } @article{SchendzielorzFroelichRaketal.2016, author = {Schendzielorz, P. and Froelich, K. and Rak, K. and Gehrke, T. and Scherzad, A. and Hagen, R. and Radeloff, A.}, title = {Labeling Adipose-Derived Stem Cells with Hoechst 33342: Usability and Effects on Differentiation Potential and DNA Damage}, series = {Stem Cells International}, journal = {Stem Cells International}, doi = {10.1155/2016/6549347}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181268}, year = {2016}, abstract = {Adipose-derived stem cells (ASCs) have been extensively studied in the field of stem cell research and possess numerous clinical applications. Cell labeling is an essential component of various experimental protocols and Hoechst 33342 (H33342) represents a cost-effective and easy methodology for live staining. The purpose of this study was to evaluate the labeling of rat ASCs with two different concentrations of H33342 (0.5 μg/mL and 5 μg/mL), with particular regard to usability, interference with cell properties, and potential DNA damage. Hoechst 33342 used at a low concentration of 0.5 μg/mL did not significantly affect cell proliferation, viability, or differentiation potential of the ASCs, nor did it cause any significant DNA damage as measured by the olive tail moment. High concentrations of 5 μg/mL H33342, however, impaired the proliferation and viability of the ASCs, and considerable DNA damage was observed. Undesirable colabeling of unlabeled cocultivated cells was seen in particular with higher concentrations of H33342, independent of varying washing procedures. Hence, H33342 labeling with lower concentrations represents a usable method, which does not affect the tested cell properties. However, the colabeling of adjacent cells is a drawback of the technique.}, language = {en} } @article{SelleHertleinOesterreichetal.2016, author = {Selle, Martina and Hertlein, Tobias and Oesterreich, Babett and Klemm, Theresa and Kloppot, Peggy and M{\"u}ller, Elke and Ehricht, Ralf and Stentzel, Sebastian and Br{\"o}ker, Barbara M. and Engelmann, Susanne and Ohlsen, Knut}, title = {Global antibody response to Staphylococcus aureus live-cell vaccination}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep24754}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181245}, year = {2016}, abstract = {The pathogen Staphylococcus aureus causes a broad range of severe diseases and is feared for its ability to rapidly develop resistance to antibiotic substances. The increasing number of highly resistant S. aureus infections has accelerated the search for alternative treatment options to close the widening gap in anti-S. aureus therapy. This study analyses the humoral immune response to vaccination of Balb/c mice with sublethal doses of live S. aureus. The elicited antibody pattern in the sera of intravenously and intramuscularly vaccinated mice was determined using of a recently developed protein array. We observed a specific antibody response against a broad set of S. aureus antigens which was stronger following i.v. than i.m. vaccination. Intravenous but not intramuscular vaccination protected mice against an intramuscular challenge infection with a high bacterial dose. Vaccine protection was correlated with the strength of the anti-S. aureus antibody response. This study identified novel vaccine candidates by using protein microarrays as an effective tool and showed that successful vaccination against S. aureus relies on the optimal route of administration.}, language = {en} } @article{CzakaiLeonhardtDixetal.2016, author = {Czakai, Kristin and Leonhardt, Ines and Dix, Andreas and Bonin, Michael and Linde, Joerg and Einsele, Hermann and Kurzai, Oliver and Loeffler, J{\"u}rgen}, title = {Kr{\"u}ppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep27990}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181185}, year = {2016}, abstract = {Invasive fungal infections are associated with high mortality rates and are mostly caused by the opportunistic fungi Aspergillus fumigatus and Candida albicans. Immune responses against these fungi are still not fully understood. Dendritic cells (DCs) are crucial players in initiating innate and adaptive immune responses against fungal infections. The immunomodulatory effects of fungi were compared to the bacterial stimulus LPS to determine key players in the immune response to fungal infections. A genome wide study of the gene regulation of human monocyte-derived dendritic cells (DCs) confronted with A. fumigatus, C. albicans or LPS was performed and Kr{\"u}ppel-like factor 4 (KLF4) was identified as the only transcription factor that was down-regulated in DCs by both fungi but induced by stimulation with LPS. Downstream analysis demonstrated the influence of KLF4 on the interleukine-6 expression in human DCs. Furthermore, KLF4 regulation was shown to be dependent on pattern recognition receptor ligation. Therefore KLF4 was identified as a controlling element in the IL-6 immune response with a unique expression pattern comparing fungal and LPS stimulation.}, language = {en} } @article{EneLohseVladuetal.2016, author = {Ene, Iuliana V. and Lohse, Matthew B. and Vladu, Adrian V. and Morschh{\"a}user, Joachim and Johnson, Alexander D. and Bennett, Richard J.}, title = {Phenotypic Profiling Reveals that Candida albicans Opaque Cells Represent a Metabolically Specialized Cell State Compared to Default White Cells}, series = {mBio}, volume = {7}, journal = {mBio}, number = {6}, doi = {10.1128/mBio.01269-16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165818}, pages = {e01269-16}, year = {2016}, abstract = {The white-opaque switch is a bistable, epigenetic transition affecting multiple traits in Candida albicans including mating, immunogenicity, and niche specificity. To compare how the two cell states respond to external cues, we examined the fitness, phenotypic switching, and filamentation properties of white cells and opaque cells under 1,440 different conditions at 25°C and 37°C. We demonstrate that white and opaque cells display striking differences in their integration of metabolic and thermal cues, so that the two states exhibit optimal fitness under distinct conditions. White cells were fitter than opaque cells under a wide range of environmental conditions, including growth at various pHs and in the presence of chemical stresses or antifungal drugs. This difference was exacerbated at 37°C, consistent with white cells being the default state of C. albicans in the mammalian host. In contrast, opaque cells showed greater fitness than white cells under select nutritional conditions, including growth on diverse peptides at 25°C. We further demonstrate that filamentation is significantly rewired between the two states, with white and opaque cells undergoing filamentous growth in response to distinct external cues. Genetic analysis was used to identify signaling pathways impacting the white-opaque transition both in vitro and in a murine model of commensal colonization, and three sugar sensing pathways are revealed as regulators of the switch. Together, these findings establish that white and opaque cells are programmed for differential integration of metabolic and thermal cues and that opaque cells represent a more metabolically specialized cell state than the default white state.}, language = {en} } @article{ChenariSeibelHauschildetal.2016, author = {Chenari, Hossein Mahmoudi and Seibel, Christoph and Hauschild, Dirk and Reinert, Friedrich and Abdollahian, Hossein}, title = {Titanium Dioxide Nanoparticles: Synthesis, X-Ray Line Analysis and Chemical Composition Study}, series = {Materials Research}, volume = {19}, journal = {Materials Research}, number = {6}, doi = {10.1590/1980-5373-MR-2016-0288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165807}, pages = {1319-1323}, year = {2016}, abstract = {TiO2 nanoparticleshave been synthesized by the sol-gel method using titanium alkoxide and isopropanolas a precursor. The structural properties and chemical composition of the TiO2 nanoparticles were studied usingX-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy.The X-ray powder diffraction pattern confirms that the particles are mainly composed of the anatase phase with the preferential orientation along [101] direction. The physical parameters such as strain, stress and energy density were investigated from the Williamson- Hall (W-H) plot assuming a uniform deformation model (UDM), and uniform deformation energy density model (UDEDM). The W-H analysis shows an anisotropic nature of the strain in nanopowders. The scanning electron microscopy image shows clear TiO2 nanoparticles with particle sizes varying from 60 to 80nm. The results of mean particle size of TiO2 nanoparticles show an inter correlation with the W-H analysis and SEM results. Our X-ray photoelectron spectroscopy spectra show that nearly a complete amount of titanium has reacted to TiO2}, language = {en} } @article{SegererHadamekZundleretal.2016, author = {Segerer, Gabriela and Hadamek, Kerstin and Zundler, Matthias and Fekete, Agnes and Seifried, Annegrit and Mueller, Martin J. and Koentgen, Frank and Gessler, Manfred and Jeanclos, Elisabeth and Gohla, Antje}, title = {An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep35160}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181094}, year = {2016}, abstract = {Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp\(^{D34N}\) mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation.}, language = {en} } @article{CicovaDejungSkalickyetal.2016, author = {Cicova, Zdenka and Dejung, Mario and Skalicky, Tomas and Eisenhuth, Nicole and Hanselmann, Steffen and Morriswood, Brooke and Figueiredo, Luisa M. and Butter, Falk and Janzen, Christian J.}, title = {Two flagellar BAR domain proteins in Trypanosoma brucei with stage-specific regulation}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep35826}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181021}, year = {2016}, abstract = {Trypanosomes are masters of adaptation to different host environments during their complex life cycle. Large-scale proteomic approaches provide information on changes at the cellular level, and in a systematic way. However, detailed work on single components is necessary to understand the adaptation mechanisms on a molecular level. Here, we have performed a detailed characterization of a bloodstream form (BSF) stage-specific putative flagellar host adaptation factor Tb927.11.2400, identified previously in a SILAC-based comparative proteome study. Tb927.11.2400 shares 38\% amino acid identity with TbFlabarin (Tb927.11.2410), a procyclic form (PCF) stage-specific flagellar BAR domain protein. We named Tb927.11.2400 TbFlabarin-like (TbFlabarinL), and demonstrate that it originates from a gene duplication event, which occurred in the African trypanosomes. TbFlabarinL is not essential for the growth of the parasites under cell culture conditions and it is dispensable for developmental differentiation from BSF to the PCF in vitro. We generated TbFlabarinL-specific antibodies, and showed that it localizes in the flagellum. Co-immunoprecipitation experiments together with a biochemical cell fractionation suggest a dual association of TbFlabarinL with the flagellar membrane and the components of the paraflagellar rod.}, language = {en} } @article{KnauerGessnerFensholtetal.2016, author = {Knauer, Kim and Gessner, Ursula and Fensholt, Rasmus and Kuenzer, Claudia}, title = {An ESTARFM Fusion Framework for the Generation of Large-Scale Time Series in Cloud-Prone and Heterogeneous Landscapes}, series = {Remote Sensing}, volume = {8}, journal = {Remote Sensing}, number = {5}, doi = {10.3390/rs8050425}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180712}, pages = {425}, year = {2016}, abstract = {Monitoring the spatio-temporal development of vegetation is a challenging task in heterogeneous and cloud-prone landscapes. No single satellite sensor has thus far been able to provide consistent time series of high temporal and spatial resolution for such areas. In order to overcome this problem, data fusion algorithms such as the Enhanced Spatial and Temporal Adaptive Reflectance Fusion Model (ESTARFM) have been established and frequently used in recent years to generate high-resolution time series. In order to make it applicable to larger scales and to increase the input data availability especially in cloud-prone areas, an ESTARFM framework was developed in this study introducing several enhancements. An automatic filling of cloud gaps was included in the framework to make best use of available, even partly cloud-covered Landsat images. Furthermore, the ESTARFM algorithm was enhanced to automatically account for regional differences in the heterogeneity of the study area. The generation of time series was automated and the processing speed was accelerated significantly by parallelization. To test the performance of the developed ESTARFM framework, MODIS and Landsat-8 data were fused for generating an 8-day NDVI time series for a study area of approximately 98,000 km\(^{2}\) in West Africa. The results show that the ESTARFM framework can accurately produce high temporal resolution time series (average MAE (mean absolute error) of 0.02 for the dry season and 0.05 for the vegetative season) while keeping the spatial detail in such a heterogeneous, cloud-prone region. The developments introduced within the ESTARFM framework establish the basis for large-scale research on various geoscientific questions related to land degradation, changes in land surface phenology or agriculture}, language = {en} } @article{MuellerMeigen2016, author = {M{\"u}ller, Philipp L. and Meigen, Thomas}, title = {M-sequences in ophthalmic electrophysiology}, series = {Journal of Vision}, volume = {16}, journal = {Journal of Vision}, number = {1,15}, doi = {10.1167/16.1.15}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165796}, pages = {1-19}, year = {2016}, abstract = {The aim of this review is to use the multimedia aspects of a purely digital online publication to explain and illustrate the highly capable technique of m-sequences in multifocal ophthalmic electrophysiology. M-sequences have been successfully applied in clinical routines during the past 20 years. However, the underlying mathematical rationale is often daunting. These mathematical properties of m-sequences allow one not only to separate the responses from different fields but also to analyze adaptational effects and impacts of former events. By explaining the history, the formation, and the different aspects of application, a better comprehension of the technique is intended. With this review we aim to clarify the opportunities of m-sequences in order to motivate scientists to use m-sequences in their future research.}, language = {en} } @article{KleistMohrGaikwadetal.2016, author = {Kleist, Christian and Mohr, Elisabeth and Gaikwad, Sadanand and Dittmar, Laura and Kuerten, Stefanie and Platten, Michael and Mier, Walter and Schmitt, Michael and Opelz, Gerhard and Terness, Peter}, title = {Autoantigen-specific immunosuppression with tolerogenic peripheral blood cells prevents relapses in a mouse model of relapsing-remitting multiple sclerosis}, series = {Journal of Translational Medicine}, volume = {14}, journal = {Journal of Translational Medicine}, number = {99}, doi = {10.1186/s12967-016-0860-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165787}, pages = {1-14}, year = {2016}, abstract = {Background: Dendritic cells (DCs) rendered suppressive by treatment with mitomycin C and loaded with the autoantigen myelin basic protein demonstrated earlier their ability to prevent experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). This provides an approach for prophylactic vaccination against autoimmune diseases. For clinical application such DCs are difficult to generate and autoantigens hold the risk of exacerbating the disease. Methods: We replaced DCs by peripheral mononuclear cells and myelin autoantigens by glatiramer acetate (Copaxone ®), a drug approved for the treatment of MS. Spleen cells were loaded with Copaxone®, incubated with mitomycin C (MICCop) and injected into mice after the first bout of relapsing-remitting EAE. Immunosuppression mediated by MICCop was investigated in vivo by daily assessment of clinical signs of paralysis and in in vitro restimulation assays of peripheral immune cells. Cytokine profiling was performed by enzyme-linked immunosorbent assay (ELISA). Migration of MICCop cells after injection was examined by biodistribution analysis of 111Indium-labelled MICCop. The number and inhibitory activity of CD4+CD25+FoxP3+ regulatory T cells were analysed by histology, flow cytometry and in vitro mixed lymphocyte cultures. In order to assess the specificity of MICCop-induced suppression, treated EAE mice were challenged with the control protein ovalbumin. Humoral and cellular immune responses were then determined by ELISA and in vitro antigen restimulation assay. Results: MICCop cells were able to inhibit the harmful autoreactive T-cell response and prevented mice from further relapses without affecting general immune responses. Administered MICCop migrated to various organs leading to an increased infiltration of the spleen and the central nervous system with CD4+CD25+FoxP3+ cells displaying a suppressive cytokine profile and inhibiting T-cell responses. Conclusion: We describe a clinically applicable cell therapeutic approach for controlling relapses in autoimmune encephalomyelitis by specifically silencing the deleterious autoimmune response.}, language = {en} } @article{CanesiGiordanoLazzarietal.2016, author = {Canesi, Margherita and Giordano, Rosaria and Lazzari, Lorenza and Isalberti, Maurizio and Isaias, Ioannis Ugo and Benti, Riccardo and Rampini, Paolo and Marotta, Giorgio and Colombo, Aurora and Cereda, Emanuele and Dipaola, Mariangela and Montemurro, Tiziana and Vigano, Mariele and Budelli, Silvia and Montelatici, Elisa and Lavazza, Cristiana and Cortelezzi, Agostino and Pezzoli, Gianni}, title = {Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy}, series = {Journal of Translational Medicine}, volume = {14}, journal = {Journal of Translational Medicine}, number = {127}, doi = {10.1186/s12967-016-0880-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165725}, pages = {1-11}, year = {2016}, abstract = {Background: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. Methods: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. Results: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. Conclusions: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach.}, language = {en} } @article{SpenstYoungWasielewskietal.2016, author = {Spenst, Peter and Young, Ryan M. and Wasielewski, Michael R. and W{\"u}rthner, Frank}, title = {Guest and solvent modulated photo-driven charge separation and triplet generation in a perylene bisimide cyclophane}, series = {Chemical Science}, volume = {7}, journal = {Chemical Science}, number = {8}, doi = {10.1039/c6sc01574c}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191252}, pages = {5428-5434}, year = {2016}, abstract = {Cofacial positioning of two perylene bisimide (PBI) chromophores at a distance of 6.5 angstrom in a cyclophane structure prohibits the otherwise common excimer formation and directs photoexcited singlet state relaxation towards intramolecular symmetry-breaking charge separation (τ\(_{CS}\) = 161 +/- 4 ps) in polar CH\(_2\)Cl\(_2\), which is thermodynamically favored with a Gibbs free energy of ΔG\(_{CS}\) = -0.32 eV. The charges then recombine slowly in τ\(_{CR}\) = 8.90 +/- 0.06 ns to form the PBI triplet excited state, which can be used subsequently to generate singlet oxygen in 27\% quantum yield. This sequence of events is eliminated by dissolving the PBI cyclophane in non-polar toluene, where only excited singlet state decay occurs. In contrast, complexation of electron-rich aromatic hydrocarbons by the host PBI cyclophane followed by photoexcitation of PBI results in ultrafast electron transfer (<10 ps) from the guest to the PBI in CH\(_2\)Cl\(_2\). The rate constants for charge separation and recombination increase as the guest molecules become easier to oxidize, demonstrating that charge separation occurs close to the peak of the Marcus curve and the recombination lies far into the Marcus inverted region.}, language = {en} } @article{WalterCollenburgJaptoketal.2016, author = {Walter, T. and Collenburg, L. and Japtok, L. and Kleuser, B. and Schneider-Schaulies, S. and M{\"u}ller, N. and Becam, J. and Schubert-Unkmeir, A. and Kong, J. N. and Bieberich, E. and Seibel, J.}, title = {Incorporation and visualization of azido-functionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells}, series = {Chemical Communications}, volume = {52}, journal = {Chemical Communications}, number = {55}, doi = {10.1039/c6cc02879a}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191263}, pages = {8612-8614}, year = {2016}, abstract = {The synthesis and biological evaluation of azido-N-oleoyl serinol is reported. It mimicks biofunctional lipid ceramides and has shown to be capable of click reactions for cell membrane imaging in Jurkat and human brain microvascular endothelial cells.}, language = {en} } @article{FleglerSchneiderPrieschletal.2016, author = {Flegler, Andreas and Schneider, Michael and Prieschl, Johannes and Stevens, Ralph and Vinnay, Thomas and Mandel, Karl}, title = {Continuous flow synthesis and cleaning of nano layered double hydroxides and the potential of the route to adjust round or platelet nanoparticle morphology}, series = {RSC Advances}, volume = {6}, journal = {RSC Advances}, number = {62}, doi = {10.1039/c6ra09553d}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191305}, pages = {57236-57244}, year = {2016}, abstract = {Here, we report a continuous flow synthesis of nano LDH, comprising a continuous precipitation process using static mixers and followed by an immediate cleaning process via a semi-continuous centrifuge to obtain the final product in one-go. Via this synthesis setup, it is possible to independently vary the concentrations of the reactants during precipitation and at the same time ensure constant reaction conditions and an immediate "quenching" of the precipitate due to "on the flow"-washing. We found that this paves the way to adjust the synthesis parameters in a way that the final morphology of the nano-LDH particles can be controlled to be either round or platelet-like.}, language = {en} } @article{PritchardFalkLarssonetal.2016, author = {Pritchard, Rory A. and Falk, Lovissa and Larsson, Mathilda and Leinders, Mathias and Sorkin, Linda S.}, title = {Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation}, series = {Pain}, volume = {157}, journal = {Pain}, number = {1}, doi = {10.1097/j.pain.0000000000000341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191312}, pages = {137-146}, year = {2016}, abstract = {Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1\% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P <= 0.01). In contrast, pretreatment with PI3K-α, -δ, and -γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P <= 0.05), -δ (P <= 0.05), and -γ (P <= 0.01), early (0-2 hour) edema -α (P <= 0.05), -δ (P <= 0.001), and -γ (P <= 0.05), and neutrophil infiltration (all P <= 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P <= 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.}, language = {en} } @article{BraunschweigKrummenacherMailaenderetal.2016, author = {Braunschweig, Holger and Krummenacher, Ivo and Mail{\"a}nder, Lisa and Pentecost, Leanne and Vargas, Alfredo}, title = {Formation of a stable radical by oxidation of a tetraorganoborate}, series = {Chemical Communications}, volume = {52}, journal = {Chemical Communications}, number = {43}, doi = {10.1039/c6cc02916g}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191321}, pages = {7005-7008}, year = {2016}, abstract = {Herein, we describe the selective formation of a stable neutral spiroborate radical by one-electron oxidation of the corresponding tetraorganoborate salt Li[B(C\(_4\)Ph\(_4\))\(_2\)], formally containing a tetrahedral borate centre and a s-cis-butadiene radical cation as the spin-bearing site. Spectroscopic and computational methods have been used to determine the spin distribution and the chromism observed in the solid state.}, language = {en} } @article{EmmertWitzelHeinrich2016, author = {Emmert, M. and Witzel, P. and Heinrich, D.}, title = {Challenges in tissue engineering - towards cell control inside artificial scaffolds}, series = {Soft Matter}, volume = {12}, journal = {Soft Matter}, number = {19}, doi = {10.1039/c5sm02844b}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191341}, pages = {4287-4294}, year = {2016}, abstract = {Control of living cells is vital for the survival of organisms. Each cell inside an organism is exposed to diverse external mechano-chemical cues, all coordinated in a spatio-temporal pattern triggering individual cell functions. This complex interplay between external chemical cues and mechanical 3D environments is translated into intracellular signaling loops. Here, we describe how external mechano-chemical cues control cell functions, especially cell migration, and influence intracellular information transport. In particular, this work focuses on the quantitative analysis of (1) intracellular vesicle transport to understand intracellular state changes in response to external cues, (2) cellular sensing of external chemotactic cues, and (3) the cells' ability to migrate in 3D structured environments, artificially fabricated to mimic the 3D environment of tissue in the human body.}, language = {en} } @article{KramerPiperEstevezetal.2016, author = {Kramer, Susanne and Piper, Sophie and Estevez, Antonio and Carrington, Mark}, title = {Polycistronic trypanosome mRNAs are a target for the exosome}, series = {Molecular and Biochemical Parasitology}, volume = {205}, journal = {Molecular and Biochemical Parasitology}, number = {1-2}, doi = {10.1016/j.molbiopara.2016.02.009}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191350}, pages = {1-5}, year = {2016}, abstract = {Eukaryotic cells have several mRNA quality control checkpoints to avoid the production of aberrant proteins. Intron-containing mRNAs are actively degraded by the nuclear exosome, prevented from nuclear exit and, if these systems fail, degraded by the cytoplasmic NMD machinery. Trypanosomes have only two introns. However, they process mRNA5 from long polycistronic precursors by trans-splicing and polycistronic mRNA molecules frequently arise from any missed splice site. Here, we show that RNAi depletion of the trypanosome exosome, but not of the cytoplasmic 5'-3' exoribonuclease XRNA or the NMD helicase UPF1, causes accumulation of oligocistronic mRNA5. We have also revisited the localization of the trypanosome exosome by expressing eYFP-fusion proteins of the exosome subunits RRP44 and RRP6. Both proteins are significantly enriched in the nucleus. Together with published data, our data suggest a major nuclear function of the trypanosome exosome in rRNA, snoRNA and mRNA quality control.}, language = {en} } @article{GershbergFennelRehmetal.2016, author = {Gershberg, Jana and Fennel, Franziska and Rehm, Thomas H. and Lochbrunner, Stefan and W{\"u}rthner, Frank}, title = {Anti-cooperative supramolecular polymerization: a new K\(_2\)-K model applied to the self-assembly of perylene bisimide dye proceeding via well-defined hydrogen-bonded dimers}, series = {Chemical Science}, volume = {7}, journal = {Chemical Science}, number = {3}, doi = {10.1039/c5sc03759j}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191428}, pages = {1729-1737}, year = {2016}, abstract = {A perylene bisimide dye bearing amide functionalities at the imide positions derived from amino acid L-alanine and a dialkoxy-substituted benzyl amine self-assembles into tightly bound dimers by π-π-stacking and hydrogen bonding in chloroform. In less polar or unpolar solvents like toluene and methylcyclohexane, and in their mixtures, these dimers further self-assemble into extended oligomeric aggregates in an anti-cooperative process in which even numbered aggregates are highly favoured. The stepwise transition from dimers into oligomers can not be properly described by conventional K\(_2\)-K model, and thus a new K\(_2\)-K aggregation model has been developed, which interpretes the present anti-cooperative supramolecular polymerization more appropriately. The newly developed K\(_2\)-K model will be useful to describe self-assembly processes of a plethora of other π-conjugated molecules that are characterized by a favored dimer species.}, language = {en} } @article{GaudronLiuScholzetal.2016, author = {Gaudron, Philipp Daniel and Liu, Dan and Scholz, Friederike and Hu, Kai and Florescu, Christiane and Herrmann, Sebastian and Bijnens, Bart and Ertl, Georg and St{\"o}rk, Stefan and Weidemann, Frank}, title = {The septal bulge - an early echocardiographic sign in hypertensive heart disease}, series = {Journal of the American Society of Hypertension}, volume = {10}, journal = {Journal of the American Society of Hypertension}, number = {1}, doi = {10.1016/j.jash.2015.11.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191433}, pages = {70-80}, year = {2016}, abstract = {Patients in the early stage of hypertensive heart disease tend to have normal echocardiographic findings. The aim of this study was to investigate whether pathology-specific echocardiographic morphologic and functional parameters can help to detect subclinical hypertensive heart disease. One hundred ten consecutive patients without a history and medication for arterial hypertension (AH) or other cardiac diseases were enrolled. Standard echocardiography and two-dimensional speckle tracking -imaging analysis were performed. Resting blood pressure (BP) measurement, cycle ergometer test (CET), and 24-hour ambulatory BP monitoring (ABPM) were conducted. Patients were referred to "septal bulge (SB)" group (basal-septal wall thickness >= 2 mm thicker than mid-septal wall thickness) or "no-SB" group. Echocardiographic SB was found in 48 (43.6\%) of 110 patients. In this SB group, 38 (79.2\%) patients showed AH either by CET or ABPM. In contrast, in the no-SB group (n = 62), 59 (95.2\%) patients had no positive test for AH by CET or ABPM. When AH was solely defined by resting BP, SB was a reasonable predictive sign for AH (sensitivity 73\%, specificity 76\%). However, when AH was confirmed by CET or ABPM the echocardiographic SB strongly predicted clinical AH (sensitivity 93\%, specificity 86\%). In addition, regional myocardial deformation of the basal-septum in SB group was significantly lower than in no-SB group (14 +/- 4\% vs. 17 +/- 4\%; P < .001). In conclusion, SB is a morphologic echocardiographic sign for early hypertensive heart disease. Sophisticated BP evaluation including resting BP, ABPM, and CET should be performed in all patients with an accidental finding of a SB in echocardiography.}, language = {en} } @article{KleberChenMichelsetal.2016, author = {Kleber, J{\"o}rg and Chen, Yi-Chun and Michels, Birgit and Saumweber, Timo and Schleyer, Michael and K{\"a}hne, Thilo and Buchner, Erich and Gerber, Bertram}, title = {Synapsin is required to "boost" memory strength for highly salient events}, series = {Learning and Memory}, volume = {23}, journal = {Learning and Memory}, number = {1}, doi = {10.1101/lm.039685.115}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191440}, pages = {9-20}, year = {2016}, abstract = {Synapsin is an evolutionarily conserved presynaptic phosphoprotein. It is encoded by only one gene in the Drosophila genome and is expressed throughout the nervous system. It regulates the balance between reserve and releasable vesicles, is required to maintain transmission upon heavy demand, and is essential for proper memory function at the behavioral level. Task-relevant sensorimotor functions, however, remain intact in the absence of Synapsin. Using an odor-sugar reward associative learning paradigm in larval Drosophila, we show that memory scores in mutants lacking Synapsin (syn\(^{97}\)) are lower than in wild-type animals only when more salient, higher concentrations of odor or of the sugar reward are used. Furthermore, we show that Synapsin is selectively required for larval short-term memory. Thus, without Synapsin Drosophila larvae can learn and remember, but Synapsin is required to form memories that match in strength to event salience-in particular to a high saliency of odors, of rewards, or the salient recency of an event. We further show that the residual memory scores upon a lack of Synapsin are not further decreased by an additional lack of the Sap47 protein. In combination with mass spectrometry data showing an up-regulated phosphorylation of Synapsin in the larval nervous system upon a lack of Sap47, this is suggestive of a functional interdependence of Synapsin and Sap47.}, language = {en} } @article{KarGehrigAllampallyetal.2016, author = {Kar, Haridas and Gehrig, Dominik W. and Allampally, Naveen Kumar and Fern{\´a}ndez, Gustavo and Laquai, Fr{\´e}d{\´e}ric and Ghosh, Suhrit}, title = {Cooperative supramolecular polymerization of an amine-substituted naphthalene-diimide and its impact on excited state photophysical properties}, series = {Chemical Science}, volume = {7}, journal = {Chemical Science}, number = {2}, doi = {10.1039/c5sc03462k}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191459}, pages = {1115-1120}, year = {2016}, abstract = {A donor-acceptor-donor (D-A-D) type naphthalene-diimide (NDI-H) chromophore exhibits highly cooperative J-aggregation leading to nanotubular self-assembly and gelation in n-decane, as demonstrated by UV/Vis, FT-IR, photoluminescence and microscopy studies. Analysis of temperature-dependent UV/Vis spectra using the nucleation-elongation model and FT-IR data reveals the molecular origin of the cooperative nature of the self-assembly. The supramolecular polymerization is initiated by H-bonding up to a degree of polymerization similar to 20-25, which in a subsequent elongation step promotes J-aggregation in orthogonal direction leading to possibly a sheet-like structure that eventually produces nanotubes. Time-resolved fluorescence and absorption measurements demonstrate that such a tubular assembly enables very effective delocalization of excited states resulting in a remarkably prolonged excited state lifetime.}, language = {en} } @article{MacdougallBircherEckhardtetal.2016, author = {Macdougall, Iain C. and Bircher, Andreas J. and Eckhardt, Kai-Uwe and Obrador, Gregorio T. and Pollock, Carol A. and Stenvinkel, Peter and Swinkels, Dorine W. and Wanner, Christoph and Weiss, G{\"u}nter and Chertow, Glenn M.}, title = {Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference}, series = {Kidney International}, volume = {89}, journal = {Kidney International}, number = {1}, doi = {10.1016/j.kint.2015.10.002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191467}, pages = {28-39}, year = {2016}, abstract = {Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.}, language = {en} } @article{BraunschweigEwingGhoshetal.2016, author = {Braunschweig, Holger and Ewing, William C. and Ghosh, Sundargopal and Kramer, Thomas and Mattock, James D. and {\"O}streicher, Sebastian and Vargas, Alfredo and Werner, Christine}, title = {Trimetallaborides as starting points for the syntheses of large metal-rich molecular borides and clusters}, series = {Chemical Science}, volume = {7}, journal = {Chemical Science}, number = {1}, doi = {10.1039/c5sc03206g}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191511}, pages = {109-116}, year = {2016}, abstract = {Treatment of an anionic dimanganaborylene complex ([{Cp(CO)\(_2\)Mn}\(_2\)B]\(^-\)) with coinage metal cations stabilized by a very weakly coordinating Lewis base (SMe\(_2\)) led to the coordination of the incoming metal and subsequent displacement of dimethylsulfide in the formation of hexametalladiborides featuring planar four-membered M\(_2\)B\(_2\) cores (M = Cu, Au) comparable to transition metal clusters constructed around four-membered rings composed solely of coinage metals. The analogies between compounds consisting of B\(_2\)M\(_2\) units and M\(_4\) (M = Cu, Au) units speak to the often overlooked metalloid nature of boron. Treatment of one of these compounds (M = Cu) with a Lewis-basic metal fragment (Pt(PCy\(_3\))\(_2\)) led to the formation of a tetrametallaboride featuring two manganese, one copper and one platinum atom, all bound to boron in a geometry not yet seen for this kind of compound. Computational examination suggests that this geometry is the result of d\(^{10}\)-d\(^{10}\) dispersion interactions between the copper and platinum fragments.}, language = {en} } @article{MavratzakisHerbertWalla2016, author = {Mavratzakis, Aimee and Herbert, Cornelia and Walla, Peter}, title = {Emotional facial expressions evoke faster orienting responses, but weaker emotional responses at neural and behavioural levels compared to scenes: a simultaneous EEG and facial EMG study}, series = {NeuroImage}, volume = {124}, journal = {NeuroImage}, number = {Part A}, doi = {10.1016/j.neuroimage.2015.09.065}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191535}, pages = {931-946}, year = {2016}, abstract = {In the current study, electroencephalography (EEG) was recorded simultaneously with facial electromyography (fEMG) to determine whether emotional faces and emotional scenes are processed differently at the neural level. In addition, it was investigated whether these differences can be observed at the behavioural level via spontaneous facial muscle activity. Emotional content of the stimuli did not affect early P1 activity. Emotional faces elicited enhanced amplitudes of the face-sensitive N170 component, while its counterpart, the scene-related N100, was not sensitive to emotional content of scenes. At 220-280 ms, the early posterior negativity (EPN) was enhanced only slightly for fearful as compared to neutral or happy faces. However, its amplitudes were significantly enhanced during processing of scenes with positive content, particularly over the right hemisphere. Scenes of positive content also elicited enhanced spontaneous zygomatic activity from 500-750 ms onwards, while happy faces elicited no such changes. Contrastingly, both fearful faces and negative scenes elicited enhanced spontaneous corrugator activity at 500-750 ms after stimulus onset. However, relative to baseline EMG changes occurred earlier for faces (250 ms) than for scenes (500 ms) whereas for scenes activity changes were more pronounced over the whole viewing period. Taking into account all effects, the data suggests that emotional facial expressions evoke faster attentional orienting, but weaker affective neural activity and emotional behavioural responses compared to emotional scenes.}, language = {en} } @article{BarbieriGardonRuizCastelletal.2016, author = {Barbieri, Flavia L. and Gardon, Jacques and Ruiz-Castell, Mar{\´i}a and Paco V., Pamela and Muckelbauer, Rebecca and Casiot, Corinne and Freydier, R{\´e}mi and Duprey, Jean-Louis and Chen, Chih-Mei and M{\"u}ller-Nordhorn, Jacqueline and Keil, Thomas}, title = {Toxic trace elements in maternal and cord blood and social determinants in a Bolivian mining city}, series = {International Journal of Environmental Health Research}, volume = {26}, journal = {International Journal of Environmental Health Research}, number = {2}, doi = {10.1080/09603123.2015.1061114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190703}, pages = {158-174}, year = {2016}, abstract = {This study assessed lead, arsenic, and antimony in maternal and cord blood, and associations between maternal concentrations and social determinants in the Bolivian mining city of Oruro using the baseline assessment of the ToxBol/Mine-Nino birth cohort. We recruited 467 pregnant women, collecting venous blood and sociodemographic information as well as placental cord blood at birth. Metallic/semimetallic trace elements were measured using inductively coupled plasma mass spectrometry. Lead medians in maternal and cord blood were significantly correlated (Spearman coefficient=0.59; p<0.001; 19.35 and 13.50 μg/L, respectively). Arsenic concentrations were above detection limit (3.30 μg/L) in 17.9\% of maternal and 34.6\% of cord blood samples. They were not associated (Fischer's p=0.72). Antimony medians in maternal and cord blood were weakly correlated (Spearman coefficient=0.15; p<0.03; 9.00 and 8.62 μg/L, respectively). Higher concentrations of toxic elements in maternal blood were associated with maternal smoking, low educational level, and partner involved in mining.}, language = {en} } @article{SinghVermaAkhoonetal.2016, author = {Singh, Krishna P. and Verma, Neeraj and Akhoon, Bashir A . and Bhatt, Vishal and Gupta, Shishir K. and Gupta, Shailendra K. and Smita, Suchi}, title = {Sequence-based approach for rapid identification of cross-clade CD8+ T-cell vaccine candidates from all high-risk HPV strains}, series = {3 Biotech}, volume = {6}, journal = {3 Biotech}, doi = {10.1007/s13205-015-0352-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191056}, pages = {10}, year = {2016}, abstract = {Human papilloma virus (HPV) is the primary etiological agent responsible for cervical cancer in women. Although in total 16 high-risk HPV strains have been identified so far. Currently available commercial vaccines are designed by targeting mainly HPV16 and HPV18 viral strains as these are the most common strains associated with cervical cancer. Because of the high level of antigenic specificity of HPV capsid antigens, the currently available vaccines are not suitable to provide cross-protection from all other high-risk HPV strains. Due to increasing reports of cervical cancer cases from other HPV high-risk strains other than HPV16 and 18, it is crucial to design vaccine that generate reasonable CD8+ T-cell responses for possibly all the high-risk strains. With this aim, we have developed a computational workflow to identify conserved cross-clade CD8+ T-cell HPV vaccine candidates by considering E1, E2, E6 and E7 proteins from all the high-risk HPV strains. We have identified a set of 14 immunogenic conserved peptide fragments that are supposed to provide protection against infection from any of the high-risk HPV strains across globe.}, language = {en} } @article{GrimmKleinKopeketal.2016, author = {Grimm, Jonathan B. and Klein, Teresa and Kopek, Benjamin G. and Shtengel, Gleb and Hess, Harald F. and Sauer, Markus and Lavis, Luke D.}, title = {Synthesis of a far-red photoactivatable silicon-containing rhodamine for super-resolution microscopy}, series = {Angewandte Chemie International Edition}, volume = {55}, journal = {Angewandte Chemie International Edition}, number = {5}, doi = {10.1002/anie.201509649}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191069}, pages = {1723-1727}, year = {2016}, abstract = {The rhodamine system is a flexible framework for building small-molecule fluorescent probes. Changing N-substitution patterns and replacing the xanthene oxygen with a dimethylsilicon moiety can shift the absorption and fluorescence emission maxima of rhodamine dyes to longer wavelengths. Acylation of the rhodamine nitrogen atoms forces the molecule to adopt a nonfluorescent lactone form, providing a convenient method to make fluorogenic compounds. Herein, we take advantage of all of these structural manipulations and describe a novel photoactivatable fluorophore based on a Si-containing analogue of Q-rhodamine. This probe is the first example of a "caged" Si-rhodamine, exhibits higher photon counts compared to established localization microscopy dyes, and is sufficiently red-shifted to allow multicolor imaging. The dye is a useful label for super-resolution imaging and constitutes a new scaffold for far-red fluorogenic molecules.}, language = {en} } @article{DietrichGoetzeGeier2016, author = {Dietrich, Christoph G. and G{\"o}tze, Oliver and Geier, Andreas}, title = {Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance}, series = {World Journal of Gastroenterology}, volume = {22}, journal = {World Journal of Gastroenterology}, number = {1}, doi = {10.3748/wjg.v22.i1.72}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191136}, pages = {72-88}, year = {2016}, abstract = {Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests.}, language = {en} } @article{EhnertParsaRoperetal.2016, author = {Ehnert, Ina and Parsa, Sepideh and Roper, Ian and Wagner, Marcus and Muller-Camen, Michael}, title = {Reporting on sustainability and HRM: a comparative study of sustainability reporting practices by the world's largest companies}, series = {International Journal of Human Resource Management}, volume = {27}, journal = {International Journal of Human Resource Management}, number = {1}, doi = {10.1080/09585192.2015.1024157}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191141}, pages = {88-108}, year = {2016}, abstract = {As a response to the growing public awareness on the importance of organisational contributions to sustainable development, there is an increased incentive for corporations to report on their sustainability activities. In parallel with this has been the development of Sustainable HRM' which embraces a growing body of practitioner and academic literature connecting the notions of corporate sustainability to HRM. The aim of this article is to analyse corporate sustainability reporting amongst the world's largest companies and to assess the HRM aspects of sustainability within these reports in comparison to environmental aspects of sustainable management and whether organisational attributes - principally country-of-origin - influences the reporting of such practices. A focus in this article is the extent to which the reporting of various aspects of sustainability may reflect dominant models of corporate governance in the country in which a company is headquartered. The findings suggest, first and against expectations, that the overall disclosure on HRM-related performance is not lower than that on environmental performance. Second, companies report more on their internal workforce compared to their external workforce. Finally, international differences, in particular those between companies headquartered in liberal market economies and coordinated market economies, are not as apparent as expected.}, language = {en} } @article{WoelflingBeckerUhletal.2016, author = {W{\"o}lfling, Mirko and Becker, Mira C. and Uhl, Britta and Traub, Anja and Fiedler, Konrad}, title = {How differences in the settling behaviour of moths (Lepidoptera) may contribute to sampling bias when using automated light traps}, series = {European Journal of Entomology}, volume = {113}, journal = {European Journal of Entomology}, doi = {10.14411/eje.2016.066}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191154}, pages = {502-506}, year = {2016}, abstract = {Quantitative community-wide moth surveys frequently employ flight-interception traps equipped with UV-light emitting sources as attractants. It has long been known that moth species differ in their responsiveness to light traps. We studied how the settling behaviour of moths at a light trap may further contribute to sampling bias. We observed the behaviour of 1426 moths at a light tower. Moths were classified as either, settling and remaining still after arrival, or continually moving on the gauze for extended periods of time. Moths that did not move after settling may not end up in the sampling container of the light trap and therefore are under-represented in automated trap samples relative to their true proportions in the community. Our analyses revealed highly significant behavioural differences between moths that differed in body size. Small moths were more likely to remain stationary after settling. As a corollary, representatives of three taxa, which in Europe are predominantly small species (Nolidae, Geometridae: Eupitheciini, Erebidae: Lithosiini), usually settled down immediately, whereas most other moths remained active on or flying around the trap for some time. Moth behaviour was also modulated by ambient temperature. At high temperatures, they were less likely to settle down immediately, but this behavioural difference was most strongly apparent among medium-sized moths. These results indicate the likely extent of the sampling bias when analysing and interpreting automated light-trap samples. Furthermore, to control for temperature modulated sampling bias temperature should always be recorded when sampling moths using flight-interception traps.}, language = {en} } @article{DaryaeeChangSchiebeletal.2016, author = {Daryaee, Fereidoon and Chang, Andrew and Schiebel, Johannes and Lu, Yang and Zhang, Zhuo and Kapilashrami, Kanishk and Walker, Stephen G. and Kisker, Caroline and Sotriffer, Christoph A. and Fisher, Stewart L. and Tonge, Peter J.}, title = {Correlating drug-target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase}, series = {Chemical Science}, volume = {7}, journal = {Chemical Science}, number = {9}, doi = {10.1039/c6sc01000h}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191218}, pages = {5945-5954}, year = {2016}, abstract = {Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In addition P. aeruginosa is a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.}, language = {en} } @article{ElHajjDittrichBoecketal.2016, author = {El Hajj, Nady and Dittrich, Marcus and B{\"o}ck, Julia and Kraus, Theo F. J. and Nanda, Indrajit and M{\"u}ller, Tobias and Seidmann, Larissa and Tralau, Tim and Galetzka, Danuta and Schneider, Eberhard and Haaf, Thomas}, title = {Epigenetic dysregulation in the developing Down syndrome cortex}, series = {Epigenetics}, volume = {11}, journal = {Epigenetics}, number = {8}, doi = {10.1080/15592294.2016.1192736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191239}, pages = {563-578}, year = {2016}, abstract = {Using Illumina 450K arrays, 1.85\% of all analyzed CpG sites were significantly hypermethylated and 0.31\% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.}, language = {en} } @article{DoranFuldeGratzetal.2016, author = {Doran, Kelly S. and Fulde, Marcus and Gratz, Nina and Kim, Brandon J. and Nau, Roland and Prasadarao, Nemani and Schubert-Unkmeir, Alexandra and Tuomanen, Elaine I. and Valentin-Weigand, Peter}, title = {Host-pathogen interactions in bacterial meningitis}, series = {Acta Neuropathologica}, volume = {131}, journal = {Acta Neuropathologica}, number = {2}, doi = {10.1007/s00401-015-1531-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191034}, pages = {185-209}, year = {2016}, abstract = {Bacterial meningitis is a devastating disease occurring worldwide with up to half of the survivors left with permanent neurological sequelae. Due to intrinsic properties of the meningeal pathogens and the host responses they induce, infection can cause relatively specific lesions and clinical syndromes that result from interference with the function of the affected nervous system tissue. Pathogenesis is based on complex host-pathogen interactions, some of which are specific for certain bacteria, whereas others are shared among different pathogens. In this review, we summarize the recent progress made in understanding the molecular and cellular events involved in these interactions. We focus on selected major pathogens, Streptococcus pneumonia, S. agalactiae (Group B Streptococcus), Neisseria meningitidis, and Escherichia coli K1, and also include a neglected zoonotic pathogen, Streptococcus suis. These neuroinvasive pathogens represent common themes of host-pathogen interactions, such as colonization and invasion of mucosal barriers, survival in the blood stream, entry into the central nervous system by translocation of the blood-brain and blood-cerebrospinal fluid barrier, and induction of meningeal inflammation, affecting pia mater, the arachnoid and subarachnoid spaces.}, language = {en} } @article{WaechtlerKuebelBarthelmesetal.2016, author = {W{\"a}chtler, Maria and K{\"u}bel, Joachim and Barthelmes, Kevin and Winter, Andreas and Schmiedel, Alexander and Pascher, Torbj{\"o}rn and Lambert, Christoph and Schubert, Ulrich S. and Dietzek, Benjamin}, title = {Energy transfer and formation of long-lived \(^3\)MLCT states in multimetallic complexes with extended highly conjugated bis-terpyridyl ligands}, series = {Physical Chemistry Chemical Physics}, volume = {18}, journal = {Physical Chemistry Chemical Physics}, number = {4}, doi = {10.1039/c5cp04447b}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191041}, pages = {2350-2360}, year = {2016}, abstract = {Multimetallic complexes with extended and highly conjugated bis-2,2':6',2''-terpyridyl bridging ligands, which present building blocks for coordination polymers, are investigated with respect to their ability to act as light-harvesting antennae. The investigated species combine Ru(II)- with Os(II)- and Fe(II)-terpyridyl chromophores, the latter acting as energy sinks. Due to the extended conjugated system the ligands are able to prolong the lifetime of the \(^3\)MLCT states compared to unsubstituted terpyridyl species by delocalization and energetic stabilization of the \(^3\)MLCT states. This concept is applied for the first time to Fe(II) terpyridyl species and results in an exceptionally long lifetime of 23 ps for the Fe(II) \(^3\)MLCT state. While partial energy (>80\%) transfer is observed between the Ru(II) and Fe(II) centers with a time-constant of 15 ps, excitation energy is transferred completely from the Ru(II) to the Os(II) center within the first 200 fs after excitation.}, language = {en} } @article{EdelmannMusialBrightGelbrichetal.2016, author = {Edelmann, Frank and Musial-Bright, Lindy and Gelbrich, Goetz and Trippel, Tobias and Radenovic, Sara and Wachter, Rolf and Inkrot, Simone and Loncar, Goran and Tahirovic, Elvis and Celic, Vera and Veskovic, Jovan and Zdravkovic, Marija and Lainscak, Mitja and Apostolović, Svetlana and Neskovic, Aleksandar N. and Pieske, Burkert and D{\"u}ngen, Hans-Dirk}, title = {Tolerability and feasibility of beta-blocker titration in HFpEF versus HFrEF: Insights from the CIBIS-ELD trial}, series = {JACC: Heart Failure}, volume = {4}, journal = {JACC: Heart Failure}, number = {2}, doi = {10.1016/j.jchf.2015.10.008}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191022}, pages = {140-149}, year = {2016}, abstract = {OBJECTIVES: This study evaluated the tolerability and feasibility of titration of 2 distinctly acting beta-blockers (BB) in elderly heart failure patients with preserved (HFpEF) and reduced (HFrEF) left ventricular ejection fraction. BACKGROUND: Broad evidence supports the use of BB in HFrEF, whereas the evidence for beta blockade in HFpEF is uncertain. METHODS: In the CIBIS-ELD (Cardiac Insufficiency Bisoprolol Study in Elderly) trial, patients >65 years of age with HFrEF (n = 626) or HFpEF (n = 250) were randomized to bisoprolol or carvedilol. Both BB were up-titrated to the target or maximum tolerated dose. Follow-up was performed after 12 weeks. HFrEF and HFpEF patients were compared regarding tolerability and clinical effects (heart rate, blood pressure, systolic and diastolic functions, New York Heart Association functional class, 6-minute-walk distance, quality of life, and N-terminal pro-B-type natriuretic peptide). RESULTS: For both of the BBs, tolerability and daily dose at 12 weeks were similar. HFpEF patients demonstrated higher rates of dose escalation delays and treatment-related side effects. Similar HR reductions were observed in both groups (HFpEF: 6.6 beats/min; HFrEF: 6.9 beats/min, p = NS), whereas greater improvement in NYHA functional class was observed in HFrEF (HFpEF: 23\% vs. HFrEF: 34\%, p < 0.001). Mean E/e' and left atrial volume index did not change in either group, although E/A increased in HFpEF. CONCLUSIONS: BB tolerability was comparable between HFrEF and HFpEF. Relevant reductions of HR and blood pressure occurred in both groups. However, only HFrEF patients experienced considerable improvements in clinical parameters and Left ventricular function. Interestingly, beta-blockade had no effect on established and prognostic markers of diastolic function in either group. Long-term studies using modern diagnostic criteria for HFpEF are urgently needed to establish whether BB therapy exerts significant clinical benefit in HFpEF. (Comparison of Bisoprolol and Carvedilol in Elderly Heart Failure HF] Patients: A Randomised, Double-Blind Multicentre Study CIBIS-ELD]; ISRCTN34827306).}, language = {en} } @article{TegtmeyerMoodleyYamaokaetal.2016, author = {Tegtmeyer, Nicole and Moodley, Yoshan and Yamaoka, Yoshio and Pernitzsch, Sandy Ramona and Schmidt, Vanessa and Traverso, Francisco Rivas and Schmidt, Thomas P. and Rad, Roland and Yeoh, Khay Guan and Bow, Ho and Torres, Javier and Gerhard, Markus and Schneider, Gisbert and Wessler, Silja and Backert, Steffen}, title = {Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA}, series = {Molecular Microbiology}, volume = {99}, journal = {Molecular Microbiology}, number = {5}, doi = {10.1111/mmi.13276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190774}, pages = {925-944}, year = {2016}, abstract = {HtrA proteases and chaperones exhibit important roles in periplasmic protein quality control and stress responses. The genetic inactivation of htrA has been described for many bacterial pathogens. However, in some cases such as the gastric pathogen Helicobacter pylori, HtrA is secreted where it cleaves the tumour-suppressor E-cadherin interfering with gastric disease development, but the generation of htrA mutants is still lacking. Here, we show that the htrA gene locus is highly conserved in worldwide strains. HtrA presence was confirmed in 992 H.pylori isolates in gastric biopsy material from infected patients. Differential RNA-sequencing (dRNA-seq) indicated that htrA is encoded in an operon with two subsequent genes, HP1020 and HP1021. Genetic mutagenesis and complementation studies revealed that HP1020 and HP1021, but not htrA, can be mutated. In addition, we demonstrate that suppression of HtrA proteolytic activity with a newly developed inhibitor is sufficient to effectively kill H.pylori, but not other bacteria. We show that Helicobacter htrA is an essential bifunctional gene with crucial intracellular and extracellular functions. Thus, we describe here the first microbe in which htrA is an indispensable gene, a situation unique in the bacterial kingdom. HtrA can therefore be considered a promising new target for anti-bacterial therapy.}, language = {en} } @article{KlaunigDekantPlotzkeetal.2016, author = {Klaunig, James E. and Dekant, Wolfgang and Plotzke, Kathy and Scialli, Anthony R.}, title = {Biological relevance of decamethylcyclopentasiloxane (D5) induced rat uterine endometrial adenocarcinoma tumorigenesis: Mode of action and relevance to humans}, series = {Regulatory Toxicology and Pharmacology}, volume = {74}, journal = {Regulatory Toxicology and Pharmacology}, number = {Supplement}, doi = {10.1016/j.yrtph.2015.06.021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190952}, pages = {S44-S56}, year = {2016}, abstract = {Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the production and formulation of consumer products with potential exposure to manufacturing workers, consumer, and the general public. Following a combined 2-year inhalation chronic bioassay performed in Fischer 344 (F344) rats, an increase in uterine endometrial adenocarcinomas was noted at the highest concentration to which animals were exposed. No other neoplasms were detected. In this study, a dose of 160 ppm produced an incidence of 8\% endometrial adenocarcinomas. Based on a number of experimental studies with D5, the current manuscript examines the biological relevance and possible modes of action for the uterine endometrial adenocarcinomas observed in the rat following chronic exposure to D5. Variable rates of spontaneous uterine endometrial adenocarcinomas have been reported for untreated F344 CrIBr rats. As such, we concluded that the slight increase in uterine endometrial adenocarcinomas observed in the D5 chronic bioassay might not be the result of D5 exposure but may be related to variability of the spontaneous tumor incidence in this strain of rat. However, if the uterine endometrial adenocarcinomas are related to D5-exposure, alteration in the estrous cycle in the aging F344 rat is the most likely mode of action. D5 is not genotoxic or estrogenic. The alteration in the estrous cycle is caused by a decrease in progesterone with an increase in the estrogen:progesterone ratio most likely induced by a decrease in prolactin concentration. Available data support that exposure to D5 influences prolactin concentration. Although the effects on prolactin concentrations in a number of experiments were not always consistent, the available data support the conclusion that D5 is acting via a dopamine receptor agonist-like mechanism to alter the pituitary control of the estrous cycle. In further support of this mode of action, studies in F344 aged animals showed that the effects of D5 on estrous cyclicity produced a response consistent with a dopamine-like effect and further suggest that D5 is accelerating the aging of the reproductive endocrine system in the F344 rat utilized in this study. This mode of action for uterine endometrial adenocarcinoma tumorigenesis is not relevant for humans.}, language = {en} } @article{ReichertsGerdesPaulietal.2016, author = {Reicherts, Philipp and Gerdes, Antje B. M. and Pauli, Paul and Wieser, Matthias J.}, title = {Psychological placebo and nocebo effects on pain rely on expectation and previous experience}, series = {Journal of Pain}, volume = {17}, journal = {Journal of Pain}, number = {2}, doi = {10.1016/j.jpain.2015.10.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190962}, pages = {203-214}, year = {2016}, abstract = {Expectation and previous experience are both well established key mediators of placebo and nocebo effects. However, the investigation of their respective contribution to placebo and nocebo responses is rather difficult because most placebo and nocebo manipulations are contaminated by pre-existing treatment expectancies resulting from a learning history of previous medical interventions. To circumvent any resemblance to classical treatments, a purely psychological placebonocebo manipulation was established, namely, the "visual stripe pattern induced modulation of pain." To this end, experience and expectation regarding the effects of different visual cues (stripe patterns) on pain were varied across 3 different groups, with either only placebo instruction (expectation), placebo conditioning (experience), or both (expectation + experience) applied. Only the combined manipulation (expectation + experience) revealed significant behavioral and physiological placebo nocebo effects on pain. Two subsequent experiments, which, in addition to placebo and nocebo cues, included a neutral control condition further showed that especially nocebo responses were more easily induced by this psychological placebo and nocebo manipulation. The results emphasize the great effect of psychological processes on placebo and nocebo effects. Particularly, nocebo effects should be addressed more thoroughly and carefully considered in clinical practice to prevent the accidental induction of side effects.}, language = {en} } @article{BornsteinAllolioArltetal.2016, author = {Bornstein, Stefan R. and Allolio, Bruno and Arlt, Wiebke and Barthel, Andreas and Don-Wauchope, Andrew and Hammer, Gary D. and Husebye, Eystein S. and Merke, Deborah P. and Murad, M. Hassan and Stratakis, Constantine A. and Torpy, David J.}, title = {Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline}, series = {Journal of Clinical Endocrinology \& Metabolism}, volume = {101}, journal = {Journal of Clinical Endocrinology \& Metabolism}, number = {2}, doi = {10.1210/jc.2015-1710}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190893}, pages = {364-389}, year = {2016}, abstract = {Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. Consensus Process: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. Conclusions: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 mu g) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (similar to 8 mg/m\(^2\)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.}, language = {en} } @article{ZhuShabalaCuinetal.2016, author = {Zhu, Min and Shabala, Lana and Cuin, Tracey A. and Huang, Xin and Zhou, Meixue and Munns, Rana and Shabala, Sergey}, title = {Nax loci affect SOS1-like Na\(^+\)/H\(^+\) exchanger expression and activity in wheat}, series = {Journal of Experimental Botany}, volume = {67}, journal = {Journal of Experimental Botany}, number = {3}, doi = {10.1093/jxb/erv493}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190908}, pages = {835-844}, year = {2016}, abstract = {Salinity stress tolerance in durum wheat is strongly associated with a plant's ability to control Na\(^+\) delivery to the shoot. Two loci, termed Nax1 and Nax2, were recently identified as being critical for this process and the sodium transporters HKT1;4 and HKT1; 5 were identified as the respective candidate genes. These transporters retrieve Na\(^+\) from the xylem, thus limiting the rates of Na\(^+\) transport from the root to the shoot. In this work, we show that the Nax loci also affect activity and expression levels of the SOS1-like Na\(^+\)/H\(^+\) exchanger in both root cortical and stelar tissues. Net Na\(^+\) efflux measured in isolated steles from salt-treated plants, using the non-invasive ion flux measuring MIFE technique, decreased in the sequence: Tamaroi (parental line)>Nax1=Nax2>Nax1:Nax2 lines. This efflux was sensitive to amiloride (a known inhibitor of the Na\(^+\)/H\(^+\) exchanger) and was mirrored by net H\(^+\) flux changes. TdSOS1 relative transcript levels were 6-10-fold lower in Nax lines compared with Tamaroi. Thus, it appears that Nax loci confer two highly complementary mechanisms, both of which contribute towards reducing the xylem Na\(^+\) content. One enhances the retrieval of Na\(^+\) back into the root stele via HKT1;4 or HKT1;5, whilst the other reduces the rate of Na\(^+\) loading into the xylem via SOS1. It is suggested that such duality plays an important adaptive role with greater versatility for responding to a changing environment and controlling Na\(^+\) delivery to the shoot.}, language = {en} } @article{DekantKlaunig2016, author = {Dekant, Wolfgang and Klaunig, James E.}, title = {Toxicology of decamethylcyclopentasiloxane (D5)}, series = {Regulatory Toxicology and Pharmacology}, volume = {74}, journal = {Regulatory Toxicology and Pharmacology}, number = {Supplement}, doi = {10.1016/j.yrtph.2015.06.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190914}, pages = {S67-S76}, year = {2016}, abstract = {Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the formulation of consumer products as well as an industrial intermediate. A summary of the previous studies on the toxicology of D5 is provided. Toxicokinetic studies with D5 after dermal administration demonstrate a very low uptake of due to rapid evaporation. Following inhalation exposure, exhalation of unchanged D5 and excretion of metabolites with urine are major pathways for clearance in mammals. Due to this rapid clearance by exhalation, the potential for bioaccumulation of D5 is considered unlikely. The available toxicity data on D5 adequately cover the relevant endpoints regarding potential human health hazards. D5 was not DNA reactive or mutagenic in standard in vitro and in vivo test systems. D5 also did not induce developmental and reproductive toxicity in appropriately performed studies. In repeated studies in rats with subacute, subchronic and chronic inhalation exposure, mild effects on the respiratory tract typically seen after inhalation of irritating materials, increases in liver weight (28- and 90-day inhalation studies), and a small increase in the incidence of uterine adenocarcinoma (uterine tumor) in female rats (two-year inhalation chronic bioassay) were observed. The liver effects induced by D5 were consistent with D5 as a weak "phenobarbital-like" inducer of xenobiotic metabolizing enzymes and these effects are considered to be an adaptive response. Mechanistic studies to elucidate the mode-of-action for uterine tumor induction suggest an interaction of D5 with dopamine signal transduction pathways altering the pituitary control of the estrus cycle. The resulting estrogen imbalance may cause the small increase in uterine tumor incidence at the highest D5-exposure concentration over that seen in control rats. A genotoxic mechanism or a direct endocrine activity of D5 is not supported as a mode-of-action to account for the induction of uterine tumors by the available data.}, language = {en} } @article{BoehmScherzerKroletal.2016, author = {B{\"o}hm, Jennifer and Scherzer, S{\"o}nke and Krol, Elzbieta and Kreuzer, Ines and von Meyer, Katharina and Lorey, Christian and Mueller, Thomas D. and Shabala, Lana and Monte, Isabel and Solano, Roberto and Al-Rasheid, Khaled A. S. and Rennenberg, Heinz and Shabala, Sergey and Neher, Erwin and Hedrich, Rainer}, title = {The Venus flytrap Dionaea muscipula counts prey-induced action potentials to induce sodium uptake}, series = {Current Biology}, volume = {26}, journal = {Current Biology}, number = {3}, doi = {10.1016/j.cub.2015.11.057}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190870}, pages = {286-295}, year = {2016}, abstract = {Carnivorous plants, such as the Venus flytrap (Dionaea muscipula), depend on an animal diet when grown in nutrient-poor soils. When an insect visits the trap and tilts the mechanosensors on the inner surface, action potentials (APs) are fired. After a moving object elicits two APs, the trap snaps shut, encaging the victim. Panicking preys repeatedly touch the trigger hairs over the subsequent hours, leading to a hermetically closed trap, which via the gland-based endocrine system is flooded by a prey-decomposing acidic enzyme cocktail. Here, we asked the question as to how many times trigger hairs have to be stimulated (e.g., now many APs are required) for the flytrap to recognize an encaged object as potential food, thus making it worthwhile activating the glands. By applying a series of trigger-hair stimulations, we found that the touch hormone jasmonic acid (JA) signaling pathway is activated after the second stimulus, while more than three APs are required to trigger an expression of genes encoding prey-degrading hydrolases, and that this expression is proportional to the number of mechanical stimulations. A decomposing animal contains a sodium load, and we have found that these sodium ions enter the capture organ via glands. We identified a flytrap sodium channel DmHKT1 as responsible for this sodium acquisition, with the number of transcripts expressed being dependent on the number of mechano-electric stimulations. Hence, the number of APs a victim triggers while trying to break out of the trap identifies the moving prey as a struggling Na\(^+\)-rich animal and nutrition for the plant.}, language = {en} } @article{ScognamiglioCabezasWallscheidThieretal.2016, author = {Scognamiglio, Roberta and Cabezas-Wallscheid, Nina and Thier, Marc Christian and Altamura, Sandro and Reyes, Alejandro and Prendergast, {\´A}ine M. and Baumg{\"a}rtner, Daniel and Carnevalli, Larissa S. and Atzberger, Ann and Haas, Simon and von Paleske, Lisa and Boroviak, Thorsten and W{\"o}rsd{\"o}rfer, Philipp and Essers, Marieke A. G. and Kloz, Ulrich and Eisenman, Robert N. and Edenhofer, Frank and Bertone, Paul and Huber, Wolfgang and van der Hoeven, Franciscus and Smith, Austin and Trumpp, Andreas}, title = {Myc depletion induces a pluripotent dormant state mimicking diapause}, series = {Cell}, volume = {164}, journal = {Cell}, number = {4}, doi = {10.1016/j.cell.2015.12.033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190868}, pages = {668-680}, year = {2016}, abstract = {Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.}, language = {en} } @article{MederKoenigOzretićetal.2016, author = {Meder, Lydia and K{\"o}nig, Katharina and Ozretić, Luka and Schultheis, Anne M. and Ueckeroth, Frank and Ade, Carsten P. and Albus, Kerstin and Boehm, Diana and Rommerscheidt-Fuss, Ursula and Florin, Alexandra and Buhl, Theresa and Hartmann, Wolfgang and Wolf, J{\"u}rgen and Merkelbach-Bruse, Sabine and Eilers, Martin and Perner, Sven and Heukamp, Lukas C. and Buettner, Reinhard}, title = {NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas}, series = {International Journal of Cancer}, volume = {138}, journal = {International Journal of Cancer}, number = {4}, doi = {10.1002/ijc.29835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190853}, pages = {927-938}, year = {2016}, abstract = {Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.}, language = {en} } @article{MuenstThierWinnemoelleretal.2016, author = {M{\"u}nst, Bernhard and Thier, Marc Christian and Winnem{\"o}ller, Dirk and Helfen, Martina and Thummer, Rajkumar P. and Edenhofer, Frank}, title = {Nanog induces suppression of senescence through downregulation of p27\(^{KIP1}\) expression}, series = {Journal of Cell Science}, volume = {129}, journal = {Journal of Cell Science}, number = {5}, doi = {10.1242/jcs.167932}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190761}, pages = {912-920}, year = {2016}, abstract = {A comprehensive analysis of the molecular network of cellular factors establishing and maintaining pluripotency as well as self renewal of pluripotent stem cells is key for further progress in understanding basic stem cell biology. Nanog is necessary for the natural induction of pluripotency in early mammalian development but dispensable for both its maintenance and its artificial induction. To gain further insight into the molecular activity of Nanog, we analyzed the outcomes of Nanog gain-of-function in various cell models employing a recently developed biologically active recombinant cell-permeant protein, Nanog-TAT. We found that Nanog enhances the proliferation of both NIH 3T3 and primary fibroblast cells. Nanog transduction into primary fibroblasts results in suppression of senescence-associated beta-galactosidase activity. Investigation of cell cycle factors revealed that transient activation of Nanog correlates with consistent downregulation of the cell cycle inhibitor p27\(^{KIP1}\) (also known as CDKN1B). By performing chromatin immunoprecipitation analysis, we confirmed bona fide Nanog-binding sites upstream of the p27\(^{KIP1}\) gene, establishing a direct link between physical occupancy and functional regulation. Our data demonstrates that Nanog enhances proliferation of fibroblasts through transcriptional regulation of cell cycle inhibitor p27 gene.}, language = {en} } @article{HowangyinZlatanovaPintoetal.2016, author = {Howangyin, Kiave-Yune and Zlatanova, Ivana and Pinto, Cristina and Ngkelo, Anta and Cochain, Cl{\´e}ment and Rouanet, Marie and Vilar, Jos{\´e} and Lemitre, Mathilde and Stockmann, Christian and Fleischmann, Bernd K. and Mallat, Ziad and Silvestre, Jean-S{\´e}bastien}, title = {Myeloid-epithelial-reproductive receptor tyrosine kinase and milk fat globule epidermal growth factor 8 coordinately improve remodeling after myocardial infarction via local delivery of vascular endothelial growth factor}, series = {Circulation}, volume = {133}, journal = {Circulation}, number = {9}, doi = {10.1161/CIRCULATIONAHA.115.020857}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190755}, pages = {826-839}, year = {2016}, abstract = {Background: In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. Methods and Results: We generated double-deficient mice for Mertk and Mfge8 (Mertk\(^{-/-}\)/Mfge8\(^{-/-}\)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk\(^{-/-}\)), or Mfge8-deficient (Mfge8\(^{-/-}\)) animals, Mertk\(^{-/-}\)/Mfge8\(^{-/-}\) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C\(^{High and Low}\) monocytes and macrophages. In parallel, Mertk\(^{-/-}\)/Mfge8\(^{-/-}\) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C\(^{High}\) and Ly6C\(^{Low}\) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C\(^{High}\)/Ly6C\(^{Low}\) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre\(^+\)/VEGFA\(^{fl/fl}\) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. Conclusions: After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart.}, language = {en} } @article{OPUS4-19073, title = {Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment}, series = {Leukemia}, volume = {30}, journal = {Leukemia}, number = {3}, organization = {SAKK}, doi = {10.1038/leu.2015.281}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190738}, pages = {562 -- 569}, year = {2016}, abstract = {Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N = 166 patients) and best available drug treatment (group B; N = 261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95\% confidence interval (CI): 0.69-0.82) vs 0.69 (95\% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high( P < 0.001) and non-high-risk disease (P = 0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56\% vs 39\%; P = 0.005) and free of drug treatment (56\% vs 6\%; P < 0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.}, language = {en} } @article{DuezelvanPraagSendtner2016, author = {D{\"u}zel, Emrah and van Praag, Henriette and Sendtner, Michael}, title = {Can physical exercise in old age improve memory and hippocampal function?}, series = {Brain}, volume = {139}, journal = {Brain}, number = {3}, doi = {10.1093/brain/awv407}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190721}, pages = {662-673}, year = {2016}, abstract = {Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer's disease. While the long-term health-promoting and protective effects of exercise are encouraging, it's potential to induce neuronal and vascular plasticity in the ageing brain is still poorly understood. It remains unclear whether exercise slows the trajectory of normal ageing by modifying vascular and metabolic risk factors and/or consistently boosts brain function by inducing structural and neurochemical changes in the hippocampus and related medial temporal lobe circuitry—brain areas that are important for learning and memory. Hence, it remains to be established to what extent exercise interventions in old age can improve brain plasticity above and beyond preservation of function. Existing data suggest that exercise trials aiming for improvement and preservation may require different outcome measures and that the balance between the two may depend on exercise intensity and duration, the presence of preclinical Alzheimer's disease pathology, vascular and metabolic risk factors and genetic variability.}, language = {en} } @article{WernerKojonazarovGassneretal.2016, author = {Werner, Franziska and Kojonazarov, Baktybek and Gaßner, Birgit and Abeßer, Marco and Schuh, Kai and V{\"o}lker, Katharina and Baba, Hideo A. and Dahal, Bhola K. and Schermuly, Ralph T. and Kuhn, Michaela}, title = {Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice}, series = {Basic Research in Cardiology}, volume = {111}, journal = {Basic Research in Cardiology}, number = {2}, doi = {10.1007/s00395-016-0541-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190664}, pages = {16}, year = {2016}, abstract = {The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmonary endothelial cells participate in the homeostatic actions of ANP. Therefore, we analyzed GC-A/cGMP signalling in lung endothelial cells and the cause and functional impact of lung endothelial GC-A dysfunction. Western blot and cGMP determinations showed that cultured human and murine pulmonary endothelial cells exhibit prominent GC-A expression and activity which were markedly blunted by hypoxia, a condition known to trigger pulmonary hypertension (PH). To elucidate the consequences of impaired endothelial ANP signalling, we studied mice with genetic endothelial cell-restricted ablation of the GC-A receptor (EC GC-A KO). Notably, EC GC-A KO mice exhibit PH already under resting, normoxic conditions, with enhanced muscularization of small arteries and perivascular infiltration of inflammatory cells. These alterations were aggravated on exposure of mice to chronic hypoxia. Lung endothelial GC-A dysfunction was associated with enhanced expression of angiotensin converting enzyme (ACE) and increased pulmonary levels of Angiotensin II. Angiotensin II/AT(1)-blockade with losartan reversed pulmonary vascular remodelling and perivascular inflammation of EC GC-A KO mice, and prevented their increment by chronic hypoxia. This experimental study indicates that endothelial effects of ANP are critical to prevent pulmonary vascular remodelling and PH. Chronic endothelial ANP/GC-A dysfunction, e.g. provoked by hypoxia, is associated with activation of the ACE-angiotensin pathway in the lung and PH.}, language = {en} } @article{BoehmScherzerShabalaetal.2016, author = {B{\"o}hm, J. and Scherzer, S. and Shabala, S. and Krol, E. and Neher, E. and Mueller, T. D. and Hedrich, R.}, title = {Venus flytrap HKT1-type channel provides for prey sodium uptake into carnivorous plant without conflicting with electrical excitability}, series = {Molecular Plant}, volume = {9}, journal = {Molecular Plant}, number = {3}, doi = {10.1016/j.molp.2015.09.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189803}, pages = {428-436}, year = {2016}, abstract = {The animal diet of the carnivorous Venus flytrap, Dionaea muscipula, contains a sodium load that enters the capture organ via an HKT1-type sodium channel, expressed in special epithelia cells on the inner trap lobe surface. DmHKT1 expression and sodium uptake activity is induced upon prey contact. Here, we analyzed the HKT1 properties required for prey sodium osmolyte management of carnivorous Dionaea. Analyses were based on homology modeling, generation of model-derived point mutants, and their functional testing in Xenopus oocytes. We showed that the wild-type HKT1 and its Na\(^+\)- and K\(^+\)-permeable mutants function as ion channels rather than K\(^+\) transporters driven by proton or sodium gradients. These structural and biophysical features of a high-capacity, Na\(^+\)-selective ion channel enable Dionaea glands to manage prey-derived sodium loads without confounding the action potential-based information management of the flytrap.}, language = {en} } @article{MotykaDyksikRyczkoetal.2016, author = {Motyka, M. and Dyksik, M. and Ryczko, K. and Weih, R. and Dallner, M. and H{\"o}fling, S. and Kamp, M. and Sęk, G. and Misiewicz, J.}, title = {Type-II quantum wells with tensile-strained GaAsSb layers for interband cascade lasers with tailored valence band mixing}, series = {Applied Physics Letters}, volume = {108}, journal = {Applied Physics Letters}, number = {10}, doi = {10.1063/1.4943193}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189795}, year = {2016}, abstract = {Optical properties of modified type II W-shaped quantum wells have been investigated with the aim to be utilized in interband cascade lasers. The results show that introducing a tensely strained GaAsSb layer, instead of a commonly used compressively strained GaInSb, allows employing the active transition involving valence band states with a significant admixture of the light holes. Theoretical predictions of multiband k.p theory have been experimentally verified by using photoluminescence and polarization dependent photoreflectance measurements. These results open a pathway for practical realization of mid-infrared lasing devices with uncommon polarization properties including, for instance, polarization-independent midinfrared light emitters.}, language = {en} } @article{CateGajendraAlsburyetal.2016, author = {Cate, Marie-Sophie and Gajendra, Sangeetha and Alsbury, Samantha and Raabe, Thomas and Tear, Guy and Mitchell, Kevin J.}, title = {Mushroom body defect is required in parallel to Netrin for midline axon guidance in Drosophila}, series = {Development}, volume = {143}, journal = {Development}, number = {6}, doi = {10.1242/dev.129684}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189770}, pages = {972-977}, year = {2016}, abstract = {The outgrowth of many neurons within the central nervous system is initially directed towards or away from the cells lying at the midline. Recent genetic evidence suggests that a simple model of differential sensitivity to the conserved Netrin attractants and Slit repellents is insufficient to explain the guidance of all axons at the midline. In the Drosophila embryonic ventral nerve cord, many axons still cross the midline in the absence of the Netrin genes (NetA and NetB) or their receptor frazzled. Here we show that mutation of mushroom body defect (mud) dramatically enhances the phenotype of Netrin or frazzled mutants, resulting in many more axons failing to cross the midline, although mutations in mud alone have little effect. This suggests that mud, which encodes a microtubule-binding coiled-coil protein homologous to NuMA and LIN-5, is an essential component of a Netrin-independent pathway that acts in parallel to promote midline crossing. We demonstrate that this novel role of Mud in axon guidance is independent of its previously described role in neural precursor development. These studies identify a parallel pathway controlling midline guidance in Drosophila and highlight a novel role for Mud potentially acting downstream of Frizzled to aid axon guidance.}, language = {en} } @article{SulimanSunPedersenetal.2016, author = {Suliman, Salwa and Sun, Yang and Pedersen, Torbjorn O. and Xue, Ying and Nickel, Joachim and Waag, Thilo and Finne-Wistrand, Anna and Steinm{\"u}ller-Nethl, Doris and Krueger, Anke and Costea, Daniela E. and Mustafa, Kamal}, title = {In vivo host response and degradation of copolymer scaffolds functionalized with nanodiamonds and bone morphogenetic protein 2}, series = {Advanced Healthcare Materials}, volume = {5}, journal = {Advanced Healthcare Materials}, number = {6}, doi = {10.1002/adhm.201500723}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189764}, pages = {730-742}, year = {2016}, abstract = {The aim is to evaluate the effect of modifying poly[(L-lactide)-co-(epsilon-caprolactone)] scaffolds (PLCL) with nanodiamonds (nDP) or with nDP+physisorbed BMP-2 (nDP+BMP-2) on in vivo host tissue response and degradation. The scaffolds are implanted subcutaneously in Balb/c mice and retrieved after 1, 8, and 27 weeks. Molecular weight analysis shows that modified scaffolds degrade faster than the unmodified. Gene analysis at week 1 shows highest expression of proinflammatory markers around nDP scaffolds; although the presence of inflammatory cells and foreign body giant cells is more prominent around the PLCL. Tissue regeneration markers are highly expressed in the nDP+BMP-2 scaffolds at week 8. A fibrous capsule is detectable by week 8, thinnest around nDP scaffolds and at week 27 thickest around PLCL scaffolds. mRNA levels of ALP, COL1 alpha 2, and ANGPT1 are signifi cantly upregulating in the nDP+BMP-2 scaffolds at week 1 with ectopic bone seen at week 8. Even when almost 90\% of the scaffold is degraded at week 27, nDP are observable at implantation areas without adverse effects. In conclusion, modifying PLCL scaffolds with nDP does not aggravate the host response and physisorbed BMP-2 delivery attenuates infl ammation while lowering the dose of BMP-2 to a relatively safe and economical level.}, language = {en} } @article{MartiniWillison2016, author = {Martini, Rudolf and Willison, Hugh}, title = {Neuroinflammation in the peripheral nerve: cause, modulator, or bystander in peripheral neuropathies?}, series = {GLIA}, volume = {64}, journal = {GLIA}, number = {4}, doi = {10.1002/glia.22899}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189696}, pages = {475-486}, year = {2016}, abstract = {The role of innate and adaptive inflammation as a primary driver or modifier of neuropathy in premorbidly normal nerves, and as a critical player in amplifying neuropathies of other known causes (e.g., genetic, metabolic) is incompletely understood and under-researched, despite unmet clinical need. Also, cellular and humoral components of the adaptive and innate immune system are substantial disease modifying agents in the context of neuropathies and, at least in some neuropathies, there is an identified tight interrelationship between both compartments of the immune system. Additionally, the quadruple relationship between Schwann cell, axon, macrophage, and endoneurial fibroblast, with their diverse membrane bound and soluble signalling systems, forms a distinct focus for investigation in nerve diseases with inflammation secondary to Schwann cell mutations and possibly others. Identification of key immunological effector pathways that amplify neuropathic features and associated clinical symptomatology including pain should lead to realistic and timely possibilities for translatable therapeutic interventions using existing immunomodulators, alongside the development of novel therapeutic targets.}, language = {en} } @article{ColvillBoothNilletal.2016, author = {Colvill, Emma and Booth, Jeremy and Nill, Simeon and Fast, Martin and Bedford, James and Oelfke, Uwe and Nakamura, Mitsuhiro and Poulsen, Per and Worm, Esben and Hansen, Rune and Ravkilde, Thomas and Rydh{\"o}g, Jonas Scherman and Pommer, Tobias and af Rosenschold, Per Munck and Lang, Stephanie and Guckenberger, Matthias and Groh, Christian and Herrmann, Christian and Verellen, Dirk and Poels, Kenneth and Wang, Lei and Hadsell, Michael and Sothmann, Thilo and Blanck, Oliver and Keall, Paul}, title = {A dosimetric comparison of real-time adaptive and non-adaptive radiotherapy: a multi-institutional study encompassing robotic, gimbaled, multileaf collimator and couch tracking}, series = {Radiotherapy and Oncology}, volume = {119}, journal = {Radiotherapy and Oncology}, number = {1}, doi = {10.1016/j.radonc.2016.03.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189605}, pages = {159-165}, year = {2016}, abstract = {Purpose: A study of real-time adaptive radiotherapy systems was performed to test the hypothesis that, across delivery systems and institutions, the dosimetric accuracy is improved with adaptive treatments over non-adaptive radiotherapy in the presence of patient-measured tumor motion. Methods and materials: Ten institutions with robotic(2), gimbaled(2), MLC(4) or couch tracking(2) used common materials including CT and structure sets, motion traces and planning protocols to create a lung and a prostate plan. For each motion trace, the plan was delivered twice to a moving dosimeter; with and without real-time adaptation. Each measurement was compared to a static measurement and the percentage of failed points for gamma-tests recorded. Results: For all lung traces all measurement sets show improved dose accuracy with a mean 2\%/2 mm gamma-fail rate of 1.6\% with adaptation and 15.2\% without adaptation (p < 0.001). For all prostate the mean 2\%/2 mm gamma-fail rate was 1.4\% with adaptation and 17.3\% without adaptation (p < 0.001). The difference between the four systems was small with an average 2\%/2 mm gamma-fail rate of <3\% for all systems with adaptation for lung and prostate. Conclusions: The investigated systems all accounted for realistic tumor motion accurately and performed to a similar high standard, with real-time adaptation significantly outperforming non-adaptive delivery methods.}, language = {en} } @article{KuhnScharfenortSchuemannetal.2016, author = {Kuhn, Manuel and Scharfenort, Robert and Sch{\"u}mann, Dirk and Schiele, Miriam A. and M{\"u}nsterk{\"o}tter, Anna L. and Deckert, J{\"u}rgen and Domschke, Katharina and Haaker, Jan and Kalisch, Raffael and Pauli, Paul and Reif, Andreas and Romanos, Marcel and Zwanzger, Peter and Lonsdorf, Tina B.}, title = {Mismatch or allostatic load? Timing of life adversity differentially shapes gray matter volume and anxious temperament}, series = {Social Cognitive and Affective Neuroscience}, volume = {11}, journal = {Social Cognitive and Affective Neuroscience}, number = {4}, doi = {10.1093/scan/nsv137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189645}, pages = {537-547}, year = {2016}, abstract = {Traditionally, adversity was defined as the accumulation of environmental events (allostatic load). Recently however, a mismatch between the early and the later (adult) environment (mismatch) has been hypothesized to be critical for disease development, a hypothesis that has not yet been tested explicitly in humans. We explored the impact of timing of life adversity (childhood and past year) on anxiety and depression levels (N = 833) and brain morphology (N = 129). Both remote (childhood) and proximal (recent) adversities were differentially mirrored in morphometric changes in areas critically involved in emotional processing (i.e. amygdala/hippocampus, dorsal anterior cingulate cortex, respectively). The effect of adversity on affect acted in an additive way with no evidence for interactions (mismatch). Structural equation modeling demonstrated a direct effect of adversity on morphometric estimates and anxiety/depression without evidence of brain morphology functioning as a mediator. Our results highlight that adversity manifests as pronounced changes in brain morphometric and affective temperament even though these seem to represent distinct mechanistic pathways. A major goal of future studies should be to define critical time periods for the impact of adversity and strategies for intervening to prevent or reverse the effects of adverse childhood life experiences.}, language = {en} } @article{ChioreanVonHoffRenietal.2016, author = {Chiorean, E. G. and Von Hoff, D. D. and Reni, M. and Arena, F. P. and Infante, J. R. and Bathini, V. G. and Wood, T. E. and Mainwaring, P. N. and Muldoon, R. T. and Clingan, P. R. and Kunzmann, V. and Ramanathan, R. K. and Tabernero, J. and Goldstein, D. and McGovern, D. and Lu, B. and Ko, A.}, title = {CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer}, series = {Annals of Oncology}, volume = {27}, journal = {Annals of Oncology}, number = {4}, doi = {10.1093/annonc/mdw006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189659}, pages = {654-660}, year = {2016}, abstract = {Background A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. Patients and methods Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. Results Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80\%) versus those without (20\%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40\% versus 13\%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15\% versus 5\%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16\% (40/252) and 6\% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79\% and 84\% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. Conclusion This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.}, language = {en} } @article{WhiteWiederholdLoeffleretal.2016, author = {White, P. Lewis and Wiederhold, Nathan P. and Loeffler, Juergen and Najvar, Laura K. and Melchers, Willem and Herrera, Monica and Bretagne, Stephane and Wickes, Brian and Kirkpatrick, William R. and Barnes, Rosemary A. and Donnelly, J. Peter and Patterson, Thomas F.}, title = {Comparison of nonculture blood-based tests for diagnosing invasive aspergillosis in an animal model}, series = {Journal of Clinical Microbiology}, volume = {54}, journal = {Journal of Clinical Microbiology}, number = {4}, doi = {10.1128/JCM.03233-15}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189674}, pages = {960-966}, year = {2016}, abstract = {The European Aspergillus PCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and beta-D-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and beta-D-glucan were 73\%, 65\%, 68\%, and 46\%, respectively. The corresponding specificities were 92\%, 79\%, 80\%, and 100\%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and beta-D-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and beta-D-glucan proved optimal (area under the curve AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests.}, language = {en} } @article{BarquistMayhoCumminsetal.2016, author = {Barquist, Lars and Mayho, Matthew and Cummins, Carla and Cain, Amy K. and Boinett, Christine J. and Page, Andrew J. and Langridge, Gemma C. and Quail, Michael A. and Keane, Jacqueline A. and Parkhill, Julian}, title = {The TraDIS toolkit: sequencing and analysis for dense transposon mutant libraries}, series = {Bioinformatics}, volume = {32}, journal = {Bioinformatics}, number = {7}, doi = {10.1093/bioinformatics/btw022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189667}, pages = {1109-1111}, year = {2016}, abstract = {Transposon insertion sequencing is a high-throughput technique for assaying large libraries of otherwise isogenic transposon mutants providing insight into gene essentiality, gene function and genetic interactions. We previously developed the Transposon Directed Insertion Sequencing (TraDIS) protocol for this purpose, which utilizes shearing of genomic DNA followed by specific PCR amplification of transposon-containing fragments and Illumina sequencing. Here we describe an optimized high-yield library preparation and sequencing protocol for TraDIS experiments and a novel software pipeline for analysis of the resulting data. The Bio-Tradis analysis pipeline is implemented as an extensible Perl library which can either be used as is, or as a basis for the development of more advanced analysis tools. This article can serve as a general reference for the application of the TraDIS methodology.}, language = {en} } @article{ThomasZengRiviereetal.2016, author = {Thomas, Anna C. and Zeng, Zhiqiang and Rivi{\`e}re, Jean-Baptiste and O'Shaughnessy, Ryan and Al-Olabi, Lara and St.-Onge, Judith and Atherton, David J. and Aubert, H{\´e}l{\`e}ne and Bagazgoitia, Lorea and Barbarot, S{\´e}bastien and Bourrat, Emmanuelle and Chiaverini, Christine and Chong, W. Kling and Duffourd, Yannis and Glover, Mary and Groesser, Leopold and Hadj-Rabia, Smail and Hamm, Henning and Happle, Rudolf and Mushtaq, Imran and Lacour, Jean-Philippe and Waelchli, Regula and Wobser, Marion and Vabres, Pierre and Patton, E. Elizabeth and Kinsler, Veronica A.}, title = {Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis}, series = {Journal of Investigative Dermatology}, volume = {136}, journal = {Journal of Investigative Dermatology}, number = {4}, doi = {10.1016/j.jid.2015.11.027}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189689}, pages = {770-778}, year = {2016}, abstract = {Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Ga subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11\(^R183C\) and GNA11\(^Q209L\) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11\(^R183C\) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.}, language = {en} } @article{BędkowskiMajekMajeketal.2016, author = {Będkowski, Janusz and Majek, Karol and Majek, Piotr and Musialik, Paweł and Pełka, Michał and N{\"u}chter, Andreas}, title = {Intelligent mobile system for improving spatial design support and security inside buildings}, series = {Mobile Networks and Applications}, volume = {21}, journal = {Mobile Networks and Applications}, number = {2}, doi = {10.1007/s11036-015-0654-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189597}, pages = {313-326}, year = {2016}, abstract = {This paper concerns the an intelligent mobile application for spatial design support and security domain. Mobility has two aspects in our research: The first one is the usage of mobile robots for 3D mapping of urban areas and for performing some specific tasks. The second mobility aspect is related with a novel Software as a Service system that allows access to robotic functionalities and data over the Ethernet, thus we demonstrate the use of the novel NVIDIA GRID technology allowing to virtualize the graphic processing unit. We introduce Complex Shape Histogram, a core component of our artificial intelligence engine, used for classifying 3D point clouds with a Support Vector Machine. We use Complex Shape Histograms also for loop closing detection in the simultaneous localization and mapping algorithm. Our intelligent mobile system is built on top of the Qualitative Spatio-Temporal Representation and Reasoning framework. This framework defines an ontology and a semantic model, which are used for building the intelligent mobile user interfaces. We show experiments demonstrating advantages of our approach. In addition, we test our prototypes in the field after the end-user case studies demonstrating a relevant contribution for future intelligent mobile systems that merge mobile robots with novel data centers.}, language = {en} } @article{ClaussYanKuenzer2016, author = {Clauss, Kersten and Yan, Huimin and Kuenzer, Claudia}, title = {Mapping Paddy Rice in China in 2002, 2005, 2010 and 2014 with MODIS Time Series}, series = {Remote Sensing}, volume = {8}, journal = {Remote Sensing}, number = {5}, doi = {10.3390/rs8050434}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180557}, year = {2016}, abstract = {Rice is an important food crop and a large producer of green-house relevant methane. Accurate and timely maps of paddy fields are most important in the context of food security and greenhouse gas emission modelling. During their life-cycle, rice plants undergo a phenological development that influences their interaction with waves in the visible light and infrared spectrum. Rice growth has a distinctive signature in time series of remotely-sensed data. We used time series of MODIS (Moderate Resolution Imaging Spectroradiometer) products MOD13Q1 and MYD13Q1 and a one-class support vector machine to detect these signatures and classify paddy rice areas in continental China. Based on these classifications, we present a novel product for continental China that shows rice areas for the years 2002, 2005, 2010 and 2014 at 250-m resolution. Our classification has an overall accuracy of 0.90 and a kappa coefficient of 0.77 compared to our own reference dataset for 2014 and correlates highly with rice area statistics from China's Statistical Yearbooks (R2 of 0.92 for 2010, 0.92 for 2005 and 0.90 for 2002). Moderate resolution time series analysis allows accurate and timely mapping of rice paddies over large areas with diverse cropping schemes.}, language = {en} } @article{BlaettnerDasPaprotkaetal.2016, author = {Bl{\"a}ttner, Sebastian and Das, Sudip and Paprotka, Kerstin and Eilers, Ursula and Krischke, Markus and Kretschmer, Dorothee and Remmele, Christian W. and Dittrich, Marcus and M{\"u}ller, Tobias and Schuelein-Voelk, Christina and Hertlein, Tobias and Mueller, Martin J. and Huettel, Bruno and Reinhardt, Richard and Ohlsen, Knut and Rudel, Thomas and Fraunholz, Martin J.}, title = {Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes}, series = {PLoS Pathogens}, volume = {12}, journal = {PLoS Pathogens}, number = {9}, doi = {10.1371/journal.ppat.1005857}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180380}, year = {2016}, abstract = {Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection.}, language = {en} } @article{FischerHelfrichFoersterPeschel2016, author = {Fischer, Robin and Helfrich-F{\"o}rster, Charlotte and Peschel, Nicolai}, title = {GSK-3 Beta Does Not Stabilize Cryptochrome in the Circadian Clock of Drosophila}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0146571}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180370}, year = {2016}, abstract = {Cryptochrome (CRY) is the primary photoreceptor of Drosophila's circadian clock. It resets the circadian clock by promoting light-induced degradation of the clock protein Timeless (TIM) in the proteasome. Under constant light, the clock stops because TIM is absent, and the flies become arrhythmic. In addition to TIM degradation, light also induces CRY degradation. This depends on the interaction of CRY with several proteins such as the E3 ubiquitin ligases Jetlag (JET) and Ramshackle (BRWD3). However, CRY can seemingly also be stabilized by interaction with the kinase Shaggy (SGG), the GSK-3 beta fly orthologue. Consequently, flies with SGG overexpression in certain dorsal clock neurons are reported to remain rhythmic under constant light. We were interested in the interaction between CRY, Ramshackle and SGG and started to perform protein interaction studies in S2 cells. To our surprise, we were not able to replicate the results, that SGG overexpression does stabilize CRY, neither in S2 cells nor in the relevant clock neurons. SGG rather does the contrary. Furthermore, flies with SGG overexpression in the dorsal clock neurons became arrhythmic as did wild-type flies. Nevertheless, we could reproduce the published interaction of SGG with TIM, since flies with SGG overexpression in the lateral clock neurons shortened their free-running period. We conclude that SGG does not directly interact with CRY but rather with TIM. Furthermore we could demonstrate, that an unspecific antibody explains the observed stabilization effects on CRY.}, language = {en} } @article{GlaserFehrholzCurstedtetal.2016, author = {Glaser, Kirsten and Fehrholz, Markus and Curstedt, Tore and Kunzmann, Steffen and Speer, Christian P.}, title = {Effects of the New Generation Synthetic Reconstituted Surfactant CHF5633 on Pro- and Anti-Inflammatory Cytokine Expression in Native and LPS-Stimulated Adult CD14\(^{+}\) Monocytes}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0146898}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180195}, year = {2016}, abstract = {Background Surfactant replacement therapy is the standard of care for the prevention and treatment of neonatal respiratory distress syndrome. New generation synthetic surfactants represent a promising alternative to animal-derived surfactants. CHF5633, a new generation reconstituted synthetic surfactant containing SP-B and SP-C analogs and two synthetic phospholipids has demonstrated biophysical effectiveness in vitro and in vivo. While several surfactant preparations have previously been ascribed immunomodulatory capacities, in vitro data on immunomodulation by CHF5633 are limited, so far. Our study aimed to investigate pro- and anti-inflammatory effects of CHF5633 on native and LPS-stimulated human adult monocytes. Methods Highly purified adult CD14\(^{+}\) cells, either native or simultaneously stimulated with LPS, were exposed to CHF5633, its components, or poractant alfa (Curosurf\(^{®}\)). Subsequent expression of TNF-α, IL-1β, IL-8 and IL-10 mRNA was quantified by real-time quantitative PCR, corresponding intracellular cytokine synthesis was analyzed by flow cytometry. Potential effects on TLR2 and TLR4 mRNA and protein expression were monitored by qPCR and flow cytometry. Results Neither CHF5633 nor any of its components induced inflammation or apoptosis in native adult CD14\(^{+}\) monocytes. Moreover, LPS-induced pro-inflammatory responses were not aggravated by simultaneous exposure of monocytes to CHF5633 or its components. In LPS-stimulated monocytes, exposure to CHF5633 led to a significant decrease in TNF-α mRNA (0.57 ± 0.23-fold, p = 0.043 at 4h; 0.56 ± 0.27-fold, p = 0.042 at 14h). Reduction of LPS-induced IL-1β mRNA expression was not significant (0.73 ± 0.16, p = 0.17 at 4h). LPS-induced IL-8 and IL-10 mRNA and protein expression were unaffected by CHF5633. For all cytokines, the observed CHF5633 effects paralleled a Curosurf®-induced modulation of cytokine response. TLR2 and TLR4 mRNA and protein expression were not affected by CHF5633 and Curosurf®, neither in native nor in LPS-stimulated adult monocytes. Conclusion The new generation reconstituted synthetic surfactant CHF5633 was tested for potential immunomodulation on native and LPS-activated adult human monocytes. Our data confirm that CHF5633 does not exert unintended pro-inflammatory effects in both settings. On the contrary, CHF5633 significantly suppressed TNF-α mRNA expression in LPS-stimulated adult monocytes, indicating potential anti-inflammatory effects.}, language = {en} } @article{KoenigWolfHeisenberg2016, author = {Koenig, Sebastian and Wolf, Reinhard and Heisenberg, Martin}, title = {Vision in Flies: Measuring the Attention Span}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {2}, doi = {10.1371/journal.pone.0148208}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179947}, year = {2016}, abstract = {A visual stimulus at a particular location of the visual field may elicit a behavior while at the same time equally salient stimuli in other parts do not. This property of visual systems is known as selective visual attention (SVA). The animal is said to have a focus of attention (FoA) which it has shifted to a particular location. Visual attention normally involves an attention span at the location to which the FoA has been shifted. Here the attention span is measured in Drosophila. The fly is tethered and hence has its eyes fixed in space. It can shift its FoA internally. This shift is revealed using two simultaneous test stimuli with characteristic responses at their particular locations. In tethered flight a wild type fly keeps its FoA at a certain location for up to 4s. Flies with a mutation in the radish gene, that has been suggested to be involved in attention-like mechanisms, display a reduced attention span of only 1s.}, language = {en} } @article{BrendtkeWiehlGroeberetal.2016, author = {Brendtke, Rico and Wiehl, Michael and Groeber, Florian and Schwarz, Thomas and Walles, Heike and Hansmann, Jan}, title = {Feasibility Study on a Microwave-Based Sensor for Measuring Hydration Level Using Human Skin Models}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0153145}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179934}, year = {2016}, abstract = {Tissue dehydration results in three major types of exsiccosis—hyper-, hypo-, or isonatraemia. All three types entail alterations of salt concentrations leading to impaired biochemical processes, and can finally cause severe morbidity. The aim of our study was to demonstrate the feasibility of a microwave-based sensor technology for the non-invasive measurement of the hydration status. Electromagnetic waves at high frequencies interact with molecules, especially water. Hence, if a sample contains free water molecules, this can be detected in a reflected microwave signal. To develop the sensor system, human three-dimensional skin equivalents were instituted as a standardized test platform mimicking reproducible exsiccosis scenarios. Therefore, skin equivalents with a specific hydration and density of matrix components were generated and microwave measurements were performed. Hydration-specific spectra allowed deriving the hydration state of the skin models. A further advantage of the skin equivalents was the characterization of the impact of distinct skin components on the measured signals to investigate mechanisms of signal generation. The results demonstrate the feasibility of a non-invasive microwave-based hydration sensor technology. The sensor bears potential to be integrated in a wearable medical device for personal health monitoring.}, language = {en} } @article{TahaClausLappannetal.2016, author = {Taha, Muhamed-Kheir and Claus, Heike and Lappann, Martin and Veyrier, Fr{\´e}d{\´e}ric J. and Otto, Andreas and Becher, D{\"o}rte and Deghmane, Ala-Eddine and Frosch, Matthias and Hellenbrand, Wiebke and Hong, Eva and du Ch{\^a}telet, Isabelle Parent and Prior, Karola and Harmsen, Dag and Vogel, Ulrich}, title = {Evolutionary Events Associated with an Outbreak of Meningococcal Disease in Men Who Have Sex with Men}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0154047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179870}, year = {2016}, abstract = {Meningococci spread via respiratory droplets, whereas the closely related gonococci are transmitted sexually. Several outbreaks of invasive meningococcal disease have been reported in Europe and the United States among men who have sex with men (MSM). We recently identified an outbreak of serogroup C meningococcal disease among MSM in Germany and France. In this study, genomic and proteomic techniques were used to analyze the outbreak isolates. In addition, genetically identical urethritis isolates were recovered from France and Germany and included in the analysis. Genome sequencing revealed that the isolates from the outbreak among MSM and from urethritis cases belonged to a clade within clonal complex 11. Proteome analysis showed they expressed nitrite reductase, enabling anaerobic growth as previously described for gonococci. Invasive isolates from MSM, but not urethritis isolates, further expressed functional human factor H binding protein associated with enhanced survival in a newly developed transgenic mouse model expressing human factor H, a complement regulatory protein. In conclusion, our data suggest that urethritis and outbreak isolates followed a joint adaptation route including adaption to the urogenital tract.}, language = {en} } @article{OrtizSotoSeibel2016, author = {Ortiz-Soto, Maria Elena and Seibel, J{\"u}rgen}, title = {Expression of Functional Human Sialyltransferases ST3Gal1 and ST6Gal1 in Escherichia coli}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0155410}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179807}, year = {2016}, abstract = {Sialyltransferases (STs) are disulfide-containing, type II transmembrane glycoproteins that catalyze the transfer of sialic acid to proteins and lipids and participate in the synthesis of the core structure oligosaccharides of human milk. Sialic acids are found at the outermost position of glycostructures, playing a key role in health and disease. Sialylation is also essential for the production of recombinant therapeutic proteins (RTPs). Despite their importance, availability of sialyltransferases is limited due to the low levels of stable, soluble and active protein produced in bacterial expression systems, which hampers biochemical and structural studies on these enzymes and restricts biotechnological applications. We report the successful expression of active human sialyltransferases ST3Gal1 and ST6Gal1 in commercial Escherichia coli strains designed for production of disulfide-containing proteins. Fusion of hST3Gal1 with different solubility enhancers and substitution of exposed hydrophobic amino acids by negatively charged residues (supercharging-like approach) were performed to promote solubility and folding. Co-expression of sialyltransferases with the chaperon/foldases sulfhydryl oxidase, protein disulfide isomerase and disulfide isomerase C was explored to improve the formation of native disulfide bonds. Active sialyltransferases fused with maltose binding protein (MBP) were obtained in sufficient amounts for biochemical and structural studies when expressed under oxidative conditions and co-expression of folding factors increased the yields of active and properly folded sialyltransferases by 20\%. Mutation of exposed hydrophobic amino acids increased recovery of active enzyme by 2.5-fold, yielding about 7 mg of purified protein per liter culture. Functionality of recombinant enzymes was evaluated in the synthesis of sialosides from the β-d-galactoside substrates lactose, N-acetyllactosamine and benzyl 2-acetamido-2-deoxy-3-O-(β-d-galactopyranosyl)-α-d-galactopyranoside.}, language = {en} } @article{SimsekyilmazLiehnWeinandyetal.2016, author = {Simsekyilmaz, Sakine and Liehn, Elisa A. and Weinandy, Stefan and Schreiber, Fabian and Megens, Remco T. A. and Theelen, Wendy and Smeets, Ralf and Jockenh{\"o}vel, Stefan and Gries, Thomas and M{\"o}ller, Martin and Klee, Doris and Weber, Christian and Zernecke, Alma}, title = {Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0155829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179745}, year = {2016}, abstract = {Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE\(^{-/-}\) carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.}, language = {en} } @article{MorisVandenBroeckToscoetal.2016, author = {Moris, Lisa and Van den Broeck, Thomas and Tosco, Lorenzo and Van Baelen, Anthony and Gontero, Paolo and Karnes, Robert Jeffrey and Everaerts, Wouter and Albersen, Maarten and Bastian, Patrick J. and Chlosta, Piotr and Claessens, Frank and Chun, Felix K. and Graefen, Markus and Gratzke, Christian and Kneitz, Burkhard and Marchioro, Giansilvio and Salas, Rafael Sanchez and Tombal, Bertrand and Van Der Poel, Henk and Walz, Jochen Christoph and De Meerleer, Gert and Bossi, Alberto and Haustermans, Karin and Montorsi, Francesco and Van Poppel, Hendrik and Spahn, Martin and Briganti, Alberto and Joniau, Steven}, title = {Impact of lymph node burden on survival of high-risk prostate cancer patients following radical prostatectomy and pelvic lymph node dissection}, series = {Frontiers in Surgery}, volume = {3}, journal = {Frontiers in Surgery}, organization = {European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT)}, issn = {2296-875X}, doi = {10.3389/fsurg.2016.00065}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195721}, year = {2016}, abstract = {Aim To determine the impact of the extent of lymph node invasion (LNI) on long-term oncological outcomes after radical prostatectomy (RP). Material and methods In this retrospective study, we examined the data of 1,249 high-risk, non-metastatic PCa patients treated with RP and pelvic lymph node dissection (PLND) between 1989 and 2011 at eight different tertiary institutions. We fitted univariate and multivariate Cox models to assess independent predictors of cancer-specific survival (CSS) and overall survival (OS). The number of positive lymph node (LN) was dichotomized according to the most informative cutoff predicting CSS. Kaplan-Meier curves assessed CSS and OS rates. Only patients with at least 10 LNs removed at PLND were included. This cutoff was chosen as a surrogate for a well performed PNLD. Results Mean age was 65 years (median: 66, IQR 60-70). Positive surgical margins were present in 53.7\% (n = 671). Final Gleason score (GS) was 2-6 in 12.7\% (n = 158), 7 in 52\% (n = 649), and 8-10 in 35.4\% (n = 442). The median number of LNs removed during PLND was 15 (IQR 12-17). Of all patients, 1,128 (90.3\%) had 0-3 positive LNs, while 126 (9.7\%) had ≥4 positive LNs. Patients with 0-3 positive LNs had significantly better CSS outcome at 10-year follow-up compared to patients with ≥4 positive LNs (87 vs. 50\%; p < 0.0001). Similar results were obtained for OS, with a 72 vs. 37\% (p < 0.0001) survival at 10 years for patients with 0-3 vs. ≥4 positive LNs, respectively. At multivariate analysis, final GS of 8-10, salvage ADT therapy, and ≥4 (vs. <4) positive LNs were predictors of worse CSS and OS. Pathological stage pT4 was an additional predictor of worse CSS. Conclusion Four or more positive LNs, pathological stage pT4, and final GS of 8-10 represent independent predictors for worse CSS in patients with high-risk PCa. Primary tumor biology remains a strong driver of tumor progression and patients having ≥4 positive LNs could be considered an enriched patient group in which novel treatment strategies should be studied.}, language = {en} } @article{DipaolaPavanCattaneoetal.2016, author = {Dipaola, Mariangela and Pavan, Esteban E. and Cattaneo, Andrea and Frazzitta, Giuseppe and Pezzoli, Gianni and Cavallari, Paolo and Frigo, Carlo A. and Isaias, Ioannis U.}, title = {Mechanical Energy Recovery during Walking in Patients with Parkinson Disease}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0156420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179739}, year = {2016}, abstract = {The mechanisms of mechanical energy recovery during gait have been thoroughly investigated in healthy subjects, but never described in patients with Parkinson disease (PD). The aim of this study was to investigate whether such mechanisms are preserved in PD patients despite an altered pattern of locomotion. We consecutively enrolled 23 PD patients (mean age 64±9 years) with bilateral symptoms (H\&Y ≥II) if able to walk unassisted in medication-off condition (overnight suspension of all dopaminergic drugs). Ten healthy subjects (mean age 62±3 years) walked both at their 'preferred' and 'slow' speeds, to match the whole range of PD velocities. Kinematic data were recorded by means of an optoelectronic motion analyzer. For each stride we computed spatio-temporal parameters, time-course and range of motion (ROM) of hip, knee and ankle joint angles. We also measured kinetic (Wk), potential (W\(_{p}\)), total (W\(_{totCM}\)) energy variations and the energy recovery index (ER). Along with PD progression, we found a significant correlation of W\(_{totCM}\) and W\(_{p}\) with knee ROM and in particular with knee extension in terminal stance phase. W\(_{k}\) and ER were instead mainly related to gait velocity. In PD subjects, the reduction of knee ROM significantly diminished both W\(_{p}\) and W\(_{totCM}\). Rehabilitation treatments should possibly integrate passive and active mobilization of knee to prevent a reduction of gait-related energetic components.}, language = {en} } @article{VieraElMerahbiNieswandtetal.2016, author = {Viera, Jonathan Trujillo and El-Merahbi, Rabih and Nieswandt, Bernhard and Stegner, David and Sumara, Grzegorz}, title = {Phospholipases D1 and D2 Suppress Appetite and Protect against Overweight}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0157607}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179729}, year = {2016}, abstract = {Obesity is a major risk factor predisposing to the development of peripheral insulin resistance and type 2 diabetes (T2D). Elevated food intake and/or decreased energy expenditure promotes body weight gain and acquisition of adipose tissue. Number of studies implicated phospholipase D (PLD) enzymes and their product, phosphatidic acid (PA), in regulation of signaling cascades controlling energy intake, energy dissipation and metabolic homeostasis. However, the impact of PLD enzymes on regulation of metabolism has not been directly determined so far. In this study we utilized mice deficient for two major PLD isoforms, PLD1 and PLD2, to assess the impact of these enzymes on regulation of metabolic homeostasis. We showed that mice lacking PLD1 or PLD2 consume more food than corresponding control animals. Moreover, mice deficient for PLD2, but not PLD1, present reduced energy expenditure. In addition, deletion of either of the PLD enzymes resulted in development of elevated body weight and increased adipose tissue content in aged animals. Consistent with the fact that elevated content of adipose tissue predisposes to the development of hyperlipidemia and insulin resistance, characteristic for the pre-diabetic state, we observed that Pld1\(^{-/-}\) and Pld2\(^{-/-}\) mice present elevated free fatty acids (FFA) levels and are insulin as well as glucose intolerant. In conclusion, our data suggest that deficiency of PLD1 or PLD2 activity promotes development of overweight and diabetes.}, language = {en} } @article{PrelogHilligardtSchmidtetal.2016, author = {Prelog, Martina and Hilligardt, Deborah and Schmidt, Christian A. and Przybylski, Grzegorz K. and Leierer, Johannes and Almanzar, Giovanni and El Hajj, Nady and Lesch, Klaus-Peter and Arolt, Volker and Zwanzger, Peter and Haaf, Thomas and Domschke, Katharina}, title = {Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder?}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0157930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179684}, year = {2016}, abstract = {Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Forkhead-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age- and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders.}, language = {en} } @article{KoenigWolfHeisenberg2016, author = {Koenig, Sebastian and Wolf, Reinhard and Heisenberg, Martin}, title = {Visual Attention in Flies-Dopamine in the Mushroom Bodies Mediates the After-Effect of Cueing}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0161412}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179564}, year = {2016}, abstract = {Visual environments may simultaneously comprise stimuli of different significance. Often such stimuli require incompatible responses. Selective visual attention allows an animal to respond exclusively to the stimuli at a certain location in the visual field. In the process of establishing its focus of attention the animal can be influenced by external cues. Here we characterize the behavioral properties and neural mechanism of cueing in the fly Drosophila melanogaster. A cue can be attractive, repulsive or ineffective depending upon (e.g.) its visual properties and location in the visual field. Dopamine signaling in the brain is required to maintain the effect of cueing once the cue has disappeared. Raising or lowering dopamine at the synapse abolishes this after-effect. Specifically, dopamine is necessary and sufficient in the αβ-lobes of the mushroom bodies. Evidence is provided for an involvement of the αβ\(_{posterior}\) Kenyon cells.}, language = {en} } @article{UeceylerSchroeterKafkeetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Schr{\"o}ter, Nils and Kafke, Waldemar and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Sommer, Claudia}, title = {Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0166484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178856}, year = {2016}, abstract = {Background The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. Methods At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. Results We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Conclusions Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.}, language = {en} } @article{BatschingWolfHeisenberg2016, author = {Batsching, Sophie and Wolf, Reinhard and Heisenberg, Martin}, title = {Inescapable Stress Changes Walking Behavior in Flies - Learned Helplessness Revisited}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0167066}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178640}, year = {2016}, abstract = {Like other animals flies develop a state of learned helplessness in response to unescapable aversive events. To show this, two flies, one 'master', one 'yoked', are each confined to a dark, small chamber and exposed to the same sequence of mild electric shocks. Both receive these shocks when the master fly stops walking for more than a second. Behavior in the two animals is differently affected by the shocks. Yoked flies are transiently impaired in place learning and take longer than master flies to exit from the chamber towards light. After the treatment they walk more slowly and take fewer and shorter walking bouts. The low activity is attributed to the fly's experience that its escape response, an innate behavior to terminate the electric shocks, does not help anymore. Earlier studies using heat pulses instead of electric shocks had shown similar effects. This parallel supports the interpretation that it is the uncontrollability that induces the state.}, language = {en} }