TY - JOUR A1 - Wölfling, Mirko A1 - Becker, Mira C. A1 - Uhl, Britta A1 - Traub, Anja A1 - Fiedler, Konrad T1 - How differences in the settling behaviour of moths (Lepidoptera) may contribute to sampling bias when using automated light traps JF - European Journal of Entomology N2 - 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. KW - Lepidoptera KW - moths KW - biodiversity assessment KW - sampling method KW - light-trapping KW - sampling bias Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191154 VL - 113 ER - TY - JOUR A1 - Dietrich, Christoph G. A1 - Götze, Oliver A1 - Geier, Andreas T1 - Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance JF - World Journal of Gastroenterology N2 - 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. KW - Liver cirrhosis KW - Drug metabolism KW - Transport KW - Breath tests KW - Lipid metabolism KW - Glucose metabolism Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191136 VL - 22 IS - 1 ER - TY - JOUR A1 - Selle, Martina A1 - Hertlein, Tobias A1 - Oesterreich, Babett A1 - Klemm, Theresa A1 - Kloppot, Peggy A1 - Müller, Elke A1 - Ehricht, Ralf A1 - Stentzel, Sebastian A1 - Bröker, Barbara M. A1 - Engelmann, Susanne A1 - Ohlsen, Knut T1 - Global antibody response to Staphylococcus aureus live-cell vaccination JF - Scientific Reports N2 - 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. KW - pathogens KW - bacterial infection KW - cell vaccines KW - Staphylococcus aureus Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181245 VL - 6 ER - TY - JOUR A1 - Howangyin, Kiave-Yune A1 - Zlatanova, Ivana A1 - Pinto, Cristina A1 - Ngkelo, Anta A1 - Cochain, Clément A1 - Rouanet, Marie A1 - Vilar, José A1 - Lemitre, Mathilde A1 - Stockmann, Christian A1 - Fleischmann, Bernd K. A1 - Mallat, Ziad A1 - Silvestre, Jean-Sébastien T1 - 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 JF - Circulation N2 - 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. KW - inflammation KW - macrophages KW - myocardial infarction KW - myocarditis KW - neovascularization, physiologic Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190755 VL - 133 IS - 9 ER - TY - JOUR A1 - Edelmann, Frank A1 - Musial-Bright, Lindy A1 - Gelbrich, Goetz A1 - Trippel, Tobias A1 - Radenovic, Sara A1 - Wachter, Rolf A1 - Inkrot, Simone A1 - Loncar, Goran A1 - Tahirovic, Elvis A1 - Celic, Vera A1 - Veskovic, Jovan A1 - Zdravkovic, Marija A1 - Lainscak, Mitja A1 - Apostolović, Svetlana A1 - Neskovic, Aleksandar N. A1 - Pieske, Burkert A1 - Düngen, Hans-Dirk T1 - Tolerability and feasibility of beta-blocker titration in HFpEF versus HFrEF: Insights from the CIBIS-ELD trial JF - JACC: Heart Failure N2 - 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). KW - beta-blockers KW - heart failure KW - HFpEF KW - HFrEF KW - tolerability Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191022 VL - 4 IS - 2 ER - TY - JOUR A1 - Schendzielorz, P. A1 - Froelich, K. A1 - Rak, K. A1 - Gehrke, T. A1 - Scherzad, A. A1 - Hagen, R. A1 - Radeloff, A. T1 - Labeling Adipose-Derived Stem Cells with Hoechst 33342: Usability and Effects on Differentiation Potential and DNA Damage JF - Stem Cells International N2 - 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. KW - cell labeling KW - adipose-derived stem cells KW - Hoechst 33342 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181268 ER - TY - JOUR A1 - Kramer, Susanne A1 - Piper, Sophie A1 - Estevez, Antonio A1 - Carrington, Mark T1 - Polycistronic trypanosome mRNAs are a target for the exosome JF - Molecular and Biochemical Parasitology N2 - 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. KW - Trypanosoma brucei KW - Exosome KW - NMD KW - Polycistronic mRNA KW - trans-splicing KW - Trypanosomes Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191350 VL - 205 IS - 1-2 ER - TY - JOUR A1 - Bornstein, Stefan R. A1 - Allolio, Bruno A1 - Arlt, Wiebke A1 - Barthel, Andreas A1 - Don-Wauchope, Andrew A1 - Hammer, Gary D. A1 - Husebye, Eystein S. A1 - Merke, Deborah P. A1 - Murad, M. Hassan A1 - Stratakis, Constantine A. A1 - Torpy, David J. T1 - Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline JF - Journal of Clinical Endocrinology & Metabolism N2 - 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. KW - glucocorticoid replacement therapy KW - Addison's disease KW - short Synacthen test KW - insulin tolerance test Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190893 VL - 101 IS - 2 ER - TY - JOUR A1 - Werner, Franziska A1 - Kojonazarov, Baktybek A1 - Gaßner, Birgit A1 - Abeßer, Marco A1 - Schuh, Kai A1 - Völker, Katharina A1 - Baba, Hideo A. A1 - Dahal, Bhola K. A1 - Schermuly, Ralph T. A1 - Kuhn, Michaela T1 - Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice JF - Basic Research in Cardiology N2 - 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. KW - Atrial natriuretic peptide KW - Endothelium KW - Guanylyl cyclase-A KW - Cyclic GMP KW - Pulmonary hypertension Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190664 VL - 111 IS - 2 ER - TY - JOUR A1 - Czakai, Kristin A1 - Leonhardt, Ines A1 - Dix, Andreas A1 - Bonin, Michael A1 - Linde, Joerg A1 - Einsele, Hermann A1 - Kurzai, Oliver A1 - Loeffler, Jürgen T1 - Krüppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans JF - Scientific Reports N2 - 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 Krüppel-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. KW - gene regulation in immune cells KW - fungal host response KW - Aspergillus fumigatus KW - Candida albicans Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181185 VL - 6 ER - TY - JOUR A1 - Motyka, M. A1 - Dyksik, M. A1 - Ryczko, K. A1 - Weih, R. A1 - Dallner, M. A1 - Höfling, S. A1 - Kamp, M. A1 - Sęk, G. A1 - Misiewicz, J. T1 - Type-II quantum wells with tensile-strained GaAsSb layers for interband cascade lasers with tailored valence band mixing JF - Applied Physics Letters N2 - 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. KW - modulation spectroscopy KW - semiconductors KW - Type-II quantum well KW - interband cascade laser KW - GaAsSb Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189795 VL - 108 IS - 10 ER - TY - JOUR A1 - Pritchard, Rory A. A1 - Falk, Lovissa A1 - Larsson, Mathilda A1 - Leinders, Mathias A1 - Sorkin, Linda S. T1 - Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation JF - Pain N2 - 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. KW - c-Fos KW - Edema KW - Macrophage KW - Neutrophil KW - Plasma extravasation KW - Pain KW - PI3K isoforms Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191312 VL - 157 IS - 1 ER - TY - JOUR A1 - Barbieri, Flavia L. A1 - Gardon, Jacques A1 - Ruiz-Castell, María A1 - Paco V., Pamela A1 - Muckelbauer, Rebecca A1 - Casiot, Corinne A1 - Freydier, Rémi A1 - Duprey, Jean-Louis A1 - Chen, Chih-Mei A1 - Müller-Nordhorn, Jacqueline A1 - Keil, Thomas T1 - Toxic trace elements in maternal and cord blood and social determinants in a Bolivian mining city JF - International Journal of Environmental Health Research N2 - 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. KW - environmental exposure KW - metallic trace elements KW - maternal exposure KW - prenatal exposure KW - risk factors Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190703 VL - 26 IS - 2 ER - TY - JOUR A1 - Meder, Lydia A1 - König, Katharina A1 - Ozretić, Luka A1 - Schultheis, Anne M. A1 - Ueckeroth, Frank A1 - Ade, Carsten P. A1 - Albus, Kerstin A1 - Boehm, Diana A1 - Rommerscheidt-Fuss, Ursula A1 - Florin, Alexandra A1 - Buhl, Theresa A1 - Hartmann, Wolfgang A1 - Wolf, Jürgen A1 - Merkelbach-Bruse, Sabine A1 - Eilers, Martin A1 - Perner, Sven A1 - Heukamp, Lukas C. A1 - Buettner, Reinhard T1 - NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas JF - International Journal of Cancer N2 - 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. KW - lung cancer KW - small cell lung cancer KW - achaete-scute homolog 1 KW - neurogenic locus notch homolog KW - retinoblastoma protein Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190853 VL - 138 IS - 4 ER - TY - JOUR A1 - Singh, Krishna P. A1 - Verma, Neeraj A1 - Akhoon, Bashir A . A1 - Bhatt, Vishal A1 - Gupta, Shishir K. A1 - Gupta, Shailendra K. A1 - Smita, Suchi T1 - Sequence-based approach for rapid identification of cross-clade CD8+ T-cell vaccine candidates from all high-risk HPV strains JF - 3 Biotech N2 - 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. KW - HPV KW - Epitope KW - Cytotoxic KW - T lymphocytes KW - Cervical cancer KW - Vaccine Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191056 VL - 6 ER - TY - JOUR A1 - Klaunig, James E. A1 - Dekant, Wolfgang A1 - Plotzke, Kathy A1 - Scialli, Anthony R. T1 - Biological relevance of decamethylcyclopentasiloxane (D5) induced rat uterine endometrial adenocarcinoma tumorigenesis: Mode of action and relevance to humans JF - Regulatory Toxicology and Pharmacology N2 - 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. KW - Reproductive toxicity KW - Carcinogenicity KW - Silicones KW - Enzyme induction KW - Uterine tumors KW - Rat Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190952 VL - 74 IS - Supplement ER - TY - JOUR A1 - Scognamiglio, Roberta A1 - Cabezas-Wallscheid, Nina A1 - Thier, Marc Christian A1 - Altamura, Sandro A1 - Reyes, Alejandro A1 - Prendergast, Áine M. A1 - Baumgärtner, Daniel A1 - Carnevalli, Larissa S. A1 - Atzberger, Ann A1 - Haas, Simon A1 - von Paleske, Lisa A1 - Boroviak, Thorsten A1 - Wörsdörfer, Philipp A1 - Essers, Marieke A. G. A1 - Kloz, Ulrich A1 - Eisenman, Robert N. A1 - Edenhofer, Frank A1 - Bertone, Paul A1 - Huber, Wolfgang A1 - van der Hoeven, Franciscus A1 - Smith, Austin A1 - Trumpp, Andreas T1 - Myc depletion induces a pluripotent dormant state mimicking diapause JF - Cell N2 - 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. KW - hematopoietic stem cells KW - leukemia inhibitory factor KW - c-Myc KW - N-Myc KW - gene expression KW - embryonic stem cells KW - self-renewal KW - protein synthesis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190868 VL - 164 IS - 4 ER - TY - JOUR A1 - Dekant, Wolfgang A1 - Klaunig, James E. T1 - Toxicology of decamethylcyclopentasiloxane (D5) JF - Regulatory Toxicology and Pharmacology N2 - 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. KW - Prolactin KW - Fischer 344 rats KW - MMQ cells KW - Reproductive toxicity KW - Carcinogenicity KW - Silicones KW - Enzyme induction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190914 VL - 74 IS - Supplement ER - TY - JOUR A1 - Knauer, Kim A1 - Gessner, Ursula A1 - Fensholt, Rasmus A1 - Kuenzer, Claudia T1 - An ESTARFM Fusion Framework for the Generation of Large-Scale Time Series in Cloud-Prone and Heterogeneous Landscapes JF - Remote Sensing N2 - 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 KW - vegetation dynamics KW - ESTARFM KW - MODIS KW - Landsat KW - phenology KW - West Africa KW - cloud gap filling KW - time series analysis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180712 VL - 8 IS - 5 ER - TY - JOUR A1 - Gaudron, Philipp Daniel A1 - Liu, Dan A1 - Scholz, Friederike A1 - Hu, Kai A1 - Florescu, Christiane A1 - Herrmann, Sebastian A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Störk, Stefan A1 - Weidemann, Frank T1 - The septal bulge - an early echocardiographic sign in hypertensive heart disease JF - Journal of the American Society of Hypertension N2 - 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. KW - Septal bulge KW - hypertension KW - blood pressure monitoring KW - echocardiography KW - heart disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191433 VL - 10 IS - 1 ER - TY - JOUR A1 - Diessner, Joachim A1 - Wischnewsky, Manfred A1 - Blettner, Maria A1 - Häusler, Sebastian A1 - Janni, Wolfgang A1 - Kreienberg, Rolf A1 - Stein, Roland A1 - Stüber, Tanja A1 - Schwentner, Lukas A1 - Bartmann, Catharina A1 - Wöckel, Achim T1 - Do Patients with Luminal A Breast Cancer Profit from Adjuvant Systemic Therapy? A Retrospective Multicenter Study JF - PLoS ONE N2 - 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. KW - breast cancer KW - hormones KW - endocrine therapy KW - cancer detection and diagnosis KW - cancer treatment KW - cancer chemotherapy KW - lymph nodes KW - hormona therapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178217 VL - 11 IS - 12 ER - TY - JOUR A1 - Wildgruber, Moritz A1 - Aschenbrenner, Teresa A1 - Wendorff, Heiko A1 - Czubba, Maria A1 - Glinzer, Almut A1 - Haller, Bernhard A1 - Schiemann, Matthias A1 - Zimmermann, Alexander A1 - Berger, Hermann A1 - Eckstein, Hans-Henning A1 - Meier, Reinhard A1 - Wohlgemuth, Walter A. A1 - Libby, Peter A1 - Zernecke, Alma T1 - The "Intermediate" CD14\(^{++}\)CD16\(^{+}\) monocyte subset increases in severe peripheral artery disease in humans JF - Scientific Reports N2 - Monocytes are key players in atherosclerotic. Human monocytes display a considerable heterogeneity and at least three subsets can be distinguished. While the role of monocyte subset heterogeneity has already been well investigated in coronary artery disease (CAD), the knowledge about monocytes and their heterogeneity in peripheral artery occlusive disease (PAOD) still is limited. Therefore, we aimed to investigate monocyte subset heterogeneity in patients with PAOD. Peripheral blood was obtained from 143 patients suffering from PAOD (Rutherford stage I to VI) and three monocyte subsets were identified by flow cytometry: CD14\(^{++}\)CD16\(^{-}\) classical monocytes, CD14\(^{+}\)CD16\(^{++}\) non-classical monocytes and CD14\(^{++}\)CD16\(^{+}\) intermediate monocytes. Additionally the expression of distinct surface markers (CD106, CD162 and myeloperoxidase MPO) was analyzed. Proportions of CD14\(^{++}\)CD16\(^{+}\) intermediate monocyte levels were significantly increased in advanced stages of PAOD, while classical and non-classical monocytes displayed no such trend. Moreover, CD162 and MPO expression increased significantly in intermediate monocyte subsets in advanced disease stages. Likewise, increased CD162 and MPO expression was noted in CD14\(^{++}\)CD16\(^{-}\) classical monocytes. These data suggest substantial dynamics in monocyte subset distributions and phenotypes in different stages of PAOD, which can either serve as biomarkers or as potential therapeutic targets to decrease the inflammatory burden in advanced stages of atherosclerosis. KW - peripheral artery occlusive disease KW - monocyte subset KW - humans Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167476 VL - 6 IS - 39483 ER - TY - JOUR A1 - Düking, Peter A1 - Hotho, Andreas A1 - Holmberg, Hans-Christer A1 - Fuss, Franz Konstantin A1 - Sperlich, Billy T1 - Comparison of Non-Invasive Individual Monitoring of the Training and Health of Athletes with Commercially Available Wearable Technologies JF - Frontiers in Physiology N2 - Athletes adapt their training daily to optimize performance, as well as avoid fatigue, overtraining and other undesirable effects on their health. To optimize training load, each athlete must take his/her own personal objective and subjective characteristics into consideration and an increasing number of wearable technologies (wearables) provide convenient monitoring of various parameters. Accordingly, it is important to help athletes decide which parameters are of primary interest and which wearables can monitor these parameters most effectively. Here, we discuss the wearable technologies available for non-invasive monitoring of various parameters concerning an athlete's training and health. On the basis of these considerations, we suggest directions for future development. Furthermore, we propose that a combination of several wearables is most effective for accessing all relevant parameters, disturbing the athlete as little as possible, and optimizing performance and promoting health. KW - sports technology KW - wearable technologies KW - performance parameters KW - health monitoring KW - performance monitoring Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165516 VL - 7 IS - 71 ER - TY - JOUR A1 - Klughammer, Christof A1 - Schreiber, Ulrich T1 - Deconvolution of ferredoxin, plastocyanin, and P700 transmittance changes in intact leaves with a new type of kinetic LED array spectrophotometer JF - Photosynthesis Research N2 - A newly developed compact measuring system for assessment of transmittance changes in the near-infrared spectral region is described; it allows deconvolution of redox changes due to ferredoxin (Fd), P700, and plastocyanin (PC) in intact leaves. In addition, it can also simultaneously measure chlorophyll fluorescence. The major opto-electronic components as well as the principles of data acquisition and signal deconvolution are outlined. Four original pulse-modulated dual-wavelength difference signals are measured (785-840 nm, 810-870 nm, 870-970 nm, and 795-970 nm). Deconvolution is based on specific spectral information presented graphically in the form of 'Differential Model Plots' (DMP) of Fd, P700, and PC that are derived empirically from selective changes of these three components under appropriately chosen physiological conditions. Whereas information on maximal changes of Fd is obtained upon illumination after dark-acclimation, maximal changes of P700 and PC can be readily induced by saturating light pulses in the presence of far-red light. Using the information of DMP and maximal changes, the new measuring system enables on-line deconvolution of Fd, P700, and PC. The performance of the new device is demonstrated by some examples of practical applications, including fast measurements of flash relaxation kinetics and of the Fd, P700, and PC changes paralleling the polyphasic fluorescence rise upon application of a 300-ms pulse of saturating light. KW - Chlorophyll fluorescence KW - Cyclic electron transport KW - FeS proteins KW - Flash relaxation kinetics KW - Photosystem I KW - Polyphasic fluorescence rise KW - Thioredoxin Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189050 VL - 128 IS - 2 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Gunreben, Ignaz A1 - Kleinschnitz, Christoph A1 - Kraft, Peter T1 - Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke JF - International Journal of Molecular Sciences N2 - Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke. KW - thrombus formation KW - immune cells KW - lymphocytes KW - mechanical thrombectomy KW - ischemic stroke KW - inflammation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166206 VL - 17 IS - 3 ER - TY - JOUR A1 - Rücker, Viktoria A1 - Keil, Ulrich A1 - Fitzgerald, Anthony P A1 - Malzahn, Uwe A1 - Prugger, Christof A1 - Ertl, Georg A1 - Heuschmann, Peter U A1 - Neuhauser, Hannelore T1 - Predicting 10-Year Risk of Fatal Cardiovascular Disease in Germany: An Update Based on the SCORE-Deutschland Risk Charts JF - PLoS ONE N2 - Estimation of absolute risk of cardiovascular disease (CVD), preferably with population-specific risk charts, has become a cornerstone of CVD primary prevention. Regular recalibration of risk charts may be necessary due to decreasing CVD rates and CVD risk factor levels. The SCORE risk charts for fatal CVD risk assessment were first calibrated for Germany with 1998 risk factor level data and 1999 mortality statistics. We present an update of these risk charts based on the SCORE methodology including estimates of relative risks from SCORE, risk factor levels from the German Health Interview and Examination Survey for Adults 2008–11 (DEGS1) and official mortality statistics from 2012. Competing risks methods were applied and estimates were independently validated. Updated risk charts were calculated based on cholesterol, smoking, systolic blood pressure risk factor levels, sex and 5-year age-groups. The absolute 10-year risk estimates of fatal CVD were lower according to the updated risk charts compared to the first calibration for Germany. In a nationwide sample of 3062 adults aged 40–65 years free of major CVD from DEGS1, the mean 10-year risk of fatal CVD estimated by the updated charts was lower by 29% and the estimated proportion of high risk people (10-year risk > = 5%) by 50% compared to the older risk charts. This recalibration shows a need for regular updates of risk charts according to changes in mortality and risk factor levels in order to sustain the identification of people with a high CVD risk. KW - fatal cardiovascular disease KW - SCORE KW - Germany Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166804 VL - 11 IS - 9 ER - TY - JOUR A1 - Asthana, Manish Kumar A1 - Brunhuber, Bettina A1 - Mühlberger, Andreas A1 - Reif, Andreas A1 - Schneider, Simone A1 - Herrmann, Martin J. T1 - Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism JF - International Journal of Neuropsychopharmacology N2 - Background: Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. Methods: An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. Results: The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Conclusions: Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans. KW - BDNF KW - brain derived neurotrophic factor KW - fear conditioning KW - genetics memory KW - reconsolidation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166217 VL - 19 IS - 6 ER - TY - JOUR A1 - Alma, Harma A1 - de Jong, Corina A1 - Jelusic, Danijel A1 - Wittmann, Michael A1 - Schuler, Michael A1 - Flokstra-de Blok, Bertine A1 - Kocks, Janwillem A1 - Schultz, Konrad A1 - van der Molen, Thys T1 - Health status instruments for patients with COPD in pulmonary rehabilitation: defining a minimal clinically important difference JF - npj Primary Care Respiration Medicine N2 - The minimal clinically important difference (MCID) defines to what extent change on a health status instrument is clinically relevant, which aids scientists and physicians in measuring therapy effects. This is the first study that aimed to establish the MCID of the Clinical chronic obstructive pulmonary disease (COPD) Questionnaire (CCQ), the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ) in the same pulmonary rehabilitation population using multiple approaches. In total, 451 COPD patients participated in a 3-week Pulmonary Rehabilitation (PR) programme (58 years, 65% male, 43 pack-years, GOLD stage II/III/IV 50/39/11%). Techniques used to assess the MCID were anchor-based approaches, including patient-referencing, criterion-referencing and questionnaire-referencing, and the distribution-based methods standard error of measurement (SEM), 1.96SEM and half standard deviation (0.5s.d.). Patient- and criterion-referencing led to MCID estimates of 0.56 and 0.62 (CCQ); 3.12 and 2.96 (CAT); and 8.40 and 9.28 (SGRQ). Questionnaire-referencing suggested MCID ranges of 0.28–0.61 (CCQ), 1.46–3.08 (CAT) and 6.86–9.47 (SGRQ). The SEM, 1.96SEM and 0.5s.d. were 0.29, 0.56 and 0.46 (CCQ); 3.28, 6.43 and 2.80 (CAT); 5.20, 10.19 and 6.06 (SGRQ). Pooled estimates were 0.52 (CCQ), 3.29 (CAT) and 7.91 (SGRQ) for improvement. MCID estimates differed depending on the method used. Pooled estimates suggest clinically relevant improvements needing to exceed 0.40 on the CCQ, 3.00 on the CAT and 7.00 on the SGRQ for moderate to very severe COPD patients. The MCIDs of the CAT and SGRQ in the literature might be too low, leading to overestimation of treatment effects for patients with COPD. KW - COPD KW - rehabilitation KW - health status instruments Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166327 VL - 26 IS - 16041 ER - TY - JOUR A1 - Canesi, Margherita A1 - Giordano, Rosaria A1 - Lazzari, Lorenza A1 - Isalberti, Maurizio A1 - Isaias, Ioannis Ugo A1 - Benti, Riccardo A1 - Rampini, Paolo A1 - Marotta, Giorgio A1 - Colombo, Aurora A1 - Cereda, Emanuele A1 - Dipaola, Mariangela A1 - Montemurro, Tiziana A1 - Vigano, Mariele A1 - Budelli, Silvia A1 - Montelatici, Elisa A1 - Lavazza, Cristiana A1 - Cortelezzi, Agostino A1 - Pezzoli, Gianni T1 - Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy JF - Journal of Translational Medicine N2 - 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. KW - Progressive supranuclear palsy KW - Mesenchymal stem/stromal cells KW - Cell therapy KW - Regenerative medicine Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165725 VL - 14 IS - 127 ER - TY - JOUR A1 - Prelog, Martina A1 - Hilligardt, Deborah A1 - Schmidt, Christian A. A1 - Przybylski, Grzegorz K. A1 - Leierer, Johannes A1 - Almanzar, Giovanni A1 - El Hajj, Nady A1 - Lesch, Klaus-Peter A1 - Arolt, Volker A1 - Zwanzger, Peter A1 - Haaf, Thomas A1 - Domschke, Katharina T1 - Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder? JF - PLoS ONE N2 - 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. KW - DNA methylation KW - antidepressants KW - regulatory T cells KW - panic disorder KW - treatment guidelines KW - telomere length KW - inflammatory diseases KW - anxiety disorders Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179684 VL - 11 IS - 6 ER - TY - JOUR A1 - Viera, Jonathan Trujillo A1 - El-Merahbi, Rabih A1 - Nieswandt, Bernhard A1 - Stegner, David A1 - Sumara, Grzegorz T1 - Phospholipases D1 and D2 Suppress Appetite and Protect against Overweight JF - PLoS ONE N2 - 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. KW - enzyme regulation KW - insulin resistance KW - body weight KW - mouse models KW - bioenergetics KW - insulin KW - hypothalamus KW - adipose tissue Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179729 VL - 11 IS - 6 ER - TY - JOUR A1 - Denner, Ansgar A1 - Dittmaier, Stefan A1 - Hecht, Markus A1 - Pasold, Christian T1 - NLO QCD and electroweak corrections to Z + γ production with leptonic Z-boson decays JF - JOURNAL OF HIGH ENERGY PHYSICS N2 - The next-to-leading-order electroweak corrections to pp→l\(^{+}\)l\(^{-}\)/ν¯¯¯ν+γ+X production, including all off-shell effects of intermediate Z bosons in the complex-mass scheme, are calculated for LHC energies, revealing the typically expected large corrections of tens of percent in the TeV range. Contributions from quark-photon and photon-photon initial states are taken into account as well, but their impact is found to be moderate or small. Moreover, the known next-to-leading-order QCD corrections are reproduced. In order to separate hard photons from jets, both a quark-to-photon fragmentation function á la Glover/Morgan and Frixione’s cone isolation are employed. The calculation is available in the form of Monte Carlo programs allowing for the evaluation of arbitrary differential cross sections. Predictions for integrated cross sections are presented for the LHC at 7 TeV, 8 TeV, and 14 TeV, and differential distributions are discussed at 14 TeV for bare muons and dressed leptons. Finally, we consider the impact of anomalous ZZγ and Zγγ couplings. KW - NLO computations KW - hadronic colliders KW - LHC Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168766 VL - 02 IS - 057 ER - TY - JOUR A1 - Batsching, Sophie A1 - Wolf, Reinhard A1 - Heisenberg, Martin T1 - Inescapable Stress Changes Walking Behavior in Flies - Learned Helplessness Revisited JF - PLoS ONE N2 - 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. KW - learning KW - locomotion KW - animal behavior KW - behavioral conditioning KW - walking KW - vibration KW - light pulses KW - conditioned response Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178640 VL - 11 IS - 11 ER - TY - JOUR A1 - Politei, Juan M. A1 - Bouhassira, Didier A1 - Germain, Dominique P. A1 - Goizet, Cyril A1 - Guerrero-Sola, Antonio A1 - Hilz, Max J. A1 - Hutton, Elspeth J. A1 - Karaa, Amel A1 - Liuori, Rocco A1 - Üceyler, Nurcan A1 - Zeltzer, Lonnie K. A1 - Burlina, Alessandro T1 - Pain in fabry disease: practical recommendations for diagnosis and treatment JF - CNS Neuroscience & Therapeutics N2 - Aims: Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed. Methods: In 2014, experts met to discuss recent advances on this topic and update clinical guidance. Results: Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Wurzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs. Conclusion: To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications. KW - Enzyme replacement therapy KW - Small fiber dysfunction KW - System involvement KW - Outcome survey KW - Fabry disease KW - Randomized controlled-trial KW - Chronic neuropathic pain KW - Agalsidase beta KW - Screening questionnaire KW - Dose reduction KW - Adult patients KW - Diagnosis KW - Pain KW - Peripheral nervous system Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188127 VL - 22 IS - 7 ER - TY - JOUR A1 - Stock, Nina Katharina A1 - Petráš, Petr A1 - Melter, Oto A1 - Kapounová, Gabriela A1 - Vopalková, Petra A1 - Kubele, Jan A1 - Vaniš, Václav A1 - Tkadlec, Jan A1 - Bukáčková, Eva A1 - Machová, Ivana A1 - Jindrák, Vlastimil T1 - Importance of Multifaceted Approaches in Infection Control: A Practical Experience from an Outbreak Investigation JF - PLoS ONE N2 - Background This study presents the results of a multidisciplinary, nosocomial MRSA outbreak investigation in an 8-bed medical intensive care unit (ICU). The identification of seven MRSA positive patients in the beginning of 2014 led to the closure of the ward for several weeks. A multidisciplinary, retrospective investigation was initiated in order to identify the reason and the source for the outbreak, describe MRSA transmission in the department and identify limitations in infection control. Methods The investigation comprised an epidemiological description of MRSA cases from 2012 to 2014 and a characterization of MRSA isolates, including phage-, spa- and PFGE-typing. Additionally, MRSA screening was performed from the hospital staff and the environment. To identify the reason for the outbreak, work-related, psychological and behavioral factors were investigated by impartial audits and staff interviews. Results Thirty-one MRSA cases were registered during the study period, and 36 isolates were investigated. Molecular typing determined the outbreak strain (phage type 54/812, PFGE type A4, spa type t003) and identified the probable index case. Nasal carriage in one employee and a high environmental contamination with the outbreak strain was documented. Important gaps in nursing procedures and general management were identified. Elevated stress levels and communication problems preceded the outbreak. Compliance with hand hygiene and isolation procedures was evaluated as appropriate. Conclusion This study demonstrates the complexity of controlling hospital-associated infections. The combined use of different typing methods is beneficial for outbreak investigations. Psychological, behavioral and other work-related factors have an important impact on the spread of nosocomial pathogens. These factors should be addressed and integrated in routine infection control practice. KW - multifaceted approaches KW - infection control KW - Methicillin resistant Staphylococcus aureus KW - MRSA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166891 VL - 11 IS - 6 ER - TY - JOUR A1 - Sperlich, Billy A1 - Achtzehn, Silvia A1 - de Marées, Markus A1 - von Papen, Henning A1 - Mester, Joachim T1 - Load management in elite German distance runners during 3-weeks of high-altitude training JF - Physiological Reports N2 - There is a debate on the optimal way of monitoring training loads in elite endurance athletes especially during altitude training camps. In this case report, including nine members of the German national middle distance running team, we describe a practical approach to monitor the psychobiological stress markers during 21 days of altitude training (~2100 m above sea‐level) to estimate the training load and to control muscle damage, fatigue, and/or chronic overreaching. Daily examination included: oxygen saturation of hemoglobin, resting heart rate, body mass, body and sleep perception, capillary blood concentration of creatine kinase. Every other day, venous serum concentration of blood urea nitrogen, venous blood concentration of hemoglobin, hematocrit, red and white blood cell were measured. If two or more of the above‐mentioned stress markers were beyond or beneath the athlete's normal individual range, the training load of the subsequent training session was reduced. Running speed at 3 mmol L\(^{−1}\) blood lactate (V\(_{3}\)) improved and no athlete showed any signs of underperformance, chronic muscle damage, decrease body and sleep perception as well as activated inflammatory process during the 21 days. The dense screening of biomarkers in the present case study may stimulate further research to identify candidate markers for load monitoring in elite middle‐ and long‐distance runners during a training camp at altitude. KW - distance running KW - training load KW - stress markers KW - biomarkers KW - high-altitude training Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171294 VL - 4 IS - 12 ER - TY - JOUR A1 - Cicova, Zdenka A1 - Dejung, Mario A1 - Skalicky, Tomas A1 - Eisenhuth, Nicole A1 - Hanselmann, Steffen A1 - Morriswood, Brooke A1 - Figueiredo, Luisa M. A1 - Butter, Falk A1 - Janzen, Christian J. T1 - Two flagellar BAR domain proteins in Trypanosoma brucei with stage-specific regulation JF - Scientific Reports N2 - 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. KW - parasite biology KW - protein translocation KW - Trypanosoma brucei Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181021 VL - 6 ER - TY - JOUR A1 - Jahnke, Frank A1 - Gies, Christopher A1 - Aßmann, Marc A1 - Bayer, Manfred A1 - Leymann, H.A.M. A1 - Foerster, Alexander A1 - Wiersig, Jan A1 - Schneider, Christian A1 - Kamp, Martin A1 - Höfling, Sven T1 - Giant photon bunching, superradiant pulse emission and excitation trapping in quantum-dot nanolasers JF - Nature Communications N2 - Light is often characterized only by its classical properties, like intensity or coherence. When looking at its quantum properties, described by photon correlations, new information about the state of the matter generating the radiation can be revealed. In particular the difference between independent and entangled emitters, which is at the heart of quantum mechanics, can be made visible in the photon statistics of the emitted light. The well-studied phenomenon of superradiance occurs when quantum–mechanical correlations between the emitters are present. Notwithstanding, superradiance was previously demonstrated only in terms of classical light properties. Here, we provide the missing link between quantum correlations of the active material and photon correlations in the emitted radiation. We use the superradiance of quantum dots in a cavity-quantum electrodynamics laser to show a direct connection between superradiant pulse emission and distinctive changes in the photon correlation function. This directly demonstrates the importance of quantum–mechanical correlations and their transfer between carriers and photons in novel optoelectronic devices. KW - photon bunching KW - quantum mechanics KW - superradiant pulse emission Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166144 VL - 7 IS - 11540 ER - TY - JOUR A1 - Conrad, Thomas A1 - Albrecht, Anne-Susann A1 - Rodrigues de Melo Costa, Veronica A1 - Sauer, Sascha A1 - Meierhofer, David A1 - Andersson Ørom, Ulf T1 - Serial interactome capture of the human cell nucleus JF - Nature Communications N2 - Novel RNA-guided cellular functions are paralleled by an increasing number of RNA-binding proteins (RBPs). Here we present ‘serial RNA interactome capture’ (serIC), a multiple purification procedure of ultraviolet-crosslinked poly(A)–RNA–protein complexes that enables global RBP detection with high specificity. We apply serIC to the nuclei of proliferating K562 cells to obtain the first human nuclear RNA interactome. The domain composition of the 382 identified nuclear RBPs markedly differs from previous IC experiments, including few factors without known RNA-binding domains that are in good agreement with computationally predicted RNA binding. serIC extends the number of DNA–RNA-binding proteins (DRBPs), and reveals a network of RBPs involved in p53 signalling and double-strand break repair. serIC is an effective tool to couple global RBP capture with additional selection or labelling steps for specific detection of highly purified RBPs. KW - human cell nucleus KW - serial RNA interactome capture KW - RNA-binding proteins Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166172 VL - 7 IS - 11212 ER - TY - JOUR A1 - Jakobson, Liina A1 - Vaahtera, Lauri A1 - Tõldsepp, Kadri A1 - Nuhkat, Maris A1 - Wang, Cun A1 - Wang, Yuh-Shuh A1 - Hõrak, Hanna A1 - Valk, Ervin A1 - Pechter, Priit A1 - Sindarovska, Yana A1 - Tang, Jing A1 - Xiao, Chuanlei A1 - Xu, Yang A1 - Talas, Ulvi Gerst A1 - García-Sosa, Alfonso T. A1 - Kangasjärvi, Saijaliisa A1 - Maran, Uko A1 - Remm, Maido A1 - Roelfsema, M. Rob G. A1 - Hu, Honghong A1 - Kangasjärvi, Jaakko A1 - Loog, Mart A1 - Schroeder, Julian I. A1 - Kollist, Hannes A1 - Brosché, Mikael T1 - Natural Variation in Arabidopsis Cvi-0 Accession Reveals an Important Role of MPK12 in Guard Cell CO\(_{2}\) Signaling JF - PLoS Biology N2 - Plant gas exchange is regulated by guard cells that form stomatal pores. Stomatal adjustments are crucial for plant survival; they regulate uptake of CO\(_{2}\) for photosynthesis, loss of water, and entrance of air pollutants such as ozone. We mapped ozone hypersensitivity, more open stomata, and stomatal CO\(_{2}\)-insensitivity phenotypes of the Arabidopsis thaliana accession Cvi-0 to a single amino acid substitution in MITOGEN-ACTIVATED PROTEIN (MAP) KINASE 12 (MPK12). In parallel, we showed that stomatal CO\(_{2}\)-insensitivity phenotypes of a mutant cis (CO\(_{2}\)-insensitive) were caused by a deletion of MPK12. Lack of MPK12 impaired bicarbonate-induced activation of S-type anion channels. We demonstrated that MPK12 interacted with the protein kinase HIGH LEAF TEMPERATURE 1 (HT1)—a central node in guard cell CO\(_{2}\) signaling—and that MPK12 functions as an inhibitor of HT1. These data provide a new function for plant MPKs as protein kinase inhibitors and suggest a mechanism through which guard cell CO\(_{2}\) signaling controls plant water management. KW - MPK12 KW - CO\(_{2}\) signaling KW - Arabidopsis thaliana KW - Cvi-0 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166657 VL - 14 IS - 12 ER - TY - JOUR A1 - Letunic, Ivica A1 - Bork, Peer T1 - Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees JF - Nucleic Acids Research N2 - Interactive Tree Of Life (http://itol.embl.de) is a web-based tool for the display, manipulation and annotation of phylogenetic trees. It is freely available and open to everyone. The current version was completely redesigned and rewritten, utilizing current web technologies for speedy and streamlined processing. Numerous new features were introduced and several new data types are now supported. Trees with up to 100,000 leaves can now be efficiently displayed. Full interactive control over precise positioning of various annotation features and an unlimited number of datasets allow the easy creation of complex tree visualizations. iTOL 3 is the first tool which supports direct visualization of the recently proposed phylogenetic placements format. Finally, iTOL's account system has been redesigned to simplify the management of trees in user-defined workspaces and projects, as it is heavily used and currently handles already more than 500,000 trees from more than 10,000 individual users. KW - Interactive Tree Of Life (iTOL) KW - phylogenetic trees KW - visualization KW - tool Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166181 VL - 44 IS - W1 ER - TY - JOUR A1 - Lotz, Christian A1 - Schmid, Freia F. A1 - Rossi, Angela A1 - Kurdyn, Szymon A1 - Kampik, Daniel A1 - De Wever, Bart A1 - Walles, Heike A1 - Groeber, Florian K. T1 - Alternative Methods for the Replacement of Eye Irritation Testing JF - ALTEX - Alternatives to Animal Experimentation N2 - In the last decades significant regulatory attempts were made to replace, refine and reduce animal testing to assess the risk of consumer products for the human eye. As the original in vivo Draize eye test is criticized for limited predictivity, costs and ethical issues, several animal-free test methods have been developed to categorize substances according to the global harmonized system (GHS) for eye irritation. This review summarizes the progress of alternative test methods for the assessment of eye irritation. Based on the corneal anatomy and current knowledge of the mechanisms causing eye irritation, different ex vivo and in vitro methods will be presented and discussed with regard to possible limitations and status of regulatory acceptance. In addition to established in vitro models, this review will also highlight emerging, full thickness cornea models that might be suited to predict all GHS categories. KW - eye irritation testing KW - alternatives KW - Draize eye test KW - OECD guideline KW - corneal equivalent Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164444 VL - 33 IS - 1 ER - TY - JOUR A1 - Kronhardt, Angelika A1 - Beitzinger, Christoph A1 - Barth, Holger A1 - Benz, Roland T1 - Chloroquine Analog Interaction with C2-and Iota-Toxin in Vitro and in Living Cells JF - Toxins N2 - C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells’ receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. KW - C2-toxin KW - iota-toxin KW - binding components KW - chloroquine KW - black lipid bilayer KW - aminoquinolinium salts Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168286 VL - 8 IS - 8 ER - TY - JOUR A1 - Kupper, Maria A1 - Stigloher, Christian A1 - Feldhaar, Heike A1 - Gross, Roy T1 - Distribution of the obligate endosymbiont Blochmannia floridanus and expression analysis of putative immune genes in ovaries of the carpenter ant Camponotus floridanus JF - Arthropod Structure & Development N2 - The bacterial endosymbiont Blochmannia floridanus of the carpenter ant Camponotus floridanus contributes to its hosts' ontogeny via nutritional upgrading during metamorphosis. This primary endosymbiosis is essential for both partners and vertical transmission of the endosymbionts is guaranteed by bacterial infestation of oocytes. Here we present a detailed analysis of the presence and localisation of B. floridanus in the ants' ovaries obtained by FISH and TEM analyses. The most apical part of the germarium harbouring germ-line stem cells (GSCs) is not infected by the bacteria. The bacteria are detectable for the first time in lower parts of the germarium when cystocytes undergo the 4th and 5th division and B. floridanus infects somatic cells lying under the basal lamina surrounding the ovarioles. With the beginning of cystocyte differentiation, the endosymbionts are exclusively transported from follicle cells into the growing oocytes. This infestation of the oocytes by bacteria very likely involves exocytosis endocytosis processes between follicle cells and the oocytes. Nurse cells were never found to harbour the endosymbionts. Furthermore we present first gene expression data in C floridanus ovaries. These data indicate a modulation of immune gene expression which may facilitate tolerance towards the endosymbionts and thus may contribute to their transovarial transmission. KW - Ecologically important traits KW - Bacterial symbionts KW - Arthropods KW - Peptidoglycan recognition KW - Transovarial transmission KW - Horizontal transfer KW - Insect hosts KW - Microorganisms KW - Reproduction KW - Hymenoptera KW - Primary endosymbiont KW - Oogenesis KW - Insects Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187482 VL - 45 IS - 5 ER - TY - JOUR A1 - Sabel, Magnus A1 - Fleischhack, Gudrun A1 - Tippelt, Stephan A1 - Gustafsson, Göran A1 - Doz, François A1 - Kortmann, Rolf A1 - Massimino, Maura A1 - Navajas, Aurora A1 - von Hoff, Katja A1 - Rutkowski, Stefan A1 - Warmuth-Metz, Monika A1 - Clifford, Steven C. A1 - Pietsch, Torsten A1 - Pizer, Barry A1 - Linnering, Birgitta T1 - Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study JF - Journal of Neurooncology N2 - The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 +/- 2 % and 78 +/- 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. > 5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 +/- 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour. KW - High-dose chemotherapy KW - Childhood medulloblastoma KW - Adolescents KW - Primitive neuroectodermal KW - Tumors KW - Recurrent medulloblastoma KW - Childrens-cancer KW - Phase-II KW - Trial KW - Therapy KW - Reirradiation KW - Medulloblastoma KW - Relapse KW - Survival KW - Treatment KW - Clinical trial KW - Chemotherapy KW - Radiotherapy KW - Paediatric KW - Secondary tumours Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187498 VL - 129 IS - 3 ER - TY - JOUR A1 - Denner, Ansgar A1 - Pellen, Mathieu T1 - NLO electroweak corrections to off-shell top-antitop production with leptonic decays at the LHC JF - Journal of High Energy Phsyics N2 - For the first time the next-to-leading-order electroweak corrections to the full off-shell production of two top quarks that decay leptonically are presented. This calculation includes all off-shell, non-resonant, and interference effects for the 6-particle phase space. While the electroweak corrections are below one per cent for the integrated cross section, they reach up to 15% in the high-transverse-momentum region of distributions. To support the results of the complete one-loop calculation, we have in addition evaluated the electroweak corrections in two different pole approximations, one requiring two on-shell top quarks and one featuring two on-shell W bosons. While the former deviates by up to 10% from the full calculation for certain distributions, the latter provides a very good description for most observables. The increased centre-of-mass energy of the LHC makes the inclusion of electroweak corrections extremely relevant as they are particularly large in the Sudakov regime where new physics is expected to be probed. KW - NLO Computations Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166415 VL - 08 IS - 155 ER - TY - JOUR A1 - Schneider, Anna A1 - Corona, Angela A1 - Spöring, Imke A1 - Jordan, Mareike A1 - Buchholz, Bernd A1 - Maccioni, Elias A1 - Di Santo, Roberto A1 - Bodem, Jochen A1 - Tramontano, Enzo A1 - Wöhrl, Birgitta M. T1 - Biochemical characterization of a multi-drug resistant HIV-1 subtype AG reverse transcriptase: antagonism of AZT discrimination and excision pathways and sensitivity to RNase H inhibitors JF - Nucleic Acids Research N2 - We analyzed a multi-drug resistant (MR) HIV-1 reverse transcriptase (RT), subcloned from a patient-derived subtype CRF02_AG, harboring 45 amino acid exchanges, amongst them four thymidine analog mutations (TAMs) relevant for high-level AZT (azidothymidine) resistance by AZTMP excision (M41L, D67N, T215Y, K219E) as well as four substitutions of the AZTTP discrimination pathway (A62V, V75I, F116Y and Q151M). In addition, K65R, known to antagonize AZTMP excision in HIV-1 subtype B was present. Although MR-RT harbored the most significant amino acid exchanges T215Y and Q151M of each pathway, it exclusively used AZTTP discrimination, indicating that the two mechanisms are mutually exclusive and that the Q151M pathway is obviously preferred since it confers resistance to most nucleoside inhibitors. A derivative was created, additionally harboring the TAM K70R and the reversions M151Q as well as R65K since K65R antagonizes excision. MR-R65K-K70R-M151Q was competent of AZTMP excision, whereas other combinations thereof with only one or two exchanges still promoted discrimination. To tackle the multi-drug resistance problem, we tested if the MR-RTs could still be inhibited by RNase H inhibitors. All MR-RTs exhibited similar sensitivity toward RNase H inhibitors belonging to different inhibitor classes, indicating the importance of developing RNase H inhibitors further as anti-HIV drugs. KW - ribonuclease H KW - HIV-1 subtype AG KW - azidothymidine KW - reverse transcriptase KW - multi-drug resistance Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166423 VL - 44 IS - 5 ER - TY - JOUR A1 - Biscotti, Maria Assunta A1 - Gerdol, Marco A1 - Canapa, Adriana A1 - Forconi, Mariko A1 - Olmo, Ettore A1 - Pallavicini, Alberto A1 - Barucca, Marco A1 - Schartl, Manfred T1 - The Lungfish Transcriptome: A Glimpse into Molecular Evolution Events at the Transition from Water to Land JF - Scientific Reports N2 - Lungfish and coelacanths are the only living sarcopterygian fish. The phylogenetic relationship of lungfish to the last common ancestor of tetrapods and their close morphological similarity to their fossil ancestors make this species uniquely interesting. However their genome size, the largest among vertebrates, is hampering the generation of a whole genome sequence. To provide a partial solution to the problem, a high-coverage lungfish reference transcriptome was generated and assembled. The present findings indicate that lungfish, not coelacanths, are the closest relatives to land-adapted vertebrates. Whereas protein-coding genes evolve at a very slow rate, possibly reflecting a “living fossil” status, transposable elements appear to be active and show high diversity, suggesting a role for them in the remarkable expansion of the lungfish genome. Analyses of single genes and gene families documented changes connected to the water to land transition and demonstrated the value of the lungfish reference transcriptome for comparative studies of vertebrate evolution. KW - lungfish KW - transcriptome KW - genome KW - sarcopterygian fish Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167753 VL - 6 IS - 21571 ER - TY - JOUR A1 - Müller, Anna A. A1 - Dolowschiak, Tamas A1 - Sellin, Mikael E. A1 - Felmy, Boas A1 - Verbree, Carolin A1 - Gadient, Sandra A1 - Westermann, Alexander J. A1 - Vogel, Jörg A1 - LeibundGut-Landmann, Salome A1 - Hardt, Wolf-Dietrich T1 - An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection JF - PLoS Pathogens N2 - Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and –injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf\(^{-/-}\) ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens. KW - NK cells KW - Salmonella Typhimurium KW - mucosal inflammation KW - diarrhea Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167429 VL - 12 IS - 6 ER - TY - JOUR A1 - Langlhofer, Georg A1 - Villmann, Carmen T1 - The Intracellular Loop of the Glycine Receptor: It's not all about the Size JF - Frontiers in Molecular Neuroscience N2 - The family of Cys-loop receptors (CLRs) shares a high degree of homology and sequence identity. The overall structural elements are highly conserved with a large extracellular domain (ECD) harboring an α-helix and 10 β-sheets. Following the ECD, four transmembrane domains (TMD) are connected by intracellular and extracellular loop structures. Except the TM3–4 loop, their length comprises 7–14 residues. The TM3–4 loop forms the largest part of the intracellular domain (ICD) and exhibits the most variable region between all CLRs. The ICD is defined by the TM3–4 loop together with the TM1–2 loop preceding the ion channel pore. During the last decade, crystallization approaches were successful for some members of the CLR family. To allow crystallization, the intracellular loop was in most structures replaced by a short linker present in prokaryotic CLRs. Therefore, no structural information about the large TM3–4 loop of CLRs including the glycine receptors (GlyRs) is available except for some basic stretches close to TM3 and TM4. The intracellular loop has been intensively studied with regard to functional aspects including desensitization, modulation of channel physiology by pharmacological substances, posttranslational modifications, and motifs important for trafficking. Furthermore, the ICD interacts with scaffold proteins enabling inhibitory synapse formation. This review focuses on attempts to define structural and functional elements within the ICD of GlyRs discussed with the background of protein-protein interactions and functional channel formation in the absence of the TM3–4 loop. KW - posttranslational modifications KW - GlyR receptors KW - synaptic inhibition KW - intracellular domain KW - interaction partners Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165394 IS - 9 ER - TY - JOUR A1 - Lehners, Nicola A1 - Tabatabai, Julia A1 - Prifert, Christiane A1 - Wedde, Marianne A1 - Puthenparambil, Joe A1 - Weissbrich, Benedikt A1 - Biere, Barbara A1 - Schweiger, Brunhilde A1 - Egerer, Gerlinde A1 - Schnitzler, Paul T1 - Long-Term Shedding of Influenza Virus, Parainfluenza Virus, Respiratory Syncytial Virus and Nosocomial Epidemiology in Patients with Hematological Disorders JF - PLoS ONE N2 - Respiratory viruses are a cause of upper respiratory tract infections (URTI), but can be associated with severe lower respiratory tract infections (LRTI) in immunocompromised patients. The objective of this study was to investigate the genetic variability of influenza virus, parainfluenza virus and respiratory syncytial virus (RSV) and the duration of viral shedding in hematological patients. Nasopharyngeal swabs from hematological patients were screened for influenza, parainfluenza and RSV on admission as well as on development of respiratory symptoms. Consecutive swabs were collected until viral clearance. Out of 672 tested patients, a total of 111 patients (17%) were infected with one of the investigated viral agents: 40 with influenza, 13 with parainfluenza and 64 with RSV; six patients had influenza/RSV or parainfluenza/RSV co-infections. The majority of infected patients (n = 75/111) underwent stem cell transplantation (42 autologous, 48 allogeneic, 15 autologous and allogeneic). LRTI was observed in 48 patients, of whom 15 patients developed severe LRTI, and 13 patients with respiratory tract infection died. Phylogenetic analysis revealed a variety of influenza A(H1N1)pdm09, A(H3N2), influenza B, parainfluenza 3 and RSV A, B viruses. RSV A was detected in 54 patients, RSV B in ten patients. The newly emerging RSV A genotype ON1 predominated in the study cohort and was found in 48 (75%) of 64 RSV-infected patients. Furthermore, two distinct clusters were detected for RSV A genotype ON1, identical RSV G gene sequences in these patients are consistent with nosocomial transmission. Long-term viral shedding for more than 30 days was significantly associated with prior allogeneic transplantation (p = 0.01) and was most pronounced in patients with RSV infection (n = 16) with a median duration of viral shedding for 80 days (range 35–334 days). Long-term shedding of respiratory viruses might be a catalyzer of nosocomial transmission and must be considered for efficient infection control in immunocompromised patients. KW - viral shedding KW - influenza virus KW - parainfluenza virus KW - respiratory syncytial virus KW - hematological disorders Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167243 VL - 11 IS - 2 ER - TY - JOUR A1 - Thomas, Anna C. A1 - Zeng, Zhiqiang A1 - Rivière, Jean-Baptiste A1 - O'Shaughnessy, Ryan A1 - Al-Olabi, Lara A1 - St.-Onge, Judith A1 - Atherton, David J. A1 - Aubert, Hélène A1 - Bagazgoitia, Lorea A1 - Barbarot, Sébastien A1 - Bourrat, Emmanuelle A1 - Chiaverini, Christine A1 - Chong, W. Kling A1 - Duffourd, Yannis A1 - Glover, Mary A1 - Groesser, Leopold A1 - Hadj-Rabia, Smail A1 - Hamm, Henning A1 - Happle, Rudolf A1 - Mushtaq, Imran A1 - Lacour, Jean-Philippe A1 - Waelchli, Regula A1 - Wobser, Marion A1 - Vabres, Pierre A1 - Patton, E. Elizabeth A1 - Kinsler, Veronica A. T1 - Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis JF - Journal of Investigative Dermatology N2 - 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. KW - uveal melanoma KW - G Protein KW - dermal melanocytosis KW - Sturge-Weber syndrom KW - cesioflammea KW - germline KW - phakomatosis pigmentovascularis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189689 VL - 136 IS - 4 ER - TY - JOUR A1 - Kalleda, Natarajaswamy A1 - Amich, Jorge A1 - Arslan, Berkan A1 - Poreddy, Spoorthi A1 - Mattenheimer, Katharina A1 - Mokhtari, Zeinab A1 - Einsele, Hermann A1 - Brock, Matthias A1 - Heinze, Katrin Gertrud A1 - Beilhack, Andreas T1 - Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens JF - Frontiers in Microbiology N2 - Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4\(^+\) or CD8\(^+\) T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b\(^+\) myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b\(^+\) myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. KW - corticosteroids and cyclophosphamide KW - aspergillus fumigatus KW - CD11b+ myeloid cells KW - immune cell recruitment Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165368 VL - 7 IS - 1107 ER - TY - JOUR A1 - Künstner, Axel A1 - Hoffmann, Margarete A1 - Fraser, Bonnie A. A1 - Kottler, Verena A. A1 - Sharma, Eshita A1 - Weigel, Detlef A1 - Dreyer, Christine T1 - The Genome of the Trinidadian Guppy, Poecilia reticulata, and Variation in the Guanapo Population JF - PLoS ONE N2 - For over a century, the live bearing guppy, Poecilia reticulata, has been used to study sexual selection as well as local adaptation. Natural guppy populations differ in many traits that are of intuitively adaptive significance such as ornamentation, age at maturity, brood size and body shape. Water depth, light supply, food resources and predation regime shape these traits, and barrier waterfalls often separate contrasting environments in the same river. We have assembled and annotated the genome of an inbred single female from a high-predation site in the Guanapo drainage. The final assembly comprises 731.6 Mb with a scaffold N50 of 5.3 MB. Scaffolds were mapped to linkage groups, placing 95% of the genome assembly on the 22 autosomes and the X-chromosome. To investigate genetic variation in the population used for the genome assembly, we sequenced 10 wild caught male individuals. The identified 5 million SNPs correspond to an average nucleotide diversity (π) of 0.0025. The genome assembly and SNP map provide a rich resource for investigating adaptation to different predation regimes. In addition, comparisons with the genomes of other Poeciliid species, which differ greatly in mechanisms of sex determination and maternal resource allocation, as well as comparisons to other teleost genera can begin to reveal how live bearing evolved in teleost fish. KW - Trinidadian guppy KW - Poecilia reticulata KW - genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166755 VL - 11 IS - 12 ER - TY - JOUR A1 - Grimmig, Tanja A1 - Moench, Romana A1 - Kreckel, Jennifer A1 - Haack, Stephanie A1 - Rueckert, Felix A1 - Rehder, Roberta A1 - Tripathi, Sudipta A1 - Ribas, Carmen A1 - Chandraker, Anil A1 - Germer, Christoph T. A1 - Gasser, Martin A1 - Waaga-Gasser, Ana Maria T1 - Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer JF - International Journal of Molecular Sciences N2 - Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer. KW - tumor growth KW - TLR2 KW - TLR4 KW - TLR9 KW - pancreatic cancer KW - inflammation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165743 VL - 17 IS - 12 ER - TY - JOUR A1 - Shepard, Blythe D. A1 - Cheval, Lydie A1 - Peterlin, Zita A1 - Firestein, Stuart A1 - Koepsell, Hermann A1 - Doucet, Alain A1 - Pluznick, Jennifer L. T1 - A Renal Olfactory Receptor Aids in Kidney Glucose Handling JF - Scientific Reports N2 - Olfactory receptors (ORs) are G protein-coupled receptors which serve important sensory functions beyond their role as odorant detectors in the olfactory epithelium. Here we describe a novel role for one of these ORs, Olfr1393, as a regulator of renal glucose handling. Olfr1393 is specifically expressed in the kidney proximal tubule, which is the site of renal glucose reabsorption. Olfr1393 knockout mice exhibit urinary glucose wasting and improved glucose tolerance, despite euglycemia and normal insulin levels. Consistent with this phenotype, Olfr1393 knockout mice have a significant decrease in luminal expression of Sglt1, a key renal glucose transporter, uncovering a novel regulatory pathway involving Olfr1393 and Sglt1. In addition, by utilizing a large scale screen of over 1400 chemicals we reveal the ligand profile of Olfr1393 for the first time, offering new insight into potential pathways of physiological regulation for this novel signaling pathway. KW - olfactory receptor KW - Olfr1393 KW - kidney KW - glucose handling Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167605 VL - 6 IS - 35215 ER - TY - JOUR A1 - Deeleman-Reinhold, Christa L. A1 - Miller, Jeremy A1 - Floren, Andreas T1 - Depreissia decipiens, an enigmatic canopy spider from Borneo revisited (Araneae, Salticidae), with remarks on the distribution and diversity of canopy spiders in Sabah, Borneo JF - ZooKeys N2 - Depreissia is a little known genus comprising two hymenopteran-mimicking species, one found in Central Africa and one in the north of Borneo. The male of D. decipiens is redescribed, the female is described for the first time. The carapace is elongated, dorsally flattened and rhombus-shaped, the rear of the thorax laterally depressed and transformed, with a pair of deep pits; the pedicel is almost as long as the abdomen. The male palp is unusual, characterized by the transverse deeply split membranous tegulum separating a ventral part which bears a sclerotized tegular apophysis and a large dagger-like retrodirected median apophysis. The female epigyne consists of one pair of large adjacent spermathecae and very long copulatory ducts arising posteriorly and rising laterally alongside the spermathecae continuing in several vertical and horizontal coils over the anterior surface. Relationships within the Salticidae are discussed and an affinity with the Cocalodinae is suggested. Arguments are provided for a hypothesis that D. decipiens is not ant-mimicking as was previously believed, but is a mimic of polistinine wasps. The species was found in the canopy in the Kinabalu area only, in primary and old secondary rainforest at 200–700 m.a.s.l. Overlap of canopy-dwelling spider species with those in the understorey are discussed and examples of species richness and endemism in the canopy are highlighted. Canopy fogging is a very efficient method of collecting for most arthropods. The canopy fauna adds an extra dimension to the known biodiversity of the tropical rainforest. In southeast Asia, canopy research has been neglected, inhibiting evaluation of comparative results of this canopy project with that from other regions. More use of fogging as a collecting method would greatly improve insight into the actual species richness and species distribution in general. KW - depreissia decipiens KW - jumping spiders KW - canopy spiders KW - taxonomy KW - biodiversity KW - ant-mimicking spiders KW - wasp-mimicking KW - Mt. Kinabalu KW - rainforest KW - Cocalodinae KW - Polistine wasps KW - endemism Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168342 VL - 556 ER - TY - JOUR A1 - Schlinkert, Hella A1 - Ludwig, Martin A1 - Batáry, Péter A1 - Holzschuh, Andrea A1 - Kovács-Hostyánszki, Anikó A1 - Tscharntke, Teja A1 - Fischer, Christina T1 - Forest specialist and generalist small mammals in forest edges and hedges JF - Wildlife Biology N2 - Agricultural intensification often leads to fragmentation of natural habitats, such as forests, and thereby negatively affects forest specialist species. However, human introduced habitats, such as hedges, may counteract negative effects of forest fragmentation and increase dispersal, particularly of forest specialists. We studied effects of habitat type (forest edge versus hedge) and hedge isolation from forests (connected versus isolated hedge) in agricultural landscapes on abundance, species richness and community composition of mice, voles and shrews in forest edges and hedges. Simultaneously to these effects of forest edge/hedge type we analysed impacts of habitat structure, namely percentage of bare ground and forest edge/hedge width, on abundance, species richness and community composition of small mammals. Total abundance and forest specialist abundance (both driven by the most abundant species Myodes glareolus, bank vole) were higher in forest edges than in hedges, while hedge isolation had no effect. In contrast, abundance of habitat generalists was higher in isolated compared to connected hedges, with no effect of habitat type (forest edge versus hedge). Species richness as well as abundance of the most abundant habitat generalist Sorex araneus (common shrew), were not affected by habitat type or hedge isolation. Decreasing percentage of bare ground and increasing forest edge/hedge width was associated with increased abundance of forest specialists, while habitat structure was unrelated to species richness or abundance of any other group. Community composition was driven by forest specialists, which exceeded habitat generalist abundance in forest edges and connected hedges, while abundances were similar to each other in isolated hedges. Our results show that small mammal forest specialists prefer forest edges as habitats over hedges, while habitat generalists are able to use unoccupied ecological niches in isolated hedges. Consequently even isolated hedges can be marginal habitats for forest specialists and habitat generalists and thereby may increase regional farmland biodiversity. KW - forest specialists KW - forest fragmentation KW - forest hedges KW - forest edges Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168333 VL - 22 IS - 3 ER - TY - JOUR A1 - Dyksik, M. A1 - Motyka, M. A1 - Kurka, M. A1 - Ryczo, K. A1 - Dallner, M. A1 - Höfling, S. A1 - Kamp, M. A1 - Sęk, G. A1 - Misiwicz, J. T1 - Photoluminescence quenching mechanisms in type IIInAs/GaInSb QWs on InAs substrates JF - Optical and Quantum Electronics N2 - Optical properties of AlSb/InAs/GaInSb/InAs/AlSb quantum wells (QWs) grown on an InAs substrate were investigated from the point of view of room temperature emission in the mid- and long-wavelength infrared ranges. By means of two independent techniques of optical spectroscopy, photoreflectance and temperature-dependent photoluminescence, it was proven that the main process limiting the performance of such InAs substrate-based type II structures is related to the escape of carriers from the hole ground state of the QW. Two nonradiative recombination channels were identified. The main process was attributed to holes tunneling to the valence band of the GaAsSb spacing layer and the second one with trapping of holes by native defects located in the same layer. KW - Interband cascade lasers KW - Quantum wells KW - MU-M KW - Fourier-transform spectroscopy KW - Mid-infrared photoluminescence KW - Type II quantum wells KW - Localized states Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204672 VL - 48 IS - 401 ER - TY - JOUR A1 - Harks, Inga A1 - Jockel-Schneider, Yvonne A1 - Schlagenhauf, Ulrich A1 - May, Theodor W. A1 - Gravemeier, Martina A1 - Prior, Karola A1 - Petersilka, Gregor A1 - Ehmke, Gregor T1 - Impact of the Daily Use of a Microcrystal Hydroxyapatite Dentifrice on De Novo Plaque Formation and Clinical/Microbiological Parameters of Periodontal Health. A Randomized Trial JF - PLoS ONE N2 - Aim This 12-week prospective, randomized, double-blind, two-center trial evaluated the impact of a microcrystalline zinc hydroxyapatite (mHA) dentifrice on plaque formation rate (PFR) in chronic periodontitis patients. We hypothesized that mHA precipitates cause delayed plaque development when compared to a fluoridated control (AmF/SnF\(_{2}\)), and therefore would improve periodontal health. Material & Methods At baseline and after 4 and 12 weeks, PFR and other clinical and microbiological parameters were recorded. Seventy periodontitis patients received a mHA or AmF/SnF\(_{2}\) dentifrice as daily oral care without hygiene instructions. Four weeks after baseline, participants received full mouth debridement and continued using the dentifrices for another 8 weeks. Results Primary outcome PFR did not change statistically significantly from baseline to weeks 4 and 12, neither in mHA (n = 33; 51.7±17.2% vs. 48.5±16.65% vs. 48.4±19.9%) nor in AmF/SnF2-group (n = 34; 52.3±17.5% vs. 52.5±21.3% vs. 46.1±21.8%). Secondary clinical parameters such as plaque control record, gingival index, bleeding on probing, and pocket probing depth improved, but between-group differences were not statistically significant. Microbiological analyses showed similar slight decreases in colony-forming units in both groups. Conclusion In patients with mild-to-moderate periodontitis, periodontal therapy and use of a mHA-or AmF/SnF\(_{2}\) dentifrice without instructions induced comparable improvements in periodontal health but did not significantly reduce the PFR. KW - microcrystalline zinc hydroxyapatiteimpact KW - plaque formation KW - periodontal health Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166853 VL - 11 IS - 7 ER - TY - JOUR A1 - Halder, Sebastian A1 - Takano, Kouji A1 - Ora, Hiroki A1 - Onishi, Akinari A1 - Utsumi, Kota A1 - Kansaku, Kenji T1 - An Evaluation of Training with an Auditory P300 Brain-Computer Interface for the Japanese Hiragana Syllabary JF - Frontiers in Neuroscience N2 - Gaze-independent brain-computer interfaces (BCIs) are a possible communication channel for persons with paralysis. We investigated if it is possible to use auditory stimuli to create a BCI for the Japanese Hiragana syllabary, which has 46 Hiragana characters. Additionally, we investigated if training has an effect on accuracy despite the high amount of different stimuli involved. Able-bodied participants (N = 6) were asked to select 25 syllables (out of fifty possible choices) using a two step procedure: First the consonant (ten choices) and then the vowel (five choices). This was repeated on 3 separate days. Additionally, a person with spinal cord injury (SCI) participated in the experiment. Four out of six healthy participants reached Hiragana syllable accuracies above 70% and the information transfer rate increased from 1.7 bits/min in the first session to 3.2 bits/min in the third session. The accuracy of the participant with SCI increased from 12% (0.2 bits/min) to 56% (2 bits/min) in session three. Reliable selections from a 10 × 5 matrix using auditory stimuli were possible and performance is increased by training. We were able to show that auditory P300 BCIs can be used for communication with up to fifty symbols. This enables the use of the technology of auditory P300 BCIs with a variety of applications. KW - gaze independence KW - assistive technology KW - electroencephalography KW - event-related potentials KW - P300 KW - auditory stimulation KW - brain-computer interface Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165465 VL - 10 IS - 446 ER - TY - JOUR A1 - Issel-Dombert, Sandra A1 - Wieders-Lohéac, Aline T1 - «Nous multiplierons les chansons, les concerts, les spectacles». L’argumentation de François Hollande face aux attaques terroristes du 13 novembre JF - promptus - Würzburger Beiträge zur Romanistik N2 - After the terrorist attacks on November 13th, the French public, the whole of Europe and many parts of the world were waiting for president François Hollande to address his fellow “citoyens”. Being the most important political figure – both by constitution and by influence on public discourse – the president’s words bear great importance for the subsequent debate and interpretation of the events. Therefore, the question arises: How did the president shape the debate in the hours and days after the attacks? To answer this question, we have identified typical structures in Hollande’s rhetorical reaction to the attacks, performing a topos as well as a keyword analysis of the speeches the president held within two weeks after November 13th. In a contrastive analysis we have compared Hollande’s speeches to the Europarl Corpus. Using the software programme sketch engine, we have filtered out the 100 most frequent keywords and classified them into semantic fields (data-driven approach). All in all, terrorism, action and nation/identity are the three predominant semantic fields, whereas references to victimhood barely appear. These findings are congruent with the results of our topos analysis that reveals a predominance of argumentative structures that form a strong main topos of resilience, emphasising the greatness of France and its people and culture, calling to action and avoiding any tendencies of resignation. KW - debate KW - Hollande, François KW - influence KW - terrorist attack, Paris, 13th November 2015 KW - Hollande, François KW - Bataclan (Paris) KW - Attentat KW - Meinungsbildung Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161637 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Brunke, Dirk T1 - Der nationalepische Pionier Esteban Echeverría. Ein Beitrag zur Entstehungsgeschichte des romantischen epischen Gedichts in Hispanoamerika JF - promptus - Würzburger Beiträge zur Romanistik N2 - This article concentrates on the Argentine author Esteban Echeverría who is known as the founding father of Romanticism in the River Plate region. The author of this article intends to show that the importance of Echeverría for the development of Argentine national literature goes beyond the spreading of Romanticist aesthetics. Especially his poem La cautiva (1837) has been regarded as the national epic poem of Argentina because it represents national landscape and the early days of national history. However, as the classification of this narrative poem as the national epic poem already indicates, Echeverría also contributed to the presence of this prestigious genre at the River Plate region. By investigating Echeverría‘s less known verse texts – namely the texts which were read by all Romantics but which have been neglected by literary studies so far – this article illustrates that Echeverría gave decisive impulses for the presence of the epic poem at the River Plate. KW - episches Gedicht KW - romantisches Gedicht KW - Hispanoamerika KW - Entstehungsgeschichte KW - Echeverría, Esteban KW - Hispanoamerika KW - Literatur KW - Gedicht Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161592 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Buch, Marina-Rafaela T1 - Madame Chrysanthème (1887) et Japoneries d’automne (1889) de Pierre Loti entre japonisme et exotisme désenchanté JF - promptus - Würzburger Beiträge zur Romanistik N2 - The novel Madame Chrysanthème (1887) and the essays collected in Japoneries d’automne (1889) written by French travel author Pierre Loti offer a paradoxical view of Japan during the Meiji period. In both travel writings, the author is torn between aesthetic japonism – which spread all over Europe at the end of the 19th century – and exotic expectations, i.e. the picturesque fascination of the Other. The latter, however, remains unsatisfied throughout his stay. In both writings, Pierre Loti provides an insight into Japan that entirely reflects the spirit of his time. Thereby, he contributes to an image of Japan, which will long remain vivid in the Occident. Contemporaries perceive Loti’s representation of Japan as a realistic testimony, tinged with both sensory impressions and his highly ambiguous feelings towards the distant country, which in the end remained incomprehensible to him. KW - Madame Chrysanthème KW - Japoneries d’automne KW - Pierre Loti KW - Loti, Pierre KW - Japan KW - Meiji-Periode Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161603 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Fliege, Daniel T1 - Le dégoût du cadavre. Une comparaison entre la représentation du corps mort dans le De Miseria Condicionis Humane d’Innocent III et dans son adaptation française Double lay de fragilité humaine d’Eustache Deschamps JF - promptus - Würzburger Beiträge zur Romanistik N2 - The study uses the category of disgust in order to analyse the representation of the human body and the corpse in one of the most influential medieval treatises, the De Miseria Condicionis Humanae (1195) written by Pope Innocent III, and its little known old French adaptation Double lay de fragilité humaine (1383) by Eustache Deschamps. Analysing how both use disgust as an aesthetic means, which appeals to emotions and turns off reason, helps to point out the pedagogical and moral function of the texts. The comparison between them shows that Deschamps stays faithful to his Latin model, but that he nevertheless has to make certain modifications in order to adapt the prose text into a lyrical form. Furthermore, this approach clearly elucidates what differences there are between the conceptions of the human body and death in the two texts, revealing at the same time divergent theological points of view. KW - De Miseria Condicionis Humanae KW - Double lay de fragilité humaine KW - Deschamps, Eustache KW - Innocent III KW - Ekel KW - Leiche KW - Körper KW - Mittelalter KW - Literatur Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161616 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Kloster, Kerstin T1 - Der Körper als Einschreibungsfläche des weiblichen Gedächtnisses. Eine Analyse der mündlichen Überlieferung in Le livre d’Emma von Marie-Célie Agnant JF - promptus - Würzburger Beiträge zur Romanistik N2 - Women in Caribbean culture traditionally occupy the role of guardians of collective memory, as tellers of stories, legends and myths. Through oral tradition, they transfer the cultural and family knowledge from one generation of women to the next. We will offer an analysis of oral transmission as a way of preserving a memory of women in Le livre d’Emma (2001) by the Québec author of Haitian origin, Marie-Célie Agnant. We will primarily analyze the transformation of communicative memory into cultural memory, following the distinction by Jan Assmann. We will interpret the oral transfer as a possibility to stabilize, to legitimize female memory and to inscribe it into the female body. KW - Agnant, Marie-Célie : Le livre d'Emma KW - Agnant, Marie-Célie : Le livre d'Emma KW - Mündliche Überlieferung Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161645 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - White, P. Lewis A1 - Wiederhold, Nathan P. A1 - Loeffler, Juergen A1 - Najvar, Laura K. A1 - Melchers, Willem A1 - Herrera, Monica A1 - Bretagne, Stephane A1 - Wickes, Brian A1 - Kirkpatrick, William R. A1 - Barnes, Rosemary A. A1 - Donnelly, J. Peter A1 - Patterson, Thomas F. T1 - Comparison of nonculture blood-based tests for diagnosing invasive aspergillosis in an animal model JF - Journal of Clinical Microbiology N2 - 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. KW - high-risk hematology KW - Guinea pig model KW - real-time PCR KW - fungal disease KW - galactomannan KW - pulmonary aspergillosis KW - amphotericin B KW - Aspergillus fumigatus KW - beta-D-glucan Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189674 VL - 54 IS - 4 ER - TY - JOUR A1 - Barquist, Lars A1 - Mayho, Matthew A1 - Cummins, Carla A1 - Cain, Amy K. A1 - Boinett, Christine J. A1 - Page, Andrew J. A1 - Langridge, Gemma C. A1 - Quail, Michael A. A1 - Keane, Jacqueline A. A1 - Parkhill, Julian T1 - The TraDIS toolkit: sequencing and analysis for dense transposon mutant libraries JF - Bioinformatics N2 - 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. KW - mechanisms KW - Transposon insertion sequencing KW - sequencing protocol KW - TraDIS Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189667 VL - 32 IS - 7 ER - TY - JOUR A1 - Schiele, Miriam A. A1 - Reinhard, Julia A1 - Reif, Andreas A1 - Domschke, Katharina A1 - Romanos, Marcel A1 - Deckert, Jürgen A1 - Pauli, Paul T1 - Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults JF - Developmental Psychobiology N2 - Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. KW - fear conditioning KW - fear generalization KW - development KW - skin conductance KW - maturation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189488 VL - 58 IS - 4 ER - TY - JOUR A1 - Manukjan, Georgi A1 - Ripperger, Tim A1 - Venturini, Letizia A1 - Stadler, Michael A1 - Göhring, Gudrun A1 - Schambach, Axel A1 - Schlegelberger, Brigitte A1 - Steinemann, Doris T1 - GABP is necessary for stem/progenitor cell maintenance and myeloid differentiation in human hematopoiesis and chronic myeloid leukemia JF - Stem Cell Research N2 - Maintenance of hematopoietic stem cells and their potential to give rise to progenitors of differentiated lymphoid and myeloid cells are accomplished by a network of regulatory processes. As a part of this network, the heteromeric transcription factor GA-binding protein (GABP) plays a crucial role in self-renewal of murine hematopoietic and leukemic stem cells. Here, we report the consequences of functional impairment of GABP in human hematopoietic and in leukemic stem/progenitor cells. Ectopic overexpression of a dominant-negative acting GABP mutant led to impaired myeloid differentiation of CD34\(^{+}\) hematopoietic stem/progenitor cells obtained from healthy donors. Moreover, drastically reduced clonogenic capacity of leukemic stem/progenitor cells isolated from bone marrow aspirates of chronic myeloid leukemia (CML) patients underlines the importance of GABP on stem/progenitor cell maintenance and confirms the relevance of GABP for human myelopoiesis in healthy and diseased states. KW - GABP KW - stem cells KW - human hematopoiesis KW - leukemia Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168165 VL - 16 IS - 3 ER - TY - JOUR A1 - Gambaryan, Stepan A1 - Subramanian, Hariharan A1 - Kehrer, Linda A1 - Mindukshev, Igor A1 - Sudnitsyna, Julia A1 - Reiss, Cora A1 - Rukoyatkina, Natalia A1 - Friebe, Andreas A1 - Sharina, Iraida A1 - Martin, Emil A1 - Walter, Ulrich T1 - Erythrocytes do not activate purified and platelet soluble guanylate cyclases even in conditions favourable for NO synthesis JF - Cell Communication and Signaling N2 - Background Direct interaction between Red blood cells (RBCs) and platelets is known for a long time. The bleeding time is prolonged in anemic patients independent of their platelet count and could be corrected by transfusion of RBCs, which indicates that RBCs play an important role in hemostasis and platelet activation. However, in the last few years, opposing mechanisms of platelet inhibition by RBCs derived nitric oxide (NO) were proposed. The aim of our study was to identify whether RBCs could produce NO and activate soluble guanylate cyclase (sGC) in platelets. Methods To test whether RBCs could activate sGC under different conditions (whole blood, under hypoxia, or even loaded with NO), we used our well-established and highly sensitive models of NO-dependent sGC activation in platelets and activation of purified sGC. The activation of sGC was monitored by detecting the phosphorylation of Vasodilator Stimulated Phosphoprotein (VASPS239) by flow cytometry and Western blot. ANOVA followed by Bonferroni’s test and Student’s t-test were used as appropriate. Results We show that in the whole blood, RBCs prevent NO-mediated inhibition of ADP and TRAP6-induced platelet activation. Likewise, coincubation of RBCs with platelets results in strong inhibition of NO-induced sGC activation. Under hypoxic conditions, incubation of RBCs with NO donor leads to Hb-NO formation which inhibits sGC activation in platelets. Similarly, RBCs inhibit activation of purified sGC, even under conditions optimal for RBC-mediated generation of NO from nitrite. Conclusions All our experiments demonstrate that RBCs act as strong NO scavengers and prevent NO-mediated inhibition of activated platelets. In all tested conditions, RBCs were not able to activate platelet or purified sGC. KW - hemoglobin KW - erythrocytes KW - nitric oxide KW - soluble guanylate cyclase KW - platelets Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161223 VL - 14 IS - 16 ER - TY - JOUR A1 - Schöpe, Kai T1 - Unaufhörliches Suchen – Gaddas Roman Quer pasticciaccio brutto de via Merulana als carmen perpetuum JF - promptus - Würzburger Beiträge zur Romanistik N2 - Gadda’s novel Quer Pasticciaccio brutto de Via Merulana tells the tale of two crimes committed in Rome in the 1920s. The search for the perpetrators turns into a pasticciaccio brutto (an awful mess), challenging the reader with its linguistic complexity and a myriad of references to history and culture; the large number of allusions to antiquity is particularly striking. References to Virgil’s Aeneid and to Rome’s mythical past do not constitute a mere transfer, but document a creative approach of transformational nature. Deformation and inversion are part of this process, changing the μορφή not only in formal terms, but also within the plot itself. These transformations of both form and content are read as Metamorphoses and analysed in comparison to Ovid’s homonymous work. The perpetual, never-ending quest for truth in Gadda’s novel necessitates a perpetual, never-ending narrative, which is conceptually related to Ovid’s carmen perpetuum. KW - Gadda, Carlo Emilio : Quer pasticciaccio brutto de Via Merulana KW - perpetual, never-ending narrative KW - Gadda, Carlo Emilio : Quer pasticciaccio brutto de Via Merulana Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161673 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Suslenkova, Anastasiya T1 - Diskursanalytische Untersuchungen der politischen Rede in Italien am Beispiel der ausgewählten Reden von Silvio Berlusconi und Matteo Renzi JF - promptus - Würzburger Beiträge zur Romanistik N2 - The present study is concerned with a critical discourse analysis of the speeches of the Italian politicians Silvio Berlusconi and Matteo Renzi in different situations. The aim of the study was to find out how historical and speech contexts influence discourse structures and argumentations, and if any similar speech patterns or speech strategies were used. The results show that both politicians in many cases tend to utilize similar speech patterns to achieve different aims; each of them shows a preference for particular words, structures and strategies. It is noteworthy that one of the important differences between speeches of Berlusconi and Renzi is the use of various speech strategies. While Renzi uses these strategies to create an image of himself as a young and honest politician, Berlusconi makes use of them to defend himself or attack his opponents. KW - Renzi, Matteo KW - Berlusconi, Silvio KW - critical discourse analysis KW - speeches KW - Diskursanalyse KW - Politische Rede KW - Berlusconi, Silvio KW - Renzi, Matteo Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161681 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Winter, Ursula T1 - Literarisierung von Musik als Intermedialitätsphänomen. Exemplarische Betrachtung der oratorischen Rezeption Dantes und Goethes bei Wolf-Ferrari und Berlioz JF - promptus - Würzburger Beiträge zur Romanistik N2 - This article deals with the reception of Dante and Goethe in Ermanno Wolf-Ferrari’s and Hector Berlioz’s compositions La Vita Nuova and La Damnation de Faust. Although Dante Alighieri’s Vita Nova and Johann Wolfgang von Goethe’s Faust belong to completely different genres and epochs, the texts provide the basis for the oratorio-style works from the Romantic era, which justifies a comparative analysis of the latter. The examined reductions, extensions, modifications and rearrangements of the texts in the libretti – which were compiled almost entirely by the composers themselves – as well as the instrumental parts and the use and functions of the orchestra, the choir and the soloists, portray the intermedia relations between literature and music in the selected compositions. The chosen examples will show that the common idea of setting literature to music and the translation studies concept of intersemiotic translation are not appropriate for all literature-based pieces of music, as the analysis of both works demonstrates that with regard to vocal music a distinction should be made between the musicalization of literature and the literarization of music. KW - Dante, Alighieri KW - Goethe, Johann Wolfgang von KW - Wolf-Ferrari, Ermanno KW - Berlioz, Hector KW - Musik KW - Literarisierung KW - Intermedialität Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161690 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Scholz, Janek T1 - Eine Künstlerkooperation ‘além das fronteiras’ – Banda desenhada de língua portuguesa JF - promptus - Würzburger Beiträge zur Romanistik N2 - Economic, academic or artistic cooperation among actors of different countries or disciplines offers numerous new perspectives, but it also confronts the ones profiting from it with several challenges. First, identity has to be firmly established, which requires intercultural skills, such as role-distance, empathy and tolerance for ambiguities. Secondly, a third space is required in which meaning can be newly negotiated to make the partnership succeed. This paper proposes that even within one and the same language-group, one can speak of intercultural communication. A particular collaboration between Portuguese-speaking comic artists will be introduced, raising questions of the conditions necessary to make such a cooperation work. Answers will be provided according to the decisions the artists made in their publications. KW - Banda desenhada de língua portuguesa KW - BDLP KW - Künstlerkooperation KW - Kooperation KW - Künstler Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161662 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Stolze, Ina A1 - Trautmann, Axel A1 - Goebeler, Matthias A1 - Stoevesandt, Johanna T1 - Dangerous Leg Cramps: Severe Pustular Exanthema Caused by an Over-the-Counter Drug JF - Acta Dermato-Venereologica N2 - Abstract is missing KW - leg cramps KW - over-the-counter drugs KW - pustular exanthema KW - quinine KW - allergy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171285 VL - 96 ER - TY - JOUR A1 - Sonnenberg, Christoph A1 - Bannert, Maria T1 - Evaluating the Impact of Instructional Support Using Data Mining and Process Mining: A Micro-Level Analysis of the Effectiveness of Metacognitive Prompts JF - Journal of Educational Data Mining N2 - In computer-supported learning environments, the deployment of self-regulatory skills represents an essential prerequisite for successful learning. Metacognitive prompts are a promising type of instructional support to activate students’ strategic learning activities. However, despite positive effects in previous studies, there are still a large number of students who do not benefit from provided support. Therefore, it may be necessary to consider explicitly the conditions under which a prompt is beneficial for a student, i.e., so-called adaptive scaffolding. The current study aims to (i) classify the effectiveness of prompts on regulatory behavior, (ii) investigate the correspondence of the classification with learning outcome, and (iii) discover the conditions under which prompts induce regulatory activities (i.e., the proper temporal positioning of prompts). The think-aloud data of an experiment in which metacognitive prompts supported the experimental group (n = 35) was used to distinguish between effective and non-effective prompts. Students’ activities preceding the prompt presentation were analyzed using data mining and process mining techniques. The results indicate that approximately half of the presented prompts induced metacognitive learning activities as expected. Moreover, the number of induced monitoring activities correlates positively with transfer performance. Finally, the occurrence of orientation and monitoring activities, which are not well-embedded in the course of learning, increases the effectiveness of a presented prompt. In general, our findings demonstrate the benefits of investigating metacognitive support using process data, which can provide implications for the design of effective instructional support. KW - process mining KW - think-aloud data KW - metacognitive prompting KW - micro-level analysis KW - instructional support KW - self-regulated learning Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-152375 UR - http://www.educationaldatamining.org/JEDM/index.php/JEDM/article/view/JEDM2016-8-2-3 N1 - Dieser Artikel ist auch Bestandteil der Dissertation: Sonnenberg, Christoph: Analyzing Technology-Enhanced Learning Processes: What Can Process Mining Techniques Contribute to the Evaluation of Instructional Support?. - Würzburg, Univ., Diss., 2017. - [online]. URN: urn:nbn:de:bvb:20-opus-152354 VL - 8 IS - 2 ER - TY - JOUR A1 - Goldmann, Julius A1 - Hornung, Christoph T1 - Interview mit Prof. (em.) Dr. Frank-Rutger Hausmann JF - promptus - Würzburger Beiträge zur Romanistik N2 - Frank-Rutger Hausmann war Professor für Romanische Philologie (Schwerpunkt französische und italienische Literatur) in Freiburg, Aachen und wiederum Freiburg. Hausmann hat sich zudem intensiv mit der Fachgeschichte der deutschen Romanistik und der Geisteswissenschaften allgemein beschäftigt. Für die zweite Ausgabe der promptus-Interviewreihe durften wir ihn nach seiner Perspektive auf die historische und aktuelle Situation der Romanistik befragen. Er arbeitet momentan u.a. an einem Romanistenlexikon, das online veröffentlicht wird, und hat das Romanistenarchiv in Augsburg gegründet. KW - Romanistik KW - Interview KW - aktuelle Situation KW - historische Situation KW - Romansitik KW - Biographisches Interview KW - Perspektive Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161586 SN - 2510-2613 VL - 2 ER - TY - JOUR A1 - Widmann, Annekathrin A1 - Artinger, Marc A1 - Biesinger, Lukas A1 - Boepple, Kathrin A1 - Peters, Christina A1 - Schlechter, Jana A1 - Selcho, Mareike A1 - Thum, Andreas S. T1 - Genetic Dissection of Aversive Associative Olfactory Learning and Memory in Drosophila Larvae JF - PLoS Genetics N2 - Memory formation is a highly complex and dynamic process. It consists of different phases, which depend on various neuronal and molecular mechanisms. In adult Drosophila it was shown that memory formation after aversive Pavlovian conditioning includes—besides other forms—a labile short-term component that consolidates within hours to a longer-lasting memory. Accordingly, memory formation requires the timely controlled action of different neuronal circuits, neurotransmitters, neuromodulators and molecules that were initially identified by classical forward genetic approaches. Compared to adult Drosophila, memory formation was only sporadically analyzed at its larval stage. Here we deconstruct the larval mnemonic organization after aversive olfactory conditioning. We show that after odor-high salt conditioning larvae form two parallel memory phases; a short lasting component that depends on cyclic adenosine 3’5’-monophosphate (cAMP) signaling and synapsin gene function. In addition, we show for the first time for Drosophila larvae an anesthesia resistant component, which relies on radish and bruchpilot gene function, protein kinase C activity, requires presynaptic output of mushroom body Kenyon cells and dopamine function. Given the numerical simplicity of the larval nervous system this work offers a unique prospect for studying memory formation of defined specifications, at full-brain scope with single-cell, and single-synapse resolution. KW - genetic dissection KW - Drosophila KW - memory formation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166672 VL - 12 IS - 10 ER - TY - JOUR A1 - Stauss, Dennis A1 - Brunner, Cornelia A1 - Berberich-Siebelt, Friederike A1 - Höpken, Uta E. A1 - Lipp, Martin A1 - Müller, Gerd T1 - The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6 JF - Embo Journal N2 - Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4\(^+\) T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by the Pou2af1 gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate the Bcl6 and Btla promoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 and BTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses. KW - follicular T helper cells KW - germinal center KW - humoral immunity KW - Pou2af1 KW - T cell differentiation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189506 VL - 35 IS - 8 ER - TY - JOUR A1 - Deeb, Wissam A1 - Giordano, James J. A1 - Rossi, Peter J. A1 - Mogilner, Alon Y. A1 - Gunduz, Aysegul A1 - Judy, Jack W. A1 - Klassen, Bryan T. A1 - Butson, Christopher R. A1 - Van Horne, Craig A1 - Deny, Damiaan A1 - Dougherty, Darin D. A1 - Rowell, David A1 - Gerhardt, Greg A. A1 - Smith, Gwenn S. A1 - Ponce, Francisco A. A1 - Walker, Harrison C. A1 - Bronte-Stewart, Helen M. A1 - Mayberg, Helen S. A1 - Chizeck, Howard J. A1 - Langevin, Jean-Philippe A1 - Volkmann, Jens A1 - Ostrem, Jill L. A1 - Shute, Jonathan B. A1 - Jimenez-Shahed, Joohi A1 - Foote, Kelly D. A1 - Wagle Shukla, Aparna A1 - Rossi, Marvin A. A1 - Oh, Michael A1 - Pourfar, Michael A1 - Rosenberg, Paul B. A1 - Silburn, Peter A. A1 - de Hemptine, Coralie A1 - Starr, Philip A. A1 - Denison, Timothy A1 - Akbar, Umer A1 - Grill, Warren M. A1 - Okun, Michael S. T1 - Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies JF - Frontiers in Integrative Neuroscience N2 - This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field. KW - deep brain stimulation KW - Parkinson’s disease KW - Alzheimer’s disease KW - closed-loop KW - depression KW - post-traumatic stress disorder KW - Tourette syndrome KW - DARPA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168493 VL - 10 IS - 38 ER - TY - JOUR A1 - Tinajero-Trejo, Mariana A1 - Rana, Namrata A1 - Nagel, Christoph A1 - Jesse, Helen E. A1 - Smith, Thomas W. A1 - Wareham, Lauren K. A1 - Hippler, Michael A1 - Schatzschneider, Ulrich A1 - Poole, Robert K. T1 - Antimicrobial Activity of the Manganese Photoactivated Carbon Monoxide-Releasing Molecule [Mn(CO)\(_3\)(tpa-kappa\(^3\)N)]\(^+\) Against a Pathogenic Escherichia coli that Causes Urinary Infections JF - Antioxidants & Redox Signaling N2 - Aims: We set out to investigate the antibacterial activity of a new Mn-based photoactivated carbon monoxide-releasing molecule (PhotoCORM, [Mn(CO)\(_3\)(tpa-kappa\(^3\)N)]\(^+\)) against an antibiotic-resistant uropathogenic strain (EC958) of Escherichia coli. Results: Activated PhotoCORM inhibits growth and decreases viability of E. coli EC958, but non-illuminated carbon monoxide-releasing molecule (CORM) is without effect. NADH-supported respiration rates are significantly decreased by activated PhotoCORM, mimicking the effect of dissolved CO gas. CO from the PhotoCORM binds to intracellular targets, namely respiratory oxidases in strain EC958 and a bacterial globin heterologously expressed in strain K-12. However, unlike previously characterized CORMs, the PhotoCORM is not significantly accumulated in cells, as deduced from the cellular manganese content. Activated PhotoCORM reacts avidly with hydrogen peroxide producing hydroxyl radicals; the observed peroxide-enhanced toxicity of the PhotoCORM is ameliorated by thiourea. The PhotoCORM also potentiates the effect of the antibiotic, doxycycline. Innovation: The present work investigates for the first time the antimicrobial activity of a light-activated PhotoCORM against an antibiotic-resistant pathogen. A comprehensive study of the effects of the PhotoCORM and its derivative molecules upon illumination is performed and mechanisms of toxicity of the activated PhotoCORM are investigated. Conclusion: The PhotoCORM allows a site-specific and time-controlled release of CO in bacterial cultures and has the potential to provide much needed information on the generality of CORM activities in biology. Understanding the mechanism(s) of activated PhotoCORM toxicity will be key in exploring the potential of this and similar compounds as antimicrobial agents, perhaps in combinatorial therapies with other agents. KW - intracellular hydrogen-peroxide KW - campylobacter-jejuni KW - oxygen-metabolism KW - deficient mutant KW - oxidative stress KW - aqueous-solution KW - metal caponyls KW - RU(CO)(3)CL(GLYCINATE) KW - bacteria KW - enzyme Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188910 VL - 24 IS - 14 ER - TY - JOUR A1 - Holtfrerich, Sarah K. C. A1 - Schwarz, Katharina A. A1 - Sprenger, Christian A1 - Reimers, Luise A1 - Diekhof, Esther K. T1 - Endogenous Testosterone and Exogenous Oxytocin Modulate Attentional Processing of Infant Faces JF - PLoS ONE N2 - Evidence indicates that hormones modulate the intensity of maternal care. Oxytocin is known for its positive influence on maternal behavior and its important role for childbirth. In contrast, testosterone promotes egocentric choices and reduces empathy. Further, testosterone decreases during parenthood which could be an adaptation to increased parental investment. The present study investigated the interaction between testosterone and oxytocin in attentional control and their influence on attention to baby schema in women. Higher endogenous testosterone was expected to decrease selective attention to child portraits in a face-in-the-crowd-paradigm, while oxytocin was expected to counteract this effect. As predicted, women with higher salivary testosterone were slower in orienting attention to infant targets in the context of adult distractors. Interestingly, reaction times to infant and adult stimuli decreased after oxytocin administration, but only in women with high endogenous testosterone. These results suggest that oxytocin may counteract the adverse effects of testosterone on a central aspect of social behavior and maternal caretaking. KW - maternal behavior KW - oxytocin KW - testosterone KW - attention KW - infant faces Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166783 VL - 11 IS - 11 ER - TY - JOUR A1 - van Unen, Jakobus A1 - Stumpf, Anette D. A1 - Schmid, Benedikt A1 - Reinhard, Nathalie R. A1 - Hordijk, Peter L. A1 - Hoffmann, Carsten A1 - Gadella, Theodorus W. J. A1 - Goedhart, Joachim T1 - A New Generation of FRET Sensors for Robust Measurement of Gα\(_{i1}\), Gα\(_{i2}\) and Gα\(_{i3}\) Activation Kinetics in Single Cells JF - PLoS ONE N2 - G-protein coupled receptors (GPCRs) can activate a heterotrimeric G-protein complex with subsecond kinetics. Genetically encoded biosensors based on Förster resonance energy transfer (FRET) are ideally suited for the study of such fast signaling events in single living cells. Here we report on the construction and characterization of three FRET biosensors for the measurement of Gα\(_{i1}\), Gα\(_{i2}\) and Gα\(_{i3}\) activation. To enable quantitative long-term imaging of FRET biosensors with high dynamic range, fluorescent proteins with enhanced photophysical properties are required. Therefore, we use the currently brightest and most photostable CFP variant, mTurquoise2, as donor fused to Gα\(_{i}\) subunit, and cp173Venus fused to the Gγ\(_{2}\) subunit as acceptor. The Gα\(_{i}\) FRET biosensors constructs are expressed together with Gβ\(_{1}\) from a single plasmid, providing preferred relative expression levels with reduced variation in mammalian cells. The Gα\(_{i}\) FRET sensors showed a robust response to activation of endogenous or over-expressed alpha-2A-adrenergic receptors, which was inhibited by pertussis toxin. Moreover, we observed activation of the Gα\(_{i}\) FRET sensor in single cells upon stimulation of several GPCRs, including the LPA\(_{2}\), M\(_{3}\) and BK\(_{2}\) receptor. Furthermore, we show that the sensors are well suited to extract kinetic parameters from fast measurements in the millisecond time range. This new generation of FRET biosensors for Gα\(_{i1}\), Gα\(_{i2}\) and Gα\(_{i3}\) activation will be valuable for live-cell measurements that probe Gα\(_{i}\) activation. KW - FRET sensors KW - G-protein coupled receptors KW - Förster resonance energy transfer KW - Gα\(_{i1}\), Gα\(_{i2}\) and Gα\(_{i3}\) activation KW - biosensors Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167387 VL - 11 IS - 1 ER - TY - JOUR A1 - Krupka, Jennifer A1 - May, Frauke A1 - Weimer, Thomas A1 - Pragst, Ingo A1 - Kleinschnitz, Christoph A1 - Stoll, Guido A1 - Panousis, Con A1 - Dickneite, Gerhard A1 - Nolte, Marc W. T1 - The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats JF - PLoS ONE N2 - Background and Purpose Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. Methods For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. Results Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. Conclusions With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury. KW - coagulation factor XIIa KW - ischemic stroke KW - contact activation system KW - FXIIa inhibitor rHA-Infestin Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167370 VL - 11 IS - 1 ER - TY - JOUR A1 - Kuhn, Manuel A1 - Scharfenort, Robert A1 - Schümann, Dirk A1 - Schiele, Miriam A. A1 - Münsterkötter, Anna L. A1 - Deckert, Jürgen A1 - Domschke, Katharina A1 - Haaker, Jan A1 - Kalisch, Raffael A1 - Pauli, Paul A1 - Reif, Andreas A1 - Romanos, Marcel A1 - Zwanzger, Peter A1 - Lonsdorf, Tina B. T1 - Mismatch or allostatic load? Timing of life adversity differentially shapes gray matter volume and anxious temperament JF - Social Cognitive and Affective Neuroscience N2 - 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. KW - VBM KW - childhood maltreatment KW - adversity KW - stressful life events KW - mismatch KW - allostatic load Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189645 VL - 11 IS - 4 ER - TY - JOUR A1 - Dix, Andreas A1 - Czakai, Kristin A1 - Springer, Jan A1 - Fliesser, Mirjam A1 - Bonin, Michael A1 - Guthke, Reinhard A1 - Schmitt, Anna L. A1 - Einsele, Hermann A1 - Linde, Jörg A1 - Löffler, Jürgen T1 - Genome-Wide Expression Profiling Reveals S100B as Biomarker for Invasive Aspergillosis JF - Frontiers in Microbiology N2 - Invasive aspergillosis (IA) is a devastating opportunistic infection and its treatment constitutes a considerable burden for the health care system. Immunocompromised patients are at an increased risk for IA, which is mainly caused by the species Aspergillus fumigatus. An early and reliable diagnosis is required to initiate the appropriate antifungal therapy. However, diagnostic sensitivity and accuracy still needs to be improved, which can be achieved at least partly by the definition of new biomarkers. Besides the direct detection of the pathogen by the current diagnostic methods, the analysis of the host response is a promising strategy toward this aim. Following this approach, we sought to identify new biomarkers for IA. For this purpose, we analyzed gene expression profiles of hematological patients and compared profiles of patients suffering from IA with non-IA patients. Based on microarray data, we applied a comprehensive feature selection using a random forest classifier. We identified the transcript coding for the S100 calcium-binding protein B (S100B) as a potential new biomarker for the diagnosis of IA. Considering the expression of this gene, we were able to classify samples from patients with IA with 82.3% sensitivity and 74.6% specificity. Moreover, we validated the expression of S100B in a real-time reverse transcription polymerase chain reaction (RT-PCR) assay and we also found a down-regulation of S100B in A. fumigatus stimulated DCs. An influence on the IL1B and CXCL1 downstream levels was demonstrated by this S100B knockdown. In conclusion, this study covers an effective feature selection revealing a key regulator of the human immune response during IA. S100B may represent an additional diagnostic marker that in combination with the established techniques may improve the accuracy of IA diagnosis. KW - human biomarker KW - invasive aspergillosis KW - allogeneic stem cell transplantation KW - gene expression data KW - fungal infection Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165386 IS - 7 ER - TY - JOUR A1 - Chagtai, Tasnim A1 - Zill, Christina A1 - Dainese, Linda A1 - Wegert, Jenny A1 - Savola, Suvi A1 - Popov, Sergey A1 - Mifsud, William A1 - Vujanic, Gordan A1 - Sebire, Neil A1 - Le Bouc, Yves A1 - Ambros, Peter F. A1 - Kager, Leo A1 - O`Sullivan, Maureen J. A1 - Blaise, Annick A1 - Bergeron, Christophe A1 - Holmquist Mengelbier, Linda A1 - Gisselsson, David A1 - Kool, Marcel A1 - Tytgat, Godelieve A.M. A1 - van den Heuvel-Eibrink, Marry M. A1 - Graf, Norbert A1 - van Tinteren, Harm A1 - Coulomb, Aurore A1 - Gessler, Manfred A1 - Williams, Richard Dafydd A1 - Pritchard-Jones, Kathy T1 - Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: a SIOP Renal Tumours Biology Consortium Study JF - Journal of Clinical Oncology N2 - Purpose Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. Materials and Methods WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. Results One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P<.001; hazard ratio, 2.33) and OS (P=.01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. Conclusion Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage. KW - Poor-prognosis KW - Mutations KW - Gene KW - Drosha KW - MYCN KW - Mechanisms KW - Reveals KW - Event KW - Relapse KW - Locus Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187478 VL - 34 IS - 26 ER - TY - JOUR A1 - Lorenzin, Francesca A1 - Benary, Uwe A1 - Baluapuri, Apoorva A1 - Walz, Susanne A1 - Jung, Lisa Anna A1 - von Eyss, Björn A1 - Kisker, Caroline A1 - Wolf, Jana A1 - Eilers, Martin A1 - Wolf, Elmar T1 - Different promoter affinities account for specificity in MYC-dependent gene regulation JF - eLife N2 - Enhanced expression of the MYC transcription factor is observed in the majority of tumors. Two seemingly conflicting models have been proposed for its function: one proposes that MYC enhances expression of all genes, while the other model suggests gene-specific regulation. Here, we have explored the hypothesis that specific gene expression profiles arise since promoters differ in affinity for MYC and high-affinity promoters are fully occupied by physiological levels of MYC. We determined cellular MYC levels and used RNA- and ChIP-sequencing to correlate promoter occupancy with gene expression at different concentrations of MYC. Mathematical modeling showed that binding affinities for interactions of MYC with DNA and with core promoter-bound factors, such as WDR5, are sufficient to explain promoter occupancies observed in vivo. Importantly, promoter affinity stratifies different biological processes that are regulated by MYC, explaining why tumor-specific MYC levels induce specific gene expression programs and alter defined biological properties of cells. KW - MYC KW - promoter affinity KW - human KW - mathematical modeling KW - mouse KW - ChIP-sequencing KW - MIZ1 KW - cancer biology KW - cell biology KW - WDR5 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162913 VL - 5 ER - TY - JOUR A1 - Weismann, Dirk A1 - Schneider, Andreas A1 - Höybye, Charlotte T1 - Clinical aspects of symptomatic hyponatremia JF - Endocrine Connections N2 - Hyponatremia (HN) is a common condition, with a large number of etiologies and a complicated treatment. Although chronic HN has been shown to be a predictor of poor outcome, sodium-increasing treatments in chronic stable and asymptomatic HN have not proven to increase life expectancy. For symptomatic HN, in contrast, the necessity for urgent treatment has broadly been accepted to avoid the development of fatal cerebral edema. On the other hand, a too rapid increase of serum sodium in chronic HN may result in cerebral damage due to osmotic demyelinisation. Recently, administration of hypertonic saline bolus has been recommended as first-line treatment in patients with moderate-to-severe symptomatic HN. This approach is easy to memorize and holds the potential to greatly facilitate the initial treatment of symptomatic HN. First-line treatment of chronic HN is fluid restriction and if ineffective treatment with tolvaptan or in some patients other agents should be considered. A number of recommendations and guidelines have been published on HN. In the present review, the management of patients with HN in relation to everyday clinical practice is summarized with focus on the acute management. KW - hyponatremia KW - clinical Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162936 VL - 5 IS - 5 ER - TY - JOUR A1 - Dreschers, Stephan A1 - Saupp, Peter A1 - Hornef, Mathias A1 - Prehn, Andrea A1 - Platen, Christopher A1 - Morschhäuser, Joachim A1 - Orlikowsky, Thorsten W. T1 - Reduced PICD in Monocytes Mounts Altered Neonate Immune Response to Candida albicans JF - PLoS ONE N2 - Background Invasive fungal infections with Candida albicans (C. albicans) occur frequently in extremely low birthweight (ELBW) infants and are associated with poor outcome. Phagocytosis of C.albicans initializes apoptosis in monocytes (phagocytosis induced cell death, PICD). PICD is reduced in neonatal cord blood monocytes (CBMO). Hypothesis Phagocytosis of C. albicans causes PICD which differs between neonatal monocytes (CBMO) and adult peripheral blood monocytes (PBMO) due to lower stimulation of TLR-mediated immune responses. Methods The ability to phagocytose C. albicans, expression of TLRs, the induction of apoptosis (assessment of sub-G1 and nick-strand breaks) were analyzed by FACS. TLR signalling was induced by agonists such as lipopolysaccharide (LPS), Pam3Cys, FSL-1 and Zymosan and blocked (neutralizing TLR2 antibodies and MYD88 inhibitor). Results Phagocytic indices of PBMO and CBMO were similar. Following stimulation with agonists and C. albicans induced up-regulation of TLR2 and consecutive phosphorylation of MAP kinase P38 and expression of TNF-α, which were stronger on PBMO compared to CBMO (p < 0.005). Downstream, TLR2 signalling initiated caspase-3-dependent PICD which was found reduced in CBMO (p < 0.05 vs PBMO). Conclusion Our data suggest direct involvement of TLR2-signalling in C. albicans-induced PICD in monocytes and an alteration of this pathway in CBMO. KW - Candida albicans KW - monocytes KW - immune response KW - PICD Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166778 VL - 11 IS - 11 ER - TY - JOUR A1 - Reynolds, David A1 - Hofmeister, Brigitte T. A1 - Cliffe, Laura A1 - Alabady, Magdy A1 - Siegel, T. Nicolai A1 - Schmitz, Robert J. A1 - Sabatini, Robert T1 - Histone H3 Variant Regulates RNA Polymerase II Transcription Termination and Dual Strand Transcription of siRNA Loci in Trypanosoma brucei JF - PLoS Genetics N2 - Base J, β-D-glucosyl-hydroxymethyluracil, is a chromatin modification of thymine in the nuclear DNA of flagellated protozoa of the order Kinetoplastida. In Trypanosoma brucei, J is enriched, along with histone H3 variant (H3.V), at sites involved in RNA Polymerase (RNAP) II termination and telomeric sites involved in regulating variant surface glycoprotein gene (VSG) transcription by RNAP I. Reduction of J in T. brucei indicated a role of J in the regulation of RNAP II termination, where the loss of J at specific sites within polycistronic gene clusters led to read-through transcription and increased expression of downstream genes. We now demonstrate that the loss of H3.V leads to similar defects in RNAP II termination within gene clusters and increased expression of downstream genes. Gene derepression is intensified upon the subsequent loss of J in the H3.V knockout. mRNA-seq indicates gene derepression includes VSG genes within the silent RNAP I transcribed telomeric gene clusters, suggesting an important role for H3.V in telomeric gene repression and antigenic variation. Furthermore, the loss of H3.V at regions of overlapping transcription at the end of convergent gene clusters leads to increased nascent RNA and siRNA production. Our results suggest base J and H3.V can act independently as well as synergistically to regulate transcription termination and expression of coding and non-coding RNAs in T. brucei, depending on chromatin context (and transcribing polymerase). As such these studies provide the first direct evidence for histone H3.V negatively influencing transcription elongation to promote termination. KW - RNA polymerase KW - Trypanosoma brucei KW - histone H3 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166738 VL - 12 IS - 1 ER - TY - JOUR A1 - Richter, K. A1 - Mathes, V. A1 - Fronius, M. A1 - Althaus, M. A1 - Hecker, A. A1 - Krasteva-Christ, G. A1 - Padberg, W. A1 - Hone, A. J. A1 - McIntosh, J. M. A1 - Zakrzewicz, A. A1 - Grau, V. T1 - Phosphocholine - an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors JF - Scientific Reports N2 - We demonstrated previously that phosphocholine and phosphocholine-modified macromolecules efficiently inhibit ATP-dependent release of interleukin-1β from human and murine monocytes by a mechanism involving nicotinic acetylcholine receptors (nAChR). Interleukin-1β is a potent pro-inflammatory cytokine of innate immunity that plays pivotal roles in host defence. Control of interleukin-1β release is vital as excessively high systemic levels cause life threatening inflammatory diseases. In spite of its structural similarity to acetylcholine, there are no other reports on interactions of phosphocholine with nAChR. In this study, we demonstrate that phosphocholine inhibits ion-channel function of ATP receptor P2X7 in monocytic cells via nAChR containing α9 and α10 subunits. In stark contrast to choline, phosphocholine does not evoke ion current responses in Xenopus laevis oocytes, which heterologously express functional homomeric nAChR composed of α9 subunits or heteromeric receptors containing α9 and α10 subunits. Preincubation of these oocytes with phosphocholine, however, attenuated choline-induced ion current changes, suggesting that phosphocholine may act as a silent agonist. We conclude that phophocholine activates immuno-modulatory nAChR expressed by monocytes but does not stimulate canonical ionotropic receptor functions. KW - phosphocholine KW - interleukin-1β KW - nicotinic acetylcholine receptors Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167655 VL - 6 IS - 28660 ER - TY - JOUR A1 - Xu, Li A1 - He, Jianzheng A1 - Kaiser, Andrea A1 - Gräber, Nikolas A1 - Schläger, Laura A1 - Ritze, Yvonne A1 - Scholz, Henrike T1 - A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila JF - PLoS ONE N2 - Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling—the serotonin transporter–in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior. KW - attraction KW - ethanol KW - Drosophila melanogaster KW - serotonin transporter Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166762 VL - 11 IS - 12 ER - TY - JOUR A1 - Chiorean, E. G. A1 - Von Hoff, D. D. A1 - Reni, M. A1 - Arena, F. P. A1 - Infante, J. R. A1 - Bathini, V. G. A1 - Wood, T. E. A1 - Mainwaring, P. N. A1 - Muldoon, R. T. A1 - Clingan, P. R. A1 - Kunzmann, V. A1 - Ramanathan, R. K. A1 - Tabernero, J. A1 - Goldstein, D. A1 - McGovern, D. A1 - Lu, B. A1 - Ko, A. T1 - 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 JF - Annals of Oncology N2 - 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. KW - CA19-9 KW - pancreatic cancer KW - chemotherapy KW - nab-paclitaxel KW - MPACT Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189659 VL - 27 IS - 4 ER - TY - JOUR A1 - Acqualagna, Laura A1 - Botrel, Loic A1 - Vidaurre, Carmen A1 - Kübler, Andrea A1 - Blankertz, Benjamin T1 - Large-Scale Assessment of a Fully Automatic Co-Adaptive Motor Imagery-Based Brain Computer Interface JF - PLoS ONE N2 - In the last years Brain Computer Interface (BCI) technology has benefited from the development of sophisticated machine leaning methods that let the user operate the BCI after a few trials of calibration. One remarkable example is the recent development of co-adaptive techniques that proved to extend the use of BCIs also to people not able to achieve successful control with the standard BCI procedure. Especially for BCIs based on the modulation of the Sensorimotor Rhythm (SMR) these improvements are essential, since a not negligible percentage of users is unable to operate SMR-BCIs efficiently. In this study we evaluated for the first time a fully automatic co-adaptive BCI system on a large scale. A pool of 168 participants naive to BCIs operated the co-adaptive SMR-BCI in one single session. Different psychological interventions were performed prior the BCI session in order to investigate how motor coordination training and relaxation could influence BCI performance. A neurophysiological indicator based on the Power Spectral Density (PSD) was extracted by the recording of few minutes of resting state brain activity and tested as predictor of BCI performances. Results show that high accuracies in operating the BCI could be reached by the majority of the participants before the end of the session. BCI performances could be significantly predicted by the neurophysiological indicator, consolidating the validity of the model previously developed. Anyway, we still found about 22% of users with performance significantly lower than the threshold of efficient BCI control at the end of the session. Being the inter-subject variability still the major problem of BCI technology, we pointed out crucial issues for those who did not achieve sufficient control. Finally, we propose valid developments to move a step forward to the applicability of the promising co-adaptive methods. KW - large-scale assessment KW - Brain Computer Interface KW - machine leaning KW - fully automatic KW - co-adaptive Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167230 VL - 11 IS - 2 ER - TY - JOUR A1 - Hershko-Shalev, Tal A1 - Odenheimer-Bergman, Ahuva A1 - Elgrably-Weiss, Maya A1 - Ben-Zvi, Tamar A1 - Govindarajan, Sutharsan A1 - Seri, Hemda A1 - Papenfort, Kai A1 - Vogel, Jörg A1 - Altuvia, Shoshy T1 - Gifsy-1 Prophage IsrK with Dual Function as Small and Messenger RNA Modulates Vital Bacterial Machineries JF - PLoS Genetics N2 - While an increasing number of conserved small regulatory RNAs (sRNAs) are known to function in general bacterial physiology, the roles and modes of action of sRNAs from horizontally acquired genomic regions remain little understood. The IsrK sRNA of Gifsy-1 prophage of Salmonella belongs to the latter class. This regulatory RNA exists in two isoforms. The first forms, when a portion of transcripts originating from isrK promoter reads-through the IsrK transcription-terminator producing a translationally inactive mRNA target. Acting in trans, the second isoform, short IsrK RNA, binds the inactive transcript rendering it translationally active. By switching on translation of the first isoform, short IsrK indirectly activates the production of AntQ, an antiterminator protein located upstream of isrK. Expression of antQ globally interferes with transcription termination resulting in bacterial growth arrest and ultimately cell death. Escherichia coli and Salmonella cells expressing AntQ display condensed chromatin morphology and localization of UvrD to the nucleoid. The toxic phenotype of AntQ can be rescued by co-expression of the transcription termination factor, Rho, or RNase H, which protects genomic DNA from breaks by resolving R-loops. We propose that AntQ causes conflicts between transcription and replication machineries and thus promotes DNA damage. The isrK locus represents a unique example of an island-encoded sRNA that exerts a highly complex regulatory mechanism to tune the expression of a toxic protein. KW - prophage KW - Gifsy-1 KW - sRNA KW - IsrK Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166717 VL - 12 IS - 4 ER - TY - JOUR A1 - Dietrich, Christof P. A1 - Steude, Anja A1 - Tropf, Laura A1 - Schubert, Marcel A1 - Kronenberg, Nils M. A1 - Ostermann, Kai A1 - Höfling, Sven A1 - Gather, Malte C. T1 - An exciton-polariton laser based on biologically produced fluorescent protein JF - Science Advances N2 - Under adequate conditions, cavity polaritons form a macroscopic coherent quantum state, known as polariton condensate. Compared to Wannier-Mott excitons in inorganic semiconductors, the localized Frenkel excitons in organic emitter materials show weaker interaction with each other but stronger coupling to light, which recently enabled the first realization of a polariton condensate at room temperature. However, this required ultrafast optical pumping, which limits the applications of organic polariton condensates. We demonstrate room temperature polariton condensates of cavity polaritons in simple laminated microcavities filled with biologically produced enhanced green fluorescent protein (eGFP). The unique molecular structure of eGFP prevents exciton annihilation even at high excitation densities, thus facilitating polariton condensation under conventional nanosecond pumping. Condensation is clearly evidenced by a distinct threshold, an interaction-induced blueshift of the condensate, long-range coherence, and the presence of a second threshold at higher excitation density that is associated with the onset of photon lasing. KW - polarition condensate KW - enhanced green fluorescent protein KW - photon lasing KW - quantum physics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171305 VL - 2 IS - 8 ER - TY - JOUR A1 - Schroeder, Katharina A1 - Meyer-ter-Vehn, Tobias A1 - Fassnacht-Riederle, Heidi A1 - Guthoff, Rainer T1 - Course of disease in multifocal choroiditis lacking sufficient immunosuppression: a case report JF - Journal of Medical Case Reports N2 - Background: Multifocal choroiditis with panuveitis is a rare disease. The educational merit of this case presentation results from the good documentation and the impressive ocular fundus pictures. Case presentation: We illustrate the 3-year course of disease in a 22-year-old myopic white woman with multifocal choroiditis with panuveitis and secondary choroidal neovascularization. The activity of the disease was evaluated clinically by optical coherence tomography and fluorescein angiography. Choroidal neovascularization was treated by intravitreal bevacizumab (2.5 mg/0.1 ml). Our patient lacked systemic therapy for the first 11 months because of noncompliance. Conclusions: The case is remarkable as the delayed onset of peripheral lesions and the additional existence of high myopia made diagnosis difficult. In addition, it demonstrates that full outbreak of disease with multiple central and peripheral fundus lesions and secondary choroidal neovascularization can develop without systemic treatment. KW - multifocal choroiditis KW - chorioretinal lesions KW - secondary CNV KW - bevacizumab KW - systemic immunosuppression KW - case report Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171317 VL - 10 IS - 298 ER - TY - JOUR A1 - Macdougall, Iain C. A1 - Bircher, Andreas J. A1 - Eckhardt, Kai-Uwe A1 - Obrador, Gregorio T. A1 - Pollock, Carol A. A1 - Stenvinkel, Peter A1 - Swinkels, Dorine W. A1 - Wanner, Christoph A1 - Weiss, Günter A1 - Chertow, Glenn M. T1 - Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference JF - Kidney International N2 - 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. KW - chronic kidney disease KW - hypersensitivity KW - infections KW - iron KW - overload KW - oxidative stress Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191467 VL - 89 IS - 1 ER -