@article{ZimmermannSubotaBatrametal.2017, author = {Zimmermann, Henriette and Subota, Ines and Batram, Christopher and Kramer, Susanne and Janzen, Christian J. and Jones, Nicola G. and Engstler, Markus}, title = {A quorum sensing-independent path to stumpy development in Trypanosoma brucei}, series = {PLoS Pathogens}, volume = {13}, journal = {PLoS Pathogens}, number = {4}, doi = {10.1371/journal.ppat.1006324}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158230}, pages = {e1006324}, year = {2017}, abstract = {For persistent infections of the mammalian host, African trypanosomes limit their population size by quorum sensing of the parasite-excreted stumpy induction factor (SIF), which induces development to the tsetse-infective stumpy stage. We found that besides this cell density-dependent mechanism, there exists a second path to the stumpy stage that is linked to antigenic variation, the main instrument of parasite virulence. The expression of a second variant surface glycoprotein (VSG) leads to transcriptional attenuation of the VSG expression site (ES) and immediate development to tsetse fly infective stumpy parasites. This path is independent of SIF and solely controlled by the transcriptional status of the ES. In pleomorphic trypanosomes varying degrees of ES-attenuation result in phenotypic plasticity. While full ES-attenuation causes irreversible stumpy development, milder attenuation may open a time window for rescuing an unsuccessful antigenic switch, a scenario that so far has not been considered as important for parasite survival.}, language = {en} } @article{ZieglerWeissSchmittetal.2017, author = {Ziegler, Sabrina and Weiss, Esther and Schmitt, Anna-Lena and Schlegel, Jan and Burgert, Anne and Terpitz, Ulrich and Sauer, Markus and Moretta, Lorenzo and Sivori, Simona and Leonhardt, Ines and Kurzai, Oliver and Einsele, Hermann and Loeffler, Juergen}, title = {CD56 Is a Pathogen Recognition Receptor on Human Natural Killer Cells}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {6138}, doi = {10.1038/s41598-017-06238-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170637}, year = {2017}, abstract = {Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response.}, language = {en} } @article{WuPonsGoudetetal.2017, author = {Wu, Yu and Pons, Val{\´e}rie and Goudet, Am{\´e}lie and Panigai, Laetitia and Fischer, Annette and Herweg, Jo-Ana and Kali, Sabrina and Davey, Robert A. and Laporte, J{\´e}r{\^o}me and Bouclier, C{\´e}line and Yousfi, Rahima and Aubenque, C{\´e}line and Merer, Goulven and Gobbo, Emilie and Lopez, Roman and Gillet, Cynthia and Cojean, Sandrine and Popoff, Michel R. and Clayette, Pascal and Le Grand, Roger and Boulogne, Claire and Tordo, No{\"e}l and Lemichez, Emmanuel and Loiseau, Philippe M. and Rudel, Thomas and Sauvaire, Didier and Cintrat, Jean-Christophe and Gillet, Daniel and Barbier, Julien}, title = {ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-15466-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173170}, year = {2017}, abstract = {Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identifed the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efciently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.}, language = {en} } @article{WolterHanselmannPattschulletal.2017, author = {Wolter, Patrick and Hanselmann, Steffen and Pattschull, Grit and Schruf, Eva and Gaubatz, Stefan}, title = {Central spindle proteins and mitotic kinesins are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cell lines and are potential targets for therapy}, series = {Oncotarget}, volume = {8}, journal = {Oncotarget}, number = {7}, doi = {10.18632/oncotarget.14466}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171851}, pages = {11160-11172}, year = {2017}, abstract = {The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells. Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.}, language = {en} } @article{WiegeringMatthesMuehlingetal.2017, author = {Wiegering, Armin and Matthes, Niels and M{\"u}hling, Bettina and Koospal, Monika and Quenzer, Anne and Peter, Stephanie and Germer, Christoph-Thomas and Linnebacher, Michael and Otto, Christoph}, title = {Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin}, series = {Neoplasia}, volume = {19}, journal = {Neoplasia}, number = {4}, doi = {10.1016/j.neo.2017.01.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171067}, pages = {301-309}, year = {2017}, abstract = {Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n = 9) including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n = 5) with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC\(_{50}\)< 3.0 μmol/l) were identified within established (4/9) and primary patient-derived (2/5) CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14) that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents.}, language = {en} } @article{WegertVokuhZiegleretal.2017, author = {Wegert, Jenny and Vokuh, Christian and Ziegler, Barbara and Ernestus, Karen and Leuschner, Ivo and Furtw{\"a}ngler, Rhoikos and Graf, Norbert and Gessler, Manfred}, title = {TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia}, series = {The Journal of Pathology: Clinical Research}, volume = {3}, journal = {The Journal of Pathology: Clinical Research}, doi = {10.1002/cjp2.77}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158302}, pages = {234-248}, year = {2017}, abstract = {TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60\% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90\% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87\%), but this rate dropped to 26\% for stages II-IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26\% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease.}, language = {en} } @article{WanzekSchwindtCapraetal.2017, author = {Wanzek, Katharina and Schwindt, Eike and Capra, John A. and Paeschke, Katrin}, title = {Mms1 binds to G-rich regions in Saccharomyces cerevisiae and influences replication and genome stability}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {13}, doi = {10.1093/nar/gkx467}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170577}, pages = {7796-7806}, year = {2017}, abstract = {The regulation of replication is essential to preserve genome integrity. Mms1 is part of the E3 ubiquitin ligase complex that is linked to replication fork progression. By identifying Mms1 binding sites genome-wide in Saccharomyces cerevisiae we connected Mms1 function to genome integrity and replication fork progression at particular G-rich motifs. This motif can form G-quadruplex (G4) structures in vitro. G4 are stable DNA structures that are known to impede replication fork progression. In the absence of Mms1, genome stability is at risk at these G-rich/G4 regions as demonstrated by gross chromosomal rearrangement assays. Mms1 binds throughout the cell cycle to these G-rich/G4 regions and supports the binding of Pif1 DNA helicase. Based on these data we propose a mechanistic model in which Mms1 binds to specific G-rich/G4 motif located on the lagging strand template for DNA replication and supports Pif1 function, DNA replication and genome integrity.}, language = {en} } @article{TemmeFriebeSchmidtetal.2017, author = {Temme, Sebastian and Friebe, Daniela and Schmidt, Timo and Poschmann, Gereon and Hesse, Julia and Steckel, Bodo and St{\"u}hler, Kai and Kunz, Meik and Dandekar, Thomas and Ding, Zhaoping and Akhyari, Payam and Lichtenberg, Artur and Schrader, J{\"u}rgen}, title = {Genetic profiling and surface proteome analysis of human atrial stromal cells and rat ventricular epicardium-derived cells reveals novel insights into their cardiogenic potential}, series = {Stem Cell Research}, volume = {25}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2017.11.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172716}, pages = {183-190}, year = {2017}, abstract = {Epicardium-derived cells (EPDC) and atrial stromal cells (ASC) display cardio-regenerative potential, but the molecular details are still unexplored. Signals which induce activation, migration and differentiation of these cells are largely unknown. Here we have isolated rat ventricular EPDC and rat/human ASC and performed genetic and proteomic profiling. EPDC and ASC expressed epicardial/mesenchymal markers (WT-1, Tbx18, CD73,CD90, CD44, CD105), cardiac markers (Gata4, Tbx5, troponin T) and also contained phosphocreatine. We used cell surface biotinylation to isolate plasma membrane proteins of rEPDC and hASC, Nano-liquid chromatography with subsequent mass spectrometry and bioinformatics analysis identified 396 rat and 239 human plasma membrane proteins with 149 overlapping proteins. Functional GO-term analysis revealed several significantly enriched categories related to extracellular matrix (ECM), cell migration/differentiation, immunology or angiogenesis. We identified receptors for ephrin and growth factors (IGF, PDGF, EGF, anthrax toxin) known to be involved in cardiac repair and regeneration. Functional category enrichment identified clusters around integrins, PI3K/Akt-signaling and various cardiomyopathies. Our study indicates that EPDC and ASC have a similar molecular phenotype related to cardiac healing/regeneration. The cell surface proteome repository will help to further unravel the molecular details of their cardio-regenerative potential and their role in cardiac diseases.}, language = {en} } @article{SteinCoulibalyStenchlyetal.2017, author = {Stein, Katharina and Coulibaly, Drissa and Stenchly, Kathrin and Goetze, Dethardt and Porembski, Stefan and Lindner, Andr{\´e} and Konat{\´e}, Souleymane and Linsenmair, Eduard K.}, title = {Bee pollination increases yield quantity and quality of cash crops in Burkina Faso, West Africa}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {17691}, doi = {10.1038/s41598-017-17970-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169914}, year = {2017}, abstract = {Mutualistic biotic interactions as among flowering plants and their animal pollinators are a key component of biodiversity. Pollination, especially by insects, is a key element in ecosystem functioning, and hence constitutes an ecosystem service of global importance. Not only sexual reproduction of plants is ensured, but also yields are stabilized and genetic variability of crops is maintained, counteracting inbreeding depression and facilitating system resilience. While experiencing rapid environmental change, there is an increased demand for food and income security, especially in sub-Saharan communities, which are highly dependent on small scale agriculture. By combining exclusion experiments, pollinator surveys and field manipulations, this study for the first time quantifies the contribution of bee pollinators to smallholders' production of the major cash crops, cotton and sesame, in Burkina Faso. Pollination by honeybees and wild bees significantly increased yield quantity and quality on average up to 62\%, while exclusion of pollinators caused an average yield gap of 37\% in cotton and 59\% in sesame. Self-pollination revealed inbreeding depression effects on fruit set and low germination rates in the F1-generation. Our results highlight potential negative consequences of any pollinator decline, provoking risks to agriculture and compromising crop yields in sub-Saharan West Africa.}, language = {en} } @article{SteijvenSpaetheSteffanDewenteretal.2017, author = {Steijven, Karin and Spaethe, Johannes and Steffan-Dewenter, Ingolf and H{\"a}rtel, Stephan}, title = {Learning performance and brain structure of artificially-reared honey bees fed with different quantities of food}, series = {PeerJ}, volume = {5}, journal = {PeerJ}, number = {e3858}, doi = {10.7717/peerj.3858}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170137}, year = {2017}, abstract = {Background Artificial rearing of honey bee larvae is an established method which enables to fully standardize the rearing environment and to manipulate the supplied diet to the brood. However, there are no studies which compare learning performance or neuroanatomic differences of artificially-reared (in-lab) bees in comparison with their in-hive reared counterparts. Methods Here we tested how different quantities of food during larval development affect body size, brain morphology and learning ability of adult honey bees. We used in-lab rearing to be able to manipulate the total quantity of food consumed during larval development. After hatching, a subset of the bees was taken for which we made 3D reconstructions of the brains using confocal laser-scanning microscopy. Learning ability and memory formation of the remaining bees was tested in a differential olfactory conditioning experiment. Finally, we evaluated how bees reared with different quantities of artificial diet compared to in-hive reared bees. Results Thorax and head size of in-lab reared honey bees, when fed the standard diet of 160 µl or less, were slightly smaller than hive bees. The brain structure analyses showed that artificially reared bees had smaller mushroom body (MB) lateral calyces than their in-hive counterparts, independently of the quantity of food they received. However, they showed the same total brain size and the same associative learning ability as in-hive reared bees. In terms of mid-term memory, but not early long-term memory, they performed even better than the in-hive control. Discussion We have demonstrated that bees that are reared artificially (according to the Aupinel protocol) and kept in lab-conditions perform the same or even better than their in-hive sisters in an olfactory conditioning experiment even though their lateral calyces were consistently smaller at emergence. The applied combination of experimental manipulation during the larval phase plus subsequent behavioral and neuro-anatomic analyses is a powerful tool for basic and applied honey bee research.}, language = {en} }