@article{LeikamHufnagelOttoetal.2015, author = {Leikam, C and Hufnagel, AL and Otto, C and Murphy, DJ and M{\"u}hling, B and Kneitz, S and Nanda, I and Schmid, M and Wagner, TU and Haferkamp, S and Br{\"o}cker, E-B and Schartl, M and Meierjohann, S}, title = {In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells}, series = {Cell Death and Disease}, volume = {6}, journal = {Cell Death and Disease}, number = {e1711}, doi = {10.1038/cddis.2015.71}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148718}, year = {2015}, abstract = {Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi-or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS\(^{61K}\) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.}, language = {en} } @article{WeissSchultz2015, author = {Weiß, Clemens Leonard and Schultz, J{\"o}rg}, title = {Identification of divergent WH2 motifs by HMM-HMM alignments}, series = {BMC Research Notes}, volume = {8}, journal = {BMC Research Notes}, number = {18}, doi = {10.1186/s13104-015-0981-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126413}, year = {2015}, abstract = {Background The actin cytoskeleton is a hallmark of eukaryotic cells. Its regulation as well as its interaction with other proteins is carefully orchestrated by actin interaction domains. One of the key players is the WH2 motif, which enables binding to actin monomers and filaments and is involved in the regulation of actin nucleation. Contrasting conserved domains, the identification of this motif in protein sequences is challenging, as it is short and poorly conserved. Findings To identify divergent members, we combined Hidden-Markov-Model (HMM) to HMM alignments with orthology predictions. Thereby, we identified nearly 500 proteins containing so far not annotated WH2 motifs. This included shootin-1, an actin binding protein involved in neuron polarization. Among others, WH2 motifs of 'proximal to raf' (ptr)-orthologs, which are described in the literature, but not annotated in genome databases, were identified. Conclusion In summary, we increased the number of WH2 motif containing proteins substantially. This identification of candidate regions for actin interaction could steer their experimental characterization. Furthermore, the approach outlined here can easily be adapted to the identification of divergent members of further domain families.}, language = {en} } @article{Meierjohann2015, author = {Meierjohann, Svenja}, title = {Hypoxia independent drivers of melanoma angiogenesis}, series = {Frontiers in Oncology}, volume = {5}, journal = {Frontiers in Oncology}, number = {120}, doi = {10.3389/fonc.2015.00102}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125586}, year = {2015}, abstract = {Tumor angiogenesis is a process which is traditionally regarded as the tumor's response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a pre-requisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia-independent mechanisms of tumor angiogenesis in melanoma.}, language = {en} } @article{AndronicShirakashiPickeletal.2015, author = {Andronic, Joseph and Shirakashi, Ryo and Pickel, Simone U. and Westerling, Katherine M. and Klein, Teresa and Holm, Thorge and Sauer, Markus and Sukhorukov, Vladimir L.}, title = {Hypotonic Activation of the Myo-Inositol Transporter SLC5A3 in HEK293 Cells Probed by Cell Volumetry, Confocal and Super-Resolution Microscopy}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {3}, doi = {10.1371/journal.pone.0119990}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126408}, year = {2015}, abstract = {Swelling-activated pathways for myo-inositol, one of the most abundant organic osmolytes in mammalian cells, have not yet been identified. The present study explores the SLC5A3 protein as a possible transporter of myo-inositol in hyponically swollen HEK293 cells. To address this issue, we examined the relationship between the hypotonicity-induced changes in plasma membrane permeability to myo-inositol Pino [m/s] and expression/localization of SLC5A3. Pino values were determined by cell volumetry over a wide tonicity range (100-275 mOsm) in myo-inositol-substituted solutions. While being negligible under mild hypotonicity (200-275 mOsm), Pino grew rapidly at osmolalities below 200 mOsm to reach a maximum of ∼3 nm/s at 100-125 mOsm, as indicated by fast cell swelling due to myo-inositol influx. The increase in Pino resulted most likely from the hypotonicity-mediated incorporation of cytosolic SLC5A3 into the plasma membrane, as revealed by confocal fluorescence microscopy of cells expressing EGFP-tagged SLC5A3 and super-resolution imaging of immunostained SLC5A3 by direct stochastic optical reconstruction microscopy (dSTORM). dSTORM in hypotonic cells revealed a surface density of membrane-associated SLC5A3 proteins of 200-2000 localizations/μm2. Assuming SLC5A3 to be the major path for myo-inositol, a turnover rate of 80-800 myo-inositol molecules per second for a single transporter protein was estimated from combined volumetric and dSTORM data. Hypotonic stress also caused a significant upregulation of SLC5A3 gene expression as detected by semiquantitative RT-PCR and Western blot analysis. In summary, our data provide first evidence for swelling-mediated activation of SLC5A3 thus suggesting a functional role of this transporter in hypotonic volume regulation of mammalian cells.}, language = {en} } @article{DuehringGermerodtSkerkaetal.2015, author = {D{\"u}hring, Sybille and Germerodt, Sebastian and Skerka, Christine and Zipfel, Peter F. and Dandekar, Thomas and Schuster, Stefan}, title = {Host-pathogen interactions between the human innate immune system and Candida albicans - understanding and modeling defense and evasion strategies}, series = {Frontiers in Microbiology}, volume = {6}, journal = {Frontiers in Microbiology}, number = {625}, doi = {10.3389/fmicb.2015.00625}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151621}, year = {2015}, abstract = {The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.}, language = {en} } @article{DandekarEisenreich2015, author = {Dandekar, Thomas and Eisenreich, Wolfgang}, title = {Host-adapted metabolism and its regulation in bacterial pathogens}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {5}, journal = {Frontiers in Cellular and Infection Microbiology}, number = {28}, issn = {2235-2988}, doi = {10.3389/fcimb.2015.00028}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196876}, year = {2015}, abstract = {No abstract available.}, language = {en} } @article{DegenHovestadtMitesseretal.2015, author = {Degen, Tobias and Hovestadt, Thomas and Mitesser, Oliver and H{\"o}lker, Franz}, title = {High female survival promotes evolution of protogyny and xexual conflict}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0118354}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143586}, pages = {e0118354}, year = {2015}, abstract = {Existing models explaining the evolution of sexual dimorphism in the timing of emergence (SDT) in Lepidoptera assume equal mortality rates for males and females. The limiting assumption of equal mortality rates has the consequence that these models are only able to explain the evolution of emergence of males before females, i.e. protandry-the more common temporal sequence of emergence in Lepidoptera. The models fail, however, in providing adaptive explanations for the evolution of protogyny, where females emerge before males, but protogyny is not rare in insects. The assumption of equal mortality rates seems too restrictive for many insects, such as butterflies. To investigate the influence of unequal mortality rates on the evolution of SDT, we present a generalised version of a previously published model where we relax this assumption. We find that longer life-expectancy of females compared to males can indeed favour the evolution of protogyny as a fitness enhancing strategy. Moreover, the encounter rate between females and males and the sex-ratio are two important factors that also influence the evolution of optimal SDT. If considered independently for females and males the predicted strategies can be shown to be evolutionarily stable (ESS). Under the assumption of equal mortality rates the difference between the females' and males' ESS remains typically very small. However, female and male ESS may be quite dissimilar if mortality rates are different. This creates the potential for an 'evolutionary conflict' between females and males. Bagworm moths (Lepidoptera: Psychidae) provide an exemplary case where life-history attributes are such that protogyny should indeed be the optimal emergence strategy from the males' and females' perspectives: (i) Female longevity is considerably larger than that of males, (ii) encounter rates between females and males are presumably low, and (iii) females mate only once. Protogyny is indeed the general mating strategy found in the bagworm family.}, language = {en} } @article{SalatWinklerUrlaubetal.2015, author = {Salat, Daniela and Winkler, Anja and Urlaub, Henning and Gessler, Manfred}, title = {Hey bHLH Proteins Interact with a FBXO45 Containing SCF Ubiquitin Ligase Complex and Induce Its Translocation into the Nucleus}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {6}, doi = {10.1371/journal.pone.0130288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125769}, pages = {e0130288}, year = {2015}, abstract = {The Hey protein family, comprising Hey1, Hey2 and HeyL in mammals, conveys Notch signals in many cell types. The helix-loop-helix (HLH) domain as well as the Orange domain, mediate homo- and heterodimerization of these transcription factors. Although distinct interaction partners have been identified so far, their physiological relevance for Hey functions is still largely unclear. Using a tandem affinity purification approach and mass spectrometry analysis we identified members of an ubiquitin E3-ligase complex consisting of FBXO45, PAM and SKP1 as novel Hey1 associated proteins. There is a direct interaction between Hey1 and FBXO45, whereas FBXO45 is needed to mediate indirect Hey1 binding to SKP1. Expression of Hey1 induces translocation of FBXO45 and PAM into the nucleus. Hey1 is a short-lived protein that is degraded by the proteasome, but there is no evidence for FBXO45-dependent ubiquitination of Hey1. On the contrary, Hey1 mediated nuclear translocation of FBXO45 and its associated ubiquitin ligase complex may extend its spectrum to additional nuclear targets triggering their ubiquitination. This suggests a novel mechanism of action for Hey bHLH factors.}, language = {en} } @article{AppelScholzMuelleretal.2015, author = {Appel, Mirjam and Scholz, Claus-J{\"u}rgen and M{\"u}ller, Tobias and Dittrich, Marcus and K{\"o}nig, Christian and Bockstaller, Marie and Oguz, Tuba and Khalili, Afshin and Antwi-Adjei, Emmanuel and Schauer, Tamas and Margulies, Carla and Tanimoto, Hiromu and Yarali, Ayse}, title = {Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0126986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-152006}, pages = {e0126986}, year = {2015}, abstract = {Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/or sequences covaried with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance- associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hairlike organs distributed across the fly's body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.}, language = {en} } @article{ShityakovDandekarFoerster2015, author = {Shityakov, Sergey and Dandekar, Thomas and F{\"o}rster, Carola}, title = {Gene expression profiles and protein-protein interaction network analysis in AIDS patients with HIV-associated encephalitis and dementia}, series = {HIV/AIDS: Research and Palliative Care}, volume = {7}, journal = {HIV/AIDS: Research and Palliative Care}, doi = {10.2147/HIV.S88438}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149494}, pages = {265-276}, year = {2015}, abstract = {Central nervous system dysfunction is an important cause of morbidity and mortality in patients with human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency virus syndrome (AIDS). Patients with AIDS are usually affected by HIV-associated encephalitis (HIVE) with viral replication limited to cells of monocyte origin. To examine the molecular mechanisms underlying HIVE-induced dementia, the GSE4755 Affymetrix data were obtained from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) between the samples from AIDS patients with and without apparent features of HIVE-induced dementia were identified. In addition, protein-protein interaction networks were constructed by mapping DEGs into protein-protein interaction data to identify the pathways that these DEGs are involved in. The results revealed that the expression of 1,528 DEGs is mainly involved in the immune response, regulation of cell proliferation, cellular response to inflammation, signal transduction, and viral replication cycle. Heat-shock protein alpha, class A member 1 (HSP90AA1), and fibronectin 1 were detected as hub nodes with degree values >130. In conclusion, the results indicate that HSP90A and fibronectin 1 play important roles in HIVE pathogenesis.}, language = {en} } @article{MatosMachadoSchartletal.2015, author = {Matos, I and Machado, M. P. and Schartl, M. and Coelho, M. M.}, title = {Gene expression dosage regulation in an allopolyploid fish}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0116309}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143565}, pages = {e0116309}, year = {2015}, abstract = {How allopolyploids are able not only to cope but profit from their condition is a question that remains elusive, but is of great importance within the context of successful allopolyploid evolution. One outstanding example of successful allopolyploidy is the endemic Iberian cyprinid Squalius alburnoides. Previously, based on the evaluation of a few genes, it was reported that the transcription levels between diploid and triploid S. alburnoides were similar. If this phenomenon occurs on a full genomic scale, a wide functional "diploidization'' could be related to the success of these polyploids. We generated RNA-seq data from whole juvenile fish and from adult livers, to perform the first comparative quantitative transcriptomic analysis between diploid and triploid individuals of a vertebrate allopolyploid. Together with an assay to estimate relative expression per cell, it was possible to infer the relative sizes of transcriptomes. This showed that diploid and triploid S. alburnoides hybrids have similar liver transcriptome sizes. This in turn made it valid to directly compare the S. alburnoides RNA-seq transcript data sets and obtain a profile of dosage responses across the S. alburnoides transcriptome. We found that 64\% of transcripts in juveniles' samples and 44\% in liver samples differed less than twofold between diploid and triploid hybrids (similar expression). Yet, respectively 29\% and 15\% of transcripts presented accurate dosage compensation (PAA/PA expression ratio of 1 instead of 1.5). Therefore, an exact functional diploidization of the triploid genome does not occur, but a significant down regulation of gene expression in triploids was observed. However, for those genes with similar expression levels between diploids and triploids, expression is not globally strictly proportional to gene dosage nor is it set to a perfect diploid level. This quantitative expression flexibility may be a strong contributor to overcome the genomic shock, and be an immediate evolutionary advantage of allopolyploids.}, language = {en} } @article{KlammertMuellerHellmannetal.2015, author = {Klammert, Uwe and M{\"u}ller, Thomas D. and Hellmann, Tina V. and Wuerzler, Kristian K. and Kotzsch, Alexander and Schliermann, Anna and Schmitz, Werner and Kuebler, Alexander C. and Sebald, Walter and Nickel, Joachim}, title = {GDF-5 can act as a context-dependent BMP-2 antagonist}, series = {BMC Biology}, volume = {13}, journal = {BMC Biology}, number = {77}, doi = {10.1186/s12915-015-0183-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125550}, year = {2015}, abstract = {Background Bone morphogenetic protein (BMP)-2 and growth and differentiation factor (GDF)-5 are two related transforming growth factor (TGF)-β family members with important functions in embryonic development and tissue homeostasis. BMP-2 is best known for its osteoinductive properties whereas GDF-5—as evident from its alternative name, cartilage derived morphogenetic protein 1—plays an important role in the formation of cartilage. In spite of these differences both factors signal by binding to the same subset of BMP receptors, raising the question how these different functionalities are generated. The largest difference in receptor binding is observed in the interaction with the type I receptor BMPR-IA. GDF-5, in contrast to BMP-2, shows preferential binding to the isoform BMPR-IB, which is abrogated by a single amino acid (A57R) substitution. The resulting variant, GDF-5 R57A, represents a "BMP-2 mimic" with respect to BMP receptor binding. In this study we thus wanted to analyze whether the two growth factors can induce distinct signals via an identically composed receptor. Results Unexpectedly and dependent on the cellular context, GDF-5 R57A showed clear differences in its activity compared to BMP-2. In ATDC-5 cells, both ligands induced alkaline phosphatase (ALP) expression with similar potency. But in C2C12 cells, the BMP-2 mimic GDF-5 R57A (and also wild-type GDF-5) clearly antagonized BMP-2-mediated ALP expression, despite signaling in both cell lines occurring solely via BMPR-IA. The BMP-2- antagonizing properties of GDF-5 and GDF-5 R57A could also be observed in vivo when implanting BMP-2 and either one of the two GDF-5 ligands simultaneously at heterotopic sites. Conclusions Although comparison of the crystal structures of the GDF-5 R57A:BMPR-IAEC- and BMP-2:BMPR-IAEC complex revealed small ligand-specific differences, these cannot account for the different signaling characteristics because the complexes seem identical in both differently reacting cell lines. We thus predict an additional component, most likely a not yet identified GDF-5-specific co-receptor, which alters the output of the signaling complexes. Hence the presence or absence of this component then switches GDF-5′s signaling capabilities to act either similar to BMP-2 or as a BMP-2 antagonist. These findings might shed new light on the role of GDF-5, e.g., in cartilage maintenance and/or limb development in that it might act as an inhibitor of signaling events initiated by other BMPs.}, language = {en} } @article{StejskalStreinzerDyeretal.2015, author = {Stejskal, Kerstin and Streinzer, Martin and Dyer, Adrian and Paulus, Hannes F. and Spaethe, Johannes}, title = {Functional Significance of Labellum Pattern Variation in a Sexually Deceptive Orchid (Ophrys heldreichii): Evidence of Individual Signature Learning Effects}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0142971}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137582}, pages = {e0142971}, year = {2015}, abstract = {Mimicking female insects to attract male pollinators is an important strategy in sexually deceptive orchids of the genus Ophrys, and some species possess flowers with conspicuous labellum patterns. The function of the variation of the patterns remains unresolved, with suggestions that these enhance pollinator communication. We investigated the possible function of the labellum pattern in Ophrys heldreichii, an orchid species in which the conspicuous and complex labellum pattern contrasts with a dark background. The orchid is pollinated exclusively by males of the solitary bee, Eucera berlandi. Comparisons of labellum patterns revealed that patterns within inflorescences are more similar than those of other conspecific plants. Field observations showed that the males approach at a great speed and directly land on flowers, but after an unsuccessful copulation attempt, bees hover close and visually scan the labellum pattern for up to a minute. Learning experiments conducted with honeybees as an accessible model of bee vision demonstrated that labellum patterns of different plants can be reliably learnt; in contrast, patterns of flowers from the same inflorescence could not be discriminated. These results support the hypothesis that variable labellum patterns in O. heldreichii are involved in flower-pollinator communication which would likely help these plants to avoid geitonogamy.}, language = {en} } @article{Morriswood2015, author = {Morriswood, Brooke}, title = {Form, fabric, and function of a flagellum-associated cytoskeletal structure.}, series = {Cells}, volume = {4}, journal = {Cells}, number = {4}, doi = {10.3390/cells4040726}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149467}, pages = {726-747}, year = {2015}, abstract = {Trypanosoma brucei is a uniflagellated protist and the causative agent of African trypanosomiasis, a neglected tropical disease. The single flagellum of T. brucei is essential to a number of cellular processes such as motility, and has been a longstanding focus of scientific enquiry. A number of cytoskeletal structures are associated with the flagellum in T. brucei, and one such structure—a multiprotein complex containing the repeat motif protein TbMORN1—is the focus of this review. The TbMORN1-containing complex, which was discovered less than ten years ago, is essential for the viability of the mammalian-infective form of T. brucei. The complex has an unusual asymmetric morphology, and is coiled around the flagellum to form a hook shape. Proteomic analysis using the proximity-dependent biotin identification (BioID) technique has elucidated a number of its components. Recent work has uncovered a role for TbMORN1 in facilitating protein entry into the cell, thus providing a link between the cytoskeleton and the endomembrane system. This review summarises the extant data on the complex, highlights the outstanding questions for future enquiry, and provides speculation as to its possible role in a size-exclusion mechanism for regulating protein entry. The review additionally clarifies the nomenclature associated with this topic, and proposes the adoption of the term "hook complex" to replace the former name "bilobe" to describe the complex.}, language = {en} } @article{StrubeBlossBrownSpaetheetal.2015, author = {Strube-Bloss, Martin F. and Brown, Austin and Spaethe, Johannes and Schmitt, Thomas and R{\"o}ssler, Wolfgang}, title = {Extracting the Behaviorally Relevant Stimulus: Unique Neural Representation of Farnesol, a Component of the Recruitment Pheromone of Bombus terrestris}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {9}, doi = {10.1371/journal.pone.0137413}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125875}, pages = {e0137413}, year = {2015}, abstract = {To trigger innate behavior, sensory neural networks are pre-tuned to extract biologically relevant stimuli. Many male-female or insect-plant interactions depend on this phenomenon. Especially communication among individuals within social groups depends on innate behaviors. One example is the efficient recruitment of nest mates by successful bumblebee foragers. Returning foragers release a recruitment pheromone in the nest while they perform a 'dance' behavior to activate unemployed nest mates. A major component of this pheromone is the sesquiterpenoid farnesol. How farnesol is processed and perceived by the olfactory system, has not yet been identified. It is much likely that processing farnesol involves an innate mechanism for the extraction of relevant information to trigger a fast and reliable behavioral response. To test this hypothesis, we used population response analyses of 100 antennal lobe (AL) neurons recorded in alive bumblebee workers under repeated stimulation with four behaviorally different, but chemically related odorants (geraniol, citronellol, citronellal and farnesol). The analysis identified a unique neural representation of the recruitment pheromone component compared to the other odorants that are predominantly emitted by flowers. The farnesol induced population activity in the AL allowed a reliable separation of farnesol from all other chemically related odor stimuli we tested. We conclude that the farnesol induced population activity may reflect a predetermined representation within the AL-neural network allowing efficient and fast extraction of a behaviorally relevant stimulus. Furthermore, the results show that population response analyses of multiple single AL-units may provide a powerful tool to identify distinct representations of behaviorally relevant odors.}, language = {en} } @article{GalluzziBravoSanPedroVitaleetal.2015, author = {Galluzzi, L. and Bravo-San Pedro, J. M. and Vitale, I. and Aaronson, S. A. and Abrams, J. M. and Adam, D. and Alnemri, E. S. and Altucci, L. and Andrews, D. and Annicchiarico-Petruzelli, M. and Baehrecke, E. H. and Bazan, N. G. and Bertrand, M. J. and Bianchi, K. and Blagosklonny, M. V. and Blomgren, K. and Borner, C. and Bredesen, D. E. and Brenner, C. and Campanella, M. and Candi, E. and Cecconi, F. and Chan, F. K. and Chandel, N. S. and Cheng, E. H. and Chipuk, J. E. and Cidlowski, J. A. and Ciechanover, A. and Dawson, T. M. and Dawson, V. L. and De Laurenzi, V. and De Maria, R. and Debatin, K. M. and Di Daniele, N. and Dixit, V. M. and Dynlacht, B. D. and El-Deiry, W. S. and Fimia, G. M. and Flavell, R. A. and Fulda, S. and Garrido, C. and Gougeon, M. L. and Green, D. R. and Gronemeyer, H. and Hajnoczky, G. and Hardwick, J. M. and Hengartner, M. O. and Ichijo, H. and Joseph, B. and Jost, P. J. and Kaufmann, T. and Kepp, O. and Klionsky, D. J. and Knight, R. A. and Kumar, S. and Lemasters, J. J. and Levine, B. and Linkermann, A. and Lipton, S. A. and Lockshin, R. A. and L{\´o}pez-Ot{\´i}n, C. and Lugli, E. and Madeo, F. and Malorni, W. and Marine, J. C. and Martin, S. J. and Martinou, J. C. and Medema, J. P. and Meier, P. and Melino, S. and Mizushima, N. and Moll, U. and Mu{\~n}oz-Pinedo, C. and Nu{\~n}ez, G. and Oberst, A. and Panaretakis, T. and Penninger, J. M. and Peter, M. E. and Piacentini, M. and Pinton, P. and Prehn, J. H. and Puthalakath, H. and Rabinovich, G. A. and Ravichandran, K. S. and Rizzuto, R. and Rodrigues, C. M. and Rubinsztein, D. C. and Rudel, T. and Shi, Y. and Simon, H. U. and Stockwell, B. R. and Szabadkai, G. and Tait, S. W. and Tang, H. L. and Tavernarakis, N. and Tsujimoto, Y. and Vanden Berghe, T. and Vandenabeele, P. and Villunger, A. and Wagner, E. F. and Walczak, H. and White, E. and Wood, W. G. and Yuan, J. and Zakeri, Z. and Zhivotovsky, B. and Melino, G. and Kroemer, G.}, title = {Essential versus accessory aspects of cell death: recommendations of the NCCD 2015}, series = {Cell Death and Differentiation}, volume = {22}, journal = {Cell Death and Differentiation}, doi = {10.1038/cdd.2014.137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121207}, pages = {58-73}, year = {2015}, abstract = {Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.}, language = {en} } @article{SubbarayalKarunakaranWinkleretal.2015, author = {Subbarayal, Prema and Karunakaran, Karthika and Winkler, Ann-Cathrin and Rother, Marion and Gonzalez, Erik and Meyer, Thomas F. and Rudel, Thomas}, title = {EphrinA2 Receptor (EphA2) Is an Invasion and Intracellular Signaling Receptor for Chlamydia trachomatis}, series = {PLoS Pathogens}, volume = {11}, journal = {PLoS Pathogens}, number = {4}, doi = {10.1371/journal.ppat.1004846}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125566}, pages = {e1004846}, year = {2015}, abstract = {The obligate intracellular bacterium Chlamydia trachomatis invades into host cells to replicate inside a membrane-bound vacuole called inclusion. Multiple different host proteins are recruited to the inclusion and are functionally modulated to support chlamydial development. Invaded and replicating Chlamydia induces a long-lasting activation of the PI3 kinase signaling pathway that is required for efficient replication. We identified the cell surface tyrosine kinase EphrinA2 receptor (EphA2) as a chlamydial adherence and invasion receptor that induces PI3 kinase (PI3K) activation, promoting chlamydial replication. Interfering with binding of C. trachomatis serovar L2 (Ctr) to EphA2, downregulation of EphA2 expression or inhibition of EphA2 activity significantly reduced Ctr infection. Ctr interacts with and activates EphA2 on the cell surface resulting in Ctr and receptor internalization. During chlamydial replication, EphA2 remains active accumulating around the inclusion and interacts with the p85 regulatory subunit of PI3K to support the activation of the PI3K/Akt signaling pathway that is required for normal chlamydial development. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Despite the depletion of EphA2 from the cell surface, Ctr infection induces upregulation of EphA2 through the activation of the ERK pathway, which keeps the infected cell in an apoptosis-resistant state. The significance of EphA2 as an entry and intracellular signaling receptor was also observed with the urogenital C. trachomatis-serovar D. Our findings provide the first evidence for a host cell surface receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate chlamydial replication. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism by which Chlamydia subverts the host cell and induces apoptosis resistance.}, language = {en} } @article{KarulinKaracsonyZhangetal.2015, author = {Karulin, Alexey Y. and Karacsony, Kinga and Zhang, Wenji and Targoni, Oleg S. and Moldova, Ioana and Dittrich, Marcus and Sundararaman, Srividya and Lehmann, Paul V.}, title = {ELISPOTs produced by CD8 and CD4 cells follow Log Normal size distribution permitting objective counting}, series = {Cells}, volume = {4}, journal = {Cells}, number = {1}, doi = {10.3390/cells4010056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149648}, pages = {56-70}, year = {2015}, abstract = {Each positive well in ELISPOT assays contains spots of variable sizes that can range from tens of micrometers up to a millimeter in diameter. Therefore, when it comes to counting these spots the decision on setting the lower and the upper spot size thresholds to discriminate between non-specific background noise, spots produced by individual T cells, and spots formed by T cell clusters is critical. If the spot sizes follow a known statistical distribution, precise predictions on minimal and maximal spot sizes, belonging to a given T cell population, can be made. We studied the size distributional properties of IFN-γ, IL-2, IL-4, IL-5 and IL-17 spots elicited in ELISPOT assays with PBMC from 172 healthy donors, upon stimulation with 32 individual viral peptides representing defined HLA Class I-restricted epitopes for CD8 cells, and with protein antigens of CMV and EBV activating CD4 cells. A total of 334 CD8 and 80 CD4 positive T cell responses were analyzed. In 99.7\% of the test cases, spot size distributions followed Log Normal function. These data formally demonstrate that it is possible to establish objective, statistically validated parameters for counting T cell ELISPOTs.}, language = {en} } @article{SimonRauskolbGunnersenetal.2015, author = {Simon, Christian M. and Rauskolb, Stefanie and Gunnersen, Jennifer M. and Holtmann, Bettina and Drepper, Carsten and Dombert, Benjamin and Braga, Massimiliano and Wiese, Stefan and Jablonka, Sibylle and P{\"u}hringer, Dirk and Zielasek, J{\"u}rgen and Hoeflich, Andreas and Silani, Vincenzo and Wolf, Eckhard and Kneitz, Susanne and Sommer, Claudia and Toyka, Klaus V. and Sendtner, Michael}, title = {Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy}, series = {Acta Neuropathologica}, volume = {130}, journal = {Acta Neuropathologica}, doi = {10.1007/s00401-015-1446-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154569}, pages = {373 -- 387}, year = {2015}, abstract = {Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.}, language = {en} } @article{LichtensteinSommerlandtSpaethe2015, author = {Lichtenstein, Leonie and Sommerlandt, Frank M. J. and Spaethe, Johannes}, title = {Dumb and Lazy? A Comparison of Color Learning and Memory Retrieval in Drones and Workers of the Buff-Tailed Bumblebee, Bombus terrestris, by Means of PER Conditioning}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0134248}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125832}, pages = {e0134248}, year = {2015}, abstract = {More than 100 years ago, Karl von Frisch showed that honeybee workers learn and discriminate colors. Since then, many studies confirmed the color learning capabilities of females from various hymenopteran species. Yet, little is known about visual learning and memory in males despite the fact that in most bee species males must take care of their own needs and must find rewarding flowers to obtain food. Here we used the proboscis extension response (PER) paradigm to study the color learning capacities of workers and drones of the bumblebee, Bombus terrestris. Light stimuli were paired with sucrose reward delivered to the insects' antennae and inducing a reflexive extension of the proboscis. We evaluated color learning (i.e. conditioned PER to color stimuli) in absolute and differential conditioning protocols and mid-term memory retention was measured two hours after conditioning. Different monochromatic light stimuli in combination with neutral density filters were used to ensure that the bumblebees could only use chromatic and not achromatic (e.g. brightness) information. Furthermore, we tested if bees were able to transfer the learned information from the PER conditioning to a novel discrimination task in a Y-maze. Both workers and drones were capable of learning and discriminating between monochromatic light stimuli and retrieved the learned stimulus after two hours. Drones performed as well as workers during conditioning and in the memory test, but failed in the transfer test in contrast to workers. Our data clearly show that bumblebees can learn to associate a color stimulus with a sugar reward in PER conditioning and that both workers and drones reach similar acquisition and mid-term retention performances. Additionally, we provide evidence that only workers transfer the learned information from a Pavlovian to an operant situation.}, language = {en} }