TY - JOUR A1 - Holzschuh, Andrea A1 - Dormann, Carsten F. A1 - Tscharntke, Teja A1 - Steffan-Dewenter, Ingolf T1 - Mass-flowering crops enhance wild bee abundance JF - Oecologia N2 - Although agricultural habitats can provide enormous amounts of food resources for pollinator species, links between agricultural and (semi-)natural habitats through dispersal and foraging movements have hardly been studied. In 67 study sites, we assessed the interactions between mass-flowering oilseed rape fields and semi-natural grasslands at different spatial scales, and their effects on the number of brood cells of a solitary cavity-nesting bee. The probability that the bee Osmia bicornis colonized trap nests in oilseed rape fields increased from 12 to 59 % when grassland was nearby, compared to fields isolated from grassland. In grasslands, the number of brood cells of O. bicornis in trap nests was 55 % higher when adjacent to oilseed rape compared to isolated grasslands. The percentage of oilseed rape pollen in the larval food was higher in oilseed rape fields and grasslands adjacent to oilseed rape than in isolated grasslands. In both oilseed rape fields and grasslands, the number of brood cells was positively correlated with the percentage of oilseed rape pollen in the larval food. We show that mass-flowering agricultural habitats—even when they are intensively managed—can strongly enhance the abundance of a solitary bee species nesting in nearby semi-natural habitats. Our results suggest that positive effects of agricultural habitats have been underestimated and might be very common (at least) for generalist species in landscapes consisting of a mixture of agricultural and semi-natural habitats. These effects might also have—so far overlooked—implications for interspecific competition and mutualistic interactions in semi-natural habitats. KW - spillover KW - trap nests KW - pollen KW - oilseed rape KW - canola Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126852 VL - 172 IS - 2 ER - TY - JOUR A1 - Schartl, Manfred A1 - Walter, Ronald B. A1 - Shen, Yingjia A1 - Garcia, Tzintzuni A1 - Catchen, Julian A1 - Amores, Angel A1 - Braasch, Ingo A1 - Chalopin, Domitille A1 - Volff, Jean-Nicolas A1 - Lesch, Klaus-Peter A1 - Bisazza, Angelo A1 - Minx, Pat A1 - Hillier, LaDeana A1 - Wilson, Richard K. A1 - Fürstenberg, Susan A1 - Boore, Jeffrey A1 - Searle, Steve A1 - Postlethwait, John H. A1 - Warren, Wesley C. T1 - The genome of the platyfish, Xiphophorus maculatus, provides insights into evolutionary adaptation and several complex traits JF - Nature Genetics N2 - Several attributes intuitively considered to be typical mammalian features, such as complex behavior, live birth and malignant disease such as cancer, also appeared several times independently in lower vertebrates. The genetic mechanisms underlying the evolution of these elaborate traits are poorly understood. The platyfish, X. maculatus, offers a unique model to better understand the molecular biology of such traits. We report here the sequencing of the platyfish genome. Integrating genome assembly with extensive genetic maps identified an unexpected evolutionary stability of chromosomes in fish, in contrast to in mammals. Genes associated with viviparity show signatures of positive selection, identifying new putative functional domains and rare cases of parallel evolution. We also find that genes implicated in cognition show an unexpectedly high rate of duplicate gene retention after the teleost genome duplication event, suggesting a hypothesis for the evolution of the behavioral complexity in fish, which exceeds that found in amphibians and reptiles. KW - genomics KW - genomic analysis KW - evolutionary biology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132152 VL - 45 IS - 5 ER - TY - JOUR A1 - Lehnen, Harald A1 - Zechner, Urlich A1 - Haaf, Thomas T1 - Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life JF - Molecular Human Reproduction N2 - The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the ‘fetal origins of adult disease’ is gestational diabetes mellitus which usually presents in 1% to >10% of third trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life. KW - metabolic disease KW - developmental origins hypothesis KW - fetal overnutrition KW - fetal programming KW - gestational diabetes mellitus Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132165 VL - 19 IS - 7 ER - TY - JOUR A1 - Herpin, Amaury A1 - Adolfi, Mateus C. A1 - Nicol, Barbara A1 - Hinzmann, Maria A1 - Schmidt, Cornelia A1 - Klughammer, Johanna A1 - Engel, Mareen A1 - Tanaka, Minoru A1 - Guiguen, Yann A1 - Schartl, Manfred T1 - Divergent Expression Regulation of Gonad Development Genes in Medaka Shows Incomplete Conservation of the Downstream Regulatory Network of Vertebrate Sex Determination JF - Molecular Biology and Evolution N2 - Genetic control of male or female gonad development displays between different groups of organisms a remarkable diversity of “master sex-determining genes” at the top of the genetic hierarchies, whereas downstream components surprisingly appear to be evolutionarily more conserved. Without much further studies, conservation of sequence has been equalized to conservation of function. We have used the medaka fish to investigate the generality of this paradigm. In medaka, the master male sex-determining gene is dmrt1bY, a highly conserved downstream regulator of sex determination in vertebrates. To understand its function in orchestrating the complex gene regulatory network, we have identified targets genes and regulated pathways of Dmrt1bY. Monitoring gene expression and interactions by transgenic fluorescent reporter fish lines, in vivo tissue-chromatin immunoprecipitation and in vitro gene regulation assays revealed concordance but also major discrepancies between mammals and medaka, notably amongst spatial, temporal expression patterns and regulations of the canonical Hedgehog and R-spondin/Wnt/Follistatin signaling pathways. Examination of Foxl2 protein distribution in the medaka ovary defined a new subpopulation of theca cells, where ovarian-type aromatase transcriptional regulation appears to be independent of Foxl2. In summary, these data show that the regulation of the downstream regulatory network of sex determination is less conserved than previously thought. KW - gonadal development KW - divergent expression regulation KW - gene regulatory network evolution KW - adaptive evolution Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132262 VL - 30 IS - 10 ER - TY - JOUR A1 - Moll, Corinna A1 - Reboredo, Jenny A1 - Schwarz, Thomas A1 - Appelt, Antje A1 - Schürlein, Sebastian A1 - Walles, Heike A1 - Nietzer, Sarah T1 - Tissue Engineering of a Human 3D in vitro Tumor Test System JF - Journal of Visualized Experiments N2 - Cancer is one of the leading causes of death worldwide. Current therapeutic strategies are predominantly developed in 2D culture systems, which inadequately reflect physiological conditions in vivo. Biological 3D matrices provide cells an environment in which cells can self-organize, allowing the study of tissue organization and cell differentiation. Such scaffolds can be seeded with a mixture of different cell types to study direct 3D cell-cell-interactions. To mimic the 3D complexity of cancer tumors, our group has developed a 3D in vitro tumor test system. Our 3D tissue test system models the in vivo situation of malignant peripheral nerve sheath tumors (MPNSTs), which we established with our decellularized porcine jejunal segment derived biological vascularized scaffold (BioVaSc). In our model, we reseeded a modified BioVaSc matrix with primary fibroblasts, microvascular endothelial cells (mvECs) and the S462 tumor cell line For static culture, the vascular structure of the BioVaSc is removed and the remaining scaffold is cut open on one side (Small Intestinal Submucosa SIS-Muc). The resulting matrix is then fixed between two metal rings (cell crowns). Another option is to culture the cell-seeded SIS-Muc in a flow bioreactor system that exposes the cells to shear stress. Here, the bioreactor is connected to a peristaltic pump in a self-constructed incubator. A computer regulates the arterial oxygen and nutrient supply via parameters such as blood pressure, temperature, and flow rate. This setup allows for a dynamic culture with either pressure-regulated pulsatile or constant flow. In this study, we could successfully establish both a static and dynamic 3D culture system for MPNSTs. The ability to model cancer tumors in a more natural 3D environment will enable the discovery, testing, and validation of future pharmaceuticals in a human-like model. KW - bioengineering KW - biomedical engineering KW - tissue engineering KW - biotechnology KW - cultured KW - tumor cells KW - cell culture KW - 3D in vitro models KW - bioreactor KW - dynamic culture conditions KW - tumor test system KW - primary cell isolation KW - BioVaSc KW - decellularization KW - equipment and supplies KW - cellular microenvironment KW - culture techniques KW - cell engineering KW - anatomy KW - physiology KW - molecular biology KW - cellular biology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132277 UR - http://www.jove.com/video/50460 VL - 78 IS - e50460 ER - TY - JOUR A1 - Volkmann, Jens A1 - Albanese, Alberto A1 - Antonini, Angelo A1 - Chaudhuri, K. Ray A1 - Clarke, Karl E. A1 - de Bie, Rob M. A. A1 - Deuschl, Günther A1 - Eggert, Karla A1 - Houeto, Jean-Luc A1 - Kulisevsky, Jaime A1 - Nyholm, Dag A1 - Odin, Per A1 - Ostergaard, Karen A1 - Poewe, Werner A1 - Pollak, Pierre A1 - Rabey, Jose Martin A1 - Rascol, Olivier A1 - Ruzicka, Evzen A1 - Samuel, Michael A1 - Speelman, Hans A1 - Sydow, Olof A1 - Valldeoriola, Francesc A1 - van der Linden, Chris A1 - Oertel, Wolfgang T1 - Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review JF - Journal of Neurology N2 - Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine. KW - Parkinson’s disease KW - apomorphine KW - deep brain stimulation KW - duodenal levodopa infusion Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132373 VL - 260 ER - TY - JOUR A1 - Horn, Anne A1 - Scheller, Carsten A1 - du Plessis, Stefan A1 - Arendt, Gabriele A1 - Nolting, Thorsten A1 - Joska, John A1 - Sopper, Sieghart A1 - Maschke, Matthias A1 - Obermann, Mark A1 - Husstedt, Ingo W. A1 - Hain, Johannes A1 - Maponga, Tongai A1 - Riederer, Peter A1 - Koutsilieri, Eleni T1 - Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals JF - Journal of Neural Transmission N2 - Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-naïve HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95 % CI 1.72–8.96; p = 0.001, Fishers exact test). 42.6 % HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5 % uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9 %, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease. KW - HIV KW - HAND KW - dopamine KW - DAT KW - polymorphism KW - CSF Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132385 VL - 120 ER - TY - JOUR A1 - Koutsilieri, E. A1 - Lutz, M. B. A1 - Scheller, C. T1 - Autoimmunity, dendritic cells and relevance for Parkinson’s disease JF - Journal of Neural Transmission N2 - Innate and adaptive immune responses in neurodegenerative diseases have become recently a focus of research and discussions. Parkinson’s disease (PD) is a neurodegenerative disorder without known etiopathogenesis. The past decade has generated evidence for an involvement of the immune system in PD pathogenesis. Both inflammatory and autoimmune mechanisms have been recognized and studies have emphasized the role of activated microglia and T-cell infiltration. In this short review, we focus on dendritic cells, on their role in initiation of autoimmune responses, we discuss aspects of neuroinflammation and autoimmunity in PD, and we report new evidence for the involvement of neuromelanin in these processes. KW - Parkinson KW - dendritic cells KW - autoimmunity KW - immune neuromelanin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132308 VL - 120 ER - TY - JOUR A1 - Hupp, Sabrina A1 - Förtsch, Christina A1 - Wippel, Carolin A1 - Ma, Jiangtao A1 - Mitchell, Timothy J. A1 - Iliev, Asparouh I. T1 - Direct Transmembrane Interaction between Actin and the Pore-Competent, Cholesterol-Dependent Cytolysin Pneumolysin JF - Journal of Molecular Biology N2 - The eukaryotic actin cytoskeleton is an evolutionarily well-established pathogen target, as a large number of bacterial factors disturb its dynamics to alter the function of the host cells. These pathogenic factors modulate or mimic actin effector proteins or they modify actin directly, leading to an imbalance of the precisely regulated actin turnover. Here, we show that the pore-forming, cholesterol-dependent cytolysin pneumolysin (PLY), a major neurotoxin of Streptococcus pneumoniae, has the capacity to bind actin directly and to enhance actin polymerisation in vitro. In cells, the toxin co-localised with F-actin shortly after exposure, and this direct interaction was verified by Förster resonance energy transfer. PLY was capable of exerting its effect on actin through the lipid bilayer of giant unilamellar vesicles, but only when its pore competence was preserved. The dissociation constant of G-actin binding to PLY in a biochemical environment was 170–190 nM, which is indicative of a high-affinity interaction, comparable to the affinity of other intracellular actin-binding factors. Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought. KW - pore-forming toxin KW - cholesterol-dependent cytolysin KW - actin KW - membrane KW - pneumolysin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132297 VL - 425 IS - 3 ER - TY - JOUR A1 - Stotz, Henrik U. A1 - Mueller, Stefan A1 - Zoeller, Maria A1 - Mueller, Martin J. A1 - Berger, Susanne T1 - TGA transcription factors and jasmonate-independent COI1 signalling regulate specific plant responses to reactive oxylipins JF - Journal of Experimental Botany N2 - Jasmonates and phytoprostanes are oxylipins that regulate stress responses and diverse physiological and developmental processes. 12-Oxo-phytodienoic acid (OPDA) and phytoprostanes are structurally related electrophilic cyclopentenones, which activate similar gene expression profiles that are for the most part different from the action of the cyclopentanone jasmonic acid (JA) and its biologically active amino acid conjugates. Whereas JA–isoleucine signals through binding to COI1, the bZIP transcription factors TGA2, TGA5, and TGA6 are involved in regulation of gene expression in response to phytoprostanes. Here root growth inhibition and target gene expression were compared after treatment with JA, OPDA, or phytoprostanes in mutants of the COI1/MYC2 pathway and in different TGA factor mutants. Inhibition of root growth by phytoprostanes was dependent on COI1 but independent of jasmonate biosynthesis. In contrast, phytoprostane-responsive gene expression was strongly dependent on TGA2, TGA5, and TGA6, but not dependent on COI1, MYC2, TGA1, and TGA4. Different mutant and overexpressing lines were used to determine individual contributions of TGA factors to cyclopentenone-responsive gene expression. Whereas OPDA-induced expression of the cytochrome P450 gene CYP81D11 was primarily regulated by TGA2 and TGA5, the glutathione S-transferase gene GST25 and the OPDA reductase gene OPR1 were regulated by TGA5 and TGA6, but less so by TGA2. These results support the model that phytoprostanes and OPDA regulate differently (i) growth responses, which are COI1 dependent but jasmonate independent; and (ii) lipid stress responses, which are strongly dependent on TGA2, TGA5, and TGA6. Identification of molecular components in cyclopentenone signalling provides an insight into novel oxylipin signal transduction pathways. KW - lipid signaling KW - reactive electrophile oxylipins KW - detoxification KW - class II TGA factors KW - biotic and abiotic stress KW - arabidopsis thaliana Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132318 VL - 64 IS - 4 ER - TY - JOUR A1 - Rössler, Wolfgang A1 - Brill, Martin F. T1 - Parallel processing in the honeybee olfactory pathway: structure, function, and evolution JF - Journal of Comparative Physiology A N2 - Animals face highly complex and dynamic olfactory stimuli in their natural environments, which require fast and reliable olfactory processing. Parallel processing is a common principle of sensory systems supporting this task, for example in visual and auditory systems, but its role in olfaction remained unclear. Studies in the honeybee focused on a dual olfactory pathway. Two sets of projection neurons connect glomeruli in two antennal-lobe hemilobes via lateral and medial tracts in opposite sequence with the mushroom bodies and lateral horn. Comparative studies suggest that this dual-tract circuit represents a unique adaptation in Hymenoptera. Imaging studies indicate that glomeruli in both hemilobes receive redundant sensory input. Recent simultaneous multi-unit recordings from projection neurons of both tracts revealed widely overlapping response profiles strongly indicating parallel olfactory processing. Whereas lateral-tract neurons respond fast with broad (generalistic) profiles, medial-tract neurons are odorant specific and respond slower. In analogy to “what-” and “where” subsystems in visual pathways, this suggests two parallel olfactory subsystems providing “what-” (quality) and “when” (temporal) information. Temporal response properties may support across-tract coincidence coding in higher centers. Parallel olfactory processing likely enhances perception of complex odorant mixtures to decode the diverse and dynamic olfactory world of a social insect. KW - multi-unit recording KW - antennal lobe KW - glomeruli KW - projection neurons KW - mushroom bodies Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132548 VL - 199 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Ritz, Eberhard A1 - Tomaschitz, Andreas A1 - Pilz, Stefan A1 - Schönfeld, Stephan A1 - Blouin, Katja A1 - Bidlingmaier, Martin A1 - Hammer, Fabian A1 - Krane, Vera A1 - März, Winfried A1 - Allolio, Bruno A1 - Fassnacht, Martin A1 - Wanner, Christoph T1 - Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients JF - European Heart Journal N2 - Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06–2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32–6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01–2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials. KW - mortality KW - kidney disease KW - cardiovascular events KW - sudden cardiac death KW - cortisol KW - aldosterone Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132562 VL - 34 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Schmiedeke, Benjamin A1 - Niemann, Markus A1 - Schmiedeke, Daniel A1 - Krämer, Johannes A1 - Turkin, Irina A1 - Blouin, Katja A1 - Emmert, Andrea A1 - Pilz, Stefan A1 - Obermayer-Pietsch, Barbara A1 - Wiedemann, Frank A1 - Breunig, Frank A1 - Wanner, Christoph T1 - Potential role of vitamin D deficiency on Fabry cardiomyopathy JF - Journal of Inherited Metabolic Disease N2 - Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 % males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial. KW - Fabry patient KW - urinary protein excretion KW - hypertrophic cardiomyopathy KW - renal fibrosis KW - left ventricular mass KW - LV mass KW - diabetic mouse KW - septal hypertrophy KW - Fabry nephropathy KW - cardiac hypertrophy KW - cornea verticillata KW - enzyme replacement therapy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132102 VL - 37 IS - 2 ER - TY - JOUR A1 - Frantz, Stefan A1 - Klaiber, Michael A1 - Baba, Hideo A. A1 - Oberwinkler, Heinz A1 - Völker, Katharina A1 - Gaßner, Birgit A1 - Bayer, Barbara A1 - Abeßer, Marco A1 - Schuh, Kai A1 - Feil, Robert A1 - Hofmann, Franz A1 - Kuhn, Michaela T1 - Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I JF - European Heart Journal N2 - Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI. Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility. KW - cyclic KW - GMPcGMP-dependent protein kinase I KW - cardiac hypertrophy KW - natriuretic peptide KW - Ca2+i handling Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134693 VL - 34 ER - TY - JOUR A1 - Wetzel, Andrea A1 - Jablonka, Sibylle A1 - Blum, Robert T1 - Cell-autonomous axon growth of young motoneurons is triggered by a voltage-gated sodium channel JF - Channels (Austin) N2 - Spontaneous electrical activity preceding synapse formation contributes to the precise regulation of neuronal development. Examining the origins of spontaneous activity revealed roles for neurotransmitters that depolarize neurons and activate ion channels. Recently, we identified a new molecular mechanism underlying fluctuations in spontaneous neuronal excitability. We found that embryonic motoneurons with a genetic loss of the low-threshold sodium channel Na\(_V\)1.9 show fewer fluctuations in intracellular calcium in axonal compartments and growth cones than wild-type littermates. As a consequence, axon growth of Na\(_V\)1.9-deficient motoneurons in cell culture is drastically reduced while dendritic growth and cell survival are not affected. Interestingly, Na\(_V\)1.9 function is observed under conditions that would hardly allow a ligand- or neurotransmitter-dependent depolarization. Thus, Na\(_V\)1.9 may serve as a cell-autonomous trigger for neuronal excitation. In this addendum, we discuss a model for the interplay between cell-autonomous local neuronal activity and local cytoskeleton dynamics in growth cone function. KW - spontaneous excitation KW - spinal muscular atrophy KW - axon growth KW - sodium channel KW - motoneurons KW - local protein synthesis KW - NaV1.9 Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132586 VL - 7 IS - 1 ER - TY - JOUR A1 - Bonn, M. A1 - Schmitt, A. A1 - Lesch, K.-P. A1 - Van Bockstaele, E. J. A1 - Asan, E. T1 - Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei JF - Brain Structure and Function N2 - Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30–40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala. KW - NPY KW - serotonergic system KW - amygdala KW - anxiety Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132591 VL - 218 IS - 2 ER - TY - JOUR A1 - Blömer, Nadja A1 - Pachel, Christina A1 - Hofmann, Urlich A1 - Nordbeck, Peter A1 - Bauer, Wolfgang A1 - Mathes, Denise A1 - Frey, Anna A1 - Bayer, Barbara A1 - Vogel, Benjamin A1 - Ertl, Georg T1 - 5-Lipoxygenase facilitates healing after myocardial infarction JF - Basic Research in Cardiology N2 - Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{−/−}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{−/−}\) bone marrow in 5-LOX\(^{−/−}\) animals), indicating that an altered function of 5-LOX\(^{−/−}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{−/−}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{−/−}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function. KW - lipoxygenase KW - myocardial infarction KW - extracellular matrix remodeling KW - inflammation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132602 VL - 108 IS - 4 ER - TY - JOUR A1 - Hofmann, Ulrich A1 - Frantz, Stefan T1 - How can we cure a heart "in flame"? A translational view on inflammation in heart failure JF - Basic Research in Cardiology N2 - The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-a led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective. KW - cytokines KW - immuno-modulation KW - heart failure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134497 VL - 108 IS - 356 ER - TY - JOUR A1 - Holzapfel, Boris Michael A1 - Chhaya, Mohit Prashant A1 - Melchels, Ferry Petrus Wilhelmus A1 - Holzapfel, Nina Pauline A1 - Prodinger, Peter Michael A1 - von Eisenhart-Rothe, Rüdiger A1 - Griensven, Martijn van A1 - Schantz, Jan-Thorsten A1 - Rudert, Maximilian A1 - Hutmacher, Dietmar Werner T1 - Can Bone Tissue Engineering Contribute to Therapy Concepts after Resection of Musculoskeletal Sarcoma? JF - Sarcoma N2 - Resection of musculoskeletal sarcoma can result in large bone defects where regeneration is needed in a quantity far beyond the normal potential of self-healing. In many cases, these defects exhibit a limited intrinsic regenerative potential due to an adjuvant therapeutic regimen, seroma, or infection. Therefore, reconstruction of these defects is still one of the most demanding procedures in orthopaedic surgery. The constraints of common treatment strategies have triggered a need for new therapeutic concepts to design and engineer unparalleled structural and functioning bone grafts. To satisfy the need for long-term repair and good clinical outcome, a paradigm shift is needed from methods to replace tissues with inert medical devices to more biological approaches that focus on the repair and reconstruction of tissue structure and function. It is within this context that the field of bone tissue engineering can offer solutions to be implemented into surgical therapy concepts after resection of bone and soft tissue sarcoma. In this paper we will discuss the implementation of tissue engineering concepts into the clinical field of orthopaedic oncology. KW - musculoskeletal sarcoma Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132465 VL - 2013 IS - Article ID 153640 ER - TY - JOUR A1 - Hedrich, Christian M. A1 - Hofmann, Sigrun R. A1 - Pablik, Jessica A1 - Morbach, Henner A1 - Girschick, Hermann J. T1 - Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO) JF - Pediatric Rheumatology N2 - Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated. KW - TNF-α KW - PAPA KW - DIRA KW - Majeed KW - CNO KW - CRMO KW - bone KW - inflammation KW - IL-10 KW - treatment KW - TLR4 Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132456 VL - 11 IS - 47 ER - TY - JOUR A1 - Grote, Stefan A1 - Noeldeke, Tatjana A1 - Blauth, Michael A1 - Mutschler, Wolf A1 - Bürklein, Dominik T1 - Mechanical torque measurement in the proximal femur correlates to failure load and bone mineral density ex vivo JF - Orthopedic Reviews (Pavia) N2 - Knowledge of local bone quality is essential for surgeons to determine operation techniques. A device for intraoperative measurement of local bone quality has been developed by the AO-Research Foundation (DensiProbe®). We used this device to experimentally measure peak breakaway torque of trabecular bone in the proximal femur and correlated this with local bone mineral density (BMD) and failure load. Bone mineral density of 160 cadaver femurs was measured by ex situ dual-energy X-ray absorptiometry. The failure load of all femurs was analyzed by side-impact analysis. Femur fractures were fixed and mechanical peak torque was measured with the DensiProbe® device. Correlation was calculated whereas correlation coefficient and significance was calculated by Fisher’s Z-transformation. Moreover, linear regression analysis was carried out. The unpaired Student’s t-test was used to assess the significance of differences. The Ward triangle region had the lowest BMD with 0.511 g/cm2 (±0.17 g/cm2), followed by the upper neck region with 0.546 g/cm2 (±0.16 g/cm2), trochanteric region with 0.685 g/cm2 (±0.19 g/cm2) and the femoral neck with 0.813 g/cm2 (±0.2 g/cm2). Peak torque of DensiProbe® in the femoral head was 3.48 Nm (±2.34 Nm). Load to failure was 4050.2 N (±1586.7 N). The highest correlation of peak torque measured by Densi Probe® and load to failure was found in the femoral neck (r=0.64, P<0.001). The overall correlation of mechanical peak torque with T-score was r=0.60 (P<0.001). A correlation was found between mechanical peak torque, load to failure of bone and BMD in vitro. Trabecular strength of bone and bone mineral density are different aspects of bone strength, but a correlation was found between them. Mechanical peak torque as measured may contribute additional information about bone strength, especially in the perioperative testing. KW - hip fracture KW - bone mineral density KW - osteoporosis KW - mechanical torque measurement KW - failure load Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132358 VL - 5 IS - e16 ER - TY - JOUR A1 - von Rüden, Christian A1 - Woltmann, Alexander A1 - Röse, Marc A1 - Wurm, Simone A1 - Rüger, Matthias A1 - Hierholzer, Christian A1 - Bühren, Volker T1 - Outcome after severe multiple trauma: a retrospective analysis JF - Journal of Trauma Management & Outcomes N2 - Background Aim of this study was to evaluate prognosis of severely injured patients. Methods All severely injured patients with an Injury Severity Score (ISS) ≥ 50 were identified in a 6-year-period between 2000 and 2005 in German Level 1 Trauma Center Murnau. Data was evaluated from German Trauma Registry and Polytrauma Outcome Chart of the German Society for Trauma Surgery and a personal interview to assess working ability and disability and are presented as average. Results 88 out of 1435 evaluated patients after severe polytrauma demonstrated an ISS ≥ 50 (6.5%), among them 23% women and 77% men. 66 patients (75%) had an ISS of 50-60, 14 (16%) 61-70, and 8 (9%) ≥ 70. In 27% of patients trauma was caused by motor bike accidents. 3.6 body regions were involved. Patients had to be operated 5.3 times and were treated 23 days in the ICU and stayed 73 days in hospital. Mortality rate was 36% and rate of multi-organ failure 28%. 15% of patients demonstrated severe senso-motoric dysfunction as well as residues of severe head injury. 25% recovered well or at least moderately. 29 out of 56 survivors answered the POLO-chart. A personal interview was performed with 13 patients. The state of health was at least moderate in 72% of patients. In 48% interpersonal problems and in 41% severe pain was observed. In 57% of patients problems with working ability regarding duration, as well as quantitative and qualitative performance were observed. Symptoms of post-traumatic stress disorder were found in 41%. The more distal the lesions were located (foot/ankle) the more functional disability affected daily life. In only 15%, working ability was not impaired. 8 out of 13 interviewed patients demonstrated complete work disability. Conclusions Even severely injured patients after multiple trauma have a good prognosis. The ISS is an established tool to assess severity and prognosis of trauma, whereas prediction of clinical outcome cannot be deducted from this score. KW - post-traumatic stress disorder KW - severe multiple trauma KW - ISS KW - POLO-chart Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132249 VL - 7 IS - 4 ER - TY - JOUR A1 - Ojha, Animesh K. A1 - Forster, Stefan A1 - Kumar, Sumeet A1 - Vats, Siddharth A1 - Negi, Sangeeta A1 - Fischer, Ingo T1 - Synthesis of well–dispersed silver nanorods of different aspect ratios and their antimicrobial properties against gram positive and negative bacterial strains JF - Journal of Nanobiotechnology N2 - In the present contribution, we describe the synthesis of highly dispersed silver nanorods (NRs) of different aspect ratios using a chemical route. The shape and size of the synthesized NRs were characterized by Transmission Electron Microscopy (TEM) and UV-visible spectroscopy. Longitudinal and transverse absorptions bands confirm the rod type structure. The experimentally recorded UV-visible spectra of NRs solutions were fitted by using an expression of the extinction coefficient for rod like nano structures under the dipole approximation. Simulated and experimentally observed UV-visible spectra were compared to determine the aspect ratios (R) of NRs. The average values of R for NR1, NR2 and NR3 solutions are estimated to be 3.0 ± 0.1, 1.8 ± 0.1 and 1.2 ± 0.1, respectively. These values are in good agreement with those obtained by TEM micrographs. The silver NRs of known aspect ratios are used to study antimicrobial activities against B. subtilis (gram positive) and E. coli (gram negative) microbes. We observed that the NRs of intermediate aspect ratio (R = 1.8) have greater antimicrobial effect against both, B. subtilis (gram positive) and E. coli (gram negative). The NRs of aspect ratio, R = 3.0 has better antimicrobial activities against gram positive than on the gram negative. KW - antimicrobial activities KW - silver KW - nano rods KW - TEM Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132222 VL - 11 IS - 42 ER - TY - JOUR A1 - Golombeck, Stefanie Kristin A1 - Wessig, Carsten A1 - Monoranu, Camelia-Maria A1 - Schütz, Ansgar A1 - Solymosi, Laszlo A1 - Melzer, Niko A1 - Kleinschnitz, Christoph T1 - Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report JF - Journal of Medical Case Reports N2 - Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions. KW - reversible posterior leukoencephalopathy syndrome KW - generalized cerebral edema KW - cerebral autoregulation KW - blood pressure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129456 VL - 7 IS - 14 ER - TY - JOUR A1 - Huang, Bei A1 - Belharazem, Djeda A1 - Li, Li A1 - Kneitz, Susanne A1 - Schnabel, Philipp A. A1 - Rieker, Ralf J. A1 - Körner, Daniel A1 - Nix, Wilfried A1 - Schalke, Berthold A1 - Müller-Hermelink, Hans Konrad A1 - Ott, German A1 - Rosenwald, Andreas A1 - Ströbel, Philipp A1 - Marx, Alexander T1 - Anti-apoptotic signature in thymic squamous cell carcinomas – functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c JF - Frontiers in Oncology N2 - The molecular pathogenesis of thymomas and thymic arcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important.This made us re-analyze historic expression data obtained in a spectrumof thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC. KW - gene expression KW - MTCH2 KW - targeted KW - myasthenia gravis KW - apoptosis KW - thymus KW - thymoma KW - thymic carcinoma Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132214 VL - 3 IS - 316 ER - TY - JOUR A1 - Bing-Shi Tan, Ariel A1 - Kress, Sebastian A1 - Castro, Leticia A1 - Sheppard, Allan A1 - Raghunath, Michael T1 - Cellular re- and de-programming by microenvironmental memory: why short TGF-β1 pulses can have long effects JF - Fibrogenesis Tissue Repair N2 - Background Fibrosis poses a substantial setback in regenerative medicine. Histopathologically, fibrosis is an excessive accumulation of collagen affected by myofibroblasts and this can occur in any tissue that is exposed to chronic injury or insult. Transforming growth factor (TGF)-β1, a crucial mediator of fibrosis, drives differentiation of fibroblasts into myofibroblasts. These cells exhibit α-smooth muscle actin (α-SMA) and synthesize high amounts of collagen I, the major extracellular matrix (ECM) component of fibrosis. While hormones stimulate cells in a pulsatile manner, little is known about cellular response kinetics upon growth factor impact. We therefore studied the effects of short TGF-β1 pulses in terms of the induction and maintenance of the myofibroblast phenotype. Results Twenty-four hours after a single 30 min TGF-β1 pulse, transcription of fibrogenic genes was upregulated, but subsided 7 days later. In parallel, collagen I secretion rate and α-SMA presence were elevated for 7 days. A second pulse 24 h later extended the duration of effects to 14 days. We could not establish epigenetic changes on fibrogenic target genes to explain the long-lasting effects. However, ECM deposited under singly pulsed TGF-β1 was able to induce myofibroblast features in previously untreated fibroblasts. Dependent on the age of the ECM (1 day versus 7 days’ formation time), this property was diminished. Vice versa, myofibroblasts were cultured on fibroblast ECM and cells observed to express reduced (in comparison with myofibroblasts) levels of collagen I. Conclusions We demonstrated that short TGF-β1 pulses can exert long-lasting effects on fibroblasts by changing their microenvironment, thus leaving an imprint and creating a reciprocal feed-back loop. Therefore, the ECM might act as mid-term memory for pathobiochemical events. We would expect this microenvironmental memory to be dependent on matrix turnover and, as such, to be erasable. Our findings contribute to the current understanding of fibroblast induction and maintenance, and have bearing on the development of antifibrotic drugs. KW - cytokine KW - fibrosis KW - transforming growth factor-beta 1 KW - extracellular matrix KW - memory KW - pulses KW - phenotype KW - kinetics Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131898 VL - 6 IS - 12 ER - TY - JOUR A1 - Ehling, Petra A1 - Göb, Eva A1 - Bittner, Stefan A1 - Budde, Thomas A1 - Ludwig, Andreas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice? JF - Experimental & Translational Stroke Medicine N2 - Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing Ih, stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model. KW - neurology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129240 VL - 5 IS - 16 ER - TY - JOUR A1 - Büdel, Burkhard A1 - Vivas, Mercedes A1 - Lange, Otto L. T1 - Lichen species dominance and the resulting photosynthetic behavior of sonoran desert soil crust types (Baja California, Mexico) JF - Ecological Processes N2 - Introduction: Lichen dominated biological soil crusts (BSCs) occur over large areas in the Sonoran Desert of the southwestern USA and northwest Mexico. In Baja California BSCs show a distinct patchiness and several types can be distinguished. Two chlorolichen- and two cyanolichen-dominated BSCs were selected. We hypothesize that patchiness and the resulting domination of certain functional lichen groups will result in patchiness of photosynthetic CO2-uptake related to environmental factors as well. Methods: Four different soil crust samples were placed in cuvettes and their CO2 exchange was recorded in an open system with an infrared gas analyzer. Air blown over the BSCs had a controlled CO2 content of 350 ppm. Four cuvettes were operated in parallel. Photosynthetic CO2 exchange was continually recorded throughout the experiment. Results: Besides the dominating chlorolichens Psora decipiens and Placidium squamulosum and the cyanolichens Peltula patellata and P. richardsii, several other lichen species and 12 cyanobacterial species were found in the biological soil crusts sampled. The chlorolichen BSCs already gained positive net photosynthesis with high air humidity alone, while the cyanolichen types did not, but showed smaller CO2-uptake depression after water suprasaturation. Such specific net photosynthesis responses to mode of hydration and to crust water content seem to correlate with precipitation characteristics of their habitat. Conclusions: Species specific photosynthetic performance related to activation of respiration and net photosynthesis as well as to crust water content help to explain niche occupation and species composition of BSCs. Different functional types have to be considered when they have a patchy distribution. KW - patchiness KW - cyanobacterium KW - desert soil KW - dominance KW - lichen KW - photosynthesis KW - reactivation KW - soil crust KW - Baja California [(PNN) Mexico] KW - Mexico [North America] KW - Sonoran Desert KW - cyanobacteria KW - peltula patellata KW - placidium KW - psora decipiens Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131878 VL - 2 IS - 6 ER - TY - JOUR A1 - Rinawati, Fitria A1 - Stein, Katharina A1 - Lindner, André T1 - Climate change impacts on biodiversity-the setting of a lingering global crisis JF - Diversity N2 - Climate change has created potential major threats to global biodiversity. The multiple components of climate change are projected to affect all pillars of biodiversity, from genes over species to biome level. Of particular concerns are "tipping points" where the exceedance of ecosystem thresholds will possibly lead to irreversible shifts of ecosystems and their functioning. As biodiversity underlies all goods and services provided by ecosystems that are crucial for human survival and wellbeing, this paper presents potential effects of climate change on biodiversity, its plausible impacts on human society as well as the setting in addressing a global crisis. Species affected by climate change may respond in three ways: change, move or die. Local species extinctions or a rapidly affected ecosystem as a whole respectively might move toward its particular "tipping point", thereby probably depriving its services to human society and ending up in a global crisis. Urgent and appropriate actions within various scenarios of climate change impacts on biodiversity, especially in tropical regions, are needed to be considered. Foremost a multisectoral approach on biodiversity issues with broader policies, stringent strategies and programs at international, national and local levels is essential to meet the challenges of climate change impacts on biodiversity. KW - biodiversity KW - climate change KW - ecosystem function KW - ecosystem service KW - tropical forest Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131866 VL - 5 IS - 1 ER - TY - JOUR A1 - Montoya Peláez, Guillermo L. A1 - Sierra, Jelver A. A1 - Alzate, Fernando A1 - Holzgrabe, Ulrike A1 - Ramirez-Pineda, José R. T1 - Pentacyclic triterpenes from Cecropia telenitida with immunomodulatory activity on dendritic cells JF - Revista Brasileira de Farmacognosia - Brazilian Journal of Pharmacognosy N2 - Pentacyclic triterpenes are a large family of plant metabolites that exhibit a wide array of biological activities. The genus Cecropia, which encompasses many plant species, has been used as traditional medicine for the treatment of inflammatory diseases and is known to produce many active pentacyclic triterpenes. In this study we investigated the chemical composition of a pentacyclic triterpene fraction from the roots of Cecropia telenitida Cuatrec., Urticaceae. A novel compound, which we termed yarumic acid, and four known molecules (serjanic acid, spergulagenic acid A, 20-hydroxy-ursolic acid and goreishic acid I) were isolated and characterised. In a dendritic cell (DC)-based assay, we demonstrated that non-toxic doses of these pentacyclic triterpenes inhibited the secretion of at least one of the proinflammatory cytokines tested (IL-1 beta, IL-12p40, IL-12p70, TNF-alpha). Spergulagenic acid A also inhibited nitric oxide production in lipopolysaccharide-stimulated dendritic cell. Serjanic acid and spergulagenic acid A, which were the most potent abundant compounds in the pentacyclic triterpene fraction, showed the most activity in the dendritic cell-based assay. These results show that all pentacyclic triterpenes might contribute to the anti-inflammatory activities of C. telenitida. Moreover, yarumic acid as well as the four known pentacyclic triterpenes, can be exploited as potential immunomodulatory/anti-inflammatory agents. KW - psidium guajava; KW - oleanane saponins KW - kappa-B activation KW - cytokine production KW - chenopodium quinoa KW - obtusifolia bertol KW - nitric oxide KW - ursolic acid KW - bone marrow KW - macrophages KW - pentacyclic triterpene KW - dendritic cells KW - anti-inflammatory activity KW - cytokine modulation KW - natural product KW - cecropia telenitida Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131851 VL - 23 ER - TY - JOUR A1 - Wolfahrt, Sonja A1 - Herman, Sandra A1 - Scholz, Claus-Jürgen A1 - Sauer, Georg A1 - Deissler, Helmut T1 - Identification of alternative transcripts of rat CD9 expressed by tumorigenic neural cell lines and in normal tissues JF - Genetics and Molecular Biology N2 - CD9 is the best-studied member of the tetraspanin family of transmembrane proteins. It is involved in various fundamental cellular processes and its altered expression is a characteristic of malignant cells of different origins. Despite numerous investigations confirming its fundamental role, the heterogeneity of CD9 or other tetraspanin proteins was considered only to be caused by posttranslational modification, rather than alternative splicing. Here we describe the first identification of CD9 transcript variants expressed by cell lines derived from fetal rat brain cells. Variant mRNA-B lacks a potential translation initiation codon in the alternative exon 1 and seems to be characteristic of the tumorigenic BT cell lines. In contrast, variant mRNA-C can be translated from a functional initiation codon located in its extended exon 2, and substantial amounts of this form detected in various tissues suggest a contribution to CD9 functions. From the alternative sequence of variant C, a different membrane topology ( 5 transmembrane domains) and a deviating spectrum of functions can be expected. KW - tetraspanin KW - CD9 KW - antigen KW - cancer KW - noncoding RNAs KW - nervous system KW - poor prognosis KW - tetraspanin protein KW - transcript KW - splice variant KW - membrane topology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131801 VL - 36 IS - 2 ER - TY - JOUR A1 - Marcus, U. A1 - Vogel, U. A1 - Schubert, A. A1 - Claus, H. A1 - Baetzing-Feigenbaum, J. A1 - Hellenbrand, W. A1 - Wichmann, O. T1 - A cluster of invasive meningococcal disease in young men who have sex with men in Berlin, October 2012 to May 2013 JF - Eurosurveillance N2 - No abstract available. KW - meningococcal disease Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131711 VL - 18 IS - 28 ER - TY - JOUR A1 - Harrison, Odile B. A1 - Claus, Heike A1 - Jiang, Ying A1 - Bennett, Julia S. A1 - Bratcher, Holly B. A1 - Jolley, Keith A. A1 - Corton, Craig A1 - Care, Rory A1 - Poolman, Jan T. A1 - Zollinger, Wendell D. A1 - Frasch, Carl E. A1 - Stephens, David S. A1 - Feavers, Ian A1 - Frosch, Matthias A1 - Parkhill, Julian A1 - Vogel, Ulrich A1 - Quail, Michael A. A1 - Bentley, Stephen D. A1 - Maiden, Martin C. J. T1 - Description and Nomenclature of Neisseria meningitidis Capsule Locus JF - Emerging Infectious Diseases N2 - Pathogenic Neisseria meningitidis isolates contain a polysaccharide capsule that is the main virulence determinant for this bacterium. Thirteen capsular polysaccharides have been described, and nuclear magnetic resonance spectroscopy has enabled determination of the structure of capsular polysaccharides responsible for serogroup specificity. Molecular mechanisms involved in N. meningitidis capsule biosynthesis have also been identified, and genes involved in this process and in cell surface translocation are clustered at a single chromosomal locus termed cps. The use of multiple names for some of the genes involved in capsule synthesis, combined with the need for rapid diagnosis of serogroups commonly associated with invasive meningococcal disease, prompted a requirement for a consistent approach to the nomenclature of capsule genes. In this report, a comprehensive description of all N. meningitidis serogroups is provided, along with a proposed nomenclature, which was presented at the 2012 XVIIIth International Pathogenic Neisseria Conference. KW - genetics KW - nuclear magnetic resonance KW - structural determination KW - meningococcal polysaccharides KW - chemical properties KW - serogroup-Y KW - group-B KW - antigen KW - biosynthesis KW - elucidation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131703 VL - 19 IS - 4 ER - TY - JOUR A1 - Latif, Baha A1 - Heo, Chong Chin A1 - Razuin, Rahimi A1 - Shamalaa, Devi V. T1 - Autochthonous Human Schistosomiasis, Malaysia JF - Emerging Infectious Diseases N2 - No abstract available. KW - japonicum Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131692 N1 - Public Domain VL - 19 IS - 8 ER - TY - JOUR A1 - Ntoukas, Vasileios A1 - Tappe, Dennis A1 - Pfütze, Daniel A1 - Simon, Michaela A1 - Holzmann, Thomas T1 - Cerebellar Cysticercosis Caused by Larval Taenia crassiceps Tapeworm in Immunocompetent Woman, Germany JF - Emerging Infectious Diseases N2 - Human cysticercosis caused by Taenia crassiceps tapeworm larvae involves the muscles and subcutis mostly in immunocompromised patients and the eye in immunocompetent persons. We report a successfully treated cerebellar infection in an immunocompetent woman. We developed serologic tests, and the parasite was identified by histologic examination and 12s rDNA PCR and sequencing. KW - helminths KW - acquired immunodeficiency-syndrome KW - foxes vulpes-vulpes KW - invasive cysticerocsis KW - infection KW - patient KW - AIDS Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131686 N1 - Public Domain VL - 19 IS - 12 ER - TY - JOUR A1 - Ness, Thomas A1 - Bley, Thorsten A. A1 - Schmidt, Wolfgang A. A1 - Lamprecht, Peter T1 - The Diagnosis and Treatment of Giant Cell Arteritis JF - Deutsches Ärzteblatt International N2 - Background: Giant cell arteritis (GCA) is the most common systemic vasculitis in persons aged 50 and above (incidence, 3.5 per 100 000 per year). It affects cranial arteries, the aorta, and arteries elsewhere in the body, e.g., in the limbs. Methods: We selectively review the pertinent literature, including guidelines and recommendations from Germany and abroad. Results: The typical symptoms of new-onset GCA are bi-temporal headaches, jaw claudiacation, scalp tenderness, visual disturbances, systemic symptoms such as fever and weight loss, and polymyalgia. The diagnostic assessment comprises laboratory testing (erythrocyte sedimentation rate, C-reactive protein), imaging studies (duplex sonography, high-resolution magnetic resonance imaging, positron-emission tomography), and temporal artery biopsy. The standard treatment is with corticosteroids (adverse effects: diabetes mellitus, osteoporosis, cataract, arterial hypertension). A meta-analysis of three randomized controlled trials led to a recommendation for treatment with methotrexate to lower the recurrence rate and spare steroids. Patients for whom methotrexate is contraindicated or who cannot tolerate the drug can be treated with azathioprine instead. Conclusion: Giant cell arteritis, if untreated, progresses to involve the aorta and its collateral branches, leading to various complications. Late diagnosis and treatment can have serious consequences, including irreversible loss of visual function. KW - systemic vasculitides KW - arteriitis temporal arteriitis KW - erythrocyte sedimentation-rate KW - complication aortic-aneurysm KW - large-vessel vasculitis KW - c-reactive protein KW - polymyalgia-rheomatica KW - corticosteroid treatment KW - double-blind KW - ocular manifestations Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131676 VL - 110 IS - 21 ER - TY - JOUR A1 - Quinkler, Marcus A1 - Beuschlein, Felix A1 - Hahner, Stefanie A1 - Meyer, Gesine A1 - Schöfl, Christof A1 - Stalla, Günter K. T1 - Adrenal Cortical Insufficiency-a Life Threatening Illness With Multiple Etiologies JF - Deutsches Ärzteblatt International N2 - Background: The clinical signs of adrenal cortical insufficiency (incidence, ca. 25 per million per year; prevalence, ca. 400 per million) are nonspecific, and misdiagnoses are therefore common. Glucocorticoid substitution therapy has been in use for 50 years but is not a wholly adequate treatment. Our understanding of this disease remains incomplete in many ways. Methods: We selectively searched the Medline database for publications on adrenal cortical insufficiency, with particular attention to studies from the year 2000 onward (search terms: "adrenal insufficiency" or "Addison's disease" or "hypopituitarism"). Results: Hydrocortisone substitution therapy is often given in doses of 10-25 mg/day, timed according to the circadian rhythm. Gastrointestinal and other, febrile infections account for 30-50% of life-threatening adrenocortical crises. Such crises affect 8 of 100 persons with adrenal cortical insufficiency per year and must be treated by the immediate administration of glucocorticoids and fluids. When persons with adrenal cortical insufficiency are acutely ill or are otherwise under unusual stress, they may need additional amounts of hydrocortisone, often in the range of 5-10 mg but occasionally as high as 200 mg. The sustained administration of excessive amounts of steroid can shorten patients' lives by several years. Inappropriate substitution therapy can cause other major medical conditions, such as metabolic syndrome and osteoporosis. Conclusion: Important measures for the prevention of adrenocortical crises include improved care by treating physicians, education of patients and their families, the provision of emergency identifying documents, and the prescription of glucocorticoid emergency kits. KW - short term KW - subjective health-status KW - modified-release hydrocortisone KW - glucocorticoid replacement regimens KW - Addisons disease KW - therapeutic management KW - hypopituitary patients KW - premature mortality KW - circadian therapy KW - adult patients Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131662 VL - 110 ER - TY - JOUR A1 - Werner, Birgit S. A1 - Boehm, Dorota A1 - Gohlke, Frank T1 - Revision to reverse shoulder arthroplasty with retention of the humeral component Good outcome in 14 patients followed for a mean of 2.5 years JF - Acta Orthopaedica N2 - Background: Revision in failed shoulder arthroplasty often requires removal of the humeral component with a significant risk of fracture and bone loss. Newer modular systems allow conversion from anatomic to reverse shoulder arthroplasty with retention of a well-fixed humeral stem. We report on a prospectively evaluated series of conversions from hemiarthroplasty to reverse shoulder arthroplasty. Methods: In 14 cases of failed hemiarthroplasty due to rotator cuff deficiency and painful pseudoparalysis (in 13 women), revision to reverse shoulder arthroplasty was performed between October 2006 and 2010, with retention of the humeral component using modular systems. Mean age at the time of operation was 70 (56-80) years. Pre- and postoperative evaluation followed a standardized protocol including Constant score, range of motion, and radiographic analysis. Mean follow-up time was 2.5 (2-5.5) years. Results: Mean Constant score improved from 9 (2-16) to 41 (17-74) points. Mean lengthening of the arm was 2.6 (0.9-4.7) cm without any neurological complications. One patient required revision due to infection. Interpretation Modular systems allow retainment of a well-fixed humeral stem with good outcome. There is a risk of excessive humeral lengthening. KW - cultures KW - etiology KW - fractures KW - prothesis KW - proximal humerus KW - failed hemiarthroplasty Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131621 VL - 84 IS - 5 ER - TY - JOUR T1 - Search for WH production with a light Higgs boson decaying to prompt electron-jets in proton–proton collisions at \(\sqrt {s}=7\)  TeV with the ATLAS detector JF - New Journal of Physics N2 - A search is performed for WH production with a light Higgs boson decaying to hidden-sector particles resulting in clusters of collimated electrons, known as electron-jets. The search is performed with \(2.04 fb^{−1}\) of data collected in 2011 with the ATLAS detector at the Large Hadron Collider in proton–proton collisions at \(\sqrt {s}=7 TeV\) . One event satisfying the signal selection criteria is observed, which is consistent with the expected background rate. Limits on the product of the WH production cross section and the branching ratio of a Higgs boson decaying to prompt electron-jets are calculated as a function of a Higgs boson mass in the range from 100 to 140 GeV. KW - Higgs boson Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131565 VL - 15 IS - 043009 ER - TY - JOUR T1 - Search for excited electrons and muons in \(\sqrt {s}=8\) TeV proton–proton collisions with the ATLAS detector JF - New Journal of Physics N2 - The ATLAS detector at the Large Hadron Collider is used to search for excited electrons and excited muons in the channel \(pp →ℓℓ^\ast→ℓℓ\gamma \), assuming that excited leptons are produced via contact interactions. The analysis is based on \(13 fb^{−1}\) of pp collisions at a centre-of-mass energy of 8 TeV. No evidence for excited leptons is found, and a limit is set at the 95% credibility level on the cross section times branching ratio as a function of the excitedlepton mass \(m_{ℓ^\ast}\) . For \(m_{ℓ^\ast}\) ≽0.8 TeV, the respective upper limits on \(\sigma B(ℓ→ ℓ\gamma)\) are 0.75 and 0.90 fb for the \(e^\ast\) and \(μ^\ast\) searches. Limits on \(\sigma B\) are converted into lower bounds on the compositeness scale \(\Lambda\). In the special case where \(\Lambda = m_{ℓ^\ast}\), excited-electron and excited-muon masses below 2.2 TeV are excluded. KW - excited electrons KW - muons Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131557 VL - 15 IS - 093011 ER - TY - JOUR T1 - Search for extra dimensions in diphoton events from proton–proton collisions at \(\sqrt {s} = 7\)  TeV in the ATLAS detector at the LHC JF - New Journal of Physics N2 - The large difference between the Planck scale and the electroweak scale, known as the hierarchy problem, is addressed in certain models through the postulate of extra spatial dimensions. A search for evidence of extra spatial dimensions in the diphoton channel has been performed using the full set of proton–proton collisions at \(\sqrt {s} = 7\) TeV recorded in 2011 with the ATLAS detector at the CERN Large Hadron Collider. This dataset corresponds to an integrated luminosity of \(4.9 fb^{−1}\). The diphoton invariant mass spectrum is observed to be in good agreement with the Standard Model expectation. In the context of the model proposed by Arkani–Hamed, Dimopoulos and Dvali, 95% confidence level lower limits of between 2.52 and 3.92 TeV are set on the ultraviolet cutoff scale MS depending on the number of extra dimensions and the theoretical formalism used. In the context of the Randall–Sundrum model, a lower limit of 2.06 (1.00) TeV at 95% confidence level is set on the mass of the lightest graviton for couplings of \(k/\overline {M}_{Pl} = 0.1 (0.01)\). Combining with the ATLAS dilepton searches based on the 2011 data, the 95% confidence level lower limit on the Randall–Sundrum graviton mass is further tightened to 2.23 (1.03) TeV for \(k/\overline {M}_{Pl} = 0.1 (0.01)\). KW - diphoton events KW - proton-proton collision Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131548 VL - 15 ER - TY - JOUR T1 - Measurement of hard double-parton interactions in W(→ℓν) + 2-jet events at \(\sqrt{s}=7\) TeV with the ATLAS detector JF - New Journal of Physics N2 - The production of W bosons in association with two jets in proton–proton collisions at a centre-of-mass energy of \(\sqrt{s}=7\),TeV has been analysed for the presence of double-parton interactions using data corresponding to an integrated luminosity of \(36 pb^{−1}\), collected with the ATLAS detector at the Large Hadron Collider. The fraction of events arising from double-parton interactions, \(f^D_{DP}\), has been measured through the pT balance between the two jets and amounts to \(f^D_{DP}\) = 0.08 ± 0.01 (stat.) ± 0.02 (sys.) for jets with transverse momentum \(p_T\) > 20 GeV and rapidity |y| < 2.8. This corresponds to a measurement of the effective area parameter for hard double-parton interactions of \(\sigma_{eff} = 15 ± 3 (stat.)^{+5}_{−3} (sys.)\) mb. KW - hard double-patron interactions Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131531 VL - 15 IS - 033038 ER - TY - JOUR A1 - Atanasov, Georgi A1 - Benkert, Christoph A1 - Thelen, Armin A1 - Tappe, Dennis A1 - Frosch, Matthias A1 - Teichmann, Dieter A1 - Barth, Thomas F. E. A1 - Wittekind, Christian A1 - Schubert, Stefan A1 - Jonas, Sven T1 - Alveolar echinococcosis-spreading disease challenging clinicians: A case report and literature review JF - World Journal of Gastroenterology N2 - Human alveolar echinococcosis (AE) is a potentially deadly disease; recent studies have shown that the endemic area of Echinococcus multilocularis, its causative agent, is larger than previously known. This disease has low prevalence and remains underreported in Europe. Emerging clinical data show that diagnostic difficulties are still common. We report on a 76-year old patient suffering from AE lesions restricted to the left lobe of the liver who underwent a curative extended left hemihepatectomy. Prior to the resection a liver biopsy under the suspicion of an atypical malignancy was performed. After the intervention he developed a pseudoaneurysm of the hepatic artery that was successfully coiled. Surprisingly, during surgery, the macroscopic appearance of the tumour revealed a growth pattern that was rather typical for cystic echinococcosis (CE), i.e., a gross tumour composed of multiple large vesicles with several centimeters in diameter. In addition, there were neither extensive adhesions nor infiltrations of the neighboring pancreas and diaphragm as was expected from previous imaging results. The unexpected diagnosis of AE was confirmed by definite histopathology, specific polymerase chain reaction and serology results. This is a rare case of unusual macroscopic presentation of AE that posed immense diagnostic challenges and had an eventful course. To our knowledge this is the first case of an autochthonous infection in this particular geographic area of Germany, the federal state of Saxony. This report may provide new hints for an expanding area of risk for AE and emphasizes the risk of complications in the scope of diagnostic procedures and the limitations of modern radiological imaging. KW - hemihepatectomy KW - multilocularis KW - Germany KW - Europe KW - liver KW - alveolar echinococcosis KW - echinococcus multilocularis KW - autochthonous infection KW - liver resection Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131525 VL - 19 IS - 26 ER - TY - JOUR A1 - Ludwig, K. U. A1 - Sämann, P. A1 - Alexander, M. A1 - Becker, J. A1 - Bruder, J. A1 - Moll, K. A1 - Spieler, D. A1 - Czisch, M. A1 - Warnke, A. A1 - Docherty, S. J. A1 - Davis, O. S. P. A1 - Plomin, R. A1 - Nöthen, M. M. A1 - Landerl, K. A1 - Müller-Myhsok, B. A1 - Hoffmann, P. A1 - Schumacher, J. A1 - Schulte-Körne, G. A1 - Czamara, D. T1 - A common variant in Myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults JF - Translational Psychiatry N2 - The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities\((P_{comb}=7.71 x 10^{-10}, n=699)\), with an effect size of 4.87%. This association was also found in a sample from the general population (P=0.048, n=1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype. KW - disability KW - sulcal morphology KW - prelevance KW - identification KW - brain KW - cancer KW - association KW - developmental dyscalculia KW - tumor-suppressor gene KW - correlate KW - disorders KW - dyscalculia KW - dyslexia KW - genomic imaging KW - mathematics KW - quantitative trait Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131513 N1 - Supplementary Information accompanies the paper on the Translational Psychiatry website (http://www.nature.com/tp). VL - 3 IS - e229 ER - TY - JOUR A1 - Arca, Francesco A1 - Tedde, Sandro F. A1 - Sramek, Maria A1 - Rauh, Julia A1 - Lugli, Paolo A1 - Hayden, Oliver T1 - Interface Trap States in Organic Photodiodes JF - Scientific Reports N2 - Organic semiconductors are attractive for optical sensing applications due to the effortless processing on large active area of several \(cm^2\), which is difficult to achieve with solid-state devices. However, compared to silicon photodiodes, sensitivity and dynamic behavior remain a major challenge with organic sensors. Here, we show that charge trapping phenomena deteriorate the bandwidth of organic photodiodes (OPDs) to a few Hz at low-light levels. We demonstrate that, despite the large OPD capacitances of similar to 10 nF \(cm^{-2}\), a frequency response in the kHz regime can be achieved at light levels as low as 20 nW \(cm^{-2}\) by appropriate interface engineering, which corresponds to a 1000-fold increase compared to state-of-the-art OPDs. Such device characteristics indicate that large active area OPDs are suitable for industrial sensing and even match medical requirements for single X-ray pulse detection in the millisecond range. KW - ultrafast photonics KW - materials for optics KW - electrical and electronic engineering KW - polymers Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131507 VL - 3 ER - TY - JOUR A1 - Klein, Diana A1 - Benchellal, Mohamed A1 - Kleff, Veronika A1 - Jakob, Heinz Günther A1 - Ergün, Süleyman T1 - Hox genes are involved in vascular wall-resident multipotent stem cell differentiation into smooth muscle cells JF - Scientific Reports N2 - Human vascular wall-resident CD44+ multipotent stem cells (VW-MPSCs) within the vascular adventitia are capable to differentiate into pericytes and smooth muscle cells (SMC). This study demonstrates HOX-dependent differentiation of CD44(+) VW-MPSCs into SMC that involves epigenetic modification of transgelin as a down-stream regulated gene. First, HOXB7, HOXC6 and HOXC8 were identified to be differentially expressed in VW-MPSCs as compared to terminal differentiated human aortic SMC, endothelial cells and undifferentiated pluripotent embryonic stem cells. Silencing these HOX genes in VW-MPSCs significantly reduced their sprouting capacity and increased expression of the SMC markers transgelin and calponin and the histone gene histone H1. Furthermore, the methylation pattern of the TAGLN promoter was altered. In summary, our findings suggest a role for certain HOX genes in regulating differentiation of human VW-MPSC into SMCs that involves epigenetic mechanisms. This is critical for understanding VW-MPSC-dependent vascular disease processes such as neointima formation and tumor vascularization. KW - expression KW - histone H1 KW - progenitor cells KW - probe level data KW - mesenchymal stromal cells KW - in vitro KW - DNA methylation KW - homebox genes KW - chromatin KW - adventitia Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131496 VL - 3 IS - 2178 ER - TY - JOUR A1 - Gerszten, Peter C. A1 - Sahgal, Arjun A1 - Sheehan, Jason P. A1 - Kersh, Ronald A1 - Chen, Stephanie A1 - Flickinger, John C. A1 - Quader, Mubina A1 - Fahim, Daniel A1 - Grills, Inga A1 - Shin, John H. A1 - Winey, Brian A1 - Oh, Kevin A1 - Sweeney, Reinhart A. A1 - Guckenberger, Matthias T1 - A multi-national report on methods for institutional credentialing for spine radiosurgery JF - Radiation Oncology N2 - Background: Stereotactic body radiotherapy and radiosurgery are rapidly emerging treatment options for both malignant and benign spine tumors. Proper institutional credentialing by physicians and medical physicists as well as other personnel is important for the safe and effective adoption of spine radiosurgery. This article describes the methods for institutional credentialing for spine radiosurgery at seven highly experienced international institutions. Methods: All institutions (n = 7) are members of the Elekta Spine Radiosurgery Research Consortium and have a dedicated research and clinical focus on image-guided spine radiosurgery. A questionnaire consisting of 24 items covering various aspects of institutional credentialing for spine radiosurgery was completed by all seven institutions. Results: Close agreement was observed in most aspects of spine radiosurgery credentialing at each institution. A formal credentialing process was believed to be important for the implementation of a new spine radiosurgery program, for patient safety and clinical outcomes. One institution has a written policy specific for spine radiosurgery credentialing, but all have an undocumented credentialing system in place. All institutions rely upon an in-house proctoring system for the training of both physicians and medical physicists. Four institutions require physicians and medical physicists to attend corporate sponsored training. Two of these 4 institutions also require attendance at a non-corporate sponsored academic society radiosurgery course. Corporate as well as non-corporate sponsored training were believed to be complimentary and both important for training. In 5 centers, all cases must be reviewed at a multidisciplinary conference prior to radiosurgery treatment. At 3 centers, neurosurgeons are not required to be involved in all cases if there is no evidence for instability or spinal cord compression. Backup physicians and physicists are required at only 1 institution, but all institutions have more than one specialist trained to perform spine radiosurgery. All centers believed that credentialing should also be device specific, and all believed that professional societies should formulate guidelines for institutions on the requirements for spine radiosurgery credentialing. Finally, in 4 institutions radiation therapists were required to attend corporate-sponsored device specific training for credentialing, and in only 1 institution were radiation therapists required to also attend academic society training for credentialing. Conclusions: This study represents the first multi-national report of the current practice of institutional credentialing for spine radiosurgery. Key methodologies for safe implementation and credentialing of spine radiosurgery have been identified. There is strong agreement among experienced centers that credentialing is an important component of the safe and effective implementation of a spine radiosurgery program. KW - cyberknife radiosurgery KW - advanced technology KW - conformal radiotherapy KW - clinical trials KW - quality assurance KW - credentialing KW - spine tumors KW - stereotactic body radiotherapy KW - spine Radiosurgery KW - paraspinal tumors KW - intensity modulated radiotherapy KW - ACR practice guidelines KW - radiation therapy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131485 VL - 8 IS - 158 ER - TY - JOUR A1 - Muranyi, Walter A1 - Malkusch, Sebastian A1 - Müller, Barbara A1 - Heilemann, Mike A1 - Kräusslich, Hans-Georg T1 - Super-Resolution Microscopy Reveals Specific Recruitment of HIV-1 Envelope Proteins to Viral Assembly Sites Dependent on the Envelope C-Terminal Tail JF - PLoS Pathogens N2 - The inner structural Gag proteins and the envelope (Env) glycoproteins of human immunodeficiency virus (HIV-1) traffic independently to the plasma membrane, where they assemble the nascent virion. HIV-1 carries a relatively low number of glycoproteins in its membrane, and the mechanism of Env recruitment and virus incorporation is incompletely understood. We employed dual-color super-resolution microscopy visualizing Gag assembly sites and HIV-1 Env proteins in virus-producing and in Env expressing cells. Distinctive HIV-1 Gag assembly sites were readily detected and were associated with Env clusters that always extended beyond the actual Gag assembly site and often showed enrichment at the periphery and surrounding the assembly site. Formation of these Env clusters depended on the presence of other HIV-1 proteins and on the long cytoplasmic tail (CT) of Env. CT deletion, a matrix mutation affecting Env incorporation or Env expression in the absence of other HIV-1 proteins led to much smaller Env clusters, which were not enriched at viral assembly sites. These results show that Env is recruited to HIV-1 assembly sites in a CT-dependent manner, while Env\((\Delta CT)\) appears to be randomly incorporated. The observed Env accumulation surrounding Gag assemblies, with a lower density on the actual bud, could facilitate viral spread in vivo. Keeping Env molecules on the nascent virus low may be important for escape from the humoral immune response, while cell-cell contacts mediated by surrounding Env molecules could promote HIV-1 transmission through the virological synapse. KW - ENV KW - fluorescent-probes KW - type-1 matrix KW - glycoprotein incorporation KW - GP41 cytoplasmic tail KW - human immunodeficiency virus KW - cellular proteins KW - plasma membrane KW - virions KW - particles Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131235 VL - 9 IS - 2 ER - TY - JOUR A1 - Rodrigues, Lénia A1 - Popov, Nikita A1 - Kaye, Kenneth M. A1 - Simas, J. Pedro T1 - Stabilization of Myc through Heterotypic Poly-Ubiquitination by mLANA Is Critical for \(\gamma\)-Herpesvirus Lymphoproliferation JF - PLoS PATHOGENS N2 - Host colonization by lymphotropic \(\gamma\)-herpesviruses depends critically on expansion of viral genomes in germinal center (GC) B-cells. Myc is essential for the formation and maintenance of GCs. Yet, the role of Myc in the pathogenesis of \(\gamma\)-cherpesviruses is still largely unknown. In this study, Myc was shown to be essential for the lymphotropic \(\gamma\)-herpesvirus MuHV- 4 biology as infected cells exhibited increased expression of Myc signature genes and the virus was unable to expand in Myc defficient GC B- cells. We describe a novel strategy of a viral protein activating Myc through increased protein stability resulting in increased progression through the cell cycle. This is acomplished by modulating a physiological posttranslational regulatory pathway of Myc. The molecular mechanism involves Myc heterotypic poly- ubiquitination mediated via the viral E3 ubiquitin- ligase mLANA protein. \(EC_5S^{mLANA}\) modulates cellular control of Myc turnover by antagonizing \(SCF^{Fbw7}\) mediated proteasomal degradation of Myc, mimicking \(SCF^{\beta-TrCP}\). The findings here reported reveal that modulation of Myc is essential for \(\gamma\)-herpesvirus persistent infection, establishing a link between virus induced lymphoproliferation and disease. KW - latency KW - murine gammaherpesvirus 68 KW - Epstein-Barr-virus KW - C-MYC KW - nuclear antigen KW - germinal center KW - B lymphocytes KW - protein KW - cells KW - beta-TRCP Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131227 VL - 9 IS - 8 ER - TY - JOUR A1 - Moll, Karin A1 - Roces, Flavio A1 - Federle, Walter T1 - How Load-Carrying Ants Avoid Falling Over: Mechanical Stability during Foraging in Atta vollenweideri Grass-Cutting Ants JF - PLoS ONE N2 - Background: Foraging workers of grass-cutting ants (Atta vollenweideri) regularly carry grass fragments larger than their Fragment length has been shown to influence the ants' running speed and thereby the colony's food intake rate. We investigated whether and how grass-cutting ants maintain stability when carrying fragments of two different lengths but identical mass. Principal Findings: Ants carried all fragments in an upright, backwards-tilted position, but held long fragments more vertically than short ones. All carrying ants used an alternating tripod gait, where mechanical stability was increased by overlapping stance phases of consecutive steps. The overlap was greatest for ants carrying long fragments, resulting in more legs contacting the ground simultaneously. For all ants, the projection of the total centre of mass (ant and fragment) was often outside the supporting tripod, i.e. the three feet that would be in stance for a non-overlapping tripod gait. Stability was only achieved through additional legs in ground contact. Tripod stability (quantified as the minimum distance of the centre of mass to the edge of the supporting tripod) was significantly smaller for ants with long fragments. Here, tripod stability was lowest at the beginning of each step, when the center of mass was near the posterior margin of the supporting tripod. By contrast, tripod stability was lowest at the end of each step for ants carrying short fragments. Consistently, ants with long fragments mainly fell backwards, whereas ants carrying short fragments mainly fell forwards or to the side. Assuming that transporting ants adjust neither the fragment angle nor the gait, they would be less stable and more likely to fall over. Conclusions: In grass-cutting ants, the need to maintain static stability when carrying long grass fragments has led to multiple kinematic adjustments at the expense of a reduced material transport rate. KW - selection KW - tissue transport KW - stepping patterns KW - size determination KW - leaf-cutter ants KW - locomotion KW - distance KW - formicidae KW - strategies KW - cephalotes Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131211 VL - 8 IS - 1 ER - TY - JOUR A1 - Wolf, Annette A1 - Akrap, Nina A1 - Marg, Berenice A1 - Galliardt, Helena A1 - Heiligentag, Martyna A1 - Humpert, Fabian A1 - Sauer, Markus A1 - Kaltschmidt, Barbara A1 - Kaltschmidt, Christian A1 - Seidel, Thorsten T1 - Elements of Transcriptional Machinery Are Compatible among Plants and Mammals JF - PLoS ONE N2 - In the present work, the objective has been to analyse the compatibility of plant and human transcriptional machinery. The experiments revealed that nuclear import and export are conserved among plants and mammals. Further it has been shown that transactivation of a human promoter occurs by human transcription factor NF-\(\kappa\) B in plant cells, demonstrating that the transcriptional machinery is highly conserved in both kingdoms. Functionality was also seen for regulatory elements of NF-\(\kappa\) B such as its inhibitor I\(\kappa\)B isoform \(\alpha\) that negatively regulated the transactivation activity of the p50/RelA heterodimer by interaction with NF-\(\kappa\)B in plant cells. Nuclear export of RelA could be demonstrated by FRAP-measurements so that RelA shows nucleo-cytoplasmic shuttling as reported for RelA in mammalian cells. The data reveals the high level of compatibility of human transcriptional elements with the plant transcriptional machinery. Thus, Arabidopsis thaliana mesophyll protoplasts might provide a new heterologous expression system for the investigation of the human NF-\(\kappa\)B signaling pathways. The system successfully enabled the controlled manipulation of NF-\(\kappa\)B activity. We suggest the plant protoplast system as a tool for reconstitution and analyses of mammalian pathways and for direct observation of responses to e. g. pharmaceuticals. The major advantage of the system is the absence of interference with endogenous factors that affect and crosstalk with the pathway. KW - complexes KW - in vivo KW - DNA-binding KW - nuclear proe KW - gene expression KW - NF-KAPPA-B KW - RNA-binding protein KW - alpha KW - inflammation KW - homodimers Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131203 VL - 8 IS - 1 ER - TY - JOUR A1 - Hartlieb, Eva A1 - Kempf, Bettina A1 - Partilla, Miriam A1 - Vigh, Balázs A1 - Spindler, Volker A1 - Waschke, Jens T1 - Desmoglein 2 Is Less Important than Desmoglein 3 for Keratinocyte Cohesion JF - PLoS ONE N2 - Desmosomes provide intercellular adhesive strength required for integrity of epithelial and some non-epithelial tissues. Within the epidermis, the cadherin-type adhesion molecules desmoglein (Dsg) 1-4 and desmocollin (Dsc) 1-3 build the adhesive core of desmosomes. In keratinocytes, several isoforms of these proteins are co-expressed. However, the contribution of specific isoforms to overall cell cohesion is unclear. Therefore, in this study we investigated the roles of Dsg2 and Dsg3, the latter of which is known to be essential for keratinocyte adhesion based on its autoantibody-induced loss of function in the autoimmune blistering skin disease pemphigus vulgaris (PV). The pathogenic PV antibody AK23, targeting the Dsg3 adhesive domain, led to profound loss of cell cohesion in human keratinocytes as revealed by the dispase-based dissociation assays. In contrast, an antibody against Dsg2 had no effect on cell cohesion although the Dsg2 antibody was demonstrated to interfere with Dsg2 transinteraction by single molecule atomic force microscopy and was effective to reduce cell cohesion in intestinal epithelial Caco-2 cells which express Dsg2 as the only Dsg isoform. To substantiate these findings, siRNA-mediated silencing of Dsg2 or Dsg3 was performed in keratinocytes. In contrast to Dsg3-depleted cells, Dsg2 knockdown reduced cell cohesion only under conditions of increased shear. These experiments indicate that specific desmosomal cadherins contribute differently to keratinocyte cohesion and that Dsg2 compared to Dsg3 is less important in this context. KW - expression KW - inhibition KW - DSG2 KW - cell adhesion KW - desmosomal cadherins KW - pemphigus vulgaris KW - phenotype KW - mice KW - transinteraction KW - reorganization Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131192 VL - 8 IS - 1 ER - TY - JOUR A1 - Dmochewitz, Lydia A1 - Förtsch, Christina A1 - Zwerger, Christian A1 - Vaeth, Martin A1 - Felder, Edward A1 - Huber-Lang, Markus A1 - Barth, Holger T1 - A Recombinant Fusion Toxin Based on Enzymatic Inactive C3bot1 Selectively Targets Macrophages JF - PLoS ONE N2 - Background: The C3bot1 protein (~23 kDa) from Clostridium botulinum ADP-ribosylates and thereby inactivates Rho. C3bot1 is selectively taken up into the cytosol of monocytes/macrophages but not of other cell types such as epithelial cells or fibroblasts. Most likely, the internalization occurs by a specific endocytotic pathway via acidified endosomes. Methodology/Principal Findings: Here, we tested whether enzymatic inactive C3bot1E174Q serves as a macrophage-selective transport system for delivery of enzymatic active proteins into the cytosol of such cells. Having confirmed that C3bot1E174Q does not induce macrophage activation, we used the actin ADP-ribosylating C2I (~50 kDa) from Clostridium botulinum as a reporter enzyme for C3bot1E174Q-mediated delivery into macrophages. The recombinant C3bot1E174Q-C2I fusion toxin was cloned and expressed as GST-protein in Escherichia coli. Purified C3bot1E174Q-C2I was recognized by antibodies against C2I and C3bot and showed C2I-specific enzyme activity in vitro. When applied to cultured cells C3bot1E174Q-C2I ADP-ribosylated actin in the cytosol of macrophages including J774A.1 and RAW264.7 cell lines as well as primary cultured human macrophages but not of epithelial cells. Together with confocal fluorescence microscopy experiments, the biochemical data indicate the selective uptake of a recombinant C3-fusion toxin into the cytosol of macrophages. Conclusions/Significance: In summary, we demonstrated that C3bot1E174Q can be used as a delivery system for fast, selective and specific transport of enzymes into the cytosol of living macrophages. Therefore, C3-based fusion toxins can represent valuable molecular tools in experimental macrophage pharmacology and cell biology as well as attractive candidates to develop new therapeutic approaches against macrophage-associated diseases. KW - C3 KW - mammalian cells KW - clostridium botulinum KW - ADP-ribosylation toxins KW - botulinum C2 toxin KW - membrane translocation KW - bacterial toxins KW - actin filaments KW - cellular uptake KW - ribosyltransferase Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131189 VL - 8 IS - 1 ER - TY - JOUR A1 - Aistleitner, Karin A1 - Heinz, Christian A1 - Hoermann, Alexandra A1 - Heinz, Eva A1 - Montanaro, Jacqueline A1 - Schulz, Frederik A1 - Maier, Elke A1 - Pichler, Peter A1 - Benz, Roland A1 - Horn, Matthias T1 - Identification and Characterization of a Novel Porin Family Highlights a Major Difference in the Outer Membrane of Chlamydial Symbionts and Pathogens JF - PLoS ONE N2 - The Chlamydiae constitute an evolutionary well separated group of intracellular bacteria comprising important pathogens of humans as well as symbionts of protozoa. The amoeba symbiont Protochlamydia amoebophila lacks a homologue of the most abundant outer membrane protein of the Chlamydiaceae, the major outer membrane protein MOMP, highlighting a major difference between environmental chlamydiae and their pathogenic counterparts. We recently identified a novel family of putative porins encoded in the genome of P. amoebophila by in silico analysis. Two of these Protochlamydia outer membrane proteins, PomS (pc1489) and PomT (pc1077), are highly abundant in outer membrane preparations of this organism. Here we show that all four members of this putative porin family are toxic when expressed in the heterologous host Escherichia coli. Immunofluorescence analysis using antibodies against heterologously expressed PomT and PomS purified directly from elementary bodies, respectively, demonstrated the location of both proteins in the outer membrane of P. amoebophila. The location of the most abundant protein PomS was further confirmed by immuno-transmission electron microscopy. We could show that pomS is transcribed, and the corresponding protein is present in the outer membrane throughout the complete developmental cycle, suggesting an essential role for P. amoebophila. Lipid bilayer measurements demonstrated that PomS functions as a porin with anion-selectivity and a pore size similar to the Chlamydiaceae MOMP. Taken together, our results suggest that PomS, possibly in concert with PomT and other members of this porin family, is the functional equivalent of MOMP in P. amoebophila. This work contributes to our understanding of the adaptations of symbiotic and pathogenic chlamydiae to their different eukaryotic hosts. KW - cell wall KW - protochlamydia amoebophila KW - escherichia coli KW - matrix protein porin KW - gram negative bacteria KW - single channel analysis KW - developmental cycle KW - mycobacterium smegmatis KW - monoclonal antibodies KW - signal peptides Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131176 VL - 8 IS - 1 ER - TY - JOUR A1 - Becker, Svetlana A1 - Oelschlaeger, Tobias A. A1 - Wullaert, Andy A1 - Pasparakis, Manolis A1 - Wehkamp, Jan A1 - Stange, Eduard F. A1 - Gersemann, Michael T1 - Bacteria Regulate Intestinal Epithelial Cell Differentiation Factors Both In Vitro and In Vivo JF - PLoS ONE N2 - Background: The human colon harbours a plethora of bacteria known to broadly impact on mucosal metabolism and function and thought to be involved in inflammatory bowel disease pathogenesis and colon cancer development. In this report, we investigated the effect of colonic bacteria on epithelial cell differentiation factors in vitro and in vivo. As key transcription factors we focused on Hes1, known to direct towards an absorptive cell fate, Hath1 and KLF4, which govern goblet cell. Methods: Expression of the transcription factors Hes1, Hath1 and KLF4, the mucins Muc1 and Muc2 and the defensin HBD2 were measured by real-time PCR in LS174T cells following incubation with several heat-inactivated E. coli strains, including the probiotic E. coli Nissle 1917+/- flagellin, Lactobacilli and Bifidobacteria. For protein detection Western blot experiments and chamber-slide immunostaining were performed. Finally, mRNA and protein expression of these factors was evaluated in the colon of germfree vs. specific pathogen free vs. conventionalized mice and colonic goblet cells were counted. Results: Expression of Hes1 and Hath1, and to a minor degree also of KLF4, was reduced by E. coli K-12 and E. coli Nissle 1917. In contrast, Muc1 and HBD2 expression were significantly enhanced, independent of the Notch signalling pathway. Probiotic E. coli Nissle 1917 regulated Hes1, Hath1, Muc1 and HBD2 through flagellin. In vivo experiments confirmed the observed in vitro effects of bacteria by a diminished colonic expression of Hath1 and KLF4 in specific pathogen free and conventionalized mice as compared to germ free mice whereas the number of goblet cells was unchanged in these mice. Conclusions: Intestinal bacteria influence the intestinal epithelial differentiation factors Hes1, Hath1 and KLF4, as well as Muc1 and HBD2, in vitro and in vivo. The induction of Muc1 and HBD2 seems to be triggered directly by bacteria and not by Notch. KW - stem cells KW - inflammatory-bowel-disease KW - Ileal Crohns-disease KW - coli nissel 1917 KW - ulcreative colitis KW - escherichia coli KW - porphyromonas gingivalis KW - antimicrobial peptides KW - colorectal cancer KW - alpha defensins Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131168 VL - 8 IS - 2 ER - TY - JOUR A1 - De Giorgi, Valeria A1 - Buonaguro, Luigi A1 - Worschech, Andrea A1 - Tornesello, Maria Lina A1 - Izzo, Francesco A1 - Marincola, Francesco M. A1 - Wang, Ena A1 - Buonaguro, Franco M. T1 - Molecular Signatures Associated with HCV-Induced Hepatocellular Carcinoma and Liver Metastasis JF - PLoS ONE N2 - Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV) infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis. Conclusions: A diagnostic molecular signature complementing conventional pathologic assessment was identified. KW - identification KW - hepatitis C virus KW - United States KW - gene expression KW - class I KW - endoplasmic reticulum KW - motile phenotype KW - bladder cancer KW - up-regulation KW - target Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131155 VL - 8 IS - 2 ER - TY - JOUR A1 - Koch, Oliver A1 - Cappel, Daniel A1 - Nocker, Monika A1 - Jäger, Timo A1 - Flohé, Leopold A1 - Sotriffer, Christoph A. A1 - Selzer, Paul M. T1 - Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase JF - PLoS ONE N2 - The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two \(Mg^{2+}\) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows \(N^1\)-glutathionylation of \(N^8\)-glutathionylspermidine, classifying \(N^8\)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for \(N^8\)-glutathionylspermidine was characterised as druggable. KW - purification KW - crithidia fasciulata KW - trypanosoma cruzi KW - RESP model KW - biosynthesis KW - chemotherapy KW - metabolism KW - brucei KW - system KW - leishmaniasis Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131070 VL - 8 IS - 2 ER - TY - JOUR A1 - Kato, Hiroki A1 - Lu, Qiping A1 - Rapaport, Doron A1 - Kozjak-Pavlovic, Vera T1 - Tom70 Is Essential for PINK1 Import into Mitochondria JF - PLoS ONE N2 - PTEN induced kinase 1 (PINK1) is a serine/threonine kinase in the outer membrane of mitochondria (OMM), and known as a responsible gene of Parkinson's disease (PD). The precursor of PINK1 is synthesized in the cytosol and then imported into the mitochondria via the translocase of the OMM (TOM) complex. However, a large part of PINK1 import mechanism remains unclear. In this study, we examined using cell-free system the mechanism by which PINK1 is targeted to and assembled into mitochondria. Surprisingly, the main component of the import channel, Tom40 was not necessary for PINK1 import. Furthermore, we revealed that the import receptor Tom70 is essential for PINK1 import. In addition, we observed that although PINK1 has predicted mitochondrial targeting signal, it was not processed by the mitochondrial processing peptidase. Thus, our results suggest that PINK1 is imported into mitochondria by a unique pathway that is independent of the TOM core complex but crucially depends on the import receptor Tom70. KW - binding KW - outer-membrane proteins KW - Parkinsons diesease KW - intracellular membranes KW - quality control KW - pathway KW - recruitment KW - biogenesis KW - mechanisms KW - complex Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131061 VL - 8 IS - 3 ER - TY - JOUR A1 - Hahn, Tim A1 - Dresler, Thomas A1 - Pyka, Martin A1 - Notebaert, Karolien A1 - Fallgatter, Andreas J. T1 - Local Synchronization of Resting-State Dynamics Encodes Gray's Trait Anxiety JF - PLoS ONE N2 - The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Gray's trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Gray's trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Gray's trait Anxiety explained 23% and 17% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Gray's trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Gray's BIS. KW - reward KW - bold activity KW - amygdala KW - brain KW - personality KW - sensitivity KW - punishment KW - dimensions KW - modulation KW - predict Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131057 VL - 8 IS - 3 ER - TY - JOUR A1 - Hohoff, Christa A1 - Gorji, Ali A1 - Kaiser, Sylvia A1 - Willscher, Edith A1 - Korsching, Eberhard A1 - Ambrée, Oliver A1 - Arolt, Volker A1 - Lesch, Klaus-Peter A1 - Sachser, Norbert A1 - Deckert, Jürgen A1 - Lewejohann, Lars T1 - Effect of Acute Stressor and Serotonin Transporter Genotype on Amygdala First Wave Transcriptome in Mice JF - PLoS ONE N2 - The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans. KW - plasticity KW - corticotropin releasing factor KW - primary response genes KW - spatial memory KW - knockout mice KW - rat brain KW - in vivo KW - expression KW - anxiety KW - emotion Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131040 VL - 8 IS - 3 ER - TY - JOUR A1 - Yan, Yan A1 - Hong, Ni A1 - Chen, Tiansheng A1 - Li, Mingyou A1 - Wang, Tiansu A1 - Guan, Guijun A1 - Qiao, Yongkang A1 - Chen, Songlin A1 - Schartl, Manfred A1 - Li, Chang-Ming A1 - Hong, Yunhan T1 - p53 Gene Targeting by Homologous Recombination in Fish ES Cells JF - PLoS One N2 - Background: Gene targeting (GT) provides a powerful tool for the generation of precise genetic alterations in embryonic stem (ES) cells to elucidate gene function and create animal models for human diseases. This technology has, however, been limited to mouse and rat. We have previously established ES cell lines and procedures for gene transfer and selection for homologous recombination (HR) events in the fish medaka (Oryzias latipes). Methodology and Principal Findings: Here we report HR-mediated GT in this organism. We designed a GT vector to disrupt the tumor suppressor gene p53 (also known as tp53). We show that all the three medaka ES cell lines, MES1 similar to MES3, are highly proficient for HR, as they produced detectable HR without drug selection. Furthermore, the positive-negative selection (PNS) procedure enhanced HR by similar to 12 folds. Out of 39 PNS-resistant colonies analyzed, 19 (48.7%) were positive for GT by PCR genotyping. When 11 of the PCR-positive colonies were further analyzed, 6 (54.5%) were found to be bona fide homologous recombinants by Southern blot analysis, sequencing and fluorescent in situ hybridization. This produces a high efficiency of up to 26.6% for p53 GT under PNS conditions. We show that p53 disruption and long-term propagation under drug selection conditions do not compromise the pluripotency, as p53-targeted ES cells retained stable growth, undifferentiated phenotype, pluripotency gene expression profile and differentiation potential in vitro and in vivo. Conclusions: Our results demonstrate that medaka ES cells are proficient for HR-mediated GT, offering a first model organism of lower vertebrates towards the development of full ES cell-based GT technology. KW - mouse KW - in-vitro KW - drug selection KW - chimera formation KW - medakafish oryzias latipes KW - embryonic stem-cells KW - zebrafish KW - differentiation KW - cultures KW - pluripotency Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133416 VL - 8 IS - 3 ER - TY - JOUR A1 - Hendriksma, Harmen P. A1 - Küting, Meike A1 - Härtel, Stephan A1 - Näther, Astrid A1 - Dohrmann, Anja B. A1 - Steffan-Dewenter, Ingolf A1 - Tebbe, Christoph C. T1 - Effect of Stacked Insecticidal Cry Proteins from Maize Pollen on Nurse Bees (Apis mellifera carnica) and Their Gut Bacteria JF - PLoS ONE N2 - Honey bee pollination is a key ecosystem service to nature and agriculture. However, biosafety research on genetically modified crops rarely considers effects on nurse bees from intact colonies, even though they receive and primarily process the largest amount of pollen. The objective of this study was to analyze the response of nurse bees and their gut bacteria to pollen from Bt maize expressing three different insecticidal Cry proteins (Cry1A.105, Cry2Ab2, and Cry3Bb1). Naturally Cry proteins are produced by bacteria (Bacillus thuringiensis). Colonies of Apis mellifera carnica were kept during anthesis in flight cages on field plots with the Bt maize, two different conventionally bred maize varieties, and without cages, 1-km outside of the experimental maize field to allow ad libitum foraging to mixed pollen sources. During their 10-days life span, the consumption of Bt maize pollen had no effect on their survival rate, body weight and rates of pollen digestion compared to the conventional maize varieties. As indicated by ELISA-quantification of Cry1A.105 and Cry3Bb1, more than 98% of the recombinant proteins were degraded. Bacterial population sizes in the gut were not affected by the genetic modification. Bt-maize, conventional varieties and mixed pollen sources selected for significantly different bacterial communities which were, however, composed of the same dominant members, including Proteobacteria in the midgut and Lactobacillus sp. and Bifidobacterium sp. in the hindgut. Surprisingly, Cry proteins from natural sources, most likely B. thuringiensis, were detected in bees with no exposure to Bt maize. The natural occurrence of Cry proteins and the lack of detectable effects on nurse bees and their gut bacteria give no indication for harmful effects of this Bt maize on nurse honey bees. KW - communities KW - 16S ribosomal-RNA KW - T-RFLP analysis KW - honey bees KW - bacillus thuringiensis KW - risk assessment KW - multivariate analyses KW - worker honeybees KW - corn pollen KW - larvae Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131025 VL - 8 IS - 3 ER - TY - JOUR A1 - Capra, Valérie A1 - Busnelli, Marta A1 - Perenna, Alessandro A1 - Ambrosio, Manuela A1 - Accomazzo, Maria Rosa A1 - Galés, Celine A1 - Chini, Bice A1 - Rovati, G. Enrico T1 - Full and Partial Agonists of Thromboxane Prostanoid Receptor Unveil Fine Tuning of Receptor Superactive Conformation and G Protein Activation JF - PLoS ONE N2 - The intrahelical salt bridge between \(E/D^{3.49}\) and \(R^{3.50}\) within the E/DRY motif on helix 3 (H3) and the interhelical hydrogen bonding between the E/DRY and residues on H6 are thought to be critical in stabilizing the class A G protein-coupled receptors in their inactive state. Removal of these interactions is expected to generate constitutively active receptors. This study examines how neutralization of \(E^{3.49/6.30}\) in the thromboxane prostanoid (TP) receptor alters ligand binding, basal, and agonist-induced activity and investigates the molecular mechanisms of G protein activation. We demonstrate here that a panel of full and partial agonists showed an increase in affinity and potency for E129V and E240V mutants. Yet, even augmenting the sensitivity to detect constitutive activity (CA) with overexpression of the receptor or the G protein revealed resistance to an increase in basal activity, while retaining fully the ability to cause agonist-induced signaling. However, direct G protein activation measured through bioluminescence resonance energy transfer (BRET) indicates that these mutants more efficiently communicate and/or activate their cognate G proteins. These results suggest the existence of additional constrains governing the shift of TP receptor to its active state, together with an increase propensity of these mutants to agonist-induced signaling, corroborating their definition as superactive mutants. The particular nature of the TP receptor as somehow "resistant" to CA should be examined in the context of its pathophysiological role in the cardiovascular system. Evolutionary forces may have favored regulation mechanisms leading to low basal activity and selected against more highly active phenotypes. KW - coupled receptor KW - ligand binding KW - intracellular loop KW - molecular dynamics KW - Beta(1)-adrenergic receptor KW - ionic look KW - Beta(2)-adrenergic receptor KW - crystal structure KW - constitutive activity Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131013 VL - 8 IS - 3 ER - TY - JOUR A1 - Palige, Katja A1 - Linde, Jörg A1 - Martin, Ronny A1 - Böttcher, Bettina A1 - Citiulo, Francesco A1 - Sullivan, Derek J. A1 - Weber, Johann A1 - Staib, Claudia A1 - Rupp, Steffen A1 - Hube, Bernhard A1 - Morschhäuser, Joachim A1 - Staib, Peter T1 - Global Transcriptome Sequencing Identifies Chlamydospore Specific Markers in Candida albicans and Candida dubliniensis JF - PLoS ONE N2 - Candida albicans and Candida dubliniensis are pathogenic fungi that are highly related but differ in virulence and in some phenotypic traits. During in vitro growth on certain nutrient-poor media, C. albicans and C. dubliniensis are the only yeast species which are able to produce chlamydospores, large thick-walled cells of unknown function. Interestingly, only C. dubliniensis forms pseudohyphae with abundant chlamydospores when grown on Staib medium, while C. albicans grows exclusively as a budding yeast. In order to further our understanding of chlamydospore development and assembly, we compared the global transcriptional profile of both species during growth in liquid Staib medium by RNA sequencing. We also included a C. albicans mutant in our study which lacks the morphogenetic transcriptional repressor Nrg1. This strain, which is characterized by its constitutive pseudohyphal growth, specifically produces masses of chlamydospores in Staib medium, similar to C. dubliniensis. This comparative approach identified a set of putatively chlamydospore-related genes. Two of the homologous C. albicans and C. dubliniensis genes (CSP1 and CSP2) which were most strongly upregulated during chlamydospore development were analysed in more detail. By use of the green fluorescent protein as a reporter, the encoded putative cell wall related proteins were found to exclusively localize to C. albicans and C. dubliniensis chlamydospores. Our findings uncover the first chlamydospore specific markers in Candida species and provide novel insights in the complex morphogenetic development of these important fungal pathogens. KW - NRG1 KW - staib agar KW - gene KW - morphogenesis KW - expression KW - regulator KW - virulence KW - growth KW - UME6 KW - epidemiology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131007 VL - 8 IS - 4 ER - TY - JOUR A1 - Forconi, Mariko A1 - Canapa, Adriana A1 - Barucca, Marco A1 - Biscotti, Maria A. A1 - Capriglione, Teresa A1 - Buonocore, Francesco A1 - Fausto, Anna M. A1 - Makapedua, Daisy M. A1 - Pallavicini, Alberto A1 - Gerdol, Marco A1 - De Moro, Gianluca A1 - Scapigliati, Giuseppe A1 - Olmo, Ettore A1 - Schartl, Manfred T1 - Characterization of Sex Determination and Sex Differentiation Genes in Latimeria JF - PLoS ONE N2 - Genes involved in sex determination and differentiation have been identified in mice, humans, chickens, reptiles, amphibians and teleost fishes. However, little is known of their functional conservation, and it is unclear whether there is a common set of genes shared by all vertebrates. Coelacanths, basal Sarcopterygians and unique "living fossils", could help establish an inventory of the ancestral genes involved in these important developmental processes and provide insights into their components. In this study 33 genes from the genome of Latimeria chalumnae and from the liver and testis transcriptomes of Latimeria menadoensis, implicated in sex determination and differentiation, were identified and characterized and their expression levels measured. Interesting findings were obtained for GSDF, previously identified only in teleosts and now characterized for the first time in the sarcopterygian lineage; FGF9, which is not found in teleosts; and DMRT1, whose expression in adult gonads has recently been related to maintenance of sexual identity. The gene repertoire and testis-specific gene expression documented in coelacanths demonstrate a greater similarity to modern fishes and point to unexpected changes in the gene regulatory network governing sexual development. KW - medaka fish KW - mullerian hormone AMH KW - DM-domain gene KW - oryzias latipes KW - monodelphis domestica KW - oreochromis niloticus KW - dimorphic expression KW - molecular mechanisms KW - genomic organization KW - regulatory regions Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130995 VL - 8 IS - 4 ER - TY - JOUR A1 - van Dinther, Maarten A1 - Zhang, Juan A1 - Weidauer, Stella E. A1 - Boschert, Verena A1 - Muth, Eva-Maria A1 - Knappik, Achim A1 - de Gorter, David J. J. A1 - van Kasteren, Puck B. A1 - Frisch, Christian A1 - Müller, Thomas D. A1 - ten Dijke, Peter T1 - Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling JF - PLoS ONE N2 - Sclerosteosis is a rare high bone mass disease that is caused by inactivating mutations in the SOST gene. Its gene product, Sclerostin, is a key negative regulator of bone formation and might therefore serve as a target for the anabolic treatment of osteoporosis. The exact molecular mechanism by which Sclerostin exerts its antagonistic effects on Wnt signaling in bone forming osteoblasts remains unclear. Here we show that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6. Unlike Dickkopf1 (DKK1), Sclerostin does not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with \([^{125} I]\) Sclerostin identified LRP6 as the main specific Sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with Sclerostin fused to recombinant green fluorescent protein (GFP) this was internalized, likely via a Clathrin-dependent process, and subsequently degraded in a temperature and proteasome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of Sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused Sclerostin. Finally, an anti-Sclerostin antibody inhibited the internalization of Sclerostin-GFP and binding of Sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of Sclerostin on canonical Wnt-induced responses. KW - gene KW - rat model KW - Dickkopf proteins KW - postmenopausal osteoporosis KW - increases bone-formation KW - WNT KW - LRP6 KW - density KW - receptor KW - ligand Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130981 VL - 8 IS - 4 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Kolleritz, Barbara A1 - Meinitzer, Andreas A1 - März, Winfried A1 - Ritz, Eberhard A1 - König, Paul A1 - Neyer, Ulrich A1 - Pilz, Stefan A1 - Wanner, Christoph A1 - Kronenberg, Florian T1 - Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study JF - PLoS ONE N2 - Background: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results: Study participants were at baseline on average 47 \(\pm\)13 years old and 65% were male. Mean \(\pm\) standard deviation of homoarginine concentrations were \(2.5 \pm 1.1 \mu mol/L\) and concentrations were incrementally lower at lower levels of GFR with mean concentrations of \(2.90 \pm 1.02 \mu mol/L\) (GFR. 90 ml/min), \(2.64 \pm 1.06 \mu mol/L\) (GFR 60-90 ml/min), \(2.52 \pm 1.24 \mu mol/L\) (GFR 30-60 ml/min) and \(2.05 \pm 0.78 \mu mol/L\) (GFR, 30 ml/min), respectively (p = 0.002). The age-and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (\(1.1 \mu mol/L\)) of homoarginine (HR 1.62, 95% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p = 0.06). Conclusions: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations. KW - risk KW - alkaline phosphatase KW - cardiovascular events KW - nictric-oxide KW - induced insulin-release KW - creatine synthesis KW - renal function KW - heart failure KW - rat kidney KW - L-arginine Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130979 VL - 8 IS - 5 ER - TY - JOUR A1 - Sporbert, Anje A1 - Cseresnyes, Zoltan A1 - Heidbreder, Meike A1 - Domaing, Petra A1 - Hauser, Stefan A1 - Kaltschmidt, Barbara A1 - Kaltschmidt, Christian A1 - Heilemann, Mike A1 - Widera, Darius T1 - Simple Method for Sub-Diffraction Resolution Imaging of Cellular Structures on Standard Confocal Microscopes by Three-Photon Absorption of Quantum Dots JF - PLoS ONE N2 - This study describes a simple technique that improves a recently developed 3D sub-diffraction imaging method based on three-photon absorption of commercially available quantum dots. The method combines imaging of biological samples via tri-exciton generation in quantum dots with deconvolution and spectral multiplexing, resulting in a novel approach for multi-color imaging of even thick biological samples at a 1.4 to 1.9-fold better spatial resolution. This approach is realized on a conventional confocal microscope equipped with standard continuous-wave lasers. We demonstrate the potential of multi-color tri-exciton imaging of quantum dots combined with deconvolution on viral vesicles in lentivirally transduced cells as well as intermediate filaments in three-dimensional clusters of mouse-derived neural stem cells (neurospheres) and dense microtubuli arrays in myotubes formed by stacks of differentiated C2C12 myoblasts. KW - HIV KW - stem-cell KW - infection Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130963 VL - 8 IS - 5 ER - TY - JOUR A1 - Scharmann, Mathias A1 - Thornham, Daniel G. A1 - Grafe, T. Ulmar A1 - Federle, Walter T1 - A Novel Type of Nutritional Ant-Plant Interaction: Ant Partners of Carnivorous Pitcher Plants Prevent Nutrient Export by Dipteran Pitcher Infauna JF - PLoS ONE N2 - Many plants combat herbivore and pathogen attack indirectly by attracting predators of their herbivores. Here we describe a novel type of insect-plant interaction where a carnivorous plant uses such an indirect defence to prevent nutrient loss to kleptoparasites. The ant Camponotus schmitzi is an obligate inhabitant of the carnivorous pitcher plant Nepenthes bicalcarata in Borneo. It has recently been suggested that this ant-plant interaction is a nutritional mutualism, but the detailed mechanisms and the origin of the ant-derived nutrient supply have remained unexplained. We confirm that N. bicalcarata host plant leaves naturally have an elevated \(^{15}N/^{14}N\) stable isotope abundance ratio (\(\delta ^{15}N\)) when colonised by C. schmitzi. This indicates that a higher proportion of the plants' nitrogen is insect-derived when C. schmitzi ants are present (ca. 100%, vs. 77% in uncolonised plants) and that more nitrogen is available to them. We demonstrated direct flux of nutrients from the ants to the host plant in a \(^{15}N\) pulse-chase experiment. As C. schmitzi ants only feed on nectar and pitcher contents of their host, the elevated foliar \(\delta ^{15}N\) cannot be explained by classic ant-feeding (myrmecotrophy) but must originate from a higher efficiency of the pitcher traps. We discovered that C. schmitzi ants not only increase the pitchers' capture efficiency by keeping the pitchers' trapping surfaces clean, but they also reduce nutrient loss from the pitchers by predating dipteran pitcher inhabitants (infauna). Consequently, nutrients the pitchers would have otherwise lost via emerging flies become available as ant colony waste. The plants' prey is therefore conserved by the ants. The interaction between C. schmitzi, N. bicalcarata and dipteran pitcher infauna represents a new type of mutualism where animals mitigate the damage by nutrient thieves to a plant. KW - community KW - alternative trapping strategies KW - leaf-litter utilization KW - nepenthes bicalcarata KW - camponotus schmitzi KW - food web KW - epiphytic fern KW - nitrogen KW - prey KW - rafflesiana Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130952 VL - 8 IS - 5 ER - TY - JOUR A1 - Kühlhorn, Franziska A1 - Rath, Matthias A1 - Schmoeckel, Katrin A1 - Cziupka, Katharina A1 - Nguyen, Huu Hung A1 - Hildebrandt, Petra A1 - Hünig, Thomas A1 - Sparwasser, Tim A1 - Huehn, Jochen A1 - Pötschke, Christian A1 - Bröker, Barbara M. T1 - \(Foxp3^+\) Regulatory T Cells Are Required for Recovery from Severe Sepsis JF - PLoS ONE N2 - The role of regulatory T cells (Tregs) in bacterial sepsis remains controversial because antibody-mediated depletion experiments gave conflicting results. We employed DEREG mice (DEpletion of REGulatory T cells) and a caecal ligation and puncture model to elucidate the role of \(CD4^+Foxp3^+\) Tregs in sepsis. In DEREG mice natural Tregs can be visualized easily and selectively depleted by diphtheria toxin because the animals express the diphtheria toxin receptor and enhanced green fluorescent protein as a fusion protein under the control of the foxp3 locus. We confirmed rapid Treg-activation and an increased ratio of Tregs to Teffs in sepsis. Nevertheless, 24 h after sepsis induction, Treg-depleted and control mice showed equally strong inflammation, immune cell immigration into the peritoneum and bacterial dissemination. During the first 36 h of disease survival was not influenced by Treg-depletion. Later, however, only Treg-competent animals recovered from the insult. We conclude that the suppressive capacity of Tregs is not sufficient to control overwhelming inflammation and early mortality, but is a prerequisite for the recovery from severe sepsis. KW - CD4(+)CD25(+) KW - toll-like receptors KW - TGF-BETA KW - mediated suppression KW - polymicrobial sepsis KW - improves survival KW - adoptive transfer KW - infected mice KW - in-vivo KW - CD4(+) Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130940 VL - 8 IS - 5 ER - TY - JOUR A1 - Hennings, Johannes M. A1 - Kohli, Martin A. A1 - Czamara, Darina A1 - Giese, Maria A1 - Eckert, Anne A1 - Wolf, Christiane A1 - Heck, Angela A1 - Domschke, Katharina A1 - Arolt, Volker A1 - Baune, Bernhard T. A1 - Horstmann, Sonja A1 - Brückl, Tanja A1 - Klengel, Torsten A1 - Menke, Andreas A1 - Müller-Myhsok, Bertram A1 - Ising, Marcus A1 - Uhr, Manfred A1 - Lucae, Susanne T1 - Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach JF - PLoS ONE N2 - Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (\(P_{corr}\) = .018, \(P_{corr}\) = .015 and \(P_{corr}\) = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies. KW - brain KW - bipolar disorder KW - mood disorder KW - treatment response KW - genome-wide association KW - major depressive disorder KW - neurotrophic factor gene KW - VAL66MET polymorphism KW - sequence variations KW - messenger RNA Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130924 VL - 8 IS - 6 ER - TY - JOUR A1 - Manchia, Mirko A1 - Adli, Mazda A1 - Akula, Nirmala A1 - Arda, Raffaella A1 - Aubry, Jean-Michel A1 - Backlund, Lena A1 - Banzato, Claudio E. M. A1 - Baune, Bernhard T. A1 - Bellivier, Frank A1 - Bengesser, Susanne A1 - Biernacka, Joanna M. A1 - Brichant-Petitjean, Clara A1 - Bui, Elise A1 - Calkin, Cynthia V. A1 - Cheng, Andrew Tai Ann A1 - Chillotti, Caterina A1 - Cichon, Sven A1 - Clark, Scott A1 - Czerski, Piotr M. A1 - Dantas, Clarissa A1 - Del Zompo, Maria A1 - DePaulo, J. Raymond A1 - Detera-Wadleigh, Sevilla D. A1 - Etain, Bruno A1 - Falkai, Peter A1 - Frisén, Louise A1 - Frye, Mark A. A1 - Fullerton, Jan A1 - Gard, Sébastien A1 - Garnham, Julie A1 - Goes, Fernando S. A1 - Grof, Paul A1 - Gruber, Oliver A1 - Hashimoto, Ryota A1 - Hauser, Joanna A1 - Heilbronner, Urs A1 - Hoban, Rebecca A1 - Hou, Liping A1 - Jamain, Stéphane A1 - Kahn, Jean-Pierre A1 - Kassem, Layla A1 - Kato, Tadafumi A1 - Kelsoe, John R. A1 - Kittel-Schneider, Sarah A1 - Kliwicki, Sebastian A1 - Kuo, Po-Hsiu A1 - Kusumi, Ichiro A1 - Laje, Gonzalo A1 - Lavebratt, Catharina A1 - Leboyer, Marion A1 - Leckband, Susan G. A1 - López Jaramillo, Carlos A. A1 - Maj, Mario A1 - Malafosse, Alain A1 - Martinsson, Lina A1 - Masui, Takuya A1 - Mitchell, Philip B. A1 - Mondimore, Frank A1 - Monteleone, Palmiero A1 - Nallet, Audrey A1 - Neuner, Maria A1 - Novák, Tomás A1 - O'Donovan, Claire A1 - Ösby, Urban A1 - Ozaki, Norio A1 - Perlis, Roy H. A1 - Pfennig, Andrea A1 - Potash, James B. A1 - Reich-Erkelenz, Daniela A1 - Reif, Andreas A1 - Reininghaus, Eva A1 - Richardson, Sara A1 - Rouleau, Guy A. A1 - Rybakowski, Janusz K. A1 - Schalling, Martin A1 - Schofield, Peter R. A1 - Schubert, Oliver K. A1 - Schweizer, Barbara A1 - Seemüller, Florian A1 - Grigoroiu-Serbanescu, Maria A1 - Severino, Giovanni A1 - Seymour, Lisa R. A1 - Slaney, Claire A1 - Smoller, Jordan W. A1 - Squassina, Alessio A1 - Stamm, Thomas A1 - Steele, Jo A1 - Stopkova, Pavla A1 - Tighe, Sarah K. A1 - Tortorella, Alfonso A1 - Turecki, Gustavo A1 - Wray, Naomi R. A1 - Wright, Adam A1 - Zandi, Peter P. A1 - Zilles, David A1 - Bauer, Michael A1 - Rietschel, Marcella A1 - McMahon, Francis J. A1 - Schulze, Thomas G. A1 - Alda, Martin T1 - Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report JF - PLoS ONE N2 - Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study. KW - age KW - observer agreement KW - prophylactic lithium KW - mapping susceptibility genes KW - mood disorders KW - onset KW - association KW - reliability KW - morality KW - illness Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130938 VL - 8 IS - 6 ER - TY - JOUR A1 - Diestel, Uschi A1 - Resch, Marcus A1 - Meinhardt, Kathrin A1 - Weiler, Sigrid A1 - Hellmann, Tina V. A1 - Mueller, Thomas D. A1 - Nickel, Joachim A1 - Eichler, Jutta A1 - Muller, Yves A. T1 - Identification of a Novel TGF-beta-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-\(\beta\)-Receptor-3 (TGFR-3) JF - PLoS ONE N2 - The zona pellucida (ZP) domain is present in extracellular proteins such as the zona pellucida proteins and tectorins and participates in the formation of polymeric protein networks. However, the ZP domain also occurs in the cytokine signaling co-receptor transforming growth factor beta (TGF-\(\beta\)) receptor type 3 (TGFR-3, also known as betaglycan) where it contributes to cytokine ligand recognition. Currently it is unclear how the ZP domain architecture enables this dual functionality. Here, we identify a novel major TGF-beta-binding site in the FG loop of the C-terminal subdomain of the murine TGFR-3 ZP domain (ZP-C) using protein crystallography, limited proteolysis experiments, surface plasmon resonance measurements and synthetic peptides. In the murine 2.7 angstrom crystal structure that we are presenting here, the FG-loop is disordered, however, well-ordered in a recently reported homologous rat ZP-C structure. Surprisingly, the adjacent external hydrophobic patch (EHP) segment is registered differently in the rat and murine structures suggesting that this segment only loosely associates with the remaining ZP-C fold. Such a flexible and temporarily-modulated association of the EHP segment with the ZP domain has been proposed to control the polymerization of ZP domain-containing proteins. Our findings suggest that this flexibility also extends to the ZP domain of TGFR-3 and might facilitate co-receptor ligand interaction and presentation via the adjacent FG-loop. This hints that a similar C-terminal region of the ZP domain architecture possibly regulates both the polymerization of extracellular matrix proteins and cytokine ligand recognition of TGFR-3. KW - coreceptor KW - receptor type III KW - growth factor beta KW - ligand binding KW - betaglycan KW - proteins KW - mutagenesis KW - polymerization KW - glycoprotein KW - superfamily Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130904 VL - 8 IS - 6 ER - TY - JOUR A1 - Zhao, Bo A1 - Zhang, Keya A1 - Bhuripanyo, Karan A1 - Choi, Chan Hee J. A1 - Villhauer, Eric B. A1 - Li, Heng A1 - Zheng, Ning A1 - Kiyokawa, Hiroaki A1 - Schindelin, Hermann A1 - Yin, Jun T1 - Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display JF - PLoS ONE N2 - The C-terminal peptides of ubiquitin (UB) and UB-like proteins (UBLs) play a key role in their recognition by the specific activating enzymes (E1s) to launch their transfer through the respective enzymatic cascades thus modifying cellular proteins. UB and Nedd8, a UBL regulating the activity of cullin-RING UB ligases, only differ by one residue at their C-termini; yet each has its specific E1 for the activation reaction. It has been reported recently that UAE can cross react with Nedd8 to enable its passage through the UB transfer cascade for protein neddylation. To elucidate differences in UB recognition by UAE and NAE, we carried out phage selection of a UB library with randomized C-terminal sequences based on the catalytic formation of UB similar to NAE thioester conjugates. Our results confirmed the previous finding that residue 72 of UB plays a "gate-keeping" role in E1 selectivity. We also found that diverse sequences flanking residue 72 at the UB C-terminus can be accommodated by NAE for activation. Furthermore heptameric peptides derived from the C-terminal sequences of UB variants selected for NAE activation can function as mimics of Nedd8 to form thioester conjugates with NAE and the downstream E2 enzyme Ubc12 in the Nedd8 transfer cascade. Once the peptides are charged onto the cascade enzymes, the full-length Nedd8 protein is effectively blocked from passing through the cascade for the critical modification of cullin. We have thus identified a new class of inhibitors of protein neddylation based on the profiles of the UB C-terminal sequences recognized by NAE. KW - protein NEDD8 KW - E1 KW - system KW - conjugation KW - pathway KW - complex KW - ligases KW - purification KW - neddylation KW - expression Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128479 SN - 1932-6203 VL - 8 IS - e70312 ER - TY - JOUR A1 - Tappe, Dennis A1 - Haeupler, Alexandra A1 - Schäfer, Hansjörg A1 - Racz, Paul A1 - Cramer, Jakob P. A1 - Poppert, Sven T1 - Armillifer armillatus Pentastomiasis in African Immigrant, Germany JF - Emerging Infectious Diseases N2 - No abstract available. Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129054 N1 - Public Domain (Source: http://wwwnc.cdc.gov/eid/page/copyright-and-disclaimers) VL - 19 IS - 3 ER - TY - JOUR A1 - Prifert, Christiane A1 - Streng, Andrea A1 - Krempl, Christine D. A1 - Liese, Johannes A1 - Weissbrich, Benedikt T1 - Novel Respiratory Syncytial Virus A Genotype, Germany, 2011-2012 JF - Emerging Infectious Diseases N2 - No abstract available. Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129041 N1 - Public Domain (Source: http://wwwnc.cdc.gov/eid/page/copyright-and-disclaimers) VL - 19 IS - 6 ER - TY - JOUR A1 - Hegemann, Peter A1 - Nagel, Georg T1 - From channelrhodopsins to optogenetics JF - EMBO Molecular Medicine N2 - We did not expect that research on the molecular mechanism of algal phototaxis or archaeal light‐driven ion transport might interest readers of a medical journal when we conceived and performed our experiments a decade ago. On the other hand, it did not escape our attention that channelrhodopsin is helping an ever‐increasing number of researchers to address their specific questions. For example, the channelrhodopsin approach is used to study the molecular events during the induction of synaptic plasticity or to map long‐range connections from one side of the brain to the other, and to map the spatial location of inputs on the dendritic tree of individual neurons. The current applications have been summarized in a number of recent reviews (Fenno et al, 2011; Yizhar et al, 2011; Zhang et al, 2011). Here, we give personal insight into the history of the discovery of channelrhodopsin and a biophysical perspective on this remarkable class of proteins that has been the main topic of our research since the 1990s. Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129036 VL - 5 IS - 2 ER - TY - JOUR A1 - Andres, Katharina T1 - 'Fashion's Final Frontier': The Correlation of Gender Roles and Fashion in Star Trek JF - Culture Unbound N2 - Since its creation in 1966, Star Trek has been a dominant part of popular culture and as thus served as the source for many cultural references. Star Trek’s creator Gene Roddenberry wanted to realize his vision of a utopia but at the same time, he used the futuristic setting of the show to comment on the present time, on actual social and political circumstances. This means that each series can be regarded as a mirror image of the time in which it was created. The clothing of the characters in the different series is one part of that image. The uniforms of The Original Se-ries show influences of the 1960s pop art movement as well as the mini-skirt trend that experienced its peak in that decade. In the course of almost 40 years, howev-er, many things changed. In the 1990s, in Deep Space Nine and Voyager, a unisex uniform replaced the mini-dresses, with few exceptions; the colorful shirts gave way to ones that were mostly black. This trend continues into the new century. This essay interprets the evolution of the female officers’ uniforms from femi-nized dresses to androgynous clothing over the development of the series as a reflection of the change of gender roles in contemporary American society. The general functions of the female characters’ uniforms are the central object of its analysis while the few, but noteworthy exceptions to this pattern are given specif-ic attention. Finally, one of the most intriguing lines of enquiry is, how the pre-quel series Enterprise, supposed to be set before The Original Series, but pro-duced and aired from 2001 to 2005, fits in the picture. KW - Star Trek KW - science fiction KW - fashion KW - women KW - 1960s KW - backlash Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128827 VL - 5 ER - TY - JOUR A1 - Fluri, Felix A1 - Heinen, Florian A1 - Kleinschnitz, Christoph T1 - Intravenous Thrombolysis in a Stroke Patient Receiving Rivaroxaban JF - Cerebrovascular Disease Extra N2 - No abstract available. KW - anticoagulants KW - intravenous thrombolysis KW - acute ischemic stroke Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128816 VL - 2013 IS - 3 ER - TY - JOUR A1 - Ljaschenko, Dmitrij A1 - Ehmann, Nadine A1 - Kittel, Robert J. T1 - Hebbian Plasticity Guides Maturation of Glutamate Receptor Fields In Vivo JF - Cell Reports N2 - Synaptic plasticity shapes the development of functional neural circuits and provides a basis for cellular models of learning and memory. Hebbian plasticity describes an activity-dependent change in synaptic strength that is input-specific and depends on correlated pre- and postsynaptic activity. Although it is recognized that synaptic activity and synapse development are intimately linked, our mechanistic understanding of the coupling is far from complete. Using Channelrhodopsin-2 to evoke activity in vivo, we investigated synaptic plasticity at the glutamatergic Drosophila neuromuscular junction. Remarkably, correlated pre- and postsynaptic stimulation increased postsynaptic sensitivity by promoting synapse- specific recruitment of GluR-IIA-type glutamate receptor subunits into postsynaptic receptor fields. Conversely, GluR-IIA was rapidly removed from synapses whose activity failed to evoke substantial postsynaptic depolarization. Uniting these results with developmental GluR-IIA dynamics provides a comprehensive physiological concept of how Hebbian plasticity guides synaptic maturation and sparse transmitter release controls the stabilization of the molecular composition of individual synapses. Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128804 VL - 3 IS - 5 ER - TY - JOUR A1 - Reddy, C. E. A1 - Albanito, L. A1 - De Marco, P. A1 - Aiello, D. A1 - Maggiolini, M. A1 - Napoli, A. A1 - Musti, A. M. T1 - Multisite phosphorylation of c-Jun at threonine 91/93/95 triggers the onset of c-Jun pro-apoptotic activity in cerebellar granule neurons JF - Cell Death & Disease N2 - Cerebellar granule cell (CGC) apoptosis by trophic/potassium (TK) deprivation is a model of election to study the interplay of pro-apoptotic and pro-survival signaling pathways in neuronal cell death. In this model, the c-Jun N-terminal kinase (JNK) induces pro-apoptotic genes through the c-Jun/activator protein 1 (AP-1) transcription factor. On the other side, a survival pathway initiated by lithium leads to repression of pro-apoptotic c-Jun/AP-1 target genes without interfering with JNK activity. Yet, the mechanism by which lithium inhibits c-Jun activity remains to be elucidated. Here, we used this model system to study the regulation and function of site-specific c-Jun phosphorylation at the S63 and T91/T93 JNK sites in neuronal cell death. We found that TK-deprivation led to c-Jun multiphosphorylation at all three JNK sites. However, immunofluorescence analysis of c-Jun phosphorylation at single cell level revealed that the S63 site was phosphorylated in all c-Jun-expressing cells, whereas the response of T91/T93 phosphorylation was more sensitive, mirroring the switch-like apoptotic response of CGCs. Conversely, lithium prevented T91T93 phosphorylation and cell death without affecting the S63 site, suggesting that T91T93 phosphorylation triggers c-Jun pro-apoptotic activity. Accordingly, a c-Jun mutant lacking the T95 priming site for T91/93 phosphorylation protected CGCs from apoptosis, whereas it was able to induce neurite outgrowth in PC12 cells. Vice versa, a c-Jun mutant bearing aspartate substitution of T95 overwhelmed lithium-mediate protection of CGCs from TK-deprivation, validating that inhibition of T91/T93/T95 phosphorylation underlies the effect of lithium on cell death. Mass spectrometry analysis confirmed multiphosphorylation of c-Jun at T91/T93/T95 in cells. Moreover, JNK phosphorylated recombinant c-Jun at T91/T93 in a T95-dependent manner. On the basis of our results, we propose that T91/T93/T95 multiphosphorylation of c-Jun functions as a sensitivity amplifier of the JNK cascade, setting the threshold for c-Jun pro-apoptotic activity in neuronal cells. KW - c-Jun KW - JNK KW - cell death KW - neurons KW - trophic/potassium deprivation KW - lithium Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128793 VL - 4 IS - e852 ER - TY - JOUR A1 - Rukoyatkina, N. A1 - Mindukshev, I. A1 - Walter, U. A1 - Gambaryan, S. T1 - Dual role of the p38 \(MAPK/cPLA_2\) pathway in the regulation of platelet apoptosis induced by ABT-737 and strong platelet agonists JF - Cell Death & Disease N2 - p38 Mitogen-activated protein (MAP) kinase is involved in the apoptosis of nucleated cells. Although platelets are anucleated cells, apoptotic proteins have been shown to regulate platelet lifespan. However, the involvement of p38 MAP kinase in platelet apoptosis is not yet clearly defined. Therefore, we investigated the role of p38 MAP kinase in apoptosis induced by a mimetic of BH3-only proteins, ABT-737, and in apoptosis-like events induced by such strong platelet agonists as thrombin in combination with convulxin (Thr/Cvx), both of which result in p38 MAP kinase phosphorylation and activation. A p38 inhibitor (SB202190) inhibited the apoptotic events induced by ABT-737 but did not influence those induced by Thr/Cvx. The inhibitor also reduced the phosphorylation of cytosolic phospholipase \(A_2\) (cPLA2), an established p38 substrate, induced by ABT-737 or Thr/Cvx. ABT-737, but not Thr/Cvx, induced the caspase 3-dependent cleavage and inactivation of cPLA2. Thus, p38 MAPK promotes ABT-737-induced apoptosis by inhibiting the cPLA2/arachidonate pathway. We also show that arachidonic acid (AA) itself and in combination with Thr/Cvx or ABT-737 at low concentrations prevented apoptotic events, whereas at high concentrations it enhanced such events. Our data support the hypothesis that the p38 MAPK-triggered arachidonate pathway serves as a defense mechanism against apoptosis under physiological conditions. KW - cPLA2 KW - platelet KW - apoptosis KW - p38 MAP kinase Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128783 VL - 4 IS - e931 ER - TY - JOUR A1 - El-Mesery, M. A1 - Trebing, J. A1 - Schafer, V. A1 - Weisenberger, D. A1 - Siegmund, D. A1 - Wajant, H. T1 - CD40-directed scFv-TRAIL fusion proteins induce CD40-restricted tumor cell death and activate dendritic cells JF - Cell Death & Disease N2 - Targeted cancer therapy concepts often aim at the induction of adjuvant antitumor immunity or stimulation of tumor cell apoptosis. There is further evidence that combined application of immune stimulating and tumor apoptosis-inducing compounds elicits a synergistic antitumor effect. Here, we describe the development and characterization of bifunctional fusion proteins consisting of a single-chain variable fragment (scFv) domain derived from the CD40-specific monoclonal antibody G28-5 that is fused to the N-terminus of stabilized trimeric soluble variants of the death ligand TNF-related apoptosis-inducing ligand (TRAIL). As shown before by us and others for other cell surface antigen-targeted scFv-TRAIL fusion proteins, scFv:G28-TRAIL displayed an enhanced capacity to induce apoptosis upon CD40 binding. Studies with scFv:G28 fusion proteins of TRAIL mutants that discriminate between the two TRAIL death receptors, TRAILR1 and TRAILR2, further revealed that the CD40 binding-dependent mode of apoptosis induction of scFv:G28-TRAIL is operable with each of the two TRAIL death receptors. Binding of scFv:G28-TRAIL fusion proteins to CD40 not only result in enhanced TRAIL death receptor signaling but also in activation of the targeted CD40 molecule. In accordance with the latter, the scFv:G28-TRAIL fusion proteins triggered strong CD40-mediated maturation of dendritic cells. The CD40-targeted TRAIL fusion proteins described in this study therefore represent a novel type of bifunctional fusion proteins that couple stimulation of antigen presenting cells and apoptosis induction. KW - dendritic cells KW - apoptosis KW - CD40 KW - TRAIL Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128777 VL - 4 IS - e916 ER - TY - JOUR A1 - Benz, Peter M. A1 - Merkel, Carla J. A1 - Offner, Kristin A1 - Abeßer, Marco A1 - Ullrich, Melanie A1 - Fischer, Tobias A1 - Bayer, Barbara A1 - Wagner, Helga A1 - Gambaryan, Stepan A1 - Ursitti, Jeanine A. A1 - Adham, Ibrahim M. A1 - Linke, Wolfgang A. A1 - Feller, Stephan M. A1 - Fleming, Ingrid A1 - Renné, Thomas A1 - Frantz, Stefan A1 - Unger, Andreas A1 - Schuh, Kai T1 - Mena/VASP and alphaII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy JF - Cell Communication and Signaling N2 - Background: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. Results: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. Conclusions: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities. KW - Mena/VASP KW - dilated cardiomyopathy KW - actin KW - heart KW - spectrin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128760 VL - 11 IS - 56 ER - TY - JOUR A1 - May-Mederake, Birgit A1 - Shehata-Dieler, Wafaa T1 - A Case Study Assessing the Auditory and Speech Development of Four Children Implanted with Cochlear Implants by the Chronological Age of 12 Months JF - Case Reports in Otolaryngology N2 - Children with severe hearing loss most likely receive the greatest benefit from a cochlear implant (CI) when implanted at less than 2 years of age. Children with a hearing loss may also benefit greater from binaural sensory stimulation. Four children who received their first CI under 12 months of age were included in this study. Effects on auditory development were determined using the German LittlEARS Auditory Questionnaire, closed- and open-set monosyllabic word tests, aided free-field, the Mainzer and Göttinger speech discrimination tests, Monosyllabic-Trochee-Polysyllabic (MTP), and Listening Progress Profile (LiP). Speech production and grammar development were evaluated using a German language speech development test (SETK), reception of grammar test (TROG-D) and active vocabulary test (AWST-R). The data showed that children implanted under 12 months of age reached open-set monosyllabic word discrimination at an age of 24 months. LiP results improved over time, and children recognized 100% of words in the MTP test after 12 months. All children performed as well as or better than their hearing peers in speech production and grammar development. SETK showed that the speech development of these children was in general age appropriate. The data suggests that early hearing loss intervention benefits speech and language development and supports the trend towards early cochlear implantation. Furthermore, the data emphasizes the potential benefits associated with bilateral implantation. KW - Otolaryngolgy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128750 VL - 2013 IS - 359218 ER - TY - JOUR A1 - Matlach, Juliane A1 - Freiberg, Florentina J. A1 - Gadeholt, Ottar A1 - Göbel, Winfried T1 - Vasculitis-like hemorrhagic retinal angiopathy in Wegener’s granulomatosis JF - BMC Research Notes N2 - Background: Granulomatosis with polyangiitis, also known as Wegener’s granulomatosis, is a chronic systemic inflammatory disease that can also involve the eyes. We report a case of massive retinal and preretinal hemorrhages with perivascular changes as the initial signs in granulomatosis with polyangiitis (Wegener’s granulomatosis). Case presentation: A 39-year-old Caucasian male presented with blurred vision in his right eye, myalgia and arthralgia, recurrent nose bleeds and anosmia. Fundus image of his right eye showed massive retinal hemorrhages and vasculitis-like angiopathy, although no fluorescein extravasation was present in fluorescein angiography. Laboratory investigations revealed an inflammation with increased C-reactive protein, elevated erythrocyte sedimentation rate and neutrophil count. Tests for antineutrophil cytoplasmic antibodies (ANCA) were positive for c-ANCA (cytoplasmatic ANCA) and PR3-ANCA (proteinase 3-ANCA). Renal biopsy demonstrated a focal segmental necrotizing glomerulonephritis. Granulomatosis with polyangiitis (Wegener’s granulomatosis) was diagnosed and a combined systemic therapy of cyclophosphamide and corticosteroids was initiated. During 3 months of follow-up, complete resorption of retinal hemorrhages was seen and general complaints as well as visual acuity improved during therapy. Conclusion: Vasculitis-like retinal changes can occur in Wegener’s granulomatosis. Despite massive retinal and preretinal hemorrhages that cause visual impairment, immunosuppressive therapy can improve ocular symptoms. KW - cyclophosphamide KW - Wegener’s granulomatosis KW - granulomatosis with polyangiitis KW - retinal vasculitis KW - hemorrhages Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128744 VL - 6 IS - 364 ER - TY - JOUR A1 - Schneider, Andreas A1 - Schneider, Markus P. A1 - Scharnagl, Hubert A1 - Jardine, Alan G. A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes JF - BMC Nephrology N2 - Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients. Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers. Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance. Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies. KW - type 2 diabetes KW - heodialysis patients Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128695 VL - 14 IS - 67 ER - TY - JOUR A1 - Rostás, Michael A1 - Maag, Daniel A1 - Ikegami, Makihiko A1 - Inbar, Moshe T1 - Gall volatiles defend aphids against a browsing mammal JF - BMC Evolutionary Biology N2 - Background: Plants have evolved an astonishing array of survival strategies. To defend against insects, for example, damaged plants emit volatile organic compounds that attract the herbivore’s natural enemies. So far, plant volatile responses have been studied extensively in conjunction with leaf chewing and sap sucking insects, yet little is known about the relationship between plant volatiles and gall-inducers, the most sophisticated herbivores. Here we describe a new role for volatiles as gall-insects were found to benefit from this plant defence. Results: Chemical analyses of galls triggered by the gregarious aphid Slavum wertheimae on wild pistachio trees showed that these structures contained and emitted considerably higher quantities of plant terpenes than neighbouring leaves and fruits. Behavioural assays using goats as a generalist herbivore confirmed that the accumulated terpenes acted as olfactory signals and feeding deterrents, thus enabling the gall-inducers to escape from inadvertent predation by mammals. Conclusions: Increased emission of plant volatiles in response to insect activity is commonly looked upon as a “cry for help” by the plant to attract the insect’s natural enemies. In contrast, we show that such volatiles can serve as a first line of insect defences that extends the ‘extended phenotype’ represented by galls, beyond physical boundaries. Our data support the Enemy hypothesis insofar that high levels of gall secondary metabolites confer protection against natural enemies. KW - capra hircus KW - enemy hypothesis KW - extended phenotype KW - herbivory KW - intraguild predation KW - plant defence KW - tannins KW - terpenes KW - volatile organic compounds Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128687 VL - 13 IS - 193 ER - TY - JOUR A1 - Karl, Stefan A1 - Dandekar, Thomas T1 - Jimena: Efficient computing and system state identification for genetic regulatory networks JF - BMC Bioinformatics N2 - Background: Boolean networks capture switching behavior of many naturally occurring regulatory networks. For semi-quantitative modeling, interpolation between ON and OFF states is necessary. The high degree polynomial interpolation of Boolean genetic regulatory networks (GRNs) in cellular processes such as apoptosis or proliferation allows for the modeling of a wider range of node interactions than continuous activator-inhibitor models, but suffers from scaling problems for networks which contain nodes with more than ~10 inputs. Many GRNs from literature or new gene expression experiments exceed those limitations and a new approach was developed. Results: (i) As a part of our new GRN simulation framework Jimena we introduce and setup Boolean-tree-based data structures; (ii) corresponding algorithms greatly expedite the calculation of the polynomial interpolation in almost all cases, thereby expanding the range of networks which can be simulated by this model in reasonable time. (iii) Stable states for discrete models are efficiently counted and identified using binary decision diagrams. As application example, we show how system states can now be sampled efficiently in small up to large scale hormone disease networks (Arabidopsis thaliana development and immunity, pathogen Pseudomonas syringae and modulation by cytokinins and plant hormones). Conclusions: Jimena simulates currently available GRNs about 10-100 times faster than the previous implementation of the polynomial interpolation model and even greater gains are achieved for large scale-free networks. This speed-up also facilitates a much more thorough sampling of continuous state spaces which may lead to the identification of new stable states. Mutants of large networks can be constructed and analyzed very quickly enabling new insights into network robustness and behavior. KW - Boolean function KW - genetic regulatory network KW - interpolation KW - stable state KW - binary decision diagram KW - Boolean tree Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128671 VL - 14 ER - TY - JOUR A1 - Leich, E. A1 - Weißbach, S. A1 - Klein, H.-U. A1 - Grieb, T. A1 - Pischimarov, J. A1 - Stühmer, T. A1 - Chatterjee, M. A1 - Steinbrunn, T. A1 - Langer, C. A1 - Eilers, M. A1 - Knop, S. A1 - Einsele, H. A1 - Bargou, R. A1 - Rosenwald, A. T1 - Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules JF - Blood Cancer Journal N2 - Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient. KW - multiple myeloma KW - somatic mutations KW - whole-exome sequencing KW - adhesion KW - receptor tyrosine kinases Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128663 VL - 3 IS - e102 ER - TY - JOUR A1 - Fischer, Kathrin H. A1 - Hemberger, Patrick A1 - Bodi, Andras A1 - Fischer, Ingo T1 - Photoionisation of the tropyl radical JF - Beilstein Journal of Organic Chemistry N2 - We present a study on the photoionisation of the cycloheptatrienyl (tropyl) radical, \(C_7H_7\), using tunable vacuum ultraviolet synchrotron radiation. Tropyl is generated by flash pyrolysis from bitropyl. Ions and electrons are detected in coincidence, permitting us to record mass-selected photoelectron spectra. The threshold photoelectron spectrum of tropyl, corresponding to the \(X^{+1}A1’ ← X^2E_2”\) transition, reveals an ionisation energy of 6.23 ± 0.02 eV, in good agreement with Rydberg extrapolations, but slightly lower than the value derived from earlier photoelectron spectra. Several vibrations can be resolved and are reassigned to the C–C stretch mode \(ν_{16}^+\) and to a combination of \(ν_{16}^+\) with the ring breathing mode \(ν_2^+\). Above 10.55 eV dissociative photoionisation of tropyl is observed, leading to the formation of \(C_5H_5^+\) and \(C_2H_2\). KW - threshold photoelectron spectroscopy KW - gas phase KW - dissociative photoionisation KW - reactive intermediates KW - synchrotron radiation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128652 VL - 9 ER - TY - JOUR A1 - Shahabfar, Alireza A1 - Eitzinger, Josef T1 - Spatio-Temporal Analysis of Droughts in Semi-Arid Regions by Using Meteorological Drought Indices JF - Atmosphere N2 - Six meteorological drought indices including percent of normal (PN), standardized precipitation index (SPI), China-Z index (CZI), modified CZI (MCZI), Z-Score (Z), the aridity index of E. de Martonne (I) are compared and evaluated for assessing spatio-temporal dynamics of droughts in six climatic regions in Iran. Results indicated that by consideration of the advantages and disadvantages of the mentioned drought predictors in Iran, the Z-Score, CZI and MCZI could be used as a good meteorological drought predictor. Depending on the month, the length of drought and climatic conditions of the region, they are an alternative to the SPI that has limitations both because of only a few available long term data series in Iran and its complex structure. KW - semi-arid region KW - standardized precipitation index KW - drought index KW - drought monitoring KW - Iran Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128644 VL - 4 IS - 2 ER - TY - JOUR A1 - Diessner, Joachim A1 - Bruttel, Valentin A1 - Becker, Kathrin A1 - Pawlik, Miriam A1 - Stein, Roland A1 - Häusler, Sebastian A1 - Dietl, Johannes A1 - Wischhusen, Jörg A1 - Hönig, Arnd T1 - Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells JF - American Journal of Cancer Research N2 - Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of \(CD44^{high}CD24^{low}HER2^{low}\) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells. KW - trastuzumab KW - breast cancer KW - tumor stem cells KW - ADCC KW - pertuzumab Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128633 VL - 3 IS - 2 ER - TY - JOUR A1 - Spitznagel, N. A1 - Durig, T. A1 - Zimanowski, B. T1 - Trigger - and heat-transfer times measured during experimental molten-fuel-interactions JF - AIP Advances N2 - A modified setup featuring high speed high resolution data and video recording was developed to obtain detailed information on trigger and heat transfer times during explosive molten fuel-coolant-interaction (MFCI). MFCI occurs predominantly in configurations where water is entrapped by hot melt. The setup was modified to allow direct observation of the trigger and explosion onset. In addition the influences of experimental control and data acquisition can now be more clearly distinguished from the pure phenomena. More precise experimental studies will facilitate the description of MFCI thermodynamics. KW - temperature measurement KW - data acquisition KW - heat transfer KW - expolsions KW - shock waves Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128625 VL - 3 IS - 102126 ER - TY - JOUR A1 - Makgotlho, Phuti E. A1 - Marincola, Gabriella A1 - Schäfer, Daniel A1 - Liu, Quian A1 - Bae, Taeok A1 - Geiger, Tobias A1 - Wasserman, Elizabeth A1 - Wolz, Christine A1 - Ziebuhr, Wilma A1 - Sinha, Bhanu T1 - SDS Interferes with SaeS Signaling of Staphylococcus aureus Independently of SaePQ JF - PLOS ONE N2 - The Staphylococcus aureus regulatory saePQRS system controls the expression of numerous virulence factors, including extracellular adherence protein (Eap), which amongst others facilitates invasion of host cells. The saePQRS operon codes for 4 proteins: the histidine kinase SaeS, the response regulator SaeR, the lipoprotein SaeP and the transmembrane protein SaeQ. S. aureus strain Newman has a single amino acid substitution in the transmembrane domain of SaeS (L18P) which results in constitutive kinase activity. SDS was shown to be one of the signals interfering with SaeS activity leading to inhibition of the sae target gene eap in strains with SaeS(L) but causing activation in strains containing SaeS(P). Here, we analyzed the possible involvement of the SaeP protein and saePQ region in SDS-mediated sae/eap expression. We found that SaePQ is not needed for SDS-mediated SaeS signaling. Furthermore, we could show that SaeS activity is closely linked to the expression of Eap and the capacity to invade host cells in a number of clinical isolates. This suggests that SaeS activity might be directly modulated by structurally non-complex environmental signals, as SDS, which possibly altering its kinase/phosphatase activity. KW - host-cell invasion KW - 2-component system KW - strain Newman KW - allelic replacement KW - genome sequence KW - locus KW - gene KW - activation KW - expression KW - infection Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128469 SN - 1932-6203 VL - 8 IS - 8 ER - TY - JOUR A1 - Gunda, Daniel W. A1 - Kasang, Christa A1 - Kidenya, Benson R. A1 - Kabangila, Rodrick A1 - Mshana, Stephen E. A1 - Kidola, Jeremiah A1 - Kalluvya, Samuel E. A1 - Kongola, Gilbert W. A1 - Klinker, Hartwig T1 - Plasma Concentrations of Efavirenz and Nevirapine among HIV-Infected Patients with Immunological Failure Attending a Tertiary Hospital in North-Western Tanzania JF - PLOS ONE N2 - Background: Sub-therapeutic and supra-therapeutic plasma concentrations of antriretrovirals are the significant causes of treatment failure and toxicity respectively among HIV-infected patients. We conducted this study to determine the pattern of efavirenz and nevirapine plasma drug concentrations among adult HIV-infected patients with immunological failure attending at a tertiary hospital in North-western Tanzania. Materials and Methods: A cross-sectional study was conducted among adult HIV-infected patients with immunological failure who have been on either efavirenz or nevirapine based antiretroviral regimen for more than 6 months. Patients were serially enrolled through routine Care and Treatment Clinic (CTC) activities. Plasma drug concentrations for efavirenz and nevirapine were determined by high performance liquid chromatography (HPLC) and Gas Chromatography (GC) respectively. Demographic, clinical and laboratory data such as viral load and CD4 counts were collected. Data analysis was done using STATA 12. Results: Of the 152 patients with immunological failure enrolled, the sub-therapeutic, therapeutic and supra-therapeutic plasma antiretroviral drug concentrations were found in 43/152 (28.3%), 76/152 (50.0%) and 33/152 (21.7%) respectively. Half of the patients were outside therapeutic window with either sub-therapeutic or supra-therapeutic plasma ARV drug concentrations. There was a significant difference in distribution of ARV adherence (p-value<0.001), NRTI backbone (p-value = 0.039), HIV stage (p-value = 0.026) and viral load (p-value = 0.007) within sub-therapeutic, therapeutic and supratherapeutic ARV plasma drug concentrations. Conclusion: There is a wide inter-individual variability of plasma ARV concentrations among HIV patients with immunological failure, with a large proportion of patients being outside therapeutic window. This variability is significant based on ARV adherence, NRTI backbone, viral load and HIV stage. Routine therapeutic drug monitoring (TDM) could assist identifying these patients early and making timely correction to avoid virological failure, poor immunological outcome and prevent associated drug toxicities. Nonetheless, ARV adherence should be strictly emphasized on HIV patients with immunological failure. KW - reverse-transcriptase inhibitors KW - randomized controlled-trial KW - routine clinical-practice KW - antiretroviral therapy KW - drug interactions KW - HIV-1-infected patients KW - management KW - indinavir KW - Uganda Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128456 SN - 1932-6203 VL - 8 IS - 9 ER - TY - JOUR A1 - Muturi, Harrison T. A1 - Dreesen, Janine D. A1 - Nilewski, Elena A1 - Jastrow, Holger A1 - Giebel, Bernd A1 - Ergun, Suleyman A1 - Singer, Berhard B. T1 - Tumor and Endothelial Cell-Derived Microvesicles Carry Distinct CEACAMs and Influence T-Cell Behavior JF - PLOS ONE N2 - Normal and malignant cells release a variety of different vesicles into their extracellular environment. The most prominent vesicles are the microvesicles (MVs, 100-1 000 nm in diameter), which are shed of the plasma membrane, and the exosomes (70-120 nm in diameter), derivates of the endosomal system. MVs have been associated with intercellular communication processes and transport numerous proteins, lipids and RNAs. As essential component of immune-escape mechanisms tumor-derived MVs suppress immune responses. Additionally, tumor-derived MVs have been found to promote metastasis, tumor-stroma interactions and angiogenesis. Since members of the carcinoembryonic antigen related cell adhesion molecule (CEACAM)-family have been associated with similar processes, we studied the distribution and function of CEACAMs in MV fractions of different human epithelial tumor cells and of human and murine endothelial cells. Here we demonstrate that in association to their cell surface phenotype, MVs released from different human epithelial tumor cells contain CEACAM1, CEACAM5 and CEACAM6, while human and murine endothelial cells were positive for CEACAM1 only. Furthermore, MVs derived from CEACAM1 transfected CHO cells carried CEACAM1. In terms of their secretion kinetics, we show that MVs are permanently released in low doses, which are extensively increased upon cellular starvation stress. Although CEACAM1 did not transmit signals into MVs it served as ligand for CEACAM expressing cell types. We gained evidence that CEACAM1-positive MVs significantly increase the CD3 and CD3/CD28-induced T-cell proliferation. All together, our data demonstrate that MV-bound forms of CEACAMs play important roles in intercellular communication processes, which can modulate immune response, tumor progression, metastasis and angiogenesis. KW - carcinoembryonic anitgen family KW - biliary glycoprotein CD66A KW - adhesion molecule-1 KW - epithelial cells KW - membrane vesicles KW - growth-factor KW - cancer KW - expression KW - proliferation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128373 SN - 1932-6203 VL - 8 IS - 9 ER - TY - JOUR A1 - Grube, Maike Miriam A1 - Koennecke, Hans-Christian A1 - Walter, Georg A1 - Meisel, Andreas A1 - Sobesky, Jan A1 - Nolte, Christian Hans A1 - Wellwood, Ian A1 - Heuschmann, Peter Ulrich T1 - Influence of Acute Complications on Outcome 3 Months after Ischemic Stroke JF - PLOS ONE N2 - Background: Early medical complications are potentially modifiable factors influencing in-hospital outcome. We investigated the influence of acute complications on mortality and poor outcome 3 months after ischemic stroke. Methods: Data were obtained from patients admitted to one of 13 stroke units of the Berlin Stroke Registry (BSR) who participated in a 3-months-follow up between June 2010 and September 2012. We examined the influence of the cumulative number of early in-hospital complications on mortality and poor outcome (death, disability or institutionalization) 3 months after stroke using multivariable logistic regression analyses and calculated attributable fractions to determine the impact of early complications on mortality and poor outcome. Results: A total of 2349 ischemic stroke patients alive at discharge from acute care were included in the analysis. Older age, stroke severity, pre-stroke dependency and early complications were independent predictors of mortality 3 months after stroke. Poor outcome was independently associated with older age, stroke severity, pre-stroke dependency, previous stroke and early complications. More than 60% of deaths and poor outcomes were attributed to age, pre-stroke dependency and stroke severity and in-hospital complications contributed to 12.3% of deaths and 9.1% of poor outcomes 3 months after stroke. Conclusion: The majority of deaths and poor outcomes after stroke were attributed to non-modifiable factors. However, early in-hospital complications significantly affect outcome in patients who survived the acute phase after stroke, underlining the need to improve prevention and treatment of complications in hospital. KW - hospital medical complications KW - quality-of-care KW - term mortality KW - Barthel-Index KW - rankin scale KW - risk-factors KW - trial KW - reliability KW - dependency KW - predictors Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128362 SN - 1932-6203 VL - 8 IS - 9 ER - TY - JOUR A1 - Dasenbrook, Elliot C. A1 - Lu, Luan A1 - Donnola, Shannon A1 - Weaver, David E. A1 - Gulani, Viskas A1 - Jakob, Peter M. A1 - Konstan, Michael W. A1 - Flask, Chris A. T1 - Normalized T1 Magnetic Resonance Imaging for Assessment of Regional Lung Function in Adult Cystic Fibrosis Patients - A Cross-Sectional Study JF - PLOS ONE N2 - Background: Cystic fibrosis (CF) patients would benefit from a safe and effective tool to detect early-stage, regional lung disease to allow for early intervention. Magnetic Resonance Imaging (MRI) is a safe, non-invasive procedure capable of providing quantitative assessments of disease without ionizing radiation. We developed a rapid normalized T1 MRI technique to detect regional lung disease in early-stage CF patients. Materials and Methods: Conventional multislice, pulmonary T1 relaxation time maps were obtained for 10 adult CF patients with normal spirometry and 5 healthy non-CF control subjects using a rapid Look-Locker MRI acquisition (5 seconds/imaging slice). Each lung absolute T1 map was separated into six regions of interest (ROI) by manually selecting upper, central, and lower lung regions in the left and right lungs. In order to reduce the effects of subject-to-subject variation, normalized T1 maps were calculated by dividing each pixel in the absolute T1 maps by the mean T1 time in the central lung region. The primary outcome was the differences in mean normalized T1 values in the upper lung regions between CF patients with normal spirometry and healthy volunteers. Results: Normalized T1 (nT1) maps showed visibly reduced subject-to-subject variation in comparison to conventional absolute T1 maps for healthy volunteers. An ROI analysis showed that the variation in the nT1 values in all regions was <= 2% of the mean. The primary outcome, the mean (SD) of the normalized T1 values in the upper right lung regions, was significantly lower in the CF subjects [.914 (.037)] compared to the upper right lung regions of the healthy subjects [.983 (.003)] [difference of .069 (95% confidence interval .032-.105); p=.001). Similar results were seen in the upper left lung region. Conclusion: Rapid normalized T1 MRI relaxometry obtained in 5 seconds/imaging slice may be used to detect regional early-stage lung disease in CF patients. KW - infants KW - disease KW - ventilation KW - infection KW - guidelines KW - diagnosis KW - children Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128346 SN - 1932-6203 VL - 8 IS - 9 ER - TY - JOUR A1 - Maudet, Claire A1 - Sourisce, Adèle A1 - Dragin, Loïc A1 - Lahouassa, Hichem A1 - Rain, Jean-Christopher A1 - Bouaziz, Serge A1 - Ramirez, Bertha Cécilia A1 - Margottin-Goguet, Florence T1 - HIV-1 Vpr Induces the Degradation of ZIP and sZIP, Adaptors of the NuRD Chromatin Remodeling Complex, by Hijacking DCAF1/VprBP JF - PLOS ONE N2 - The Vpr protein from type 1 and type 2 Human Immunodeficiency Viruses (HIV-1 and HIV-2) is thought to inactivate several host proteins through the hijacking of the DCAF1 adaptor of the Cul4A ubiquitin ligase. Here, we identified two transcriptional regulators, ZIP and sZIP, as Vpr-binding proteins degraded in the presence of Vpr. ZIP and sZIP have been shown to act through the recruitment of the NuRD chromatin remodeling complex. Strikingly, chromatin is the only cellular fraction where Vpr is present together with Cul4A ubiquitin ligase subunits. Components of the NuRD complex and exogenous ZIP and sZIP were also associated with this fraction. Several lines of evidence indicate that Vpr induces ZIP and sZIP degradation by hijacking DCAF1: (i) Vpr induced a drastic decrease of exogenously expressed ZIP and sZIP in a dose-dependent manner, (ii) this decrease relied on the proteasome activity, (iii) ZIP or sZIP degradation was impaired in the presence of a DCAF1-binding deficient Vpr mutant or when DCAF1 expression was silenced. Vpr-mediated ZIP and sZIP degradation did not correlate with the growth-related Vpr activities, namely G2 arrest and G2 arrest-independent cytotoxicity. Nonetheless, infection with HIV-1 viruses expressing Vpr led to the degradation of the two proteins. Altogether our results highlight the existence of two host transcription factors inactivated by Vpr. The role of Vpr-mediated ZIP and sZIP degradation in the HIV-1 replication cycle remains to be deciphered. KW - immunodeficiency-virus type-1 KW - MI-2/NURD complex KW - cell-cycle arrest KW - CUL4-DDB1 ubiquitin ligase KW - viral protein-R KW - NF-KAPPA-B KW - macrophage infection KW - enzyme APOBEC3G KW - in-vivo KW - transcription Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128316 SN - 1932-6203 VL - 8 IS - 10 ER -