TY - JOUR A1 - Patil, Sandeep S. A1 - Gentschev, Ivaylo A1 - Adelfinger, Marion A1 - Donat, Ulrike A1 - Hess, Michael A1 - Weibel, Stephanie A1 - Nolte, Ingo A1 - Frentzen, Alexa A1 - Szalay, Aladar A. T1 - Virotherapy of Canine Tumors with Oncolytic Vaccinia Virus GLV-1h109 Expressing an Anti-VEGF Single-Chain Antibody JF - PLoS One N2 - Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for cancer therapy. We have previously reported that oncolytic vaccinia virus strains expressing an anti-VEGF (Vascular Endothelial Growth Factor) single-chain antibody (scAb) GLAF-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. Here, we describe the use of oncolytic vaccinia virus GLV-1h109 encoding GLAF-1 for canine cancer therapy. In this study we analyzed the virus-mediated delivery and production of scAb GLAF-1 and the oncolytic and immunological effects of the GLV-1h109 vaccinia virus strain against canine soft tissue sarcoma and canine prostate carcinoma in xenograft models. Cell culture data demonstrated that the GLV-1h109 virus efficiently infect, replicate in and destroy both tested canine cancer cell lines. In addition, successful expression of GLAF-1 was demonstrated in virus-infected canine cancer cells and the antibody specifically recognized canine VEGF. In two different xenograft models, the systemic administration of the GLV-1h109 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. Furthermore, tumor-specific virus infection led to a continued production of functional scAb GLAF-1, resulting in inhibition of angiogenesis. Overall, the GLV-1h109-mediated cancer therapy and production of immunotherapeutic anti-VEGF scAb may open the way for combination therapy concept i.e. vaccinia virus mediated oncolysis and intratumoral production of therapeutic drugs in canine cancer patients. KW - angiogenesis KW - microenvironment KW - model KW - cancer KW - therapy KW - pet dogs KW - nude-mice KW - breast-tumors KW - microvascular density KW - endothelial growth-factor Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130039 VL - 7 IS - 10 ER - TY - JOUR A1 - Heddergott, Niko A1 - Krüger, Timothy A1 - Babu, Sujin B. A1 - Wei, Ai A1 - Stellamanns, Erik A1 - Uppaluri, Sravanti A1 - Pfohl, Thomas A1 - Stark, Holger A1 - Engstler, Markus T1 - Trypanosome Motion Represents an Adaptation to the Crowded Environment of the Vertebrate Bloodstream JF - PLoS Pathogens N2 - Blood is a remarkable habitat: it is highly viscous, contains a dense packaging of cells and perpetually flows at velocities varying over three orders of magnitude. Only few pathogens endure the harsh physical conditions within the vertebrate bloodstream and prosper despite being constantly attacked by host antibodies. African trypanosomes are strictly extracellular blood parasites, which evade the immune response through a system of antigenic variation and incessant motility. How the flagellates actually swim in blood remains to be elucidated. Here, we show that the mode and dynamics of trypanosome locomotion are a trait of life within a crowded environment. Using high-speed fluorescence microscopy and ordered micro-pillar arrays we show that the parasites mode of motility is adapted to the density of cells in blood. Trypanosomes are pulled forward by the planar beat of the single flagellum. Hydrodynamic flow across the asymmetrically shaped cell body translates into its rotational movement. Importantly, the presence of particles with the shape, size and spacing of blood cells is required and sufficient for trypanosomes to reach maximum forward velocity. If the density of obstacles, however, is further increased to resemble collagen networks or tissue spaces, the parasites reverse their flagellar beat and consequently swim backwards, in this way avoiding getting trapped. In the absence of obstacles, this flagellar beat reversal occurs randomly resulting in irregular waveforms and apparent cell tumbling. Thus, the swimming behavior of trypanosomes is a surprising example of micro-adaptation to life at low Reynolds numbers. For a precise physical interpretation, we compare our high-resolution microscopic data to results from a simulation technique that combines the method of multi-particle collision dynamics with a triangulated surface model. The simulation produces a rotating cell body and a helical swimming path, providing a functioning simulation method for a microorganism with a complex swimming strategy. KW - simulation KW - multiparticle collision dynamics KW - propulsion KW - viscosity KW - flagellar KW - motility KW - solvent KW - model KW - hydrodynamics KW - spiroplasma Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134595 VL - 8 IS - 11 ER - TY - JOUR A1 - Bischler, Thorsten A1 - Kopf, Matthias A1 - Voss, Bjoern T1 - Transcript mapping based on dRNA-seq data JF - BMC Bioinformatics N2 - Background: RNA-seq and its variant differential RNA-seq (dRNA-seq) are today routine methods for transcriptome analysis in bacteria. While expression profiling and transcriptional start site prediction are standard tasks today, the problem of identifying transcriptional units in a genome-wide fashion is still not solved for prokaryotic systems. Results: We present RNASEG, an algorithm for the prediction of transcriptional units based on dRNA-seq data. A key feature of the algorithm is that, based on the data, it distinguishes between transcribed and un-transcribed genomic segments. Furthermore, the program provides many different predictions in a single run, which can be used to infer the significance of transcriptional units in a consensus procedure. We show the performance of our method based on a well-studied dRNA-seq data set for Helicobacter pylori. Conclusions: With our algorithm it is possible to identify operons and 5'- and 3'-UTRs in an automated fashion. This alleviates the need for labour intensive manual inspection and enables large-scale studies in the area of comparative transcriptomics. KW - transcriptional start site KW - dynamic programming KW - RNA-seq KW - differential KW - segmentation KW - transcriptional uni KW - transcriptome KW - reveals KW - model Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116663 SN - 1471-2105 VL - 15 IS - 122 ER - TY - JOUR A1 - Ermert, Volker A1 - Fink, Andreas H. A1 - Morse, Andrew P. A1 - Paeth, Heiko T1 - The Impact of Regional Climate Change on Malaria Risk due to Greenhouse Forcing and Land-Use Changes in Tropical Africa JF - Environmental Health Perspectives N2 - BACKGROUND: Climate change will probably alter the spread and transmission intensity of malaria in Africa. OBJECTIVES: In this study, we assessed potential changes in the malaria transmission via an integrated weather disease model. METHODS: We simulated mosquito biting rates using the Liverpool Malaria Model (LMM). The input data for the LMM were bias-corrected temperature and precipitation data from the regional model (REMO) on a 0.5 degrees latitude longitude grid. A Plasmodium falciparum infection model expands the LMM simulations to incorporate information on the infection rate among children. Malaria projections were carried out with this integrated weather disease model for 2001 to 2050 according to two climate scenarios that include the effect of anthropogenic land-use and land-cover changes on climate. RESULTS: Model-based estimates for the present climate (1960 to 2000) are consistent with observed data for the spread of malaria in Africa. In the model domain, the regions where malaria is epidemic are located in the Sahel as well as in various highland territories. A decreased spread of malaria over most parts of tropical Africa is projected because of simulated increased surface temperatures and a significant reduction in annual rainfall. However, the likelihood of malaria epidemics is projected to increase in the southern part of the Sahel. In most of East Africa, the intensity of malaria transmission is expected to increase. Projections indicate that highland areas that were formerly unsuitable for malaria will become epidemic, whereas in the lower-altitude regions of the East African highlands, epidemic risk will decrease. CONCLUSIONS: We project that climate changes driven by greenhouse-gas and land-use changes will significantly affect the spread of malaria in tropical Africa well before 2050. The geographic distribution of areas where malaria is epidemic might have to be significantly altered in the coming decades. KW - climate change KW - West Africa KW - highland malaria KW - malaria KW - malaria model KW - malaria projection KW - Sahel KW - transmission KW - model KW - highlands KW - temperatures KW - validation KW - resurgence KW - scenarios KW - epidemic KW - deseases Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135562 VL - 120 IS - 1 ER - TY - JOUR A1 - Münch, Miriam A1 - Hsin, Chih-Hsuan A1 - Ferber, Elena A1 - Berger, Susanne A1 - Müller, Martin J. T1 - Reactive electrophilic oxylipins trigger a heat stress-like response through HSFA1 transcription factors JF - Journal of Experimental Botany N2 - Electrophilic oxylipins trigger a heat-shock-like response in the absence of heat through the canonical heat-shock transcription factor A1, thereby helping to cope with stresses associated with protein damage.Abiotic and biotic stresses are often characterized by an induction of reactive electrophile species (RES) such as the jasmonate 12-oxo-phytodienoic acid (OPDA) or the structurally related phytoprostanes. Previously, RES oxylipins have been shown massively to induce heat-shock-response (HSR) genes including HSP101 chaperones. Moreover, jasmonates have been reported to play a role in basal thermotolerance. We show that representative HSR marker genes are strongly induced by RES oxylipins through the four master regulator transcription factors HSFA1a, b, d, and e essential for short-term adaptation to heat stress in Arabidopsis. When compared with Arabidopsis seedlings treated at the optimal acclimation temperature of 37 A degrees C, the exogenous application of RES oxylipins at 20 A degrees C induced a much weaker induction of HSP101 at both the gene and protein expression levels which, however, was not sufficient to confer short-term acquired thermotolerance. Moreover, jasmonate-deficient mutant lines displayed a wild-type-like HSR and were not compromised in acquiring thermotolerance. Hence, the OPDA- and RES oxylipin-induced HSR is not sufficient to protect seedlings from severe heat stress but may help plants to cope better with stresses associated with protein unfolding by inducing a battery of chaperones in the absence of heat. KW - arabidopsis-thaliana KW - shock response KW - gene-expression KW - model KW - acquired thermotolerance KW - 12-oxo-phytodienoic acid KW - thermotolerance KW - plants KW - detoxification KW - acquisition KW - activation KW - heat stress KW - jasmonates KW - phytoprostanes KW - reactive electrophilic species KW - unfolded protein response Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186766 VL - 67 IS - 21 ER - TY - JOUR A1 - Sagiv, Jitka Y. A1 - Michaeli, Janna A1 - Assi, Simaan A1 - Mishalian, Inbal A1 - Kisos, Hen A1 - Levy, Liran A1 - Damti, Pazzit A1 - Lumbroso, Delphine A1 - Polyansky, Lola A1 - Sionov, Ronit V. A1 - Ariel, Amiram A1 - Hovav, Avi-Hai A1 - Henke, Erik A1 - Fridlender, Zvi G. A1 - Granot, Zvi T1 - Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer JF - Cell Reports N2 - Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro-and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consist of both immature myeloid-derived suppressor cells (MDSCs) and mature cells that are derived from HDNs in a TGF-beta-dependent mechanism. Our findings identify three distinct populations of circulating neutrophils and challenge the concept that mature neutrophils have limited plasticity. Furthermore, our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer. KW - tumorigenic properties KW - innate immunity KW - adenocarcinoma KW - inhibition KW - model KW - suppressor cells KW - tumor KW - TGF-beta KW - mice KW - lung Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144102 VL - 10 IS - 4 ER - TY - JOUR A1 - Rousochatzakis, Ioannis A1 - Reuther, Johannes A1 - Thomale, Ronny A1 - Rachel, Stephan A1 - Perkins, N. B. T1 - Phase Diagram and Quantum Order by Disorder in the Kitaev K\(_1\) - K\(_2\) Honeycomb Magnet JF - Physical Review X N2 - We show that the topological Kitaev spin liquid on the honeycomb lattice is extremely fragile against the second-neighbor Kitaev coupling K\(_2\), which has recently been shown to be the dominant perturbation away from the nearest-neighbor model in iridate Na\(_2\)IrO\(_3\), and may also play a role in \(\alpha\)-RuCl\(_3\) and Li\(_2\)IrO\(_3\). This coupling naturally explains the zigzag ordering (without introducing unrealistically large longer-range Heisenberg exchange terms) and the special entanglement between real and spin space observed recently in Na\(_2\)IrO\(_3\). Moreover, the minimal K\(_1\) - K\(_2\) model that we present here holds the unique property that the classical and quantum phase diagrams and their respective order-by-disorder mechanisms are qualitatively different due to the fundamentally different symmetries of the classical and quantum counterparts. KW - model KW - anyons KW - lattice KW - confinement-deconfinement transition Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137235 VL - 5 IS - 041035 ER - TY - JOUR A1 - Hurd, Paul J. A1 - Grübel, Kornelia A1 - Wojciechowski, Marek A1 - Maleszka, Ryszard A1 - Rössler, Wolfgang T1 - Novel structure in the nuclei of honey bee brain neurons revealed by immunostaining JF - Scientific Reports N2 - In the course of a screen designed to produce antibodies (ABs) with affinity to proteins in the honey bee brain we found an interesting AB that detects a highly specific epitope predominantly in the nuclei of Kenyon cells (KCs). The observed staining pattern is unique, and its unfamiliarity indicates a novel previously unseen nuclear structure that does not colocalize with the cytoskeletal protein f-actin. A single rod-like assembly, 3.7-4.1 mu m long, is present in each nucleus of KCs in adult brains of worker bees and drones with the strongest immuno-labelling found in foraging bees. In brains of young queens, the labelling is more sporadic, and the rod-like structure appears to be shorter (similar to 2.1 mu m). No immunostaining is detectable in worker larvae. In pupal stage 5 during a peak of brain development only some occasional staining was identified. Although the cellular function of this unexpected structure has not been determined, the unusual distinctiveness of the revealed pattern suggests an unknown and potentially important protein assembly. One possibility is that this nuclear assembly is part of the KCs plasticity underlying the brain maturation in adult honey bees. Because no labelling with this AB is detectable in brains of the fly Drosophila melanogaster and the ant Camponotus floridanus, we tentatively named this antibody AmBNSab (Apis mellifera Brain Neurons Specific antibody). Here we report our results to make them accessible to a broader community and invite further research to unravel the biological role of this curious nuclear structure in the honey bee central brain. KW - mushroom body calyx KW - synaptic complexes KW - bodies KW - insect KW - plasticity KW - insights KW - genome KW - model KW - proteins KW - methylation KW - biological techniques KW - cell biology KW - developmental biology KW - molecular biology KW - neuroscience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260059 VL - 11 ER - TY - JOUR A1 - Ohlebusch, Barbara A1 - Borst, Angela A1 - Frankenbach, Tina A1 - Klopocki, Eva A1 - Jakob, Franz A1 - Liedtke, Daniel A1 - Graser, Stephanie T1 - Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development JF - Scientific Reports N2 - Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term. KW - nonspecific alkaline-phosphae KW - in situ hybridization KW - hypophosphatasia KW - promotes KW - model KW - neurotransmission KW - differentiation KW - mineraliztion KW - metabolism KW - vertebrate Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230024 VL - 10 ER - TY - JOUR A1 - Nolte, Thomas A1 - Zadeh-Khorasani, Maryam A1 - Safarov, Orkhan A1 - Rueff, Franziska A1 - Varga, Rita A1 - Herbach, Nadja A1 - Wanke, Rüdiger A1 - Wollenberg, Andreas A1 - Mueller, Thomas A1 - Gropp, Roswitha A1 - Wolf, Eckhard A1 - Siebeck, Matthias T1 - Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid IL2R \(γ^{null}\) mice engrafted with human peripheral blood mononuclear cells JF - Disease Models & Mechanisms N2 - Animal models mimicking human diseases have been used extensively to study the pathogenesis of autoimmune diseases and the efficacy of potential therapeutics. They are, however, limited with regard to their similarity to the human disease and cannot be used if the antagonist and its cognate receptor require high similarity in structure or binding. Here, we examine the induction of oxazolone-mediated features of atopic dermatitis (AD) in NOD-scid IL2R \(γ^{null}\) mice engrafted with human peripheral blood mononuclear cells (PBMC). The mice developed the same symptoms as immunocompetent BALB/c mice. Histological alterations induced by oxazolone were characterized by keratosis, epithelial hyperplasia and influx of inflammatory cells into the dermis and epidermis. The cellular infiltrate was identified as human leukocytes, with T cells being the major constituent. In addition, oxazolone increased human serum IgE levels. The response, however, required the engraftment of PBMC derived from patients suffering from AD, which suggests that this model reflects the immunological status of the donor. Taken together, the model described here has the potential to evaluate the efficacy of therapeutics targeting human lymphocytes in vivo and, in addition, might be developed further to elucidate molecular mechanisms inducing and sustaining flares of the disease. KW - expression KW - model KW - pbl KW - differentiation KW - mechanisms KW - antagonists KW - gamma KW - human interleukin-4 KW - rheumatoid-arthritis KW - T-cells Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122189 VL - 6 ER -