TY - JOUR A1 - Cecil, Alexander A1 - Gentschev, Ivaylo A1 - Adelfinger, Marion A1 - Dandekar, Thomas A1 - Szalay, Aladar A. T1 - Vaccinia virus injected human tumors: oncolytic virus efficiency predicted by antigen profiling analysis fitted boolean models JF - Bioengineered N2 - Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a promising approach for cancer therapy. Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a therapeutic potential in treating human prostate and hepatocellular carcinomas in xenografted mice. In this study, we describe the use of dynamic boolean modeling for tumor growth prediction of vaccinia virus-injected human tumors. Antigen profiling data of vaccinia virus GLV-1h68-injected human xenografted mice were obtained, analyzed and used to calculate differences in the tumor growth signaling network by tumor type and gender. Our model combines networks for apoptosis, MAPK, p53, WNT, Hedgehog, the T-killer cell mediated cell death, Interferon and Interleukin signaling networks. The in silico findings conform very well with in vivo findings of tumor growth. Similar to a previously published analysis of vaccinia virus-injected canine tumors, we were able to confirm the suitability of our boolean modeling for prediction of human tumor growth after virus infection in the current study as well. In summary, these findings indicate that our boolean models could be a useful tool for testing of the efficacy of VACV-mediated cancer therapy already before its use in human patients. KW - boolean modeling KW - oncolytic virus KW - human xenografted mouse models KW - cancer therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200507 VL - 10 IS - 1 ER - TY - JOUR A1 - Derakhshani, Shaghayegh A1 - Kurz, Andreas A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Pilgram, Lisa A1 - Steinke, Maria A1 - Kleuser, Burkhard A1 - Sauer, Markus A1 - Schneider-Schaulies, Sibylle A1 - Avota, Elita T1 - Measles virus infection fosters dendritic cell motility in a 3D environment to enhance transmission to target cells in the respiratory epithelium JF - Frontiers in Immunology N2 - Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit. KW - dendritic cell KW - cell migration KW - measles virus KW - 3D tissue model KW - sphingosine-1-phosphate Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201818 VL - 10 IS - 1294 ER - TY - JOUR A1 - Paponov, Ivan A. A1 - Dindas , Julian A1 - Król , Elżbieta A1 - Friz, Tatyana A1 - Budnyk, Vadym A1 - Teale, William A1 - Paponov, Martina A1 - Hedrich , Rainer A1 - Palme, Klaus T1 - Auxin-Induced plasma membrane depolarization is regulated by Auxin transport and not by AUXIN BINDING PROTEIN1 JF - Frontiers in Plant Science N2 - Auxin is a molecule, which controls many aspects of plant development through both transcriptional and non-transcriptional signaling responses. AUXIN BINDING PROTEIN1 (ABP1) is a putative receptor for rapid non-transcriptional auxin-induced changes in plasma membrane depolarization and endocytosis rates. However, the mechanism of ABP1-mediated signaling is poorly understood. Here we show that membrane depolarization and endocytosis inhibition are ABP1-independent responses and that auxin-induced plasma membrane depolarization is instead dependent on the auxin influx carrier AUX1. AUX1 was itself not involved in the regulation of endocytosis. Auxin-dependent depolarization of the plasma membrane was also modulated by the auxin efflux carrier PIN2. These data establish a new connection between auxin transport and non-transcriptional auxin signaling. KW - auxin KW - ABP1 KW - plasma membrane depolarization KW - AUX1 KW - endocytosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195914 SN - 1664-462X VL - 9 ER - TY - JOUR A1 - Roth, Nicolas A1 - Doerfler, Inken A1 - Bässler, Claus A1 - Blaschke, Markus A1 - Bussler, Heinz A1 - Gossner, Martin M. A1 - Heideroth, Antje A1 - Thorn, Simon A1 - Weisser, Wolfgang W. A1 - Müller, Jörg T1 - Decadal effects of landscape-wide enrichment of dead wood on saproxylic organisms in beech forests of different historic management intensity JF - Diversity and Distributions N2 - Aim: European temperate forests have lost dead wood and the associated biodiversity owing to intensive management over centuries. Nowadays, some of these forests are being restored by enrichment with dead wood, but mostly only at stand scales. Here, we investigated effects of a seminal dead-wood enrichment strategy on saproxylic organisms at the landscape scale. Location: Temperate European beech forest in southern Germany. Methods: In a before-after control-impact design, we compared assemblages and gamma diversities of saproxylic organisms in strictly protected old-growth forest areas (reserves) and historically moderately and intensively managed forest areas before and a decade after starting a landscape-wide strategy of dead-wood enrichment. Results: Before enrichment with dead wood, the gamma diversity of saproxylic organisms in historically intensively managed forest stands was significantly lower than in reserves and historically moderately managed forest stands; this difference disappeared after 10 years of dead-wood enrichment. The species composition of beetles in forest stands of the three historical management intensities differed before the enrichment strategy, but a decade thereafter, the species compositions of previously intensively logged and forest reserve plots were similar. However, the differences in fungal species composition between historical management categories before and after 10 years of enrichment persisted. Main conclusions: Our results demonstrate that intentional enrichment of dead wood at the landscape scale is a powerful tool for rapidly restoring saproxylic beetle communities and for restoring wood-inhabiting fungal communities, which need longer than a decade for complete restoration. We propose that a strategy of area-wide active restoration combined with some permanent strict refuges is a promising means of promoting the biodiversity of age-long intensively managed Central European beech forests. KW - dead-wood enrichment KW - integrative management strategy KW - land sharing KW - lowland beech forests KW - saproxylic organisms Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227061 VL - 25 IS - 3 ER - TY - JOUR A1 - Liedtke, Daniel A1 - Orth, Melanie A1 - Meissler, Michelle A1 - Geuer, Sinje A1 - Knaup, Sabine A1 - Köblitz, Isabell A1 - Klopocki, Eva T1 - ECM alterations in fndc3a (fibronectin domain containing protein 3A) deficient zebrafish cause temporal fin development and regeneration defects JF - Scientific Reports N2 - Fin development and regeneration are complex biological processes that are highly relevant in teleost fish. They share genetic factors, signaling pathways and cellular properties to coordinate formation of regularly shaped extremities. Especially correct tissue structure defined by extracellular matrix (ECM) formation is essential. Gene expression and protein localization studies demonstrated expression of fndc3a (fibronectin domain containing protein 3a) in both developing and regenerating caudal fins of zebrafish (Danio rerio). We established a hypomorphic fndc3a mutant line (fndc3a\(^{wue1/wue1}\)) via CRISPR/Cas9, exhibiting phenotypic malformations and changed gene expression patterns during early stages of median fin fold development. These developmental effects are mostly temporary, but result in a fraction of adults with permanent tail fin deformations. In addition, caudal fin regeneration in adult fndc3a\(^{wue1/wue1}\) mutants is hampered by interference with actinotrichia formation and epidermal cell organization. Investigation of the ECM implies that loss of epidermal tissue structure is a common cause for both of the observed defects. Our results thereby provide a molecular link between these developmental processes and foreshadow Fndc3a as a novel temporal regulator of epidermal cell properties during extremity development and regeneration in zebrafish. KW - Extracellular matrix KW - Limb development KW - Self-renewal Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202141 VL - 9 ER - TY - JOUR A1 - Streinzer, Martin A1 - Chakravorty, Jharna A1 - Neumayer, Johann A1 - Megu, Karsing A1 - Narah, Jaya A1 - Schmitt, Thomas A1 - Bharti, Himender A1 - Spaethe, Johannes A1 - Brockmann, Axel T1 - Species composition and elevational distribution of bumble bees (Hymenoptera, Apidae, Bombus Latreille) in the East Himalaya, Arunachal Pradesh, India JF - ZooKeys N2 - The East Himalaya is one of the world’s most biodiverse ecosystems. However, very little is known about the abundance and distribution of many plant and animal taxa in this region. Bumble bees are a group of cold-adapted and high elevation insects that fulfil an important ecological and economical function as pollinators of wild and agricultural flowering plants and crops. The Himalayan mountain range provides ample suitable habitats for bumble bees. Systematic study of Himalayan bumble bees began a few decades ago and the main focus has centred on the western region, while the eastern part of the mountain range has received little attention and only a few species have been verified. During a three-year survey, more than 700 bumble bee specimens of 21 species were collected in Arunachal Pradesh, the largest of the north-eastern states of India. The material included a range of species that were previously known from a limited number of collected specimens, which highlights the unique character of the East Himalayan ecosystem. Our results are an important first step towards a future assessment of species distribution, threat, and conservation. Clear elevation patterns of species diversity were observed, which raise important questions about the functional adaptations that allow bumble bees to thrive in this particularly moist region in the East Himalaya. KW - Alpine habitats KW - Apidae KW - conservation KW - global change KW - insect collection KW - pollination Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201937 VL - 851 ER - TY - JOUR A1 - Eisenreich, Wolfgang A1 - Rudel, Thomas A1 - Heesemann, Jürgen A1 - Goebel, Werner T1 - How viral and intracellular bacterial pathogens reprogram the metabolism of host cells to allow their intracellular replication JF - Frontiers in Cellular and Infection Microbiology N2 - Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections. KW - metabolic adaptation KW - viruses KW - intracellular bacterial pathogens KW - metabolism of infected and uninfected host cells KW - reprogamming of host cell metabolism Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197188 SN - 2235-2988 VL - 9 ER - TY - JOUR A1 - Panzer, Sabine A1 - Brych, Annika A1 - Batschauer, Alfred A1 - Terpitz, Ulrich T1 - Opsin 1 and Opsin 2 of the corn smut fungus ustilago maydis are green light-driven proton pumps JF - Frontiers in Microbiology N2 - In fungi, green light is absorbed by rhodopsins, opsin proteins carrying a retinal molecule as chromophore. The basidiomycete Ustilago maydis, a fungal pathogen that infects corn plants, encodes three putative photoactive opsins, called ops1 (UMAG_02629), ops2 (UMAG_00371), and ops3 (UMAG_04125). UmOps1 and UmOps2 are expressed during the whole life cycle, in axenic cultures as well as in planta, whereas UmOps3 was recently shown to be absent in axenic cultures but highly expressed during plant infection. Here we show that expression of UmOps1 and UmOps2 is induced by blue light under control of white collar 1 (Wco1). UmOps1 is mainly localized in the plasma membrane, both when expressed in HEK cells and U. maydis sporidia. In contrast, UmOps2 was mostly found intracellularly in the membranes of vacuoles. Patch-clamp studies demonstrated that both rhodopsins are green light-driven outward rectifying proton pumps. UmOps1 revealed an extraordinary pH dependency with increased activity in more acidic environment. Also, UmOps1 showed a pronounced, concentration-dependent enhancement of pump current caused by weak organic acids (WOAs), especially by acetic acid and indole-3-acetic acid (IAA). In contrast, UmOps2 showed the typical behavior of light-driven, outwardly directed proton pumps, whereas UmOps3 did not exhibit any electrogenity. With this work, insights were gained into the localization and molecular function of two U. maydis rhodopsins, paving the way for further studies on the biological role of these rhodopsins in the life cycle of U. maydis. KW - Ustilago maydis KW - patch-clamp KW - fungal rhodopsins KW - microbial rhodopsins KW - acetate KW - indole-3-acetic acid KW - structured illumination microscopy KW - sporidia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201453 VL - 10 ER - TY - JOUR A1 - Kühnisch, Jirko A1 - Herbst, Christopher A1 - Al‐Wakeel‐Marquard, Nadya A1 - Dartsch, Josephine A1 - Holtgrewe, Manuel A1 - Baban, Anwar A1 - Mearini, Giulia A1 - Hardt, Juliane A1 - Kolokotronis, Konstantinos A1 - Gerull, Brenda A1 - Carrier, Lucie A1 - Beule, Dieter A1 - Schubert, Stephan A1 - Messroghli, Daniel A1 - Degener, Franziska A1 - Berger, Felix A1 - Klaassen, Sabine T1 - Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3 JF - Clinical Genetics N2 - The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP. KW - cardiomyopathy KW - genetics KW - pediatrics KW - sarcomere KW - TNNI3 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213958 VL - 96 IS - 6 SP - 549 EP - 559 ER - TY - JOUR A1 - Schartl, Manfred A1 - Kneitz, Susanne A1 - Volkoff, Helene A1 - Adolfi, Mateus A1 - Schmidt, Cornelia A1 - Fischer, Petra A1 - Minx, Patrick A1 - Tomlinson, Chad A1 - Meyer, Axel A1 - Warren, Wesley C. T1 - The piranha genome provides molecular insight associated to its unique feeding behavior JF - Genome Biology and Evolution N2 - The piranha enjoys notoriety due to its infamous predatory behavior but much is still not understood about its evolutionary origins and the underlying molecular mechanisms for its unusual feeding biology. We sequenced and assembled the red-bellied piranha (Pygocentrus nattereri) genome to aid future phenotypic and genetic investigations. The assembled draft genome is similar to other related fishes in repeat composition and gene count. Our evaluation of genes under positive selection suggests candidates for adaptations of piranhas’ feeding behavior in neural functions, behavior, and regulation of energy metabolism. In the fasted brain, we find genes differentially expressed that are involved in lipid metabolism and appetite regulation as well as genes that may control the aggression/boldness behavior of hungry piranhas. Our first analysis of the piranha genome offers new insight and resources for the study of piranha biology and for feeding motivation and starvation in other organisms. KW - whole-genome sequencing KW - genome annotation KW - comparative genomics KW - RNA-seq transcriptome KW - energy homeostasis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202218 VL - 11 IS - 8 ER -