TY - JOUR A1 - Sajko, Sara A1 - Grishkovskaya, Irina A1 - Kostan, Julius A1 - Graewert, Melissa A1 - Setiawan, Kim A1 - Trübestein, Linda A1 - Niedermüller, Korbinian A1 - Gehin, Charlotte A1 - Sponga, Antonio A1 - Puchinger, Martin A1 - Gavin, Anne-Claude A1 - Leonard, Thomas A. A1 - Svergun, Dimitri I. A1 - Smith, Terry K. A1 - Morriswood, Brooke A1 - Djinovic-Carugo, Kristina T1 - Structures of three MORN repeat proteins and a re-evaluation of the proposed lipid-binding properties of MORN repeats JF - PLoS One N2 - MORN (Membrane Occupation and Recognition Nexus) repeat proteins have a wide taxonomic distribution, being found in both prokaryotes and eukaryotes. Despite this ubiquity, they remain poorly characterised at both a structural and a functional level compared to other common repeats. In functional terms, they are often assumed to be lipid-binding modules that mediate membrane targeting. We addressed this putative activity by focusing on a protein composed solely of MORN repeats-Trypanosoma brucei MORN1. Surprisingly, no evidence for binding to membranes or lipid vesicles by TbMORN1 could be obtained either in vivo or in vitro. Conversely, TbMORN1 did interact with individual phospholipids. High- and low-resolution structures of the MORN1 protein from Trypanosoma brucei and homologous proteins from the parasites Toxoplasma gondii and Plasmodium falciparum were obtained using a combination of macromolecular crystallography, small-angle X-ray scattering, and electron microscopy. This enabled a first structure-based definition of the MORN repeat itself. Furthermore, all three structures dimerised via their C-termini in an antiparallel configuration. The dimers could form extended or V-shaped quaternary structures depending on the presence of specific interface residues. This work provides a new perspective on MORN repeats, showing that they are protein-protein interaction modules capable of mediating both dimerisation and oligomerisation. KW - recognition nexus domain KW - trypanosoma brucei KW - blood stream KW - phosphatidylserine transport KW - biological macromolecules KW - membrane occupation KW - solution scattering KW - molecular cloning KW - flagellar pocket KW - endocytosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231261 VL - 15 IS - 23 ER - TY - JOUR A1 - Krauss, Jochen A1 - Vikuk, Veronika A1 - Young, Carolyn A. A1 - Krischke, Markus A1 - Mueller, Martin J. A1 - Baerenfaller, Katja T1 - Correction: Krauss, J., et al. Epichloë endophyte infection rates and alkaloid content in commercially available grass seed mixtures in Europe. Microorganisms 2020, 8, 498 JF - Microorganisms N2 - No abstract available. KW - Epichloë KW - endophyte Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216254 SN - 2076-2607 VL - 8 IS - 10 ER - TY - JOUR A1 - Baur, Florentin A1 - Nietzer, Sarah L. A1 - Kunz, Meik A1 - Saal, Fabian A1 - Jeromin, Julian A1 - Matschos, Stephanie A1 - Linnebacher, Michael A1 - Walles, Heike A1 - Dandekar, Thomas A1 - Dandekar, Gudrun T1 - Connecting cancer pathways to tumor engines: a stratification tool for colorectal cancer combining human in vitro tissue models with boolean in silico models JF - Cancers N2 - To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification. KW - in silico simulation KW - 3D tissue models KW - colorectal cancer KW - BRAF mutation KW - targeted therapy KW - stratification Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193798 SN - 2072-6694 VL - 12 IS - 1 ER - TY - JOUR A1 - Beer, Katharina A1 - Helfrich-Förster, Charlotte T1 - Model and Non-model Insects in Chronobiology JF - Frontiers in Behavioral Neuroscience N2 - The fruit fly Drosophila melanogaster is an established model organism in chronobiology, because genetic manipulation and breeding in the laboratory are easy. The circadian clock neuroanatomy in D. melanogaster is one of the best-known clock networks in insects and basic circadian behavior has been characterized in detail in this insect. Another model in chronobiology is the honey bee Apis mellifera, of which diurnal foraging behavior has been described already in the early twentieth century. A. mellifera hallmarks the research on the interplay between the clock and sociality and complex behaviors like sun compass navigation and time-place-learning. Nevertheless, there are aspects of clock structure and function, like for example the role of the clock in photoperiodism and diapause, which can be only insufficiently investigated in these two models. Unlike high-latitude flies such as Chymomyza costata or D. ezoana, cosmopolitan D. melanogaster flies do not display a photoperiodic diapause. Similarly, A. mellifera bees do not go into “real” diapause, but most solitary bee species exhibit an obligatory diapause. Furthermore, sociality evolved in different Hymenoptera independently, wherefore it might be misleading to study the social clock only in one social insect. Consequently, additional research on non-model insects is required to understand the circadian clock in Diptera and Hymenoptera. In this review, we introduce the two chronobiology model insects D. melanogaster and A. mellifera, compare them with other insects and show their advantages and limitations as general models for insect circadian clocks. KW - circadian clock KW - complex behavior KW - diapause KW - sociality KW - Drosophila melanogaster KW - Apis mellifera Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218721 SN - 1662-5153 VL - 14 ER - TY - JOUR A1 - Bae, Soyeon A1 - Heidrich, Lea A1 - Levick, Shaun R. A1 - Gossner, Martin M. A1 - Seibold, Sebastian A1 - Weisser, Wolfgang W. A1 - Magdon, Paul A1 - Serebryanyk, Alla A1 - Bässler, Claus A1 - Schäfer, Deborah A1 - Schulze, Ernst-Detlef A1 - Doerfler, Inken A1 - Müller, Jörg A1 - Jung, Kirsten A1 - Heurich, Marco A1 - Fischer, Markus A1 - Roth, Nicolas A1 - Schall, Peter A1 - Boch, Steffen A1 - Wöllauer, Stephan A1 - Renner, Swen C. A1 - Müller, Jörg T1 - Dispersal ability, trophic position and body size mediate species turnover processes: Insights from a multi-taxa and multi-scale approach JF - Diversity and Distribution N2 - Aim: Despite increasing interest in β-diversity, that is the spatial and temporal turnover of species, the mechanisms underlying species turnover at different spatial scales are not fully understood, although they likely differ among different functional groups. We investigated the relative importance of dispersal limitations and the environmental filtering caused by vegetation for local, multi-taxa forest communities differing in their dispersal ability, trophic position and body size. Location: Temperate forests in five regions across Germany. Methods: In the inter-region analysis, the independent and shared effects of the regional spatial structure (regional species pool), landscape spatial structure (dispersal limitation) and environmental factors on species turnover were quantified with a 1-ha grain across 11 functional groups in up to 495 plots by variation partitioning. In the intra-region analysis, the relative importance of three environmental factors related to vegetation (herb and tree layer composition and forest physiognomy) and spatial structure for species turnover was determined. Results: In the inter-region analysis, over half of the explained variation in community composition (23% of the total explained 35%) was explained by the shared effects of several factors, indicative of spatially structured environmental filtering. Among the independent effects, environmental factors were the strongest on average over 11 groups, but the importance of landscape spatial structure increased for less dispersive functional groups. In the intra-region analysis, the independent effect of plant species composition had a stronger influence on species turnover than forest physiognomy, but the relative importance of the latter increased with increasing trophic position and body size. Main conclusions: Our study revealed that the mechanisms structuring assemblage composition are associated with the traits of functional groups. Hence, conservation frameworks targeting biodiversity of multiple groups should cover both environmental and biogeographical gradients. Within regions, forest management can enhance β-diversity particularly by diversifying tree species composition and forest physiognomy. KW - body size KW - dispersal ability KW - environmental filtering KW - forest physiognomy KW - neutral processes KW - plant composition KW - regional species pool KW - species turnover KW - trophic position KW - β-diversity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236117 VL - 27 IS - 3 ER - TY - JOUR A1 - Jessen, Christina A1 - Kreß, Julia K. C. A1 - Baluapuri, Apoorva A1 - Hufnagel, Anita A1 - Schmitz, Werner A1 - Kneitz, Susanne A1 - Roth, Sabine A1 - Marquardt, André A1 - Appenzeller, Silke A1 - Ade, Casten P. A1 - Glutsch, Valerie A1 - Wobser, Marion A1 - Friedmann-Angeli, José Pedro A1 - Mosteo, Laura A1 - Goding, Colin R. A1 - Schilling, Bastian A1 - Geissinger, Eva A1 - Wolf, Elmar A1 - Meierjohann, Svenja T1 - The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression JF - Oncogene N2 - The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma. KW - NRF2 KW - melanoma malignancy KW - COX2 expression Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235064 SN - 0950-9232 VL - 39 ER - TY - JOUR A1 - Isaacs, Darren A1 - Mikasi, Sello Given A1 - Obasa, Adetayo Emmanuel A1 - Ikomey, George Mondinde A1 - Shityakov, Sergey A1 - Cloete, Ruben A1 - Jacobs, Graeme Brendon T1 - Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors JF - Viruses N2 - The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance. KW - integrase KW - naturally occurring polymorphisms KW - HIV-1 KW - molecular modelling KW - molecular docking KW - diversity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211170 SN - 1999-4915 VL - 12 IS - 9 ER - TY - JOUR A1 - Leal, Andrea Zurita A1 - Schwebs, Marie A1 - Briggs, Emma A1 - Weisert, Nadine A1 - Reis, Helena A1 - Lemgruber, Leondro A1 - Luko, Katarina A1 - Wilkes, Jonathan A1 - Butter, Falk A1 - McCulloch, Richard A1 - Janzen, Christian J. T1 - Genome maintenance functions of a putative Trypanosoma brucei translesion DNA polymerase include telomere association and a role in antigenic variation JF - Nucleic Acids Research N2 - Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to off-spring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of one putative translesion Pol in African trypanosomes, which we now name TbPolIE. Previously, we demonstrated that TbPolIE is associated with telomeric sequences and here we show that RNAi-mediated depletion of TbPolIE transcripts results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. We also show that TbPolIE displays pronounced localization at the nuclear periphery, and that its depletion leads to chromosome segregation defects and increased levels of endogenous DNA damage. Finally, we demonstrate that TbPolIE depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this putative translesion DNA polymerase to host immune evasion by antigenic variation. KW - cross-link repair KW - cell cycle KW - gene expression KW - low fidelity KW - replication KW - bypass KW - theta KW - reveals KW - binding Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230579 VL - 48 IS - 17 ER - TY - JOUR A1 - Stiegler, Jonas A1 - von Hoermann, Christian A1 - Müller, Jörg A1 - Benbow, M. Eric A1 - Heurich, Marco T1 - Carcass provisioning for scavenger conservation in a temperate forest ecosystem JF - Ecosphere N2 - Carrion plays an essential role in shaping the structure and functioning of ecosystems and has far‐reaching implications for biodiversity conservation. The change in availability and type of carcasses throughout ecosystems can involve negative effects for scavenging communities. To address this issue, there have been recent conservation management measures of carrion provision in natural systems. However, the optimal conditions under which exposing carcasses to optimize conservation outcomes are still limited. Here, we used camera traps throughout elevational and vegetational gradients to monitor the consumption of 48 deer carcasses over a study period of six years by evaluating 270,279 photographs resulting out of 15,373 trap nights. We detected 17 species visiting carcass deployments, including five endangered species. Our results show that large carcasses, the winter season, and a heterogeneous surrounding habitat enhanced the frequency of carcass visits and the species richness of scavenger assemblages. Contrary to our expectations, carcass species, condition (fresh/frozen), and provision schedule (continuous vs single exposure) did not influence scavenging frequency or diversity. The carcass visitation frequency increased with carcass mass and lower temperatures. The effect of large carcasses was especially pronounced for mesopredators and the Eurasian lynx (Lynx lynx). Lynx were not too influenced in its carrion acquisition by the season, but exclusively preferred remote habitats containing higher forest cover. Birds of prey, mesopredators, and top predators were also positively influenced by the visiting rate of ravens (Corvus corax), whereas no biotic or abiotic preferences were found for wild boars (Sus scrofa). This study provides evidence that any ungulate species of carrion, either in a fresh or in previously frozen condition, attracts a high diversity of scavengers especially during winter, thereby supporting earlier work that carcass provisions may support scavenger communities and endangered species. KW - anthropogenic food subsidies KW - carrion ecology KW - diversity KW - nature conservation KW - necrobiome KW - vertebrate scavenger KW - wildlife management Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218054 VL - 11 IS - 4 ER - TY - JOUR A1 - Naseem, Muhammad A1 - Othman, Eman M. A1 - Fathy, Moustafa A1 - Iqbal, Jibran A1 - Howari, Fares M. A1 - AlRemeithi, Fatima A. A1 - Kodandaraman, Geema A1 - Stopper, Helga A1 - Bencurova, Elena A1 - Vlachakis, Dimitrios A1 - Dandekar, Thomas T1 - Integrated structural and functional analysis of the protective effects of kinetin against oxidative stress in mammalian cellular systems JF - Scientific Reports N2 - Metabolism and signaling of cytokinins was first established in plants, followed by cytokinin discoveries in all kingdoms of life. However, understanding of their role in mammalian cells is still scarce. Kinetin is a cytokinin that mitigates the effects of oxidative stress in mammalian cells. The effective concentrations of exogenously applied kinetin in invoking various cellular responses are not well standardized. Likewise, the metabolism of kinetin and its cellular targets within the mammalian cells are still not well studied. Applying vitality tests as well as comet assays under normal and hyper-oxidative states, our analysis suggests that kinetin concentrations of 500 nM and above cause cytotoxicity as well as genotoxicity in various cell types. However, concentrations below 100 nM do not cause any toxicity, rather in this range kinetin counteracts oxidative burst and cytotoxicity. We focus here on these effects. To get insights into the cellular targets of kinetin mediating these pro-survival functions and protective effects we applied structural and computational approaches on two previously testified targets for these effects. Our analysis deciphers vital residues in adenine phosphoribosyltransferase (APRT) and adenosine receptor (A2A-R) that facilitate the binding of kinetin to these two important human cellular proteins. We finally discuss how the therapeutic potential of kinetin against oxidative stress helps in various pathophysiological conditions. KW - cytokinins KW - 6-benzylaminopurine Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231317 VL - 10 ER -