Publications by authors named "Daniela Beisser"

28 Publications

  • Page 1 of 1

A multi-omics study on quantifying antimicrobial resistance in European freshwater lakes.

Environ Int 2021 12 14;157:106821. Epub 2021 Aug 14.

Department of Biodiversity, University of Duisburg-Essen, Universitätsstr. 5, Essen 45141, Germany.

The surveillance of wastewater for the Covid-19 virus during this unprecedented pandemic and mapped to the distribution and magnitude of the infected in the population near real-time exemplifies the importance of tracking rapidly changing trends of pathogens or public health problems at a large scale. The rising trends of antimicrobial resistance (AMR) with multidrug-resistant pathogens from the environmental water have similarly gained much attention in recent years. Wastewater-based epidemiology from water samples has shown that a wide range of AMR-related genes is frequently detected. Albeit sewage is treated before release and thus, the abundance of pathogens should be significantly reduced or even pathogen-free, several studies indicated the contrary. Pathogens are still measurable in the released water, ultimately entering freshwaters, such as rivers and lakes. Furthermore, socio-economic and environmental factors, such as chemical industries and animal farming nearby, impact the presence of AMR. Many bacterial species from the environment are intrinsically resistant and also contribute to the resistome of freshwater lakes. This study collected the most extensive standardized freshwater data set from hundreds of European lakes and conducted a comprehensive multi-omics analysis on antimicrobial resistance from these freshwater lakes. Our research shows that genes encoding for AMR against tetracyclines, cephalosporins, and quinolones were commonly identified, while for some, such as sulfonamides, resistance was less frequently present. We provide an estimation of the characteristic resistance of AMR in European lakes, which can be used as a comprehensive resistome dataset to facilitate and monitor temporal changes in the development of AMR in European freshwater lakes.
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http://dx.doi.org/10.1016/j.envint.2021.106821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364379PMC
December 2021

Nutrient-driven genome evolution revealed by comparative genomics of chrysomonad flagellates.

Commun Biol 2021 03 12;4(1):328. Epub 2021 Mar 12.

Department of Biodiversity, University of Duisburg-Essen, Essen, Germany.

Phototrophic eukaryotes have evolved mainly by the primary or secondary uptake of photosynthetic organisms. A return to heterotrophy occurred multiple times in various protistan groups such as Chrysophyceae, despite the expected advantage of autotrophy. It is assumed that the evolutionary shift to mixotrophy and further to heterotrophy is triggered by a differential importance of nutrient and carbon limitation. We sequenced the genomes of 16 chrysophyte strains and compared them in terms of size, function, and sequence characteristics in relation to photo-, mixo- and heterotrophic nutrition. All strains were sequenced with Illumina and partly with PacBio. Heterotrophic taxa have reduced genomes and a higher GC content of up to 59% as compared to phototrophic taxa. Heterotrophs have a large pan genome, but a small core genome, indicating a differential specialization of the distinct lineages. The pan genome of mixotrophs and heterotrophs taken together but not the pan genome of the mixotrophs alone covers the complete functionality of the phototrophic strains indicating a random reduction of genes. The observed ploidy ranges from di- to tetraploidy and was found to be independent of taxonomy or trophic mode. Our results substantiate an evolution driven by nutrient and carbon limitation.
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http://dx.doi.org/10.1038/s42003-021-01781-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954800PMC
March 2021

Quantification of the covariation of lake microbiomes and environmental variables using a machine learning-based framework.

Mol Ecol 2021 05 31;30(9):2131-2144. Epub 2021 Mar 31.

Faculty of Mathematics and Computer Science, University of Marburg, Marburg (Lahn), Germany.

It is known that microorganisms are essential for the functioning of ecosystems, but the extent to which microorganisms respond to different environmental variables in their natural habitats is not clear. In the current study, we present a methodological framework to quantify the covariation of the microbial community of a habitat and environmental variables of this habitat. It is built on theoretical considerations of systems ecology, makes use of state-of-the-art machine learning techniques and can be used to identify bioindicators. We apply the framework to a data set containing operational taxonomic units (OTUs) as well as more than twenty physicochemical and geographic variables measured in a large-scale survey of European lakes. While a large part of variation (up to 61%) in many environmental variables can be explained by microbial community composition, some variables do not show significant covariation with the microbial lake community. Moreover, we have identified OTUs that act as "multitask" bioindicators, i.e., that are indicative for multiple environmental variables, and thus could be candidates for lake water monitoring schemes. Our results represent, for the first time, a quantification of the covariation of the lake microbiome and a wide array of environmental variables for lake ecosystems. Building on the results and methodology presented here, it will be possible to identify microbial taxa and processes that are essential for functioning and stability of lake ecosystems.
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http://dx.doi.org/10.1111/mec.15872DOI Listing
May 2021

Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis.

Oncogenesis 2020 Nov 19;9(11):102. Epub 2020 Nov 19.

Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
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http://dx.doi.org/10.1038/s41389-020-00286-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369PMC
November 2020

Natrix: a Snakemake-based workflow for processing, clustering, and taxonomically assigning amplicon sequencing reads.

BMC Bioinformatics 2020 Nov 16;21(1):526. Epub 2020 Nov 16.

Department of Biodiversity, University of Duisburg-Essen, Essen, Germany.

Background: Sequencing of marker genes amplified from environmental samples, known as amplicon sequencing, allows us to resolve some of the hidden diversity and elucidate evolutionary relationships and ecological processes among complex microbial communities. The analysis of large numbers of samples at high sequencing depths generated by high throughput sequencing technologies requires efficient, flexible, and reproducible bioinformatics pipelines. Only a few existing workflows can be run in a user-friendly, scalable, and reproducible manner on different computing devices using an efficient workflow management system.

Results: We present Natrix, an open-source bioinformatics workflow for preprocessing raw amplicon sequencing data. The workflow contains all analysis steps from quality assessment, read assembly, dereplication, chimera detection, split-sample merging, sequence representative assignment (OTUs or ASVs) to the taxonomic assignment of sequence representatives. The workflow is written using Snakemake, a workflow management engine for developing data analysis workflows. In addition, Conda is used for version control. Thus, Snakemake ensures reproducibility and Conda offers version control of the utilized programs. The encapsulation of rules and their dependencies support hassle-free sharing of rules between workflows and easy adaptation and extension of existing workflows. Natrix is freely available on GitHub ( https://github.com/MW55/Natrix ) or as a Docker container on DockerHub ( https://hub.docker.com/r/mw55/natrix ).

Conclusion: Natrix is a user-friendly and highly extensible workflow for processing Illumina amplicon data.
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http://dx.doi.org/10.1186/s12859-020-03852-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667751PMC
November 2020

Factors shaping community patterns of protists and bacteria on a European scale.

Environ Microbiol 2020 06 6;22(6):2243-2260. Epub 2020 Apr 6.

Biodiversity, University of Duisburg-Essen, Universitätsstr. 5, 45141, Essen, Germany.

Factors shaping community patterns of microorganisms are controversially discussed. Physical and chemical factors certainly limit the survival of individual taxa and maintenance of diversity. In recent years, a contribution of geographic distance and dispersal barriers to distribution patterns of protists and bacteria has been demonstrated. Organismic interactions such as competition, predation and mutualism further modify community structure and maintenance of distinct taxa. Here, we address the relative importance of these different factors in shaping protists and bacterial communities on a European scale using high-throughput sequencing data obtained from lentic freshwater ecosystems. We show that community patterns of protists are similar to those of bacteria. Our results indicate that cross-domain organismic factors are important variables with a higher influence on protists as compared with bacteria. Abiotic physical and chemical factors also contributed significantly to community patterns. The contribution of these latter factors was higher for bacteria, which may reflect a stronger biogeochemical coupling. The contribution of geographical distance was similar for both microbial groups.
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http://dx.doi.org/10.1111/1462-2920.14992DOI Listing
June 2020

Propionate supplementation promotes the expansion of peripheral regulatory T-Cells in patients with end-stage renal disease.

J Nephrol 2020 Aug 6;33(4):817-827. Epub 2020 Mar 6.

Medical Department I , Centre for Translational Medicine, Marienhospital Herne, Universitätsklinikum Der Ruhr-Universität Bochum, Ruhr-Universität Bochum, Hölkeskampring 40, 44623, Herne, Germany.

Patients with end-stage renal disease (ESRD) suffer from a progressively increasing low-grade systemic inflammation, which is associated with higher morbidity and mortality. Regulatory T cells (Tregs) play an important role in regulation of the inflammatory process. Previously, it has been demonstrated that short-chain fatty acids reduce inflammation in the central nervous system in a murine model of multiple sclerosis through an increase in tissue infiltrating Tregs. Here, we evaluated the effect of the short-chain fatty acid propionate on the chronic inflammatory state and T-cell composition in ESRD patients. Analyzing ESRD patients and healthy blood donors before, during, and 60 days after the propionate supplementation by multiparametric flow cytometry we observed a gradual and significant expansion in the frequencies of CD25CD127 Tregs in both groups. Phenotypic characterization suggests that polarization of naïve T cells towards Tregs is responsible for the observed expansion. In line with this, we observed a significant reduction of inflammatory marker CRP under propionate supplementation. Of interest, the observed anti-inflammatory surroundings did not affect the protective pathogen-specific immunity as demonstrated by the stable frequencies of effector/memory T cells specific for tetanus/diphtheria recall antigens. Collectively, our data suggest that dietary supplements with propionate have a beneficial effect on the elevated systemic inflammation of ESRD patients. The effect can be achieved through an expansion of circulating Tregs without affecting the protective pathogen-reactive immunity.
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http://dx.doi.org/10.1007/s40620-019-00694-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381474PMC
August 2020

Ecological Differentiation in Two Major Freshwater Bacterial Taxa Along Environmental Gradients.

Front Microbiol 2020 13;11:154. Epub 2020 Feb 13.

Department of Biodiversity, University of Duisburg Essen, Essen, Germany.

(, ) and (, ) are abundant freshwater bacteria comprising large genetic and taxonomic diversities, with species adapted to physico-chemically distinct types of freshwater systems. The relative importance of environmental drivers, i.e., physico-chemistry, presence of microeukaryotes and geographic position for the diversity and prevalence has not been investigated for both taxa before. Here, we present the first pan-European study on this topic, comprising 255 freshwater lakes. We investigated and using an amplicon sequencing approach of partial 16S rRNA genes along environmental gradients. We show that physico-chemical factors had the greatest impact on both genera. Analyses on environmental gradients revealed an exceptionally broad ecological spectrum of operational taxonomic units (OTUs). Despite the coarse resolution of the genetic marker, we found OTUs with contrasting environmental preferences within and subclusters. Such an ecological differentiation has been characterized for PnecC and LimC before but was so far unknown for less well studied subclusters such as PnecA and PnecB. Richness and abundance of OTUs are geographically clustered, suggesting that geographic diversity patterns are attributable to region-specific physico-chemical characteristics (e.g., pH and temperature) rather than latitudinal gradients or lake sizes.
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http://dx.doi.org/10.3389/fmicb.2020.00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031163PMC
February 2020

Intraspecific Variation in Protists: Clues for Microevolution from Poteriospumella lacustris (Chrysophyceae).

Genome Biol Evol 2019 09;11(9):2492-2504

Department of Biodiversity, Duisburg-Essen, Germany.

Species delimitation in protists is still a challenge, attributable to the fact that protists are small, difficult to observe and many taxa are poor in morphological characters, whereas most current phylogenetic approaches only use few marker genes to measure genetic diversity. To address this problem, we assess genome-level divergence and microevolution in strains of the protist Poteriospumella lacustris, one of the first free-living, nonmodel organisms to study genome-wide intraspecific variation. Poteriospumella lacustris is a freshwater protist belonging to the Chrysophyceae with an assumed worldwide distribution. We examined three strains from different geographic regions (New Zealand, China, and Austria) by sequencing their genomes with the Illumina and PacBio platforms. The assembled genomes were small with 49-55 Mb but gene-rich with 16,000-19,000 genes, of which ∼8,000 genes could be assigned to functional categories. At least 68% of these genes were shared by all three species. Genetic variation occurred predominantly in genes presumably involved in ecological niche adaptation. Most surprisingly, we detected differences in genome ploidy between the strains (diploidy, triploidy, and tetraploidy). In analyzing intraspecific variation, several mechanisms of diversification were identified including SNPs, change of ploidy and genome size reduction.
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http://dx.doi.org/10.1093/gbe/evz171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738136PMC
September 2019

Interaction-Specific Changes in the Transcriptome of Caused by Varying Protistan Communities.

Front Microbiol 2019 9;10:1498. Epub 2019 Jul 9.

Biodiversity, University of Duisburg-Essen, Essen, Germany.

We studied the impact of protist grazing and exudation on the growth and transcriptomic response of the prokaryotic prey species . Different single- and multi-species communities of chrysophytes were used to determine a species-specific response to the predators and the effect of chrysophyte diversity. We sequenced the mRNA of in communities with three single chrysophyte species ( and ) and all combinations. The molecular responses of significantly changed in the presence of predators with different trophic modes and combinations of species. In the single-species samples we observed significant differences related to the relative importance of grazing and exudation in the protist-bacteria interaction, i.e., to the presence of either the heterotrophic or the mixotrophic . When grazing dominates the interaction, as in the presence of , genes acting in stress response are up-regulated. Further genes associated with transcription and translation are down-regulated indicating a reduced growth of . In contrast, when the potential use of algal exudates dominates the interaction, genes affiliated with iron transport are up-regulated. Rapid phototrophic growth of chrysophytes, with a high demand on soluble iron, could thus lead to iron-limitation and cause changes in the iron metabolism of . Additionally, we observe a benefit for from a more diverse protistan community, which could be due to shifts in the relative importance of phototrophy in the mixotrophic chrysophytes when competing for food with other species. Our study highlights the importance of biotic interactions and the specificity of such interactions, in particular the differential effect of grazing and algal exudation in the interaction of bacteria with mixotrophic protists.
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http://dx.doi.org/10.3389/fmicb.2019.01498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629928PMC
July 2019

Putatively asexual chrysophytes have meiotic genes: evidence from transcriptomic data.

PeerJ 2019 16;6:e5894. Epub 2019 Jan 16.

Department of Ecology, University of Kaiserslautern, Kaiserslautern, Germany.

Chrysophytes are a large group of heterotrophic, phototrophic, or even mixotrophic protists that are abundant in aquatic as well as terrestrial environments. Although much is known about chrysophyte biology and ecology, it is unknown if they are sexual or not. Here we use available transcriptomes of 18 isolates of 15 putatively asexual species to inventory the presence of genes used in meiosis. Since we were able to detect a set of nine meiosis-specific and 29 meiosis-related genes shared by the chrysophytes, we conclude that they are secretively sexual and therefore should be investigated further using genome sequencing to uncover any missed genes from the transcriptomes.
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http://dx.doi.org/10.7717/peerj.5894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339481PMC
January 2019

Silver stress differentially affects growth of phototrophic and heterotrophic chrysomonad flagellate populations.

Environ Pollut 2019 Jan 11;244:314-322. Epub 2018 Oct 11.

Aquatic Ecology, University of Duisburg-Essen, Universitätsstr. 5, 45141 Essen, Germany; Centre for Water and Environmental Research (ZWU), University of Duisburg-Essen, Universitätsstr. 5, 45141 Essen, Germany.

Silver ions are among the predominant anthropogenic introduced pollutants in aquatic systems. As silver has effects on species at all trophic levels the community composition in aquatic habitats can be changed as a result of silver stress. The response of planktonic protists to environmental stressors is particularly important as they act both as producers and consumers in complex planktonic communities. Chrysomonad flagellates are of major interest, since this group includes heterotrophic, mixotrophic and phototrophic taxa, and therefore allows analysis of silver stress in organisms with contrasting nutritional strategies independent of a potential taxonomic bias. In a series of lab experiments, we compared the response of different trophic chrysophyte strains to low (5 μg L), medium (10 μg L) and high (20 μg L) nominal Ag concentrations in combination with changes in temperature and light intensity (phototrophs), temperature and food concentration (heterotrophs), or a combination of the above settings (mixotrophs). All tested strains were negatively affected by silver in their growth rates. The phototrophic strains reacted strongly to silver stress, whereas light intensity and temperature had only minor effects on growth rates. For heterotrophic strains, high food concentration toned down the effect of silver, whereas temperatures outside the growth optimum had a combined stress effect. The mixotrophic strains reacted differently depending on whether their nutritional mode was dominated by heterotrophy or by phototrophy. The precise response pattern across all variables was uniquely different for every single species we tested. The present work contributes to a deeper understanding of the effects of environmental stressors on complex planktonic communities. It indicates that silver will negatively impact planktonic communities and may create shifts in their composition and functioning.
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http://dx.doi.org/10.1016/j.envpol.2018.09.146DOI Listing
January 2019

Evolution of heterotrophy in chrysophytes as reflected by comparative transcriptomics.

FEMS Microbiol Ecol 2018 04;94(4)

Biodiversity, Faculty of Biology, University of Duisburg-Essen, Universitätsstr. 5, D-45141 Essen, Germany.

Shifts in the nutritional mode between phototrophy, mixotrophy and heterotrophy are a widespread phenomenon in the evolution of eukaryotic diversity. The transition between nutritional modes is particularly pronounced in chrysophytes and occurred independently several times through parallel evolution. Thus, chrysophytes provide a unique opportunity for studying the molecular basis of nutritional diversification and of the accompanying pathway reduction and degradation of plastid structures. In order to analyze the succession in switching the nutritional mode from mixotrophy to heterotrophy, we compared the transcriptome of the mixotrophic Poterioochromonas malhamensis with the transcriptomes of three obligate heterotrophic species of Ochromonadales. We used the transcriptome of P. malhamensis as a reference for plastid reduction in the heterotrophic taxa. The analyzed heterotrophic taxa were in different stages of plastid reduction. We investigated the reduction of several photosynthesis related pathways e.g. the xanthophyll cycle, the mevalonate pathway, the shikimate pathway and the tryptophan biosynthesis as well as the reduction of plastid structures and postulate a presumable succession of pathway reduction and degradation of accompanying structures.
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http://dx.doi.org/10.1093/femsec/fiy039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019013PMC
April 2018

TaxMapper: an analysis tool, reference database and workflow for metatranscriptome analysis of eukaryotic microorganisms.

BMC Genomics 2017 Oct 16;18(1):787. Epub 2017 Oct 16.

Genome Informatics, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, Essen, 45147, Germany.

Background: High-throughput sequencing (HTS) technologies are increasingly applied to analyse complex microbial ecosystems by mRNA sequencing of whole communities, also known as metatranscriptome sequencing. This approach is at the moment largely limited to prokaryotic communities and communities of few eukaryotic species with sequenced genomes. For eukaryotes the analysis is hindered mainly by a low and fragmented coverage of the reference databases to infer the community composition, but also by lack of automated workflows for the task.

Results: From the databases of the National Center for Biotechnology Information and Marine Microbial Eukaryote Transcriptome Sequencing Project, 142 references were selected in such a way that the taxa represent the main lineages within each of the seven supergroups of eukaryotes and possess predominantly complete transcriptomes or genomes. From these references, we created an annotated microeukaryotic reference database. We developed a tool called TaxMapper for a reliably mapping of sequencing reads against this database and filtering of unreliable assignments. For filtering, a classifier was trained and tested on each of the following: sequences of taxa in the database, sequences of taxa related to those in the database, and random sequences. Additionally, TaxMapper is part of a metatranscriptomic Snakemake workflow developed to perform quality assessment, functional and taxonomic annotation and (multivariate) statistical analysis including environmental data. The workflow is provided and described in detail to empower researchers to apply it for metatranscriptome analysis of any environmental sample.

Conclusions: TaxMapper shows superior performance compared to standard approaches, resulting in a higher number of true positive taxonomic assignments. Both the TaxMapper tool and the workflow are available as open-source code at Bitbucket under the MIT license: https://bitbucket.org/dbeisser/taxmapper and as a Bioconda package: https://bioconda.github.io/recipes/taxmapper/README.html .
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http://dx.doi.org/10.1186/s12864-017-4168-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644092PMC
October 2017

Comprehensive transcriptome analysis provides new insights into nutritional strategies and phylogenetic relationships of chrysophytes.

PeerJ 2017 10;5:e2832. Epub 2017 Jan 10.

Biodiversity, University of Duisburg-Essen, Essen, Germany.

Background: Chrysophytes are protist model species in ecology and ecophysiology and important grazers of bacteria-sized microorganisms and primary producers. However, they have not yet been investigated in detail at the molecular level, and no genomic and only little transcriptomic information is available. Chrysophytes exhibit different trophic modes: while phototrophic chrysophytes perform only photosynthesis, mixotrophs can gain carbon from bacterial food as well as from photosynthesis, and heterotrophs solely feed on bacteria-sized microorganisms. Recent phylogenies and megasystematics demonstrate an immense complexity of eukaryotic diversity with numerous transitions between phototrophic and heterotrophic organisms. The question we aim to answer is how the diverse nutritional strategies, accompanied or brought about by a reduction of the plasmid and size reduction in heterotrophic strains, affect physiology and molecular processes.

Results: We sequenced the mRNA of 18 chrysophyte strains on the Illumina HiSeq platform and analysed the transcriptomes to determine relations between the trophic mode (mixotrophic vs. heterotrophic) and gene expression. We observed an enrichment of genes for photosynthesis, porphyrin and chlorophyll metabolism for phototrophic and mixotrophic strains that can perform photosynthesis. Genes involved in nutrient absorption, environmental information processing and various transporters (e.g., monosaccharide, peptide, lipid transporters) were present or highly expressed only in heterotrophic strains that have to sense, digest and absorb bacterial food. We furthermore present a transcriptome-based alignment-free phylogeny construction approach using transcripts assembled from short reads to determine the evolutionary relationships between the strains and the possible influence of nutritional strategies on the reconstructed phylogeny. We discuss the resulting phylogenies in comparison to those from established approaches based on ribosomal RNA and orthologous genes. Finally, we make functionally annotated reference transcriptomes of each strain available to the community, significantly enhancing publicly available data on Chrysophyceae.

Conclusions: Our study is the first comprehensive transcriptomic characterisation of a diverse set of Chrysophyceaen strains. In addition, we showcase the possibility of inferring phylogenies from assembled transcriptomes using an alignment-free approach. The raw and functionally annotated data we provide will prove beneficial for further examination of the diversity within this taxon. Our molecular characterisation of different trophic modes presents a first such example.
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http://dx.doi.org/10.7717/peerj.2832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228505PMC
January 2017

Quantitative Proteomics Reveals Ecophysiological Effects of Light and Silver Stress on the Mixotrophic Protist Poterioochromonas malhamensis.

PLoS One 2017 5;12(1):e0168183. Epub 2017 Jan 5.

Chemical Biology, Center for Medical Biotechnology (ZMB), Faculty of Biology, University of Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany.

Aquatic environments are heavily impacted by human activities including climate warming and the introduction of xenobiotics. Due to the application of silver nanoparticles as bactericidal agent the introduction of silver into the environment strongly has increased during the past years. Silver ions affect the primary metabolism of algae, in particular photosynthesis. Mixotrophic algae are an interesting test case as they do not exclusively rely on photosynthesis which may attenuate the harmful effect of silver. In order to study the effect of silver ions on mixotrophs, cultures of the chrysophyte Poterioochromonas malhamensis were treated in a replicate design in light and darkness with silver nitrate at a sub-lethal concentration. At five time points samples were taken for the identification and quantitation of proteins by mass spectrometry. In our analysis, relative quantitative protein mass spectrometry has shown to be a useful tool for functional analyses in conjunction with transcriptome reference sequences. A total of 3,952 proteins in 63 samples were identified and quantified, mapping to 4,829 transcripts of the sequenced and assembled transcriptome. Among them, 720 and 104 proteins performing various cellular functions were differentially expressed after eight days in light versus darkness and after three days of silver treatment, respectively. Specifically pathways of the energy and primary carbon metabolism were differentially affected by light and the utilization of expensive reactions hints to an energy surplus of P. malhamensis under light conditions. The excess energy is not invested in growth, but in the synthesis of storage metabolites. The effects of silver were less explicit, observable especially in the dark treatments where the light effect could not mask coinciding but weaker effects of silver. Photosynthesis, particularly the light harvesting complexes, and several sulphur containing enzymes were affected presumably due to a direct interference with the silver ions, mainly affecting energy supply.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168183PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215829PMC
August 2017

Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells.

Oncotarget 2016 11;7(46):74415-74426

Center for Neuropathology, Ludwig-Maximilians University, Munich, Germany.

Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies.
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http://dx.doi.org/10.18632/oncotarget.12766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342675PMC
November 2016

Trade-off between taxon diversity and functional diversity in European lake ecosystems.

Mol Ecol 2016 Dec 14;25(23):5876-5888. Epub 2016 Nov 14.

Biodiversity Department and Centre for Water and Environmental Research, University of Duisburg-Essen, 45141, Essen, Germany.

Inferring ecosystem functioning and ecosystem services through inspections of the species inventory is a major aspect of ecological field studies. Ecosystem functions are often stable despite considerable species turnover. Using metatranscriptome analyses, we analyse a thus-far unparalleled freshwater data set which comprises 21 mainland European freshwater lakes from the Sierra Nevada (Spain) to the Carpathian Mountains (Romania) and from northern Germany to the Apennines (Italy) and covers an altitudinal range from 38 m above sea level (a.s.l) to 3110 m a.s.l. The dominant taxa were Chlorophyta and streptophytic algae, Ciliophora, Bacillariophyta and Chrysophyta. Metatranscriptomics provided insights into differences in community composition and into functional diversity via the relative share of taxa to the overall read abundance of distinct functional genes on the ecosystem level. The dominant metabolic pathways in terms of the fraction of expressed sequences in the cDNA libraries were affiliated with primary metabolism, specifically oxidative phosphorylation, photosynthesis and the TCA cycle. Our analyses indicate that community composition is a good first proxy for the analysis of ecosystem functions. However, differential gene regulation modifies the relative importance of taxa in distinct pathways. Whereas taxon composition varies considerably between lakes, the relative importance of distinct metabolic pathways is much more stable, indicating that ecosystem functioning is buffered against shifts in community composition through a functional redundancy of taxa.
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http://dx.doi.org/10.1111/mec.13878DOI Listing
December 2016

Epigenetic dynamics of monocyte-to-macrophage differentiation.

Epigenetics Chromatin 2016 29;9:33. Epub 2016 Jul 29.

Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.

Background: Monocyte-to-macrophage differentiation involves major biochemical and structural changes. In order to elucidate the role of gene regulatory changes during this process, we used high-throughput sequencing to analyze the complete transcriptome and epigenome of human monocytes that were differentiated in vitro by addition of colony-stimulating factor 1 in serum-free medium.

Results: Numerous mRNAs and miRNAs were significantly up- or down-regulated. More than 100 discrete DNA regions, most often far away from transcription start sites, were rapidly demethylated by the ten eleven translocation enzymes, became nucleosome-free and gained histone marks indicative of active enhancers. These regions were unique for macrophages and associated with genes involved in the regulation of the actin cytoskeleton, phagocytosis and innate immune response.

Conclusions: In summary, we have discovered a phagocytic gene network that is repressed by DNA methylation in monocytes and rapidly de-repressed after the onset of macrophage differentiation.
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http://dx.doi.org/10.1186/s13072-016-0079-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967341PMC
August 2016

Human TLR8 senses UR/URR motifs in bacterial and mitochondrial RNA.

EMBO Rep 2015 Dec 6;16(12):1656-63. Epub 2015 Nov 6.

Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany

Toll-like receptor (TLR) 13 and TLR2 are the major sensors of Gram-positive bacteria in mice. TLR13 recognizes Sa19, a specific 23S ribosomal (r) RNA-derived fragment and bacterial modification of Sa19 ablates binding to TLR13, and to antibiotics such as erythromycin. Similarly, RNase A-treated Staphylococcus aureus activate human peripheral blood mononuclear cells (PBMCs) only via TLR2, implying single-stranded (ss) RNA as major stimulant. Here, we identify human TLR8 as functional TLR13 equivalent that promiscuously senses ssRNA. Accordingly, Sa19 and mitochondrial (mt) 16S rRNA sequence-derived oligoribonucleotides (ORNs) stimulate PBMCs in a MyD88-dependent manner. These ORNs, as well as S. aureus-, Escherichia coli-, and mt-RNA, also activate differentiated human monocytoid THP-1 cells, provided they express TLR8. Moreover, Unc93b1(-/-)- and Tlr8(-/-)-THP-1 cells are refractory, while endogenous and ectopically expressed TLR8 confers responsiveness in a UR/URR RNA ligand consensus motif-dependent manner. If TLR8 function is inhibited by suppression of lysosomal function, antibiotic treatment efficiently blocks bacteria-driven inflammatory responses in infected human whole blood cultures. Sepsis therapy might thus benefit from interfering with TLR8 function.
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http://dx.doi.org/10.15252/embr.201540861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687425PMC
December 2015

Mutational dynamics between primary and relapse neuroblastomas.

Nat Genet 2015 Aug 29;47(8):872-7. Epub 2015 Jun 29.

Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
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http://dx.doi.org/10.1038/ng.3349DOI Listing
August 2015

xHeinz: an algorithm for mining cross-species network modules under a flexible conservation model.

Bioinformatics 2015 Oct 27;31(19):3147-55. Epub 2015 May 27.

Life Sciences, Centrum Wiskunde & Informatica (CWI), Amsterdam, The Netherlands, Centre for Integrative Bioinformatics VU, VU University Amsterdam, The Netherlands, Erable Team, INRIA, Lyon, France.

Motivation: Integrative network analysis methods provide robust interpretations of differential high-throughput molecular profile measurements. They are often used in a biomedical context-to generate novel hypotheses about the underlying cellular processes or to derive biomarkers for classification and subtyping. The underlying molecular profiles are frequently measured and validated on animal or cellular models. Therefore the results are not immediately transferable to human. In particular, this is also the case in a study of the recently discovered interleukin-17 producing helper T cells (Th17), which are fundamental for anti-microbial immunity but also known to contribute to autoimmune diseases.

Results: We propose a mathematical model for finding active subnetwork modules that are conserved between two species. These are sets of genes, one for each species, which (i) induce a connected subnetwork in a species-specific interaction network, (ii) show overall differential behavior and (iii) contain a large number of orthologous genes. We propose a flexible notion of conservation, which turns out to be crucial for the quality of the resulting modules in terms of biological interpretability. We propose an algorithm that finds provably optimal or near-optimal conserved active modules in our model. We apply our algorithm to understand the mechanisms underlying Th17 T cell differentiation in both mouse and human. As a main biological result, we find that the key regulation of Th17 differentiation is conserved between human and mouse.

Availability And Implementation: xHeinz, an implementation of our algorithm, as well as all input data and results, are available at http://software.cwi.nl/xheinz and as a Galaxy service at http://services.cbib.u-bordeaux2.fr/galaxy in CBiB Tools.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btv316DOI Listing
October 2015

Effects of silver nitrate and silver nanoparticles on a planktonic community: general trends after short-term exposure.

PLoS One 2014 22;9(4):e95340. Epub 2014 Apr 22.

Aquatic Ecology and Centre for Water and Environmental Research, University of Duisburg-Essen, Essen, Germany.

Among metal pollutants silver ions are one of the most toxic forms, and have thus been assigned to the highest toxicity class. Its toxicity to a wide range of microorganisms combined with its low toxicity to humans lead to the development of a wealth of silver-based products in many bactericidal applications accounting to more than 1000 nano-technology-based consumer products. Accordingly, silver is a widely distributed metal in the environment originating from its different forms of application as metal, salt and nanoparticle. A realistic assessment of silver nanoparticle toxicity in natural waters is, however, problematic and needs to be linked to experimental approaches. Here we apply metatranscriptome sequencing allowing for elucidating reactions of whole communities present in a water sample to stressors. We compared the toxicity of ionic silver and ligand-free silver nanoparticles by short term exposure on a natural community of aquatic microorganisms. We analyzed the effects of the treatments on metabolic pathways and species composition on the eukaryote metatranscriptome level in order to describe immediate molecular responses of organisms using a community approach. We found significant differences between the samples treated with 5 µg/L AgNO3 compared to the controls, but no significant differences in the samples treated with AgNP compared to the control samples. Statistical analysis yielded 126 genes (KO-IDs) with significant differential expression with a false discovery rate (FDR) <0.05 between the control (KO) and AgNO3 (NO3) groups. A KEGG pathway enrichment analysis showed significant results with a FDR below 0.05 for pathways related to photosynthesis. Our study therefore supports the view that ionic silver rather than silver nanoparticles are responsible for silver toxicity. Nevertheless, our results highlight the strength of metatranscriptome approaches for assessing metal toxicity on aquatic communities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095340PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995725PMC
January 2015

Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum.

BMC Syst Biol 2012 Jun 19;6:72. Epub 2012 Jun 19.

Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, Würzburg 97074, Germany.

Background: Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress.

Results: In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurable metabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration.

Conclusions: The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner.
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http://dx.doi.org/10.1186/1752-0509-6-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534414PMC
June 2012

Robustness and accuracy of functional modules in integrated network analysis.

Bioinformatics 2012 Jul 11;28(14):1887-94. Epub 2012 May 11.

Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.

Motivation: High-throughput molecular data provide a wealth of information that can be integrated into network analysis. Several approaches exist that identify functional modules in the context of integrated biological networks. The objective of this study is 2-fold: first, to assess the accuracy and variability of identified modules and second, to develop an algorithm for deriving highly robust and accurate solutions.

Results: In a comparative simulation study accuracy and robustness of the proposed and established methodologies are validated, considering various sources of variation in the data. To assess this variation, we propose a jackknife resampling procedure resulting in an ensemble of optimal modules. A consensus approach summarizes the ensemble into one final module containing maximally robust nodes and edges. The resulting consensus module identifies and visualizes robust and variable regions by assigning support values to nodes and edges. Finally, the proposed approach is exemplified on two large gene expression studies: diffuse large B-cell lymphoma and acute lymphoblastic leukemia.
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http://dx.doi.org/10.1093/bioinformatics/bts265DOI Listing
July 2012

Transcriptome analysis in tardigrade species reveals specific molecular pathways for stress adaptations.

Bioinform Biol Insights 2012 23;6:69-96. Epub 2012 Apr 23.

Dept. of Bioinformatics, Biocenter University of Würzburg, 97074 Würzburg, Germany.

Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade Milnesium tardigradum were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from Hypsibius dujardini, revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for M. tardigradum are different from typical motifs known from higher animals. M. tardigradum and H. dujardini protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of M. tardigradum. These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and M. tardigradum in particular so highly stress resistant.
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http://dx.doi.org/10.4137/BBI.S9150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342025PMC
August 2012

BioNet: an R-Package for the functional analysis of biological networks.

Bioinformatics 2010 Apr 25;26(8):1129-30. Epub 2010 Feb 25.

Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.

Motivation: Increasing quantity and quality of data in transcriptomics and interactomics create the need for integrative approaches to network analysis. Here, we present a comprehensive R-package for the analysis of biological networks including an exact and a heuristic approach to identify functional modules.

Results: The BioNet package provides an extensive framework for integrated network analysis in R. This includes the statistics for the integration of transcriptomic and functional data with biological networks, the scoring of nodes as well as methods for network search and visualization.

Availability: The BioNet package and a tutorial are available from http://bionet.bioapps.biozentrum.uni-wuerzburg.de.
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http://dx.doi.org/10.1093/bioinformatics/btq089DOI Listing
April 2010

Tardigrade workbench: comparing stress-related proteins, sequence-similar and functional protein clusters as well as RNA elements in tardigrades.

BMC Genomics 2009 Oct 12;10:469. Epub 2009 Oct 12.

Dept of Bioinformatics, Biocenter University of Würzburg, 97074 Würzburg, Germany.

Background: Tardigrades represent an animal phylum with extraordinary resistance to environmental stress.

Results: To gain insights into their stress-specific adaptation potential, major clusters of related and similar proteins are identified, as well as specific functional clusters delineated comparing all tardigrades and individual species (Milnesium tardigradum, Hypsibius dujardini, Echiniscus testudo, Tulinus stephaniae, Richtersius coronifer) and functional elements in tardigrade mRNAs are analysed. We find that 39.3% of the total sequences clustered in 58 clusters of more than 20 proteins. Among these are ten tardigrade specific as well as a number of stress-specific protein clusters. Tardigrade-specific functional adaptations include strong protein, DNA- and redox protection, maintenance and protein recycling. Specific regulatory elements regulate tardigrade mRNA stability such as lox P DICE elements whereas 14 other RNA elements of higher eukaryotes are not found. Further features of tardigrade specific adaption are rapidly identified by sequence and/or pattern search on the web-tool tardigrade analyzer http://waterbear.bioapps.biozentrum.uni-wuerzburg.de. The work-bench offers nucleotide pattern analysis for promotor and regulatory element detection (tardigrade specific; nrdb) as well as rapid COG search for function assignments including species-specific repositories of all analysed data.

Conclusion: Different protein clusters and regulatory elements implicated in tardigrade stress adaptations are analysed including unpublished tardigrade sequences.
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http://dx.doi.org/10.1186/1471-2164-10-469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768748PMC
October 2009
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