Publications

@article{Gerresheim:20,

title = {Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication},

author = {Gesche K. Gerresheim and Carolin S. Hess and Lyudmila A. Shalamova and Markus Fricke and Manja Marz and Dmitri E. Andreev and Ivan N. Shatsky and Michael Niepmann},

doi = {10.3390/ijms21186955},

year  = {2020},

date = {2020-09-22},

urldate = {2020-09-22},

journal = {Int J Mol Sci},

volume = {21},

number = {18},

pages = {6955},

publisher = {MDPI AG},

abstract = {Hepatitis C virus (HCV) infects liver cells and often causes chronic infection, also leading to liver cirrhosis and cancer. In the cytoplasm, the viral structural and non-structural (NS) proteins are directly translated from the plus strand HCV RNA genome. The viral proteins NS3 to NS5B proteins constitute the replication complex that is required for RNA genome replication via a minus strand antigenome. The most C-terminal protein in the genome is the NS5B replicase, which needs to initiate antigenome RNA synthesis at the very 3′-end of the plus strand. Using ribosome profiling of cells replicating full-length infectious HCV genomes, we uncovered that ribosomes accumulate at the HCV stop codon and about 30 nucleotides upstream of it. This pausing is due to the presence of conserved rare, inefficient Wobble codons upstream of the termination site. Synonymous substitution of these inefficient codons to efficient codons has negative consequences for viral RNA replication but not for viral protein synthesis. This pausing may allow the enzymatically active replicase core to find its genuine RNA template in cis, while the protein is still held in place by being stuck with its C-terminus in the exit tunnel of the paused ribosome.

},

keywords = {cancer, liver, ncRNAs, RNA structure, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Collatz:20,

title = {EpiDope: A Deep Neural Network for linear B-cell epitope prediction},

author = {Maximilian Collatz and Florian Mock and Emanuel Barth and Martin Hölzer and Konrad Sachse and Manja Marz},

editor = {Lenore Cowen},

url = {http://github.com/mcollatz/EpiDope},

doi = {10.1093/bioinformatics/btaa773},

year  = {2020},

date = {2020-09-11},

urldate = {2020-09-11},

journal = {Bioinformatics},

volume = {37},

number = {4},

pages = {448–455},

publisher = {Oxford University Press (OUP)},

abstract = {By binding to specific structures on antigenic proteins, the so-called epitopes, B-cell antibodies can neutralize pathogens. The identification of B-cell epitopes is of great value for the development of specific serodiagnostic assays and the optimization of medical therapy. However, identifying diagnostically or therapeutically relevant epitopes is a challenging task that usually involves extensive laboratory work. In this study, we show that the time, cost and labor-intensive process of epitope detection in the lab can be significantly reduced using in silico prediction.

Here, we present EpiDope, a python tool which uses a deep neural network to detect linear B-cell epitope regions on individual protein sequences. With an area under the curve between 0.67 ± 0.07 in the receiver operating characteristic curve, EpiDope exceeds all other currently used linear B-cell epitope prediction tools. Our software is shown to reliably predict linear B-cell epitopes of a given protein sequence, thus contributing to a significant reduction of laboratory experiments and costs required for the conventional approach.},

keywords = {machine learning, software, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Mock:20,

title = {VIDHOP, viral host prediction with Deep Learning},

author = {Florian Mock and Adrian Viehweger and Emanuel Barth and Manja Marz},

editor = {Jinbo Xu},

url = {https://github.com/flomock/vidhop},

doi = {10.1093/bioinformatics/btaa705},

year  = {2020},

date = {2020-08-10},

urldate = {2020-08-10},

journal = {Bioinformatics},

volume = {37},

number = {3},

pages = {318–325},

publisher = {Oxford University Press (OUP)},

abstract = {Zoonosis, the natural transmission of infections from animals to humans, is a far-reaching global problem. The recent outbreaks of Zikavirus, Ebolavirus and Coronavirus are examples of viral zoonosis, which occur more frequently due to globalization. In case of a virus outbreak, it is helpful to know which host organism was the original carrier of the virus to prevent further spreading of viral infection. Recent approaches aim to predict a viral host based on the viral genome, often in combination with the potential host genome and arbitrarily selected features. These methods are limited in the number of different hosts they can predict or the accuracy of the prediction.

Here, we present a fast and accurate deep learning approach for viral host prediction, which is based on the viral genome sequence only. We tested our deep neural network (DNN) on three different virus species (influenza A virus, rabies lyssavirus and rotavirus A). We achieved for each virus species an AUC between 0.93 and 0.98, allowing highly accurate predictions while using only fractions (100–400 bp) of the viral genome sequences. We show that deep neural networks are suitable to predict the host of a virus, even with a limited amount of sequences and highly unbalanced available data. The trained DNNs are the core of our virus–host prediction tool VIrus Deep learning HOst Prediction (VIDHOP). VIDHOP also allows the user to train and use models for other viruses.},

keywords = {machine learning, software, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Schulte-Schrepping:20,

title = {Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment},

author = {Jonas Schulte-Schrepping and Nico Reusch and Daniela Paclik and Kevin Baßler and Stephan Schlickeiser and Bowen Zhang and Benjamin Krämer and Tobias Krammer and Sophia Brumhard and Lorenzo Bonaguro and Elena De Domenico and Daniel Wendisch and Martin Grasshoff and Theodore S. Kapellos and Michael Beckstette and Tal Pecht and Adem Saglam and Oliver Dietrich and Henrik E. Mei and Axel R. Schulz and Claudia Conrad and Désirée Kunkel and Ehsan Vafadarnejad and Cheng-Jian Xu and Arik Horne and Miriam Herbert and Anna Drews and Charlotte Thibeault and Moritz Pfeiffer and Stefan Hippenstiel and Andreas Hocke and Holger Müller-Redetzky and Katrin-Moira Heim and Felix Machleidt and Alexander Uhrig and Laure Bosquillon Jarcy and Linda Jürgens and Miriam Stegemann and Christoph R. Glösenkamp and Hans-Dieter Volk and Christine Goffinet and Markus Landthaler and Emanuel Wyler and Philipp Georg and Maria Schneider and Chantip Dang-Heine and Nick Neuwinger and Kai Kappert and Rudolf Tauber and Victor Corman and Jan Raabe and Kim Melanie Kaiser and Michael To Vinh and Gereon Rieke and Christian Meisel and Thomas Ulas and Matthias Becker and Robert Geffers and Martin Witzenrath and Christian Drosten and Norbert Suttorp and Christof Kalle and Florian Kurth and Kristian Händler and Joachim L. Schultze and Anna C. Aschenbrenner and Yang Li and Jacob Nattermann and Birgit Sawitzki and Antoine-Emmanuel Saliba and Leif Erik Sander and Deutsche COVID-19 OMICS Initiative (DeCOI)

},

doi = {10.1016/j.cell.2020.08.001},

year  = {2020},

date = {2020-08-05},

urldate = {2020-01-01},

journal = {Cell},

volume = {182},

number = {6},

pages = {1419-1440.e23},

publisher = {Elsevier BV},

abstract = {Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.},

keywords = {coronavirus, RNA / transcriptomics, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Overholt:20,

title = {Inclusion of Oxford Nanopore long reads improves all microbial and viral metagenome-assembled genomes from a complex aquifer system},

author = {Will A. Overholt and Martin Hölzer and Patricia Geesink and Celia Diezel and Manja Marz and Kirsten Küsel},

doi = {10.1111/1462-2920.15186},

year  = {2020},

date = {2020-08-05},

urldate = {2020-08-05},

journal = {Environ Microbiol},

volume = {22},

number = {9},

pages = {4000-4013},

publisher = {Wiley},

abstract = {Assembling microbial and viral genomes from metagenomes is a powerful and appealing method to understand structure–function relationships in complex environments. To compare the recovery of genomes from microorganisms and their viruses from groundwater, we generated shotgun metagenomes with Illumina sequencing accompanied by long reads derived from the Oxford Nanopore Technologies (ONT) sequencing platform. Assembly and metagenome-assembled genome (MAG) metrics for both microbes and viruses were determined from an Illumina-only assembly, ONT-only assembly, and a hybrid assembly approach. The hybrid approach recovered 2× more mid to high-quality MAGs compared to the Illumina-only approach and 4× more than the ONT-only approach. A similar number of viral genomes were reconstructed using the hybrid and ONT methods, and both recovered nearly fourfold more viral genomes than the Illumina-only approach. While yielding fewer MAGs, the ONT-only approach generated MAGs with a high probability of containing rRNA genes, 3× higher than either of the other methods. Of the shared MAGs recovered from each method, the ONT-only approach generated the longest and least fragmented MAGs, while the hybrid approach yielded the most complete. This work provides quantitative data to inform a cost–benefit analysis of the decision to supplement shotgun metagenomic projects with long reads towards the goal of recovering genomes from environmentally abundant groups.},

keywords = {assembly, DNA / genomics, groundwater, metagenomics, nanopore, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Hoelzer:20a,

title = {PoSeiDon: a Nextflow pipeline for the detection of evolutionary recombination events and positive selection},

author = {Martin Hölzer and Manja Marz},

editor = {Alfonso Valencia},

url = {https://github.com/hoelzer/poseidon},

doi = {10.1093/bioinformatics/btaa695},

year  = {2020},

date = {2020-07-31},

urldate = {2020-07-31},

journal = {Bioinformatics},

volume = {37},

number = {7},

pages = {1018-1020},

publisher = {Oxford University Press (OUP)},

abstract = {PoSeiDon is an easy-to-use pipeline that helps researchers to find recombination events and sites under positive selection in protein-coding sequences. By entering homologous sequences, PoSeiDon builds an alignment, estimates a best-fitting substitution model and performs a recombination analysis followed by the construction of all corresponding phylogenies. Finally, significantly positive selected sites are detected according to different models for the full alignment and possible recombination fragments. The results of PoSeiDon are summarized in a user-friendly HTML page providing all intermediate results and the graphical representation of recombination events and positively selected sites.



},

keywords = {alignment, evolution, phylogenetics, software},

pubstate = {published},

tppubtype = {article}

}

@article{Hufsky:20,

title = {Computational Strategies to Combat COVID-19: Useful Tools to Accelerate SARS-CoV-2 and Coronavirus Research},

author = {Franziska Hufsky and Kevin Lamkiewicz and Alexandre Almeida and Abdel Aouacheria and Cecilia Arighi and Alex Bateman and Jan Baumbach and Niko Beerenwinkel and Christian Brandt and Marco Cacciabue and Sara Chuguransky and Oliver Drechsel and Robert D. Finn and Adrian Fritz and Stephan Fuchs and Georges Hattab and Anne-Christin Hauschild and Dominik Heider and Marie Hoffmann and Martin Hölzer and Stefan Hoops and Lars Kaderali and Ioanna Kalvari and Max Kleist and Rene Kmiecinski and Denise Kühnert and Gorka Lasso and Pieter Libin and Markus List and Hannah F. Löchel and Maria J. Martin and Roman Martin and Julian Matschinske and Alice C. McHardy and Pedro Mendes and Jaina Mistry and Vincent Navratil and Eric Nawrocki and Áine Niamh O'Toole and Nancy Palacios-Ontiveros and Anton I. Petrov and Guillermo Rangel-Piñeros and Nicole Redaschi and Susanne Reimering and Knut Reinert and Alejandro Reyes and Lorna Richardson and David L. Robertson and Sepideh Sadegh and Joshua B. Singer and Kristof Theys and Chris Upton and Marius Welzel and Lowri Williams and Manja Marz},

doi = {10.20944/preprints202005.0376.v1},

year  = {2020},

date = {2020-05-23},

urldate = {2020-05-23},

journal = {Preprints},

publisher = {MDPI AG},

abstract = {SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding, and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are freely available online, either through web applications or public code repositories.

},

note = {Now published in Brief Bioinform: https://dx.doi.org/10.1093/bib/bbaa232},

keywords = {coronavirus, evolution, review, software, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Samuel:20,

title = {A virtual "Werkstatt" for digitization in the sciences},

author = {Sheeba Samuel and Maha Shadaydeh and Sebastian Böcker and Bernd Brügmann and Solveig Franziska Bucher and Volker Deckert and Joachim Denzler and Peter Dittrich and Ferdinand Eggeling and Daniel Güllmar and Orlando Guntinas-Lichius and Birgitta König-Ries and Frank Löffler and Lutz Maicher and Manja Marz and Mirco Migliavacca and Jürgen R. Reichenbach and Markus Reichstein and Christine Römermann and Andrea Wittig},

doi = {10.3897/rio.6.e54106},

year  = {2020},

date = {2020-05-11},

urldate = {2020-01-01},

journal = {Res Ideas Outcomes},

volume = {6},

pages = {e54106},

publisher = {Pensoft Publishers},

abstract = {Data is central in almost all scientific disciplines nowadays. Furthermore, intelligent systems have developed rapidly in recent years, so that in many disciplines the expectation is emerging that with the help of intelligent systems, significant challenges can be overcome and science can be done in completely new ways. In order for this to succeed, however, first, fundamental research in computer science is still required, and, second, generic tools must be developed on which specialized solutions can be built. In this paper, we introduce a recently started collaborative project funded by the Carl Zeiss Foundation, a virtual manufactory for digitization in the sciences, the “Werkstatt”, which is being established at the Michael Stifel Center Jena (MSCJ) for data-driven and simulation science to address fundamental questions in computer science and applications. The Werkstatt focuses on three key areas, which include generic tools for machine learning, knowledge generation using machine learning processes, and semantic methods for the data life cycle, as well as the application of these topics in different disciplines. Core and pilot projects address the key aspects of the topics and form the basis for sustainable work in the Werkstatt.},

keywords = {machine learning},

pubstate = {published},

tppubtype = {article}

}

@article{VanDamme:20,

title = {Metagenomics workflow for hybrid assembly, differential coverage binning, transcriptomics and pathway analysis (MUFFIN)},

author = {Renaud Van Damme and Martin Hölzer and Adrian Viehweger and Bettina Müller and Erik Bongcam-Rudloff and Christian Brandt},

doi = {10.1101/2020.02.08.939843},

year  = {2020},

date = {2020-02-08},

urldate = {2020-02-08},

journal = {bioRxiv},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Metagenomics has redefined many areas of microbiology. However, metagenome-assembled genomes (MAGs) are often fragmented, primarily when sequencing was performed with short reads. Recent long-read sequencing technologies promise to improve genome reconstruction. However, the integration of two different sequencing modalities makes downstream analyses complex. We, therefore, developed MUFFIN, a complete metagenomic workflow that uses short and long reads to produce high-quality bins and their annotations. The workflow is written by using Nextflow, a workflow orchestration software, to achieve high reproducibility and fast and straightforward use. This workflow also produces the taxonomic classification and KEGG pathways of the bins and can be further used by providing RNA-Seq data (optionally) for quantification and annotation. We tested the workflow using twenty biogas reactor samples and assessed the capacity of MUFFIN to process and output relevant files needed to analyze the microbial community and their function. MUFFIN produces functional pathway predictions and if provided de novo transcript annotations across the metagenomic sample and for each bin.



},

note = {Now published in PLOS Comput Biol: https://dx.doi.org/10.1371/journal.pcbi.1008716},

keywords = {annotation, assembly, classification, DNA / genomics, metagenomics, RNA / transcriptomics, software},

pubstate = {published},

tppubtype = {article}

}

@article{Hölzer:20,

title = {Comparative Genome Analysis of 33 \textit{Chlamydia} Strains Reveals Characteristic Features of \textit{Chlamydia Psittaci} and Closely Related Species},

author = {Martin Hölzer and Lisa-Marie Barf and Kevin Lamkiewicz and Fabien Vorimore and Marie Lataretu and Alison Favaroni and Christiane Schnee and Karine Laroucau and Manja Marz and Konrad Sachse},

url = {github.com/hoelzer-lab/ribap},

doi = {10.3390/pathogens9110899},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Pathogens},

volume = {9},

number = {11},

pages = {899},

publisher = {MDPI AG},

abstract = {To identify genome-based features characteristic of the avian and human pathogen Chlamydia (C.) psittaci and related chlamydiae, we analyzed whole-genome sequences of 33 strains belonging to 12 species. Using a novel genome analysis tool termed Roary ILP Bacterial Annotation Pipeline (RIBAP), this panel of strains was shown to share a large core genome comprising 784 genes and representing approximately 80% of individual genomes. Analyzing the most variable genomic sites, we identified a set of features of C. psittaci that in its entirety is characteristic of this species: (i) a relatively short plasticity zone of less than 30,000 nt without a tryptophan operon (also in C. abortus, C. avium, C. gallinacea, C. pneumoniae), (ii) a characteristic set of of Inc proteins comprising IncA, B, C, V, X, Y (with homologs in C. abortus, C. caviae and C. felis as closest relatives), (iii) a 502-aa SinC protein, the largest among Chlamydia spp., and (iv) an elevated number of Pmp proteins of subtype G (14 in C. psittaci, 14 in Cand. C. ibidis). In combination with future functional studies, the common and distinctive criteria revealed in this study provide important clues for understanding the complexity of host-specific behavior of individual Chlamydia spp.},

keywords = {annotation, bacteria, DNA / genomics, software},

pubstate = {published},

tppubtype = {article}

}

@article{Barth:20,

title = {Robustness during Aging—Molecular Biological and Physiological Aspects},

author = {Emanuel Barth and Patricia Sieber and Heiko Stark and Stefan Schuster},

doi = {10.3390/cells9081862},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Cells},

volume = {9},

number = {8},

pages = {1862},

publisher = {MDPI AG},

abstract = {Understanding the process of aging is still an important challenge to enable healthy aging and to prevent age-related diseases. Most studies in age research investigate the decline in organ functionality and gene activity with age. The focus on decline can even be considered a paradigm in that field. However, there are certain aspects that remain surprisingly stable and keep the organism robust. Here, we present and discuss various properties of robust behavior during human and animal aging, including physiological and molecular biological features, such as the hematocrit, body temperature, immunity against infectious diseases and others. We examine, in the context of robustness, the different theories of how aging occurs. We regard the role of aging in the light of evolution.},

keywords = {aging, review},

pubstate = {published},

tppubtype = {article}

}

@article{Liebler-Tenorio:20,

title = {Regeneration of Pulmonary Tissue in a Calf Model of Fibrinonecrotic Bronchopneumonia Induced by Experimental Infection with Chlamydia psittaci},

author = {Elisabeth M. Liebler-Tenorio and Jacqueline Lambertz and Carola Ostermann and Konrad Sachse and Petra Reinhold},

doi = {10.3390/ijms21082817},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Int J Mol Sci},

volume = {21},

number = {8},

pages = {2817},

publisher = {MDPI AG},

abstract = {Pneumonia is a cause of high morbidity and mortality in humans. Animal models are indispensable to investigate the complex cellular interactions during lung injury and repair in vivo. The time sequence of lesion development and regeneration is described after endobronchial inoculation of calves with Chlamydia psittaci. Calves were necropsied 2–37 days after inoculation (dpi). Lesions and presence of Chlamydia psittaci were investigated using histology and immunohistochemistry. Calves developed bronchopneumonia at the sites of inoculation. Initially, Chlamydia psittaci replicated in type 1 alveolar epithelial cells followed by an influx of neutrophils, vascular leakage, fibrinous exudation, thrombosis and lobular pulmonary necrosis. Lesions were most extensive at 4 dpi. Beginning at 7 dpi, the number of chlamydial inclusions declined and proliferation of cuboidal alveolar epithelial cells and sprouting of capillaries were seen at the periphery of necrotic tissue. At 14 dpi, most of the necrosis had been replaced with alveoli lined with cuboidal epithelial cells resembling type 2 alveolar epithelial cells and mild fibrosis, and hyperplasia of organized lymphoid tissue were observed. At 37 dpi, regeneration of pulmonary tissue was nearly complete and only small foci of remodeling remained. The well-defined time course of development and regeneration of necrotizing pneumonia allows correlation of morphological findings with clinical data or treatment regimen.

},

keywords = {bacteria},

pubstate = {published},

tppubtype = {article}

}

@article{Srivastava:20,

title = {Tissue-specific Gene Expression Changes Are Associated with Aging in Mice},

author = {Akash Srivastava and Emanuel Barth and Maria A. Ermolaeva and Madlen Guenther and Christiane Frahm and Manja Marz and Otto W. Witte},

doi = {10.1016/j.gpb.2020.12.001},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Genomics Proteomics Bioinformatics},

volume = {18},

number = {4},

pages = {430--442},

publisher = {Elsevier BV},

abstract = {Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes. Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans. Our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue’s specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.},

keywords = {aging, differential expression analysis, liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Mostajo:20,

title = {A comprehensive annotation and differential expression analysis of short and long non-coding RNAs in 16 bat genomes},

author = {Nelly F. Mostajo and Marie Lataretu and Sebastian Krautwurst and Florian Mock and Daniel Desirò and Kevin Lamkiewicz and Maximilian Collatz and Andreas Schoen and Friedemann Weber and Manja Marz and Martin Hölzer},

url = {https://www.rna.uni-jena.de/supplements/bats/index.html},

doi = {10.1093/nargab/lqz006},

year  = {2019},

date = {2019-09-30},

urldate = {2019-09-30},

journal = {NAR Genomics Bioinf},

volume = {2},

number = {1},

pages = {lqz006},

abstract = {Although bats are increasingly becoming the focus of scientific studies due to their unique properties, these exceptional animals are still among the least studied mammals. Assembly quality and completeness of bat genomes vary a lot and especially non-coding RNA (ncRNA) annotations are incomplete or simply missing. Accordingly, standard bioinformatics pipelines for gene expression analysis often ignore ncRNAs such as microRNAs or long antisense RNAs. The main cause of this problem is the use of incomplete genome annotations. We present a complete screening for ncRNAs within 16 bat genomes. NcRNAs affect a remarkable variety of vital biological functions, including gene expression regulation, RNA processing, RNA interference and, as recently described, regulatory processes in viral infections. Within all investigated bat assemblies, we annotated 667 ncRNA families including 162 snoRNAs and 193 miRNAs as well as rRNAs, tRNAs, several snRNAs and lncRNAs, and other structural ncRNA elements. We validated our ncRNA candidates by six RNA-Seq data sets and show significant expression patterns that have never been described before in a bat species on such a large scale. Our annotations will be usable as a resource (rna.uni-jena.de/supplements/bats) for deeper studying of bat evolution, ncRNAs repertoire, gene expression and regulation, ecology and important host–virus interactions.},

keywords = {annotation, assembly, differential expression analysis, evolution, ncRNAs, RNA / transcriptomics, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Hoelzer:19a,

title = {Virus- and interferon alpha-induced transcriptomes of cells from the microbat \textit{Myotis daubentonii}},

author = {Martin Hölzer and Andreas Schoen and Julia Wulle and Marcel A. Müller and Christian Drosten and Manja Marz and Friedemann Weber},

doi = {10.1016/j.isci.2019.08.016},

year  = {2019},

date = {2019-09-27},

urldate = {2019-01-01},

journal = {iScience},

volume = {19},

pages = {647-661},

publisher = {Elsevier BV},

abstract = {Antiviral interferons (IFN-alpha/beta) are possibly responsible for the high tolerance of bats to zoonotic viruses. Previous studies focused on the IFN system of megabats (suborder Yinpterochiroptera). We present statistically robust RNA sequencing (RNA-seq) data on transcriptomes of cells from the “microbat” Myotis daubentonii (suborder Yangochiroptera) responding at 6 and 24 h to either an IFN-inducing virus or treatment with IFN. Our data reveal genes triggered only by virus, either in both humans and Myotis (CCL4, IFNL3, CH25H), or exclusively in Myotis (STEAP4). Myotis cells also express a series of conserved IFN-stimulated genes (ISGs) and an unusually high paralog number of the antiviral ISG BST2 (tetherin) but lack several ISGs that were described for megabats (EMC2, FILIP1, IL17RC, OTOGL, SLC24A1). Also, in contrast to megabats, we detected neither different IFN-alpha subtypes nor an unusually high baseline expression of IFNs. Thus, Yangochiroptera microbats, represented by Myotis, may possess an IFN system with distinctive features.

},

keywords = {differential expression analysis, RNA / transcriptomics, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Morales-Prieto:19,

title = {Identification of miRNAs and associated pathways regulated by Leukemia Inhibitory Factor in trophoblastic cell lines.},

author = {Diana M. Morales-Prieto and Emanuel Barth and Jose Martín Murrieta-Coxca and Rodolfo R. Favaro and Ruby N. Gutiérrez-Samudio and Wittaya Chaiwangyen and Stephanie Ospina-Prieto and Bernd Gruhn and Ekkehard Schleußner and Manja Marz and Udo R. Markert},

doi = {10.1016/j.placenta.2019.09.005},

year  = {2019},

date = {2019-09-12},

urldate = {2019-09-12},

journal = {Placenta},

volume = {88},

pages = {20--27},

abstract = {Leukemia Inhibitory Factor (LIF) regulates behavior of trophoblast cells and their interaction with immune and endothelial cells. In vitro, trophoblast cell response to LIF may vary depending on the cell model. Reported differences in the miRNA profile of trophoblastic cells may be responsible for these observations. Therefore, miRNA expression was investigated in four trophoblastic cell lines under LIF stimulation followed by in silico analysis of altered miRNAs and their associated pathways. Low density TaqMan miRNA assays were used to quantify levels of 762 mature miRNAs under LIF stimulation in three choriocarcinoma-derived (JEG-3, ACH-3P and AC1-M59) and a trophoblast immortalized (HTR-8/SVneo) cell lines. Expression of selected miRNAs was confirmed in primary trophoblast cells and cell lines by qPCR. Targets and associated pathways of the differentially expressed miRNAs were inferred from the miRTarBase followed by a KEGG Pathway Enrichment Analysis. HTR-8/SVneo and JEG-3 cells were transfected with miR-21-mimics and expression of miR-21 targets was assessed by qPCR. A similar number of miRNAs changed in each tested cell line upon LIF stimulation, however, low coincidence of individual miRNA species was observed and occurred more often among choriocarcinoma-derived cells (complete data set at http://www.ncbi.nlm.nih.gov/geo/ under GEO accession number GSE130489). Altered miRNAs were categorized into pathways involved in human diseases, cellular processes and signal transduction. Six cascades were identified as significantly enriched, including JAK/STAT and TGFB-SMAD. Upregulation of miR-21-3p was validated in all cell lines and primary cells and STAT3 was confirmed as its target. Dissimilar miRNA responses may be involved in differences of LIF effects on trophoblastic cell lines.},

keywords = {differential expression analysis, ncRNAs, pregnancy},

pubstate = {published},

tppubtype = {article}

}

@article{Viehweger:19a,

title = {Direct RNA nanopore sequencing of full-length coronavirus genomes provides novel insights into structural variants and enables modification analysis.},

author = {Adrian Viehweger and Sebastian Krautwurst and Kevin Lamkiewicz and Ramakanth Madhugiri and John Ziebuhr and Martin Hölzer and Manja Marz},

doi = {10.1101/gr.247064.118},

year  = {2019},

date = {2019-08-22},

urldate = {2019-08-22},

journal = {Genome Res},

volume = {29},

pages = {1545-1554},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Sequence analyses of RNA virus genomes remain challenging owing to the exceptional genetic plasticity of these viruses. Because of high mutation and recombination rates, genome replication by viral RNA-dependent RNA polymerases leads to populations of closely related viruses, so-called “quasispecies.” Standard (short-read) sequencing technologies are ill-suited to reconstruct large numbers of full-length haplotypes of (1) RNA virus genomes and (2) subgenome-length (sg) RNAs composed of noncontiguous genome regions. Here, we used a full-length, direct RNA sequencing (DRS) approach based on nanopores to characterize viral RNAs produced in cells infected with a human coronavirus. By using DRS, we were able to map the longest (∼26-kb) contiguous read to the viral reference genome. By combining Illumina and Oxford Nanopore sequencing, we reconstructed a highly accurate consensus sequence of the human coronavirus (HCoV)-229E genome (27.3 kb). Furthermore, by using long reads that did not require an assembly step, we were able to identify, in infected cells, diverse and novel HCoV-229E sg RNAs that remain to be characterized. Also, the DRS approach, which circumvents reverse transcription and amplification of RNA, allowed us to detect methylation sites in viral RNAs. Our work paves the way for haplotype-based analyses of viral quasispecies by showing the feasibility of intra-sample haplotype separation. Even though several technical challenges remain to be addressed to exploit the potential of the nanopore technology fully, our work illustrates that DRS may significantly advance genomic studies of complex virus populations, including predictions on long-range interactions in individual full-length viral RNA haplotypes.},

keywords = {assembly, coronavirus, nanopore, nucleic acid modifications, RNA / transcriptomics, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Dukhovny:19,

title = {A CRISPR activation screen identifies genes protecting from Zika virus infection},

author = {Anna Dukhovny and Kevin Lamkiewicz and Qian Chen and Markus Fricke and Nabila Jabrane-Ferrat and Manja Marz and Jae U. Jung and Ella H. Sklan},

doi = {10.1128/JVI.00211-19},

year  = {2019},

date = {2019-07-30},

urldate = {2019-07-30},

journal = {J Virol},

volume = {93},

number = {16},

publisher = {American Society for Microbiology Journals},

abstract = {Zika virus (ZIKV) is an arthropod borne emerging pathogen causing febrile illness. ZIKV is associated Guillain-Barré syndrome and other neurological complications. Infection during pregnancy is associated with pregnancy complications and developmental and neurological abnormalities collectively defined as congenital Zika syndrome. There is still no vaccine or specific treatment for ZIKV infection. To identify host factors that can rescue cells from ZIKV infection we used a genome scale CRISPR activation screen. Our highly ranking hits included a short list of interferon stimulated genes (ISGs) previously reported to have antiviral activity. Validation of the screen results highlighted IFNL2 and IFI6 as genes providing high levels of protection from ZIKV. Activation of these genes had an effect on an early stage in viral infection. In addition, infected cells expressing sgRNAs for both of these genes displayed lower levels of cell death compared to controls. Furthermore, the identified genes were significantly induced in ZIKV infected placenta explants. Thus, these results highlight a set of ISGs directly relevant for rescuing cells from ZIKV infection or its associated cell death and substantiates CRISPR activation screens as a tool to identify host factors impeding pathogen infection.IMPORTANCE Zika virus (ZIKV) is an emerging vector-borne pathogen causing a febrile disease. ZIKV infection might also trigger Guillain-Barré syndrome, neuropathy and myelitis. Vertical transmission of ZIKV can cause fetus demise, still birth or severe congenital abnormalities and neurological complications. There is no vaccine or specific antiviral treatment against ZIKV. We used a genome wide CRISPR activation screen, where genes are activated from their native promoters to identify host cell factors that protect cells from ZIKV infection or associated cell death. The results provide better understanding of key host factors that protect cells from ZIKV infection and might assist in identifying novel antiviral targets.},

keywords = {pregnancy, RNA / transcriptomics, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Kallies:19,

title = {Evaluation of Sequencing Library Preparation Protocols for Viral Metagenomic Analysis from Pristine Aquifer Groundwaters.},

author = {René Kallies and Martin Hölzer and Rodolfo Brizola Toscan and Ulisses Nunes da Rocha and John Anders and Manja Marz and Antonis Chatzinotas},

doi = {10.3390/v11060484},

year  = {2019},

date = {2019-05-28},

urldate = {2019-01-01},

journal = {Viruses},

volume = {11},

number = {6},

pages = {484},

abstract = {Viral ecology of terrestrial habitats is yet-to be extensively explored, in particular the terrestrial subsurface. One problem in obtaining viral sequences from groundwater aquifer samples is the relatively low amount of virus particles. As a result, the amount of extracted DNA may not be sufficient for direct sequencing of such samples. Here we compared three DNA amplification methods to enrich viral DNA from three pristine limestone aquifer assemblages of the Hainich Critical Zone Exploratory to evaluate potential bias created by the different amplification methods as determined by viral metagenomics. Linker amplification shotgun libraries resulted in lowest redundancy among the sequencing reads and showed the highest diversity, while multiple displacement amplification produced the highest number of contigs with the longest average contig size, suggesting a combination of these two methods is suitable for the successful enrichment of viral DNA from pristine groundwater samples. In total, we identified 27,173, 5,886 and 32,613 viral contigs from the three samples from which 11.92 to 18.65% could be assigned to taxonomy using blast. Among these, members of the order were the most abundant group (52.20 to 69.12%) dominated by and . Those, and the high number of unknown viral sequences, substantially expand the known virosphere.},

keywords = {DNA / genomics, groundwater, metagenomics, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Peter:19,

title = {Structure and Hierarchy of Influenza Virus Models Revealed by Reaction Network Analysis},

author = {Stephan Peter and Martin Hölzer and Kevin Lamkiewicz and Pietro Speroni Fenizio and Hassan Al Hwaeer and Manja Marz and Stefan Schuster and Peter Dittrich and Bashar Ibrahim},

doi = {10.3390/v11050449},

year  = {2019},

date = {2019-05-16},

urldate = {2019-01-01},

journal = {Viruses},

volume = {11},

number = {5},

pages = {449},

publisher = {MDPI AG},

abstract = {Influenza A virus is recognized today as one of the most challenging viruses that threatens both human and animal health worldwide. Understanding the control mechanisms of influenza infection and dynamics is crucial and could result in effective future treatment strategies. Many kinetic models based on differential equations have been developed in recent decades to capture viral dynamics within a host. These models differ in their complexity in terms of number of species elements and number of reactions. Here, we present a new approach to understanding the overall structure of twelve influenza A virus infection models and their relationship to each other. To this end, we apply chemical organization theory to obtain a hierarchical decomposition of the models into chemical organizations. The decomposition is based on the model structure (reaction rules) but is independent of kinetic details such as rate constants. We found different types of model structures ranging from two to eight organizations. Furthermore, the model’s organizations imply a partial order among models entailing a hierarchy of model, revealing a high model diversity with respect to their long-term behavior. Our methods and results can be helpful in model development and model integration, also beyond the influenza area. },

keywords = {virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Hoelzer:19,

title = {\textit{De novo} transcriptome assembly: A comprehensive cross-species comparison of short-read RNA-Seq assemblers},

author = {Martin Hölzer and Manja Marz},

doi = {10.1093/gigascience/giz039},

year  = {2019},

date = {2019-05-11},

urldate = {2019-01-01},

journal = {GigaScience},

volume = {8},

number = {5},

pages = {giz039},

publisher = {Oxford University Press (OUP)},

abstract = {Background: In recent years, massively parallel complementary DNA sequencing (RNA sequencing [RNA-Seq]) has emerged as a fast, cost-effective, and robust technology to study entire transcriptomes in various manners. In particular, for non-model organisms and in the absence of an appropriate reference genome, RNA-Seq is used to reconstruct the transcriptome de novo. Although the de novo transcriptome assembly of non-model organisms has been on the rise recently and new tools are frequently developing, there is still a knowledge gap about which assembly software should be used to build a comprehensive de novo assembly.



Results: Here, we present a large-scale comparative study in which 10 de novo assembly tools are applied to 9 RNA-Seq data sets spanning different kingdoms of life. Overall, we built >200 single assemblies and evaluated their performance on a combination of 20 biological-based and reference-free metrics. Our study is accompanied by a comprehensive and extensible Electronic Supplement that summarizes all data sets, assembly execution instructions, and evaluation results. Trinity, SPAdes, and Trans-ABySS, followed by Bridger and SOAPdenovo-Trans, generally outperformed the other tools compared. Moreover, we observed species-specific differences in the performance of each assembler. No tool delivered the best results for all data sets.



Conclusions: We recommend a careful choice and normalization of evaluation metrics to select the best assembling results as a critical step in the reconstruction of a comprehensive de novo transcriptome assembly.},

keywords = {assembly, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Hufsky:19,

title = {The Third Annual Meeting of the European Virus Bioinformatics Center},

author = {Franziska Hufsky and Bashar Ibrahim and Sejal Modha and Martha R. J. Clokie and Stefanie Deinhardt-Emmer and Bas E. Dutilh and Samantha Lycett and Peter Simmonds and Volker Thiel and Aare Abroi and Evelien M. Adriaenssens and Marina Escalera-Zamudio and Jenna Nicole Kelly and Kevin Lamkiewicz and Lu Lu and Julian Susat and Thomas Sicheritz and David L. Robertson and Manja Marz},

doi = {10.3390/v11050420},

year  = {2019},

date = {2019-05-05},

urldate = {2019-05-05},

journal = {Viruses},

volume = {11},

number = {5},

pages = {420},

publisher = {MDPI AG},

abstract = {The Third Annual Meeting of the European Virus Bioinformatics Center (EVBC) took place in Glasgow, United Kingdom, 28–29 March 2019. Virus bioinformatics has become central to virology research, and advances in bioinformatics have led to improved approaches to investigate viral infections and outbreaks, being successfully used to detect, control, and treat infections of humans and animals. This active field of research has attracted approximately 110 experts in virology and bioinformatics/computational biology from Europe and other parts of the world to attend the two-day meeting in Glasgow to increase scientific exchange between laboratory- and computer-based researchers. The meeting was held at the McIntyre Building of the University of Glasgow; a perfect location, as it was originally built to be a place for “rubbing your brains with those of other people”, as Rector Stanley Baldwin described it. The goal of the meeting was to provide a meaningful and interactive scientific environment to promote discussion and collaboration and to inspire and suggest new research directions and questions. The meeting featured eight invited and twelve contributed talks, on the four main topics: (1) systems virology, (2) virus-host interactions and the virome, (3) virus classification and evolution and (4) epidemiology, surveillance and evolution. Further, the meeting featured 34 oral poster presentations, all of which focused on specific areas of virus bioinformatics. This report summarizes the main research findings and highlights presented at the meeting. },

keywords = {classification, conference report, evolution, metagenomics, software, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Gerresheim:19,

title = {Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling},

author = {Gesche Gerresheim and Jochen Bathke and Audrey Michel and Dmitri Andreev and Lyudmila Shalamova and Oliver Rossbach and Pan Hu and Dieter Glebe and Markus Fricke and Manja Marz and Alexander Goesmann and Stephen Kiniry and Pavel Baranov and Ivan Shatsky and Michael Niepmann},

doi = {10.3390/ijms20061321},

year  = {2019},

date = {2019-03-15},

urldate = {2019-03-15},

journal = {Int J Mol Sci},

volume = {20},

number = {6},

pages = {1321},

publisher = {MDPI AG},

abstract = {Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here. },

keywords = {cancer, differential expression analysis, liver, RNA structure, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Barth:19,

title = {Conserved aging-related signatures of senescence and inflammation in different tissues and species.},

author = {Emanuel Barth and Akash Srivastava and Milan Stojiljkovic and Christiane Frahm and Hubertus Axer and Otto W Witte and Manja Marz},

doi = {10.18632/aging.102345},

year  = {2019},

date = {2019-02-26},

urldate = {2019-02-26},

journal = {Aging},

volume = {11},

number = {19},

pages = {8556—8572},

abstract = {Increasing evidence indicates that chronic inflammation and senescence are the cause of many severe age-related diseases, with both biological processes highly upregulated during aging. However, until now, it has remained unknown whether specific inflammation- or senescence-related genes exist that are common between different species or tissues. These potential markers of aging could help to identify possible targets for therapeutic interventions of aging-associated afflictions and might also deepen our understanding of the principal mechanisms of aging. With the objective of identifying such signatures of aging and tissue-specific aging markers, we analyzed a multitude of cross-sectional RNA-Seq data from four evolutionarily distinct species (human, mouse and two fish) and four different tissues (blood, brain, liver and skin). In at least three different species and three different tissues, we identified several genes that displayed similar expression patterns that might serve as potential aging markers. Additionally, we show that genes involved in aging-related processes tend to be tighter controlled in long-lived than in average-lived individuals. These observations hint at a general genetic level that affect an individual's life span. Altogether, this descriptive study contributes to a better understanding of common aging signatures as well as tissue-specific aging patterns and supplies the basis for further investigative age-related studies.},

keywords = {aging, liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Wegner:19,

title = {Biogeochemical regimes in shallow aquifers reflect the metabolic coupling of elements of nitrogen, sulfur and carbon.},

author = {Carl-Eric Wegner and Michael Gaspar and Patricia Geesink and Martina Herrmann and Manja Marz and Kirsten Küsel},

doi = {10.1128/AEM.02346-18},

year  = {2019},

date = {2019-02-20},

urldate = {2019-01-01},

journal = {Appl Environ Microbiol},

volume = {85},

number = {5},

pages = {e02346-18},

abstract = {Near-surface groundwaters are prone to receive (in)organic matter input from their recharge areas and are known to harbour autotrophic microbial communities linked to nitrogen and sulfur metabolism. Here, we use multi-"omic" profiling to gain holistic insights into the turnover of inorganic nitrogen compounds, carbon fixation processes and organic matter processing in groundwater. We sampled microbial biomass from two superimposed aquifers via monitoring wells that follow groundwater flow from its recharge area through differences in hydrogeochemical settings and land use. Functional profiling revealed that groundwater microbiomes are mainly driven by nitrogen (nitrification, denitrification, anammox) and to a lesser extent sulfur cycling (sulfur oxidation and sulfate reduction), dependent on local hydrochemical differences. Surprisingly, the differentiation potential of the groundwater microbiome surpasses that of hydrochemistry for individual monitoring wells. Dominated by few phyla (Bacteroidetes, Proteobacteria, Planctomycetes, Thaumarchaeota), the taxonomic profiling of groundwater metagenomes and metatranscriptomes revealed pronounced differences between merely present microbiome members and those actively participating in community gene expression and biogeochemical cycling. Unexpectedly, we observed a constitutive expression of carbohydrate-active enzymes, encoded by different microbiome members, along with the groundwater flow path. The turnover of organic carbon apparently complements for lithoautotrophic carbon assimilation pathways mainly used by the groundwater microbiome dependent on the availability of oxygen and inorganic electron donors like ammonium. Groundwater is a key resource for drinking water production and irrigation. The interplay between geological setting, hydrochemistry, carbon storage and groundwater microbiome ecosystem functioning is crucial for our understanding of these important ecosystem services. We targeted the encoded and expressed metabolic potential of groundwater microbiomes along an aquifer transect that diversifies in terms of hydrochemistry and land use. Our results showed that the groundwater microbiome has a higher spatial differentiation potential than hydrochemistry.},

keywords = {bacteria, groundwater, metagenomics},

pubstate = {published},

tppubtype = {article}

}

@article{Sieber:19,

title = {The landscape of the alternatively spliced transcriptome remains stable during aging across different species and tissues},

author = {Patricia Sieber and Emanuel Barth and Manja Marz},

doi = {10.1101/541417},

year  = {2019},

date = {2019-02-05},

urldate = {2019-02-05},

journal = {bioRxiv},

pages = {541417},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Aging is characterized by a decline of cellular homeostasis over time, leading to various severe disorders and death. Alternative splicing is an important regulatory level of gene expression and thus takes on a key role in the maintenance of accurate cell and tissue function. Missplicing of certain genes has already been linked to several age-associated diseases, such as progeria, Alzheimer’s disease, Parkinson’s disease and cancer. Nevertheless, many studies focus only on transcriptional variations of single genes or the expression changes of spliceosomal genes, coding for the proteins that aggregate to the spliceosomal machinery. Little is known on the general change of present and switching isoforms in different tissues over time. In this descriptive RNA-Seq study, we report differences and commonalities of isoform usage during aging among different tissues within one species and compare changes of alternative splicing among different, evolutionarily distinct species. Although we identified a multitude of differntially spliced genes among different time points, we observed little to no general changes in the transcriptomic landscape of the investigated samples. Although there is undoubtedly considerable influence of specifically spliced genes on certain age-associated processes, this work shows that alternative splicing remains stable for the majority of genes with aging.},

keywords = {aging, RNA / transcriptomics, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Viehweger:19,

title = {An encoding of genome content for machine learning},

author = {Adrian Viehweger and Sebastian Krautwurst and Brigitte Koenig and Manja Marz},

url = {https://github.com/phiweger/nanotext},

doi = {10.1101/524280},

year  = {2019},

date = {2019-01-18},

urldate = {2019-01-18},

journal = {bioRxiv},

pages = {524280},

publisher = {Cold Spring Harbor Laboratory},

abstract = {An ever-growing number of metagenomes can be used for biomining and the study of microbial functions. The use of learning algorithms in this context has been hindered, because they often need input in the form of low-dimensional, dense vectors of numbers. We propose such a representation for genomes called nanotext that scales to very large data sets.



The underlying model is learned from a corpus of nearly 150 thousand genomes spanning 750 million protein domains. We treat the protein domains in a genome like words in a document, assuming that protein domains in a similar context have similar “meaning”. This meaning can be distributed by a neural net over a vector of numbers.



The resulting vectors efficiently encode function, preserve known phylogeny, capture subtle functional relationships and are robust against genome incompleteness. The “functional” distance between two vectors complements nucleotide-based distance, so that genomes can be identified as similar even though their nucleotide identity is low. nanotext can thus encode (meta)genomes for direct use in downstream machine learning tasks. We show this by predicting plausible culture media for metagenome assembled genomes (MAGs) from the Tara Oceans Expedition using their genome content only. nanotext is freely released under a BSD licence (https://github.com/phiweger/nanotext).},

keywords = {assembly, machine learning, metagenomics},

pubstate = {published},

tppubtype = {article}

}

@article{Chen:18,

title = {Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation},

author = {Zhiyang Chen and Elias Moris Amro and Friedrich Becker and Martin Hölzer and Seyed Mohammad Mahdi Rasa and Sospeter Ngoci Njeru and Bing Han and Simone Di Sanzo and Yulin Chen and Duozhuang Tang and Si Tao and Ronny Haenold and Marco Groth and Vasily S. Romanov and Joanna M. Kirkpatrick and Johann M. Kraus and Hans A. Kestler and Manja Marz and Alessandro Ori and Francesco Neri and Yohei Morita and K. Lenhard Rudolph},

doi = {10.1084/jem.20181505},

year  = {2018},

date = {2018-12-07},

urldate = {2018-01-01},

journal = {J Exp Med},

volume = {216},

number = {1},

pages = {152--175},

publisher = {Rockefeller University Press},

abstract = {Organism aging is characterized by increased inflammation and decreased stem cell function, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells (HSPCs) exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signaling, which increases chromatin accessibility in the vicinity of NF-κB target genes in response to inflammation. Rad21 is required for normal differentiation, but limits self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB–dependent manner. HSCs from aged mice fail to down-regulate Rad21/cohesin and inflammation/differentiation signals in the resolution phase of inflammation. Inhibition of cohesin/NF-κB reverts hypersensitivity of aged HSPCs to inflammation-induced differentiation and myeloid-biased HSCs with disrupted/reduced expression of Rad21/cohesin are increasingly selected during aging. Together, Rad21/cohesin-mediated NF-κB signaling limits HSPC function during aging and selects for cohesin-deficient HSCs with myeloid-skewed differentiation.},

keywords = {aging, differential expression analysis, DNA / genomics},

pubstate = {published},

tppubtype = {article}

}

@article{Morales-Prieto:18a,

title = {Peripheral blood exosomes pass blood-brain-barrier and induce glial cell activation},

author = {Diana M. Morales-Prieto and Milan Stojiljkovic and Celia Diezel and Priska-Elisabeth Streicher and Franziska Roestel and Julia Lindner and Sebastian Weis and Christian Schmeer and Manja Marz},

doi = {10.1101/471409},

year  = {2018},

date = {2018-11-29},

urldate = {2018-11-29},

journal = {bioRxiv},

pages = {471409},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Background Exosomes are involved in intracellular communication and contain proteins, mRNAs, miRNAs, and signaling molecules. Exosomes were shown to act as neuroinflammatory mediators involved in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS). Brain aging has been associated to increased neuroinflammation. In addition, a decreased extracellular vesicle concentration was observed in aging tissues. The specific mechanisms how exosomes and aging are connected are not known yet.



Results Here we have shown that peripheral injection had almost no effect on selected gene expression in the liver. However, exosome injection has led to changes in the specific markers of glial cell activation (CD68, Iba1, GFAP). Interestingly, only injection of exosomes isolated from aged mice induced significant activation of astrocyte cells, as shown by increased GFAP expression.



Conclusion Transcription levels of genes GFAP, TGF-β, CD68, Iba1 known to be involved in glial cell function are significantly changing after introduction of peripheral extracellular vesicles. Exosomes were able to pass blood brain barrier and induce glial cell activation. GFAP known to be a specific astrocyte activation marker was significantly higher expressed after injection of old but not young exosomes, indicating a possible role of exosomes in the mechanisms of brain aging.},

keywords = {aging, extracellular vesicles, liver, ncRNAs},

pubstate = {published},

tppubtype = {article}

}

@article{Desiro:18,

title = {SilentMutations (SIM): a tool for analyzing long-range RNA-RNA interactions in viral genomes and structured RNAs},

author = {Daniel Desiro and Martin Hölzer and Bashar Ibrahim and Manja Marz},

url = {https://github.com/desiro/silentMutations},

doi = {10.1016/j.virusres.2018.11.005},

year  = {2018},

date = {2018-11-12},

urldate = {2018-11-12},

journal = {Virus Res},

volume = {260},

pages = {135-141},

abstract = {A single nucleotide change in the coding region can alter the amino acid sequence of a protein. In consequence, natural or artificial sequence changes in viral RNAs may have various effects not only on protein stability, function and structure but also on viral replication. In recent decades, several tools have been developed to predict the effect of mutations in structured RNAs such as viral genomes or non-coding RNAs. Some tools use multiple point mutations and also take coding regions into account. However, none of these tools was designed to specifically simulate the effect of mutations on viral long-range interactions. Here, we developed SilentMutations (SIM), an easy-to-use tool to analyze the effect of multiple point mutations on the secondary structures of two interacting viral RNAs. The tool can simulate disruptive and compensatory mutants of two interacting single-stranded RNAs. This allows a fast and accurate assessment of key regions potentially involved in functional long-range RNA-RNA interactions and will eventually help virologists and RNA-experts to design appropriate experiments. SIM only requires two interacting single-stranded RNA regions as input. The output is a plain text file containing the most promising mutants and a graphical representation of all interactions. We applied our tool on two experimentally validated influenza A virus and hepatitis C virus interactions and we were able to predict potential double mutants for in vitro validation experiments. The source code and documentation of SIM are freely available at github.com/desiro/silentMutations.},

keywords = {RNA structure, RNA-RNA interactions, software, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Lamkiewicz:18,

title = {Identification of potential microRNAs associated with Herpesvirus family based on bioinformatic analysis},

author = {Kevin Lamkiewicz and Emanuel Barth and Manja Marz and Bashar Ibrahim},

doi = {10.1101/417782},

year  = {2018},

date = {2018-11-09},

urldate = {2018-11-09},

journal = {bioRxiv},

pages = {417782},

publisher = {Cold Spring Harbor Laboratory},

abstract = {MicroRNAs (miRNAs) are known key regulators of gene expression on posttranscriptional level in many organisms encoded in mammals, plants and also several viral families. To date, no homologous gene of a virus-originated miRNA is known in other organisms. To date, only a few homologous miRNA between two different viruses are known, however, no gene of a virus-originated miRNA is known in any organism of other kingdoms. This can be attributed to the fact that classical miRNA detection approaches such as homology-based predictions fail at viruses due to their highly diverse genomes and their high mutation rate.



Here, we applied the virus-derived precursor miRNA (pre-miRNA) prediction pipeline ViMiFi, which combines information about sequence conservation and machine learning-based approaches, on Human Herpesvirus 7 (HHV7) and Epstein-Barr virus (EBV). ViMiFi was able to predict 61 candidates in EBV, which has 25 known pre-miRNAs. From these 25, ViMiFi identified 20. It was further able to predict 18 candidates in the HHV7 genome, in which no miRNA had been described yet. We also studied the undescribed candidates of both viruses for potential functions and found similarities with human snRNAs and miRNAs from mammals and plants.},

keywords = {machine learning, ncRNAs, RNA / transcriptomics, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Gerst:18,

title = {PCAGO: An interactive web service to analyze RNA-Seq data with principal component analysis},

author = {Ruman Gerst and Martin Hölzer},

url = {http://github.com/hoelzer-lab/pcago},

doi = {10.1101/433078},

year  = {2018},

date = {2018-10-03},

urldate = {2018-10-03},

journal = {bioRxiv},

pages = {433078},

publisher = {Cold Spring Harbor Laboratory},

abstract = {The initial characterization and clustering of biological samples is a critical step in the analysis of any transcriptomics study. In many studies, principal component analysis (PCA) is the clustering algorithm of choice to predict the relationship of samples or cells based solely on differential gene expression. In addition to the pure quality evaluation of the data, a PCA can also provide initial insights into the biological background of an experiment and help researchers to interpret the data and design the subsequent computational steps accordingly. However, to avoid misleading clusterings and interpretations, an appropriate selection of the underlying gene sets to build the PCA and the choice of the most fitting principal components for the visualization are crucial parts. Here, we present PCAGO, an easy-to-use and interactive tool to analyze gene quantification data derived from RNA sequencing experiments with PCA. The tool includes features such as read-count normalization, filtering of read counts by gene annotation, and various visualization options. In addition, PCAGO helps to select appropriate parameters such as the number of genes and principal components to create meaningful visualizations.},

keywords = {annotation, differential expression analysis, RNA / transcriptomics, software},

pubstate = {published},

tppubtype = {article}

}

@article{Morales-Prieto:18,

title = {Identification of miRNAs and associated pathways regulated by Leukemia Inhibitory Factor in trophoblastic cell lines},

author = {Diana M. Morales-Prieto and Emanuel Barth and Ruby N. Gutièrrez-Samudio and Wittaya Chaiwangyen and Stephanie Ospina-Prieto and Bernd Gruhn and Ekkehard Schleußner and Manja Marz and Udo R. Markert},

doi = {10.1101/410381},

year  = {2018},

date = {2018-09-06},

urldate = {2018-09-06},

journal = {bioRxiv},

pages = {410381},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Introduction Leukemia Inhibitory Factor (LIF) regulates behavior of trophoblast cells and their interaction with immune and endothelial cells. In vitro, trophoblast cell response to LIF may vary depending on the cell model. Reported differences in the miRNA profile of trophoblastic cells may be responsible for these observations. Therefore, miRNA expression was investigated in four trophoblastic cell lines under LIF stimulation followed by in silico analysis of altered miRNAs and their associated pathways.



Methods Low density TaqMan miRNA assays were used to quantify levels of 762 mature miRNAs under LIF stimulation in three choriocarcinoma-derived (JEG-3, ACH-3P and AC1-M59) and a trophoblast immortalized (HTR-8/SVneo) cell lines. Expression of selected miRNAs was confirmed in primary trophoblast cells and cell lines by qPCR. Targets and associated pathways of the differentially expressed miRNAs were inferred from the miRTarBase followed by a KEGG Pathway Enrichment Analysis. HTR-8/SVneo and JEG-3 cells were transfected with miR-21-mimics and expression of miR-21 targets was assessed by qPCR.



Results A similar number of miRNAs changed in each tested cell line upon LIF stimulation, however, low coincidence of individual miRNA species was observed and occurred more often among choriocarcinoma-derived cells (complete data set at http://www.ncbi.nlm.nih.gov/geo/ under GEO accession number GSE130489). Altered miRNAs were categorized into pathways involved in human diseases, cellular processes and signal transduction. Six cascades were identified as significantly enriched, including JAK/STAT and TGFB-SMAD. Upregulation of miR-21-3p was validated in all cell lines and primary cells and STAT3 was confirmed as its target.



Discussion Dissimilar miRNA responses may be involved in differences of LIF effects on trophoblastic cell lines.},

note = {Now published in Placenta: https://doi.org/10.1016/j.placenta.2019.09.005},

keywords = {differential expression analysis, ncRNAs, pregnancy},

pubstate = {published},

tppubtype = {article}

}

@article{Fricke:18,

title = {Global importance of RNA secondary structures in protein coding sequences},

author = {Markus Fricke and Ruman Gerst and Bashar Ibrahim and Michael Niepmann and Manja Marz},

doi = {10.1093/bioinformatics/bty678},

year  = {2018},

date = {2018-08-07},

urldate = {2018-08-07},

journal = {Bioinformatics},

volume = {35},

number = {4},

pages = {579–583},

abstract = {The protein-coding sequences of messenger RNAs are the linear template for translation of the gene sequence into protein. Nevertheless, the RNA can also form secondary structures by intramolecular base-pairing. We show that the nucleotide distribution within codons is biased in all taxa of life on a global scale. Thereby, RNA secondary structures that require base-pairing between the position 1 of a codon with the position 1 of an opposing codon (here named RNA secondary structure class c1) are under-represented. We conclude that this bias may result from the co-evolution of codon sequence and mRNA secondary structure, suggesting that RNA secondary structures are generally important in protein coding regions of mRNAs. The above result also implies that codon position 2 has a smaller influence on the amino acid choice than codon position 1.},

keywords = {evolution, RNA / transcriptomics, RNA structure, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Ibrahim:18,

title = {Bioinformatics Meets Virology: The European Virus Bioinformatics Center's Second Annual Meeting},

author = {Bashar Ibrahim and Ksenia Arkhipova and Arno C Andeweg and Susana Posada-Céspedes and François Enault and Arthur Gruber and Eugene V Koonin and Anne Kupczok and Philippe Lemey and Alice C McHardy and Dino P McMahon and Brett E Pickett and David L Robertson and Richard H Scheuermann and Alexandra Zhernakova and Mark P Zwart and Alexander Schönhuth and Bas E Dutilh and Manja Marz},

doi = {10.3390/v10050256},

year  = {2018},

date = {2018-05-14},

urldate = {2018-05-14},

journal = {Viruses},

volume = {10},

abstract = {The Second Annual Meeting of the European Virus Bioinformatics Center (EVBC), held in Utrecht, Netherlands, focused on computational approaches in virology, with topics including (but not limited to) virus discovery, diagnostics, (meta-)genomics, modeling, epidemiology, molecular structure, evolution, and viral ecology. The goals of the Second Annual Meeting were threefold: (i) to bring together virologists and bioinformaticians from across the academic, industrial, professional, and training sectors to share best practice; (ii) to provide a meaningful and interactive scientific environment to promote discussion and collaboration between students, postdoctoral fellows, and both new and established investigators; (iii) to inspire and suggest new research directions and questions. Approximately 120 researchers from around the world attended the Second Annual Meeting of the EVBC this year, including 15 renowned international speakers. This report presents an overview of new developments and novel research findings that emerged during the meeting.},

keywords = {conference report, evolution, software, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Ibrahim:18a,

title = {A new era of virus bioinformatics},

author = {Bashar Ibrahim and Dino P McMahon and Franziska Hufsky and Martin Beer and Li Deng and Philippe Le Mercier and Massimo Palmarini and Volker Thiel and Manja Marz},

doi = {10.1016/j.virusres.2018.05.009},

year  = {2018},

date = {2018-05-08},

urldate = {2018-01-01},

journal = {Virus Res},

volume = {251},

pages = {86--90},

abstract = {Despite the recognized excellence of virology and bioinformatics, these two communities have interacted surprisingly sporadically, aside from some pioneering work on HIV-1 and influenza. Bringing together the expertise of bioinformaticians and virologists is crucial, since very specific but fundamental computational approaches are required for virus research, particularly in an era of big data. Collaboration between virologists and bioinformaticians is necessary to improve existing analytical tools, cloud-based systems, computational resources, data sharing approaches, new diagnostic tools, and bioinformatic training. Here, we highlight current progress and discuss potential avenues for future developments in this promising era of virus bioinformatics. We end by presenting an overview of current technologies, and by outlining some of the major challenges and advantages that bioinformatics will bring to the field of virology.},

keywords = {review, software, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Hufsky:18,

title = {Virologists-Heroes need weapons},

author = {Franziska Hufsky and Bashar Ibrahim and Martin Beer and Li Deng and Philippe Le Mercier and Dino P McMahon and Massimo Palmarini and Volker Thiel and Manja Marz},

doi = {10.1371/journal.ppat.1006771},

year  = {2018},

date = {2018-02-08},

urldate = {2018-02-08},

journal = {PLoS Pathog},

volume = {14},

number = {2},

pages = {e1006771},

abstract = {Virologists. You might know a couple of them, but unless you are a virologist yourself, the probability that you have collaborated with one in the past is low. The community is relatively small, but they pack a heavy punch and are expected to play a leading role in the research into pathogens that lies ahead. You may ask why we think virologists are our future. Suffice it to say that it is not just because they have invented technologies that belong to the space age, including use of viruses as vehicles to shuttle genes into cells[1], organic nanoparticles with specific tools attached to their surfaces to get inside target cells[2], and using genetically modified viruses as therapies to fight against cancer[3]. Did you know that virologists currently only know of about 3,200 viral species but that more than 320,000 mammal-associated viruses[4] are thought to await discovery? Just think about the viruses hidden in the Arctic ice[5] or in the insects and other animals from once cut-off regions in the world, which now face ever-increasing human exposure[6]. But a heroic (as well as an apocalyptic) role for virologists may also be on the horizon, as the adoption of phage therapy may, in the future, be used to control harmful bacteria when antibiotics fail[7].},

keywords = {review, software, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Hillmann:18,

title = {Multiple Roots of Fruiting Body Formation in Amoebozoa},

author = {Falk Hillmann and Gillian Forbes and Silvia Novohradská and Iuliia Ferling and Konstantin Riege and Marco Groth and Martin Westermann and Manja Marz and Thomas Spaller and Thomas Winckler and Pauline Schaap and Gernot Glöckner},

doi = {10.1093/gbe/evy011},

year  = {2018},

date = {2018-01-25},

urldate = {2018-01-25},

journal = {Genome Biol Evol},

volume = {10},

pages = {591--606},

abstract = {Establishment of multicellularity represents a major transition in eukaryote evolution. A subgroup of Amoebozoa, the dictyosteliids, has evolved a relatively simple aggregative multicellular stage resulting in a fruiting body supported by a stalk. Protosteloid amoeba, which are scattered throughout the amoebozoan tree, differ by producing only one or few single stalked spores. Thus, one obvious difference in the developmental cycle of protosteliids and dictyosteliids seems to be the establishment of multicellularity. To separate spore development from multicellular interactions, we compared the genome and transcriptome of a Protostelium species (Protostelium aurantium var. fungivorum) with those of social and solitary members of the Amoebozoa. During fruiting body formation nearly 4,000 genes, corresponding to specific pathways required for differentiation processes, are upregulated. A comparison with genes involved in the development of dictyosteliids revealed conservation of >500 genes, but most of them are also present in Acanthamoeba castellanii for which fruiting bodies have not been documented. Moreover, expression regulation of those genes differs between P. aurantium and Dictyostelium discoideum. Within Amoebozoa differentiation to fruiting bodies is common, but our current genome analysis suggests that protosteliids and dictyosteliids used different routes to achieve this. Most remarkable is both the large repertoire and diversity between species in genes that mediate environmental sensing and signal processing. This likely reflects an immense adaptability of the single cell stage to varying environmental conditions. We surmise that this signaling repertoire provided sufficient building blocks to accommodate the relatively simple demands for cell-cell communication in the early multicellular forms.},

keywords = {evolution, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Graf:18,

title = {Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity},

author = {Laura Graf and Alexej Dick and Franziska Sendker and Emanuel Barth and Manja Marz and Oliver Daumke and Georg Kochs},

doi = {10.1074/jbc.M117.812784},

year  = {2018},

date = {2018-01-01},

urldate = {2018-01-01},

journal = {J Biol Chem},

volume = {293},

number = {9},

pages = {3056--3072},

abstract = {Only a minority of patients infected with seasonal influenza A viruses exhibit a severe or fatal outcome of infection, but the reasons for this inter-individual variability in influenza susceptibility are unclear. To gain further insights into the molecular mechanisms underlying this variability, we investigated naturally occurring allelic variations of the myxovirus resistance 1 ( ) gene coding for the influenza restriction factor MxA. The interferon-induced dynamin-like GTPase consists of an N-terminal GTPase domain, a bundle signaling element, and a C-terminal stalk responsible for oligomerization and viral target recognition. We used online databases to search for variations in the gene. Deploying approaches, we found that non-synonymous variations in the GTPase domain cause the loss of antiviral and enzymatic activities. Furthermore, we showed that these amino acid substitutions disrupt the interface for GTPase domain dimerization required for the stimulation of GTP hydrolysis. Variations in the stalk were neutral or slightly enhanced or abolished MxA antiviral function. Remarkably, two other stalk variants altered MxA's antiviral specificity. Variations causing the loss of antiviral activity were found only in heterozygous carriers. Interestingly, the inactive stalk variants blocked the antiviral activity of WT MxA in a dominant-negative way, suggesting that heterozygotes are phenotypically MxA-negative. In contrast, the GTPase-deficient variants showed no dominant-negative effect, indicating that heterozygous carriers should remain unaffected. Our results demonstrate that naturally occurring mutations in the human gene can influence MxA function, which may explain individual variations in influenza virus susceptibility in the human population.},

keywords = {viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Steinbach:18,

title = {Analysis of molecular mechanism of progression of non-muscle-invasive bladder cancer (NMIBC) by genome-wide exome and UTR mutation analysis},

author = {D Steinbach and Martin Hölzer and Manja Marz and M Gajda and F-C Von Rundstedt and M-O Grimm},

year  = {2018},

date = {2018-01-01},

urldate = {2018-01-01},

journal = {Eur Urol Suppl},

volume = {17},

number = {2},

pages = {e1523},

publisher = {Elsevier},

keywords = {cancer},

pubstate = {published},

tppubtype = {article}

}

@article{Madhugiri:18,

title = {Structural and functional conservation of cis-acting RNA elements in coronavirus 5'-terminal genome regions},

author = {Ramakanth Madhugiri and Nadja Karl and Daniel Petersen and Kevin Lamkiewicz and Markus Fricke and Ulrike Wend and Robina Scheuer and Manja Marz and John Ziebuhr},

doi = {10.1016/j.virol.2017.11.025},

year  = {2017},

date = {2017-12-06},

urldate = {2017-12-06},

journal = {Virology},

volume = {517},

pages = {44--55},

abstract = {Structure predictions suggest a partial conservation of RNA structure elements in coronavirus terminal genome regions. Here, we determined the structures of stem-loops (SL) 1 and 2 of two alphacoronaviruses, human coronavirus (HCoV) 229E and NL63, by RNA structure probing and studied the functional relevance of these putative cis-acting elements. HCoV-229E SL1 and SL2 mutants generated by reverse genetics were used to study the effects on viral replication of single-nucleotide substitutions predicted to destabilize the SL1 and SL2 structures. The data provide conclusive evidence for the critical role of SL1 and SL2 in HCoV-229E replication and, in some cases, revealed parallels with previously characterized betacoronavirus SL1 and SL2 elements. Also, we were able to rescue viable HCoV-229E mutants carrying replacements of SL2 with equivalent betacoronavirus structural elements. The data obtained in this study reveal a remarkable degree of structural and functional conservation of 5'-terminal RNA structural elements across coronavirus genus boundaries.},

keywords = {coronavirus, phylogenetics, RNA / transcriptomics, RNA structure, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Hoelzer:17,

title = {Software Dedicated to Virus Sequence Analysis },

author = {Martin Hölzer and Manja Marz},

doi = {10.1016/bs.aivir.2017.08.004},

year  = {2017},

date = {2017-09-28},

urldate = {2017-09-28},

journal = {Adv Virus Res},

volume = {99},

pages = {233--257},

abstract = {Computer-assisted technologies of the genomic structure, biological function, and evolution of viruses remain a largely neglected area of research. The attention of bioinformaticians to this challenging field is currently unsatisfying in respect to its medical and biological importance. The power of new genome sequencing technologies, associated with new tools to handle "big data", provides unprecedented opportunities to address fundamental questions in virology. Here, we present an overview of the current technologies, challenges, and advantages of Next-Generation Sequencing (NGS) in relation to the field of virology. We present how viral sequences can be detected de novo out of current short-read NGS data. Furthermore, we discuss the challenges and applications of viral quasispecies and how secondary structures, commonly shaped by RNA viruses, can be computationally predicted. The phylogenetic analysis of viruses, as another ubiquitous field in virology, forms an essential element of describing viral epidemics and challenges current algorithms. Recently, the first specialized virus-bioinformatic organizations have been established. We need to bring together virologists and bioinformaticians and provide a platform for the implementation of interdisciplinary collaborative projects at local and international scales. Above all, there is an urgent need for dedicated software tools to tackle various challenges in virology.},

keywords = {DNA / genomics, evolution, phylogenetics, review, RNA / transcriptomics, RNA structure, software, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Baumgart:17,

title = {A miRNA catalogue and ncRNA annotation of the short-living fish \textit{Nothobranchius furzeri}},

author = {Mario Baumgart and Emanuel Barth and Aurora Savino and Marco Groth and Philipp Koch and Andreas Petzold and Ivan Arisi and Matthias Platzer and Manja Marz and Alessandro Cellerino},

doi = {10.1186/s12864-017-3951-8},

year  = {2017},

date = {2017-09-05},

urldate = {2017-01-01},

journal = {BMC Genomics},

volume = {18},

pages = {693},

abstract = {The short-lived fish Nothobranchius furzeri is the shortest-lived vertebrate that can be cultured in captivity and was recently established as a model organism for aging research. Small non-coding RNAs, especially miRNAs, are implicated in age dependent control of gene expression. Here, we present a comprehensive catalogue of miRNAs and several other non-coding RNA classes (ncRNAs) for Nothobranchius furzeri. Analyzing multiple small RNA-Seq libraries, we show most of these identified miRNAs are expressed in at least one of seven Nothobranchius species. Additionally, duplication and clustering of N. furzeri miRNAs was analyzed and compared to the four fish species Danio rerio, Oryzias latipes, Gasterosteus aculeatus and Takifugu rubripes. A peculiar characteristic of N. furzeri, as compared to other teleosts, was a duplication of the miR-29 cluster. The completeness of the catalogue we provide is comparable to that of the zebrafish. This catalogue represents a basis to investigate the role of miRNAs in aging and development in this species.},

keywords = {aging, annotation, ncRNAs, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Moebius:17,

title = {Complete Genome Sequence of JII-1961, a Bovine \textit{Mycobacterium avium} subsp. \textit{paratuberculosis} Field Isolate from Germany},

author = {Petra Möbius and Gabriele Nordsiek and Martin Hölzer and Michael Jarek and Manja Marz and Heike Köhler},

doi = {10.1128/genomeA.00870-17},

year  = {2017},

date = {2017-08-24},

urldate = {2017-01-01},

journal = {Genome Announc},

volume = {5},

number = {34},

abstract = {Mycobacterium avium subsp. paratuberculosis causes Johne’s disease in ruminants and was also detected in nonruminant species, including human beings, and in milk products. We announce here the 4.829-Mb complete genome sequence of the cattle-type strain JII-1961 from Germany, which is very similar to cattle-type strains recovered from different continents.

},

keywords = {assembly, bacteria, DNA / genomics},

pubstate = {published},

tppubtype = {article}

}

@article{Fuchs:17,

title = {Evolution and Antiviral Specificities of Interferon-Induced Mx Proteins of Bats against Ebola, Influenza, and Other RNA Viruses},

author = {Jonas Fuchs and Martin Hölzer and Mirjam Schilling and Corinna Patzina and Andreas Schoen and Thomas Hoenen and Gert Zimmer and Manja Marz and Friedemann Weber and Marcel A Müller and Georg Kochs},

doi = {10.1128/JVI.00361-17},

year  = {2017},

date = {2017-07-12},

urldate = {2017-07-12},

journal = {J Virol},

volume = {91},

abstract = {Bats serve as a reservoir for various, often zoonotic viruses, including significant human pathogens such as Ebola and influenza viruses. However, for unknown reasons, viral infections rarely cause clinical symptoms in bats. A tight control of viral replication by the host innate immune defense might contribute to this phenomenon. Transcriptomic studies revealed the presence of the interferon-induced antiviral myxovirus resistance (Mx) proteins in bats, but detailed functional aspects have not been assessed. To provide evidence that bat Mx proteins might act as key factors to control viral replication we cloned cDNAs from three bat families, Pteropodidae, Phyllostomidae, and Vespertilionidae. Phylogenetically these bat genes cluster closely with their human ortholog MxA. Using transfected cell cultures, minireplicon systems, virus-like particles, and virus infections, we determined the antiviral potential of the bat Mx1 proteins. Bat Mx1 significantly reduced the polymerase activity of viruses circulating in bats, including Ebola and influenza A-like viruses. The related Thogoto virus, however, which is not known to infect bats, was not inhibited by bat Mx1. Further, we provide evidence for positive selection in bat genes that might explain species-specific antiviral activities of these proteins. Together, our data suggest a role for Mx1 in controlling these viruses in their bat hosts. Bats are a natural reservoir for various viruses that rarely cause clinical symptoms in bats but are dangerous zoonotic pathogens, like Ebola or rabies virus. It has been hypothesized that the interferon system might play a key role in controlling viral replication in bats. We speculate that the interferon-induced Mx proteins might be key antiviral factors of bats and have coevolved with bat-borne viruses. This study evaluated for the first time a large set of bat Mx1 proteins spanning three major bat families for their antiviral potential, including activity against Ebola virus and bat influenza A-like virus, and we describe here their phylogenetic relationship, revealing patterns of positive selection that suggest a coevolution with viral pathogens. By understanding the molecular mechanisms of the innate resistance of bats against viral diseases, we might gain important insights into how to prevent and fight human zoonotic infections caused by bat-borne viruses.},

keywords = {evolution, phylogenetics, RNA / transcriptomics, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}