Members » Emanuel Barth

@article{nokey_42,

title = {PAPAS Suppresses Breast Carcinogenesis by Promoting Differentiation of Mammary Epithelial Cells},

author = {Sijia Ren and Feng Bai and Clara Stanko and Muriel Ritsch and Tino Schenk and Emanuel Barth and Xin-Hai Pei and Holger Bierhoff

},

doi = {10.2139/ssrn.4436847},

year  = {2023},

date = {2023-05-23},

journal = {Cell Reports},

abstract = {Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoid breast cancer development. Here we show that lactogenic differentiation of murine MECs requires epigenetic silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcript PAPAS. Accordingly, knockdown of PAPAS derepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. Restoring PAPAS levels in breast cancer cells reduces tumorigenicity and, as revealed by transcriptomics, immune evasion potential. Mechanistically, we show that PAPAS transcription depends on R-loop formation at the 3’ end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion of PAPAS, and upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Identification of altered miRNAs and their targets in placenta accreta},

author = {José M Murrieta-Coxca and Emanuel Barth and Paulina Fuentes-Zacarias and Ruby N Gutiérrez-Samudio and Tanja Groten and Alexandra Gellhaus and Angela Köninger and Manja Marz and Udo R Markert and Diana M Morales-Prieto

},

doi = {10.3389/fendo.2023.1021640},

year  = {2023},

date = {2023-03-03},

journal = {Front Endocrinol},

volume = {14},

pages = {1021640},

abstract = {Placenta accreta spectrum (PAS) is one of the major causes of maternal morbidity and mortality worldwide with increasing incidence. PAS refers to a group of pathological conditions ranging from the abnormal attachment of the placenta to the uterus wall to its perforation and, in extreme cases, invasion into surrounding organs. Among them, placenta accreta is characterized by a direct adhesion of the villi to the myometrium without invasion and remains the most common diagnosis of PAS. Here, we identify the potential regulatory miRNA and target networks contributing to placenta accreta development. Using small RNA-Seq followed by RT-PCR confirmation, altered miRNA expression, including that of members of placenta-specific miRNA clusters (e.g., C19MC and C14MC), was identified in placenta accreta samples compared to normal placental tissues. In situ hybridization (ISH) revealed expression of altered miRNAs mostly in trophoblast but also in endothelial cells and this profile was similar among all evaluated degrees of PAS. Kyoto encyclopedia of genes and genomes (KEGG) analyses showed enriched pathways dysregulated in PAS associated with cell cycle regulation, inflammation, and invasion. mRNAs of genes associated with cell cycle and inflammation were downregulated in PAS. At the protein level, NF-κB was upregulated while PTEN was downregulated in placenta accreta tissue. The identified miRNAs and their targets are associated with signaling pathways relevant to controlling trophoblast function. Therefore, this study provides miRNA:mRNA associations that could be useful for understanding PAS onset and progression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Nanopore sequencing for mapping of retrotransposon integration sites in the \textit{Dictyostelium discoideum} genome},

author = {Emanuel Barth and Johannes Burggraaff and Akash Srivastava and Thomas Winckler

},

doi = {10.17912/micropub.biology.000543},

year  = {2022},

date = {2022-03-18},

journal = {MicroPubl Biol},

abstract = {The unicellular eukaryote \textit{Dictyostelium discoideum} has a gene-dense haploid genome. This configuration presents mobile elements with the particular challenge of replicating without causing excessive damage to the host through insertional mutagenesis or recombination between repetitive sequences. \textit{D. discoideum} harbors an active population of the retrotransposon TRE5-A that integrates in a narrow window of ~50 bp upstream of tRNA genes. We assume that this integration preference was developed to avoid the disruption of protein-coding genes. Therefore, we recently mapped new integrations of a genetically tagged TRE5-A element at tRNA genes using PCR-based enrichment of integration junctions. However, the PCR-based enrichment produced several artificial DNA fusions that prevented the mapping of integration sites in unknown places of the genome. Here, we reanalyzed the previous experiment using nanopore sequencing. We summarize the advantages and limitations of direct genome resequencing for the mapping of mobile element integrations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Draft genome assembly and sequencing dataset of the marine diatom Skeletonema cf. costatum RCC75},

author = {Maria Sorokina and Emanuel Barth and Mahnoor Zulfiqar and Michiel Kwantes and Georg Pohnert and Christoph Steinbeck

},

doi = {10.1016/j.dib.2022.107931},

year  = {2022},

date = {2022-02-19},

urldate = {2022-02-05},

journal = {Data Brief},

volume = {41},

pages = {107931},

abstract = {Diatoms (Bacillariophyceae) are a major constituent of the phytoplankton and have a universally recognized ecological importance. Between 1,000 and 1,300 diatom genera have been described in the literature, but only 10 nuclear genomes have been published and made available to the public up to date. Skeletonema costatum is a cosmopolitan marine diatom, principally occurring in coastal regions, and is one of the most abundant members of the Skeletonema genus. Here we present a draft assembly of the Skeletonema cf. costatum RCC75 genome, obtained from PacBio and Illumina NovaSeq data. This dataset will expand the knowledge of the Bacillariophyceae genetics and contribute to the global understanding of phytoplankton's physiological, ecological, and environmental functioning.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging},

author = {Emanuel Barth and Akash Srivastava and Diane Wengerodt and Milan Stojiljkovic and Hubertus Axer and Otto W Witte and Alexandra Kretz and Manja Marz

},

doi = {10.18632/aging.203788},

year  = {2021},

date = {2021-12-19},

journal = {Aging},

volume = {13},

number = {24},

pages = {25694-25716},

abstract = {The circadian clock system influences the biology of life by establishing circadian rhythms in organisms, tissues, and cells, thus regulating essential biological processes based on the day/night cycle. Circadian rhythms change over a lifetime due to maturation and aging, and disturbances in the control of the circadian system are associated with several age-related pathologies. However, the impact of chronobiology and the circadian system on healthy organ and tissue aging remains largely unknown. Whether aging-related changes of the circadian system's regulation follow a conserved pattern across different species and tissues, hence representing a common driving force of aging, is unclear. Based on a cross-sectional transcriptome analysis covering 329 RNA-Seq libraries, we provide indications that the circadian system is subjected to aging-related gene alterations shared between evolutionarily distinct species, such as Homo sapiens, Mus musculus, Danio rerio, and Nothobranchius furzeri. We discovered differentially expressed genes by comparing tissue-specific transcriptional profiles of mature, aged, and old-age individuals and report on six genes (per2, dec2, cirp, klf10, nfil3, and dbp) of the circadian system, which show conserved aging-related expression patterns in four organs of the species examined. Our results illustrate how the circadian system and aging might influence each other in various tissues over a long lifespan and conceptually complement previous studies tracking short-term diurnal and nocturnal gene expression oscillations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Analysis of microRNA expression reveals convergent evolution of the molecular control of diapause in annual fish},

author = {Emanuel Barth and Mario Baumgart and Luca Dolfi and Rongfeng Cui and Marco Groth and Roberto Ripa and Aurora Savino and Dario R. Valenzano and Manja Marz and Alessandro Cellerino},

doi = {10.21203/rs.3.rs-744922/v1},

year  = {2021},

date = {2021-07-01},

urldate = {2021-07-01},

journal = {Research Square},

abstract = {Background. Diapause is a key adaptation that enabled the colonization of ephemeral habitats subject to the alternation of dry and wet seasons by annual killifishes. Upon desiccation of the ponds, killifish embryos remain vital but quiescent in the clay, where they can survive months or even years. Diapause can occur at three different developmental stages, but Diapause II (DII), which occurs at mid-somitogenesis, is the primary point of developmental arrest. However, diapause is not obligatory, and some embryos can proceed to direct development, skipping one or more diapauses. The precise molecular mechanisms that regulate entry and exit from diapause are beginning to be investigated, but this knowledge is yet fragmentary.

Diapause has evolved independently several times in killifish clades from Africa and South America, enabling the identification of possible molecular determinants of diapause by comparative expression analysis. MicroRNAs are small RNAs that represent central nodes in the control of gene expression at the post-transcriptional level and are involved in many developmental processes. Here, we compare microRNA expression profiles of annual killifishes during DII with non-annual killifish in a comparable stage of morphological development.



Results. We used smallRNA-Seq to quantify microRNA expression from four annual- and four non-annual killifish species from three independent clades and from direct-developing embryos of the annual fish Nothobranchius furzeri. We analyzed the expression of broadly conserved microRNAs and microRNAs that appear to have evolved in the killifish lineage.

We found several microRNAs that showed convergent regulation in the three different clades, and for some microRNAs also a phenomenon of switch in the prevalent form between 3p and 5p or vice versa was noted. In addition, we detected a significant overlap between the microRNA regulation during diapause and aging.

Particularly interesting is the regulation of the miR-430 family. These microRNAs represent the second most expressed microRNA family in the killifish embryos, and diapause is associated with dramatic down-regulation of the prevalent -3p form and up-regulation of the -5p form. Members of the miR-430 family are contained in a large repetitive cluster whose organization is variable among teleost. Analysis of recently sequenced 45 low-coverage killifish genomes revealed that the miR-430 locus contains a lower number of copies in annual- as opposed to non-annual killifish.



Conclusions. The Evolution of diapause is reflected in the convergent evolution of microRNA regulation in killifishes. A prominent feature is a dramatic down-regulation of miR-430 expression that could be partially explained with a reduction of its copy numbers in the genome.},

keywords = {},

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 = {https://github.com/rnajena/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 = {},

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/rnajena/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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

pubstate = {published},

tppubtype = {article}

}

@article{Riege:17,

title = {Massive Effect on LncRNAs in Human Monocytes During Fungal and Bacterial Infections and in Response to Vitamins A and D},

author = {Konstantin Riege and Martin Hölzer and Tilman E Klassert and Emanuel Barth and Julia Bräuer and Maximilian Collatz and Franziska Hufsky and Nelly F. Mostajo and Magdalena Stock and Bertram Vogel and Hortense Slevogt and Manja Marz},

doi = {10.1038/srep40598},

year  = {2017},

date = {2017-01-17},

urldate = {2017-01-17},

journal = {Sci Rep},

volume = {7},

pages = {40598},

abstract = {Mycoses induced by C.albicans or A.fumigatus can cause important host damage either by deficient or exaggerated immune response. Regulation of chemokine and cytokine signaling plays a crucial role for an adequate inflammation, which can be modulated by vitamins A and D. Non-coding RNAs (ncRNAs) as transcription factors or cis-acting antisense RNAs are known to be involved in gene regulation. However, the processes during fungal infections and treatment with vitamins in terms of therapeutic impact are unknown. We show that in monocytes both vitamins regulate ncRNAs involved in amino acid metabolism and immune system processes using comprehensive RNA-Seq analyses. Compared to protein-coding genes, fungi and bacteria induced an expression change in relatively few ncRNAs, but with massive fold changes of up to 4000. We defined the landscape of long-ncRNAs (lncRNAs) in response to pathogens and observed variation in the isoforms composition for several lncRNA following infection and vitamin treatment. Most of the involved antisense RNAs are regulated and positively correlated with their sense protein-coding genes. We investigated lncRNAs with stimulus specific immunomodulatory activity as potential marker genes: LINC00595, SBF2-AS1 (A.fumigatus) and RP11-588G21.2, RP11-394l13.1 (C.albicans) might be detectable in the early phase of infection and serve as therapeutic targets in the future.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hoelzer:16,

title = {Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells},

author = {Martin Hölzer and Verena Krähling and Fabian Amman and Emanuel Barth and Stephan H. Bernhart and Victor A. O. Carmelo and Maximilian Collatz and Gero Doose and Florian Eggenhofer and Jan Ewald and Jörg Fallmann and Lasse M. Feldhahn and Markus Fricke and Juliane Gebauer and Andreas J. Gruber and Franziska Hufsky and Henrike Indrischek and Sabina Kanton and Jörg Linde and Nelly F. Mostajo and Roman Ochsenreiter and Konstantin Riege and Lorena Rivarola-Duarte and Abdullah H. Sahyoun and Sita J. Saunders and Stefan E. Seemann and Andrea Tanzer and Bertram Vogel and Stefanie Wehner and Michael T. Wolfinger and Rolf Backofen and Jan Gorodkin and Ivo Grosse and Ivo Hofacker and Steve Hoffmann and Christoph Kaleta and Peter F. Stadler and Stephan Becker and Manja Marz},

doi = {10.1038/srep34589},

year  = {2016},

date = {2016-10-07},

urldate = {2016-10-07},

journal = {Sci Rep},

volume = {6},

pages = {34589},

abstract = {The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Barth:16,

title = {The Evolution of COP9 Signalosome in Unicellular and Multicellular Organisms},

author = {Emanuel Barth and Ron Hübler and Aria Baniahmad and Manja Marz},

doi = {10.1093/gbe/evw073},

year  = {2016},

date = {2016-01-01},

urldate = {2016-01-01},

journal = {Genome Biol Evol},

volume = {8},

number = {4},

pages = {1279--1289},

abstract = {The COP9 signalosome (CSN) is a highly conserved protein complex, recently being crystallized for human. In mammals and plants the COP9 complex consists of nine subunits, CSN 1-8 and CSNAP. The CSN regulates the activity of culling ring E3 ubiquitin and plays central roles in pleiotropy, cell cycle, and defense of pathogens. Despite the interesting and essential functions, a thorough analysis of the CSN subunits in evolutionary comparative perspective is missing. Here we compared 61 eukaryotic genomes including plants, animals, and yeasts genomes and show that the most conserved subunits of eukaryotes among the nine subunits are CSN2 and CSN5. This may indicate a strong evolutionary selection for these two subunits. Despite the strong conservation of the protein sequence, the genomic structures of the intron/exon boundaries indicate no conservation at genomic level. This suggests that the gene structure is exposed to a much less selection compared with the protein sequence. We also show the conservation of important active domains, such as PCI (proteasome lid-CSN-initiation factor) and MPN (MPR1/PAD1 amino-terminal). We identified novel exons and alternative splicing variants for all CSN subunits. This indicates another level of complexity of the CSN. Notably, most COP9-subunits were identified in all multicellular and unicellular eukaryotic organisms analyzed, but not in prokaryotes or archaeas. Thus, genes encoding CSN subunits present in all analyzed eukaryotes indicate the invention of the signalosome at the root of eukaryotes. The identification of alternative splice variants indicates possible "mini-complexes" or COP9 complexes with independent subunits containing potentially novel and not yet identified functions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Graf:15,

title = {ID: 187: Allelic variations in the interferon-induced human MxA protein affect its antiviral activity against influenza A virus},

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

doi = {10.1016/j.cyto.2015.08.192},

year  = {2015},

date = {2015-09-11},

urldate = {2015-09-11},

journal = {Cytokine},

volume = {76},

number = {1},

pages = {98},

publisher = {Elsevier},

abstract = {Human myxovirus resistance protein A (MxA) is an interferon-induced GTPase and part of the host cell defense against influenza viruses. It has a three-domain architecture with an amino-terminal GTPase (G) domain and a carboxy-terminal stalk responsible for oligomerization and viral target recognition. The MX1 gene, encoding MxA, is highly conserved and only a few single nucleotide polymorphisms are described in the human population. In this study we investigate whether and how allelic variations in MxA influence its antiviral function. Two rare nucleotide changes identified in the MX1 gene of healthy individuals result in amino acid exchanges at positions 255 and 268 in the G domain. GTPase and Minireplicon assays revealed that the V268M exchange showed some reduction in GTP hydrolysis, but only a slightly reduced antiviral activity against influenza A virus. However, the G255E exchange caused a complete loss of GTPase and antiviral activity of MxA. Further biochemical analyses of this naturally occurring mutation revealed the central role of GTP binding and hydrolysis for the antiviral mechanism of MxA. Using bioinformatics tools we are currently identifying additional allelic variations in MxA. Their characterization will answer the question how polymorphisms in the MX1 gene influence the antiviral capacity of MxA and whether these are enriched in patients suffering from severe influenza as has been described recently for IFITM3, another interferon-induced antiviral restriction factor.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gimpel:12,

title = {SR1 - a small RNA with two remarkably conserved functions},

author = {Matthias Gimpel and Heike Preis and Emanuel Barth and Lydia Gramzow and Sabine Brantl},

doi = {10.1093/nar/gks895},

year  = {2012},

date = {2012-10-02},

urldate = {2012-01-01},

journal = {Nucleic Acids Res},

volume = {40},

pages = {11659--11672},

abstract = {SR1 is a dual-function sRNA that acts as a base-pairing regulatory RNA on the ahrC mRNA and as a peptide-encoding mRNA on the gapA operon. The SR1-encoded peptide SR1P binds GapA thereby stabilizing gapA mRNA. Under glycolytic conditions, SR1 transcription is repressed by CcpN and CcpA. A computer-based search identified 23 SR1 homologues in Bacillus, Geobacillus, Anoxybacillus and Brevibacillus species. All homologues share a high structural identity with Bacillus subtilis SR1, and the encoded SR1P peptides are highly similar. In the Bacillus cereus group, the sr1p region is present in triplicate or duplicate resulting in longer SR1 species. In all cases, sr1 expression is under control of CcpN, and transcriptional lacZ fusions of nine examined SR1 homologues were sensitive to glucose. Two homologues showed an additional glucose-independent repression by CcpN and an unknown factor. A total of 10 out of 11 tested SR1P homologues complemented a B. subtilis Δsr1 strain in their ability to stabilize gapA mRNA, but only five of them bound GapA tightly. In vitro binding assays with six SR1/ahrC pairs suggest that-despite divergent primary sequences-the base-pairing function is also preserved. In summary, SR1 is an sRNA with two functions that have been conserved over ≈1 billion years.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}