Institute of Molecular Biology gGmbH
Institute of Molecular Biology gGmbH
Taskova K.,Johannes Gutenberg University Mainz |
Taskova K.,Institute of Molecular Biology gGmbH |
Fontaine J.-F.,Johannes Gutenberg University Mainz |
Fontaine J.-F.,Institute of Molecular Biology gGmbH |
And 3 more authors.
Methods | Year: 2017
Toxicity affecting humans is studied by observing the effects of chemical substances in animal organisms (in vivo) or in animal and human cultivated cell lines (in vitro). Toxicogenomics studies collect gene expression profiles and histopathology assessment data for hundreds of drugs and pollutants in standardized experimental designs using different model systems. These data are an invaluable source for analyzing genome-wide drug response in biological systems. However, a problem remains that is how to evaluate the suitability of heterogeneous in vitro and in vivo systems to model the many different aspects of human toxicity. We propose here that a given model system (cell type or animal organ) is supported to appropriately describe a particular aspect of human toxicity if the set of compounds associated in the literature with that aspect of toxicity causes a change in expression of genes with a particular function in the tested model system. This approach provides candidate genes to explain the toxicity effect (the differentially expressed genes) and the compounds whose effect could be modeled (the ones producing both the change of expression in the model system and that are associated with the human phenotype in the literature). Here we present an application of this approach using a computational pipeline that integrates compound-induced gene expression profiles (from the Open TG-GATEs database) and biomedical literature annotations (from the PubMed database) to evaluate the suitability of (human and rat) in vitro systems as well as rat in vivo systems to model human toxicity. © 2017.
Villaverde A.F.,University of Vigo |
Villaverde A.F.,University of Minho |
Villaverde A.F.,CSIC - Institute of Marine Research |
Becker K.,Institute of Molecular Biology GGmbH |
Banga J.R.,CSIC - Institute of Marine Research
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2016
A common approach for reverse engineering biological networks from data is to deduce the existence of interactions among nodes from information theoretic measures. Estimating these quantities in a multidimensional space is computationally demanding for large datasets. This hampers the application of elaborate algorithms – which are crucial for discarding spurious interactions and determining causal relationships – to large-scale network inference problems. To alleviate this issue we have developed PREMER, a software tool which can automatically run in parallel and sequential environments, thanks to its implementation of OpenMP directives. It recovers network topology and estimates the strength and causality of interactions using information theoretic criteria, and allowing the incorporation of prior knowledge. A preprocessing module takes care of imputing missing data and correcting outliers if needed. PREMER (https://sites.google.com/site/premertoolbox/) runs on Windows, Linux and OSX, it is implemented in Matlab/Octave and Fortran 90, and it does not require any commercial software. © Springer International Publishing AG 2016.
Ammerpohl O.,University of Kiel |
Bens S.,University of Kiel |
Appari M.,University of Kiel |
Werner R.,University of Lübeck |
And 11 more authors.
PLoS ONE | Year: 2013
Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases. © 2013 Ammerpohl et al.
News Article | November 14, 2016
Nominated by Johannes Gutenberg University Mainz (JGU) and the Institute of Molecular Biology gGmbH (IMB), chromosome researcher Professor Peter Baumann has been awarded an Alexander von Humboldt Professorship, which comes with the best endowed research grant in Germany. Baumann is an internationally renowned expert in the field of chromosome biology and is currently working in the United States of America as a researcher at the Howard Hughes Medical Institute and the Stowers Institute for Medical Research in Kansas City. Every year since 2008, the Alexander von Humboldt Foundation has awarded up to ten professorships to top level international researchers to pursue groundbreaking research at universities and research institutions in Germany. Academics working in experimental research receive EUR 5 million in financing over the first five years. When nominating a candidate, the universities also submit a concept on how they intend to continue to fund this professorship after this period. In his research, Professor Peter Baumann investigates two fundamental aspects of chromosome biology, namely the architecture and dynamics of the chromosome ends and the passing on of genetic information. Both aspects have enormous consequences for the maintenance of genome stability and genetic diversity. Baumann will continue to work in these research areas as Professor of Molecular Biology at the Faculty of Biology at Johannes Gutenberg University Mainz and also as Adjunct Director of the Institute of Molecular Biology. "The acquisition of this Alexander von Humboldt Professorship by Johannes Gutenberg University Mainz again confirms that the German federal state of Rhineland-Palatinate is an internationally visible and attractive location for life science research. Top-level research and innovation proven continuously over the years form the basis for the reputation of this region, not just when it comes to fundamental life sciences research but also in application-based research. We intend to promote and extend both these areas in future," emphasized Professor Konrad Wolf, the Minister of Science, Continuing Education, and Culture of the state of Rhineland-Palatinate. "The approval of this Humboldt Professorship represents exceptional recognition of our efforts to restructure and further develop the biological research fields at the university," announced Professor Georg Krausch, President of Johannes Gutenberg University Mainz. "Professor Baumann's appointment will augment our fundamental biological and biomedical research in key areas and form a direct link with the work being done at IMB." Krausch also pointed out that this is already the third Humboldt Professorship that has been obtained by JGU over a mere four year period. In 2012, a Humboldt Professorship was granted to blood coagulation researcher Professor Wolfram Ruf of the Scripps Institute in La Jolla, USA, who then relocated to the Mainz University Medical Center, another went in 2013 to theoretical physicist Professor Jairo Sinova, who transferred to Mainz from Texas A&M University in the USA. Professor Peter Baumann's research focuses on the fragile ends of chromosomes. These are protected by complex structures called telomeres and can be reconstituted by the enzyme called telomerase. Without appropriately functioning telomeres, chromosomes can become progressively shorter with each new cell division. At the same time, however, elevated telomerase activity is believed to be responsible for the metastasis of cancer cells. While he uses fission yeast and human cell culture for his work in this field, Baumann's second core research area concerns the investigation of the unique features of whiptail lizards. Some of the species in this family have all-female populations and reproduce by means of parthenogenesis. The surprising thing about these reptiles is that they are able to maintain genetic diversity, thus enabling them to survive changes to the environment. It is the molecular and cellular principles at work here that Baumann hopes to better understand. "The Alexander von Humboldt Professorship and the appointment of Professor Peter Baumann to the Faculty of Biology at JGU will allow us to pursue a two-pronged strategy. One aim is to foster the life sciences disciplines here in Mainz to ensure we become trailblazers in the field of telomere biology. In addition, we will assign Professor Baumann an active role in the integration of complementary research topics and groups, thus creating the basis to enable us to acquire third-party funding for coordinated projects," added the Dean of the Faculty of Biology Faculty, Professor Hans Zischler. "We are absolutely delighted that Peter Baumann has been awarded this prestigious professorship and look forward to welcoming him to IMB," emphasized Professor René Ketting, IMB Executive Director. "His ground-breaking research in chromosome biology will be a great asset to Mainz and help strengthen the growing expertise here in this exciting area of biology." Once contract negotiations have been successfully completed, it is likely that Baumann will take up his work at JGU and IMB in the coming year. Interdisciplinary cooperation with other life sciences groups at the Mainz University Medical Center is also planned. The Faculty of Biology is currently experiencing a generational shift among its professors. Thus, the strategy for appointing new professors can be used to achieve a major re-orientation of its work. This opportunity will be used to create focal research areas in groundbreaking fields, to combine resources, and to supplement available skills by means of targeted new appointments. The appointment of Professor Peter Baumann to an Alexander von Humboldt Professorship at JGU epitomizes this strategy. The Institute of Molecular Biology gGmbH (IMB) is an excellence center for life sciences founded in 2011. Research at IMB concentrates on three areas of current interest: epigenetics, developmental biology, and genome stability.
Ericson M.,Yale University |
Janes M.A.,Yale University |
Janes M.A.,San Francisco General Hospital |
Butter F.,Max Planck Institute of Biochemistry |
And 4 more authors.
BMC Biology | Year: 2014
Background: Although technical advances in genomics and proteomics research have yielded a better understanding of the coding capacity of a genome, one major challenge remaining is the identification of all expressed proteins, especially those less than 100 amino acids in length. Such information can be particularly relevant to human pathogens, such as Trypanosoma brucei, the causative agent of African trypanosomiasis, since it will provide further insight into the parasite biology and life cycle.Results: Starting with 993 T. brucei transcripts, previously shown by RNA-Sequencing not to coincide with annotated coding sequences (CDS), homology searches revealed that 173 predicted short open reading frames in these transcripts are conserved across kinetoplastids with 13 also conserved in representative eukaryotes. Mining mass spectrometry data sets revealed 42 transcripts encoding at least one matching peptide. RNAi-induced down-regulation of these 42 transcripts revealed seven to be essential in insect-form trypanosomes with two also required for the bloodstream life cycle stage. To validate the specificity of the RNAi results, each lethal phenotype was rescued by co-expressing an RNAi-resistant construct of each corresponding CDS. These previously non-annotated essential small proteins localized to a variety of cell compartments, including the cell surface, mitochondria, nucleus and cytoplasm, inferring the diverse biological roles they are likely to play in T. brucei. We also provide evidence that one of these small proteins is required for replicating the kinetoplast (mitochondrial) DNA.Conclusions: Our studies highlight the presence and significance of small proteins in a protist and expose potential new targets to block the survival of trypanosomes in the insect vector and/or the mammalian host. © 2014 Ericson et al.; licensee BioMed Central Ltd.
Frohlich D.,University of Mainz |
Kuo W.P.,University of Mainz |
Fruhbeis C.,University of Mainz |
Sun J.-J.,University Hospital Freiburg |
And 9 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014
Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell-cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen-glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
PubMed | University of Mainz, Institute of Molecular Biology gGmbH, University Medical Center, University Hospital Freiburg and 2 more.
Type: Journal Article | Journal: Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014
Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell-cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen-glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance.
Wiench B.,Johannes Gutenberg University Mainz |
Eichhorn T.,Johannes Gutenberg University Mainz |
Korn B.,Institute of Molecular Biology gGmbH |
Paulsen M.,Institute of Molecular Biology gGmbH |
Efferth T.,Johannes Gutenberg University Mainz
Methods | Year: 2012
The precise detection of pharmaceutical drug uptake and knowledge of a drug's efficacy at the single-cell level is crucial for understanding a compound's performance. Many pharmaceutical drugs, like the model substances Doxorubicin, Mitoxantrone or Irinotecan, have a distinctive natural fluorescence that can be readily exploited for research purposes. Utilizing this respective natural fluorescence, we propose a method analyzing simultaneously in real-time the efficiency, effects and the associated kinetics of compound-uptake and efflux in mammalian cells by flow cytometry. We show that real-time flow cytometric quantification of compound-uptake is reliably measured and that analyzing their respective uptake kinetic provides additional valuable information which can be used for improving drug dosage and delivery. Exploiting the native fluorescence of natural compounds is clearly advantageous compared to the usage of non-related fluorescent uptake-reporter substances, possibly yielding in unphysiological data. Flow cytometric analysis allows live-dye based multi-parametric high-throughput screening of pharmaceutical compound activity, improving cytotoxicity testing by combining several assays into a single, high resolution readout. This approach can be a useful tool identifying potential inhibitors for multiple drug resistance (MDR), representing a major challenge to the targeted treatment of various diseases. © 2012 Elsevier Inc.