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  • 1.
    Andersson, Erik
    et al.
    Örebro University, School of Medical Sciences.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    D'Amato, M.
    Department of Medicine, Karolinska Institutet Solna, Stockholm, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences.
    Inflammatory biomarkers in serum discriminate Crohn's disease and ulcerative colitis from healthy controls2016In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, no Suppl. 1, p. S86-S87Article in journal (Other academic)
  • 2.
    Andersson, Erik
    et al.
    Örebro University, School of Medical Sciences.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Neumann, Gunter
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    D'Amato, Mauro
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; BioDonostia Health Research Institute, San Sebastian, Spain; IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Subphenotypes of inflammatory bowel disease are characterized by specific serum protein profiles2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 10, article id e0186142Article in journal (Refereed)
    Abstract [en]

    Objective: Genetic and immunological data indicate that inflammatory bowel disease (IBD) are characterized by specific inflammatory protein profiles. However, the serum proteome of IBD is still to be defined. We aimed to characterize the inflammatory serum protein profiles of Crohn's disease (CD) and ulcerative colitis (UC), using the novel proximity extension assay.

    Methods: A panel of 91 inflammatory proteins were quantified in a discovery cohort of CD (n = 54), UC patients (n = 54), and healthy controls (HCs; n = 54). We performed univariate analyses by t-test, with false discovery rate correction. A sparse partial least-squares (sPLS) approach was used to identify additional discriminative proteins. The results were validated in a replication cohort.

    Results: By univariate analysis, 17 proteins were identified with significantly different abundances in CD and HCs, and 12 when comparing UC and HCs. Additionally, 64 and 45 discriminant candidate proteins, respectively, were identified with the multivariate approach. Correspondingly, significant cross-validation error rates of 0.12 and 0.19 were observed in the discovery cohort. Only FGF-19 was identified from univariate comparisons of CD and UC, but 37 additional discriminant candidates were identified using the multivariate approach. The observed cross-validation error rate for CD vs. UC remained significant when restricting the analyses to patients in clinical remission. Using univariate comparisons, 16 of 17 CD-associated proteins and 8 of 12 UC-associated proteins were validated in the replication cohort. The area under the curve for CD and UC was 0.96 and 0.92, respectively, when the sPLS model from the discovery cohort was applied to the replication cohort.

    Conclusions: By using the novel PEA method and a panel of inflammatory proteins, we identified proteins with significantly different quantities in CD patients and UC patients compared to HCs. Our data highlight the potential of the serum IBD proteome as a source for identification of future diagnostic biomarkers.

  • 3. Andorf, Sandra
    et al.
    Altmann, T
    Witucka-Wall, H
    Selbig, Joachim
    Repsilber, Dirk
    Institute of Genetics and Biometry, Bioinformatics and Biomathematics Unit, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Molecular network structures in heterozygotes: A systems-biology approach to heterosis2009Conference paper (Refereed)
  • 4.
    Andorf, Sandra
    et al.
    Bioinformatics and Biomathematics Group, Genetics and Biometry Unit, Research Institute for the Biology of Farm Animals (FBN), Dummersdorf, Germany.
    Gärtner, Tanja
    Institute for Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
    Steinfath, Matthias
    Institute for Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
    Witucka-Wall, Hanna
    Institute for Genetics, University of Potsdam, Potsdam-Golm, Germany.
    Altmann, Thomas
    Institute for Genetics, University of Potsdam, Potsdam-Golm, Germany.
    Repsilber, Dirk
    Bioinformatics and Biomathematics Group, Genetics and Biometry Unit, Research Institute for the Biology of Farm Animals (FBN), Dummersdorf, Germany.
    Towards systems biology of heterosis: a hypothesis about molecular network structure applied for the Arabidopsis metabolome2009In: EURASIP Journal on Bioinformatics and Systems Biology, ISSN 1687-4145, E-ISSN 1687-4153, article id 147157Article in journal (Refereed)
    Abstract [en]

    We propose a network structure-based model for heterosis, and investigate it relying on metabolite profiles from Arabidopsis. A simple feed-forward two-layer network model (the Steinbuch matrix) is used in our conceptual approach. It allows for directly relating structural network properties with biological function. Interpreting heterosis as increased adaptability, our model predicts that the biological networks involved show increasing connectivity of regulatory interactions. A detailed analysis of metabolite profile data reveals that the increasing-connectivity prediction is true for graphical Gaussian models in our data from early development. This mirrors properties of observed heterotic Arabidopsis phenotypes. Furthermore, the model predicts a limit for increasing hybrid vigor with increasing heterozygosity--a known phenomenon in the literature.

  • 5.
    Andorf, Sandra
    et al.
    Department Genetics and Biometry, Bioinformatics and Biomathematics Group, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany; Department of Medicine, Institute for Biostatistics and Informatics in Medicine and Ageing Research, University of Rostock, Rostock, Germany.
    Meyer, Rhonda C
    Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Selbig, Joachim
    Bioinformatics Chair, Institute for Biochemistry and Biology, University of Potsdam, Potsdam, Germany.
    Altmann, Thomas
    Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Repsilber, Dirk
    Department Genetics and Biometry, Bioinformatics and Biomathematics Group, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Integration of a systems biological network analysis and QTL results for biomass heterosis in Arabidopsis thaliana2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, article id e49951Article in journal (Refereed)
    Abstract [en]

    To contribute to a further insight into heterosis we applied an integrative analysis to a systems biological network approach and a quantitative genetics analysis towards biomass heterosis in early Arabidopsis thaliana development. The study was performed on the parental accessions C24 and Col-0 and the reciprocal crosses. In an over-representation analysis it was tested if the overlap between the resulting gene lists of the two approaches is significantly larger than expected by chance. Top ranked genes in the results list of the systems biological analysis were significantly over-represented in the heterotic QTL candidate regions for either hybrid as well as regarding mid-parent and best-parent heterosis. This suggests that not only a few but rather several genes that influence biomass heterosis are located within each heterotic QTL region. Furthermore, the overlapping resulting genes of the two integrated approaches were particularly enriched in biomass related pathways. A chromosome-wise over-representation analysis gave rise to the hypothesis that chromosomes number 2 and 4 probably carry a majority of the genes involved in biomass heterosis in the early development of Arabidopsis thaliana.

  • 6. Andorf, Sandra
    et al.
    Repsilber, Dirk
    Institute of Genetics and Biometry, Bioinformatics and Biomathematics Unit, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Molecular network structures in heterozygotes: A systems biological approach to heterosis2009In: Neue Methoden der Biometrie: 55. Biometrisches Kolloquium / [ed] R. Foraita, T. Gerds, L. A. Hothorn, M. Kieser, O. Kuß, U. Munzel, R. Vonk, A. Ziegler, 2009Conference paper (Refereed)
  • 7.
    Andorf, Sandra
    et al.
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Selbig, Joachim
    University of Potsdam, Potsdam-Golm, Germany.
    Altmann, T
    Leibniz Institute of Plant Genetics and Crop Plant Research, Gatersleben, Germany.
    Witucka-Wall, H
    University of Potsdam, Potsdam-Golm, Germany.
    Repsilber, Dirk
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Gremany.
    Heterosis in Arabidopsis thaliana: A metabolite network structure approach2010In: 11th Day of the Doktoral Student: abstract; 19 May 2010, Dummerstorf, Dummerstorf, Germany: FBN , 2010, p. 7-10Conference paper (Refereed)
  • 8.
    Andorf, Sandra
    et al.
    Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany.
    Selbig, Joachim
    Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany.
    Altmann, Thomas
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Poos, Kathrin
    University of Applied Sciences Gelsenkirchen Site Recklinghausen, Recklinghausen, Germany .
    Witucka-Wall, Hanna
    Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany.
    Repsilber, Dirk
    Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany.
    Enriched partial correlations in genome-wide gene expression profiles of hybrids (A. thaliana): a systems biological approach towards the molecular basis of heterosis2010In: Theoretical and Applied Genetics, ISSN 0040-5752, E-ISSN 1432-2242, Vol. 120, no 2, p. 249-59Article in journal (Refereed)
    Abstract [en]

    Heterosis is a well-known phenomenon but the underlying molecular mechanisms are not yet established. To contribute to the understanding of heterosis at the molecular level, we analyzed genome-wide gene expression profile data of Arabidopsis thaliana in a systems biological approach. We used partial correlations to estimate the global interaction structure of regulatory networks. Our hypothesis states that heterosis comes with an increased number of partial correlations which we interpret as increased numbers of regulatory interactions leading to enlarged adaptability of the hybrids. This hypothesis is true for mid-parent heterosis for our dataset of gene expression in two homozygous parental lines and their reciprocal crosses. For the case of best-parent heterosis just one hybrid is significant regarding our hypothesis based on a resampling analysis. Summarizing, both metabolome and gene expression level of our illustrative dataset support our proposal of a systems biological approach towards a molecular basis of heterosis.

  • 9. Andorf, Sandra
    et al.
    Selbig, Joachim
    Meyer, Rhonda
    Altmann, Thomas
    Repsilber, Dirk
    Integrating a molecular network hypothesis and QTL results for heterosis in Arabidopsis thaliana2010In: Statistical Computings 2010: Abstracts der 42. Arbeitstagung, 2010, Vol. 5Conference paper (Refereed)
  • 10.
    Baxter, Charles J
    et al.
    Department of Plant Sciences, University of Oxford, Oxford, United Kingdom.
    Redestig, Henning
    Max-Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany.
    Schauer, Nicolas
    Max-Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany.
    Repsilber, Dirk
    ax-Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany.
    Patil, Kiran R
    Center for Microbial Biotechnology, BioCentrum Technical University of Denmark, Kongens Lyngby, Denmark.
    Nielsen, Jens
    Max-Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany.
    Selbig, Joachim
    Max-Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany.
    Liu, Junli
    Genetics Programme, Scottish Crop Research Institute, Dundee, United Kingdom .
    Fernie, Alisdair R
    Max-Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany.
    Sweetlove, Lee J
    Department of Plant Sciences, University of Oxford, Oxford, United Kingdom.
    The metabolic response of heterotrophic Arabidopsis cells to oxidative stress2007In: Plant Physiology, ISSN 0032-0889, E-ISSN 1532-2548, Vol. 143, no 1, p. 312-25Article in journal (Refereed)
    Abstract [en]

    To cope with oxidative stress, the metabolic network of plant cells must be reconfigured either to bypass damaged enzymes or to support adaptive responses. To characterize the dynamics of metabolic change during oxidative stress, heterotrophic Arabidopsis (Arabidopsis thaliana) cells were treated with menadione and changes in metabolite abundance and (13)C-labeling kinetics were quantified in a time series of samples taken over a 6 h period. Oxidative stress had a profound effect on the central metabolic pathways with extensive metabolic inhibition radiating from the tricarboxylic acid cycle and including large sectors of amino acid metabolism. Sequential accumulation of metabolites in specific pathways indicated a subsequent backing up of glycolysis and a diversion of carbon into the oxidative pentose phosphate pathway. Microarray analysis revealed a coordinated transcriptomic response that represents an emergency coping strategy allowing the cell to survive the metabolic hiatus. Rather than attempt to replace inhibited enzymes, transcripts encoding these enzymes are in fact down-regulated while an antioxidant defense response is mounted. In addition, a major switch from anabolic to catabolic metabolism is signaled. Metabolism is also reconfigured to bypass damaged steps (e.g. induction of an external NADH dehydrogenase of the mitochondrial respiratory chain). The overall metabolic response of Arabidopsis cells to oxidative stress is remarkably similar to the superoxide and hydrogen peroxide stimulons of bacteria and yeast (Saccharomyces cerevisiae), suggesting that the stress regulatory and signaling pathways of plants and microbes may share common elements.

  • 11.
    Björkqvist, Olle
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Seifert, M.
    Microbiol Tumor & Cell Biol, Karolinska Inst, Stockholm, Sweden.
    Engstrand, L.
    Microbiol Tumor & Cell Biol, Karolinska Inst, Stockholm, Sweden.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences.
    Increasing abundance of faecalibacterium prausnitzii is associated with decreased intestinal inflammation in Crohn's disease: A longitudinal study2018In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, no Suppl. 1, p. S468-S469Article in journal (Other academic)
  • 12.
    Brand, Bodo
    et al.
    Research Group of Functional Genomics, Leibniz Institute of Farm Animal Biology, Dummerstorf, Germany .
    Hartmann, Anja
    Research Group of Functional Genomics, Leibniz Institute of Farm Animal Biology, Dummerstorf, Germany .
    Repsilber, Dirk
    Research Unit of Genetics and Biometry, Leibniz Institute of Farm Animal Biology, Dummerstorf, Germany .
    Griesbeck-Zilch, Bettina
    Institute of Physiology, Technical University Munich, Freising, Germany.
    Wellnitz, Olga
    Veterinary Physiology, Vetsuisse Faculty, University of Bern, Posieux, Switzerland .
    Kühn, Christa
    Research Unit of Molecular Biology, Leibniz Institute of Farm Animal Biology, Dummerstorf, Germany.
    Ponsuksili, Siriluck
    Research Group of Functional Genomics, Leibniz Institute of Farm Animal Biology, Dummerstorf, Germany .
    Meyer, Heinrich H D
    Institute of Physiology, Technical University Munich, Freising, Germany.
    Schwerin, Manfred
    Research Group of Functional Genomics, Leibniz Institute of Farm Animal Biology, Dummerstorf, Germany; Institute of Farm Animal Science and Technology, University of Rostock, Rostock, Germany .
    Comparative expression profiling of E. coli and S. aureus inoculated primary mammary gland cells sampled from cows with different genetic predispositions for somatic cell score2011In: Genetics Selection Evolution, ISSN 0999-193X, E-ISSN 1297-9686, Vol. 43, no 1, article id 24Article in journal (Refereed)
    Abstract [en]

    Background: During the past ten years many quantitative trait loci (QTL) affecting mastitis incidence and mastitis related traits like somatic cell score (SCS) were identified in cattle. However, little is known about the molecular architecture of QTL affecting mastitis susceptibility and the underlying physiological mechanisms and genes causing mastitis susceptibility. Here, a genome-wide expression analysis was conducted to analyze molecular mechanisms of mastitis susceptibility that are affected by a specific QTL for SCS on Bos taurus autosome 18 (BTA18). Thereby, some first insights were sought into the genetically determined mechanisms of mammary gland epithelial cells influencing the course of infection.

    Methods: Primary bovine mammary gland epithelial cells (pbMEC) were sampled from the udder parenchyma of cows selected for high and low mastitis susceptibility by applying a marker-assisted selection strategy considering QTL and molecular marker information of a confirmed QTL for SCS in the telomeric region of BTA18. The cells were cultured and subsequently inoculated with heat-inactivated mastitis pathogens Escherichia coli and Staphylococcus aureus, respectively. After 1, 6 and 24 h, the cells were harvested and analyzed using the microarray expression chip technology to identify differences in mRNA expression profiles attributed to genetic predisposition, inoculation and cell culture.

    Results: Comparative analysis of co-expression profiles clearly showed a faster and stronger response after pathogen challenge in pbMEC from less susceptible animals that inherited the favorable QTL allele 'Q' than in pbMEC from more susceptible animals that inherited the unfavorable QTL allele 'q'. Furthermore, the results highlighted RELB as a functional and positional candidate gene and related non-canonical Nf-kappaB signaling as a functional mechanism affected by the QTL. However, in both groups, inoculation resulted in up-regulation of genes associated with the Ingenuity pathways 'dendritic cell maturation' and 'acute phase response signaling', whereas cell culture affected biological processes involved in 'cellular development'.

    Conclusions: The results indicate that the complex expression profiling of pathogen challenged pbMEC sampled from cows inheriting alternative QTL alleles is suitable to study genetically determined molecular mechanisms of mastitis susceptibility in mammary epithelial cells in vitro and to highlight the most likely functional pathways and candidate genes underlying the QTL effect.

  • 13.
    Degenkolbe, Thomas
    et al.
    Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam, Germany .
    Do, Phuc Thi
    Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam, Germany .
    Zuther, Ellen
    Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam, Germany .
    Repsilber, Dirk
    Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam, Germany; Forschungsinstitut für Die Biologie Landwirtschaftlicher Nutztiere (FBN), Dummerstorf, Germany.
    Walther, Dirk
    Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam, Germany .
    Hincha, Dirk K
    Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam, Germany .
    Köhl, Karin I
    Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam, Germany .
    Expression profiling of rice cultivars differing in their tolerance to long-term drought stress2009In: Plant Molecular Biology, ISSN 0167-4412, E-ISSN 1573-5028, Vol. 69, no 1-2, p. 133-53Article in journal (Refereed)
    Abstract [en]

    Understanding the molecular basis of plant performance under water-limiting conditions will help to breed crop plants with a lower water demand. We investigated the physiological and gene expression response of drought-tolerant (IR57311 and LC-93-4) and drought-sensitive (Nipponbare and Taipei 309) rice (Oryza sativa L.) cultivars to 18 days of drought stress in climate chamber experiments. Drought stressed plants grew significantly slower than the controls. Gene expression profiles were measured in leaf samples with the 20 K NSF oligonucleotide microarray. A linear model was fitted to the data to identify genes that were significantly regulated under drought stress. In all drought stressed cultivars, 245 genes were significantly repressed and 413 genes induced. Genes differing in their expression pattern under drought stress between tolerant and sensitive cultivars were identified by the genotype x environment (G x E) interaction term. More genes were significantly drought regulated in the sensitive than in the tolerant cultivars. Localizing all expressed genes on the rice genome map, we checked which genes with a significant G x E interaction co-localized with published quantitative trait loci regions for drought tolerance. These genes are more likely to be important for drought tolerance in an agricultural environment. To identify the metabolic processes with a significant G x E effect, we adapted the analysis software MapMan for rice. We found a drought stress induced shift toward senescence related degradation processes that was more pronounced in the sensitive than in the tolerant cultivars. In spite of higher growth rates and water use, more photosynthesis related genes were down-regulated in the tolerant than in the sensitive cultivars.

  • 14.
    Edebol-Carlman, Hanna
    et al.
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre.
    Ljotsson, Brjann
    Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Linton, Steven J.
    Örebro University, School of Law, Psychology and Social Work.
    Boersma, Katja
    Schrooten, Martien
    Örebro University, School of Law, Psychology and Social Work.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre.
    Brummer, Robert J.
    Örebro University Hospital. Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre.
    Face-to-Face Cognitive-Behavioral Therapy for Irritable Bowel Syndrome: The Effects on Gastrointestinal and Psychiatric Symptoms2017In: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, article id 8915872Article in journal (Refereed)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a gastrointestinal disorder linked to disturbances in the gut-brain axis. Visceral hypersensitivity and pain are hallmarks of IBS and linked to the physiological and psychological burden and to the nonadaptive coping with stress. Cognitive-behavioral therapy (CBT) for IBS has proven effective in reducing gastrointestinal and psychiatric symptoms in IBS by means of coping with stress. The present pilot study evaluated for the first time whether CBT for IBS affected visceral sensitivity and pain. Individual CBT was performed for 12 weeks in 18 subjects with IBS and evaluated in terms of visceral sensitivity and pain during rectal distensions using the barostat method and self-rated visceral sensitivity and gastrointestinal and psychiatric symptoms. Visceral discomfort, urge, and pain induced by the barostat were not affected by CBT but were stable across the study. However, the level of self-rated visceral sensitivity and gastrointestinal and psychiatric symptoms decreased after the intervention. Central working mechanisms and increased ability to cope with IBS-symptoms are suggested to play a key role in the alleviation of IBS symptoms produced by CBT.

  • 15.
    Ganda Mall, John-Peter
    et al.
    Örebro University, School of Medical Sciences.
    Östlund-Lagerström, Lina
    Department of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Nutrition and Physical Activity Research Centre, Department of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Algilani, Samal
    Örebro University, School of Health Sciences.
    Rasoal, Dara
    Örebro University, School of Health Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    V. Keita, Åsa
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?2018In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 18, no 1, article id 75Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite the substantial number of older adults suffering from gastrointestinal (GI) symptoms little is known regarding the character of these complaints and whether they are associated with an altered intestinal barrier function and psychological distress. Our aim was to explore the relationship between self-reported gut health, intestinal permeability and psychological distress among older adults.

    METHODS: Three study populations were included: 1) older adults with GI symptoms (n = 24), 2) a group of older adults representing the general elderly population in Sweden (n = 22) and 3) senior orienteering athletes as a potential model of healthy ageing (n = 27). Questionnaire data on gut-health, psychological distress and level of physical activity were collected. Intestinal permeability was measured by quantifying zonulin in plasma. The level of systemic and local inflammation was monitored by measuring C-reactive protein (CRP), hydrogen peroxide in plasma and calprotectin in stool samples. The relationship between biomarkers and questionnaire data in the different study populations was illustrated using a Principal Component Analysis (PCA).

    RESULTS: Older adults with GI symptoms displayed significantly higher levels of both zonulin and psychological distress than both general older adults and senior orienteering athletes. The PCA analysis revealed a separation between senior orienteering athletes and older adults with GI symptoms and showed an association between GI symptoms, psychological distress and zonulin.

    CONCLUSIONS: Older adults with GI symptoms express increased plasma levels of zonulin, which might reflect an augmented intestinal permeability. In addition, this group suffer from higher psychological distress compared to general older adults and senior orienteering athletes. This relationship was further confirmed by a PCA plot, which illustrated an association between GI symptoms, psychological distress and intestinal permeability.

  • 16.
    Graunke, K L
    et al.
    Research Unit Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Langbein, Jan
    Research Unit Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Repsilber, Dirk
    Research Unit Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Schön, P C
    Research Unit Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Objectively measuring behaviour traits in an automated restraint-test for ungulates: towards making temperament measurable2012In: Journal of Agricultural Science, ISSN 0021-8596, Vol. 151, no 1, p. 141-149Article in journal (Refereed)
    Abstract [en]

    The personality of an animal is described by traits that cause consistent actions and reactions to environmental stimuli. An important part of personality is the reaction to unpleasant or uncontrollable situations. Methods described in the literature to measure personality in animals are often based on measuring or rating escape behaviour in these situations. In the methods described, human handlers are frequently part of the experiment or the animals’ personalities are scored by humans. Thus, these methods are at least partly subjective. In the current study, an appliance to measure objectively the escape behaviour of ungulates and their reluctance during an uncontrollable situation (restraint) with a rather simple and comprehensible methodology is presented using a force transducer with adequate peripheral equipment. While the animals were restrained, a tractive forcetime diagram describing escape behaviour was recorded and later analysed with software developed specifically. To evaluate this newly developed technical method, 24 three-month-old calves were restrained by being tethered for 30 min on a halter that was connected to the force transducer. From the tractive force-time diagram, tractive force, maximal tractive force and the number of pulls that the calves performed during 5-min intervals were calculated. The multivariate results were analysed with a k-means-algorithm (function ‘kcca’) and a hierarchical clustering (function ‘hclust’) included in R version 2.12.1. Both analyses revealed two clearly separated clusters including the same individuals in each analysis. The animals of cluster 1 showed a continuously higher reaction level than those of cluster 2 with a strong reaction in the beginning, a short decrease before increasing during the middle of the experiment and a final decrease at the end of the test. The animals of cluster 2 had a lower and quite steady reaction level throughout the experiment, although even here a slight increase during the middle of the experiment could be detected before a final decrease towards the end of the test was shown. There was no significant difference in weight between the two clusters. The results showed that this newly developed method was able to detect differences in the animals’ escape behaviour patterns and reluctance with the measured parameters.

  • 17.
    Graunke, K L
    et al.
    Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Nürnberg, Gerd
    Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Repsilber, Dirk
    Institute of Genetics and Biometry, Bioinformatics and Biomathematics Unit, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Schön, P C
    Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Langbein, Jan
    Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Temperamentbeschreibung am Beispiel des Rinds: ein multidimensionaler Ansatz mit Originaldaten2012In: 13th Day of the Doctoral Student: abstracts, 24 May 2012 Dummerstorf, Dummerstorf: FBN , 2012, p. 39-42Conference paper (Refereed)
  • 18.
    Graunke, Katharina L
    et al.
    Ethology Unit, Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany; Faculty of Agricultural and Environmental Sciences (AUF), PHENOMICS office, University of Rostock, Rostock, Germany.
    Nürnberg, Gerd
    Institute of Genetics and Biometry, Bioinformatics and Biomathematics Unit, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Repsilber, Dirk
    Institute of Genetics and Biometry, Bioinformatics and Biomathematics Unit, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Puppe, Birger
    Ethology Unit, Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany; Faculty of Agricultural and Environmental Sciences (AUF), Behavioural Sciences, University of Rostock, Rostock, Germany.
    Langbein, Jan
    Ethology Unit, Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Describing temperament in an ungulate: a multidimensional approach2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, article id e74579Article in journal (Refereed)
    Abstract [en]

    Studies on animal temperament have often described temperament using a one-dimensional scale, whereas theoretical framework has recently suggested two or more dimensions using terms like "valence" or "arousal" to describe these dimensions. Yet, the valence or assessment of a situation is highly individual. The aim of this study was to provide support for the multidimensional framework with experimental data originating from an economically important species (Bos taurus). We tested 361 calves at 90 days post natum (dpn) in a novel-object test. Using a principal component analysis (PCA), we condensed numerous behaviours into fewer variables to describe temperament and correlated these variables with simultaneously measured heart rate variability (HRV) data. The PCA resulted in two behavioural dimensions (principal components, PC): novel-object-related (PC 1) and exploration-activity-related (PC 2). These PCs explained 58% of the variability in our data. The animals were distributed evenly within the two behavioural dimensions independent of their sex. Calves with different scores in these PCs differed significantly in HRV, and thus in the autonomous nervous system's activity. Based on these combined behavioural and physiological data we described four distinct temperament types resulting from two behavioural dimensions: "neophobic/fearful--alert", "interested--stressed", "subdued/uninterested--calm", and "neoophilic/outgoing--alert". Additionally, 38 calves were tested at 90 and 197 dpn. Using the same PCA-model, they correlated significantly in PC 1 and tended to correlate in PC 2 between the two test ages. Of these calves, 42% expressed a similar behaviour pattern in both dimensions and 47% in one. No differences in temperament scores were found between sexes or breeds. In conclusion, we described distinct temperament types in calves based on behavioural and physiological measures emphasising the benefits of a multidimensional approach.

  • 19.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medicine, Div. of Gastroenterol., Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Department of Medicine, Div of Gastroenterol, Örebro Univ Hosp, Örebro, Sweden; Fac of Med and Hlth, Örebro Univ, Örebro, Sweden.
    Hultgren, Olof
    Örebro University, School of Medical Sciences. Department of Microbiology and Immunology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Oligoclonal T-cell Receptor Repertoire in Colonic Biopsies of Patients with Microscopic Colitis and Ulcerative Colitis2017In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 23, no 6, p. 932-945Article in journal (Refereed)
    Abstract [en]

    Background: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a type of variation of inflammatory bowel diseases. Local T-cell infiltration in the mucosa plays a major role in MC immunopathology.

    Methods: To understand diversity and clonality of infiltrating T cells, we analyzed the T-cell receptor beta (TCR beta) chains in colonic biopsies of MC, ulcerative colitis (UC), and their remission counterparts (CC/LC-HR [histological remission] or UC-R [remission]) compared with patients with non-inflamed colons using next-generation sequencing.

    Results: Compared with controls and patients with CC, patients with LC had significantly lower diversity with significantly lower evenness and richness in TCRVb-Jb gene segments. Similarly, patients with LC-HR had lower diversity because of significantly lower TCRVb-Jb clone richness. Patients with UC and UC-R showed significantly higher diversity and richness. Univariate and multivariate analyses were performed to identify TCRVb-Jb gene segments differentiating disease types from controls or their remission counterparts. Patients with LC were discriminated from controls by 12 clones and from patients with CC by 8 clones. Neither univariate nor multivariate analyses showed significance for patients with CC or CC-HR compared with controls. Patients with UC and UC-R had 16 and 14 discriminating clones, respectively, compared with controls.

    Conclusions: Altogether, patients with MC and UC showed an oligoclonal TCRb distribution. TCRVb-Jb clone types and their diversity were distinctive between patients with CC and LC, as well as for patients with UC, suggesting different pathophysiological mechanisms according to disease type and stage. This study suggests that CC and LC are different entities because of differences in immunoregulatory responses, as mirrored by their T-cell repertoire.

  • 20.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Wegman, Pia
    Linköping University Hospital, Linköping, Sweden.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, UK .
    Sollie, Tomas
    Örebro University Hospital, Örebro, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Gene expression profiles in breast tumors from tamoxifen treated patients with and without distant recurrenceManuscript (preprint) (Other academic)
  • 21.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patientsManuscript (preprint) (Other academic)
  • 22.
    Günther, Juliane
    et al.
    Research Institute for the Biology of Farm Animals (FBN), Molecular Biology Research Unit, Dummerstorf, Germany.
    Koczan, Dirk
    Institute for Immunology, Steinbeis Transfercenter for Proteome Analysis, Core Facility for Transcriptome Analysis, Rostock, Germany.
    Yang, Wei
    Research Institute for the Biology of Farm Animals (FBN), Molecular Biology Research Unit, Dummerstorf, Germany; Department of Anesthesiology, Duke University Medical Center, Durham, United States .
    Nürnberg, Gerd
    Research Institute for the Biology of Farm Animals (FBN), Molecular Biology Research Unit, Dummerstorf, Germany.
    Repsilber, Dirk
    Research Institute for the Biology of Farm Animals (FBN), Molecular Biology Research Unit, Dummerstorf, Germany.
    Schuberth, Hans-Joachim
    University of Veterinary Medicine, Immunology Unit, Hannover, Germany.
    Park, Zaneta
    AgResearch, Palmerston North, New Zealand.
    Maqbool, Nauman
    AgResearch, Ruakura Research Centre in Hamilton, New Zealand.
    Molenaar, Adrian
    AgResearch, Ruakura Research Centre in Hamilton, New Zealand.
    Seyfert, Hans-Martin
    Research Institute for the Biology of Farm Animals (FBN), Molecular Biology Research Unit, Dummerstorf, Germany.
    Assessment of the immune capacity of mammary epithelial cells: comparison with mammary tissue after challenge with Escherichia coli2009In: Veterinary research (Print), ISSN 0928-4249, E-ISSN 1297-9716, Vol. 40, no 4, article id 31Article in journal (Refereed)
    Abstract [en]

    We examined the repertoire and extent of inflammation dependent gene regulation in a bovine mammary epithelial cell (MEC) model, to better understand the contribution of the MEC in the immune defence of the udder. We challenged primary cultures of MEC from cows with heat inactivated Escherichia coli pathogens and used Affymetrix DNA-microarrays to profile challenge related alterations in their transcriptome. Compared to acute mastitis, the most prominently activated genes comprise those encoding chemokines, interleukins, beta-defensins, serum amyloid A and haptoglobin. Hence, the MEC exert sentinel as well as effector functions of innate immune defence. E. coli stimulated a larger fraction of genes (30%) in the MEC belonging to the functional category Inflammatory Response than we recorded with the same microarrays during acute mastitis in the udder (17%). This observation underscores the exquisite immune capacity of MEC. To more closely examine the adequacy of immunological regulation in MEC, we compared the inflammation dependent regulation of factors contributing to the complement system between the udder versus the MEC. In the MEC we observed only up regulation of several complement factor-encoding genes. Mastitis, in contrast, in the udder strongly down regulates such genes encoding factors contributing to both, the classical pathway of complement activation and the Membrane Attack Complex, while the expression of factors contributing to the alternative pathway may be enhanced. This functionally polarized regulation of the complex complement pathway is not reflected in the MEC models.

  • 23.
    Hartmann, Anja
    et al.
    Research Group Functional Genomics.
    Nürnberg, Gerd
    Research Unit Genetics and Biometrics.
    Repsilber, Dirk
    Research Unit Genetics and Biometrics.
    Janczyk, Pawel
    Institute of Veterinary Anatomy, Department of Veterinary Medicine, Free University of Berlin, Berlin, Germany.
    Walz, Chrsitina
    Research Group Functional Genomics.
    Ponsuksili, Siriluck
    Research Group Functional Genomics.
    Souffrant, Wolfgang-Bernhard
    Research Unit Nutritional Physiology, »Oskar Kellner«, Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany.
    Schwerin, Manfred
    Research Group Functional Genomics; Institute of Farm Animal Sciences and Technology, University of Rostock, Rostock, Germany.
    Effects of threshold choice on the results of gene expression profiling, using microarray analysis, in a model feeding experiment with rat2009In: Archiv für Tierzucht, ISSN 0003-9438, Vol. 52, no 1, p. 65-78Article in journal (Refereed)
    Abstract [en]

    Global gene expression studies using microarray technology are widely employed to identify biological processes which are influenced by a treatment e.g. a specific diet. Affected processes are characterized by a significant enrichment of differentially expressed genes (functional annotation analysis). However, different choices of statistical thresholds to select candidates for differential expression will alter the resulting candidates list. This study was conducted to investigate the effect of applying a False Discovery Rate (FDR) correction and different fold change thresholds in statistical analysis of microarray data on diet-affected biological processes based on a significantly increased proportion of differentially expressed genes. In a model feeding experiment with rats fed genetically modified food additives, animals received a supplement of either lyophilized inactivated recombinant VP60 baculovirus (rBV-VP60) or lyophilized inactivated wild type baculovirus (wtBV). Comparative expression profiling was done in spleen, liver and small intestine mucosa. We demonstrated the extent to which threshold choice can affect the biological processes identified as significantly regulated and thus the conclusion drawn from the microarray data. In our study, the combined application of a moderate fold change threshold (FC≥1.5) and a stringent FDR threshold (q≤0.05) exhibited high reliability of biological processes identified as differentially regulated. The application of a stringent FDR threshold of q≤0.05 seems to be an essential prerequisite to reduce considerably the number of false positives. Microarray results of selected differentially expressed molecules were validated successfully by using real-time RT-PCR.

  • 24.
    Hoefig, Kai P
    et al.
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Thorns, Christoph
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Roehle, Anja
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Kaehler, Christian
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Wesche, Kai O
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Repsilber, Dirk
    Biomathematics / Bioinformatics Group, Research Institute for the Biology of Farm Animals FBN, Dummerstorf, Germany.
    Branke, Biggi
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Thiere, Marlen
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Feller, Alfred C
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Merz, Hartmut
    Institute for Pathology, UKSH Campus Luebeck, Luebeck.
    Unlocking pathology archives for microRNA-profiling2008In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 28, no 1A, p. 119-23Article in journal (Refereed)
    Abstract [en]

    Background: MicroRNAs (miRNAs) are approximately 22 nucleotide long, non-coding RNAs that regulate gene expression by binding to the 3'-untranslated region of target mRNAs and also a variety of cellular processes. It has recently been established that dysregulation of miRNA expression can be detected in the majority of human cancers. A variety of high-throughput screening methods has been developed to identify dysregulated miRNA species in tumours. For retrospective clinical studies formalin-fixed, paraffin-embedded (FFPE) tissue is the most widely used material.

    Materials and methods: The miRNA expression profiles of freshly frozen (CRYO) and FFPE tissues of seven tonsil and four liver samples were compared, using a qPCR-based assay, profiling 157 miRNA species.

    Results: The significance of miRNA-profiles was barely influenced by FFPE treatment in both tissues and the variance induced by FFPE treatment was much smaller than the variance caused by biologically based differential expression.

    Conclusion: FFPE material is well suited for miRNA profiling.

  • 25.
    Hofner, Benjamin
    et al.
    Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
    Vaas, Lea
    Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany.
    Lawo, John-Philip
    Global Drug Discovery Statistics, Bayer Pharma AG, Berlin, Germany.
    Müller, Tina
    Biostatistics / CRD Global Clinical Services, CSL Behring, Marburg, Germany.
    Sikorski, Johannes
    Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany.
    Repsilber, Dirk
    Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Biologists meet Statisticians: A Workshop for young scientists to foster interdisciplinary team work2012Report (Other academic)
  • 26.
    Holster, Savanne
    et al.
    Örebro University, School of Medical Sciences.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    König, Julia
    Örebro University, School of Medical Sciences.
    Faecal microbiota transfer in irritable bowel syndrome – clinical outcomes of a randomised placebo- controlled trial2017Conference paper (Refereed)
  • 27.
    Holster, Savanne
    et al.
    Örebro University, School of Medical Sciences.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    König, Julia
    Örebro University, School of Medical Sciences.
    Fecal Microbiota Transplantation in Irritable Bowel Syndrome – A randomized placebo- controlled trial2017Conference paper (Refereed)
  • 28.
    Höfig, Kai Peter
    et al.
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Repsilber, Dirk
    Biomathematics/Bioinformatics group, Gentics and Biometry, Research Institute for the Biology of Farm Animals FBN, Dummerstorf, Germany .
    Branke, Biggi
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Roehle, Anja
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Thorns, Christoph
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Jarutat, Tiantom
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Lenfert, Eva
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Kaehler, Christian
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Feller, Alfred
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    Merz, Hartmut
    Institute for Pathology, UKSH Campus Lübeck, Lübeck, Germany.
    New Application for the LightCycler® 480 System: qPCR-based microRNA-Profiling2007In: Biochemica, ISSN 0946-1310, Vol. 4, p. 7-9Article in journal (Refereed)
  • 29.
    Jacobsen, Marc
    et al.
    Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.
    Mattow, Jens
    Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany; Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany .
    Repsilber, Dirk
    Research Institute for the Biology of Farm Animals, Genetics and Biometry, Dummerstorf, Germany.
    Kaufmann, Stefan H E
    Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.
    Novel strategies to identify biomarkers in tuberculosis2008In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 389, no 5, p. 487-95Article in journal (Refereed)
    Abstract [en]

    The more we learn about the immune response against tuberculosis (TB) and particularly about the features which distinguish protective immunity, disease susceptibility and pathology, the better we can define biomarkers which correlate with these different stages of infection. The most widely used biomarker in TB, which without a doubt is an important component of protective immunity, is IFNgamma secreted by antigen-specific CD4 T-cells. However, the complexity of the immune response against TB makes it more than likely that additional biomarkers are required for a reliable correlate of protection. As a corollary, we assume that a set of biomarkers will be required, termed a biosignature.

  • 30.
    Jacobsen, Marc
    et al.
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany .
    Repsilber, Dirk
    Institute of Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany; Institute for Biology and Biochemistry, University Potsdam, Potsdam-Golm, Germany.
    Gutschmidt, Andrea
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany .
    Neher, A
    Asklepios Center for Respiratory Medicine and Thoracic Surgery, Munich-Gauting, Germany .
    Feldmann, K
    Asklepios Center for Respiratory Medicine and Thoracic Surgery, Munich-Gauting, Germany .
    Mollenkopf, H J
    Microarray Core Facilities, Max Planck Institute for Infection Biology, Berlin, Germany.
    Kaufmann, S H E
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany .
    Ziegler, Andreas
    Institute of Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany.
    Deconfounding microarray analysis: independent measurements of cell type proportions used in a regression model to resolve tissue heterogeneity bias2006In: Methods of Information in Medicine, ISSN 0026-1270, Vol. 45, no 5, p. 557-63Article in journal (Refereed)
    Abstract [en]

    Objectives: Microarray analysis requires standardized specimens and evaluation procedures to achieve acceptable results. A major limitation of this method is caused by heterogeneity in the cellular composition of tissue specimens, which frequently confounds data analysis. We introduce a linear model to deconfound gene expression data from tissue heterogeneity for genes exclusively expressed by a single cell type.

    Methods: Gene expression data are deconfounded from tissue heterogeneity effects by analyzing them using an appropriate linear regression model. In our illustrating data set tissue heterogeneity is being measured using flow cytometry. Gene expression data are determined in parallel by real time quantitative polymerase chain reaction (qPCR) and microarray analyses. Verification of deconfounding is enabled using protein quantification for the respective marker genes.

    Results: For our illustrating dataset, quantification of cell type proportions for peripheral blood mononuclear cells (PBMC) from tuberculosis patients and controls revealed differences in B cell and monocyte proportions between both study groups, and thus heterogeneity for the tissue under investigation. Gene expression analyses reflected these differences in celltype distribution. Fitting an appropriate linear model allowed us to deconfound measured transcriptome levels from tissue heterogeneity effects. In the case of monocytes, additional differential expression on the single cell level could be proposed. Protein quantification verified these deconfounded results.

    Conclusions: Deconfounding of transcriptome analyses for cellular heterogeneity greatly improves interpretability, and hence the validity of transcriptome profiling results.

  • 31.
    Jacobsen, Marc
    et al.
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Repsilber, Dirk
    Institute for Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany; Institute for Biochemistry and Biology, University Potsdam, Potsdam-Golm, Germany.
    Gutschmidt, Andrea
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Neher, Albert
    Asklepios Center for Respiratory Medicine and Thoracic Surgery, Munich-Gauting, Germany .
    Feldmann, Knut
    Asklepios Center for Respiratory Medicine and Thoracic Surgery, Munich-Gauting, Germany .
    Mollenkopf, Hans J
    Microarray Core Facilities, Max Planck Institute for Infection Biology, Berlin, Germany.
    Ziegler, Andreas
    Kaufmann, Stefan H E
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Candidate biomarkers for discrimination between infection and disease caused by Mycobacterium tuberculosis2007In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 85, no 6, p. 613-21Article in journal (Refereed)
    Abstract [en]

    Infection with Mycobacterium tuberculosis is controlled by an efficacious immune response in about 90% of infected individuals who do not develop disease. Although essential mediators of protection, e.g., interferon-gamma, have been identified, these factors are insufficient to predict the outcome of M. tuberculosis infection. As a first step to determine additional biomarkers, we compared gene expression profiles of peripheral blood mononuclear cells from tuberculosis patients and M. tuberculosis-infected healthy donors by microarray analysis. Differentially expressed candidate genes were predominantly derived from monocytes and comprised molecules involved in the antimicrobial defense, inflammation, chemotaxis, and intracellular trafficking. We verified differential expression for alpha-defensin 1, alpha-defensin 4, lactoferrin, Fcgamma receptor 1A (cluster of differentiation 64 [CD64]), bactericidal permeability-increasing protein, and formyl peptide receptor 1 by quantitative polymerase chain reaction analysis. Moreover, we identified increased protein expression of CD64 on monocytes from tuberculosis patients. Candidate biomarkers were then assessed for optimal study group discrimination. Using a linear discriminant analysis, a minimal group of genes comprising lactoferrin, CD64, and the Ras-associated GTPase 33A was sufficient for classification of (1) tuberculosis patients, (2) M. tuberculosis-infected healthy donors, and (3) noninfected healthy donors.

  • 32.
    Jacobsen, Marc
    et al.
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Repsilber, Dirk
    Institute for Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
    Gutschmidt, Andrea
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Neher, Albert
    Asklepios Center for Respiratory Medicine and Thoracic Surgery, Munich-Gauting, Germany .
    Feldmann, Knut
    Asklepios Center for Respiratory Medicine and Thoracic Surgery, Munich-Gauting, Germany .
    Mollenkopf, Hans J
    Microarray Core Facilities, Max Planck Institute for Infection Biology, Berlin, Germany .
    Ziegler, Andreas
    Institute for Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
    Kaufmann, Stefan H E
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Ras-associated small GTPase 33A, a novel T cell factor, is down-regulated in patients with tuberculosis2005In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 192, no 7, p. 1211-8Article in journal (Refereed)
    Abstract [en]

    Ras-associated small GTPases (Rabs) are specific regulators of intracellular vesicle trafficking. Interference with host cell vesicular transport is a hallmark of many intracellular pathogens, including the notable example Mycobacterium tuberculosis. We performed, by quantitative polymerase chain reaction, gene-expression analyses for selected Rab molecules in peripheral-blood mononuclear cells from patients with tuberculosis (TB) and healthy control subjects, to identify candidate genes that are critically involved in the host immune response. Comparison revealed significant differences in the expression of genes for Rab13, Rab24, and Rab33A. Rab33A gene expression was down-regulated in patients with TB and was predominantly expressed in CD8+ T cells. We excluded possible influences of differences in T cell percentages between the 2 study groups, demonstrating that Rab33A gene expression changes on the single-cell level. In vitro, Rab33A RNA expression was induced in T cells on activation and by dendritic cells infected with M. tuberculosis. Our findings identify Rab33A as a T cell regulatory molecule in TB and suggest its involvement in disease processes.

  • 33.
    Jacobsen, Marc
    et al.
    Department of Immunology, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany; Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Repsilber, Dirk
    Research Institute for the Biology of Farm Animals, Genetics and Biometry, Dummerstorf, Germany.
    Kleinsteuber, K
    Department of Immunology, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.
    Gutschmidt, Andrea
    Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, DST and NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.
    Schommer-Leitner, S
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Black, G
    Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, DST and NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.
    Walzl, G
    Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, DST and NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.
    Kaufmann, S H E
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Suppressor of cytokine signaling-3 is affected in T-cells from tuberculosis TB patients2011In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 17, no 9, p. 1323-31Article in journal (Refereed)
    Abstract [en]

    T-cells and T-cell-derived cytokines are crucial mediators of protection against Mycobacterium tuberculosis infection, but these factors are insufficient as biomarkers for disease susceptibility. In order to define T-cell molecules involved in tuberculosis (TB), we compared gene expression profiles of T-cells from patients with active TB, healthy donors with latent M. tuberculosis infection (LTBIs) and non-infected healthy donors (NIDs) by microarray analysis. Pathway-focused analyses identified a prevalent subset of candidate genes involved in the Janus kinase (JAK)-signal transducer and activator of transcription signalling pathway, including those encoding suppressor of cytokine signalling (SOCS) molecules, in the subset of protection-associated genes. Differential expression was verified by quantitative PCR analysis for the cytokine-inducible SH2-containing protein (CISH), SOCS3, JAK3, interleukin-2 receptor α-chain (IL2RA), and the proto-oncogene serine/threonine protein kinase (PIM1). Classification analyses revealed that this set of molecules was able to discriminate efficiently between T-cells from TB patients and those from LTBIs, and, notably, to achieve optimal discrimination between LTBIs and NIDs. Further characterization by quantitative PCR revealed highly variable candidate gene expression in CD4(+) and CD8(+) T-cells from TB patients and only minor differences between CD4(+) and CD8(+) T-cell subpopulations. These results point to a role of cytokine receptor signalling regulation in T-cells in susceptibility to TB.

  • 34.
    Koskela von Sydow, Anita
    et al.
    Department of Clinical Research Laboratory, Örebro University Hospital, Örebro, Sweden.
    Janbaz, Chris
    Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Plastic and Reconstructive Surgery, Örebro University Hospital, Örebro, Sweden .
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Ivarsson, Mikael
    Örebro University, School of Health Sciences.
    IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts2016In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 117, no 7, p. 1622-1632Article in journal (Refereed)
    Abstract [en]

    Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1α) counteracts TGF-β-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-β regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-β in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-β and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-β and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-β on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-β regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. This article is protected by copyright. All rights reserved.

  • 35.
    Krappmann, K
    et al.
    Research Unit Molecular Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany .
    Wurmser, C
    Chair of Animal Breeding, Technische Universität München, Freising, Germany.
    Repsilber, Dirk
    Research Unit Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Fries, R
    Chair of Animal Breeding, Technische Universität München, Freising, Germany.
    Weikard, R
    Research Unit Molecular Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Kesting, U
    Landeskontrollverband für Leistungs- und Qualitätsprüfung Mecklenburg-Vorpommern, Güstrow, Germany.
    Kühn, Christa
    Research Unit Molecular Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Short communication: evaluation of bovine milk residues from routine milk testing programs as DNA source for genotyping2012In: Journal of Dairy Science, ISSN 0022-0302, E-ISSN 1525-3198, Vol. 95, no 9, p. 5436-41Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies and genomic evaluation using a dense set of genetic markers both require a large number of genotyped individuals. Collection of the respective samples contributes substantially to the cost of the approach. In dairy cattle research, the use of residues from routine milk recording would be a cost-saving alternative to obtain samples for an appropriate number of individuals with specific phenotypes in a very short time. To assess the suitability of milk recording residues, we concurrently investigated milk residues obtained after standardized milk recording procedures and blood samples from 115 cows originating from 3 farms with different milking systems by genotyping 15 microsatellite markers. We found that 4% of the milk samples were possibly assigned to the wrong animal (i.e., conflicts) and that at least 27% of the milk residues were contaminated, as indicated by an extra allele not present in the blood sample. These additional alleles primarily originated from a sample with a higher somatic cell score that went through the milk sample analyzer in the milk laboratory before the target sample. Furthermore, additional allele carryover was observed across more than one sample, when the difference in somatic cell count between samples exceeded 100,000 cells/mL. Finally, in several samples, the extra allele could not be traced back to previous samples passing through the milk sample analyzer. One source of those contaminations might be sample collection on-farm due to milk traces from the previously milked cow in the hose. No correlation was found between the farm management and conflicts or contaminations. We conclude that residues from routine milk recording are not suitable for genomic evaluation or genome-wide association studies because of the high prevalence of contamination generated at several steps during the collection and processing of milk residual samples.

  • 36.
    König, I R
    et al.
    Institute of Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany.
    Repsilber, Dirk
    Institute of Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany.
    Dahmen, Gerlinde
    Institute of Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany.
    Kleensag, A
    Institute of Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany.
    Ziegler, Andreas
    Institute of Medical Biometry and Statistics, University at Lübeck, Lübeck, Germany.
    Anwendungsorientierte Ausbildung im Teil "Medizinische Biometrie" des Querschnittsfachs Q1 durch Einbettung von Konzepten der Evidenzbasierten Medizin: Ein Erfahrungsbericht nach Umstellung auf die neue Ärztliche Approbationsordnung2004In: Informatik, Biometrie und Epidemiologie in Medizin und Biologie, ISSN 0943-5581, Vol. 35, no 4, p. 220-228Article in journal (Refereed)
    Abstract [en]

    Often, students do not recognize the use of the course „Medizinische Biometrie für Mediziner“, and the course is criticized as being too theoretical. To tackle this problem, the Institute of Medical Biometry and Statistics of the University Hospital Schleswig-Holstein, Campus Lüeck, at the University at Lüeck re-structured the course. The aim was to teach not only understanding and performing statistical analyses but also the foundations of evidence-based medicine, and thus to introduce more practical elements. While in the lecture, foundations of descriptive and inferential statistics are taught, the seminar is divided into two parts. In the first, biometrical problems are solved, in the second, evidence-based medicine is introduced. To this end, the students receive scientific articles in English and German, from which they extract both content and evaluation according to evidence criteria. Details of the studies are then discussed thoroughly during the seminar From the beginning on, the connection between both parts of the course is emphasized: Understanding the solution of biometrical problems is a prerequisite for critically evaluating medical evidence and thus for evidence-based medicine. The results of the final test for the course „edizinische Biometrie fü Mediziner“ are used to assess the success of re-structuring the course. Furthermore, the students evaluate the lecture and the seminar during the semester The results indicated that at the end of the semester; the students are familiar with the important concepts of evidence-based medicine, and that the acceptance of the course has reached a satisfying level.

  • 37.
    Lindroos, Hillevi L
    et al.
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Mira, Alex
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala; División de Microbiología, Universidad Miguel Hernández, Alicante, Spain.
    Repsilber, Dirk
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala; Institute for Medical Biometry and Statistics, University Lübeck, Lübeck, Germany .
    Vinnere, Olga
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Näslund, Kristina
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Dehio, Michaela
    Division of Molecular Microbiology, Biozentrum of the University of Basel, Basel, Switzerland .
    Dehio, Christoph
    Division of Molecular Microbiology, Biozentrum of the University of Basel, Basel, Switzerland .
    Andersson, Siv G E
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Characterization of the genome composition of Bartonella koehlerae by microarray comparative genomic hybridization profiling2005In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 187, no 17, p. 6155-65Article in journal (Refereed)
    Abstract [en]

    Bartonella henselae is present in a wide range of wild and domestic feline hosts and causes cat-scratch disease and bacillary angiomatosis in humans. We have estimated here the gene content of Bartonella koehlerae, a novel species isolated from cats that was recently identified as an agent of human endocarditis. The investigation was accomplished by comparative genomic hybridization (CGH) to a microarray constructed from the sequenced 1.93-Mb genome of B. henselae. Control hybridizations of labeled DNA from the human pathogen Bartonella quintana with a reduced genome of 1.58 Mb were performed to evaluate the accuracy of the array for genes with known levels of sequence divergence. Genome size estimates of B. koehlerae by pulsed-field gel electrophoresis matched that calculated by the CGH, indicating a genome of 1.7 to 1.8 Mb with few unique genes. As in B. quintana, sequences in the prophage and the genomic islands were reported absent in B. koehlerae. In addition, sequence variability was recorded in the chromosome II-like region, where B. koehlerae showed an intermediate retention pattern of both coding and noncoding sequences. Although most of the genes missing in B. koehlerae are also absent from B. quintana, its phylogenetic placement near B. henselae suggests independent deletion events, indicating that host specificity is not solely attributed to genes in the genomic islands. Rather, the results underscore the instability of the genomic islands even within bacterial populations adapted to the same host-vector system, as in the case of B. henselae and B. koehlerae.

  • 38.
    Lindroos, Hillevi
    et al.
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala .
    Vinnere, Olga
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Mira, Alex
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Repsilber, Dirk
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Näslund, Kristina
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Andersson, Siv G E
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala.
    Genome rearrangements, deletions, and amplifications in the natural population of Bartonella henselae2006In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 188, no 21, p. 7426-39Article in journal (Refereed)
    Abstract [en]

    Cats are the natural host for Bartonella henselae, an opportunistic human pathogen and the agent of cat scratch disease. Here, we have analyzed the natural variation in gene content and genome structure of 38 Bartonella henselae strains isolated from cats and humans by comparative genome hybridizations to microarrays and probe hybridizations to pulsed-field gel electrophoresis (PFGE) blots. The variation in gene content was modest and confined to the prophage and the genomic islands, whereas the PFGE analyses indicated extensive rearrangements across the terminus of replication with breakpoints in areas of the genomic islands. We observed no difference in gene content or structure between feline and human strains. Rather, the results suggest multiple sources of human infection from feline B. henselae strains of diverse genotypes. Additionally, the microarray hybridizations revealed DNA amplification in some strains in the so-called chromosome II-like region. The amplified segments were centered at a position corresponding to a putative phage replication initiation site and increased in size with the duration of cultivation. We hypothesize that the variable gene pool in the B. henselae population plays an important role in the establishment of long-term persistent infection in the natural host by promoting antigenic variation and escape from the host immune response.

  • 39.
    Maertzdorf, Jeroen
    et al.
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Ota, Martin
    Medical Research Council Laboratories, Banjul, The Gambia.
    Repsilber, Dirk
    Leibniz Institute for Farm Animal Biology Genetics and Biometry, Dummersdorf, Germany.
    Mollenkopf, Hans J
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Weiner, January
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Hill, Philip C
    Medical Research Council Laboratories, Banjul, The Gambia.
    Kaufmann, Stefan H E
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Functional correlations of pathogenesis-driven gene expression signatures in tuberculosis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 10, article id e26938Article in journal (Refereed)
    Abstract [en]

    Tuberculosis remains a major health threat and its control depends on improved measures of prevention, diagnosis and treatment. Biosignatures can play a significant role in the development of novel intervention measures against TB and blood transcriptional profiling is increasingly exploited for their rational design. Such profiles also reveal fundamental biological mechanisms associated with the pathology of the disease. We have compared whole blood gene expression in TB patients, as well as in healthy infected and uninfected individuals in a cohort in The Gambia, West Africa and validated previously identified signatures showing high similarities of expression profiles among different cohorts. In this study, we applied a unique combination of classical gene expression analysis with pathway and functional association analysis integrated with intra-individual expression correlations. These analyses were employed for identification of new disease-associated gene signatures, identifying a network of Fc gamma receptor 1 signaling with correlating transcriptional activity as hallmark of gene expression in TB. Remarkable similarities to characteristic signatures in the autoimmune disease systemic lupus erythematosus (SLE) were observed. Functional gene clusters of immunoregulatory interactions involving the JAK-STAT pathway; sensing of microbial patterns by Toll-like receptors and IFN-signaling provide detailed insights into the dysregulation of critical immune processes in TB, involving active expression of both pro-inflammatory and immunoregulatory systems. We conclude that transcriptomics (i) provides a robust system for identification and validation of biosignatures for TB and (ii) application of integrated analysis tools yields novel insights into functional networks underlying TB pathogenesis.

  • 40.
    Maertzdorf, Jeroen
    et al.
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany .
    Repsilber, Dirk
    Leibniz Institute for Farm Animal Biology, Genetics and Biometry, Dummerstorf, Germany.
    Parida, S K
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany .
    Stanley, K
    Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, Stellenbosch University, Cape Town, South Africa .
    Roberts, T
    Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, Stellenbosch University, Cape Town, South Africa .
    Black, G
    Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, Stellenbosch University, Cape Town, South Africa .
    Walzl, G
    Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, Stellenbosch University, Cape Town, South Africa .
    Kaufmann, S H E
    Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany .
    Human gene expression profiles of susceptibility and resistance in tuberculosis2011In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 12, no 1, p. 15-22Article in journal (Refereed)
    Abstract [en]

    Tuberculosis (TB) still poses a profound burden on global health, owing to significant morbidity and mortality worldwide. Although a fully functional immune system is essential for the control of Mycobacterium tuberculosis infection, the underlying mechanisms and reasons for failure in part of the infected population remain enigmatic. Here, whole-blood microarray gene expression analyses were performed in TB patients and in latently as well as uninfected healthy controls to define biomarkers predictive of susceptibility and resistance. Fc gamma receptor 1B (FCGRIB)was identified as the most differentially expressed gene, and, in combination with four other markers, produced a high degree of accuracy in discriminating TB patients and latently infected donors. We determined differentially expressed genes unique for active disease and identified profiles that correlated with susceptibility and resistance to TB. Elevated expression of innate immune-related genes in active TB and higher expression of particular gene clusters involved in apoptosis and natural killer cell activity in latently infected donors are likely to be the major distinctive factors determining failure or success in controlling M. tuberculosis infection. The gene expression profiles defined in this study provide valuable clues for better understanding of progression from latent infection to active disease and pave the way for defining predictive correlates of protection in TB.

  • 41.
    Melzer, Nina
    et al.
    FBN Dummerstorf, Dummerstorf, Germany.
    Jakubowski, S
    LKV, Güstrow, Germany.
    Hartwig, S
    LKV, Güstrow, Germany.
    Kesting, U
    LKV, Güstrow, Germany.
    Wolf, S
    LKV, Güstrow, Germany.
    Nürnberg, Gerd
    FBN Dummerstorf, Dummerstorf, Germany.
    Reinsch, Norbert
    FBN Dummerstorf, Dummerstorf, Germany.
    Repsilber, Dirk
    FBN Dummerstorf, Dummerstorf, Germany.
    Design, infrastructure and database structure for a study on predicting milk phenotypes from genome-wide SNP markers and metabolite profiles2010In: Proceedings of the 9th World Congress on Genetics Applied to Livestock Production, German Society for Animal Science , 2010, p. 427-431Conference paper (Refereed)
  • 42.
    Melzer, Nina
    et al.
    Research Unit Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Wittenburg, Dörte
    Research Unit Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Hartwig, S
    Landeskontrollverband für Leistungs-und Qualitatsprufung Mecklenburg-Vorpommern e.V. (LKV), Güstrow, Germany.
    Jakubowski, S
    Landeskontrollverband für Leistungs-und Qualitatsprufung Mecklenburg-Vorpommern e.V. (LKV), Güstrow, Germany.
    Kesting, U
    Landeskontrollverband für Leistungs-und Qualitatsprufung Mecklenburg-Vorpommern e.V. (LKV), Güstrow, Germany.
    Willmitzer, Lothar
    Max Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany .
    Lisec, Jan
    Max Planck Institute for Molecular Plant Physiology, Potsdam-Golm, Germany .
    Reinsch, Norbert
    Research Unit Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Repsilber, Dirk
    Research Unit Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Investigating associations between milk metabolite profiles and milk traits of Holstein cows2013In: Journal of Dairy Science, ISSN 0022-0302, E-ISSN 1525-3198, Vol. 96, no 3, p. 1521-34Article in journal (Refereed)
    Abstract [en]

    In the field of dairy cattle research, it is of great interest to improve the detection and prevention of diseases (e.g., mastitis and ketosis) and monitor specific traits related to the state of health and management. During the standard milk performance test, traditional milk traits are monitored, and quality and quantity are screened. In addition to the standard test, it is also now possible to analyze milk metabolites in a high-throughput manner and to consider them in connection with milk traits to identify functionally important metabolites that can also serve as biomarker candidates. We present a study in which 190 milk metabolites and 14 milk traits of 1,305 Holstein cows on 18 commercial farms were investigated to characterize interrelations of milk metabolites between each other, to milk traits from the milk standard performance test, and to influencing factors such as farm and sire effect (half-sib structure). The effect of influencing factors (e.g., farm) varied among metabolites and traditional milk traits. The investigations of associations between metabolites and milk traits revealed groups of metabolites that show, for example, positive correlations to protein and casein, and negative correlations to lactose and pH. On the other hand, groups of metabolites jointly associated with the investigated milk traits can be identified and functionally discussed. To enable a multivariate investigation, 2 machine learning methods were applied to detect important metabolites that are highly correlated with the investigated traditional milk traits. For somatic cell score, uracil, lactic acid, and 9 other important metabolites were detected. Lactic acid has already been proposed as a biomarker candidate for mastitis in the recent literature. In conclusion, we found sets of metabolites eligible to predict milk traits, enabling the analysis of milk traits from a metabolic perspective and discussion of the possible functional background for some of the detected associations.

  • 43. Melzer, Nina
    et al.
    Wittenburg, Dörte
    Repsilber, Dirk
    Accounting for a complex genotype-phenotype map in milk phenotypes from genome-wide data2010In: Statistical Computing 2010: Abstracts der 42. Arbeitstagung, 2010, Vol. 5Conference paper (Refereed)
  • 44.
    Melzer, Nina
    et al.
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Wittenburg, Dörte
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Repsilber, Dirk
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Including metabolomic profiles to improve genetic value prediction: an integrated bioinformatics approach using weighted genome-wide marker information2011In: 12th Day of the Doctoal Student: abstracts; 19 May 2011, Dummerstorf / [ed] Seyfert, H.-M., Viereck, G., Dummerstorf, Germany: FBN , 2011, p. 55-58Conference paper (Refereed)
  • 45.
    Melzer, Nina
    et al.
    Institute for Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Wittenburg, Dörte
    Institute for Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Repsilber, Dirk
    Institute for Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Integrating milk metabolite profile information for the prediction of traditional milk traits based on SNP information for Holstein cows2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, article id e70256Article in journal (Refereed)
    Abstract [en]

    In this study the benefit of metabolome level analysis for the prediction of genetic value of three traditional milk traits was investigated. Our proposed approach consists of three steps: First, milk metabolite profiles are used to predict three traditional milk traits of 1,305 Holstein cows. Two regression methods, both enabling variable selection, are applied to identify important milk metabolites in this step. Second, the prediction of these important milk metabolite from single nucleotide polymorphisms (SNPs) enables the detection of SNPs with significant genetic effects. Finally, these SNPs are used to predict milk traits. The observed precision of predicted genetic values was compared to the results observed for the classical genotype-phenotype prediction using all SNPs or a reduced SNP subset (reduced classical approach). To enable a comparison between SNP subsets, a special invariable evaluation design was implemented. SNPs close to or within known quantitative trait loci (QTL) were determined. This enabled us to determine if detected important SNP subsets were enriched in these regions. The results show that our approach can lead to genetic value prediction, but requires less than 1% of the total amount of (40,317) SNPs., significantly more important SNPs in known QTL regions were detected using our approach compared to the reduced classical approach. Concluding, our approach allows a deeper insight into the associations between the different levels of the genotype-phenotype map (genotype-metabolome, metabolome-phenotype, genotype-phenotype).

  • 46.
    Melzer, Nina
    et al.
    Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Wittenburg, Dörte
    Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Repsilber, Dirk
    Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Investigating a complex genotype-phenotype map for the development of methods to predict genetic values based on genome-wide marker data – a simulation study for the livestock perspective2013In: Archiv für Tierzucht, ISSN 0003-9438, Vol. 56, no 38, p. 380-398Article in journal (Refereed)
    Abstract [en]

    Phenotypic variation can partly be explained by genetic variation, such as variation in single nucleotide polymorphism (SNP) genotypes. Genomic selection methods seek to predict genetic values (breeding values) based on SNP genotypes. To develop and to optimize these methods, simulated data are often used, which follow a rather simple genotype-phenotype map. Is the conventional approach for data simulation in this field an appropriate basis to optimize such methods in view of experimental data? Here, we present an alternative approach, striving to simulate more realistic data based on a genotype-phenotype map which includes a simulated metabolome level. This level was used to simulate genetic values, implicitly including additive and non-additive genetic effects, whereas in a conventional approach additive and dominance effects were explicitly simulated and assembled to genetic values. For both simulation approaches, different scenarios regarding numbers of quantitative trait loci (QTLs) and SNPs were analysed using fastBayesB as prediction method. We observed that our alternative map showed a smaller prediction precision (at least 3.75 %) compared to the conventional approach in all investigated scenarios. The observed degree of linearity is at least 94.12 % of the conventional approach or less. Additionally, we present results for different simulated data and experimental data to allow a comparison on a purely conceptual level. Concluding, simulating a more complex genotype-phenotype map including a molecular level, allows to study processing of variation from the genetic to the phenotype level in more detail and may prepare the ground for modern methods of genomic selection.

  • 47.
    Melzer, Nina
    et al.
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Wittenburg, Dörte
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Repsilber, Dirk
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Metabolites as new molecular traits and their role for genetic evaluation of traditional milk traits2012In: Book of Abstracts of the 63rd Annual Meeting of the European Federation of Animal Science: Bratislava, Slovakia, 27 - 31 August 2012, Wageningen: Wageningen Academic Publishers , 2012, p. 88-88Conference paper (Refereed)
  • 48.
    Melzer, Nina
    et al.
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany..
    Wittenburg, Dörte
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Repsilber, Dirk
    Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
    Simulating SNP data: influence of simulation design on the extent of linkage disequilibrium2010In: 11th Day of the Doctoral Student: abstracts; 19 May 2010, Dummerstorf / [ed] Seyfert, H.-M., Viereck, G., Dummerstorf, Germany: FBN , 2010, p. 19-22Conference paper (Refereed)
  • 49.
    Meyer, Rhonda C
    et al.
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Witucka-Wall, Hanna
    Department of Genetics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
    Becher, Martina
    Department of Genetics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
    Blacha, Anna
    Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
    Boudichevskaia, Anastassia
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Dörmann, Peter
    Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
    Fiehn, Oliver
    Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
    Friedel, Svetlana
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    von Korff, Maria
    Department of Genetics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
    Lisec, Jan
    Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
    Melzer, Michael
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Repsilber, Dirk
    Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Schmidt, Renate
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Scholz, Matthias
    Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
    Selbig, Joachim
    Department of Bioinformatics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
    Willmitzer, Lothar
    Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany; King Abdulaziz University, P.O., Jeddah, Saudi Arabia.
    Altmann, Thomas
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany; Department of Genetics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
    Heterosis manifestation during early Arabidopsis seedling development is characterized by intermediate gene expression and enhanced metabolic activity in the hybrids2012In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 71, no 4, p. 669-83Article in journal (Refereed)
    Abstract [en]

    Heterosis-associated cellular and molecular processes were analyzed in seeds and seedlings of Arabidopsis thaliana accessions Col-0 and C24 and their heterotic hybrids. Microscopic examination revealed no advantages in terms of hybrid mature embryo organ sizes or cell numbers. Increased cotyledon sizes were detectable 4 days after sowing. Growth heterosis results from elevated cell sizes and numbers, and is well established at 10 days after sowing. The relative growth rates of hybrid seedlings were most enhanced between 3 and 4 days after sowing. Global metabolite profiling and targeted fatty acid analysis revealed maternal inheritance patterns for a large proportion of metabolites in the very early stages. During developmental progression, the distribution shifts to dominant, intermediate and heterotic patterns, with most changes occurring between 4 and 6 days after sowing. The highest incidence of heterotic patterns coincides with establishment of size differences at 4 days after sowing. In contrast, overall transcript patterns at 4, 6 and 10 days after sowing are characterized by intermediate to dominant patterns, with parental transcript levels showing the largest differences. Overall, the results suggest that, during early developmental stages, intermediate gene expression and higher metabolic activity in the hybrids compared to the parents lead to better resource efficiency, and therefore enhanced performance in the hybrids.

  • 50.
    Rangel, Ignacio
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sundin, Johanna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fuentes, S.
    Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    de Vos, W. M.
    Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands; Departments of Bacteriology & Immunology and Veterinary Biosciences, University of Helsinki, Helsinki, Finland .
    Brummer, Robert Jan
    Örebro University, School of Medicine, Örebro University, Sweden.
    The relationship between faecal-associated and mucosal-associated microbiota in irritable bowel syndrome patients and healthy subjects2015In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 42, no 10, p. 1211-1221Article in journal (Refereed)
    Abstract [en]

    Background: The faecal-associated microbiota is commonly seen as a surrogate of the mucosal-associated microbiota. However, previous studies indicate that they are different. Furthermore, analyses of the mucosal microbiota are commonly done after standard bowel cleansing, affecting the microbial composition.

    Aim: To compare the mucosal-associated microbiota, obtained from unprepared colon, with faecal-associated microbiota in healthy subjects and irritable bowel syndrome (IBS) patients.

    Methods: Faecal and mucosal biopsies were obtained from 33 IBS patients and 16 healthy controls. Of IBS patients, 49% belonged to the diarrhoea-predominant subgroup and 80% suffered from IBS symptoms during at least 5 years. Biopsies were collected from unprepared sigmoid colon and faecal samples a day before colonoscopy. Microbiota analyses were performed with a phylogenetic microarray and redundancy discriminant analysis.

    Results: The composition of the mucosal- and the faecal-associated microbiota in unprepared sigmoid colon differs significantly (P = 0.002). Clinical characteristics of IBS did not correlate with this difference. Bacteroidetes dominate the mucosal-associated microbiota. Firmicutes, Actinobacteria and Proteobacteria dominate the faecal-associated microbiota. Healthy subjects had a significantly higher (P < 0.005) abundance (1.9%) of the bacterial group uncultured Clostridiales I in the mucosal-associated microbiota than IBS patients (0.3%). Bacterial diversity was higher in faecal- compared with mucosal-associated microbiota in IBS patients (P < 0.005). No differences were found in healthy subjects.

    Conclusions: Differences in the mucosal-associated microbiota between healthy individuals and IBS patients are minimal (one bacterial group) compared to differences in the faecal microbiota of both groups (53 bacterial groups). Microbial aberrations characterising IBS are more pronounced in the faeces than in the mucosa.

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