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  • 1
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; CLASSIFICATION ; SUPPORT ; SYSTEM ; SYSTEMS ; GENE ; GENE-EXPRESSION ; PROTEIN ; MICE ; ACTIVATION ; animals ; RATS ; BIOLOGY ; fibroblasts ; PHOSPHORYLATION ; PROTEIN-KINASE ; SEQUENCE ; gene expression ; HUMANS ; PROMOTER ; REQUIRES ; SIGNALING PATHWAY ; DOSE-RESPONSE ; TRANSFORMATION ; PREDICTION ; KINETICS ; SELECTION ; REVEALS ; systems biology ; BEHAVIOR ; Ras ; signaling ; MAPK ; regulation ; mRNA ; PHOSPHATASE ; EXTENT ; Oligonucleotide Array Sequence Analysis ; RNA Stability ; INVESTIGATE ; Extracellular ; cellular response ; CELLULAR-RESPONSE ; SEQUENCE DATA ; hypothesis ; *Genes,ras ; *Models,Biological ; Cells,Cultured ; *Feedback,Biochemical ; Dual Specificity Phosphatase 6/*physiology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Fibroblasts/metabolism ; MAP Kinase Signaling System/physiology ; RNA,Messenger/metabolism ; Signal Transduction/physiology
    Abstract: Mitogen-activated protein kinase (MAPK) signaling determines crucial cell fate decisions in most cell types, and mediates cellular transformation in many types of cancer. The activity of MAPK is controlled by reversible phosphorylation, and the quantitative characteristics of MAPK activation determine the cellular response. Many systems biological studies have analyzed the activation kinetics and the dose-response behavior of the MAPK signaling pathway. Here we investigate how the pathway activity is controlled by transcriptional feedback loops. Initially, we predict that MAPK signaling regulates phosphatases, by integrating promoter sequence data and ontology-based classification of gene function. From this, we deduce that MAPK signaling might be controlled by transcriptional negative feedback regulation via dual-specificity phosphatases (DUSPs), and implement a mathematical model to further test this hypothesis. Using time-resolved measurements of pathway activity and gene expression, we employ a model selection approach, and select DUSP6 as a highly likely candidate for shaping the activity of the MAPK pathway during cellular transformation caused by oncogenic RAS. Two predictions from the model were confirmed: first, feedback regulation requires that DUSP6 mRNA and protein are unstable; and second, the activation kinetics of MAPK are ultrasensitive. Taken together, an integrated systems biological approach reveals that transcriptional negative feedback controls the kinetics and the extent of MAPK activation under both physiological and pathological conditions.
    Type of Publication: Journal article published
    PubMed ID: 19154344
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  • 2
    Keywords: MODEL ; SYSTEM ; HUMANS ; CLOCK ; LIGHT ; TEMPERATURE ; NEUROSPORA-CRASSA ; OSCILLATIONS ; INTRINSIC PERIOD ; PACEMAKER
    Abstract: The circadian clock coordinates daily physiological, metabolic and behavioural rhythms. These endogenous oscillations are synchronized with external cues ('zeitgebers'), such as daily light and temperature cycles. When the circadian clock is entrained by a zeitgeber, the phase difference psi between the phase of a clock-controlled rhythm and the phase of the zeitgeber is of fundamental importance for the fitness of the organism. The phase of entrainment psi depends on the mismatch between the intrinsic period tau and the zeitgeber period T and on the ratio of the zeitgeber strength to oscillator amplitude. Motivated by the intriguing complexity of empirical data and by our own experiments on temperature entrainment of mouse suprachiasmatic nucleus (SCN) slices, we present a theory on how clock and zeitgeber properties determine the phase of entrainment. The wide applicability of the theory is demonstrated using mathematical models of different complexity as well as by experimental data. Predictions of the theory are confirmed by published data on Neurospora crassa strains for different period mismatches tau - T and varying photoperiods. We apply a novel regression technique to analyse entrainment of SCN slices by temperature cycles. We find that mathematical models can explain not only the stable asymptotic phase of entrainment, but also transient phase dynamics. Our theory provides the potential to explore seasonal variations of circadian rhythms, jet lag and shift work in forthcoming studies.
    Type of Publication: Journal article published
    PubMed ID: 26136227
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  • 3
    Keywords: SIMULATIONS ; CELLS ; CELL ; Germany ; MODEL ; MODELS ; NETWORKS ; SYSTEM ; SYSTEMS ; TOOL ; DISEASE ; DISEASES ; GENE ; TIME ; COMPLEX ; COMPLEXES ; MECHANISM ; mechanisms ; SIMULATION ; BIOLOGY ; ASSOCIATION ; FIELD ; RECOGNITION ; PATTERNS ; DATABASE ; bioinformatics ; SELECTION ; systems biology ; PROJECT ; EUROPE ; PRODUCTS ; RESOURCE ; pattern recognition ; TECHNOLOGY ; RECOMMENDATIONS ; modelling ; mathematical models ; INVESTIGATE
    Abstract: The following report selects and summarises some of the conclusions and recommendations generated throughout a series of workshops and discussions that have lead to the publication of the Science Policy Briefing (SPB) Nr. 35, published by the European Science Foundation. (Large parts of the present text are directly based on the ESF SPB. Detailed recommendations with regard to specific application areas are not given here but can be found in the SPB. Issues related to mathematical modelling, including training and the need for an infrastructure supporting modelling are discussed in greater detail in the present text.) The numerous reports and publications about the advances within the rapidly growing field of systems biology have led to a plethora of alternative definitions for key concepts. Here, with 'mathematical modelling' the authors refer to the modelling and simulation of subcellular, cellular and macro-scale phenomena, using primarily methods from dynamical systems theory. The aim of such models is encoding and testing hypotheses about mechanisms underlying the functioning of cells. Typical examples are models for molecular networks, where the behaviour of cells is expressed in terms of quantitative changes in the levels of transcripts and gene products. Bioinformatics provides essential complementary tools, including procedures for pattern recognition, machine learning, statistical modelling (testing for differences, searching for associations and correlations) and secondary data extracted from databases. Dynamical systems theory is the natural language to investigate complex biological systems demonstrating nonlinear spatio-temporal behaviour. However, the generation of experimental data suitable to parameterise, calibrate and validate such models is often time consuming and expensive or not even possible with the technology available today. In our report, we use the term 'computational model' when mathematical models are complemented with information generated from bioinformatics resources. Hence, 'the model' is, in reality, an integrated collection of data and models from various (possibly heterogeneous) sources. The present report focuses on a selection of topics, which were identified as appropriate case studies for medical systems biology, and adopts a particular perspective which the authors consider important. We strongly believe that mathematical modelling represents a natural language with which to integrate data at various levels and, in doing so, to provide insight into complex diseases: Modelling necessitates the statement of explicit hypotheses, a process which often enhances comprehension of the biological system and can uncover critical points where understanding is lacking. Simulations can reveal hidden patterns and/or counter-intuitive mechanisms in complex systems. Theoretical thinking and mathematical modelling constitute powerful tools to integrate and make sense of the biological and clinical information being generated and, more importantly, to generate new hypotheses that can then be tested in the laboratory. Medical Systems Biology projects carried out recently across Europe have revealed a need for action: While the need for mathematical modelling and interdisciplinary collaborations is becoming widely recognised in the biological sciences, with substantial implications for the training and research funding mechanisms within this area, the medical sciences have yet to follow this lead. To achieve major breakthroughs in Medical Systems Biology, existing academic funding schemes for large-scale projects need to be reconsidered. The hesitant stance of the pharmaceutical industry towards major investment in systems biology research has to be addressed. Leading medical journals should be encouraged to promote mathematical modelling
    Type of Publication: Journal article published
    PubMed ID: 19449974
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  • 4
    Keywords: EXPRESSION ; IN-VIVO ; GENES ; METABOLISM ; CELL-CYCLE ; TUMOR PROGRESSION ; COLORECTAL-CANCER ; REGULATORY ELEMENTS ; DNA-DAMAGE RESPONSE ; RHYTHMS
    Abstract: Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARgamma, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.
    Type of Publication: Journal article published
    PubMed ID: 24875049
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  • 5
    Keywords: proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; SUPPORT ; SYSTEM ; SYSTEMS ; PROTEIN ; ACTIVATION ; MECHANISM ; CARCINOGENESIS ; mechanisms ; BIOLOGY ; CYCLE ; SUPPRESSION ; STIMULATION ; HUMANS ; MUTATION ; MUTATIONS ; ONCOGENE ; KINETICS ; OVEREXPRESSION ; Ras ; cell proliferation ; CORE ; LEVEL ; EVENTS ; signalling ; modelling ; DIVISION ; STATE ; Extracellular ; signalling cascades ; SILENT ; *Genes,ras ; *Models,Biological ; Cell Transformation,Neoplastic/genetics/*metabolism ; ras Proteins/*biosynthesis
    Abstract: Minor (5-10 fold) activation of mitogenic signalling cascades typically induces cell division upon extracellular stimulation and is sufficient to support tumourigenesis when permanently triggered by activating mutations. Surprisingly, even strong signalling protein overexpression usually does not trigger deregulated cell proliferation, suggesting that basal state signalling is insensitive to wildtype protein overexpression. Using kinetic modelling of the core Ras cycle, we show that basal RasGTP signalling can be insensitive to Ras overexpression and thus identify a possible tumour suppression mechanism. We further show how phenotypically silent overexpression events within signalling cascades cooperate to bring about carcinogenesis. Our analyses underscore the need for a systems level understanding of tumour formation.
    Type of Publication: Journal article published
    PubMed ID: 19059249
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters A 194 (1994), S. 289-294 
    ISSN: 0375-9601
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters A 122 (1987), S. 121-125 
    ISSN: 0375-9601
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Chaos, Solitons and Fractals 4 (1994), S. 97-113 
    ISSN: 0960-0779
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Mathematics , Physics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters A 145 (1990), S. 418-424 
    ISSN: 0375-9601
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1433-0458
    Keywords: Schlüsselwörter Digitale Hochgeschwindigkeitskinematographie ; Stimmlippen ; Schwingungsmoden ; Irregularitäten ; Stimmlippenasymmetrie ; Key words High-speed digital imaging ; Vocal folds ; Modes of vibration ; Irregularity ; Vocal fold asymmetry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Vocal fold vibration patterns during phonation are presented with different digital imaging systems. With newly developed technical equipment color images up to 1000 digital images/s were obtained without light intensifying enhancement techniques via rigid and flexible endoscopy. With this color high-speed system, morphologic structures, such as small blood vessels, were visualized in high-resolution quality as a result of additional color information. In another system, zooming of endoscopic pictures via pixel interpolation algorithms provided full-monitor presentation of vocal fold vibratory patterns. This system allows PC-based synchronization with microphone and electroglottographic signals in a frame-by-frame technique. Although only processing gray scale images, analyses of dynamic changes in modes of vibration were faciliated by the higher frame rate recording of up to 2000 frames/s and, in addition, they display corresponding analog signals. Both methods provide clinically important information. Furthermore, we demonstrated irregular vocal fold vibration patterns in a healthy adult volunteer. In this experiment, the irregular vibratory modes were induced by voluntarily applying asymmetric vocal fold tension. The asymmetric vocal fold vibration pattern resulted in (functionally induced) roughness of the voice as predicted by computer models of asymmetric vocal fold vibration. Digital high-speed cinematography proved to be a highly promising technique in the analysis of dysphonia and provided physiological examples that could be compared with models of coupled nonlinear oscillators.
    Notes: Zusammenfassung Hochgeschwindigkeitsaufnahmen von Stimmlippenschwingungen können durch technische Verbesserungen der Signalverarbeitung neuerdings in Farbe und ohne elektronische Lichtverstärkung mit einer Aufnahmerate von bis zu 1000 Bildern/s digital aufgezeichnet werden. Mit dem Farbsystem wird hinsichtlich der Detailgenauigkeit in der Abbildung eine Erhöhung der Bildinformation erreicht, so daß kleinere morphologische Strukturunterschiede differenzierbar sind. Mit einem Kamerasystem eines anderen Herstellers werden bei 2000 Bildern/s automatisch synchrone Aufzeichnungen analoger Signal wie z.B. Mikrophon- und Elektroglottographiesignal, allen Einzelbildern zugeordnet. Dieses System verarbeitet allerdings nur Schwarzweißaufnahmen mit Grauwertabstufung. Das Schwarzweißsystem verfügt über eine bedienungsfreundliche Hard- und Software, so daß dynamische Analysen von Schwingungs(ir)regularitäten mit entsprechendem Vergleich zu den simultan aufgezeichneten analogen Signalen ohne größeren Aufwand möglich sind. In der hier vorliegenden Arbeit werden Vor- und Nachteile dieser 2 verschiedenen Aufnahmesysteme präsentiert. Es wird gezeigt, daß bei einem stimmgesunden Erwachsenen Schwingungsirregularitäten beider Stimmlippen, die durch seitendifferente Stimmlippenspannung willkürlich hervorgerufen werden, über längere Zeitabschnitte induziert werden konnten. Durch die digital aufgezeichneten Hochgeschwindigkeitsaufnahmen konnten asynchrone Schwingungsmuster analysiert werden, wie sie von der Theorie nicht-linearer gekoppelter Oszillatoren vorhergesagt werden.
    Type of Medium: Electronic Resource
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