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  • 1.
    Fagerlind, Magnus G.
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Webb, Jeremy S.
    Univ Southampton, Sch Biol Sci, Southampton SO16 7PX, Hants, England .
    Barraud, Nicolas
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia .
    McDougald, Diane
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia / Nanyang Technol Univ, Adv Environm Biotechnol Ctr, Singapore 639798, Singapore .
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Harlen, Mikael
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Kjelleberg, Staffan
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia / Nanyang Technol Univ, Singapore Ctr Environm Life Sci Engn, Singapore 639798, Singapore .
    Rice, Scott A.
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia / Nanyang Technol Univ, Singapore Ctr Environm Life Sci Engn, Singapore 639798, Singapore .
    Dynamic modelling of cell death during biofilm development2012In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 295, p. 23-36Article in journal (Refereed)
    Abstract [en]

    Biofilms are currently recognised as the predominant bacterial life-style and it has been suggested that biofilm development is influenced by a number of different processes such as adhesion, detachment, mass transport, quorum sensing, cell death and active dispersal. One of the least understood processes and its effects on biofilm development is cell death. However, experimental studies suggest that bacterial death is an important process during biofilm development and many studies show a relationship between cell death and dispersal in microbial biofilms. We present a model of the process of cell death during biofilm development, with a particular focus on the spatial localisation of cell death or cell damage. Three rules governing cell death or cell damage were evaluated which compared the effects of starvation, damage accumulation, and viability during biofilm development and were also used to design laboratory based experiments to test the model. Results from model simulations show that actively growing biofilms develop steep nutrient gradients within the interior of the biofilm that affect neighbouring microcolonies resulting in cell death and detachment. Two of the rules indicated that high substrate concentrations lead to accelerated cell death, in contrast to the third rule, based on the accumulation of damage, which predicted earlier cell death for biofilms grown with low substrate concentrations. Comparison of the modelling results with experimental results suggests that cell death is favoured under low nutrient conditions and that the accumulation of damage may be the main cause of cell death during biofilm development. (C) 2011 Elsevier Ltd. All rights reserved.

  • 2.
    Fagerlind, Magnus
    et al.
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Karlsson, Sandra
    University of Skövde, School of Life Sciences.
    Rice, Scott A.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia / Ctr. Mar. Biofouling and Bio-Innov., University of New South Wales, Sydney, NSW 2052, Australia.
    Kjelleberg, Staffan
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia / Ctr. Mar. Biofouling and Bio-Innov., University of New South Wales, Sydney, NSW 2052, Australia.
    Modeling the effect of acylated homoserine lactone antagonists in Pseudomonas aeruginosa2005In: Biosystems (Amsterdam. Print), ISSN 0303-2647, E-ISSN 1872-8324, Vol. 80, no 2, p. 201-213Article in journal (Refereed)
    Abstract [en]

    Pseudomonas aeruginosa is a gram-negative bacterium that causes serious illnesses, particularly in immunocompromised individuals, often with a fatal outcome. The finding that the acylated homoserine lactone quorum sensing (QS) system controls the production of virulence factors in P. aeruginosa makes this system a possible target for antimicrobial therapy. It has been suggested that an N-(3-oxododecanoyl)-homoserine lactone (3O-C12-HSL) antagonist, a QS blocker (QSB), would interfere efficiently with the quorum sensing system in P. aeruginosa and thus reduce the virulence of this pathogen. In this work, a mathematical model of the QS system in P. aeruginosa has been developed. The model was used to virtually add 3O-C12-HSL antagonists that differed in their affinity for the receptor protein and for their ability to mediate degradation of the receptor. The model suggests that very small differences in these parameters for different 3O-C12-HSL antagonists can greatly affect the success of QSB based inhibition of the QS system in P. aeruginosa. Most importantly, it is proposed that the ability of the 3O-C12-HSL antagonist to mediate degradation of LasR is the core parameter for successful QSB based inhibition of the QS system in P. aeruginosa. Finally, this study demonstrates that QSBs can shift the system to a low steady state, corresponding to an uninduced state and thus, suggests that the use of 3O-C12-HSL antagonists may constitute a promising therapeutic approach against P. aeruginosa involved infections.

  • 3.
    Fagerlind, Magnus
    et al.
    University of Skövde, School of Life Sciences. The School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia.
    Rice, Scott A.
    The School of Biotechnology and Biomolecular Sciences, and The Center for Marine Biofouling and Bio-Innovation, The University of New South Wales, Sydney, Australia.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    James, Sally
    The School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia.
    Charlton, Timothy
    The School of Biotechnology and Biomolecular Sciences, and The Center for Marine Biofouling and Bio-Innovation, The University of New South Wales, Sydney, Australia.
    Kjelleberg, Staffan
    The School of Biotechnology and Biomolecular Sciences, and The Center for Marine Biofouling and Bio-Innovation, The University of New South Wales, Sydney, Australia.
    The Role of Regulators in the Expression of Quorum-Sensing Signals in Pseudomonas aeruginosa2003In: Journal of Molecular Microbiology and Biotechnology, ISSN 1464-1801, Vol. 6, no 2, p. 88-100Article in journal (Refereed)
    Abstract [en]

    Quorum-sensing systems provide Pseudomonas aeruginosa with a sensitive regulatory mechanism that allows for the induction of several phenotypic genes in a cell density fashion. In this work, a mathematical model of the acylated homoserine lactones regulatory network system in P. aeruginosa has been developed. It is the first integrated model to consider both quorum-sensing systems. The model has allowed us to disentangle the complex behavior exhibited by the system as the concentration of extracellular OdDHL is increased. At either low or high levels of extracellular OdDHL, the bacterium remains in an uninduced or induced state, respectively. At moderate levels, the behavior is characterized by several states. Here, the bacteria can switch suddenly from an uninduced to an induced phenotype in response to small changes in the concentration of extracellular OdDHL. Additionally, we have been able to address the roles of RsaL and Vfr as regulators of the quorum-sensing system. An important result from this analysis suggests that RsaL will increase the concentration of extracellular OdDHL required to induce the system, and it is a key regulator of the inhibition of the quorum-sensing system under low cell densities. Most importantly, our results suggest that Vfr has strong regulatory effects on the system as an increased affinity between the LasR/OdDHL complex, and the lasR promoter leads to significant qualitative changes in induction patterns. We also show experimental data that demonstrate that Vfr is required for signal production in the early phase of growth, but that in the latter stages of growth, the vfr mutant is able to synthesize wild-type levels of signal.

  • 4.
    Gamalielsson, Jonas
    et al.
    University of Skövde, School of Humanities and Informatics.
    Nilsson, Patric
    University of Skövde, School of Humanities and Informatics.
    Olsson, Björn
    University of Skövde, School of Humanities and Informatics.
    A GO-based Method for Assessing the Biological Plausibility of Regulatory Hypotheses2006In: ICCS 2006: 6th International Conference on Computational Science, 2006, p. 879-886Conference paper (Other academic)
    Abstract [en]

    Many algorithms have been proposed for deriving regulatory networks from microarray gene expression data. The performance of such algorithms is often measured by how well the resulting network can recreate the gene expression data that it was derived from. However, this kind of performance does not necessarily mean that the regulatory hypotheses in the network are biologically plausible. We therefore propose a method for assessing the biological plausibility of regulatory hypotheses using prior knowledge in the form of regulatory pathway databases and Gene Ontology-based annotation of gene products. A set of templates is derived by generalising from known interactions to typical properties of interacting gene product pairs. By searching for matches in this set of templates, the plausibility of regulatory hypotheses can be assessed. We evaluate to what degree the collection of templates can separate true from false positive interactions, and we illustrate the practical use of the method by applying it to an example network reconstruction problem.

  • 5.
    Gamalielsson, Jonas
    et al.
    University of Skövde, School of Humanities and Informatics.
    Olsson, Björn
    University of Skövde, School of Humanities and Informatics.
    Nilsson, Patric
    University of Skövde, School of Humanities and Informatics.
    A Gene Ontology based Method for Assessing the Biological Plausibility of Regulatory Hypotheses2005Report (Other academic)
    Abstract [en]

    Many algorithms that derive gene regulatory networks from microarray gene expression data have been proposed in the literature. The performance of such an algorithm is often measured by how well a genetic network can recreate the gene expression data that the network was derived from. However, this kind of performance does not necessarily mean that the regulatory hypotheses in the network are biologically plausible. We therefore propose a Gene Ontology based method for assessing the biological plausibility of regulatory hypotheses at the gene product level using prior biological knowledge in the form of Gene Ontology annotation of gene products and regulatory pathway databases. Templates are designed to encode general knowledge, derived by generalizing from known interactions to typical properties of interacting gene product pairs. By matching regulatory hypotheses to templates, the plausible hypotheses can be separated from inplausible ones. In a cross-validation test we verify that the templates reliably identify interactions which have not been used in the template creation process, thereby confirming the generality of the approach. The method also proves useful when applied to an example network reconstruction problem, where a Bayesian approach is used to create hypothetical relations which are evaluated for biological plausibility. The cell cycle pathway and the MAPK signaling pathway for S. cerevisiae and H. sapiens are used in the experiments.

  • 6.
    Gustafsson, Erik
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Jacobsson, Gunnar
    Department of Infectious Diseases, Skaraborg Hospital, Skövde.
    Nilsson, Patric
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Enroth, Helena
    Department of Clinical Microbiology, Skaraborg Hospital, Capio Diagnostic AB, Skövde.
    Beronius, Marie Kia
    Centre for General Medicine, Kungsbacka.
    Andersson, Rune
    6Research and Development Centre, Skaraborg Hospital, Skövde, Sweden.
    Arvidson, Staffan
    Department of Microbiology, Tumour and Cell Biology (MTC), Karolinska Institutet, Stockholm.
    Invasive Staphylococcus aureus strains are highly variable in PFGE patterns, agr group and exoprotein production2009In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 41, no 8, p. 577-583Article in journal (Refereed)
    Abstract [en]

    In the present study, we have investigated 37 invasive Staphylococcus aureus strains (collected between 1997 and 2005) from 33 human episodes of septicaemia causing either endocarditis or vertebral osteomyelitis. All S. aureus strains were typed using pulsed field gel electrophoresis (PFGE), and most strains belonged to any of 4 different PFGE clusters. There was no correlation between any of the PFGE clusters with site of infection. All strains showed highly different expression patterns of extracellular proteins, i.e. we found a vast variation in the number of proteins and amount of individual proteins expressed by the different strains. There was no correlation between any cluster of exoprotein patterns with endocarditis or with vertebral osteomyelitis. We did not find any correlation between agr group and endocarditis, as previously reported. On the other hand, a correlation between some of the PFGE clusters with a certain agr group was found. Known risk factors for S. aureus infections were observed in a majority of the patients.

  • 7.
    Gustafsson, Erik
    et al.
    University of Skövde, School of Life Sciences.
    Karlsson, Stefan
    University of Skövde, School of Life Sciences.
    Oscarsson, Jan
    Sögård, Peter
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Arvidson, Staffan
    Mathematical modelling of the regulation of spa (protein A) transcription in Staphylococcus aureus2009In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 299, no 1, p. 65-74Article in journal (Refereed)
    Abstract [en]

    In the present work a general systems biology approach has been used to study the complex regulatory network controlling the transcription of the spa gene, encoding protein A, a major surface protein and an important virulence factor of Staphylococcus aureus. A valid mathematical model could be formulated using parameter values, which were fitted to quantitative Northern blot data from various S. aureus regulatory mutants using a gradient search method. The model could correctly predict spa expression levels in 4 different regulatory mutants not included in the parameter value search, and in 2 other S. aureus strains, SH 1000 and UAMS-1. The mathematical model revealed that sarA and sarS seem to balance each other in a way that when the activating impact of sarS is small, e.g. in the wild-type, the repressive impact of sarA is small, while in an agr-deficient background, when the impact of sarS is maximal, the repressive impact of sarA is close to its maximum. Furthermore, the model revealed that Rot and SarS act synergistically to stimulate spa expression, something that was not obvious from experimental data. We believe that this mathematical model can be used to evaluate the significance of other putative interactions in the regulatory network governing spa transcription. (C) 2008 Elsevier GmbH. All rights reserved.

  • 8.
    Gustafsson, Erik
    et al.
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Karlsson, Stefan
    University of Skövde, School of Life Sciences.
    Arvidson, Staffan
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Characterizing the Dynamics of the Quorum-Sensing System in Staphylococcus aureus2005In: Journal of Molecular Microbiology and Biotechnology, ISSN 1464-1801, Vol. 8, no 4, p. 232-242Article in journal (Refereed)
    Abstract [en]

    The virulence determinants of Staphylococcus aureus are expressed in a growth phase-dependent manner governed by the autoinducible quorum-sensing system agr. Activation of the agr system results in a rapid increase in the regulator RNAIII and occurs in response to accumulation of AIP. In order to activate the agr system, a basal transcription of agr components must be assumed. This basal transcription of agr components seems to be stimulated by sarA. To better understand how SarA would affect activation of the agr system by modulating the basal agr activity, a mathematical model for autoactivation of the agr system was set up. The model predicted that the agr system is hysteretic, meaning that the agr system is activated at a specific concentration of autoinducing peptide (AIP), whereas it is inactivated at a specific lower concentration of AIP. According to the model, changing the basal agr activity only had a marginal effect on steady-state levels of RNAIII but changed the sensitivity of the cells to AIP. This was supported by Northern blot analysis of RNAIII in S. aureus mutants with different levels of SarA expression. Since natural antagonistic AIPs have been demonstrated, the effect of adding inhibitors to the system was analyzed.

  • 9.
    James, John R.
    et al.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    McColl, James
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Oliveira, Marta I.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Dunne, Paul D.
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Huang, Elizabeth
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sleep, David L.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Goncalves, Carine M.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Morgan, Sara H.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Felce, James H.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Mahen, Robert
    Hutchison MRC Res Ctr, Med Res Council Canc Cell Unit, Cambridge CB2 0XZ, England.
    Fernandes, Ricardo A.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Carmo, Alexandre M.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Klenerman, David
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Davis, Simon J.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    The T Cell Receptor Triggering Apparatus Is Composed of Monovalent or Monomeric Proteins2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 37, p. 31993-32001Article in journal (Refereed)
    Abstract [en]

    Understanding the component stoichiometry of the T cell antigen receptor (TCR) triggering apparatus is essential for building realistic models of signal initiation. Recent studies suggesting that the TCR and other signaling-associated proteins are preclustered on resting T cells relied on measurements of the behavior of membrane proteins at interfaces with functionalized glass surfaces. Using fluorescence recovery after photo-bleaching, we show that, compared with the apical surface, the mobility of TCRs is significantly reduced at Jurkat T cell/glass interfaces, in a signaling-sensitive manner. Using two biophysical approaches that mitigate these effects, bioluminescence resonance energy transfer and two-color coincidence detection microscopy, we show that, within the uncertainty of the methods, the membrane components of the TCR triggering apparatus, i.e. the TCR complex, MHC molecules, CD4/Lck and CD45, are exclusively monovalent or monomeric in human T cell lines, implying that TCR triggering depends only on the kinetics of TCR/pMHC interactions. These analyses also showed that constraining proteins to two dimensions at the cell surface greatly enhances random interactions versus those between the membrane and the cytoplasm. Simulations of TCR-pMHC complex formation based on these findings suggest how unclustered TCR triggering-associated proteins might nevertheless be capable of generating complex signaling outputs via the differential recruitment of cytosolic effectors to the cell membrane.

  • 10.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Barnes, Eleanor
    Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
    Klenerman, Paul
    Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Sørensen, Poul
    LEO Pharma, Ballerup, Denmark.
    Davis, Simon J.
    Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom / Medical Research Council Human Immunology Unit and Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    A Theoretical Framework for Quantitative Analysis of the Molecular Basis of Costimulation2005In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 175, no 3, p. 1575-1585Article in journal (Refereed)
    Abstract [en]

    We present a theoretical framework for simulating the synaptic accumulation of the costimulatory molecules CD28, CTLA-4, B7-1, and B7-2, based on a system of mean-field, ordinary differential equations, and rigorous biophysical and expression data. The simulations show that binding affinity, stoichiometric properties, expression levels, and, in particular, competition effects all profoundly influence complex formation at cellular interfaces. B7-2 engages 33-fold more CD28 than CTLA-4 at the synapse in contrast to B7-1, which ligates ~7-fold more CTLA-4 than CD28. Although B7-1 completely dominates interactions with CTLA-4, forming linear arrays of 7-18 receptor-ligand pairs, CTLA-4 is fully engaged by B7-2 when B7-1 is absent. Additional simulations reveal the sensitivity of CD28 interactions to modeled transport processes. The results support the concept that B7-2 and B7-1 are the dominant ligands of CD28 and CTLA-4, respectively, and indicate that the inability of B7-2 to recruit CTLA-4 to the synapse cannot be due to the differential binding properties of B7-1 and B7-2 only. We discuss the apparent redundancy of B7-1 in the context of a potentially dynamic synaptic microenvironment, and in light of functions other than the direct enhancement of T cell inhibition by CTLA-4.

  • 11.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Fagerlind, Magnus
    University of Skövde, School of Life Sciences.
    Karlsson, Diana
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Cooley, Margaret
    School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
    In silico simulations suggest that Th-cell development is regulated by both selective and instructive mechanisms2006In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 84, no 2, p. 218-226Article in journal (Refereed)
    Abstract [en]

    Th-cell differentiation is highly influenced by the local cytokine environment. Although cytokines such as IL-12 and IL-4 are known to polarize the Th-cell response towards Th1 or Th2, respectively, it is not known whether these cytokines instruct the developmental fate of uncommitted Th cells or select cells that have already been committed through a stochastic process. We present an individual based model that accommodates both stochastic and deterministic processes to simulate the dynamic behaviour of selective versus instructive Th-cell development. The predictions made by each model show distinct behaviours, which are compared with experimental observations. The simulations show that the instructive model generates an exclusive Th1 or Th2 response in the absence of an external cytokine source, whereas the selective model favours coexistence of the phenotypes. A hybrid model, including both instructive and selective development, shows behaviour similar to either the selective or the instructive model dependent on the strength of activation. The hybrid model shows the closest qualitative agreement with a number of well-established experimental observations. The predictions by each model suggest that neither pure selective nor instructive Th development is likely to be functional as exclusive mechanisms in Th1/Th2 development.

  • 12.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Karlsson, Stefan
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Cooley, Margaret
    School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2033, Australia.
    3D computation modelling of the influence of cytokine secretion on Th-cell development suggests that negative selection (inhibition of Th1 cells) is more effective than positive selection by IL-4 for Th2 cell dominance2007In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 85, no 3, p. 189-196Article in journal (Refereed)
    Abstract [en]

    Th-cell development has been suggested to include selective mechanisms in which certain cytokines select either Th1 or Th2 cells to proliferate and grow. The selective theory is based on the observation that Th2 cells secrete IL-4, a cytokine that promotes Th2 development, whereas Th1 cells secrete interferon-gamma (IFN-italic gamma) that favours Th1 development, and both positive and negative selective influences have been suggested to operate. In this study, we investigate the role of autocrine secretion and utilization of IL-4 by Th2 cells and address the question of whether an activated Th2 cell can be positively selected by IL-4 secreted from other Th2 cells. We present a spatial three dimensional (3D) modelling approach to simulate the interaction between the IL-4 ligand and its IL-4 receptors expressed on discrete IL-4 secreting cells. The simulations, based on existing experimental data on the IL-4 receptor–ligand system, illustrate how Th-cell development is highly dependent on the distance between cells that are communicating. The model suggests that a single Th2 cell is likely to communicate with possible target cells within a range of approximately 100 mum and that an activated Th2 cell manages to fill most of its own IL-4 receptors, even at a low secretion rate. The predictions made by the model suggest that negative selection against Th1 cells is more effective than positive selection by IL-4 for promoting Th2 dominance.

  • 13.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Jirstrand, Mats
    Fraunhofer-Chalmers Research Centre for Industrial Mathematics, Gothenburg, Sweden.
    Hornquist, Elisabeth Hultgren
    Univ Örebro, Sch Hlth & Med Sci, Dept Biomed, Örebro, Sweden.
    Toward Quantifying the Thymic Dysfunctional State in Mouse Models of Inflammatory Bowel Disease2013In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 19, no 4, p. 881-888Article, review/survey (Refereed)
    Abstract [en]

    Inflammatory bowel disease is characterized by a number of immunological alterations, not the least in the T-cell compartment. Numerous animal models of colitis have revealed aberrant thymocyte dynamics associated with skewed thymocyte development. The recent advancements in quantitative methods have proposed critical kinetic alterations in the thymocyte development during the progression of colitis. This review focuses on the aberrant thymocyte dynamics in G alpha i2-deficient mice as this mouse model provides most quantitative data of the thymocyte development associated with colitis. Herein, we discuss several dynamic changes during the progression of colitis and propose a hypothesis for the underlying causes for the skewed proportions of the thymocyte populations seen in the G alpha i2-deficient mice and in other mouse models of colitis. (Inflamm Bowel Dis 2013; 19: 881-888)

  • 14.
    Karlsson, Diana
    et al.
    University of Skövde, School of Life Sciences.
    Jansson, Andreas
    University of Skövde, School of Life Sciences.
    Normark, Birgitta Henriques
    Karolinska Inst, Swedish Inst Infect Dis Control, Dept Bacteriol, SE-17182 Solna, Sweden / Karolinska Inst, Dept Microbiol Tumor Biol & Cell Biol, SE-17177 Stockholm, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    An individual-based network model to evaluate interventions for controlling pneumococcal transmission2008In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 8, p. 83-Article in journal (Refereed)
    Abstract [en]

    Background: Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, but also a common colonizer of the upper respiratory tract. The emergence and spread of antibiotic resistant pneumococcal strains has threatened effective therapy. The long-term effects of measures aiming to limit pneumococcal spread are poorly understood. Computational modeling makes it possible to conduct virtual experiments that are impractical to perform in real life and thereby allows a more full understanding of pneumococcal epidemiology and control efforts. Methods: We have developed a contact network model to evaluate the efficacy of interventions aiming to control pneumococcal transmission. Demographic data from Sweden during the mid-2000s were employed. Analyses of the model's parameters were conducted to elucidate key determinants of pneumococcal spread. Also, scenario simulations were performed to assess candidate control measures. Results: The model made good predictions of previous findings where a correlation has been found between age and pneumococcal carriage. Of the parameters tested, group size in day-care centers was shown to be one of the most important factors for pneumococcal transmission. Consistent results were generated from the scenario simulations. Conclusion: We recommend, based on the model predictions, that strategies to control pneumococcal disease and organism transmission should include reducing the group size in day-care centers.

  • 15.
    Karlsson, Diana
    et al.
    University of Skövde, School of Life Sciences.
    Karlsson, Stefan
    University of Skövde, School of Life Sciences.
    Gustafsson, Erik
    University of Skövde, School of Life Sciences.
    Henriques Normark, Birgitta
    Swedish Institute for Infectious Disease Control, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Modeling the regulation of the competence-evoking quorum sensing network in Streptococcus pneumoniae2007In: Biosystems (Amsterdam. Print), ISSN 0303-2647, E-ISSN 1872-8324, Vol. 90, no 1, p. 211-223Article in journal (Refereed)
    Abstract [en]

    Competence for genetic transformation seems to play a fundamental role in the biology of Streptococcus pneumoniae and is believed to account for serotype switching, evolution of virulence factors, and rapid emergence of antibiotic resistance. The initiation of competence is regulated by the quorum sensing system referred as the ComABCDE pathway. Experimental studies reveal that competence is down-regulated a short time after its induction and several hypotheses about the mechanism(s) responsible for this shut-down have been presented. Possibly, a ComX-dependent gene product, such as a repressor or a phosphatase, is involved. To better understand the down-regulation of the competence-evoking system in S. pneumoniae, a mathematical model was set up. By analyzing the model, we suggest that shut-down of competence possibly occurs at the transcriptional level on the comCDE operon. As a result of introducing a putative comX-dependent repressor, which inhibits expression of comCDE and comX, in the mathematical model, competence is demonstrated to appear in waves. This is supported by experimental studies showing the appearance of successive competence cycles in pneumococcal batch cultures.

  • 16.
    Laurio, Kim
    et al.
    University of Skövde, School of Humanities and Informatics. University of Skövde, The Systems Biology Research Centre.
    Svensson, Thomas
    Biovitrum AB, Göteborg, Sweden.
    Jirstrand, Mats
    Fraunhofer-Chalmers Research Center for Industrial Mathematics, Göteborg, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Gamalielsson, Jonas
    University of Skövde, School of Humanities and Informatics. University of Skövde, The Systems Biology Research Centre.
    Olsson, Björn
    University of Skövde, School of Humanities and Informatics. University of Skövde, The Systems Biology Research Centre.
    Evolutionary search for improved path diagrams2007In: Evolutionary Computation, Machine Learning and Data Mining in Bioinformatics: 5th European Conference, EvoBIO 2007, Valencia, Spain, April 11-13, 2007. Proceedings / [ed] Elena Marchiori, Jason H. Moore, Jagath C. Rajapakse, Springer Berlin/Heidelberg, 2007, p. 114-121Conference paper (Refereed)
    Abstract [en]

    A path diagram relates observed, pairwise, variable correlations to a functional structure which describes the hypothesized causal relations between the variables. Here we combine path diagrams, heuristics and evolutionary search into a system which seeks to improve existing gene regulatory models. Our evaluation shows that once a correct model has been identified it receives a lower prediction error compared to incorrect models, indicating the overall feasibility of this approach. However, with smaller samples the observed correlations gradually become more misleading, and the evolutionary search increasingly converges on suboptimal models. Future work will incorporate publicly available sources of experimentally verified biological facts to computationally suggest model modifications which might improve the model’s fitness.

  • 17.
    Olsson, Björn
    et al.
    University of Skövde, School of Humanities and Informatics.
    Nilsson, Patric
    University of Skövde, School of Humanities and Informatics.
    Gawronska, Barbara
    University of Skövde, School of Humanities and Informatics.
    Persson, Anne
    University of Skövde, School of Humanities and Informatics.
    Ziemke, Tom
    University of Skövde, School of Humanities and Informatics.
    Andler, Sten F.
    University of Skövde, School of Humanities and Informatics.
    An Information Fusion Approach to Controlling Complexity in Bioinformatics Research2005In: 2005 IEEE Computational Systems Bioinformatics Conference: Workshops & Poster Abstracts: CSB 2005, IEEE Computer Society, 2005, p. 299-304Conference paper (Refereed)
    Abstract [en]

    Information Fusion (IF) is about combining, or fusing, information from different sources in order to facilitate our understanding of a complex system and thereby provide insights that could not be gained from any of the individual data sources in isolation. We argue in this paper that there is a need for applying an IF approach in bioinformatics research, since the aim of bioinformatics is to understand complex biological systems using many different data sources providing complementary views of the system. We illustrate this argument with two application examples, where IF-based bioinformatics is applied to the study of stem cell differentiation and lipid digestion, respectively. We also discuss the use of automated information extraction from text sources, which is an essential component of a bioinformatics IF approach, given the abundant literature.

  • 18.
    Ritchie, A. J.
    et al.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    Jansson, Andreas
    University of Skövde, School of Life Sciences.
    Stallberg, J.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Lysaght, P.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    Cooley, M. A.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    The Pseudomonas aeruginosa Quorum-Sensing Molecule N-3-(Oxododecanoyl)-L-Homoserine Lactone Inhibits T-Cell Differentiation and Cytokine Production by a Mechanism Involving an Early Step in T-Cell Activation2005In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 73, no 3, p. 1648-1655Article in journal (Refereed)
    Abstract [en]

    The Pseudomonas aeruginosa quorum-sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone (OdDHL) has been reported to have immunomodulatory activity in several systems, although the mechanism of that activity remains to be fully characterized. We demonstrate here, using a defined in vitro model of antigen responses by T-cell receptor (TCR)-transgenic mouse splenic CD4 T cells, that the effect of OdDHL on activation and cytokine production is complete within 4 h of antigen or mitogen stimulation and does not depend on the insertion of OdDHL in the cell membrane, despite a previous report that immunosuppression by homoserine lactones required a minimum acyl chain length of 11 carbons (S. R. Chhabra, C. Harty, D. S. W. Hooi, M. Daykin, B. W. Bycroft, P. Williams, and D. Pritchard, J. Med. Chem. 46:97-104, 2003). We also demonstrate that while OdDHL can have toxic effects on nonlymphoid leukocytes, it does not induce significant cell death in T cells at the concentrations (≤10 µM) used in these experiments. In addition, we show that primary and secondary antigen-specific cytokine responses are equally susceptible to inhibition by OdDHL and that the compound inhibits the differentiation of both Th1 and Th2 cells. However, the precise balance of cytokine production by CD4 T cells stimulated in the presence of OdDHL varies with both the antigen concentration and its affinity for the transgenic TCR. Thus, conflicting reports of the nature of the immunosuppression by OdDHL may be due in part to the differences in antigen affinity and concentration in different models.

  • 19.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences.
    Adak, Sudeshna
    GE John F Welch Technol Ctr Export Promot Ind Pk, Bangalore, Karnataka, India.
    Englund, Mikael
    Celllartis AB, SE-43146 Gothenburg, Sweden.
    Giesler, Theresa
    GE Healthcare, Piscataway, NJ 08855 USA.
    Noaksson, Karin
    Celllartis AB, SE-43146 Gothenburg, Sweden.
    Lindahl, Anders
    Sahlgrens Univ Hosp, Dept Clin Chem Transfus Med, SE-41345 Gothenburg, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Nelson, Deirdre
    GE Global Res Ctr, Moscow 123098, Russia.
    Abbot, Stewart
    GE Global Res Ctr, Moscow 123098, Russia.
    Olsson, Björn
    University of Skövde, School of Life Sciences.
    Sartipy, Peter
    Celllartis AB, SE-43146 Gothenburg, Sweden.
    Cardiomyogenic gene expression profiling of differentiating human embryonic stem cells2008In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 134, no 1-2, p. 162-170Article in journal (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESCs) can differentiate into a variety of specialized cell types. Thus, they provide a model system for embryonic development to investigate the molecular processes of cell differentiation and lineage commitment. The development of the cardiac lineage is easily detected in mixed cultures by the appearance of spontaneously contracting areas of cells. We performed gene expression profiling of undifferentiated and differentiating hESCs and monitored 468 genes expressed during cardiac development and/or in cardiac tissue. Their transcription during early differentiation of hESCs through embryoid bodies (EBs) was investigated and compared with spontaneously differentiating hESCs maintained on feeders in culture without passaging (high-density (HD) protocol). We observed a larger variation in the gene expression between cells from a single cell line that were differentiated using two different protocols than in cells from different cell lines that were cultured according to the same protocol. Notably, the EB protocol resulted in more reproducible transcription profiles than the HD protocol. The results presented here provide new information about gene regulation during early differentiation of hESCs with emphasis on the cardiomyogenic program. In addition, we also identified regulatory elements that could prove critical for the development of the cardiomyocyte lineage.

  • 20.
    Synnergren, Jane
    et al.
    University of Skövde, School of Humanities and Informatics.
    Giesler, Therese L.
    GE Healthcare, Piscataway, NJ, United States.
    Adak, Sudeshna
    GE John F. Welch Technology Centre Export Promotion Industrial Park, Bangalore, India.
    Tandon, Reeti
    GE John F. Welch Technology Centre Export Promotion Industrial Park, Bangalore, India.
    Noaksson, Karin
    Cellartis AB, Göteborg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Nelson, Deirdre
    GE Global Research Center, Niskayuna, NY, United States.
    Olsson, Björn
    University of Skövde, School of Humanities and Informatics.
    Englund, Mikael C. O.
    Cellartis AB, Göteborg, Sweden.
    Abbott, Stewart
    GE Global Research Center, Niskayuna, NY, United States.
    Sartipy, Peter
    Cellartis AB, Göteborg, Sweden / Cellartis AB, Arvid Wallgrens Backe 20, SE-41346 Göteborg, Sweden.
    Differentiating human embryonic stem cells express a unique housekeeping gene signature2007In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 25, no 2, p. 473-480Article in journal (Refereed)
    Abstract [en]

    Housekeeping genes (HKGs) are involved in basic functions needed for the sustenance of the cell and are assumed to be constitutively expressed at a constant level. Based on these features, HKGs are frequently used for normalization of gene expression data. In the present study, we used the CodeLink Gene Expression Bioarray system to interrogate changes in gene expression occurring during differentiation of human ESCs (hESCs). Notably, in the three hESC lines used for the study, we observed that the RNA levels of 56 frequently used HKGs varied to a degree that rendered them inappropriate as reference genes. Therefore, we defined a novel set of HKGs specifically for hESCs. Here we present a comprehensive list of 292 genes that are stably expressed (coefficient of variation <20%) in differentiating hESCs. These genes were further grouped into high-, medium-, and low-expressed genes. The expression patterns of these novel HKGs show very little overlap with results obtained from somatic cells and tissues. We further explored the stability of this novel set of HKGs in independent, publicly available gene expression data from hESCs and observed substantial similarities with our results. Gene expression was confirmed by real-time quantitative polymerase chain reaction analysis. Taken together, these results suggest that differentiating hESCs have a unique HKG signature and underscore the necessity to validate the expression profiles of putative HKGs. In addition, this novel set of HKGs can preferentially be used as controls in gene expression analyses of differentiating hESCs.

  • 21.
    Synnergren, Jane
    et al.
    University of Skövde, School of Humanities and Informatics.
    Giesler, Therese L
    Sudeshna, Adak
    Tandon, Reeti
    Noaksson, Karin
    Lindahl, Anders
    Nilsson, Patric
    Nelson, Deidre
    Olsson, Björn
    University of Skövde, School of Humanities and Informatics.
    Englund, Mikael C O
    Abbot, Stewart
    Sartipy, Peter
    Differentiating human embryonic stem cells express a unique housekeeping gene signature2006In: 4th ISSCR Annual Meeting, 2006Conference paper (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESCs) represent populations of pluripotent undifferentiated cells with unlimited replication capacity which can be coaxed to differentiate into a variety of specialized cells. As a result, there is great hope that hESCs will be extremely useful by providing platforms for various in vitro applications (e.g. in drug discovery) as well as for future use of hESCs and their differentiated progeny in cell replacement therapies. In order to realize the potential of hESCs, it is necessary to gain much deeper knowledge about the processes that govern differentiation of these cells.

    In recent years, significant progress towards understanding cellular differentiation has been fuelled, in part, by studying gene expression using microarrays. In this large scale studies, statistical methods are used to normalize the gene expression data and render comparisons between different samples. In lower throughput analyses, RNA levels in hESCs are also measured using RT-PCR requiring normalization of the gene expression data to adequately correct for inter-sample variation. In general, investigators have used the traditional housekeeping genes (HKGs) (e.g. GAPDH, b-tubulin, b-actin) in studies of hESCs. HKGs are involved in basic functions needed for the sustenance of the cell and are assumed to be constitutively expressed at a constant level. Based on these features, HKGs are frequently used for normalization of gene expression data. However, it is well known that the expression of several of these genes vary considerably in adult tissues and their suitability as HKGs in hESCs remains to be proven. In this regard, the RNA levels of HPRT and b-tubulin were shown to vary substantially in differentiating mouse ESCs.

    In the present study, we used the CodeLinkTM Gene Expression Bioarray system to interrogate changes in gene expression occurring during differentiation of hESCs. Notably, in the three hESC lines used for the study, we observed that the RNA levels of 56 frequently used HKGs varied to a degree that rendered them inappropriate as reference genes. Therefore, we defined a novel set of HKGs specifically for hESCs. Here we present a comprehensive list of 292 genes that are stably expressed (coefficient of variation<20%) in differentiating hESCs. These genes were further grouped into high, medium, and low expressed genes. The expression patterns of these novel HKGs show very little overlap with results obtained from somatic cells and tissues. We further explored the stability of this novel set of HKGs in independent, publicly available gene expression data from hESCs and observed substantial similarities in terms of stably expressed genes. Taken together, these results suggest that hESCs have a unique HKG signature and underscore the necessity to validate the expression profiles of putative HKGs. In addition, the novel set of identified HKGs can preferentially be used as controls in gene expression analyses of differentiating hESCs.

  • 22.
    Sögård, Peter
    et al.
    University of Skövde, School of Life Sciences. Department of Surgical Sciences, Karolinska Institute, Stockholm, Sweden.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Svensson, L. T.
    Arexis AB, Gothenburg, Sweden.
    Zierath, J. R.
    Department of Surgical Sciences, Karolinska Institute, Stockholm, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Integration of mathematical and experimental approaches to resolve insulin signaling2005In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 183, no 1, p. 125-126Article in journal (Refereed)
1 - 22 of 22
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